Podcasts about duke clinical research institute

Carly Brantner is an assistant professor of Biostatistics & Bioinformatics at Duke University and Duke Clinical Research Institute. Resources from this episode: multicate: R package for estimating conditional average treatment effects across one or more studies using machine learning methods PCORnet® Front Door: Access point for potential investigators, patient groups, and other stakeholders to connect with PCORnet and get support for potential research studies Patient-Centered Outcomes Data Repository (PDOCR): De-identified data from 24 (and counting) PCORI-funded studies Follow along on Bluesky: Carly: @carlybrantner.bsky.social Ellie: @epiellie.bsky.social Lucy: @lucystats.bsky.social  

The US leads the world in biomedical innovation, with about 40% of patents being filed by US scientists and companies. The FDA plays a critical role in supporting and enabling this innovation pipeline and our guest Dr. Robert Califf was commissioner of the agency not once, but twice under Presidents Obama and Biden. He joins us to talk about what Americans should know about FDA's critical role and the threats to its functioning from the dramatic cuts the Trump administration has made over the last three months.We discuss:The broad sweep of FDA's purview from drugs and medical devices to cosmetics, food, tobacco and dog foodConcern that the FDA is now “decapitated and eviscerated” from the massive and multiple rounds of dismissalsWhile most industries want less regulation, the pharma industry wants more information and guidance from the FDACaliff has been affiliated with Duke for 50 of its 100 years, but a part of his heart is still with ClemsonWhat would Califf's “Make America Healthy Again” agenda be?“We need to develop reliable, repetitive sources of information that help people do things that are healthy and beneficial. That part of MAHA I like a lot…The second thing is… I'm developing connections with people who are thinking differently about primary care because I think everybody agrees there's no way you can take the current workforce and deliver what's needed. So it's got to be linked up with AI and digital technologies, but also with a very different looking workforce that gets paid differently, has more respect.”Relevant LinksRead Califf's WSJ opinion letter: “Work with the Bureaucracy, Not Against It”Peter Marks' resignation letter NYT article on the impact of FDA layoffsCaliff's “Public Health on Call” podcast episode on the state of the FDA Opinion article from 7 previous FDA commissioners on how recent changes are undermining credibility of the FDAAbout Our GuestRobert M. Califf, MD served as FDA Commmissioner under Presidents Biden and Obama. Califf is a nationally recognized expert in cardiovascular medicine, health outcomes research, health care quality, and clinical research, and a leader in the growing field of translational research. Prior to rejoining the FDA in 2022, Califf was head of medical strategy and senior advisor at Alphabet, contributing to strategy and policy for its health subsidiaries Verily Life Sciences and Google Health. Prior to Alphabet, he was professor of medicine and vice chancellor for clinical and translational research at Duke University, director of the Duke Translational Medicine Institute, and founding director of the Duke Clinical Research Institute. Dr. Califf is a graduate of Duke University School of Medicine. He completed a residency in internal medicine at the University of California, San Francisco and a fellowship in cardiology at Duke.Connect With UsFor more information on...

Have you ever felt like you're losing your grip on your teen? Asking yourself: "How do I get my teen to open up?" "Why does my kid seem to shut me out?" "How do I become the steady, trusted leader my teen needs?" If those questions resonate, you're in the right place.  Become the best husband and leader you can: www.thedadedge.com/mastermind Today's guest, Kristin MacDermott is a licensed marriage and family therapist, author, and creator of The MacDermott Method with over a decade of research in resilience. Her resilience training curriculum has been validated in four studies with researchers from The Duke Clinical Research Institute, published in peer-reviewed journals, and proven to promote clinically-significant improvement in distress, depression, anxiety, PTSD, and self-efficacy. Kristin MacDermott shares three crucial insights every father needs to hear: The single most important thing dads can do to support their teen's mental health. The #1 complaint she hears from teens about their parents. How to create a relationship where your teen doesn't feel the need to lie to you. Kristin MacDermott's passion is reconnecting parents and teens, and her methods are backed by rigorous research. Here's what evidence supports her approach: Studies show that strong parent-teen relationships are correlated with a 40% reduction in teen depression and anxiety. Effective communication skills training for parents leads to a 30% decrease in risky behavior among teens. Teens who perceive their parents as trustworthy are 50% less likely to engage in substance abuse. If you're ready for practical tools, real talk, and a new perspective on fatherhood, this is one conversation you don't want to miss. Let's get into it. ---------------------------- Gentlemen, if you're ready to level up, don't miss The Forge: A Gathering of Men—an exclusive event created by leaders like Connor Beaton, Larry Hagner, Matt Beaudreau, and Ryan Michler to help you connect, grow, and become the best version of yourself. Learn more at The Men's Forge. ---------------------------- Transform your parent-teen relationship this May! Use code DADEDGE30 for 30% off he Parent/Teen Relationship Reset program, starting May 2nd, valid within 30 days only. www.thedadedge.com/523 www.themensforge.com | www.thedadedge.com/alliance www.macdermottmethod.com Instagram | Facebook | TikTok | YouTube

The following question refers to Sections 7.3.3 and 7.3.6 of the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure.The question is asked by Palisades Medical Center medicine resident & CardioNerds Academy Fellow Dr. Maryam Barkhordarian, answered first by UTSW AHFT Cardiologist & CardioNerds FIT Ambassador Dr. Natalie Tapaskar, and then by expert faculty Dr. Robert Mentz.Dr. Mentz is associate professor of medicine and section chief for Heart Failure at Duke University, a clinical researcher at the Duke Clinical Research Institute, and editor-in-chief of the Journal of Cardiac Failure. Dr. Mentz has been a mentor for the CardioNerds Clinical Trials Network as lead principal investigator for PARAGLIDE-HF and is a series mentor for this very Decipher the Guidelines Series. For these reasons and many more, he was awarded the Master CardioNerd Award during ACC22.The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance.Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. American Heart Association's Scientific Sessions 2024As heard in this episode, the American Heart Association's Scientific Sessions 2024 is coming up November 16-18 in Chicago, Illinois at McCormick Place Convention Center. Come a day early for Pre-Sessions Symposia, Early Career content, QCOR programming and the International Symposium on November 15. It's a special year you won't want to miss for the premier event for advancements in cardiovascular science and medicine as AHA celebrates its 100th birthday. Registration is now open, secure your spot here!When registering, use code NERDS and if you're among the first 20 to sign up, you'll receive a free 1-year AHA Professional Membership! Question #39 Ms. Kay Lotsa is a 48-year-old woman with a history of CKD stage 2 (baseline creatinine ~1.2 mg/dL) & type 2 diabetes mellitus. She has recently noticed progressively reduced exercise tolerance, leg swelling, and trouble lying flat. This prompted a hospital admission with a new diagnosis of decompensated heart failure. A transthoracic echocardiogram reveals LVEF of 35%. Ms. Lotsa is diuresed to euvolemia, and she is started on carvedilol 25mg BID, sacubitril/valsartan 49-51mg BID, and empagliflozin 10mg daily, which she tolerates well. Her eGFR is at her baseline of 55 mL/min/1.73 m2 and serum potassium concentration is 3.9 mEq/L. Your team is anticipating she will be discharged home in the next one to two days and wants to start spironolactone. Which of the following is most important regarding her treatment with mineralocorticoid antagonists?ASpironolactone is contraindicated based on her level of renal impairment and should not be startedBSerum potassium levels and kidney function should be assessed within 1-2 weeks of starting spironolactoneCEplerenone confers a higher risk of gynecomastia than does spironolactoneDThe patient will likely not benefit from initiation of spironolactone if her cardiomyopathy is ischemic in origin Answer #39 ExplanationThe correct answer is B – after starting a mineralocorticoid receptor antagonist (MRA), it is important to closely monitor renal function and serum potassium levels.MRA (also known as aldosterone antagonists or anti-mineralocorticoids) show consistent improvements in all-cause mortality, HF hospitalizations, and SCD across a wide range of patients with HFrEF.

Our guests share how their experiences with building relationships between organizations have lead to stronger successes in the clinic and in the labs to advance MSK care.Guests:Adam Lutz, ATI Director Care Quality & InnovationTrevor Lentz of the Duke Clinical Research Institute, explained his NIH workpartnering with ATI.Chris Lane of University of North Carolina, shared his dissertation work partneringwith Adam Lutz & ATI.FROM ATIHave you ever thought about where your career in physical therapy could take you?It's not just about the job; it's about making real connections that help patients get better faster.Imagine working somewhere you can grow through mentorship, and get leadership training that matters.Sounds like a place you'd fit right in?Click to find out more about what working with ATI is really like. Let's grow and learn together!

About David Rhew:Since August 2019, David has served as Chief Medical Officer & VP of Healthcare for Microsoft's Worldwide Commercial Business (WCB). David and his team's main goal is to demonstrate how a large-scale data-driven approach can lead to smarter decision-making, more proactive care, and improved health outcomes, as well as lower costs for patients and populations.Additionally, David is an adjunct professor at the Department of Medicine, Division of Primary Care and Population Health at Stanford University.About Marcella Dalrymple:Marcella is the Associate Director of Strategic Development and Business Partnerships at Duke AI Health. Her goal is to operationalize novel ideas by using big data to achieve the most meaningful results, leading to improved clinical practices.Prior to that role, she was the Commercial Leadership Associate in the marketing sector for AstraZeneca and a project manager for Duke Clinical Research Institute.About Michael Pencina:Michael Pencina, PhD, is Duke Health's Chief Data Scientist and serves as Vice Dean for Data Science, Director of Duke AI Health, and Professor of Biostatistics and Bioinformatics at the Duke University School of Medicine. He develops and implements quantitative science strategies for the School of Medicine, co-chairs Duke Health's Algorithm-Based Clinical Decision Support (ABCDS) Oversight Committee, and co-directs Duke's Collaborative to Advance Clinical Health Equity (CACHE).Things You'll Learn:AI's potential to revolutionize healthcare requires a focus on responsible and trustworthy implementation.The collaboration between Microsoft and Duke Health aims to create a Center of Excellence for trustworthy AI.The four principles for trustworthy AI are: prioritize the human person, define use cases, anticipate consequences, and establish governance.Public mistrust of AI in healthcare highlights the need for community engagement and bidirectional communication.Automation in governance processes can streamline AI integration and reduce friction in workflows.Resources:Connect with and follow David Rhew on LinkedIn.Follow Microsoft on LinkedIn and visit their website.Connect with and follow Marcella Dalrymple on LinkedIn.Connect with and follow Michael Pencina on LinkedIn.Follow Duke Health AI on LinkedIn and visit their website.

The following question refers to Sections 7.3.2, 7.3.8, and 7.6.2 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. The question is asked by Palisades Medical Center medicine resident & CardioNerds Intern Dr. Maryam Barkhordarian, answered first by Hopkins Bayview medicine resident & CardioNerds Academy Fellow Dr. Ty Sweeny, and then by expert faculty Dr. Robert Mentz. Dr. Mentz is associate professor of medicine and section chief for Heart Failure at Duke University, a clinical researcher at the Duke Clinical Research Institute, and editor-in-chief of the Journal of Cardiac Failure. Dr. Mentz is a mentor for the CardioNerds Clinical Trials Network as lead principal investigator for PARAGLIDE-HF and is a series mentor for this very Decipher the Guidelines Series. For these reasons and many more, he was awarded the Master CardioNerd Award during ACC22. The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #20 Ms. Betty Blocker is a 60-year-old woman with a history of alcohol-related dilated cardiomyopathy who presents for follow up. She has been working hard to improve her health and is glad to report that she has just reached her 5-year sobriety milestone. Her current medications include metoprolol succinate 100mg daily, sacubitril-valsartan 97-103mg BID, spironolactone 25mg daily, and empagliflozin 10mg daily. She is asymptomatic at rest and up to moderate exercise, including chasing her grandchildren around the yard. A recent transthoracic echocardiogram shows recovered LVEF from previously 35% now to 60%. Ms. Blocker does not love taking so many medications and asks about discontinuing her metoprolol. Which of the following is the most appropriate response to Ms. Blocker's request? A Since the patient is asymptomatic, metoprolol can be stopped without risk B Stopping metoprolol increases this patient's risk of worsening cardiomyopathy regardless of current LVEF or symptoms C Because the LVEF is now >50%, the patient is now classified as having HFpEF and beta-blockade is no longer indicated; metoprolol can be safely discontinued D Metoprolol should be continued, but it is safe to discontinue either ARNi or spironolactone Answer #20 Explanation The correct answer is B – stopping metoprolol would increase her risk of worsening cardiomyopathy. Heart failure tends to be a chronically sympathetic state. The use of beta-blockers (specifically bisoprolol, metoprolol succinate, and carvedilol) targets this excess adrenergic output and has been shown to reduce the risk of death in patients with HFrEF. Beyond their mortality benefit, beta-blockers can improve LVEF, lessen the symptoms of HF, and improve clinical status. Therefore, in patients with HFrEF, with current or previous symptoms, use of 1 of the 3 beta blockers proven to reduce mortality (e.g., bisoprolol, carvedilol, sustained-release metoprolol succinate) is recommended to reduce mortality and hospitalizations (Class 1, LOE A). Beta-blockers in this setting provide a high economic value. Table 14 of the guidelines provides recommendations for target doses for GDMT medications. Specifically for beta blockers, those targets are 25-50mg twice daily for carvedilol (or 80mg once daily for the continuous release formulation), 200mg once daily for metoprolol succinate,

The following question refers to Section 7.3.1 of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure.  The question is asked by Palisades Medical Center medicine resident & CardioNerds Intern Dr. Maryam Barkhordarian, answered first by MedStar Washington Hospital Center cardiology hospitalist & CardioNerds Academy Graduate Dr. Luis Calderon, and then by expert faculty Dr. Robert Mentz.  Dr. Mentz is associate professor of medicine and section chief for Heart Failure at Duke University, a clinical researcher at the Duke Clinical Research Institute, and editor-in-chief of the Journal of Cardiac Failure. Dr. Mentz is a mentor for the CardioNerds Clinical Trials Network as lead principal investigator for PARAGLIDE-HF and is a series mentor for this very 2022 heart failure Decipher the Guidelines Series. For these reasons and many more, he was awarded the Master CardioNerd Award during ACC22. Welcome Dr. Mentz!  The Decipher the Guidelines: 2022 AHA / ACC / HFSA Guideline for The Management of Heart Failure series was developed by the CardioNerds and created in collaboration with the American Heart Association and the Heart Failure Society of America. It was created by 30 trainees spanning college through advanced fellowship under the leadership of CardioNerds Cofounders Dr. Amit Goyal and Dr. Dan Ambinder, with mentorship from Dr. Anu Lala, Dr. Robert Mentz, and Dr. Nancy Sweitzer. We thank Dr. Judy Bezanson and Dr. Elliott Antman for tremendous guidance. Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values. Question #7 Ms. Valarie Sartan is a 55-year-old woman with a history of HFrEF (EF 35%) and well controlled, non-insulin dependent diabetes mellitus who presents to heart failure clinic for routine follow up. She is currently being treated with metoprolol succinate 200mg daily, lisinopril 10mg daily, empagliflozin 10mg daily, and spironolactone 50mg daily. She notes stable dyspnea with moderate exertion, making it difficult to do her yardwork. On exam she is well appearing, and blood pressure is 115/70 mmHg with normal jugular venous pulsations and trace bilateral lower extremity edema. On labs, her potassium is 4.0 mmol/L and creatinine is 0.7 mg/dL with an eGFR > 60 mL/min/1.73m2. Which of the following options would be the most appropriate next step in heart failure therapy?  A  Increase lisinopril to 40mg daily  B  Increase spironolactone to 100mg daily  C  Add sacubitril-valsartan to her regimen  D  Discontinue lisinopril and start sacubitril-valsartan in 36 hours  E  No change  Answer #7 Explanation   The correct answer is D – transitioning from an ACEi to an ARNi is the most appropriate next step in management.   The renin-angiotensin aldosterone system (RAAS) is upregulated in patients with chronic heart failure with reduced ejection fraction (HFrEF). Blockade of the RAAS system with ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), or angiotensin receptor neprilysin inhibitors (ARNi) have proven mortality benefit in these patients.   The PARADIGM-HF trial compared sacubitril-valsartan (an ARNi) with enalapril in symptomatic patients with HFrEF. Patients receiving ARNi incurred a 20% relative risk reduction in the composite primary endpoint of cardiovascular death or heart failure hospitalization. Based on these results, the 2022 heart failure guidelines recommend replacing an ACEi or ARB for an ARNi in patients with chronic symptomatic HFrEF with NYHA class II or III symptoms to further reduce morbidity and mortality (Option D). This is a class I recommendation with level of evidence of B-R and is also of high economic value. Making no changes at this time would be inappropriate (Option E).  While it would be reasonable to increase the dose of lisinopril to 40mg (Option A), this should be pursued only if ARNi therapy is not tolerated.   Mineralocorticoid receptor antagonists (MRAs) have a class I (LOE A...

Spain - Teresa López-Fernández, MD is a clinical investigator and consultant cardiologist at La Paz University Hospital in Madrid, Spain. Brazil - Renato Lopes, MD, Professor of Medicine. Member in the Duke Clinical Research Institute, USA Carolina Silva, MD, PhD, cardio-oncologist, consultant cardiologist, clinical investigator at Brazilian Clinical Research Institute Ariane Vieira Scarlatelli Macedo, MD, MHSAssistant physician and coordinator of the cardio-oncology clinic at Santa Casa de São Paulo School of Medicine, São Paulo, Brazil United Kingdom - Mark Westwood, MD, consultant cardiologist at OneWelbeck Heart Health, specializing in cardiac MRI and cardio-oncology.

Dr. Eric Perakslis is the chief science and digital officer at the Duke Clinical Research Institute. Stephen Morrissey, the interviewer, is the Executive Managing Editor of the Journal. E. Perakslis. Responding to the Escalating Cybersecurity Threat to Health Care. N Engl J Med 2022;387:767-770.

Hi, I'm Tom Rhoads, CEO of Spencer Health Solutions. We are proud of the amazing work that pharmacies do to support patient health and wellbeing. The need for innovation in the clinical trial ecosystem has challenged traditional pharmacies to rethink their strategy since they are the ones with the greatest access to a diverse and underserved population. On this episode of People Always, Patients Sometimes, we hear from a member of the clinical trials team at Walgreens that recently announced a corporate launch into providing clinical trial services at neighborhood store locations. Adam Sampson, head of clinical delivery operations for Walgreens is one of the team members tasked with managing the plan at clinical trial services to brick and mortar locations by the end of the year. I hope you enjoy this conversation on People Always, Patients Sometimes.   Janet Kennedy: (00:53) Hi, I'm Janet Kennedy and a member of the Spencer Health Solutions team. I'm looking forward to speaking with today's podcast guest, Adam Samson on People Always, Patients Sometimes. Adam is the Head of Clinical Delivery Operations for Walgreens, and he has a really big project in front of him. Welcome to the podcast, Adam!   Adam Samson: (01:12) Thanks so much, Janet. I really appreciate you having me on the show.   Janet Kennedy: (01:15) Well, you know, we've heard a little bit about you from my CEO, Tom Rhoads, but I'd really like to figure out how you got where you are today, especially from your startup background. So do you mind giving us a little bit of a catch up with your career and how you ended up where you are today?   Adam Samson: (01:31) Yeah, I'd be glad to. So I started my career in clinical trials as many people do, you know the cliches - to say that we kind of fell into the industry. I was a registered dietician out of undergrad and very quickly found my way into interacting directly with patients as part of clinical trials and worked as a clinical research coordinator for a few years and transitioned from there about 10 years ago into the more business side of our industry. So I worked at a couple mid-size CROs, took a very standard path. I was a regional monitor, worked in project management in line management. And then about seven years ago, my wife and I moved out here to North Carolina and I worked at Duke Clinical Research Institute for a few years. While at Duke, I did a lot of work in government funded trials in the pediatric space and completed a master's degree through George Washington in clinical trials.   Adam Samson: (02:28) And then I moved to a large pharma company and was conducting global, late phase studies. And then the pandemic hit, like many of us, I was, scrambling to keep my study going. You know, it's a hundred sites in eight countries. And how do we, possibly kind of keep operations, running lots of challenges. It was an eye opening experience around how in this industry, we really are under utilizing technology. That's no surprise to anyone we've gotten a bit better, but especially at that time, the start of the pandemic, getting even things like e-consent and other things approved was very challenging. So I decided to kind of take a leap of faith and join a very small time startup that was in the decentralized clinical trial space and had a great software product, but wanted to really build out their services and operations.   Adam Samson: (03:22) I joined the team when there were about 15 people and was with the team until series B and about 130 people. It was a really exciting couple years and enjoyed working in that space of how do we bring trials into patients homes and give them additional options to participate in trials? The one thing that remains a pervasive challenge when we're trying to do decentralized trials is that technology of course, is not enough. Sometimes patients there's a lack of trust. If things come through via email or they see them on the internet, not everybody wants somebody in their home. Sometimes people want to, go to a trusted healthcare provider, that's local to them. So when I saw this opportunity open up at Walgreens recently, where Walgreens was getting into the clinical trials business kind of light bulb went off, I'd been watching what's happening just overall in the retail pharmacy space.   Adam Samson: (04:16) And, I saw this as just an incredible opportunity to be able to take what I had learned across my career and kind of running trials in the traditional site based model, as well as, more recently working in the decentralized trials model and saying, "What if, we can take the best of both?" And we've got the technology and Walgreens has 9,000 approximately stores in the US. So 78% of the, the us population is within five miles of the Walgreens. What if we can take and plug clinical trials into that, right? There's the existing trust within the Walgreens brand and with the pharmacists that these patients are seeing every day. And we can really build a model on a really strong foundation that Walgreens has started to build in the healthcare space. So I joined the team as Head of Clinical Delivery Operations, as you said. And my role here is really to operationalize our stores, our physical footprint. How do we make sure that we have the right people process and technologies to be able to start seeing clinical trial patients within some of Walgreen's locations?   Janet Kennedy: (05:26) All right. So let's go back a little bit to joining Walgreens in clinical trials. This is very new for them and you are in a very new group at Walgreens, are you not?   Adam Samson: (05:37) Absolutely. Yeah, you're correct. So about seven months ago, actually I might even take a step farther back than that and say spring of last year, we had our new - no longer new, I guess - CEO, Roz Brewer, joined. And Roz, very quickly - I believe it was by, by fall of last year - announced that we were moving into the healthcare space with the offering of Walgreen's Health. As part of that vision that she had, right? Overall moving to a more interoperable health type framework to ensure for our patients, our main constituents here at Walgreens, that we were not decoupling them from their healthcare providers, but really helping to bridge that care continuum. Part of that offering, they realized clinical trials could be part of this, right? So about seven months ago, my boss, Ramita Tandon, our Chief Clinical Trials Officer, joined the team, joined Walgreens Health, and she began to lay the framework for what this clinical trial business would look like. What services we might offer to begin with, what are the key roles that we needed leadership to get going?   Adam Samson: (06:50) And then Ramita, a couple months ago started bringing on other folks like myself. So I've been with Walgreens - I believe this is the end of week six for me - we've had some folks on a couple weeks longer, or a couple weeks less than me, but we're coming from different backgrounds. We have folks on the product side, we have folks who are really accustomed on digital optimization and how do we engage with patients in a meaningful way, making sure that we leverage our footprint to engage with folks in diverse communities. so really exciting to be part of this new and growing team.   Janet Kennedy: (07:29) I am both thrilled and awestruck for a huge company like that to make such a big move is amazing. And I keep thinking, you're trying to move a tank when the industry needs to be on motorcycles. That might be a horrible analogy, but it's a huge company you said over what, 7,000 locations within five miles of individuals. So how do you do that? Are you cherry picking certain markets or certain states where you already have some of those type of services in play or is this literally you're starting from a blackboard and you're just starting from the very beginning.   Adam Samson: (08:09) Yeah, it's a really good question. And honestly kind of going back to when I first saw the opportunity open up here for a position with Walgreens, my first thought similar to years I think was how could this possibly happen as a company so big, right? how could you possibly get something this big done, and after a call with Ramita, it was quite clear to me that Walgreens was very much invested in this, but also that they had the leadership team Ramita included to really make this happen. I've been blown away since I've joined at not just our small core group that is starting, but outside of that, in the Walgreens ecosystem, just a lot of excitement around Walgreen's health and clinical trials in particular. So obviously we're part of this larger company, but we are somewhat entrepreneurs, right?   Adam Samson: (08:54) We are being given the opportunity to start something new within a very large business and allowing some flexibility around how we might be able to make sure that we can do that in a way that is both effective and compliant, but also nimble. Now 9,000 stores - obviously we're not gonna try and open them all at once and, and activate them as clinical trial sites. The biggest thing on my mind right now is I'm traveling to a number of different locations. We have other folks on our team who are as well meeting with stores, understanding capabilities. We have identified already a number of stores that really are the ideal kind of first step, if you will, to be clinical trial sites. So we have a few investments, key investments that we've made, and some companies that I'll talk about that will really support that.   Adam Samson: (09:47) And also, I will say that Walgreens has, we've started building out what we call health corners. So this has already been happening for a year. Plus health corners are a place where there are a small physical footprint within a Walgreen store. That's staffed with a registered nurse or a registered pharmacist. They have private health rooms and they have places to interact with technology. And it's a place where our patients can go and they can have deep discussions that can help them with chronic care. They can have blood pressure drawn, maybe they could have, blood taken, these type of things to help with chronic disease management and others questions that might come up. Our idea first is to leverage these existing capabilities, as you can probably draw the connection there, right? We've already got nurses, we've got a private health space.   Adam Samson: (10:39) So we're gonna use that and make sure that we put trained clinical research professionals in place to support these activities within these spaces and support them with centralized staff as well. Now we don't wanna stop there. we don't wanna be limited. Now we are somewhere in the range of 200 health corners. I believe by the end of the year, we don't wanna only focus there. As I mentioned, we have some, some other key partners. One is village me medical or village MD. So village MD is actually a primary care offering in a community based setting. And these will be co-located with Walgreen. So this is actually 3,200 square feet of a Walgreen store that will be dedicated to primary care staffed with physicians and other clinicians. So this is another great opportunity for us to be able to leverage the existing Walgreens Health enterprise, to be able to plug clinical trials in make sure that we're doing it in compliant way, but utilizing the existing infrastructure.   Adam Samson: (11:38) There are some other exciting partnerships we have with Shields Health and specialty pharmacy, as well as CareCentrix in post-acute and, and home care. But as far as the physical space and building that out, that's where my focus is right now. How do we activate existing health corners and Village MD, but also looking at our our physical footprint that's out there that has private health rooms because of the immunizations. We administered approximately 63 million COVID vaccines. These spaces are already being used for healthcare purposes. How can we staff those stores and make sure that they are compliant to do certain clinical trial procedures, lots to think about long winded answer there, but really, really kind of cool work to start conceptualizing.   Janet Kennedy: (12:27) I've spent a little bit of time in the shopping center industry. So I feel like I've got a grasp of retail space issues and questions. And let me ask you this. A lot of the Walgreens, I would imagine in more rural or suburban areas have lots of space, but not necessarily in downtown Atlanta or downtown Raleigh or downtown New York city, are you gonna be able to find the space you need in those urban populations, which also are in areas that wouldn't be dealing with underserved populations?   Adam Samson: (12:58) Yeah. And I'm glad you mentioned that too, because this is as we've been very public about in our announcement, one of our biggest focuses right now is making sure that as we are opening up these type of health corners for healthcare purposes, but also our clinical trial purposes. So more than 50% of Walgreens stores are in socially vulnerable areas. And right now there is a huge push in industry and for very good reason to increase, diversity and inclusion within clinical trials, as we're looking at potential locations of where do we start doing this? We're not making it easy on ourselves. We're not, yeah. Let's, to your point, right, go to just the stores with the highest volume or anything. We're very much focused on going into places where there is not as much access to clinical trials or healthcare overall, and areas that are in communities that are overall just underserved. We have already started having these discussions with the the regional managers to identify those stores where, to your point there's only so much retail space or pharmacy space, and this is another thing that we're bringing into stores.   Janet Kennedy: (14:08) Well, you know, I'm wondering about how you're finding out what the needs are. Have you been in communication with some of the larger pharmaceutical companies in a, a, what if scenario, you know, if this were available, what kind of things could we bring to the table? What would you need to get from us? Obviously, patient records are a big part of what you have and also from the geographic location. I mean, so often now clinical trials are done where the principal investigators are. And a lot of the principal investigators are in larger city centers where there are medical centers and universities. How do you balance those needs with what do you actually have to have for the space to conduct a clinical trial?   Adam Samson: (14:51) Great question. And so, yeah, when it comes down to it and what I've spent a lot of the past two years prior to coming to Walgreens doing is trying to figure out how can we leverage some of these new models, right? So how can we leverage, not necessarily even fully decentralized hybrid type models. And we're looking at that with Walgreens too, right? How can we potentially have something at something like a Village MD where there's primary care and physicians and have kind of a hub and spoke model potentially right. Where we would have a PI within a certain region that might be conducting activities within a larger clinical type site, but then have within perhaps a 40 or 50 mile radius, we have X number of Walgreens locations and patients are able to go there for perhaps some of the follow up, right? They can meet with coordinators and have their blood drawn. They can have assessments done, and then if need be, they could come into the to the larger, location for certain procedures throughout the course of that trial. So looking at it in a very broad way and saying, we need to make sure that there's that PI oversight. How can we enable that though over a bit of a larger distance through centralized administrative support, as well as really best in class technology,   Janet Kennedy: (16:07) As I think about a Walgreen's on every street corner, what about the idea of the local Walgreen staff actually going to the patient to their home? Is that something you've discussed?   Adam Samson: (16:18) So we are absolutely looking at also as an option, not just in store, but also bringing this at home, in a doctor's office via mobile app. So we will be in addition to the existing Walgreen staff, which we very well are looking at opportunities for folks to be upskilled into clinical trials. We will be partnering with folks like, those that we have potentially over at CareCentrix and others that are accustomed to working within patients homes so that we can offer that as a service as well, where we could if it's permitted by the protocol, be able to, rather than have patients come all the way into a larger clinic or even to have to drive 10 minutes down the road to a Walgreens that we could potentially go out for certain things like blood draws and other things, and be able to see patients in their home, especially for those type of conditions patients might have where it makes access to clinical trials has decreased because of decreased mobility.   Janet Kennedy: (17:16) Now, the patient is obviously an important part of what we're talking about because that's one of the reasons that clinical trials do struggle that it isn't wrapped around what the patient needs, what the patient expects and how to support them best. Have patients been involved in these kinds of conversations, has Walgreen committed to any kind of patient advocacy committee group or focus group or anything of that sort?   Adam Samson: (17:41) Yeah, I mean, it's very early days, I will say, right. So we did launch just last month, but I am thrilled that we have on board, some folks like Kendal Whitlock who comes with just vast experience in this area, right? Working with patient groups and ensuring that we get that type of representative voice within our research program. we're also talking some other organizations right now that I can't share publicly just yet. but really positioning ourselves very early on. Like I said, we're only a month or so in since our launch to make sure that we are not assuming what our constituents and what our patients want, but making sure that we're hearing directly from people within the communities. Another thing just to kind of bridge off of that is we're looking at not just how do we inform Walgreen's patients and customers about clinical trials that, that might qualify for them, but also how do we kind of help the industry and our patients with this grassroots basic general clinical research, understanding and education, because as you well know, the barriers in a lot of these communities to clinical trials is either a lack of understanding or a lack of trust.   Adam Samson: (18:56) And if we just go in and, and start advertising clinical trials and every single Walgreens, I don't think that that's really gonna solve the problem. So we wanna be able to do some of that foundational clinical trial education through our pharmacist, through, through other staff to really start to build those connections with patients and hear from them so that that can help us inform our strategy.   Janet Kennedy: (19:21) Well, that's really exciting because aside from the two things you already mentioned, just awareness that a patient could be eligible for a clinical trial is a real challenge. So I think the opportunity that you have to make folks aware that it's happening on my street corner is a lot different than, you know, what a lot of patients experience. And certainly if there is at all, a silver lining to the pandemic is that I believe people became aware that clinical trials are an essential part of forwarding health and forwarding the learning about drugs and new ways to deal with illnesses and diseases. So hopefully people have also understood that it is a process that while doesn't happen overnight, we were able to escalate that during the pandemic, but that it's essential that we have patients a part of the process.   Adam Samson: (20:16) Absolutely. Yeah. And this idea of trying to assume what patients might want or to kind of do those checkbox activities of like, oh, well, we talked to a patient. I think, as an industry we're, we're moving past that. We're understanding that this is more than that, that we really need to engage in a meaningful way and that it's not a one and done kind thing. And I've been really glad to see that Walgreens very much is taking that approach to everything. And across the Walgreens health platform we have 160 million approximately lives that we service through Walgreens. And the trust that we have with those customers and those patients is something that is really first and foremost to Walgreen. So as we look at things like supporting, recruitment, as part of clinical trials, looking at insights gained through real world evidence, we have a really robust foundation around regulatory and privacy to make sure that we're not in any way violating that trust. And we're giving our patients, our customer the opportunity to opt in and opt out of these type of things. So that it's again seen as something that we can engage with them on, in a way that works for them, get their feedback. But if they're not interested also be able to not push the issue beyond the point where it should.   Janet Kennedy: (21:44) Absolutely. I think that should be the tenant of any healthcare organization patient first and what are they going to be comfortable with? Well, I'm really excited that I was able to capture you so early and fresh in your experience with Walgreens and at the very beginning of your more public announcements related to getting involved in clinical trials. And I'm not gonna put you on the spot per se, or hold you to this, but what does it really mean? What's it gonna take to get you up and running? And, and when will the first clinical trials be supported at a local Walgreens   Adam Samson: (22:19) We're shooting for this year, right. We, we want this to take months, not years to get off the ground. There's already, as I mentioned, been some groundwork done even before this initial team has started, there's been some really great work done by folks here at Walgreens to make sure that we're gonna be able to roll this thing out in a very compliant way. And now we got the folks on board that are needed to really start executing. And we're not starting from zero as well because we have as I mentioned, some physical locations that are very well staffed and set up to be able to support clinical trials. So we don't wanna rush, we do wanna walk before we run, but we anticipate that this year we will enroll patients within, a small number of clinical trials and start to get the wheels moving on this and then learn and, and build over time to be able to offer an increasing number of services and to be able to, service protocols of increasing complexity. So yeah, I would say, and expect by the end of the year to hear that we've had our first patient in store and certainly even before then, that we're, supporting recruitment in different ways as well.   Janet Kennedy: (23:27) Oh, that is very exciting. Well, I look forward to not only catching up with you in six months, or a year and finding out how things rolled out, but also speaking to other members of your team, hearing maybe a little bit more about how real world data and real world evidence will be incorporated into the programs; how patient engagement is going. So let's continue the conversation and thank you very much for being a part of People Always, Patients Sometimes.   Adam Samson: (23:54) Absolutely. Thanks so much, Janet for the opportunity. I look forward to reconnecting, and thanks so much everybody who listens.

This week, please join author Philipp Lurz and Editorialist Daniel Burkhoff as they discuss the article "Characteristics of Heart Failure With Preserved Ejection Fraction Across the Range of Left Ventricular Ejection Fraction" and the editorial "HF?EF: The Mysterious Relationship Between Heart Failure and Ejection Fraction Continues." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: I just cannot wait to tell you about today's feature discussion, Greg. It's about heart failure with preserved ejection fraction and characteristics in the range of that ejection fraction that's above 50%. So, okay. I know, I know. It's like, "Oh my gosh. Wow. How much are we going to be talking about this ejection fraction thing?" But I'm telling you, everybody has to listen to this. It's really a big stride forward in our understanding of these patients with heart failure and a higher ejection fraction. Plus it includes one of my mentors from Mayo Clinic days, and I just can't wait for everyone to hear this. But before we go there, we've got really, really cool original papers in today's issue too. Would you like to start first? Dr. Greg Hundley: You bet Carolyn, and I can't wait for that feature discussion, especially this is a real area of your expertise. So listeners, hold on for that feature discussion. Well, my first paper, Carolyn, really pertains to physical activity. And Carolyn, the study is led by Dr. Don Hoon Lee from the Harvard T.H. Chan School of Public Health. And it evaluated a total of 116,000 adults from two large prospective US cohorts, the Nurse's Health Study and the Health Professional's Follow up Study that took place from 1988 to 2018. And they were examining self-reported leisure time physical activity and assessed the association between long term leisure time physical activity intensity and all cause and cause specific mortality. Dr. Greg Hundley: Now Carolyn, two types of physical activity were assessed. First, moderate physical activity and we're going to abbreviate that as MPA and that was 150 to 300 minutes per week, which is really recommended. Or second, vigorous physical activity for which it's really recommended that one performs 75 to 150 minutes per week. Now, Carolyn, as you know, some individuals accomplish both of these in their routine, some neither, some one or the other. And so it really remains unclear whether higher levels of long term vigorous or moderate are independently or perhaps jointly associated with lower mortality. Dr. Carolyn Lam: Oh, that's so interesting, Greg. Quick, quick, quick, tell us the results. Dr. Greg Hundley: Right Carolyn. So the nearly maximum association with lower mortality overall was achieved by performing approximately 150 to 300 minutes per week of long term leisure time vigorous physical activity or 300 to 600 minutes per week of long term leisure time moderate physical activity or an equivalent combination of both, so mixing those minutes. Also Carolyn, very interestingly, higher levels, suppose you go beyond those limits of either long term leisure time vigorous physical activity of more than 300 minutes per week or moderate physical activity of more than 600 minutes per week did not show clearly further lower all cause cardiovascular disease or non-cardiovascular disease mortality and nor did they show harm. So if you went above those thresholds, you really didn't experience greater harm. Dr. Carolyn Lam: Thanks, Greg. You know I'm going to be trying to apply that. That's so cool. All right. Well the next paper refers to the Cabana Trial, which I'll remind you is a trial in which catheter ablation did not significantly reduce the primary endpoint of death, disabling stroke, serious bleeding or cardiac arrest compared to drug therapy by intention to treat, but did improve quality of life and freedom from atrial fibrillation recurrence. In Cabana, the heart failure subgroup, ablation appeared to improve both survival and quality of life. The current paper led by Dr. Mark and colleagues from Duke Clinical Research Institute looked at the cost effectiveness of this ablation versus angio-rhythmic drug therapy in atrial fibrillation and which was a pre-specified Cabana secondary endpoint. Dr. Greg Hundley: Ah, Carolyn. So what did they find? Dr. Carolyn Lam: Well in this trial based economic evaluation, catheter ablation was estimated to cost $57,893 per QALY or Quality Adjusted Life Year gained compared to drug therapy in the overall cohort. And this was primarily driven by improvement in quality of life. It also cost $54,135 per QALY gained in the heart failure subgroup, driven by both gains in quality of life and survival. In summary, catheter ablation of atrial fibrillation was found to be economically attractive compared to drug therapy in the Cabana trial overall at present benchmarks of healthcare value in the US and based on projected incremental qualities, but not live years alone. Dr. Greg Hundley: Very nice Carolyn. Well, my next paper comes to us from the world of Preclinical Science and it's corresponding author is Dr. Swapnil Sonkusare from University of Virginia School of Medicine. So Carolyn, calcium signals in smooth muscle cells contribute to vascular resistance and control blood pressure. Now increased vascular resistance in hypertension has been attributed to impaired smooth muscle cell calcium signaling mechanisms. And in this regard, transient receptor potential vanilloid four or TRPV4 smooth muscle cell ion channels are crucial calcium entry pathways for smooth muscle cells. However, their role in blood pressure regulation has not been identified. Dr. Carolyn Lam: Wow. TRPV4 smooth muscle cells. Cool Greg. So what did they find? Dr. Greg Hundley: Right, Carolyn. So these authors provide the first evidence that TRPV4 smooth muscle cell channel activity elevates resting blood pressure in normal mice. A1AR stimulation activated TRPV4 smooth muscle cell channels through protein kinase calcium signaling, which contributed significantly to vasoconstriction and blood pressure elevation. Dr. Greg Hundley: Surprisingly, intraluminal pressure induced TRPV4 smooth muscle cell channel activity, opposed vasoconstriction through activation of calcium sensitive potassium channels indicating functionally opposite pools of TRPV4 smooth muscle cell channels. And so Carolyn, this team identified novel smooth muscle cell calcium signaling nano domains that regulate blood pressure and demonstrate impairment in hypertension. Dr. Carolyn Lam: Oh wow, Greg. Thank you so much for that. Well, let's cover the other articles in today's issue. There's a primer by Dr. Jaffe on High Sensitivity Cardiac Troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation and diagnosis of acute chest pain. There's also Research [Letter] in there by Dr. Fordyce on the eligibility for non-invasive testing based on the 2021 American Heart Association and ACC guideline for the evaluation and diagnosis of chest pain, implications from the Promise trial. Dr. Greg Hundley: Great Carolyn. Well, I've also got an exchange of letters to the editor from Professors Benali and Professor Della Bella regarding a previously published article, “Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients with an Implantable Cardioverter Defibrillator, Results from the Multicenter Randomized Partita Trial.” And also there's a very nice Perspective piece from Dr. Udelson entitled “Glucose Insulin Potassium Therapy for Acute Myocardial Infarction, 50 years on and Time for a Relook.” Well, Carolyn, I can't wait to hear more of the discourse between you, the authors and editors on heart failure and preserved ejection fraction. Dr. Carolyn Lam: Yay. Here we go. I'm so excited about today's feature discussion. It's on my favorite topic, heart failure with preserved ejection fraction. Although thanks to one of the authors, Dr. Daniel Burkhoff of the editorial that accompanies it, I don't even know how to pronounce, it's Heart Failure question mark Ejection Fraction. I love it. How would you pronounce that? Dr. Daniel Burkhoff: Yeah, no, we debated how to pronounce it. HFQRef…a question mark? Dr. Carolyn Lam: HFQRef. Oh my goodness. What are we going to come up with next? Dr. Daniel Burkhoff: And we actually thought the editors would have a problem with that. Whenever we put something cute in the title, we always get knocked down. So we haven't yet got knocked down, so we'll see. Dr. Carolyn Lam: No, I'm not knocking you down. Dr. Daniel Burkhoff: But it just really emphasizes that we're in a very confusing time now as it comes to heart failure and ejection fraction, that we have to move on beyond ejection fraction. And although we have these strict buckets and upper and lower limits for each range, that maybe this is in a little bit of a way, doing us a disservice and doing the patients at disservice in terms of treatment. Dr. Carolyn Lam: That's really great. And everybody that was Dr. Daniel Burkhoff from the Cardiovascular Research Foundation in New York. He's the editorialist of today's feature paper. And I'm so excited that we have the corresponding author of today's feature paper as well, Dr. Philipp Lurz from Heart Center Leipzig in Germany. So first, I mean, or second, heartfelt congratulations on this beautiful paper, Philipp. If you could start with telling us all about what you did and what you looked at and what made Dr. Daniel Burkhoff call it now, Heart Failure, QREF? Dr. Philipp Lurz: Yeah. So thank you so much, first of all, obviously for having me for the kind introduction and your kind words about our work. The whole thing started with the observation that in recent drug trials, the response in HFpEF patients to drugs which were before proven to be quite successful in HFrEF actually showed a quite heterogeneous response in HFpEF patients. And that there were some patterns according to the range of ejection fractions. So it seemed that those HFpEF patients with the lower ejection fractions, they respond a little bit better to HFrEF medication than those with a higher ejection fraction. Dr. Philipp Lurz: And HFpEF studies, they included patients within and ejection fraction or 40 and above who normally would probably would consider HFpEF to start with 50 and above. But even in those truly HFpEF patients, so from 50 and anything above to 70, there was a suggestion that there might be differences. 50 to 60 might be something else and then 60 and above. And this is where we started to look into our cohort and to group them according to ejection fraction and see whether we can see some important and clinically meaningful differences in morphology, obviously in function, but then even also in terms of our biopsy results. Dr. Philipp Lurz: And that also implies that we did quite a deep phenotyping of our patients. So we use imaging, echo obviously. We use magnetic resonance imaging. We were able to acquire in a larger percentage of that cohort, by the way, it was 56 patients in total, we were able to get some left ventricular biopsies. And most importantly, when it comes to the functional properties of the left ventricle, we also acquired pressure volume loops. And that has the great advantage that we obviously we can look at low dependent parameters, but more important, also low independent in disease of both systolic and diastolic function. And that's pretty much what we did. Dr. Carolyn Lam: Oh my goodness. I mean, as an editor at Circulation, can I just first tell you that's what really, really stood out? It's the comprehensive, careful, in-depth characterization. It may be 56 patients, but MRI, echo, biopsies, exercise, PV loops. I mean, it was a lot, a lot that you did. Could you boil it down to what you found and maybe just to first clarify to the audience, how did you bend the ejection fraction? And then what you found? Dr. Philipp Lurz: We divided the cohort in two groups. One with an ejection fraction 50 to 60, and the other groups higher than 60% left ventricular ejection fraction. We ended up in lower group, 21 patients, in the higher group with 35 patients. And they were quite different. They had distinct features in terms of morphology, means that the lower injection fraction group, they had larger ventricles. That's probably what you would expect when you group them according to eject fractions. So not that surprising. Dr. Philipp Lurz: And at that point, and they had the same stroke volume. The low ejection fraction group, you could say that they had a certain degree of eccentric modeling, whereas those were the high ejection fraction group, that concentric modeling. When we then looked at the biopsies, the group with the low ejection fraction group, so 50 to 60, they had higher percentage of myocardial fibrosis at 15%. Dr. Philipp Lurz: And then on left ventricular biopsy, we saw that patients with a high ejection fraction group, they had less myocardial fibrosis, so more fibrosis in those with the lower ejection fraction group. And this is really interesting because when we then look at the real size of the pressure volume loop analysis, despite the fact that the high ejection fraction group had less fibrosis, they had the most stiff ventricles on pressure volume loop analysis. So that's already a very important point because it illustrates once again that we should not mistake fibrosis with stiffness, and also not the other way around. There are other parameters which can cause stiffness such as cellular stiffness, and it's not just the extracellular matrix. Dr. Philipp Lurz: So that's an important point. Those patients with high ejection fraction, they had the most stiff ventricles. They had the most relevant limitations in left ventricular filling, so the most marked diastolic dysfunction. We also looked at systolic parameters and there we found that they had a very high contractility. So this is the end systolic pressure volume relationship or also called elastics and that's a marker for contractility. So these ventricles with high ejection fraction, they can contract very well. They have high contractivity. But this is also a marker of systolic stiffness. So they stiff, both in terms of diastolic properties, but also systolic properties. And there, their most important limitation is the limitation in filling. Dr. Philipp Lurz: The other group, injection fraction 50 to 60, they do have some stiffness. Obviously we are talking about HFpEF. This is a disease of a diastolic dysfunction. So they have increased stiffness, but to a lesser extent. They can feel a little bit better, but what we see there is a reduction in contractility, so systolic properties. So you could argue that in some extent, that group 50 to 60, they behave a little bit more like HFrEF. Whereas those with high ejection fraction, they're completely different. Very stiff, both doing diastolically and sistolly. Dr. Carolyn Lam: Thank you so much. Now I really have to get the gurus insight into this. And of course by guru, I mean, Dr. Daniel Burkhoff. First, I'm going to take this opportunity to share a little private personal story that it's very hard for me to call Dr. Burkhoff, "Dan", although if you will allow me it's because I was a fellow when I first met Dr. Burkhoff. And one of my first papers was actually communicating with Dr. Burkhoff trying to draw these PV loops based on the noninvasive measurements that I was obtaining at the Mayo Clinic in the Olmsted County Cohort. And so this is just really making me smile. So Dan, if I may, what do you make of all this? And if you could give us what you think may be the clinical take home message. Dr. Daniel Burkhoff: Thank you so much, Carolyn. And also again, Philipp, congratulations on really a really important paper. I think as Carolyn was saying, one of the many things that impressed me was the multifaceted aspects of the thorough evaluation using multi modality characterization, which is in my mind, unprecedented, especially for this particular group of patients. And you summarized the main results very well. But to me, the thing that really struck me and that we really tried to emphasize in our editorial was the differential response to exercise, to hand grip exercise in this point. Dr. Daniel Burkhoff: As you already said, and I don't think this could be understated, that in the lower range, the 50 to 60, these patients were able to fill, the ventricle was able to fill more, the end diastolic pressure still went up significantly into an abnormal range, which is of course is one of the requirements for the diagnosis of HFpEF. But those patients, the end diastolic volume was able to increase and that helped them to increase their cardiac output. Dr. Daniel Burkhoff: In the higher EF group, the greater than 60, the end diastolic pressure went up, but the volume did not increase. So the end diastolic pressure volume relationship became higher elevated. And this of course, was reminiscent of what was identified in the early nineties by Dalane Kitzman. And really, he didn't make this distinction between the lower half and the higher half. And we had also in a paper that we did with David K and others, seen a similar finding a couple years ago. And I think this is really, to me, was the along with the apparently disparate findings on myocardial biopsies with fibrosis going the wrong way, if you will, as you already commented on. So this is at least for the higher EF group, is identifying what I would refer to as really true diastolic dysfunction. Dr. Daniel Burkhoff: That means that the patients can't fill, there really is some problem why the EDP can go up, but the volume does not increase. And this is obviously for future research, we have to understand what is the difference between these two groups. There are several speculations about why it might. For example, one thing that has been proposed in the literature is the pericardial restraints. If the heart is constrained in a tight pericardium, the volume is recruited from the venous system, which is another what I think is a very important part of this HFpEF phenotype, but the heart is already constrained. That would elevate both the CVP and the wedge pressure without concomitant increases in RV or LV volumes, and therefore limit the ability to increase the cardiac output. Dr. Daniel Burkhoff: Another alternative is delayed relaxation. That means a true abnormality of active relaxation. The tau if you will, but I believe in your study, if I remember correctly, the tau was not that abnormal and did not really change very much in either group. So it was harder to really pin it on an abnormality of active relaxation. So that was one really, I think, really important finding. Dr. Daniel Burkhoff: The second is now in the group 50 to 60 where they could fill, one of the limitations of the study that you pointed out was that there's no control group. So why this population, this HFpEF population, the EDP increased, but the EDV the end diastolic volume also increased, so what's different between those patients and normals? That we don't really have an answer for yet. So that would be one thing is to compliment these findings with results in a true control group that does not have HFpEF. Dr. Daniel Burkhoff: So we still have this mystery of why does EDP go up in this group? My perspective is not an abnormality of diastolly. It's not a diastolic dysfunction, even though it's a HFpEF. I've been trying to promote this idea for more than 20 years, that all HFpEF is not an abnormality of diastolic ventricular properties. There may be extra cardiac factors even beyond the pericardium in this group. So I think these results are just further telling us how complicated and individualized our approach to the pathophysiology of these patients should be. Dr. Daniel Burkhoff: And also just one final comment, making a strict cutoff at 60% or 57% as we saw from Valsartan Cuba trial, Valsartan study, is clearly also not going to do us justice. Let's say that we're dealing with anyway, patients with two different pathophysiologies. There's going to be a distribution of these different mechanisms and there's going to be an overlap of these distributions. So we need to start thinking about how we individualize and characterize the pathophysiology in individual patients. So maybe patients with EF of 55, certain patients with EF 55 will not respond to Sacubitril- Valsartan and maybe some patients with an EF of 62 will. So we need to go more deep into the clinical characterization. Dr. Daniel Burkhoff: And methods that you use in particular, the pressure volume loop, seem to separate, very nicely, these two different, at least two different subtypes. So I think it's very exciting, and I think people should really take notice of what you found and build on this as a foundation and understand that we need to go deeper on the clinical side to phenotype these patients. Dr. Carolyn Lam: Philip, what are your thoughts? Dr. Philipp Lurz: No, I think that the concept about stress and unstressed volume is extremely important and fascinating, but that's where it gets really complex because you could make the conclusion from our results that especially the high ejection fraction group, they are have a very high preload sensibility, which means that when we reduce pre-load too much in them, they drop the stroke volume very suddenly. So that's probably also the clinical question for the future. There are many patients, HFpEF patients in whom we should reduce stress volume and they can benefit from that. Dr. Philipp Lurz: But I also believe that there is a cord of patients, and those are probably more those with high ejection fraction. They actually, they could experience some harm if you reduce preload too much because of the severe filling restrictions, because of the inability to increase end diastolic volumes, especially as an adaptation to exercise. And I think if we find out ways to differentiate who will benefit from preload reduction and from decongestion and who actually might experience even harm from these interventions, then we are certainly one step further. Dr. Carolyn Lam: If I may, I just, I could go on forever, but I know that there's going to be this question that the audience is immediately thinking. Here we are going into the weeds, hemodynamics, we all love it. In fact, I think we're all kind of a little bit geeky about it, but then you've got, Emperor preserved, the Deliver Trial sort of being positive in heart failure with ejection fraction above 40. So, do we really need to understand the different hemodynamic? What do you think is happening that this sort of blanket benefit can occur? Dr. Philipp Lurz: I don't think that everyone will benefit. And I think that a better understanding of the underlying pathophysiology will help to even increase the rate of responders and dissect of those who will not respond or we need a different therapy. Obviously here we group patients according to ejection fraction. We just discussed that this is a very rough way to characterize patients. So the next step certainly would be to understand or to see distinct patterns in left ventricular functional behavior irrespective of ejection fraction. Because you might can skip ejection fraction at one day, but the conclusion is not, at least not in my opinion, that all heart failure is the same. Dr. Carolyn Lam: Nice. And Dan, what do you think? Dr. Daniel Burkhoff: Well, I think with STLT2 inhibitors, first of all, we're looking forward to actually seeing the results from Deliver what the details of it in terms of mortality versus hospitalizations and quality of life. But with regard to HSGL2 inhibitors, I don't think we know the mechanism. I mean, I've read about six papers that definitively talk about different mechanisms of action. I think we don't know. And even despite, let's say positive studies, there's still a significant residual risk that these patients have. So these are not the end of the story by any means. I think this is the beginning of the story and there's still going to be a lot to learn. Dr. Daniel Burkhoff: I think with SGLT2 inhibitors, I think it's difficult to identify who is or how do you define a responder on an individual patient basis? When we look at groups and you look at mortality and hospitalizations, yes, you can identify them. But that group does not overlap exactly with those who have an improvement in quality of life. So I think that we're just at the beginning, Dr. Daniel Burkhoff: I do think that a deeper phenotyping is going to be the way to go ultimately and I think we're going to need more therapies. Thanks again, Carolyn for inviting me to do the editorial and to participate in this. And I would really be remiss if I did not mention the extraordinary contributions for Mickey Brener and also Barry Borlaug who were equal contributors to this editorial and the evaluation of this paper. So I'm really indebted to both of them for this interpretations. And thank you again, Philipp, for just a wonderful paper. Dr. Carolyn Lam: Couldn't have said it better and I just want to thank you once again for providing that deeper phenotyping for opening the door. Many of us said it again and again, this is the beginning and we need more studies, frankly, in yours. I mean, I think Dr. Burkhoff wants you to send normal, healthy people for MRI biopsies, exercise, echo. I'm kidding, on PV loops, but it's true. We need that data. We need the same and the HFrEF and really just to understand the whole thing. I'm so excited about what this paper opens up. Dr. Carolyn Lam: I am thrilled to see your editorial, Dan. I'm sure it's going to be well received. Everyone who's listening to this, Pick up the paper, pick up the editorial. Thank you so much for joining us today. You've been listening to Circulation on the Run and from Greg and I, don't forget to tune in again next week, Dr. Greg Hundley: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit hajournals.org.

In an extended and extensive interview, Dr. Perakslis drew on his experience in industry, regulatory agencies, and academia as well as his book co-authored with Martin Stanley, Digital Health: Understanding the Benefit-Risk Patient-Provider Framework, to address the following questions: How do we tackle the challenges of the unintended (and undesired) effects of healthcare inventions and innovations for patients? How do the perspectives of leaders of inventors/innovators/developers, regulators, and researchers in healthcare vary from one another in evaluating the importance of the work they oversee? What are the attributes of effective leaders of healthcare organizations that are more or less generic and which are more specific to organizations engaged in drug and device development, in regulating healthcare innovations, and in evaluating the effectiveness and safety of new products and services? Where do you see the newest frontiers for breakthrough developments stemming from digital health? Immediately prior to joining the Duke Clinical Research Institute, Dr. Perakslis was senior vice president and head of the Research & Development Institute of Takeda Pharmaceuticals and that company's work in oncology, rare diseases, neuroscience, and other fields.  Previously, he also held positions at: Harvard Medical School and Boston Children's Hospital; U.S. Food and Drug Administration; senior vice president at Johnson & Johnson's Pharmaceutical R&D Information Technology;  and ArQule, a drug development company acquired by Merck. Innovators is a podcast production of Harris Search Associates.  *The views and opinions shared by the guests on Innovators do not necessarily reflect the views of the interviewee's institution or organization.*

Ivermectin, an FDA-approved treatment for parasites in humans, and sold over-the-counter for domestic livestock, is increasingly being taken by people to prevent or treat COVID-19. We hear from an ivermectin enthusiast, the president of the Center for Science in the Public Interest who warns about off-label use, and a physician at Duke Clinical Research Institute leading an ivermectin theraputic intervention study. An attorney with ACLU-Arkansas also discusses a federal lawsuit his team recently filed against a northwest Arkansas physician for treating county jail inmates with prescription ivermectin.

The last two years have been driving many discussions of the need for change in the pharmaceutical industry, particularly in the clinical trial arena. Discussions have not always led to actions, however. Hi, I'm Tom Rhoads, CEO of Spencer Health Solutions. As we look towards 2022, I believe we will record this as a year of make it so. The time for moving on from debate is here, as patients are demanding action and forward momentum on today's episode of People Always, Patients Sometimes, our host Janet Kennedy has a conversation with the new executive director of the Clinical Trials Transformation Initiative, Sally Okun. Sally brings a unique and essential perspective to CTTI, as a former nurse and VP of Patients Like Me. They have a detailed discussion of the Transforming Trials 2030 initiative, one that Spencer Health Solutions is 100% behind. I hope you enjoy this episode of People Always, Patients Sometimes.   Janet Kennedy: (00:59) It's very exciting for me to have today's guest. Sally Okun is now the executive director of the Clinical Trials Transformation Initiative. The last time I spoke with her was on the Get Social Health podcast, where she was the vice president of Patients Like Me. So interesting that we're going to have another conversation, but in a totally different role, and yet, still very patient centric. So please join me in welcoming Sally Okun to the People Always, Patients Sometimes podcast. Sally, I'm so glad to have you here. I know it's been very, very odd over the past few years in working and collaborating and life transitions, but we had an opportunity to talk to your predecessor, Pamela Tenaerts, who was the executive director of the Clinical Trials Transformation Initiative. We spoke to her pre-COVID. So now we're in the middle and maybe hopefully heading towards the end. And there are a lot of exciting things happening at CTTI. So welcome to the podcast, and I'd love to hear a little bit about how you ended up joining CTTI.   Sally Okun: (02:09) Janet, it's so nice to be here, and I really appreciate the opportunity to talk more about the Clinical Trials Transformation Initiative, and certainly the shoes that Pam left are large, and I'm still trying to find ways of filling them, and I think that's gonna take some time. How did I get to my current role? Well, interestingly enough, I had left Patients Like Me in 2020 and I was working on a variety of interesting projects at the time across the health spectrum. You know, I was consulting on a variety of different things and also enjoying some newfound freedom of semi-retirement, which was an interesting experience for the first time in my career. You know, by about mid 2021, maybe in light of the time that we were all spending at home as opposed to spending out enjoying each other's company socially or professionally, I started thinking more and more about the next chapter of my professional career.   Sally Okun: (02:57) So it wasn't long after that, that I was approached about the position of executive director at CTTI. And frankly, initially I didn't see the fit for me. You know, I've not spent my career in clinical trial work. I've spent a lot of my career in research and clinical research with patients and others, but hadn't really focused specifically on clinical trials and the clinical trial enterprise. So at first I really wasn't exactly sure it would be a good fit for me. However, after talking with some trusted colleagues and others, including the chairs of CTTI's executive committee, I was truly intrigued by the organization's impressive portfolio of work. I really hadn't been aware of just how much they have done over the last 15 years, 14 years, in terms of contributing to the improvement overall of the clinical trial experience, not just for participants, but for investigators as well as sponsors and others.   Sally Okun: (03:48) So, you know, I then looked a little more closely at the transforming trials vision, and I thought, you know what, here's an organization that is setting goals as a priority to be seeing clinical trials as patient centric and easily accessible as its number one pillar. And I thought, well, you know what, I think maybe this fit might be just right. So I spent a bit more time thinking about it and then made the leap in October of just a couple months ago - just hit my two month anniversary.   Janet Kennedy: (04:13) You mentioned something just now about the Transforming Trials 2030 program. What is that?   Sally Okun: (04:20) Well, you know, a couple of years ago, again, under Pam's leadership, they discussed the need to set some milestones to really stop sort of talking about improving clinical trials, but actually putting some stakes in the ground or pillars up to suggest that we need to have a goal for that transformation; that have to have things that we're working towards as a community in order to be able to achieve a better experience for everyone involved in clinical trials.   Sally Okun: (04:49) So what came out of that initial discussion was a set of five pillars that actually articulate quite specifically what we believe clinical trials should be like by 2030. And each one of them has a host of different objectives beneath the goal, that actually really describe how we might ultimately get to the point where we can say, "Yes, indeed, we have clinical trials that are now patient centered and easily accessible," for example, for the first pillar. But each one of them is complex. Each one of them requires a lot of understanding of what needs to get unpacked to better get at the kinds of things that need to get changed. So we are in the process right now of beginning a strategic plan for doing just that: taking each of the pillars and starting to think about how will we know that we've achieved success on this pillar? What will be the metrics we need to start thinking about for those.   Janet Kennedy: (05:42) Alright. So let's do some metrics here. What are the other four pillars?   Sally Okun: (05:46) Number one, as I said, is that clinical trials will be patient centered and easily accessible. And if we don't reach that, then some of the others are almost irrelevant. So that is actually the place to begin. But then the second one is that they're fully integrated into health processes. So that gives us an opportunity to really begin thinking about the continuously learning health system, where we embed within the care environment, the opportunity to research and learn, and then put that learning back into the care environment again, so that we have a full circle loop. The third one is that they are designed with a quality approach, and CTTI has done an incredible amount of work on something called quality by design.   Sally Okun: (06:27) It has a whole set of recommendations around how to determine how the quality of your trial based on a variety of different things - whether it's your recruitment numbers or other aspects of what the trial efficiency looks like. The fourth one is that clinical trials take full advantage; they maximally leverage all available clinical and nonclinical data, including data that's collected now with digital technologies to ensure that we max - minimize - the collection burden of getting data and actually improve the opportunity to make data more meaningful and impactful as part of the trial experience. And then lastly, although not least, is that clinical trials contribute knowledge to how to prevent diagnosis and treat disease. And that becomes something that's an objective around improving population health and the health of our people.   Janet Kennedy: (07:12) Okay. Those are very large topics, very large goals. Who is the Clinical Trials Transformation Initiative? Who's going to do this work?   Sally Okun: (07:23) We are a group of people who have come together within the organization that includes project managers who oversee our projects, and then strategic and engagement and communications team that oversees all of our communications with our steering committee members in our member organizations. So to give you an idea of what that structure looks like: we have a steering committee that includes about 80 organizations who are actually members of CTTI, Clinical Trials Transformation Initiative, and they commit to have a person assigned as a steering committee representative. So as we begin to think about tackling a new topic or a new initiative, we go to the steering committee and we make available to them the opportunity to join the project team. That project team then starts to create the infrastructure for accomplishing that project, which can include, first of all, the project plan and setting the aims and the objectives.   Sally Okun: (08:17) In many ways, it's creating a research study for the topic under consideration with that. Then they set out to consider what's the literature already say? Who are the expert people we need to be speaking to? So there's a lot of qualitative interviewing that goes on as part of the social science team from the Duke Clinical Research Institute; that is a connection for our team to be able to work with. And then the findings from those interviews begin to shape the recommendations that will come out about a particular topic area. For example, thinking about trials in healthcare setting; what do we need to know about the various barriers for those and the opportunities for those as well as the current landscape within which the clinical experience might or might not include participation in research activities? So there's an entire project management approach that is put on any topic we tackle.   Sally Okun: (09:08) The problem with it; it's an incredible opportunity for us to be able to map out these topics and really think about the issues as a group, but it's a labor intensive and time consuming. It can take up to two years to complete some of our projects because they are so intense in terms of diving deep into the problem and trying to come up with resources and tools to address it. So where we are faced today is thinking about how will transformed trials by 2030 if we continue to take this much time to get through our project? Which is why we're now starting to focus quite specifically on each of the pillars, and in many ways, making a project around that pillar. So if we take the first one, for example, and we say trials will be patient centered and easily accessible. The first question I have is how will we know that?   Sally Okun: (09:55) So we're starting to look at ways of being able to measure whether clinical trials today are, or are not patient centered. And that can be evidenced by whether or not patients were involved in the design of the trial, which is work we've already done in some other projects that we've done. Also, how is the enrollment handled? Did it include a diverse population? A variety of different ways of able to measure patient centricity around a trial. But you're right, each one of these has a lot embedded in it and our strategic approach to it right now is taking each one. I've assigned a project manager to every pillar. And we are now just beginning the process of setting a goal for the metrics for each one, and then identifying where we will go next in terms of what resources we know exist already within CTTI that we can map to it, and then what resources may exist in related efforts, whether it's transCelerate or the Multi-Regional Clinical Trials Initiative, others that are related efforts and aligned with our work, and starting to see where their resources could help to get us closer to realizing that particular vision or that pillar.   Janet Kennedy: (10:59) Now, I know your members represent nonprofit organizations, for profit organizations; I think you even have some patient volunteers who are part of your program. But where does the funding come from to make these things happen?   Sally Okun: (11:12) Well, you know, we are a public/private partnership with the FDA. We have been very fortunate to have an excellent relationship with the FDA over the last number of years, their interest in having us be available to tackle some of the more problematic issues that they are not in a position to do on their own. So the funding comes through a grant that supports that public/private partnership. Also our members, depending on the type of organization or company that they are, pay a membership fee to participate. And so that helps to offset some of the costs as well for maintaining our team and the other resources that we put to bear to get the work done on a regular basis.   Janet Kennedy: (11:50) And then how does it actually get done? So if you come up with these guidelines or these recommendations, is there a commitment on the part of these for-profit organizations that they'll actually start to modify, or is the science and the evidence so evident that it makes no sense not to implement these changes?   Sally Okun: (12:10) Yeah, that's a good question. It would be nice if everything seemed that intuitive. That yes, indeed, this is something we ought to be doing because it's just the right thing to do, right? And many of our recommendations would fall into that category. And I think many of our organizations commit to ensuring that they make attempts to incorporate those recommendations into the work that they're doing. Right now, we do have a method of identifying as part of the project itself. Towards the latter part of it, opportunities for adoption of the recommendation. So what that project team will think about is, so now what? How will we see these things come to life in the real world? So opportunities for providing some insights into how they might be best adopted are offered as part of the overall project deliverable at the end of the day. Now at the same time, we don't have an accountability measure to be able to say, "Yes, we believe these recommendations should be incorporated into the clinical trial on this particular topic area, and we expect that you will deliver on that."   Sally Okun: (13:09) So that is, I think, a professional courtesy that we afford to our members to say, "We appreciate that you committed a lot of time to helping us get to the point where we have these recommendations; now what we'd like to ask of you is to start sharing your experiences of using these recommendations and resources." So we actually - just this past year created the Building Better Trials case study exchange. And it's a portal where our members and non-members actually can contribute their experiences of using CTTI tools and resources for a particular purpose within their organization to advance or improve the efficiency and quality of clinical trial experiences. And those have been great. It's a wonderful opportunity for us to showcase how members and even non-members, as I said, use the CTTI resources in a way that actually do have an impact. And it's also a place where, from my perspective, most importantly, we can have continuous and shared learning. So what one group might have learned as a result of incorporating the recommendations for a single IRB, for example - that can be brought forth for others who are now facing the need to do that, the kinds of challenges and other ways that the organization actually met the recommendations that were set forth.   Janet Kennedy: (14:23) And for those listening, if you visit the website and go to this podcast episode, I'll make sure that there is a link there. Tell me a little bit about the patient's role; obviously you come in with a very unique background and a very wrong patient-centric experience and support system set up. So how are patients involved? Because let's face it, they don't have the kind of money it would take to join an organization. They may not even have the time to commit to some of the work that's being done here. But how do you incorporate the patient voice into the work of CTTI?   Sally Okun: (14:55) Well, it is an incredibly important voice and we pay a lot of attention to ensuring that we have mechanisms to get that. We actually have three members of the steering committee who are patient representatives and they come into the role with that responsibility. So they are - similar to being an organization - they have been identified through an application process as people who are willing and interested in contributing in a very substantive way to our understanding of what it means to be a patient in the context of clinical trials. So there's three of them on our steering committee itself, and one of them is actually a caregiver and the other two are patients, one living with breast cancer and the other with ALS, or Lou Gehrig's disease. And so the opportunity for them to be a part of the steering committee team, when a project comes up is wide open.   Sally Okun: (15:44) So we're always looking for ways of having them be involved. Now at the same time, we have many patient organizations that are members. You're so right; these organizations and patients individually don't have the resources to be able to pay a membership fee that would be sort of out of their range. Our membership fees vary on a sliding scale depending on the organizational type and the revenue that those organizations have. So a patient organization would - I think the highest amount is a $500 membership fee. And I think, you know, obviously, thinking about other organizations that may even be a challenge for, we would certainly work with them and talk with them about how we could make a membership opportunity come to fruition. So the other thing that we do is we do have a relationship with the FDA in terms of being able to help them support their patient engagement collaborative.   Sally Okun: (16:31) Now, this is a group of sixteen individuals who again, apply to be a part of the patient collaborative, and we actually help support that group. And it's an opportunity for us also to work more closely with FDA on how they can have access to patients in a way that helps them better understand the patient experience. So I think we try really hard to ensure that all of our projects have a patient representative on them, whether it's a patient individual or a patient group, or potentially having some relationship back to the patient engagement collaborative at FDA itself.   Janet Kennedy: (17:03) I think the work you're doing is so exciting and so important. I worry a little bit that your projects are huge, and you do have, you know, your goal of transforming trials by 2030. However, you know, in order to get there, you gotta take a few steps. So will you be releasing work along the way?   Sally Okun: (17:24) You know, as I said, one of the things that I did right from the very first day I arrived was to start talking with the team about measurement and data. As you know, coming out of Patients Like Me, one of the things that was a hallmark of our work with data, and we just felt like we needed to be data driven in order to be able to answer important questions for patients. It's no different here. It's very much the same. In order to be able to achieve these lofty goals of this transforming trials vision, we have to know where we're at now. What's the baseline data we know about the percentage of trials that are currently patient-centric? I really have no idea. We have to start thinking about ways of being able to find metrics that will tell us some of that. What's the evidence of a trial being patient-centric?   Sally Okun: (18:04) And there are tools out there that we will be starting to inventory and start to determine whether or not these will be ones that we'll put into the ways that we think about this. The short answer to your question is my objective with taking each pillar and intentionally unpacking it, is to better understand where do we need to begin? How will we know that we're making some progress? And that will be metrics and data. And then what are the resources that we are gonna need to start thinking about beyond just adoption? So it's not simply gonna be enough to say, "Here's the recommendations we're making about patient-centric trials for you to be able to, you know, have available to you." We'd like very much to start thinking about the ways of being able to have a bit of a scorecard on that. How do we know we've made a difference?   Sally Okun: (18:49) How do we know that some of the work and the learnings that we've been generating are actually going to translate into something that happens at the clinical trial level itself? And those are still things in development, but they are very important, to me personally, as part of my own work, but also for me as the executive director of the organization today to say, "Let's start measuring how well we're doing on every one of these," and better understand at what point we believe we've actually shifted the needle enough to be able to say, "We're reaching closer to that goal." Now, will we get there by 2030 on every one of them? You know what, I'm gonna remain optimistic. But I also recognize that there's so much that can happen between now and then that could interrupt our progress. And just taking into example, the COVID pandemic over the last year and a half, that stopped so many other kinds of research because we had to focus on that.   Sally Okun: (19:40) Our hope is that in some of the things that we've taken away and learned from that, as we look at each of these pillars, we wanna be able to say, will this stand up during a time of public emergency. Also are the things that we're coming up with applicable beyond the US. That's another important aspect that we have to start thinking about; clinical trials take place everywhere. And in fact, more people are recruited outside of the US than they are in the US. So we have to be thinking about that quite intentionally. And then lastly, the one area that we have not worked specifically in integrating into our prior projects is how can technology itself enable the success on this particular pillar? What are the opportunities that are available today and even tomorrow or two years from now that weren't available previously, that we can start to take advantage of that, help us move that goal closer to achieving it?   Janet Kennedy: (20:30) Well, you come in at an interesting time where you probably were interviewing during the process of all the stopping and starting and having to rethink about how clinical trials were going to go ahead in the midst of the pandemic. And now you've started when, you know, we thought we saw the light at the end of the tunnel and things have managed to pick up, and a lot of companies were able to pivot and use digital technology to move some clinical trials forward. However, I'm curious to know, as you come in and you were getting feedback from your steering committees, did you hear them say that this pandemic has accelerated our vision for decentralized clinical trials for the use of digital health technology?   Sally Okun: (21:14) Yes. And I may not have been hearing that because I wasn't here at the time, but definitely the projects that we had that as a result of some of the work being done through COVID and some webinars that we ran with some of our esteem colleagues - including Rob Califf and Harlan Krumholz, and Deb Estrin - just the idea that we have learned a lot as a result of the COVID experience, and we do need to ensure that what we've learned and those things that actually have benefited the clinical trial experience, not only for participants, but potentially for investigators as well, and outcomes more coming more quickly, that we have to ensure that these are not compromised as we move forward. That we don't fall back simply because it's a little easier to fall back and then it might be to fall forward. And that we take advantage of the things that we've learned, especially that technology is now a new enabler for improving the efficiency and quality of clinical trials. When used appropriately, when used in the right context, and when used with tools that actually have the ability to be used for regulatory decision making. You know, we have to ensure that we're not just simply falling back onto technology for technology's sake. We have to ensure that we're using the kinds of tools that actually can be helpful and useful for regulatory decision making.   Janet Kennedy: (22:30) Tell me a little bit about incorporating patient voice through patient reported outcomes and real world evidence. Is that something that is now you would almost consider mandated as part of a clinical trial?   Sally Okun: (22:42) Not so sure we're at mandated yet, but I think we can recognize just how important and valuable real world data is to understanding the real world experiences of real people, right? And yet I think we still have a fair amount of work yet to do on translating that - all of those different types, disparate types of data - into the totality of evidence, within which real world evidence will be one piece of it, that then contributes to a regulator's understanding of the sponsors data. So I think, yes, I think real world data and real world evidence have definitely achieved the validity of being important as part of the clinical trial and clinical research experience. And we're seeing, increasingly, opportunities where that's now starting to become more important to regulators. For example, you know, FDA is continuing to meet its mandate from the 21st Century Cures Act, where it was required to issue guidance on the use of real world data and real world evidence for regulatory decision making.   Sally Okun: (23:42) So they now have I think issued, I wanna say four of the four, but the last one or two are still in draft and will have no final rule yet. But those are important considerations; to think that the regulator themselves has now put forth what they feel will be required for the use of real world data and real world evidence for their ability to make good decisions. Additionally, EMA just recently stated a vision that enabling the use of real world evidence and establishing its value for regulatory decision making is going to be required in Europe by 2025. So these, you know, different entities are putting a stake in the ground and they're saying okay, similar to what we're doing with our vision, right? The idea is that we need to ensure that all the data that could contribute to our understanding of what it takes to have a medicine or device developed so that it can be used to improve outcomes for people needs to come to bear.   Sally Okun: (24:37) And we can't simply just look at it and say, "It's too complicated, or it's too difficult to translate that data into something that's understood by the regulators." We have to figure that out. And I think there's going to be a lot of work in the coming year or two on that very topic. You know, there's a lot of work being done. For example, Duke Margolis has had a point of care working group now for some time that I've actually enjoyed being a part of, and they're aligned very much with our work being done in trials and healthcare settings. So you can see those two things are both totally aligned and related. We're working at it from a different perspective. Duke Margolis, a little more from the policy side and CTTI, a little more from sort of the actual operational side, and bringing those groups together, some of which actually - some of our senior committee members sit on the Duke Margolis's working group too. So there's definitely starting to see this overlap of the attention paid to the value and the importance of this data. So I don't think it'll be long before it becomes something that's just a part of clinical trial experiences. But I think we still have a little ways to go before we actually see it integrated into every clinical trial.   Janet Kennedy: (25:41) Now before we started recording, we talked a Little bit about where and when we'll be able to interact with CTTI in public, and it sounds like you're shooting for a live meeting about a year from now?   Sally Okun: (25:53) The meeting we were talking about in fact was our steering committee meeting. So we have two meetings a year where we gather our executive committee and our steering committee for two days of meetings. One will be in March, which we're going to be doing virtually. And the other will be in September. In the meantime, throughout the course of the year, we actually do a number of webinars and other events that actually are open to the public to learn about some of the work we're doing. And we will definitely continue to do those. Those right now are quarterly, but we might likely start to increase those depending on how the work is going on. Each of the pillars for the transforming trials vision. But the September meeting will be the first time our steering committee and executive committee see each other in person since the pandemic. So we're very excited to shoot towards that. And obviously we'll be flexible and adaptable as needed, but right now we've made that commitment that we will see each other in person in the fall.   Janet Kennedy: (26:44) That is exciting. And I hope we get to meet in person sometime in 2022. The conference season looks like it's kicking back in with protocols in place, but that we're gonna be face to face more than we have been in the last two years. So hopefully I will get a chance to run across you at one of the conferences coming up in the spring.   Sally Okun: (27:05) I would enjoy that very much, Janet. Yes, I've actually just recently had my first foray out into the professional traveling again. And that was a quick trip to Boston and followed by a quick one to D.C. Both of which felt very odd, but also at the same time felt very good. And it was wonderful to see friends and colleagues that I just haven't seen in way too long.   Janet Kennedy: (27:26) It is surprising what good friendships are developed in the professional environment. We talked a lot about family and COVID'S impact on family units. But for many of us, our colleagues are also just as much our family members, and not being around these people who stimulate our minds and get us really interested in new ideas; it really is very draining and disappointing not to be near some of these amazing people.   Sally Okun: (27:55) That's such a good point. I mean, I know I thrive on just having conversations with people face to face and hearing their ideas about what they're doing or giving me some feedback on a presentation I just did. You know, I just always loved the after experience of being a part of a panel or part of a, you know, presentation that was being held at a conference, and just the feedback you would get from people on the things that you talked about is, was just - really provided me with professional learning that I couldn't get anywhere else, frankly.   Janet Kennedy: (28:22) Absolutely. Alright, well, hopefully a cup of coffee in real life is going to be on our agenda sometime in 2022. Well, Sally Okun, executive director for the Clinical Trials Transformation Initiative, thank you so very much for joining me on the People Always, Patients Sometimes podcast.   Sally Okun: (28:40) Janet, it has been my true pleasure to connect with you again, and I look forward to many times of having the opportunity to see you and spend some time again. Thank you so much. And thank you for the highlight for the Clinical Trials Transformation Initiative and our work. We really appreciate it.   Janet Kennedy: (28:55) Absolutely.

Eric Perakslis, the chief science and digital officer for the Duke Clinical Research Institute at the Duke School of Medicine

Dr. Eric Perakslis, PhD is the Chief Science and Digital Officer at the Duke Clinical Research Institute.  In this incisive discussion, Eric exposes the curious nature of healthcare data. He proposes treating data like a digital specimen: one that requires clear consent and protection against misuse. Expanding our view beyond the doctor's office, Eric shows why adverse effects from data misuse can be much harder to cure than a rash. As well as our innate human tendency to focus on technology's potential while overlooking patient vulnerabilities. While discussing current data protections, Eric lays the foundation for a shift from privacy toward non-discrimination. Along the way, Kimberly and Eric discuss the many ways anonymous data can compromise patient privacy and the research it underpins. In doing so, a critical loophole in existing institutional review boards (IRB) and regulatory safeguards is exposed. An avid data advocate, Eric adroitly argues that proper patient and data protection will accelerate innovation and life-saving research. Finally, Eric makes a case for doing the hard things first and why the greatest research opportunities are rooted in equity.  A transcript of this episode can be found here. Our next episode features Yonah Welker. They are a ‘tech explorer' and leading voice regarding the need for diversity and zero exclusion in AI as well as the role of social AI. Subscribe now so you don't miss it.  

AJ Overton is a respected statistician at Duke Clinical Research Institute, but what I really admire about AJ is his willingness to enter uncomfortable situations to grow and become a better leader. Whether that is moving to Uganda, standing on stage, or completing an endurance challenge, AJ is willing to be "in the arena" in order to grow and develop authentic relationships. It's a privilege to call AJ a friend and a bonus that he is one of my neighbors, enjoy this conversation! You can connect with AJ on LinkedIn at https://www.linkedin.com/in/aj-overton-65b717179/.

melissa@blendedfamilypodcast.com www.blendedfamilypodcast.com   Kristin MacDermott is a licensed marriage and family therapist with a decade of research in resilience. Her resilience-training programs have been validated in four studies with researchers from the Duke Clinical Research Institute, published in peer-reviewed journals, and proven to improve key mental health and resilience outcomes, including anxiety, depression, distress, self-efficacy, and PTSD. Kristin has designed resilience-training programs for some of the highest-performing people on the planet, including Navy SEALS and the LAPD. Her programs have been used in more than 20 hospitals across the country, including at the Duke Cancer Institute and the National Institutes of Health. She has also designed programs for schools, corporations, non-profits, and mentors who support at-risk kids. Kristin is the author of It Takes Two Minutes to Shift Your Mindset and Build Resilience, a book that breaks resilience down into bite-size skills you can apply to your life immediately. She has recently launched two online courses for parents, one called Resilience-Based Parenting and the other called Parenting Through Divorce. She has a private practice in Palm Beach Gardens, Florida where she lives with her husband of 28 years and her three children. In this interview we discuss Her personal story Why conflict resolution and resiliency work well together The MacDermott Method, Kristin's unique practice Conflict between co parents and tips on managing it Why it's important to get your own needs met How to stay calm in conflict Teaching our children conflict resolution Kristin's offerings And much more! Connect with Kristin Website Facebook Instagram LinkedIn Twitter   Connect with me Join the Private Facebook Group Connect with me on Facebook Schedule an interview or coaching session HERE Send questions or feedback to melissa@blendedfamilypodcast.com Send me a voicemail at Speakpipe Visit the website at www.blendedfamilypodcast.com Sign up for my monthly newsletter Listen and Rate/Review on Itunes   Affiliate   Living the Good Life Naturally To receive discount, use promo code BLENDED                  

Dr. William Schuyler Jones, of the Duke Clinical Research Institute, Durham, North Carolina, discusses the ADAPTABLE trial with Dr. Ron Waksman. The study, which was presented as a late-breaking trial at ACC.21 Virtual, found no difference in a composite outcome of death, myocardial infarction or stroke between patients assigned to a low dose (81 mg) vs. a high dose (325 mg) of aspirin with a median 26-month follow-up. Of interest was that patients were recruited and randomized remotely, with no in-person study visits, which helped the investigators recruit 15,000 patients during the COVID-19-related restrictions on travel and office visits.

This podcast is all about you! We’re sharing our conversation with resilience and emotional intelligence expert Kristin MacDermott who says anyone can learn resilience, emotional intelligence and conflict management and she shows us how. She is the founder and President of the MacDermott Method, which provides resilience-based resources for individuals and organizations. She is a licensed marriage and family therapist with over a decade of research in resilience. Her resilience-training programs have been validated in four studies with researchers from the Duke Clinical Research Institute, Duke Cancer Institute and the National Institutes of Health. They have also been published in peer-reviewed journals, and her methodology has been shown to improve key mental health and resilience outcomes, including anxiety, depression, distress, conflict management and PTSD.  We think you’ll agree she part of the Crazy Amazing Humans (CAH) tribe because she has taken her expertise and applied it to help others by designing resilience-training programs for some of the highest-performing people on the planet and beyond; including Navy SEALS, LAPD, schools, corporations, non-profits, and mentors who support at-risk kids. Kristin is the co-founder of Pathfinders, an Aspen-based nonprofit dedicated to improving the lives of people living with cancer as well as those experiencing grief. She also helped start Zero Hour Expeditions, a nonprofit that helps combat veterans reintegrate into civilian life and overcome the effects of PTSD by experiencing 30-day wilderness trips.  Kristin is the author of It Takes Two Minutes to Shift Your Mindset and Build Resilience, a book that breaks resilience down into bite-size skills you can apply to your life immediately. She has recently launched two online courses for parents, one called Resilience-Based Parenting and the other called Parenting Through Divorce. She has a private practice in Palm Beach Gardens, Florida where she lives with her husband of 28 years and her three children. Tune in and have fun listening! Please feel free to share it with anyone you know who would benefit from this episode. Remember that every small kindness has the potential to create a Crazy Amazing Human experience, one person at a time. You have the power to create that every day. And we, at Crazy Amazing Humans, are in your corner, we’re rooting for you, and really appreciate you as part of our community and we think YOU are crazy amazing! Subscribe to Our Newsletter: https://bit.ly/3hGk32N Our Linktree: bit.ly/CAHLinktree Be Part of the Crazy Amazing Humans Community: Instagram: https://bit.ly/2Zkk06V Facebook: https://bit.ly/2ZpA2wq Website: https://bit.ly/2Zqypyi Twitter: https://bit.ly/2ZnCymMWebsite: http://www.katrinacarlson.com iTunes: https://itunes.apple.com/us/artist/katrina-carlson/3563718 Facebook: https://www.facebook.com/katrina.carlson/

Today we have with us Kristin MacDermott! Kristin is a resilience expert, and a family & business therapist. Most people avoid conflict. Kristin loves it. She feels conflict is an opportunity to learn, grow and get your needs met. Done right, it is a catalyst for building a stronger mindset and healthier relationships. She uses conflict to build resilience—in individuals, couples, families, and in businesses. Her evidence-based method has been validated in four studies (including two randomized-controlled trials) with researchers from the Duke Clinical Research Institute, published in peer-reviewed journals, and proven to improve key resilience and mental health benchmarks, including anxiety, depression, distress, PTSD, and self- efficacy. In episode # 146 of the Fraternity Foodie Podcast, we find out why Kristin chose Duke University, why should we tell empowering stories about yourself, what is the MacDermott Method Resiliency Model, what are the communication skills that de-escalate conflict, what is emotional intelligence and why is that important, how college students can create a plan for themselves that allows them to feel hopeful, focused, and confident, what are the non-profit organizations she works with called Pathfinders and Zero Hour Expeditions, and Kristin's favorite restaurants in the Palm Beach area of Florida. Link: https://www.youtube.com/watch?v=vwvW1tSVP1E https://www.youtube.com/watch?v=vwvW1tSVP1E

In this episode, Dr. Stephen Greene, of the Duke Clinical Research Institute, breaks down a recent study he led comparing the sensitivity of NYHA class versus patient-reported outcomes for capturing changes in disease state among patients with HFrEF.

Morten met online with prof. Steven George, who is a professor and the director of musculoskeletal research at Duke Clinical Research Institute. If you have questions regarding our episodes, or ideas for future episodes, feel free to contact us or engage with us on social media.Visit the SMOF Facebook-page hereVisit the SMOF Instagram hereVisit the SMOF webpage here

Christine Goertz, DC, PhD, is a Professor in Musculoskeletal Research at the Duke Clinical Research Institute and Director of System Development and Coordination for Spine Health in the Department of Orthopaedic Surgery at Duke University. She is also the Chief Executive Officer of the Spine Institute for Quality and Adjunct Professor in the Department of Epidemiology, College of Public Health at the University of Iowa. Formerly, she was Vice Chancellor of Research and Health Policy at Palmer College of Chiropractic for 11 years.Goertz received her Doctor of Chiropractic (DC) degree from Northwestern Health Sciences University in 1991 and her PhD in health services research, policy, and administration from the School of Public Health at the University of Minnesota in 1999.Her 25-year research career has focused on working with multidisciplinary teams to design and implement clinical and health services research studies designed to increase knowledge regarding the effectiveness and cost of complementary and integrative healthcare delivery. She has extensive experience in the administration of federal grants, both as a principal investigator and as a program official at the National Institutes of Health (NIH).Goertz has received nearly $32 million in federal funding as either principal investigator or co-principal investigator, primarily from NIH and the Department of Defense, and has authored or coauthored nearly 100 peer-reviewed papers. Her primary area of focus is the investigation of patient-centered, non-pharmacological treatments for spine-related disorders.Goertz is a former member of NIH's National Advisory Council for Complementary and Integrative Health. She also currently serves on the Board of Governors for the Patient-Centered Outcomes Research Institute (PCORI), where she has assumed numerous leadership roles, including her appointment in September 2019 as Chairperson of the PCORI Board of Governors by the Comptroller General of the United States.ABOUT WORLD OF CHIROPRACTIC: World of Chiropractic is a web series and podcast interviewing chiropractic leaders around the globe. To learn more about world chiropractic, visit www.wfc.org.

Vaccine hesitancy can have a negative impact on rollout. A striking example comes from long-term care facilities. Approximately 78 percent of residents received a vaccine. In contrast, only 37 percent of staff members agreed to be vaccinated. Reasons for refusal include: perceived rapidity of vaccine development inadequate information received about vaccine safety, side effects, and administration skepticism regarding the clinical trials and vaccine approval process HERO-TOGETHER is an opportunity for people working in health care to continue the fight against COVID-19. HERO-TOGETHER participants will receive learnings and study updates, and compensation for their time. Taking part is an easy way to help fight COVID-19 and learn how to keep our communities and families healthy and virus-free. Signup at heroesresearch.org/together (https://heroesresearch.org/together/?utm_source=kevinmd&utm_medium=podcast&utm_campaign=podcast-signup) Emily O’Brien is an epidemiologist, an associate professor in population health sciences at Duke University School of Medicine, and a faculty member of the Duke Clinical Research Institute. Emily is also the principal investigator of the HERO-TOGETHER study. Jessica Mega is co-founder and chief medical and scientific officer at Verily. Verily’s mission is to develop the infrastructure and solutions to harness the profusion of health information for good. Their data-driven solutions across research, care, and innovation aim to improve the well-being of our communities.

In this episode of the NIH Collaboratory Grand Rounds podcast, Dr. Adrian Hernandez speaks with Dr. Emily O'Brien of the Duke Clinical Research Institute about the HERO-TOGETHER study that is evaluating how people do over time after receiving the COVID-19 vaccine.

We are looking at 2020 in our rear-view mirror, but we’re still in the thick of COVID.  With lockdowns, social distancing, virtual work and online schooling, some of us are experiencing higher levels of stress and finding both parenting and leadership challenging.  On this episode of Authentic Living with Roxanne, we welcome Marriage and Family Therapist, Kristin MacDermott to share some of her ideas about how resilience can help to improve relationships with your kids, spouse, family and team members.      Quote: “The root of most interpersonal conflict is unmet needs.”  Kristin MacDermott Kristin is a licensed marriage and family therapist with a decade of research in resilience. Her resilience-training programs have been validated in four studies with researchers from the Duke Clinical Research Institute, published in peer-reviewed journals, and proven to improve key mental health and resilience outcomes, including anxiety, depression, distress, self-efficacy, and PTSD. Kristin has designed resilience-training programs for some of the highest-performing people on the planet, including Navy SEALS and the LAPD. Her programs have been used in more than 20 hospitals across the country, including at the Duke Cancer Institute and the National Institutes of Health. She has also designed programs for school, corporations, and non-profits that support at-risk kids. Authentic Touch Points: Scale it down to make it accessible.  2:00 Unplug to find your inner wisdom.  6:00 Use resilience to build relationships.  10:30 Have meaningful conversations.  15:00 Teach your kids responsibility early.  20:15 Resiliency strategies for parenting.  25:30 COVID is affecting everyone!  30:00 Ask what others’ need.  33:00 Kristin is the author of It Takes Two Minutes to Shift Your Mindset and Build Resilience, a book that breaks resilience down into bite-size skills you can apply to your life immediately. She has recently launched two online courses for parents, one called Resilience-Based Parenting and the other called Parenting Through Divorce. She has a private practice in Palm Beach Gardens, Florida where she lives with her husband of 28 years and her three children. With many of us working from home and feeling the pressure of the pandemic, I encourage you to reach out with thoughts or questions about creating a healthier mindset.  Click here to contact me at your convenience or click here to book a complementary call with me.   You can find more information about me and how I can help you live a more authentic and resilient life at RoxanneDerhodge.com Thank you, Roxanne Links: Kristin’s website:  https://www.macdermottmethod.com/ Kristin’s Special Offer and Free ResourcesKristin’s books:  It Takes Two Minutes Canada It Takes Two Minutes USA Two Minute Mindset Shifts CanadaTwo Minute Mindset Shifts USARoxanne’s email:  roxanne@roxannederhodge.com Book a complementary call with Roxanne Roxanne’s previous podcasts

Dr. Jeffrey Berger is an Associate Professor of Medicine and Surgery (on tenure track) with appointments in Cardiology, Hematology, and Vascular Surgery, and Director of Cardiovascular Thrombosis at New York University School of Medicine. During his training, he received a Master's degree in clinical research from the NIH K30 program at Albert Einstein College of Medicine. He completed fellowships in Cardiology at Duke University, Cardiovascular Research training at Duke Clinical Research Institute, and Vascular Medicine and Thrombosis and Hemostasis at the University of Pennsylvania. Dr. Berger has been the recipient of several grants, honors and awards, including the American Heart Association's Fellow Faculty award, amongst many others. He has also established an independent NIH-funded research program, investigating the role of platelet activity and thrombotic biomarkers in cardiovascular disease. How can we develop a more positive environment in medicine? For starters, says Dr. Jeffrey Berger, is finding ways to bring out the best in those around us. On top of that, Dr. Berger believes hard work, perseverance, and curiosity are the key principles for success. Today, he teaches us how to construct the mindset we need to persevere in medicine—and how to help others succeed along the way, too. Pearls of Wisdom: 1. Ask yourself the questions you want to answer and do not pursue meaningless paths in life. Ask yourself how you can make fresh contributions to your field that few others are making. 2. Be different. Do not conform to a specific mold but be willing to go places, do stuff, and try things others might not attempt. 3. Create an environment of encouragement. Do your best to bring out the best in those around you. 4. Persevere through difficult seasons. Be curious and willing to try hard, fail, and then try again.

In this episode, we share an American Medical Informatics Association teleconference that features a discussion with leaders from the Duke Clinical Research Institute around how an EHR-enabled Learning Health Network can move the needle on COVID-19 research.

The CardioNerds discuss Lipid Management with Dr. Ann Marie Navar and Dr. Nishant Shah from Duke Medical Center, Division of Cardiology. Amit, Carine and Dan take a deep dive into the greasy world of lipids and cholesterol, covering lipid metabolism, therapeutic targets, approach across the entire spectrum of predicted risk, and key common management scenarios (statin intolerance, hypertriglyceridemia, elevated LP(a)), and more. Episode 42. Lipids and Cholesterol with Drs. Drs. Ann Marie Navar and Nishant Shah Take me to the Cardionerds Cardiovascular Prevention PageTake me to episode topics page The Cardionerds CV prevention series will include in-depth deep dives on so many topics related to prevention starting with this case discussion. Stay tuned for upcoming episodes on the ABCs of prevention, obesity, hypertension, diabetes mellitus and anti-diabetes agents, personalized risk and genetic risk assessments, hyperlipidemia, women’s cardiovascular prevention, coronary calcium scoring and so much more! Key references: Toth, P. P. (2020). Familial Hypercholesterolemia and Lipoprotein(a): Unraveling the Knot That Binds Them. Journal of the American College of Cardiology, 75(21), 2694–2697.Michos, E. D., McEvoy, J. W., & Blumenthal, R. S. (2019). Lipid management for the prevention of atherosclerotic cardiovascular disease. New England Journal of Medicine, 381(16), 1557–1567. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology, 73(24), e285–e350.Lloyd-Jones, D. M., Braun, L. T., Ndumele, C. E., Smith, S. C., Sperling, L. S., Virani, S. S., & Blumenthal, R. S. (2019). Use of Risk Assessment Tools to Guide Decision-Making in the Primary Prevention of Atherosclerotic Cardiovascular Disease: A Special Report from the American Heart Association and American College of Cardiology. Circulation, 139(25), E1162–E1177.Laufs, U., Parhofer, K. G., Ginsberg, H. N., & Hegele, R. A. (2020). Clinical review on triglycerides. European Heart Journal, 41(1), 99–109.ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology, 74(10), 1376–1414. We are truly honored to be producing the Cardionerds CVD Prevention Series in collaboration with the American Society for Preventive Cardiology! The ASPC is an incredible resource for learning, networking, and promoting the ideals of cardiovascular prevention! This series is kicked off by a message from Dr. Amit Khera, President of the American Society for Preventive Cardiology and President of the SouthWest Affiliate of the American Heart Association. Cardionerds Cardiovascular Prevention Series Dr. Ann Marie Navar is a cardiologist and epidemiologist at the Duke Clinical Research Institute focusing on cardiovascular disease prevention. She received an MD from Duke University and a PhD in Global Disease Epidemiology and Control from the Johns Hopkins School of Public Health in 2009 before completing residency in internal medicine and pediatrics and fellowship in cardiology at Duke. Dr. Navar’s research focuses on improving cardiovascular disease prevention through better identification of at-risk populations, targeted interventions to improve quality of care and patient engagement through the electronic health record, and better treatment of hypertension and cholesterol to lower CV risk. She also studies the impact of payer-imposed barriers to novel therapies. Her areas of expertise include risk prediction, patient risk communication, real world data analyses using EHR- and claims-based datasets, and registries. She is an associate editor at JAMA-Cardiology and a board membe...

Dr. Robert Mentz, director of the Heart Failure section in the Duke Division of Cardiology, discusses diuretics, anti-hyperglycemic therapies including SGLT2/GLP1 agents, angiotensin receptor-neprilysin inhibitors (ARNi), iron as therapies for Heart Failure with Preserved Ejection Fraction (HFpEF). Additionally, study design and ongoing research in HFpEF is discussed. At the end of the episode Dr. Mentz provides an additional update that highlights how the COVID-19 pandemic has influenced clinical trials around the world. Special thanks to guest interviewers, Duke cardiology fellows, Dr. Kelly Arps and Dr. Rahul Loungani! On the CardioNerds Heart Failure topic page you’ll podcast episodes, references, guest experts and contributors, and so much more. Take me to the Heart Failure Topic PageTake me to episode topics pageAcute Decompensated Heart Failure Primer – Youtube Dr. Robert Mentz completed internal medicine training at Brigham and Women’s Hospital and cardiology fellowship followed by advanced heart failure and transplant cardiology training at Duke University Hospital and the Duke Clinical Research Institute. He is the new director of the Heart Failure section in the Duke Division of Cardiology. His areas of clinical and research focus include treating comorbid diseases in heart failure patients, use of biomarkers and surrogate and non-fatal outcomes in heart failure trials, and novel therapeutic approaches to heart failure. Dr. Mentz is heavily involved in many clinical trials and serves as the associate editor at Circulation: Heart Failure. In addition to his clinical and research endeavors, Dr. Mentz is heavily invested in the cardiology fellowship where he serves as associated program director and renown mentor for which he has won many fellow-nominated awards. Finally, as former director of the Duke University Cooperative Cardiovascular Society, he expanded the network of current and former Duke trainees to be a leading enroller in clinical trials. We are really excited about him joining the show to discuss Diuretics ARNi SGLT2/GLP1 therapies for HFpEF. Dr. Rahul Loungani completed medical school at the medical university of SC and then traveled to Baltimore for internal medicine training in the Osler Residency Program at the Johns Hopkins Hospital.  Here he fell in love with the management and hemodynamics of critically ill patients. He is currently a third-year cardiology fellow at Duke University Medical Center where he will also be pursuing fellowship in advanced heart failure and transplant cardiology next year. His current interests are in Cardiac amyloid, in particular it's arrhythmic manifestations, early diagnosis, and novel therapeutics. He also loves teaching the housestaff and was awarded the Cassell-Saperstein award at Duke,  recognizing the fellow who most demonstrates a commitment to teaching and passion for clinical education. Outside of the hospital loves being a new dad to baby Arya. Dr. Kelly Arps completed medical school at Emory University school of medicine and internal medicine training in the Osler Residency Program at the Johns Hopkins Hospital. She is currently is pursuing her cardiology fellowship at Duke University Medical Center.  CardioNerds Heart Failure Series

In a shocking development, a widely-publicized pair of studies relating to COVID-19 were quickly retracted when their authors couldn't confirm their data or analysis. What the health?? Dr. Adrian Hernandez is a cardiologist and director of the Duke Clinical Research Institute. His group has created the HERO Registry to enroll healthcare professionals in clinical trials to help solve the coronavirus dilemma, including a randomized controlled trial using hydroxychloroquine for prevention. More at https://heroesresearch.org/ Links and more info (transcript soon) at https://zdoggmd.com/heroes-registry Your support makes what we do possible! Join the SuperPac and get exclusive content, live discussions, and other crazy perks: YouTube: https://www.youtube.com/user/zdoggmd/... Facebook: http://facebook.com/becomesupporter/z... Patreon: http://patreon.com/zdoggmd PayPal: https://www.paypal.me/zdoggmd Website: https://ZDoggMD.com Podcast: https://ZDoggMD.com/podcasts Facebook: http://facebook.com/zdoggmd Newsletter: http://eepurl.com/gD8_D1 Twitter: http://twitter.com/zdoggmd Instagram: http://instagram.com/zdoggmd Send Us Email: zubin@turntablehealth.com Send Us Hate Mail: 1025 Alameda De Las Pulgas #218 Belmont, CA 94002

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg Hundley, associate editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: We've got a juicy, juicy feature discussion coming up. It's on a pre-specified analysis of the ODYSSEY OUTCOMES randomized clinical trial, this time to ascertain whether PCSK9 inhibition reduces the risk of peripheral arterial disease events or venous thromboembolism after acute coronary syndrome. And, also to answer, these effects are related to levels of lipoprotein(a) or LDL cholesterol. I'm going to keep everyone guessing, as we get on our coffee chat and talk about the other papers in this issue. And I want to go first, because the first original paper I want to discuss is really quite related to the feature discussion too. And it asks the question, what is the relationship between cholesterol levels and risk of venous thromboembolism? And, what is the effect of PCSK9 inhibition on the risk of venous thromboembolism? So this is from Dr Marston from the TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School in Boston, Massachusetts, and colleagues who performed a post hoc analysis of the FOURIER trial, testing whether evolocumab reduces the risk of venous thromboembolic events. That is, deep venous thrombosis, a pulmonary embolism. The authors then looked at data from FOURIER and the ODYSSEY OUTCOMES trial and combined them in a meta-analysis to assess whether there was a class effect of PCSK9 inhibition on the risk of venous thromboembolism. As a reminder, the ODYSSEY OUTCOMES trial tested alirocumab as the PCSK9 inhibitor. Dr Greg Hundley: Well, Carolyn, what did they find? Dr Carolyn Lam: Well, first Greg, remember, this is the first study to demonstrate a significant reduction in venous thromboembolism with PCSK9 inhibition. Interestingly, the reduction in venous thromboembolism was associated with the degree of lipoprotein(a) lowering and not LDL cholesterol lowering, suggesting that lipoprotein(a) may be the mediator of venous thromboembolic risk. More coming up in our feature discussion. Dr Greg Hundley: Wow, Carolyn. Well, I'm going to go into the world of PCSKs, but talk about PCSK6. So this study involves a secretome analysis of cardiomyocytes as novel players in cardiac remodeling after myocardial infarction and the corresponding author is Dr Florian Leuschner from Heidelberg University. So Carolyn, we know that acute occlusion of coronary artery results in swift tissue necrosis and bordering areas of the infarcted myocardium may also experience impaired blood supply and reduced oxygen delivery leading to altered metabolic and mechanical processes. While transcriptional changes in hypoxic cardiomyocytes are well-studied, little is known about the proteins that are actively secreted from these bordering cells. So in this study, the authors established a novel secretome analysis of cardiomyocytes by combining stable isotope labeling and click chemistry with subsequent mass spectrometry analysis. Dr Carolyn Lam: Wow, sounds like very advanced methods and what did they find? Dr Greg Hundley: Okay. Carolyn lots of results here. They found that PCSK6 expression was elevated in hearts of mice, following three days of ligation of the left anterior descending artery, a finding confirmed by immunohistochemistry. ELISA measurements and human serum also indicated distinct kinetics for PCSK6 in patients suffering from acute myocardial infarction with a peak on day three post infarction. One of these beautiful studies combining basic science and human subjects in the same paper. In addition, adeno-associated virus nine mediated cardiomyocyte specific overexpression of PCSK6 in mice resulted in increased collagen expression and cardiac fibrosis as well as decreased left ventricular function after MI. So Carolyn, this study demonstrates how novel mass spectrometry-based approach allows the investigation of the secretome of primary cardiomyocytes. That's a first for that technique. And then analysis of hypoxia-induced secretion led to the identification of PCSK6 to be crucially involved in cardiac remodeling after MI, demonstrating increased collagen expression and cardiac fibrosis in those border zones. Dr Carolyn Lam: Wow, fascinating, Greg. Well, I want to switch tracks here. Maybe ask, when you're choosing between antithrombotic therapies for patients with atrial fibrillation and a recent acute coronary syndrome, have you ever wondered what is the tradeoff of risk? Risk of bleeding and benefit that would be in terms of prevention of ischemic events over time? Well, guess what, I'm not going to put you on the spot here because our next paper addresses this very question. And it's from corresponding author, Dr Alexander from Duke Clinical Research Institute and colleagues who performed a post hoc analysis of the AUGUSTUS trial. Dr Greg Hundley: Okay, Carolyn. I'm going to digress for just a minute here. We have this wonderful producer, Augie Rivera, and he's just fantastic and we should give him accolades because he really helps put all these together. Now I'm not going to ask him this time, but maybe in one of our future discussions, we may need to bring him into one of these because of his expanded knowledge of all of science, but getting back, Carolyn, can you remind us what is the AUGUSTUS trial? Dr Carolyn Lam: All right, so in the AUGUSTUS trial, patients with AF and a recent ACS and/or PCI taking a P2Y12 inhibitor had less bleeding and rehospitalization with apixaban, than vitamin K antagonists and less bleeding with placebo than aspirin. The composite of death or hospitalization was also reduced with placebo compared to aspirin. However, the risk of several recurrent ischemic events, including stent thrombosis, where numerically higher in patients assigned placebo. Further analysis of the stent thrombosis outcomes suggested that most of the increase in risk was early within 30 days of randomization. And hence the objective of the current paper, which is a post hoc analysis to explore the balance of risk and benefit using a variety of composite outcomes between randomization and 30 days and between 30 days and six months over time comparing apixaban versus vitamin K antagonists and aspirin versus placebo. So, here's what they found. Apixaban caused fewer ischemic and bleeding events than warfarin in the first 30 days after ACS and/or PCI and similar or fewer ischemic and bleeding events from day 30 to six months. Use of aspirin acutely, and for up to 30 days, resulted in an equal tradeoff between an increase in severe bleeding and reduction in severe ischemic events. However, after 30 days aspirin continued to increase bleeding without significantly reducing the ischemic events. So these results really informed shared patient-centric decision making regarding the ideal duration of use of aspirin after an ACS and/or PCI in patients with AF already receiving oral anticoagulation. Dr Greg Hundley: Very nice, Carolyn. You know, lots of data coming out about how we perform anticoagulation, the administration of aspirin, both an atrial fibrillation, ischemic events, those with stents and this is just another piece of important data that we're so fortunate to have published in circulation. Well in the rest of the issue Carolyn, there's a lot of information. I want to talk about a research letter from Dr Armand Killick from the University of Pittsburgh, and he describes the outcomes of the first 1300 adult heart transplants in the United States following a policy change in the U S related to allocation of hearts. In an EKG challenge, Dr Nobuhiro Takasugi from Gifu University and colleagues reviewed the etiology of wide complexes. Are they aberrantly conducted supraventricular beats? Are they premature ventricular complexes or intermittent ventricular prereq citation in an individual 70 years old presenting with symptoms of palpitations? Then Carolyn, in one of our COVID-19 articles, there's an in-depth piece by Dr Kevin Clerkin and associates from Columbia University. And they review coronavirus disease that is caused by severe acute respiratory syndrome, coronavirus 2 or SARS-CoV-2, which invades cells through the angiotensin converting enzyme or ACE-2 receptor. Among those with COVID-19, they note there is a higher prevalence of cardiovascular disease and more than 7% of patients suffer myocardial injury as evidence from elevated cardiac troponin values from the infection and in 22% of those that were critically ill. And despite ACE-2 serving as a portal for infection, the role of ACE inhibitors or angiotensin receptor blockers requires further investigation. And right now, as you know, in your field is a heart failure expert, they are not recommendations to consider discontinuation for those drugs. And then lastly, in a prospective piece, Professor Gianluigi Condorelli from Humanitas University in Milan, presents critical organizational issues for cardiologists in this COVID-19 outbreak, including prioritization of unstable patients with cardiovascular disorders by postponing visits, and in this situation they did so by 80%, reorganizing clinical activities in terms of ward, ICU beds and outpatient visits, using a hub-and-spoke model to prioritize management acute MI, and then finally rapidly acquiring and training physicians and staff in the correct use of PPE. All very valuable lessons from Italy that was so hard hit by this devastating disease. Dr Carolyn Lam: Indeed, and you know what, Greg, I just want to tell everybody about our circulation YouTube channel, where we have frontline interviews with people dealing with this from all over the world. Thank you to Augie and his team for making all of this happen. Let's go on to our future discussion, shall we? Dr Greg Hundley: Absolutely. Dr Carolyn Lam: Patients with acute coronary syndrome are at risk of peripheral artery disease events and venous thromboembolic events. Now we've heard a lot about PCSK9 inhibitors in patients with acute coronary syndrome, but what is the effect of PCSK9 inhibition on the risk of PAD or venous thromboembolic events? Well, we're about to find out. The feature paper is a pre specified analysis of the ODYSSEY OUTCOMES trial. And I'm so pleased to have the first and corresponding author, Dr Greg Schwartz with us from the University of Colorado, School of Medicine, as well as our guest editor, Dr Erin Michos from Johns Hopkins School of Medicine. So welcome. And Greg, could I ask you to start us off. Tell us why you looked at this in ODYSSEY OUTCOMES and what you found. Dr Gregory Schwartz: All of our patients or nearly all of our patients with acute coronary syndrome have had an atherothrombotic event and most of them also have a heightened inflammatory state. These factors are also thought to have a role in the pathogenesis of peripheral artery disease events, and perhaps also venous thromboembolism. We typically think of the risk factors for peripheral artery disease as being diabetes and smoking, and less so dyslipidemia, although dyslipidemia may play a role in PAD events as well. And although the association of LDL cholesterol levels with PAD events has been inconsistent in the literature, there's more consistency actually with levels of lipoprotein(a) and the risk of PAD events. And that kind of makes sense because we think that Lp(a) has both atherogenic and pro-inflammatory and perhaps also prothrombotic properties. So elevated levels of that lipoprotein might promote the risk of PAD events. Now statins, which are obviously the mainstay of our treatment of patients with atherosclerosis, lower levels of LDL cholesterol, but they don't affect the levels of Lp(a). In contrast, inhibitors of PCSK9 lower the levels of both of those key lipoproteins. So we looked at the relationship of baseline and on treatment levels of both LDL cholesterol and lipoprotein(a) on the risk of PAD events and also venous thromboembolism, which has been associated with lipoprotein(a) in some observational studies. Dr Carolyn Lam: Nice. So, could you tell us what were the results? Dr Gregory Schwartz: So first, we used data from the ODYSSEY OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab with placebo in nearly 19,000 patients with a recent acute coronary syndrome. And as you mentioned, Carolyn, those patients may be at elevated risk for other types of arterial and venous atherothrombotic or thrombotic events. We had three goals in our analysis. First, we looked at the relationship of PAD and venous thromboembolic events to the baseline levels of lipoprotein(a) and LDL in the trial cohort. Second, we looked at the effects of randomized treatment on both of those types of events, PAD events, and venous thromboembolism. And lastly, we determined the relationship of treatment effects on lipoproteins to the risk of those events in the alirocumab active treatment group. What we found are four principle findings. First, although this was an acute coronary syndrome cohort, and there were only four percent of the trial cohort who had a prior history of PAD, there was nonetheless a substantial risk of PAD events. About two percent of the placebo group suffered a PAD event during the trial and about one percent had a venous thromboembolic event. In the placebo group. We found that there was a very strong association between baseline lipoprotein(a) concentration and the risk of PAD events. So to put that in a quantitative framework, if we compared the highest quartile of baseline lipoprotein(a) with patients in the lowest quartile of baseline lipoprotein(a), there was a more than twofold elevated risk of PAD events. And by that, I mean, critical limb ischemia, revascularization, or amputation for ischemia, more than a twofold elevated risk in the highest quartile of baseline lipoprotein(a). There was a non-significant relationship of venous thromboembolic events to the baseline concentration of lipoprotein(a). The patients who were treated with alirocumab, the PCSK9 inhibitor, achieved the expected approximately 50 percent reduction in LDL cholesterol and a median 23 percent reduction in lipoprotein(a) concentration. And those effects were associated with significant reduction in PAD events, a hazard ratio of point six nine, and a nearly significant peak, well point zero six reduction in the risk of venous thromboembolic events with a hazard ratio of point six seven. And incidentally, in the same issue of circulation, there is a companion paper from the FOURIER study, which looked at the risk of venous thromboembolic events with another PCSK9 inhibitor, evolocumab. They found something very, very similar. And again, the results of that trial individually were kind of on the margins of statistical significance, but putting the two trials together in their analysis, there was a highly significant reduction in the risk of venous thromboembolic events with PCSK9 inhibition, compared with placebo. They also related those effects to lipoprotein(a), but not to LDL cholesterol levels. So we found that the magnitude of the reduction in lipoprotein(a) was related to the reduced risk of PAD and VTE events, but a similar relationship between the magnitude of LDL cholesterol reduction and the risk of those events was not found. So to put it all together, lipoprotein(a) may be the stone that we haven't turned over, but should, when we encounter patients with PAD events or VTE events that we can't otherwise explain. And although these two trials were not purposed primarily to look at PAD events, the findings certainly suggest that treating elevated levels of lipoprotein(a) might be an effective strategy to reduce risk of PAD events and VTE. Dr Carolyn Lam: Wow. Congratulations, Greg, that was beautifully summarized. A novel on at least two levels, right? One is the PCSK9 inhibition effects on these two outcomes that we never thought of before. And second, that role of lipoprotein(a). Erin, could I bring you into this discussion? You were guest editor when this paper came across your desk. Could you tell us what were the considerations and frame how novel these findings are for us? Dr Erin Michos: Oh, Carolyn excited to be the associate editor for this paper. People who know me know; I love all things lipids. So as a preventive cardiologist, I'm very excited to have drugs like PCSK9 inhibitors in my toolbox. They are certainly known for their powerful LDL lowering effects, but also further lipoprotein little a reducing effect who these combined data show the PCSK9 inhibitors, not only reduced incident major adverse cardiovascular events and PAD events, but potentially can reduce VTE events as well in patients prescribed this therapy. So I thought it was really interesting and this new analysis from ODYSSEY, that it was the levels of lipoprotein little a, but not LDL cholesterol that predicted the risk of future PAD event and we saw a similar trend with VTE. And then furthermore, on treatment with alirocumab. It was the magnitude of Lp(a) little a reduction, but not LDL reduction that was associated with reduced PAD and VTE events. And so this suggests that the reduction of PAD events is mediated by the lipoprotein little a lowering and not the LDL lowering. You know, lipoprotein(a) is a particularly risky type of LDL. It's strongly inheritable it's atherogenic similar to LDL, but prothrombotic, so it's this double whammy of badness due to its structural homology with plasminogen competes with berberine binding and inhibits tissue plasminogen activator and ultimately inhibits fibrinolysis. And so that's why lipoprotein(a) may be a mediator of this apparent effect of PCSK9 inhibitors with PAD and VTE incidents. So how do I put this in practice? Prior to PCSK9 inhibitors, we really didn't have any lipid modifying therapies to actually lower lipoprotein little a, except niacin, which we don't really use. This was mentioned by Greg, statins don't really lower lipoprotein(a) and they actually increase lipoprotein little as levels. Although we do know that statins of course reduce ASCBD risk. So, I'm checking lipoprotein little a now in all my secondary prevention patients with established CVD and in high risk primary prevention with those with family history. While we're all anxiously awaiting outcome trials, such as the antisense oligonucleotides that can lower lipoprotein(a) by 80 percent, that therapy is not here now, we don't have that available in practice. But we do have PCSK9 inhibitors now, which can reduce lipoprotein little a by 20 to 25 percent and have meaningful outcome data like the alirocumab data we see here in this ODYSSEY OUTCOMES study. With a 31 percent reduction of PAD, that is really meaningful. So I'm particularly excited about PCSK9 inhibitors and my patients with PAD who often have concomitant CAD, polyvascular disease, and then regarding the VTE effects, I think we should point out that the absolute risk reduction of VTE was pretty modest. We didn't really see significance until we combined it with the FOURIER data. So I think given the cost of the drug, it's not warranted to prescribe PCSK9 inhibitors to the general population, specifically for VTE prevention alone. But in patients with ASCBD, who would be recommended for a PCSK9 inhibitor to reduce incident CBD, you know, there may be this added special benefit of reducing risk of VTE as well. Dr Gregory Schwartz: I just wanted to comment on a few things that Erin said, I think we’re really important. All of these patients were on intensive statin therapy in the background. So although we did not see a relationship between the further reduction in LDL cholesterol with alirocumab and the risk of these events, it doesn't mean that lowering LDL cholesterol has nothing to do with the risk of those events because everybody was on background statin therapy, 90 plus percent. So, I think that's important to point out. And I think the comment that was made about when to check a lipoprotein(a) level is very pertinent. And, in the European guidelines, they direct us to check lipoprotein(a) at least once in a lifetime for everyone, even if there's no other signs or risk factors for cardiovascular disease. So I think as Erin indicated, with some tools in the toolbox now, and more tools, perhaps on the way with both the antisense, and also there are small interfering RNA approaches to lower lipoprotein(a), we should get more accustomed to looking at this, to turning over that stone. Even if we're not a hundred percent certain what to do with what we find underneath it, we should still look because there may be some things we can do in the interim. Dr Carolyn Lam: Thanks, Greg. Erin, can I give you the last word? Any take home messages? Dr Erin Michos: I definitely think that as we move forward with other therapies such as the small interfering RNA and the antisense oligonucleotides, we need really more phase three clinical trials specifically assessing VTE. And then I just want to mention, although I didn't write an editorial for this study, I did have the pleasure of writing an editorial for another ODYSSEY OUTCOMES analysis that was published in December. You know, my editorial was entitled, "Achievement, a Very Low LDL. Is it Time to Unlearn the Concern for Hemorrhagic Stroke?" And I mention this because one of the barriers I get in clinical practices, people get very worried about the very low LDL levels that we see with PCSK9 inhibitors and I think important to point out from ODYSSEY that, with the reduction in ischemic stroke, that there was no signal for increased hemorrhagic stroke and that provides additional reassurance. So I think that's important to mention, I think this PCSK9 therapy is being under-utilized in clinical practice and ASCBD and PAD, these are really high-risk patients who have really high risk of recurrent events and our efforts to ward off these devastating consequences. We need to make sure that we're appropriately utilizing this important therapy. Dr Carolyn Lam: Thank you so much, Erin. Thank you so much, Greg. You've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr Greg Hundley: This program is copyright, The American Heart Association, 2020.  

Duke cardiology fellow, Rahul Loungani, interviews Dr. Jonathan Piccini, director of the Electrophysiology Clinical Trials Program and Arrhythmia Core Laboratory at Duke University, about atrial fibrillation management in patients with heart failure. They discuss rate vs rhythm control and strategies for both, new onset AF in the context of critical illness, wearable devices in AF, escalation of therapy in AF, ideal patient for catheter ablation, and AF patients with cardiac resynchronization therapy. On the CardioNerds Heart Failure topic page you’ll podcast episodes, references, guest experts and contributors, and so much more. Take me to the Heart Failure Topic Page Take me to episode topics page Acute Decompensated Heart Failure Primer – Youtube Jonathan P. Piccini, MD, MHS is a clinical cardiac electrophysiologist and Associate Professor of Medicine at Duke University Medical Center and the Duke Clinical Research Institute. His research interests include the conduct of clinical trials and the assessment of cardiovascular therapeutics for the care of patients with heart rhythm disorders. At present, he is the Director of the EP Clinical Trials Program and Arrhythmia Core Laboratory at Duke University. He also serves on the Clinical Working Group of the American Heart Association’s Get With The Guidelines – Atrial fibrillation (GWTG-Afib) registry program. He is an associate editor for the American Heart Journal and serves on the editorial board of Heart Rhythm, the European Heart Journal, and the Journal of Cardiac Electrophysiology. He is the Principal Investigator of the data and coordinating center for ORBIT AF, a 25,000 patient registry focused on quality of care and improving outcomes in patients with atrial fibrillation. He is also the PI of the GENETIC AF clinical trial, the first clinical trial to study genotype-directed rhythm control therapy for atrial fibrillation. He also serves on the steering committees of multiple international randomized trials focused on the treatment of atrial fibrillation.  Dr. Piccini has more than 175 publications in the field of heart rhythm medicine. Clinically, his focus is on the care of patients with atrial fibrillation and complex arrhythmias, with particular emphasis on catheter ablation and lead extraction. Dr. Rahul Loungani completed medical school at the medical university of SC and then traveled to Baltimore for internal medicine training in the Osler Residency Program at the Johns Hopkins Hospital.  Here he fell in love with the management and hemodynamics of critically ill patients. He is currently a third-year cardiology fellow at Duke University Medical Center where he will also be pursuing fellowship in advanced heart failure and transplant cardiology next year. His current interests are in Cardiac amyloid, In particular its arrhythmic manifestations, early diagnosis, and novel therapeutics. He also loves teaching the housestaff and was awarded the Cassell-Saperstein award at Duke,  recognizing the fellow who most demonstrates a commitment to teaching and passion for clinical education. Outside of the hospital loves being a new dad to baby Arya

In this episode of the Mastering Intensive Care podcast we replay a previous episode which featured Paul Wischmeyer (broadcast originally as episode 35). Paul is a Professor of Anesthesiology and Surgery, the Director of Perioperative Research at the Duke Clinical Research Institute and the Co-Director of the Nutrition Support Service at Duke University Hospital in the United States. Paul works mainly as a perioperative, critical care, and nutrition physician focused on enhancing preparation and recovery from surgery and critical care. His academic career has led to large numbers of publications, grants and invited presentations. And what’s unique about Paul is that his passion for helping patients stems from his own personal experience as a patient. In this replayed interview from 2018, Paul describes how he ended up as a physician, after having disturbing and traumatic patient experiences (including procedures, medications and suboptimal communication) and how this has helped him to be a better doctor and an example and teacher to others. He also discusses topics including ward rounds, cooperating with a palliative care team, caring for ourselves, the importance of nutrition and exercise, good onstage presentation techniques, and some valuable closing tips for all of us.   I invite you to listen to this replay episode with Paul Wischmeyer.   Andrew Davies   --------------------   About the Mastering Intensive Care podcast: The podcast is aimed to inspire and empower you to bring your best self to the intensive care unit, through conversations with thought-provoking guests. The hope is you’ll glean insights to move you closer towards being the best and most human healthcare professionals you can be, so you can make the most valuable contribution to your patient’s lives.   --------------------   Links related to Paul Wischmeyer Paul Wischmeyer website Paul Wischmeyer at Duke University Paul Wischmeyer at Duke Health Paul Wischmeyer on Twitter: @Paul_Wischmeyer Paul Wischmeyer on LinkedIn   Links to other resources (in order of mentioning) 2019/2020 Australian Bush Fires American Delirium Society Prof Wes Ely SCCM ICU liberation initiative Book “Presentation Zen Design” (by Garr Reynolds) Prof Jean-Louis Vincent Prof Mervyn Singer   Links related to Mastering Intensive Care podcast Mastering Intensive Care podcast - Episode 31 with Jean-Louis Vincent Mastering Intensive Care podcast - Episode 33 with Wes Ely Mastering Intensive Care podcast - Episode 35 with Paul Wischmeyer Mastering Intensive Care podcast - Episode 49 with Hugh Montgomery Mastering Intensive Care podcast - Episode 52 with Martin Bromiley Mastering Intensive Care podcast Mastering Intensive Care page on Facebook Mastering Intensive Care at Life In The Fast Lane Andrew Davies on Twitter: @andrewdavies66 Andrew Davies on Instagram: @andrewdavies66 Andrew Davies on LinkedIn Email Andrew Davies Audio Producer Chris Burke Burke Sound & Media

Clinical trials haven’t changed much in decades. These industry leaders show us why it’s time for disruption – and how to make it happen. Spencer Health Solutions is proud to present the Voice of Disruption. Tom Rhoads:                   00:00                   Clinical trials are ripe for disruption. The process is expensive, unwieldy, complicated, lengthy, inhospitable and more likely to fail than to succeed. I'm Tom Rhodes, CEO Spencer Health Solutions. As I traveled to conferences, business meetings and clinical trials sites across the US Canada and Europe, I've had the pleasure to meet and connect with some exceptional professionals and thought leaders who are committed to changing the clinical trials process through disruption, transformation and innovation. We have asked some of them to share their ideas with us on the people, always patients, sometimes podcast. We ask them to tell us what is holding back the industry or what could propel it forward with a little push. I hope you enjoy hearing these ideas and will join me to bring innovation to clinical research. Here are the Voices of Disruption. Janet Kennedy:                00:52                   Hi, this is Janet Kennedy. I'm a member of the marketing team at Spencer Health Solutions and also the host for the "People Always, Patients Sometimes" podcast. I had the honor of interviewing everyone for the Voices of Disruption eBook and this podcast and I was so impressed with their thoughts and suggestions to improve clinical trials. We did find an interesting trend reflected in all of their comments. It's all about the patients. So much so that we were able to group their ideas into three different topics. The first topic category is titled Put Patients First. The second topic combines ideas about training the staff to be more patient-centric, and the third category revolves around ideas to make the clinical trial process much more patient-friendly. We've had so many good comments that we wanted to give them to you in their entirety, so we're breaking this podcast into three episodes. Welcome to the first episode, Put Patients First. Gayle McCracken:           01:55                   Hi, I'm Gail McCracken, vice president of market innovation at Spencer Health Solutions. Remember ePatient, Dave and his 2012 TED MED cry for inclusion with the "gimme my damn data" video and how the next year the pharmaceutical industry began inching toward the patient, with it's "Beyond the Pill" movement? Meanwhile, payers turn their attention to value-based care delivery in pursuit of better treatment outcomes at lower costs. Yet we find ourselves on the threshold of the next decade with a continuing dialogue about how to bring people to the center of their care and to the center of treatment development. There is no disagreement that when people are informed and are active participants in their health and in clinical research, the outcomes are better for everyone. The patient, the payer, the research community and yes, the drug company. How do we walk the talk, especially when it comes to bringing the patient voice to clinical research and eventually to research as a treatment option for every person as Spencer Health Solutions. Gayle McCracken:           03:11                   All that we do from design to manufacturing to introducing intuitive digital technology to the home starts and stops with the individual wherever they may be on their health journey. That's exactly why we launched our podcast. People always patient, sometimes host Janet Kennedy, senior digital brand manager at Spencer health and vice leaders of change in health medicine and clinical research to exchange ideas on how we can work together to accelerate research, reform and inclusion. This podcast presents a collection of excerpts from hours of discussion among patients and pharmacy industry leaders about obstacles to change the critical need for innovation and what single action today my propel us toward better outcomes for all. I hope that in listening to Voices of Disruption, you'll find both a sense of urgency and inspiration to see new opportunities for bringing patients to the heart of care delivery and to clinical research. Janet Kennedy:                04:28                   There's a lot of agreement these days about the need to disrupt clinical trials. The lengthy, costly and complex process of evaluating therapies hasn't changed much in several decades. What's more, the process is simply not designed with the patients in mind. Many industry leaders want to change that, but how? What should they focus on? Where are the opportunities to bring in more patients and ensure a better experience? In this podcast, Spencer Health Solutions brings you the perspectives of thought leaders, including patients who are providing some answers. We call it Voices of Disruption because that's exactly what they're advocating. Clinical research isn't going to embrace patient-centeredness real-world data and evidence or digital technologies. Without some upheaval. Incremental change is no longer enough. We asked more than a dozen industry leaders and patients what one thing they would do to change about clinical trials. No surprise that we got a variety of responses, but almost everyone kept coming back to an overriding theme. How to make clinical research better for patients. Eva Mae is a patient community partnership creator and a cancer survivor. Her advice is very simple. Give participants a voice. Higher patient engagement has been demonstrated to help participants complete clinical trials for Ava engagement means greater communication between researchers and patients. Eva May:                           06:09                   Hi, I'm Eva May, a patient-powered research advocate and a patient community partnerships creator. If I could change one thing about clinical trials, I would ensure that researchers develop and implement a bi-directional engagement program with the real patient or consumer community if done properly, this would improve recruitment and retention of a truly representative participant group. It would reduce the disparities of typically underrepresented participant cohorts. It would improve the relevance and robustness of patient-reported data and it would give participants the opportunity to become partners in meaningful research. Janet Kennedy:                06:53                   We asked podcast guest, Darcy Forman, who's the CEO of Centricity Clinical and formerly with Forma Clinical Trials what she would recommend and boy she went right to the crux of the matter. Innovate faster. Innovation is a word that pops up frequently when discussing improvements in clinical research. Darcy who consults with clinical trial sponsors sees that current innovation efforts are occurring too slowly. Darcy Forman:                 07:21                   It would really be that the sponsors and the sites and everybody adopt the changes faster, take a little bit more risk and do it with high quality, but we need to innovate at a faster pace. Janet Kennedy:                07:36                   It's one of the most common refrains in healthcare today. Let's make sure patients are truly in charge of their own health, but how and what does this really mean? Our Voices of Disruption of given the concept of patient-centeredness a lot of thought and while there's much work to be done to put patients first, most are optimistic about the prospect for making it happen, including patient-centered clinical trials. We asked Craig Lipset a clinical trials innovator and consultant what he thought about changing clinical trials and he felt it was imperative to aggregate patient health data for the patient. Craig Lipset:                     08:19                   So one thing that's already changing that will continue to change and have a tremendous impact on how we're running our clinical trials and developing our medicines is the power that patients have to access and control their health data. The ability for patients to aggregate their own health data sparked by different apps and patient portals and the proliferation of fire as a new data standard. This is creating the future where patients are the ideal aggregator of health data that if I go to one data provider or one health system and try to get data on a are really only going to get one slice about that patient, but if I go directly to the source, the patient themselves, they are now in the unique position to aggregate all of this diverse health data from different pharmacies they may go to from different doctors or hospitals or health systems where they make out now that patients are in control and have that diverse health data together, they now become the place that I can turn to when I want deep data on patient journeys to answer research questions and that includes for prospective clinical trials where so many of the questions that we're asking of investigators and study coordinators are to enter data that already exists in an electronic health record somewhere else, but we don't have access to it. Craig Lipset:                     09:38                   The other awesome aspect about what happens when patients are in control over their data is we don't have HIPAA excuses standing in the way any longer. HIPAA doesn't block a patient from sharing data wherever they want to, and so a disruptive force that's going to change and streamline how studies are run in the future. That's going to be the data empowered patient. Craig Lipset:                     10:01                   Let me put my patient hat on though and say that I'm fortunate. I only have maybe two or three physicians that I work with on a regular basis, but every one of them has a different portal. I even have two different portals at my current physician depending on whether I use Google to log in or an email to login. So that all sounds wonderful, but if we're not dealing with a universal standard, how does that work? Craig Lipset:                     10:27                   It is an unfortunate reality that even when patients in the United States have access to their health data, it's through a cacophony of different patient portals or different logins for what look and feel like the same portal. For example, many of my providers are using Epic, but I have five different logins for Epic's My chart app for each of the providers, instances of My Chart. Now, third party apps are emerging that are streamlining some of this and we see new products like Hugo Health, like Seekstr, like Citizen and others that are helping patients to not only access the data in these diverse places where they may live, but bring that data together to give patients and those with whom they choose to share their data an integrated view. So agnostic to whether this lab test was run at Provider A or provider B, pull it all together so I could just see my labs rather than view it in that artificial silos that healthcare boundaries have created. So again, I think that it's a challenge today, but I believe that many of the emerging products that are being built to leverage FHIR and pull that data together are creating awesome new views that are great for patients and researchers and providers. Janet Kennedy:                11:48                   Clinical trial participants tend to feel that the benefit is for someone else, other patients, or perhaps even the drug companies sponsoring the trial. Jennifer Byrne of Javara Research wants to change that perception. The lack of knowledge about the purpose process and benefits of clinical trials can be addressed by changing how to discuss clinical trial participation with patients. She says if you could change one thing about clinical trials, what would it be? Jennifer Byrne:                12:20                   The lack of general knowledge about what being in a clinical trial for an individual patient participant actually means. How would you solve that? Well, first of all, I probably would use different terminology. I would be thinking about positioning clinical trial participation as an innovative care option. Janet Kennedy:                12:46                   Oh, I like that idea. Is there a problem in clinical trial participation in that people only assume you have to be really sick to be in one? Jennifer Byrne:                12:55                   I don't know that it's so much assumed that you have to be really sick, but I do think that on the patient, the general public side, there is still a connotation of Guinea pig. So it's, I am part of a scientific experiment and that scientific experiment is not about benefiting me. It is about benefiting a company or potentially benefiting other people to come. Janet Kennedy:                13:26                   So do you feel that if you participate in a clinical trial you should feel better or do better when it's over? Jennifer Byrne:                13:35                   I think that you should expect to have some benefit and I don't know that that expectation should be that you have treatment or condition benefit, but I think that you should expect to be better informed about your medical condition. I think you should expect to be able to leave that clinical trial being better informed in terms of what other options for care or research or treatment you might have access to. I think that you should expect to have an exceptional care delivery experience. Janet Kennedy:                14:11                   All right, so now you are officially the genie who has to answer that wish and solve the problem of getting more people involved. How do we solve that problem? Jennifer Byrne:                14:21                   I think we have to bring better alignment with health care. This conference is terrific, but I think this conference and other conferences in the clinical research space focus heavily on pharma and CRS and then the workforce with respect to clinical research coordinators. I think that we need more health care. Those people who are leading organizations and that are charged every day in their job to find better ways to deliver or reducing cost of care, improving outcomes for the patients for whom that organization or institution serves. And finding ways to bring about more satisfying patient experiences. Because I think that clinical research can be a tool in that toolbox to help accomplish that. So in that way, it's not about clinical research being a means to an end for pharma companies to get a drug approved, but that clinical trial access is actually beneficial to that individual in their care at that moment. Jennifer Byrne:                15:42                   And it is beneficial to that health system to better understand is an active participant and as part of an active learning health system that in real-time is also bringing benefit. It's a tremendous shared value opportunity. We talk a lot about we need to have patients at more conferences. I'm wondering if we need to also have at every American Academy of Pediatrics or the Academy of Family Physicians at every one of those general practice types of conferences, panels on clinical trials and how to translate them for your patients. Absolutely and I think we also need to be including people who are opposed to clinical trials. I think it'd be a great learning experience to hear from a physician who has refused to participate in clinical research, which is different from a physician who hasn't participated because they haven't had the opportunity or they don't have the infrastructure to support that, but I would like to hear from physicians who perhaps participated in research those "one and done" physicians that we talk about. I'd like to hear why, what we can learn from them to make that better. Janet Kennedy:                17:06                   We invited patient advocates to also be a part of the Voices of Disruption. Carly Flumer, a scientific data analyst, patient advocate and cancer survivor goes right to the gist of it. Use plain language. Carly Flumer:                   17:23                   I'm Carly Flumer. I'm a scientific data analyst, a patient advocate and a cancer survivor. If I could change one thing about clinical trials, it would be the language that they're written in. Health literacy is such an important component of healthcare, yet it's not recognized, so it's whole. It's potential clinical trial enrollment numbers are pretty low and I believe one of the causes of this is some of the language that's used specifically medical terms that patients aren't able to understand on their own. Rather they need a doctor or a nurse or other healthcare provider to explain the trial to them and that's only if one, the patient brings up the trial during an appointment and the provider has enough time to discuss it, which is another issue or two, the provider recommends the trial to the patient as a form of care. Without this guidance, the majority of patients may have a hard time understanding what they're reading and if they don't understand it, they're less likely to take an interest in it. Janet Kennedy:                18:26                   To fully engage patients. It's essential that clinical trials accurately represent the population of patients who are intended to benefit from the therapy under a study. We asked Julius Wilder, assistant professor at Duke university school of medicine and the Duke clinical research Institute, what he thought, he explained that with clinical trials historically under-representing certain types of patients. There's work to be done. Julius Wilder:                   18:54                   My name is Julius Wilder. I am an assistant professor in the Duke school of medicine within the division of gastroenterology as well as the Duke Clinical Research Institute. As I reflect on how we can improve clinical trial research, I believe a key component to that will be ensuring that clinical trials reflect the diversity of the population of people with the diseases that are being studied. Historically, minority populations including blacks and Latinx as well as women have been underrepresented in clinical trials. This has significance for many reasons, including the potential creation of therapies that may be dangerous or not efficacious in these populations. This historically has been a problem for decades and we have been able to address it. I believe the solution for this problem includes a mixture of policies including policies around ensuring that the clinical trials report participation of minorities and women in clinical trials incentives. These could be financial or related to FDA approval to provide motivation for pharma to invest in diversity and research on what are the barriers and to identify potential interventions to increase diversity within clinical trials. Janet Kennedy:                20:08                   Tom Rhodes, CEO of Spencer house solutions and the founder of the company brings the conversation right back to the essential element of what Voices of Disruption is all about. That clinical trials should start and end with the patient. Tom Rhoads:                   20:25                   I think to be patient-centric really means that we begin with the patient and work out today. A lot of the approaches I see are attempting to modify decades-old processes and make them patient-centric and I don't see that as a winning strategy. I think you have to rethink what are the endpoints you're trying to accomplish here and if you're that, then you really begin with what does the patient need, what do they expect, what kind of feedback and support will enable them to provide adequate insights to the protocol or the molecule or whatever you might be testing. And I think a lot of the approaches today miss that point. It seems like a simple point, but it's actually complex if you really dig in to try to understand how to best engage someone in their home environment. Ideally, as an example, family patients have a rather significant, in many cases, family support system in place and those don't go away just because they're in a trial. Tom Rhoads:                   21:26                   Oftentimes the family needs to drive them to the clinic. They need to help them answering questions they need to help them with their daily living activities. There are a lot of aspects of that that are already happening on a day to day basis, but oftentimes we don't see any engagement with the family and I think that's an example of an area that we need to get better at, which starts with the person and I say person because we acknowledge that there are always people in their patients at times and often too often, whether it's in clinical trials or in the healthcare system, those systems are set up to treat them as a patient, which means that they're going to do the processes they need to do to reach the endpoints they need to get to and that may or may not include informing those individuals of what's going on, why it's going on, what the feedback is, what the prognosis is. Tom Rhoads:                   22:19                   All of those aspects that any normal person may wonder, especially if they're suffering from either a chronic or life threatening disease. So as we think about platforms and innovation, they really need to start contemplating how might a patient use integrate all the tools we talk about wearables. There's lots of wearables coming to the market, which means there are lots of wearables coming into the home. The medications are using the titration schedules that might follow those, the telehealth aspects. How can I talk to someone when I feel like I'm having an adverse event? The ability for them to be mobile. A lot of these people still have lives, are working in many cases and, and how can I carry this with me, but still participating in, in a meaningful way while getting feedback. I think right now there's so many good ideas that are creating a bit of a technology avalanche. Tom Rhoads:                   23:13                   And so we need to begin working across companies, through partnerships and into more of an integrated perspective and approach, which means that we're going to have to start picking some platforms that might be able to enable this. AARP had a study a few years back and they called the family, the chief of staff. And it's usually the daughter who is responsible and she wants to know everything that is going on at all times. So respecting that as we integrate the technology, respecting that those not only need to be informed and will frankly demand to be informed, but they also can be used to help the individual in the trial. That's the subject to be you know, more effective, make sure they're keeping up with their diary, make sure they're giving appropriate honest feedback, et cetera. That's where we kind of land on where does that patient want to be? Tom Rhoads:                   24:08                   It's convenient for them to be in a clinic. That's where the physicians are, that's where the nurses are, the, the pie, et cetera. And that's the easiest place to care for an individual. But it is not the easiest place for that subject to be that subject. The easiest place for that person to be is at home. And so I think there's a lot of excitement around the model shifting to a direct to patient focus and I think that's putting a lot of pressure on clinical trials to begin to honor that and figure out how to modify processes, how to modify regulations, how to modify, you know, the approach general that we take to ensure that we can serve them in their home. Because let's face it right now, we're still saying 30% dropout rates from trials. As you get in the more and more orphan Ty drugs, it's more and more difficult to recruit patients. So if we can begin to allow them to participate in these trials from afar in their home, minimally reducing the number of site visits that may be required, I think we're going to get a much better participation rate feedback and frankly data to determine whether the molecule is working as it should. Janet Kennedy:                25:21                   Thanks for listening to the first episode of the Voices of Disruption. We'd like to thank our contributors to this podcast episode, including Eva May, Darcy Forman, Craig Lipset, Jennifer Byrne, Carly Flumer, Julius Wilder, and our own Gail McCracken and Tom Rhoads. Look for our next episode of Voices of Disruption, where we look at the importance of the staff training that you do to make your clinical trial teams more patient-centric. If you've enjoyed this episode, please share it on LinkedIn and Twitter where you can find us @spencerhealth. Subscribing to the podcast ensures you'll always have the latest episode in your favorite podcast player. I'm Janet Kennedy and I thank you for listening to "People Always, Patients Sometimes".

In this series, first recorded at the 6th annual Patients as Partners US conference, is led by Craig Lipset, formerly with Pfizer discusses the ideas of patients 'donating' data, patient data ownership, data rights, and why this is a disruptive force in advancing clinical trials, we address the need to ensure we have the appropriate systems, security, and the ability to withstand a Facebook/Cambridge Analytica Scenario. Craig is joined by Mark Scrimshire, NewWave/CMS and Bray Patrick-Lake, Duke Clinical Research Institute. To learn more about the 7th annual Patients as Partners US conference happening June 29-30, 2020 in Philadelphia, PA please visit theconferenceforum.org.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia, from VCU Health. Dr Carolyn Lam: You know what, Greg, I may have a hoarse voice today and I'm a little bit scratchy, but my goodness, I couldn't be more excited about this issue. It's the TCT issue. Dr Greg Hundley: Well Carolyn, I cannot wait to discuss with our listeners the feature article that compares Apixaban and a P2Y12 inhibitor without Aspirin, versus regimens with Aspirin in patients with AFib who have ACS, whether managed medically or with PCI, or also those undergoing elective PCI that experience regimens that include vitamin K antagonists, aspirin, or both, but more to come later. Carolyn, should I start with my first discussion article and we grab a cup of coffee? Dr Carolyn Lam: You bet, Greg. Dr Greg Hundley: So my first article is from Seung-Jung Park from the Asan Medical Center at the University of Ulsan College of Medicine. So Carolyn, here's our first quiz question. In terms of Ticagrelor, have studies been performed in those from Asia evaluating bleeding risk? Dr Carolyn Lam: You know, I have to admit, Greg, I'm not totally familiar with the literature, but I do know that it's a very important question for us practicing in Asia. We have a perception that the bleeding risk, especially intracranial bleeding, may be higher in Asians. Dr Greg Hundley: Absolutely. Well, in this multicenter trial, 800 Korean patients hospitalized for acute coronary syndromes with or without ST elevation, and intended for invasive management, were randomly assigned to receive in a one to one ratio, Ticagrelor with a 180 milligram loading dose, and then 90 milligrams twice daily, or Clopidogrel with a 600 milligram loading dose and 75 milligrams daily thereafter, and the primary safety outcome was clinically significant bleeding, which was a composite of major bleeding or minor bleeding according to the PLATO outcomes criteria at 12 months. Dr Carolyn Lam: Oh, so what did they find? Dr Greg Hundley: Well Carolyn, at 12 months, the incidence of clinically significant bleeding was higher in the Ticagrelor group than in the Clopidogrel group. So it was 11.7% versus 5.3, and that included major bleeding and fatal bleeding. They were also higher in the Ticagrelor group. The incidents of death from cardiovascular causes, myocardial infarction or stroke, was not significantly different between the Ticagrelor group and the Clopidogrel group, although there was a strong trend toward a higher incidence in the Ticagrelor group with a P value of 0.07. So consequently, Carolyn, these results identified safety concerns regarding bleeding complications of standard dose Ticagrelor in East Asian, Korean patients with acute coronary syndromes, and therefore large adequately powered randomized trials are needed to determine the optimal antithrombotic regimen in this patient population. Dr Carolyn Lam: Very important data for our patients, as is this next paper, which really examines the cost effectiveness of transcatheter mitral valve repair versus medical therapy in patients with heart failure and secondary mitral regurgitation. Now, these are results from the COAPT trial. As a reminder, the COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair using the MitraClip resulted in reduced mortality and heart failure hospitalizations and improved quality of life when compared with maximally tolerated guideline directed medical therapy in patients with heart failure and three to four plus secondary mitral regurgitation. In the current paper, first author Dr Baron from Lahey Hospital and Medical Center in Burlington, Massachusetts and St. Luke’s Mid America Heart Institute in Kansas City, as well as corresponding author Dr Cohen from University of Missouri, Kansas City, and their colleagues used data from the COAPT trial to perform a formal patient level economic analysis of the COAPT from the perspective of the US healthcare system, and they found that although the follow up costs were lower with the MitraClip compared with guideline directed medical therapy, and lower by more than $11,000 per patient. However, the cumulative two year costs remain higher by about $35,000 per patient with the transcatheter mitral valve repair, and this is all due to the upfront costs of the index procedure. Now when in trial survival, health, utilities, and costs were modeled over a lifetime horizon, transcatheter mitral valve repair was projected to increase life expectancy by 1.13 years, and quality adjusted life years, or QALYs, by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost effectiveness ratio, or ICER, of $40,361 per life year gained, and $55,600 per QALY gained. Dr Greg Hundley: Very interesting. So how do we interpret these results for clinical practice? Dr Carolyn Lam: Ah, good question. So in order to place this in context, perhaps the most comparable case is the use of transcatheter aortic valve replacement, or TAVR. So based on the partner 1B trial, the ICER for TAVR, compared to medical therapy, was $61,889 per QALY gains. So this is very similar to what you just heard as the ICER for the transcatheter mitral valve repair. The cost effectiveness is also comparable for other commonly used treatments such as the implantable cardiac defibrillators for biventricular pacing, and was interestingly substantially more than the cost effectiveness of continuous flow LVADs, for example, and this is really discussed in a beautiful editorial by Dr Bonow, Mark, and O'Gara, and in this editorial, I think it's really important that they say the cost effectiveness projections really need to be placed in the context of continuing uncertainties regarding the interpretation of COAPT compared to that of the MITRA-FR trial, which reported no benefit of transcatheter mitral valve replacement compared to medical therapy, and so they warn that the current cost effectiveness analysis is not a carte blanche for interventional cardiologists to dramatically escalate their use of MitraClip procedure, and the data do support the thoughtful and deliberate use of this potentially life lengthening procedure in carefully selected patients and under very careful circumstances. You've got to read their editorial. Dr Greg Hundley: That sounds excellent, Carolyn. I really like that, putting that editorial that puts that data in perspective. Well, my next study really emanates from the ABSORB III trial, and it's from Dr Dean Kereiakes at the Christ Hospital Heart and Vascular Center. The manuscript addresses the long-term cardiovascular event rates among bioresorbable vascular scaffolds and drug eluting metallic stents. Dr Carolyn Lam: Greg, remind me, what were the results of the original ABSORB trial? Dr Greg Hundley: Right, Carolyn. So the ABSORB III trial demonstrated non-inferior rates of target lesion failure, cardiac death, target vessel myocardial infarction, or ischemia driven target lesion revascularization at one year with the bioresorbable vascular scaffolds compared with cobalt chromium everolimus-eluting stents, but between one year and three years, and therefore the cumulative to 3 year time point, the adverse event rates, particularly for target vessel myocardial infarction and scaffold thrombosis, were increased with this bioresorbable vascular scaffold. Dr Carolyn Lam: Ah, I see. Okay, so this current study evaluated the outcomes from three to five years beyond the implantation? Dr Greg Hundley: Exactly. So what this study did is they looked at an interval of time between three and five years out, and they found reductions in the relative hazards for the bioresorbable vascular scaffolds compared to the common coated stents, and that particularly occurred for target lesion failure, either cardiac death or target vessel MI or ischemia driven target revascularization when compared to the earlier zero to three year time period. So therefore Carolyn, the authors conclude that improved scaffold design and development techniques to mitigate that zero to three year bio resorbable vascular scaffold risk may enhance the late benefits that one sees in this three to five year time point, because of the complete bioresorption. Dr Carolyn Lam: So that's interesting Greg. Well, my next paper is kind of related. It is the first report of a randomized comparison between magnesium based bioresorbable scaffold and sirolimus-eluting stent in this clinical setting of STEMI with one year clinical and angiographic follow-up. So this study is from the Spanish group, Dr Sabaté and colleagues from the Interventional Cardiology Department and Cardiovascular Institute in Barcelona in Spain, and they found that at one year when compared to the sirolimus-eluting stent, the magnesium based bioresorbable scaffold demonstrated a higher capacity of vasal motor response to pharmacological agents, either endothelium, independent or dependent, at one year. However, the magnesium based bioresorbable scaffolds were also associated with a lower angiographic efficacy, a higher rate of target lesion revascularization, but without thrombotic safety concerns. Dr Greg Hundley: Wow, Carolyn, very interesting, and Dr Lorenz Räber and Yasushi Ueki wrote a very nice editorial on this whole topic of bioresorbable scaffolds, and they wonder about some of the unfulfilled prophecies. Great for our readers to put these two articles together. Now, how about in that mailbox, Carolyn? What have you got in there? Dr Carolyn Lam: First there's a research letter by Dr Kimura entitled Very Short Dual Antiplatelet Therapy After Drug-eluting Stent Implantation in Patients with High Bleeding Risk, and that's insights from the STOPDAPT-2 trial. There's another research letter by Dr Lopes entitled The Hospitalization Among Patients with Atrial Fibrillation and a Recent Acute Coronary Syndrome, or PCI, Treated with Apixaban or Aspirin, and that's insights from the AUGUSTUS trial. A very interesting perspective piece by Dr Rob Califf entitled The Balanced Dysfunction in the Health Care Ecosystem Harms Patients, a really, really interesting read, especially those working in the U.S. healthcare system. An ECG challenge deals with fast and slow, long and shorter. I would love to give you a clue to what it is. It's got to do with the atrial ventricular nodes, but I'll let you take a look and test yourself. There’re highlights from the TCT by Drs Giustino, Leon, and Greg Stone, and finally there's Highlights from the Circulation Family of Journals by Sara O'Brien. Dr Greg Hundley: Very nice, Carolyn. Well, I've got just a couple reviews. Richard Whitlock in a primer provides a nice historical review of anticoagulation for mechanical valves. How do we get here in anticoagulating this particular patient population? Next, Dr Mark Brzezinski from Brigham Women's Hospital in the Harvard Medical School in an on my mind piece provides very elegant figures, beautiful figures, demonstrating inadequate angiogenesis within the fibrous cap of atherosclerotic plaques, and indicates this could be a source or thought of as a contributing factor toward plaque rupture. What an issue, and I can't wait to get onto that featured discussion. Dr Carolyn Lam: For our featured discussion today, it is a super-hot topic, and a question that comes up again and again in clinical practice. What is the right antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome, not just those treated with PCI, but also in those treated medically? Well guess what? We're going to have answers right here. I'm so pleased to have with us Dr Renato Lopes, who's a corresponding author from Duke Clinical Research Institute and our associate editor, Dr Stefan James from Uppsala University in Sweden. Wow. Very, very important question here. Renato, could you just start by outlining what is the AUGUSTUS trial? Dr Renato Lopes: The AUGUSTUS trial was basically one of the four trials trying to give an answer, or help answering about the antithrombotic therapy in patients with anti fibrillation and/or NACS and/or PCI. So in other words, this combination of patients undergoing PCI who require antiplatelet therapy and also patients with AFib who requires anticoagulation therapy, and in summary, what the AUGUSTUS trial did was randomize patients to Apixaban versus VKA, or aspirin placebo in a double blind fashion, and this was a two by two factorial design. So these were basically the two questions that we wanted to answer. Is Apixaban better than VKA, and is it safe to drop aspirin from this treatment strategy? Remembering that everybody received a P2Y12 inhibitor for at least eight months. So this was basically the design of the AUGUSTUS trial, trying to answer two questions in the same study, a two by two factorial design. Dr Greg Hundley: Very, very nice. And Renato, if I could, I mean I said it in the intro, but may I make sure I got it right. This is the only trial in the field that included patients with ACS that was managed medically. So that's a very important group of patients that we still don't know what the best regimen is, is that right? Dr Renato Lopes: That is correct. The other trials, the PIONEER, the RE-DUAL PCI and the VPCI, they only included patients undergoing PCI, and when we designed the trial, we thought that it would be important to also include the whole spectrum of ACS, including not only the PCI treated patients, but also the medically managed patients. Dr Greg Hundley: Well, super. So could you tell us now what were the results? Dr Renato Lopes: So first, in terms of the breakdown, we found that the breakdown of the PCI, ACS versus elective PCI, was really nice. We had about 60% of the trial being ACS patients, and about 39%-40% elective PCI, and then within the PCI, I think that our results pretty much reflect practice in a lot of parts of the world, which was about 39% medically managed and about 61% PCI treated patients. So to begin with, I think a very nice breakdown that gives us power to look at these three separate groups: ACS medically managed, ACS PCI treated, and also elective PCI, which allows us to understand the whole spectrum of coronary disease in patients also with AFib, and in summary, what we showed for the primary endpoint, which was clinical major or relevant non-major bleeding. Let's start with the Apixaban versus VKA comparison, and we show that Apixaban was safer than VKA in all three groups, in the ACS medically managed, in the PCI treated patients, and also in the elective PCI patients. There was no significant direction for those three subgroups, although it was borderline 0.052, just showing maybe a little bit less pronounced results in the elective PCI group, but nonetheless, I would say that in general, very consistent, and in terms of Aspirin for the primary endpoint, also no difference, no interaction among those three groups. In other words, as we increase substantially the risk of bleeding about two folds in all the three groups, ACS medically managed, PCI treated patients, and elective PCI patients, with about again, two fold increase in bleeding compared to placebo. If we go to ischemic events, again, that's our hospitalization and other that are ischemic events. In terms of Apixaban versus VKA, the results were very consistent with the overall trial among these three groups, and in terms of as ACS versus placebo, the results also for the ischemic events were also similar among the three groups. So again, reassuring that the main results of the trial were very consistent, regardless how patients were managed in terms of the ACS, medically or through PCI, and also included in the elect PCI group. Dr Carolyn Lam: Thank you for explaining that so well. Stephan, I would love for you to take us under the hood. What were the editors thinking when we saw this paper, why we're highlighting it now, and what do you think are the implications? Dr Stefan James: The AUGUSTUS trial was unique in many aspects. I think Renato highlighted a few of them. As he told, there have been several similar trials without the other DOAX, factor 10A inhibitors and the dabigatran, but the AUGUSTUS trial was larger. It includes, as you mentioned previously, patients with ACS and medical management, and it also was designed as a two by two factorial design. So it actually asks two different questions and made two different randomizations, both anticoagulation with the two different agents, Warfarin versus Apixaban, but also Aspirin versus placebo, and so it's possible from this trial to understand more of the different aspects of treating patients, these complex patients with atrial fibrillation, NACS or PCI, and gave the study group and us an opportunity to better understand all these complexities. So with that, I'd like to turn to Renato and try to, with that background that I just outlaid, and you just try to make us understand what are the clinical implications of these aspects of the trial and the treatment of Apixaban and Aspirin in these patients? Dr Renato Lopes: I think we were in the area that we desperately needed randomized data, because basically until five years ago, the standard of care of treating these patients was the classic triple therapy with Aspirin, Clopidogrel, and Warfarin, and this was based on no randomized trials and all observational data, and we know how problematic this is, and this field has evolved tremendously almost year after year since the PIONEER trial, since the RE-DUAL trial, and this year, we had AUGUSTUS and ENTRUST and I think now, as Mike Gibson used to say, that we have about 2.8 million different combination of antithrombotic strategies to treat these patients because we have different anticoagulants, different anti-platelets, different doses, different durations, different types of stents, which makes it really impossible for physicians or for any guidelines to contemplate all these options. So we really needed a few trials to at least try to give a few options that are evidence based and not just based on low quality of data, and I think now, if you look at the Augustus results, and the totality of the data from all these trials, which now is about almost 11,000 patients all together, actually almost 12,000 patients all together. I think that what we know today is that yes, the initial period in hospital for some time it's important to use Aspirin. I think this is an important point to highlight, Stephan, that Aspirin still needs to be used for the acute treatment, and I would say at least for the first few initial days while patients are still in the hospital, but then by the time of discharge, which sometimes might be five days, six days, seven days, I think that now the totality of data show that it's reasonable to drop Aspirin for most patients. So based on the AUGUSTUS results, what we show is that if you're going to use anticoagulation as Apixaban at the dose that is approved for stroke preventions in atrial fibrillation, combined with a P2Y12 inhibitor without Aspirin after the initial period, you have the best outcomes in terms of lower rates of bleeding, lower rates of hospitalizations, and we don't have to pay a cost in terms of ischemic events when we actually drop Aspirin and keep only the NOAC, in this case was Apixaban, plus a P2Y12 inhibitor, which most of the time was Clopidogrel, and here with AUGUSTUS, we basically show that this is true for patients with AFib and ACS, irrespective of the management with medical managing, with medical therapy, or with PCI. So I think that's an additional piece that that is true irrespective of how we're going to treat your ACS patient, or if the patient basically underwent elective PCI, and I think we learned today that the classic treatment therapy of VKA plus Aspirin plus P2Y12 inhibitor, so in other words, the triple classic triple therapy should generally be avoided. Dr Stefan James: Thank you Renato. I think that that was a very complete answer in this complex arena. I'd like just to mention that of course the AUGUSTUS, as well as the other trials, have their limitations, as all trials. Although it was large, it was powered for safety, for bleeding events, and it was not powered for ischemic events. Having said that, we still want to look at ischemic events and clinical outcomes, and to what degree do you think we can do that? What conclusions can we draw from an ischemic point of view because of the fact that the trial was underpowered for that interpretation? Dr Renato Lopes: That is a great question, Stephan, and in fact, if we look at events like stent thrombosis, they are very rare, and if you really want to attack a significant difference between Aspirin versus placebo in patients having stent thrombosis, we're really going to need a trial with about 30-40,000 people, which would be not feasible and not doable. So we need to be cautious when we analyze those events in the power trial for ischemic events. Nonetheless, there was a signal, if you look at all trials, and even in the meta-analysis that we published recently, that dropping Aspirin probably increased the risk of ischemic events, not in a statistically significant fashion, but nonetheless, this trend exists. The signal exists. So probably keeping Aspirin, add some protection for ischemic events, primarily stent thrombosis and myocardial infarction. The problem is a tradeoff. The problem is that the cost of adding aspirin is too high. So now the question to us, Stephan, is to look further into our data and in the combined data sets that we're trying to work with the other authors and try to identify, okay, Aspirin really increased the risk of bleeding, but is there a group of patients who might benefit from a little bit longer Aspirin? So that's the first question. Who are those patients? May be complex PCI, maybe bifurcation lesions, maybe multiple lesions, multiple stents, and second, if we decide to give Aspirin longer, how much longer should we give? Because again, the cost is very high in terms of bad bleeds. So we are trying now to identify what is the trade off, and who most benefit from keeping Aspirin longer, and for how long in a way the cost might be worth it to pay in exchange of potentially save some ischemic events? And with that, we can further refine the treatment that I think I highlighted before. For most patients, I think what I said before is probably reasonable. We can drop Aspirin by the time of discharge after a few days, but for a few patients, for some patients, it might be wise to keep Aspirin a little bit longer, and we are trying now to identify first, who those patients are and second, form how much longer should we keep Aspirin, since the 40,000 patient trial is very unlikely to happen. Dr Stefan James: I like his interpretation, Renato, although I wanted to highlight that there are limitations, I think this trial is extremely informant for clinicians. We learned a lot how to treat these very complex patients with complex treatments. Dr Carolyn Lam: No, I couldn't have agreed more. I mean quoting Mike Gibson, 2.8 million combinations. Well, at least we've talked about some of them here and had a very clear take home message, although with the caveats that we were discussing. Thank you so much, Stefan and Renato. This was really a great discussion, and thank you audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week. This program is copyright American Heart Association 2019.  

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, we are going to have a great discussion coming right up regarding intensive versus standard ambulatory blood pressure control and its effects on cerebrovascular outcomes in older people. It's the INFINITY trial, but that's all I'm going to tell you for now because I want to hear all about your picks for this week's journal first. Dr Greg Hundley: Absolutely Carolyn and I can't wait to hear about that discussion regarding hypertension. My first paper though is about titin and it comes from Dr Charles Murry from the University of Washington. The giant sarcomere protein titin is important in both heart health and disease as mutations in the gene encoding for titin are the leading cause of familial dilated cardiomyopathy. The uneven distribution of these mutations within titin motivated the authors of this article to seek a more complete understanding of this gene and the isoform it encodes in cardiomyocyte sarcomere formation and function. Dr Carolyn Lam: Cool. What did these investigators find? Dr Greg Hundley: Using genetically engineered human induced pluripotent stem cell derived cardiomyocytes, the authors experimentally confirmed that the gene encoding for the giant sarcomere protein titin includes an internal promoter and start site. This internal start site encodes for the isoform Cronos, which the authors demonstrate support some sarcomere formation in these human induced pluripotent stem cell derived cardiomyocytes. Dr Carolyn Lam: Oh, nicely summarized. What are the clinical implications Greg? Dr Greg Hundley: Well, Carolyn identification that Cronos titin, a previously unstudied form of titin is necessary for normal human cardiomyocyte function could be contributing to some of these titinopathies that are relevant for some patients with dilated cardiomyopathy. Dr Carolyn Lam: Cool. Mine has to do with heart failure as well and presents new results regarding heart failure and heart failure related outcomes from the EXSCEL trial. Dr Greg Hundley: Carolyn, what was the EXSCEL trial? What did it find? Dr Carolyn Lam: Ah, so as a reminder, EXSCEL was the largest glucagon-like peptide-1 receptor agonist or GLP-1 receptor agonist trial reported to date where once weekly, exenatide had a neutral effect on hospitalization for heart failure with no differential treatment effect on major adverse cardiovascular events or MACE, by baseline heart failure status. However, the question remains, what about exenatide's effects on secondary endpoints based on the heart failure status? This is from Dr Rob Mentz and colleagues from Duke Clinical Research Institute who aim to explore the effects of exenatide on secondary outcomes in patients with and without baseline heart failure and test the effects of exenatide on recurrent heart failure hospitalization events. Now they found that out of more than 14,750 EXSCEL participants, 16% had heart failure at baseline and when stratified by the presence or absence of baseline heart failure, there was no observed reduction in all cause death with exenatide in patients with baseline heart failure. While the risk of mortality was reduced with exenatide in the no heart failure group. And that was a significant interaction P value of 0.031. Similar results were observed for the combined outcome of all cause death or heart failure hospitalizations. Now regarding recurrent heart failure hospitalizations, 450 patients experienced at least one hospitalization for heart failure, but there were 713 hospitalization heart failure events in total. The effect estimate that included the recurrent events was separately, statistically significant while the primary analysis based on just first events was not. In conclusion in EXSCEL, the use of exenatide in patients with or without heart failure was well tolerated, but the benefits of exenatide on reduction in all cause death and first heart failure hospitalization were attenuated in patients with baseline heart failure. Now this is accompanied by a great editorial by Bruce Neil and Claire Arnett who caution against using post talk subgroup analysis, but the interaction of exenatide tout with baseline heart failure, it's interesting, although should be treated with caution until confirmed by findings from another trial. Dr Greg Hundley: Very nice Carolyn, especially a nice issue regarding heart failure and I'm going to steer a little bit away from that and talk about atrial fibrillation duration and CHA2DS2-VASc scores. Putting those two together and this article comes from Rod Passman from Northwestern University. Studies of patients with cardiovascular implantable electronic devices show a relationship between atrial fibrillation duration and stroke risk though the interaction with a CHA2DS2-VASc score is poorly defined. The objective of their study was to evaluate rates of stroke and systemic embolism in those patients with cardiovascular implantable electronic devices as a function of both the CHA2DS2-VASc2 score and A-fib duration. Dr Carolyn Lam: Interesting. What did the authors do? Dr Greg Hundley: They had 21,768 non-anticoagulated cardiovascular implanted electronic device patients from the Optum electronic health record, de-identified database from 2007 to 2017 and they link those to the Medtronic CareLink TM database of CIEDs capable of continuous AF monitoring. Now the age averaged about 69 years and 63% were men and they found that increasing a fib duration, and of course increasing CHA2DS2-VASc2 score were both significantly associated with annualized risk of stroke and systemic embolism. These rates were low however, in those individuals with CHA2DS2-VASc2 scores of zero to one, regardless of the device detected a fib duration. Dr Carolyn Lam: Ah. Were there any particular threshold values that seemed important? Dr Greg Hundley: Great question, Carolyn. Yes, the stroke risk crossed an actionable threshold defined as greater than 1% per year in those with CHA2DS2-VASc2 score patients of two or more with greater than 23 and a half hours of a fib or those patients with CHA2DS2-VASc2 scores of three or four with greater than six minutes of a fib duration or finally in those individuals with CHA2DS2-VASc2 scores greater than five even if they had no atrial fibrillation. Dr Carolyn Lam: Wow. Very nice clinically relevant conclusions here. Thanks Greg. I'm going to tell you what else is in this issue. There's also a research letter by Dr Rosenmeier entitled, “Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin 6 Receptor Dependent Mechanism.” And this is a cardiac analysis of a double blind randomized controlled trial in abdominal obese humans. We have an on my mind paper by Dr Delbridge entitled “HFpEF, It's Time to Explore the Role of Genetic Heterogeneity in Conferring Phenotypic Variability.” And this discusses among other things, the role of induced pluripotent stem cells and functional studies of bioengineered HFpEF patient derived cardiac micro tissues that could potentially enable several important questions to be answered for the first time. There's an ECG challenge as well by Dr Naru Kanya, and it's really interesting. It's a hiccup artifact. If you haven't heard about that, you should take a look. And finally cardiology news by Dr Kuhn and it's entitled, “Nourishing Native American Communities by Increasing Access to Traditional Food.” A very interesting paper right there. Dr Greg Hundley: Carolyn, I have a few papers. Robert Gerszten provides a perspective piece regarding emerging affinity reagents for high throughput proteomics, sort of an emerging field, everyone doing proteomic studies, we have to pay a special attention to the reagents that are being used. And then Andrew DeFilippis from University of Louisville as well as Johns Hopkins reviews important concepts related to the definition of MI. Dr Carolyn Lam: Is this pertaining to that fourth universal definition of MI? Dr Greg Hundley: Yes, Carolyn. Absolutely. And basically in this white paper, the authors review the epidemiology, risk factor associations and diagnostic tools that may assist in differentiating between non-ischemic myocardial injury, type 1 MI and type 2 MI. And then finally from Suowen Xu from the University of Rochester, there's a letter discussing the CCN family of matricellular proteins CCN 1, CCN 2 and CCN 3, that are mechano-sensitive proteins that are differentially regulated by sheer stress, the frictional force exerted by blood flow in our vessels. Well Carolyn, that's a great issue. How about we move on to our feature article? Dr Carolyn Lam: Let's go Greg. For our feature discussion today we are talking about intensive versus standard ambulatory blood pressure control and that effect on cerebral vascular outcomes in older people or the INFINITY trial. Very, very important stuff and I'm so pleased to be with the corresponding author, Dr William White from Calhoun Cardiology Center in University of Connecticut School of Medicine. Dr White, thank you so much for being here. Could you maybe set up already the background of what you were thinking when you started this trial? Especially given the results that we know from SPRINT and SPRINT mind. Could you perhaps comment on how this INFINITY trial is different? Dr William White: We started work in this area about 15 years ago and we initially were interested in interactions among vascular risk factors including ambulatory blood pressure, lipids and other sort of thrombotic factors and so forth with the development of small vessel disease in the brain that led to these fairly classic images on MRI called white matter hyperintensity lesions. And we learned from a prospective cohort study that we started about 15 years ago, that there was a very strong relationship between ambulatory blood pressure and the development and progression of these white matter hyperintensity lesions on MRI, but not very nice relationship with the clinical blood pressures measured in the standard office practice. We decided to pursue a clinical trial, a randomized clinical trial in which we would evaluate different levels of ambulatory blood pressure versus the development of the small vessel disease as imaged by MRI, but very importantly we also wanted to link it to functional outcomes because this was in older people, typically in their late seventies, eighties and even nineties in which cognitive impairment begins to develop. There's problem with mobility, bladder function and things of that nature. And since our funder was always the National Institute of Aging of the NIH, there's a great deal of interest in more than just the vascular risk factors and even the cerebral vascular disease that we would detect on the MRI. That was the background of why the study got developed the way it did. Dr Carolyn Lam: That's so interesting. You've already pointed out ways that this was very different from SPRINT OR SPRINT MIND in looking at ambulatory instead of clinic blood pressure and I suppose in the population you selected, out of curiosity, you mentioned that your prior work showed a relationship between white matter hyperintensity on MRI and perhaps future dementia. In which direction? And is there any basis to suspect low, too low blood pressure may also be bad in these older people who already have microvascular brain disease? Dr William White: Absolutely. Very important point. When we look at our prospective cohort which was about a 100 older people, we followed for four years without any intervention. This was just a mixture of normal tensive and hypertensive individuals. Some on meds, some not on meds. But we did show that when you got too low or if you stay too low during those four years with a systolic blood pressure of under 115 on a 24-hour blood pressure monitor, it seemed like there was an almost like U shaped relationship with progression of white matter disease. Below 115 there was more accrual of white matter disease. Above 150 there was a systolic blood pressure, there was also a greater accrual, but in between about 125 and 145 we weren't really sure if there was going to be a difference. And that there was the target is that everybody's talking about for clinical measurement, so we decided to pursue that in this study to determine if we could figure out whether or not there was a sweet spot for the desk blood pressure without getting into trouble with hypotensive symptoms. Dr Carolyn Lam: Nice. Thank you for drawing that up so nicely. Now I get it that you chose the targets that you did, which just for everyone, just a reminder, it was a 24 hour mean systolic blood pressure by ambulatory blood pressure control and the two targets were 130 millimeters mercury and less versus 145 millimeters mercury and less. With that, could you please tell us the results? Dr William White: Right. We called the 130 or less systolic group, the intensive treatment group and the 145, the standard group. We focused on the primary endpoint was changes in mobility parameters in conjunction with changes in white matter hyperintensity lesion growth. And after a period of about three to four months of randomization, post randomization, we achieved a 24-hour systolic blood pressure about 128 millimeters of mercury in the intensive treatment group and 144 in the standard group. And we maintained a pretty good separation in blood pressure, ambulatory blood pressure throughout the three years of treatment. Now the changes in gait speed, which was one of our primary parameters for mobility actually turned out not to be different between the treatment groups. That is intensive versus standard. However, the changes in the accrual of light matter hyperintensity volume was smaller in the intensive treatment group of a 0.29% versus a 0.48% in the standard treatment group. That was significant at a P value of 0.03. We actually also had a pre-specified sensitivity analysis, sort of a per protocol analysis that allowed us to look at people who stayed in their sort of assigned treatment groups based on blood pressure throughout the three years of the trial. And in that circumstance, there was actually a stronger separation because these are people who stayed clearly at 130 or less than about 145 throughout the three years and now the differences were approximately 0.23% in the intensive group and 0.58% in the standard group. And now the P value is smaller, .0028. I think we proved in the study that maintaining a systolic blood pressure on the ambulatory recorder over 24 hours of 130 or less benefited patients by reducing the accrual of white matter hyperintensity lesions by about 40% relatively speaking compared to a standard ambulatory blood pressure value of a 145. One of course caveat is that after that happened within three years, but we did not see the expected benefit on mobility or on most of the cognitive parameters either. And while we were a little bit surprised about that, when we went back and analyzed our situation with where people started from as far as this particular cohort of patients, they might've been a little on the healthy side compared to some other studies. A very educated group, very compliant with everything that they did. And probably three years was just not long enough to show the result of this white matter hyperintensity benefit on some of the functional outcomes. Dr Carolyn Lam: That's really interesting and I'm glad you sort of tackled head on that sort of apparent dissociation between the clinical end points and the MRI end point. Could I also ask, wouldn't those findings also be consistent with SPRINT and SPRINT MIND? Dr William White: In many ways our results were consistent with SPRINT MIND, a sub-study on the SPRINT MRI sub-study. Of course, just let me mention the differences between the two studies. Of course, SPRINT was very large but there are sub-studies were not as large as the parent study. The MRI study had about 300 plus patients randomized into it, but the measurement of blood pressure was done in the standard clinical fashion and used that digital device that was able to take measurements without somebody present in the exam room. Though they were a bit lower than what I would have seen on an ambulatory monitor during the day time. And their goals were 120 systolic versus 140, whereas ours were an ambulatory systolic of 135 and 145. But the results were actually comparable because they showed a benefit with regards to lesser accrual of white matter hyperintensity volume in the intensive group versus this banner treatment group. But they also showed no differences after 3.4 years in the incidence of dementia. And they also showed in a separate study, no differences in gait speed in the population who are in intensive versus standard treatment. One would say that results were really actually comparable despite the age differences and the blood pressure measurement differences. And I think both studies really point to the fact that lower systolic blood pressures in older people should be our target because it's safer actually then than maintaining people in the 140s. Dr Carolyn Lam: Maybe the follow-up period was not long enough. Could it be possible too that maybe blood pressure control should start earlier in life. Could that be it? And then also, could you give us an idea of the kinds of changes, the magnitude of the change on MRI that you see for those of us that don't think about this all the time, is this a big change considered for your cohort or is it a little change? Dr William White: I think it's true that these people started out around 81 years old in this trial and so by the time they got to that age and had systolic hypertension for probably as many as 20 years, that some of the damage that was done was obviously permanent and we don't really know how long it took for that to accrue. What we did know is that with three years of intensive treatment, we benefited patients by reducing the continued growth or confluency of these small vessel lesions in the brain. Now the range in the amount of damage varies from about half a percent of the overall brain volume to about 5%, so a 10-fold magnitude difference in our cohort. And as a result of that, certainly somebody who's got about two to 3% of their brain occupied by better hyperintensity lesions or damage is going to have a great deal more functional disability than somebody who's .5%. I think we have to look at the outliers as well as the mean and median changes that we saw. The mean changes are not huge. The difference between 0.2 and 0.6% for example, in our protocol analysis, 0.4% to me it's clinically relevant because I know that that means that there are some people who went up by a percent or two over the years versus the standard versus the intensive treatment group. That's a big difference in an individual over that period of time. Dr Carolyn Lam: Yeah, I'd hate to think that I'm losing 1% of my brain. Dr William White: Yeah. Plus it's also where it's located because the lesions are typically around the ventricles of the brain and it's exactly where neurons are going sort of posteriorly to anteriorly to transmit information. For example, from the visual center to the sort of spatial motor cortex. And when those are interrupted, even if it's in one or 2% of the tissue, it can cause substantial difficulties for people. And it's for both the flow of cognitive information as well as this flow of a mobility and balance. I think that it is very relevant, but the gray matter is affected much less by this compared to the white matter. But there are still studies that show that gray matter sort of follows in line with that so that of course also enhances thought processes and cognitive function as well. Dr Carolyn Lam: Wow. I love the way you explained that. Very important question would of course be the safety and tolerability of this more intensive approach. Any comments there? Dr William White: Our sponsor, the National Institute of Aging did recruit a data safety monitoring board that was independent from the study for all the years. Impressively over the course of this trial, even though there wasn't a large sample, it was a 199 people, we saw a significant benefit in the intensive group for cardiovascular events, so there were less admissions for heart failure. There were less myocardial infarctions, there was less strokes. All these kinds of things that we worry about in our patients as they get older with vascular disease was reduced by about 75% in the intensive treatment arm versus the standard arm. As far as the events that we were concerned about, such as falls and syncope and presyncope and things of that nature, they were virtually identical in the intensive treatment group and `the standard treatment group. When you take that into consideration, along with the fact that you're reducing the accrual of small vessel disease in the brain, it's clear that this population, even though they're older, would benefit from a lower systolic blood pressure. Dr Carolyn Lam: Oh my goodness. Thank you so much, Dr White. That was a beautiful summary. That is the take home message right there. Listeners, I'm sure you agree with me. Thank you so much for joining us this week, and don't forget to tune in again next week. This program is copyright American Heart Association 2019.  

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and    backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Poly Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue is super exciting. It's the ESC simultaneous publication issue, isn't it? So the original papers were simultaneous publications at the European Society of Cardiology meeting this year. Dr Greg Hundley: Oh, wow. Carolyn can't wait to get to these. So Carolyn, later we're going to listen to the authors of this feature discuss the association between ICD use and all-cause mortality in a contemporary heart failure reduced ejection fraction cohort and examine relevant subgroups. So Carolyn, I'm going to get started with my first paper and it's a randomized trial of one hour, one-hour deponent T protocol and suspected acute coronary syndromes and it's a rapid assessment in emergency rooms and it's from professor Derek Chew from Flinders Medical Center. High sensitivity troponin assays promise earlier discrimination of MI, yet the benefits and harms of this improved discriminatory performance when incorporated within rapid testing protocols with respect to subsequent testing and clinical events has not been evaluated in an in-practice, patient level, randomized study. So this multicenter study evaluated the non-inferiority of a zero to one hour, zero to one-hour, high sensitivity troponin T protocol compared with a more traditional zero to three-hour mask, high sensitivity troponin T protocol in those suspected with ACS. Dr Carolyn Lam: Interesting. So what did the study show? Dr Greg Hundley: So participants in the zero to one-hour arm were more likely to be discharged from the ED quicker and that would be expected. So 45% versus the standard arm, which was 32%. Also their median ED length of stay was shorter, and we would expect that. Four and a half versus five and a half hours. Those randomized to the zero to one-hour protocol were less likely to undergo functional cardiac testing. The zero to one-hour high sensitivity troponin T protocol was not inferior to standard of care and among patients discharged from the ED, the zero to one-hour protocol had a negative predictive value of 99.6% for 30-day death or MI. So Carolyn, how about your first study? Dr Carolyn Lam: Well, from MI risk stratification to heart failure risk stratification. I'm going to tell you about a paper describing the TIMI Risk Score for heart failure in diabetes, which is a novel integer base clinical risk score for predicting hospitalization for heart failure in patients with type two diabetes. This is from Dr Mark Sabatine and the TIMI study group who developed a clinical risk score for heart failure hospitalization in more than 8,200 patients with type two diabetes in the placebo arm of saver TIMI 53, as well as externally validated this score in more than 8,500 patients with type two diabetes in the placebo arm of declare TIMI 58. They found that five clinical variables were independent risk predictors of heart failure hospitalization. These were prior heart failure, history of atrial fibrillation, coronary artery disease, estimated GFR, and urine albumin-to- creatinine ratio, a simple integer base score from zero to seven points. Using these predictors identified a more than 20 full gradient of heart failure hospitalization risk in both the derivation and validation cohorts with high SES statistics. Although the relative risk reductions with dapagliflozin were similar for patients across the risk scores, the absolute risk reductions were greater in those with higher baseline risks. Dr Greg Hundley: Wow, Carolyn. So tell us what are the clinical implications of this really thorough study? Dr Carolyn Lam: In summary, the risk score had excellent discrimination in two large clinical trial cohorts. It was well calibrated, and it identified a strong gradient of increasing absolute reduction in risk of heart failure hospitalization with the SGLT two inhibitor dapagliflozin. So by using this TIMI Risk Score for heart failure in diabetes, which is a simple validated clinical risk score, clinicians could better educate patients about their risk for heart failure hospitalizations and could perhaps better identify those patients who have a greater absolute risk reduction in heart failure risk with SGLT two inhibitors. Dr Greg Hundley: Very good, Carolyn. Well, I'm going to go back to the world of troponins and talk about a paper from Nicholas Mills from University of Edinburgh. And in this study, they evaluated the safety and effectiveness of risk stratification thresholds of high sensitivity troponin in patients with suspected acute coronary syndrome. 48,282 consecutive patients with suspected ACS were enrolled in a multicenter trial from 10 hospitals within Scotland and they're pre-specified secondary and observational analyses. They compared the performance of the limit of a detection of less than two nanograms per liter versus the optimized stratification threshold of less than five nanograms per liter using the Abbott high sensitivity troponin I assay. Patients with myocardial injury at presentation with less than two hours of symptoms or with ST segment elevation myocardial infarction were excluded and the negative predictive value was determined in all patients in subgroups for a primary outcome of MI or cardiac death within 30 days. And they had a secondary outcome that was MI or cardiac death at 12 months. Dr Carolyn Lam: Nice. So Greg, which threshold of troponin was the optimal one? Dr Greg Hundley: So the negative predictive value for the primary outcome was 99.8% and 99.9% in those with cardiac troponin I concentrations of less than five or less than two nanograms per leader respectively. At both thresholds, the negative predictive value was consistent in men and women across all age groups. Although the proportion of patients identified at low risk fell with increasing age. Compared to patients with cardiac troponin I concentrations of greater than five nanograms per liter but less than the 99th percentile, the risk of MI or cardiac death at 12 months was 77% lower in those with less than five nanograms per liter and 80% lower in those with less than two nanograms per liter. So in conclusion, use of risk stratification thresholds for high sensitivity cardiac troponin I identified patients with suspected acute coronary syndrome in at least two hours of symptoms at low risk presentation irrespective of both age and sex. Dr Carolyn Lam: Very nice. Well, more risk stratification in this next paper, which really evaluated the application of the 2018 ACC AHA Cholesterol Management Guideline recommendations for additional lipid lowering therapies in patients with established atherosclerotic cardiovascular disease and residual dyslipidemia despite maximum tolerated Statin who were enrolled in the ODYSSEY OUTCOMES trial. Now, just as a reminder, the 2018 US Cholesterol Management Guidelines recommend additional lipid lowering therapies for secondary prevention in patients with LDL above 70 or non-HDL above a hundred despite maximum tolerated Statin therapy. Such patients are considered at very high risk based on a history of more than one major atherosclerotic cardiovascular disease event or a single event and multiple high-risk conditions. So in this paper from Dr Matt Roe from Duke Clinical Research Institute and colleagues, they found that in the ODYSSEY OUTCOMES trial, patients classified as very high risk by these 2018 ACC AHA guidelines and either because of a history of multiple atherosclerotic cardiovascular events or a single event, which is a trial qualifying acute coronary syndrome and multiple high risk conditions, these very high risk patients had more than double the risk of recurrent cardiovascular events as compared to patients classified as not very high risk.  They further looked at the association of Alirocumab with outcomes and found that Alirocumab was associated with a consistent relative risk reduction in both risk categories. But the absolute risk reduction for major adverse cardiovascular events was numerically greater, although not statistically different, in the very high-risk group versus those not at very high risk and among patients at very high risks with multiple prior events versus a single prior event. Dr Greg Hundley: Wow, Carolyn. Can you put all this together? This is a lot of information in this study. Dr Carolyn Lam: Yes, so it would appear that the application of the new ACC AHA 2018 guideline recommendations for risk stratification and the use of additional lipid lowering therapies in patients with established cardiovascular disease clearly identifies patients at very high risk of recurrent cardiovascular events after an acute coronary syndrome and these patients may derive substantial benefit from additional lipid lowering therapy, for example, with a PCSK nine inhibitor. Dr Greg Hundley: Very nice, Carolyn. Well, let me just finish off with what other articles we have in this ESC featured issue of our journal. So Jonathan Stamler and John Lundberg in separate letters discuss findings related to whether hemoglobin beta 93 cystine is not required for export of nitric oxide bio activity from the red blood cell. And in additional separate letters, Doug Lewandowski and Heng-Chen Yao discuss preservation of ACL CoA and attenuation of pathological and metabolic cardiac remodeling through selective lipid trafficking. In a perspective piece, Blake Thomson from the University of Oxford discusses what Medicare for all in the United States can mean for US medical research and provides lessons from the United Kingdom. In a letter from the United States, Gregory Marcus from University of California San Francisco discusses incident atrial fibrillation among American Indians in California and then both Marco Bergonti from University of Milan and Derek Chew from University of Calgary present two separate cases in our ECG challenge feature. Well, Carolyn, what a great issue and how about we turn to our feature discussion? Dr Carolyn Lam: Yes, let's go. Thanks, Greg. Dr Greg Hundley: Welcome, everyone, to our feature discussion today we have Gianluigi Savarese from Karolinska Institute in Stockholm, Sweden and our own associate editor, Sana Al-Khatib from Duke University. We're going to be discussing implantable cardioverter defibrillators in their mortality and looking at a more recent take on this relative to some of the previous published studies. So Gianluigi, I'd like to start with you. Could you tell us a little bit about the hypothesis and why you wanted to perform your study? Dr Gianluigi Savarese: Yes. Basically we design our study based on three main considerations. First one is recent studies show that the advance in heart-failure therapies have impact patients' risk profile leading to roughly 40% reduction risk of sudden cardiac death in HFrEF and RCTs on ICD use for primary prevention of sudden cardiac death and rural patients more than 20 years ago and thus, nowadays the beneficial prognostic effects of ICD may be different due to the improved risk profile in this population. The second consideration was that efficacy of ICD patients with heart failure with non-ischemic cardiomyopathy patients receiving a contemporary heart failure therapy as being a question in Danish trial and the third consideration is that efficacy of ICD in elderly is still debated due to findings again from the Danish trial showing a significant reduction in all-cause death associated with ICD use in patients age younger versus older than 70 years old. Based on these considerations, we decided to assess the use of ICD for primary prevention propose in a contemporary and selected FRF population and to assess the association between ICD use and outcomes in such a population. Dr Greg Hundley: So it sounds like we're doing an update on the utility of ICDs. Can you tell us a little more about your study population and your study design and then let's hear a little bit about your results. Dr Gianluigi Savarese: Sure. First of all, I would like to first highlight of course the observational natural of this study. Our analysis is performed using data from the Swedish Heart Failure Registry, which is a large enough select court of heart failure patients, enrolling patients regardless of ejection fraction. So today we have roughly around 70,000 patients. And of course for the current analysis we select the patients with HFrEF. There were around 15,000 patients with the HFrEF who were eligible for ICD use for primary prevention according to the ESC guidelines. A study design, we used propensity score matching design in order to try to address the issue of potential compounders. Of course this is a very important point in observational studies. So basically, we amassed patients receiving the ICD versus those not receiving ICDs. And we assessed the association between ICD use and all-cause death and cardiovascular death and we accessed one year and five-year outcome. Dr Greg Hundley: And so what were some of those results? Dr Gianluigi Savarese: What we observed is that there was a statistically significant 25 relative risk reduction in all-cause mortality in ICD recipients versus those who didn't receive an ICD within one year and there was also a 12% reduction erased within five years. And we also serve a statistically significant 29% reduction in risk of cardiovascular mortality within one year. But we were not able to observe any association for cardiovascular mortality within five years. We thought it was particularly relevant to have subgroup analysis in our studies since there are so many questions regarding ICD use in specific subgroups, which are, for example, older versus younger patients, those with versus without ischemic heart disease, males versus the females and so on. So what we observed was that results in terms of all-cause mortality were consistent in all of the subgroups considered such as patients older versus younger than 70 years old, versus those without history of ischemic heart disease and those with versus without concurrent CRT use. Dr Greg Hundley: What about the frequency of implanting ICDs? Was the frequency expected in your results? Dr Gianluigi Savarese: We add that only 10% of our patients received an ICD at the baseline. This person's age is quite low in particular. If we compare these with other studies in US for example, or also in other European countries and basically, we can only speculate about the underuse of ICD in primary prevention propose. First of all, a certain proportion of ICD underuse may be explained by the fact that we could not assess whether life expectancy was longer than one year, and this is one of the eligibility criteria for ICD according to the guidelines. Then another point is that in Sweden, the majority of heart failure patients are seen by primary care physician and general practitioners who may have less knowledge and acceptance of device therapy and then higher perception of contraindication. In our previous analysis, we showed that patients not seen by cardiologists have lower likelihood of receiving an ICD and use of devices is higher in centers who do implants, CRT, ICD. So this may be some of the explanation that I can anticipate that some more analysis will follow where we will try to assess the predictors for an under use of ICD for primary prevention. Dr Greg Hundley: Well, thank you very much. Sana, now we're going to turn to you and help us put this study in perspective to what we have already found or observed in other prior studies related to implantation of cardio defibrillators. Dr Sana Al-Khatib: As was mentioned earlier, I was the handling associate editor for this paper, so I really enjoyed the handling it and writing an editorial on it. The main points that I wanted to touch on are number one, the significantly low or reduced utilization rate of ICDs. So as was mentioned, the 10% of this patient population received a primary prevention ICDs. Even if you account for some of the new ones is that you can't estimate life expectancy. You can't capture granular clinical data on these patients. So of course some of the non-use of ICDs may have been appropriate. I think 10% by anyone's definition is still pretty low and I'm very encouraged to hear that there are plans to look at predictors of non-use, the characteristics of those patients and hopefully the office can build on their findings and try to implement some strategies to improve the utilization of this life saving therapy. The other thing that I wanted to touch on is clearly the results are positive in favor of the implantable cardioverter defibrillator. Showing that it significantly reduces all-cause mortality within one year, within five years, certainly reduces cardiovascular mortality within one year. As was mentioned, the reduction in cardiovascular mortality within five years was not significant and to me that is probably mostly explained by competing causes of death in this patient population, but I also cannot rule out the possibility of some mis-classification of causes of death, which is not uncommon. I do want to commend the authors for the great and robust methods that they applied in their analysis. As was mentioned, this was a comparative effectiveness research using observational data. These kinds of analyses can be pretty challenging, but the authors defined their patient population very clearly. They used propensity score matching. In fact, they took it a step further by doing a negative control analysis, meaning looking at hospitalizations for renal failure, for pneumonia, respiratory infections, things like that that you don't expect to be affected by the ICD and they found no difference in that. And that is amazing to kind of see this level of analysis that I believe really lends their results more credibility. It is important though to keep in mind that when you have 10% of patients getting an ICD, I suspect that this was a highly selected patient population and most likely people who were thought to benefit the most from ICDs were implanted with an ICD. And yet, as I said, that given the robustness of the methods that they use, I actually believe the results. I think the results are credible. The one last point that I want to comment on is the subgroup analyses that were mentioned. Absolutely important subgroups to look at from a clinical perspective. But I point out the fact that when you start looking at subgroup analyses, and especially when you have a smaller sample sizes and lower event rates that it makes you start thinking about, "Well, are these results valid? Are they believable?" I mean, even honestly, in the setting of a randomized clinical trial, I look at subgroup analyses as hypothesis generating. So I liked that they included those just to kind of really emphasize the importance of looking at these subgroups. But I certainly would not put too much weight on the subgroup analysis results, but overall great results and congratulations to the authors. Dr Greg Hundley: Fantastic overview, Sana and Gianluigi. So on behalf of Carolyn Lam and myself, we wish you a great week and we look forward to speaking with you next week. Dr Carolyn Lam: This program is copyright American Heart Association 2019.  

Dr. Rob Califf is the former Commissioner of the Food & Drug Administration (FDA), founding director of the world's largest academic research organization - the Duke Clinical Research Institute, and a professor at Duke and Stanford. He is one of the top 10 most cited medical authors, with more than 1,200 publications. Dr. Califf is also a senior health advisor for Google's life sciences division, Verily. We discuss the regulation of medical technology and the challenges of regulating AI.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             I'm Greg Hundley, associated editor from the Pauley Heart Center at VCU Health Sciences in Richmond, Virginia. Dr Carolyn Lam:                A big number of acute ischemic stroke patients receiving endovascular therapy in the United States are receiving this therapy only after inter-hospital transfer. What are the temporal transient outcomes following this inter-hospital transfer? Very important discussion coming right up with our featured paper. But for now, sit back, relax with us. We're going to discuss a couple of papers that we found were interesting in this week's journal. Dr Greg Hundley:             Very good, so thanks Carolyn. I'll start off, and I'm going to talk a little bit about stress induced cardiomyopathy, and we also know it as takotsubo cardiomyopathy, looking at a paper from Dana Dawson from the University of Aberdeen in the United Kingdom. Takotsubo cardiomyopathy can result in a heart failure phenotype with a prognosis comparable to myocardial infarction.                                                 In this study, the investigators hypothesize that inflammation is central to the pathophysiology in natural history of takotsubo cardiomyopathy. They prospectively recruited 55 patients with takotsubo cardiomyopathy, and 51 age, sex, and comorbidity match control subjects.                                                 During the index event, and at five months of follow-up, the patients with takotsubo cardiomyopathy underwent a cardiac MRI study in which they looked at ultra-small, super paramagnetic particles of iron oxide, or USPIOs, enhancement for detection of inflammatory macrophages in the myocardium. What would the studies show? Patients with acute takotsubo cardiomyopathy had macrophage-mediated myocardial inflammation.                                                 They also demonstrated modulation of peripheral monocyte subsets and increased systemic pro-inflammatory cytokines. This systemic inflammation persisted for five months, and then at that five-month time point, the cardiac MRI evidence of the macrophage presence was diminished. Dr Carolyn Lam:                Wow, Greg. So this is right up your wheelhouse, isn't it? Can you explain? What are the clinical implications of these MRI findings? Dr Greg Hundley:             It was really interesting. For the first time, they've linked an ongoing inflammatory process using the USPIO contrast agent with MRI actually going on or operative in the heart, and they associate that with systemic markers in the circulation.                                                 They help us elucidate the mechanisms and the pathogenesis of takotsubo cardiomyopathy, and systemic and myocardial inflammation really may start to now serve as a therapeutic target for patients with acute takotsubo cardiomyopathy. Dr Carolyn Lam:                Very interesting. From stress-induced cardiomyopathy to early onset myocardial infarction. The first paper I chose really answers the question, "What is the relative prevalence and clinical importance of monogenic mutations, that is, a single mutation that significantly increases risk, versus a polygenic score, which really measures the cumulative impact of many common variants, in early onset myocardial infarction?"                                                 The co-corresponding authors were Doctor Amit Khera and Sekar Kathiresan and both from Massachusetts General Hospital, and they performed deep coverage, whole genome sequencing of more than 2,000 patients from four racial subgroups hospitalized in the United States with early onset myocardial infarction defined as myocardial infarction before the age of 55 years, and compared this to 3,761 population base controls.                                                 What they found was that a monogenic mutation related to familial hypercholesterolemia was identified in 1.7% of the patients, and associated with a 3.8-fold increased odd of myocardial infarction. In comparison, the high polygenic score, which was composed of 6.6 million common DNA variants and defined as the top 5% of the control population distribution, now, that was identified in 10 times as many patients, so 17% of patients, and associated with a similar 3.7-fold increased odds of myocardial infarction. Dr Greg Hundley:             Interesting. How do we apply this clinically, Carolyn? Dr Carolyn Lam:                These findings really lay the scientific foundation for the systematic identification of individuals born with a substantially increased risk of myocardial infarction. The important point is both familial hypercholesterol mutations and a high polygenic score are associated with more than three-fold increased odds of an early onset myocardial infarction.                                                 However, the high polygenic score cannot be reliably identified on the basis of elevated LDL cholesterol, and yet has a 10-fold higher prevalence among patients presenting with early onset myocardial infarction. So very intriguing that both groups matter. Dr Greg Hundley:             Very good. My next paper is from Adrian Hobbs at the London School of Medicine, and is looking at the role of endothelial C type natriuretic peptide as a critical regulator of angiogenesis and vascular remodeling. We know that a central pathway coordinating both neovascularization and ischemic extremities in PAD is driven by vascular endothelial growth factor or VEGF-A4.                                                 But preclinical studies and other large scale clinical trials have been disappointing because administering or using VEGF-A to promote angiogenesis or arteriogenesis in PAD really hasn't occurred. This group focused on endothelial-derived CMP. Why? Because it plays a fundamental role in regulating vascular homeostasis. It controls local blood flow and the resistance vasculature, and systemic blood pressure, and reduces the reactivity of leukocytes and platelets.                                                 So, what were the results? Clinical vascular ischemia was associated with reduced levels of CMP and it's cognate NPR-C. Moreover, genetic and pharmacological inhibition of CNP and NPR-C reduced the angiogenic potential of the pulmonary microvascular endothelial cells and the human umbilical vein endothelial, and it isolated vessels ex vivo.                                                 So, the study really defines a central pathophysiological role for endothelium-derived C type natriuretic peptide via activation of cognate natriuretic peptide receptor C in angiogenesis and in vascular remodeling. Moreover, the work demonstrates the therapeutic utility of pharmacologically targeting NPR-C to restore deficits in these processes following ischemia and injury. Dr Carolyn Lam:                Interesting, from new mechanisms and targets to good, old, major risk factors for coronary heart disease. Back to the basics but in a really, I think, nicely done paper from Dr Pencina and colleagues from Duke Clinical Research Institute.                                                 Now, their objective in this next paper was to compare the associations of key, modifiable coronary heart disease risk factors with incident coronary heart disease events based on their prognostic performance, the attributable risk fractions and treatment benefits overall and by age.                                                 And so really aiming at quantifying the importance of these major, modifiable risk factors for coronary heart disease. What they did is they used pool participant level data from four observational cohort studies sponsored by the NHLBI, and they created a cohort of more than 22,600 individuals ages 45 to 84 years old who are initially free of cardiovascular disease.                                                 And these individuals were followed for 10 years from baseline evaluation and followed for incident coronary heart disease. They estimated that age, sex and race captured up to 80% of the prognostic performance of cardiovascular risk models. When we add either systolic blood pressure or non-HDL cholesterol, diabetes or smoking to model with the other risk factors, the prognostic performance, as measured by the C index, increased by only 0.004 to 0.013.                                                 However, if you look at it from the attributable risk and absolute risk reduction standpoint, lowering the systolic blood pressure of all individuals to less than 130, or lowering LDL cholesterol by 30% would be expected to lower a baseline, 10-year coronary heart disease risk of 10% to 7% and 8% respectively. Dr Greg Hundley:             That's a lot of data, Carolyn. Help me synthesize all that. Dr Carolyn Lam:                This is a take-home message. Although the individual modifiable risk factors contribute only modestly to the overall model prognostic performance, when we eliminate or control these risk factors, they would actually lead to a substantial reduction in total population coronary heart disease.                                                 That's because if we look at the attributable fraction and the absolute risk reductions, we see that they actually really matter. The take-home message too from Dr Pencina was that metrics used to judge the importance of these risk factors should therefore be tailored to the question being asked. Dr Greg Hundley:             Very good. That was a very nice summary, Carolyn. Dr Carolyn Lam:                Thanks. Let's move on now to our feature discussion, shall we? Dr Greg Hundley:             Very good. Dr Carolyn Lam:                Trials have established that endovascular thrombectomy dramatically reduces disability after acute ischemic stroke due to intracranial large vessel occlusion. In fact, guidelines almost immediately adopted endovascular thrombectomy as a standard of care. However, that has created some problems.                                                 The main one being that hospitals equipped to carry out this procedure are largely limited to tertiary centers in urban areas. This is, of course, important because that means that patients may need to be transferred from another center to receive such treatment.                                                 Today's feature paper discusses this very issue, a terribly important one, and I'm so pleased to have the author with us, Dr Shreyansh Shah from Duke University Medical Center. We have our editorialist, Dr James Grotta who's director of the Mobile Stroke Unit project at Memorial Herman Hospital.                                                 And we have an associate editor, Dr Graeme Hankey from University of Western Australia. So, such an important topic. I think Shrey, could you just jump right in and tell us what your study showed. Dr Shreyansh Shah:         I'm very excited to present findings of our study, and as a Carolyn mentioned, this study is going to have a very important implication in our country here in US on the creation of systems of stroke. I think the findings are already applicable to other countries also where we are seeing endovascular care getting more and more used.                                                 As Carolyn was talking, endovascular treatment is very important and lifesaving measure. But unfortunately, it is not available at every hospital. Patients are often transferred across different hospital or institution before they can receive this endovascular care.                                                 What we did in our project was we looked at the data from the hospital that's participating in Get With The Guidelines®® Stroke, which is a quality improvement program here in US. It looked at the endovascular thrombectomy used especially in relation to inter-hospital transfer.                                                 What we found was big proportion of patients receiving endovascular care, up to about 43% to 45% of patients, were getting the care after transferring across different hospital. The outcomes in this patient were worse compared to the patient who were receiving endovascular care if they had come directly to the hospital.                                                 While there was no difference in mortality between these two groups, the endovascular care, after inter-hospital transfer, resulted in a higher rate of symptomatic ICH, patients are less likely to be discharged to home, which is the preferred outcome. And patient was also less likely to be able to ambulate independently prior to the hospital discharge.                                                 There was also delay in endovascular care initiation for patient who received this after inter-hospital transfer. I think this particular study highlights the magnitude of this problem, and that's why it's going to be important for people who are studying systems of care. The fact that about 45% of patient had to get inter-hospital transfer before endovascular care tells us that we still need to take significant steps in increasing access to this lifesaving therapy. Dr Carolyn Lam:                Thank you and indeed James, I really love the editorial you wrote that accompanied this. I mean you highlighted its importance, and you also noted that what was unusual about the paper was that even after controlling for the delay in initiating endovascular thrombectomy, there was still worse outcomes in the patients who were transferred. Could you share some thoughts? Dr James Grotta:              It is a very timely issue. Now that we have a very effective treatment, the big challenge we have is getting it to the patients as fast as possible. Right now, our system, as is pointed out, means shuffling patients from one hospital to another.                                                 I think that clearly with stroke treatment, any sort of stroke treatment, the faster we deliver it, the better. Other studies have shown that transferring patients is associated with a delay of treatment, and this study showed the same thing.                                                 There was a substantial delay in getting the patients treated if they required a transfer. And as you pointed out, however, this did not explain the entire or was not at least the entire explanation for the worst outcome. So, it is a little bit of a mystery.                                                 I do know from personal experience that transferring patients from hospital to hospital, it's not exactly a black hole, but you lose control of the patient when they're being transferred. These are patients who have large artery occlusions. That means they have their middle cerebral artery is blocked.                                                 And so, the area of brain that's affected is in a very tenuous shape. So, any drop-in oxygen concentration from breathing problems or of any drop-in blood pressure might further worsen the stroke. So, this could happen in transit. So, it's possible that in the process of transfer, these sorts of things happen.                                                 I do think that we do have to be a little bit careful in that by remembering that this was not a randomized comparison, so patients that were treated directly and those that were transferred were not randomized. And so, although they appear to be balanced in a lot of the important variables like their stroke severity, there may be other things that we can't account for that could explain some of the worst outcomes.                                                 I'd like to ask Dr Shah whether he identified any things in ... well, he and his co-authors think might have contributed to some of the worst outcomes.  Dr Shreyansh Shah:        To answer Dr Grotta's question about what other factors may have played a role in the worst outcome that we saw in patients who were getting inter-hospital transfer, I think as we correctly pointed out, transferring this very sick patient is very tricky. As we know, the hemodynamic instability or variability plays an important role in outcomes of stroke patient.                                                 And it is very likely that during the transfer process, there is not adequate control of their blood pressure variability, their oxygen saturation, and this ends up affecting their brain leading to worst outcome. The other possibilities also, as Dr Grotta was explaining, this is not a randomized control trial.                                                 And although we balance for number of important factors that can affect stroke outcome, there might be a selection bias in transferring patient who are more sicker and also patients who received thrombolysis with TPA but did not improve, while the patient who were directly arriving to the hospitals and getting endovascular care, they received the TPA.                                                 It is possible that they started to improve and still received a thrombectomy at the same time. So that group may have been more favorable in that respect, which could have also played a role in better outcomes with patient who are directly arriving. Dr Carolyn Lam:                Interesting. And, you know, with the mention of TPA, I really have to bring James back. I loved your mention about potential solution using mobile stroke units. And since you direct one of them, could you tell us what you meant there? Dr James Grotta:              Yes, of course, I have to state at the outset that I have a little bit of a bias about mobile strokes, and so I do it every day. What a mobile stroke unit is, for those who don't know, it's basically taking the emergency department to the patient.                                                 It's an ambulance with a CT scanner on board and the ability to treat with TPA in the field. But in addition, it's also the CT scanner. We can do CT angio and identify large vessel occlusions on the mobile stroke unit, not to mention the fact that you have a vascular neurologist either in-person or by telemedicine examining the patient.                                                 So clinically, you can make the determination also much more accurately than any sort of pre-hospital stroke scale, whether the patient has a large artery occlusion. That way, you don't have to take the patient to the nearest hospital. You can bypass the nearest hospital, take them right to the thrombectomy center, therefore, avoiding the transfer process.                                                 We've been implementing this in Houston, and there are now about 30 mobile stroke units around the world. The innovation actually started in Germany by Dr Fassbender about a decade ago in Hamburg, Germany. We are conducting a randomized trial, comparing mobile stroke unit care to standard management to see how much better outcomes occur as a result of this faster treatment.                                                 We obviously can treat patients with TPA faster. For example, a similar study from the Get With The Guidelines® a few years ago showed that only 1% of patients treated with TPA in emergency departments get treated within the first hour after symptom onset simply because it takes an hour in the emergency room itself to do the evaluation of the patient and get them treated.                                                 Whereas on our mobile stroke unit, at least a third and probably 40% of the patients we're treating with TPA, we can get treated within that first hour where there may be an exponential better benefit. But we don't yet know really how much that translates to better benefit, and also, of course, mobile stroke units are more intensive in terms of the amount of facilities on board and costs.                                                 So, we need to look at the cost-effectiveness. If it produces only a marginal reduction in disability but costs a fortune, then it's not worth it. But in fact, in our experience, it's pretty practical. We can cover almost the entire City of Houston, which is the fourth largest city in the country, with one mobile stroke unit. When it's well-integrated, it requires careful integration with the fire department and other hospitals in the city.  Dr Shreyansh Shah:        At those two conferences, I came across a very interesting talk from Dr Grotta's group about rendezvous with the EMS which allows extending their coverage area significantly. I think we definitely need more and more innovative solutions like this where we can identify patients by their origin, whether they have large vessel occlusion or not, and then triage them appropriately at the centers that can perform endovascular therapy. So as a result, we can provide them earlier therapy and hopefully, it will lead to better outcome. Dr Carolyn Lam:                Thank you Shrey and James for these incredible insights. Now, Graeme, I want you to have the last word and reflections from down under. Dr Graeme Hankey:        Firstly, just to congratulate Dr Shrey and colleagues on this terrific study that reports a contemporary United States experience, a very broad one across the country, really highlighting how since 2012, until a year ago, there's been a six-fold increase in the number of patients being transferred for endovascular therapy.                                                 And we're all experiencing that around the world. And moreover, since the DAWN trial and the DEFUSE trial were published just over a year ago, which is when this study stopped, there's been an expansion of the window from six hours out to 24 hours.                                                 So, in the last year, which this study doesn't cover, we've seen an exponential increase in the number of people being transferred from rural and remote areas who have had a stroke up to 24 hours ago being considered for endovascular therapy if their CT angiogram at the base hospital shows a large vessel occlusion.                                                 This is likely to be not only internally valid, but externally valid to all of us around the world. It reflects our experience of this avalanche of cases coming. And it's provided a lot of challenges for those who are trying to deliver the service at the tertiary referral center.                                                 And it highlights that nearly half of the cases who are having endovascular therapy are coming from external sites. As Jim has really highlighted in his editorial, it challenges us to reassess the current practice of inter-hospital transfer. Dr Carolyn Lam:                Thank you so much for publishing this paper with us and the editorial. And listeners, don't forget to tune in again next week. This program is copyright American Heart Association, 2019.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and it's editors. We're your co-hosts. I'm Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, also Associate Editor from the Pauley Heart Center in Richmond, Virginia, VCU Health Sciences. Dr Carolyn Lam:                How well are we doing with guideline-directed stroke prevention therapy in atrial fibrillation? Well, there are going to be very important results that you need to hear about from Get With the Guidelines Atrial Fibrillation. That's our feature paper coming right up in a future discussion. But first, you've got Greg and I discussing really important papers that we've spotted in The Journal. Greg. Dr Greg Hundley:             Absolutely, Carolyn. And my favorite kind of follows from that 'cause it's really about left atrial electromechanical remodeling following two years of high intensity exercise training in sedentary middle-aged adults, kind of like me. The studies from Ben Levine at University of Texas Southwestern Medical Center in Dallas. So, what he's driving at here are moderate-intensity exercises associated with a decrease in incidents of atrial fibrillation. However, extensive training in competitive athletes is associated with an increased atrial fibrillation risk.                                                 So, in this study, they're looking at the effects of 24 months of high-intensity exercise training on left atrial mechanical as well as electrical remodeling in sedentary, healthy, middle-aged adults. So, he had 61 individuals, their average age was 53.5 years, quite young, who were randomized to 10 months of exercise training followed by 14 months of maintenance exercise and some stretching or stretching and balance control. He also had another group of 14 master's athletes that were added for a comparison and he looked at three of the echocardiograms to assess left atrial and left ventricular volumes and also had signal average EKG's for filtered P-wave durations and atrial light potentials. He made assessments at baseline, so before everyone started, and 10 and 24 months. Dr Carolyn Lam:                Hold on, hold on. Let's really understand here how much exercise were these sedentary middle-aged adults subjected to. Dr Greg Hundley:             So, let's talk about that because that was very interesting because a lot of us are out there exercising. So briefly the way he started this, there was an initial phase that was comprised of six months of regressive training during which an increase in the frequency, the duration, and the intensity of exercise, including two high-intensity aerobic interval sessions per week that were prescribed to peak training load. The peak training load included five to six hours of exercise per week that included two interval sessions, at least one being an hour-long session, and then two 30-minute sessions.                                                 Once you got that peak training load, that was sustained for four months and then he made these 10-month measurements as part of his study design. Now following that phase, a 14-month sort of a continuation, all of the 24 months, a 14-month period of maintenance exercise was completed where the frequency of high-intensity intervals was reduced to once per week plus continuous training all the way to that 24-month time point. And during the maintenance phase, participants performed a total of about three hours a week of aerobic exercise. Dr Carolyn Lam:                Well, don't keep us in suspense now. What did the study show? Dr Greg Hundley:             So at the 24 month time point of high-intensity exercise, it led to a disproportionate dilation of the left atrium compared to the left ventricle. So, mechanical changes, but no electrical remodeling was seen. And interesting, and remember he had that comparison cohort with master's athletes. Those participants randomized exercise training demonstrated lower absolute left atrial and left ventricular volumes, but a similar left atrial to left ventricular ratio after 24 months of exercise training.                                                 So, what's going on here, if you're middle-aged or young, some of us like to think, and you start one of these aggressive training sessions, you do have some changes mechanically in the shaping of your left atrium and left ventricle, but they're concordant, but no electrical remodeling that was observed in this situation. So, how do those elite athletes develop atrial fibrillation in the electrical remodeling? Don't know. It may be they need a longer duration of exercise. Maybe they start at a different time point because these are relatively sedentary individuals, and maybe their training regimen is very different.                                                 So, more research is needed, but it was interesting that these middle-aged folks that start with this little bit more aggressive regimen really didn't develop the electrical remodeling. So, Carolyn, you've got a couple of papers that are sort of tied together. Dr Carolyn Lam:                Indeed. A couple of papers centered on lipoprotein little A. Now, we know that lipoprotein little A levels predict the risk of myocardial infarction and this has been shown in populations of European ancestry, however there's very little data available in other ethnic groups. And so, this was addressed by Dr Paré from McMaster University and the Interheart Investigators who looked at more than 6000 cases of first myocardial infarction and more than 6800 controls, all from the Interheart study, and were stratified by ethnicity and included African, American, Chinese, European, Latin American, South Asian, and Southeast Asian ancestries.                                                 Lipoprotein little A concentration was measured in each participant, first using an SA that was insensitive to iso-form size and then iso-form size itself was also assessed by Western Blot in a subset of more than 4200 participants. So, what they found was that lipoprotein little A concentration and iso-form size varied markedly among the ethnic groups. Africans had the highest concentrations with the smallest iso-form size whereas Chinese had the lowest concentrations with the largest iso-form size.                                                 Furthermore, higher lipoprotein little A concentrations were associated with an increased risk of myocardial infarction and carried an especially high population burden in South Asians and Latin Americans. And a high concentration above 15 milligrams per deciliter was associated with significantly increased risk of myocardial infarction in all populations except Arabs and Africans. The iso-form size, on the other hand, was inversely associated with lipoprotein little A concentrations and did not significantly contribute to the risk. Dr Greg Hundley:             So, Carolyn, how do we use this clinically? I mean, do we measure this in folks? Dr Carolyn Lam:                Yeah. So, there are two take-home messages. I think one is about the monitoring or measuring and it supports a clinical use of the actual lipoprotein A concentration rather than iso-form size as a marker of myocardial infarction in this ethnically diverse population. But this is, other than Africans and Arabs where, remember that cut off did not seem to associate with a risk of MI's in these two ethnicities. The second take-home is that the effects of clinical interventions that reduce lipoprotein A should be investigated especially in South Asians and Latin Americans where the population attributable risk is really high. And that actually brings me to the second study.                                                 So, we've always been looking for intervention that can reduce lipoprotein A and this current paper is really interesting 'cause it talks about insights from the Fourier trial. So, we may finally have a therapy that can reduce it. Dr O'Donoghue from the TIMI study group and Brigham and Women's Hospital in Boston, Massachusetts and colleagues looked at the relationship between lipoprotein A levels, PCSK9 inhibition, and cardiovascular risk in the Fourier trial, which you remember is a randomized trial of Evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease.                                                 So, they found that patients with a higher concentration of lipoprotein little A were at increased risk of coronary events independent of the LDL concentration. And individuals with a higher baseline LP little A concentration tended to have a greater relative and absolute coronary risk reduction with Evolocumab and therefore a lower number needed to treat. It was as low as four T for individuals with a lipoprotein A above the median versus 105 number needed to treat for those at or below a lipoprotein A level below the median. Dr Greg Hundley:             So should we start checking this in all our patients now, these lipoprotein little A levels? Dr Carolyn Lam:                Yeah. So, this issue was discussed beautifully in a company editorial by Dr Thanassoulis from McGill University Health Center. And here he mentions that there remains tremendous clinical inertia honestly for the measurement of lipoprotein A in North America and in fact, worldwide. For this to be successful, we really need to be proactively screening our patients with myocardial infarction and stroke and especially those with premature events or a family history. And particular attention will need to be made on screening individuals with recurrent events despite adequate lipid or LDL lowering who frequently may still have high lipoprotein little A. It's encouraging to know that the most recent version of the US Lipid Guidelines has newly recommended LP little A measurements in select individuals as a risk enhancer and so this should further raise awareness of lipoprotein little A as a risk marker.                                                 Finally, the editorialist mentioned that common misconception that we have a lack of therapeutic options to lower high LP little A. Still, we need to remember that these individuals may obtain significant benefit from more aggressive lifestyle modifications. And now we have these results of this trial that suggest that PCSK9 may be one of the few drugs that can lower lipoprotein little A. And so, the editorialist actually ended with targeting therapy for lipoprotein A is around the corner and a test of this hypothesis is really imminent, so we should watch this space. Dr Greg Hundley:             Yeah, so it sounds like another wonderment of PCSK9 inhibitors. Dr Carolyn Lam:                Yeah. Dr Greg Hundley:             Well Carolyn, let me jump in and finish our chat here talking about iron. This particular paper is from Dr Jean-Sébastien Silvestre from Paris, France, and he's looking at the iron regulator Hepcidin. So, we know that iron deficiency is frequent in patients with coronary artery disease and increases morbidity in those with high risk profiles such as those with diabetes and anemia and then conversely, excess iron is also detrimental to cardiac function. We see this with iron overload cardiomyopathies and as a major co-morbidity in patients with genetic hemochromatosis.                                                 So, among the multiple regulators of iron homeostasis is Hepcidin. It plays an instrumental role in fine-tuning systemic iron trafficking by modulating the transfer of dietary, recycled, and stored iron from intracellular compartments to extracellular fluids. Hepcidin is a catatonic peptide hormone. It's produced primarily by hepatocytes, but also, it's produced in macrophages. So, given the role of Hepcidin to locally regulate cardiac function and that inflammation guides cardiac remodeling after acute MI, the investigators hypothesized that inflammatory macrophages may control cardiac repair through a Hepcidin-dependent mechanism. And until now, the role of Hepcidin in some other cardiac diseases challenged by inflammation hasn't really been explored. Dr Carolyn Lam:                Huh, interesting. So, what did they find? Dr Greg Hundley:             Great question and let's lead to the main results of this study. The hormone Hepcidin, they found, was produced by a distinct sub-population of inflammatory cardiac macrophages residing in infarcted heart tissue and the deletion of Hepcidin in macrophages improved tissue remodeling and stimulated cardiomyocyte renewal in both, just as our wonderful basic science studies have, in both adult mice with myocardial infarction, neonatal animals with apical resection and also in human subjects. And so, this study provided novel insights into the complex roles of the immune response during cardiac repair following MI and suggests and deleterious role for the macrophage-derived Hepcidin in cardiac repair.                                                 Interesting, Carolyn. Another role for iron in acute MI and more research to come. Dr Carolyn Lam:                Indeed. Well, thanks Greg. Let's move on to our feature discussion, shall we?                                                 For our feature discussion today, we are talking about the first results from the Get With the Guidelines atrial fibrillation. That is huge, and I have none other than the first author, Dr Jonathan Piccini from Duke Clinical Research Institute, as well as Dr William Lewis from Case Western Reserve University here to discuss these really important results, so listen up. I think to start with it is such an honor to have you with us, Bill. I mean, as Chair of the Get With the Guidelines atrial fibrillation work group, could you give us a background on how did this start? How far has it come? Dr William Lewis:             The Get With the Guidelines program started in 2000. Greg Fonarow figured out that if we put in place mechanisms to improve adherence, that we could get people on appropriate therapies. In 2012, there was some focus on atrial fibrillation and I had been participating in the program since 2004 and I kept telling them that A-fib was a big, big problem. And in 2012, they said, "Let's do this," so we built this program to try to improve adherence in atrial fibrillation. Get With the Guidelines is a national, hospital-based, quality improvement program that improves adherence to guidelines over time and it has been very successful at doing that.                                                 So, by 2013 we were ready to start enrolling patients and we started getting patients in the database and we're now up to about 162 hospitals nationwide, in the United States, and we've enrolled about 75000 patients in the program. So, it's been very successful from that standpoint. Dr Carolyn Lam:                Congratulation. And today we're actually going to be talking about that very question you asked. Adherence. How well are we adhering to guideline-directed stroke prevention therapy for atrial fibrillation? Jonathan, wanna share the key results? Dr Jonathan Piccini:         I think you're getting exactly to the point of what was the rationale for this study and I think most individuals that are familiar with the field and atrial fibrillation and also clinicians across the world who are treating patients with atrial fibrillation know that most large reports, most nationwide studies have shown that adherence for oral anticoagulation to prevent stroke in patients with atrial fibrillation usually ranges in the 50, 60, 70 percent range at best. And there's been some notable publications in the past several years from nationwide registries that have shown rates as low as 50 percent or lower in high-risk patients. So, one of the main goals of the program, as Bill articulated, was to try and improve the use of oral anticoagulation in patients who had a guideline recommendation. So, patients who had a CHA2DS2-VASc score of two and higher with atrial fibrillation.                                                 And so, looking at over 30000 admissions between 2013 and 2017 and the guidelines A-fib program, we saw that just under 60 percent of patients who had known AF at the time of admission were on oral anticoagulation. And not surprisingly, the patients who were on oral anticoagulation had lower rates of stroke during their hospitalization. But the major finding from the program was that in this quality improvement program, the program was able to improve adherence to oral anticoagulation at discharge from 60 percent to admission all the way up to 93.5 percent in the overall cohort. And if you looked at results over time, adherence improved from 80 percent at discharge all the way to 96 percent and those improvements were sustained in follow up as well. Dr Carolyn Lam:                Could you tell us, what do you think are the key elements that help this improvement? Is it just because there's a program and people know they're being watched? Is it that there was a change? I mean, when you say oral anticoagulants I bet you mean both Warfarin and the newer oral anticoagulants, so how much did that help? What do you think is the key ingredient here? Dr Jonathan Piccini:         It was several things. Having visited several of these hospitals and spoken with them about the impact of the program, I think you can't emphasize enough that if you don't measure something, you can't really expect to improve it. So, just the fact that hospitals were having systematic data on their atrial fibrillation patients at discharge illustrating who was and who was not getting oral anticoagulation makes a big difference. Between the program itself and the conferences affiliated with the program and teaching sessions affiliated with the program, there's a heavy emphasis on education of the importance of guideline recommended treatments for atrial fibrillation, so that's a second component.                                                 And then there's an iterative relationship between the sites and the American Heart Association where improvements in the rates of oral anticoagulation are recognized and celebrated. And I think it's not any one thing, in my opinion. I think it's all of those things taken together. And again, Bill, who's been with the program since its inception probably has additional thoughts on that as well. Dr Carolyn Lam:                Bill, did you expect such remarkable results? Dr William Lewis:             No. I actually didn't expect 96, but in a previous study where we were looking at patients who had had a stroke in the stroke database, we were able to achieve 93 percent adherence. And so, 96 is remarkable and it's the highest number that's ever been seen in any A-fib program. I was going to mention about the idea of what makes the special sauce, if you will, and I think John put forth a number of items. I think, again, celebrating success, those kinds of things, but I think that docs, by their very nature, are very competitive and when you get a data report that says you're doing x percent and somebody else is doing y percent and their percentage is higher, you tend to get motivated to actually do better. And so, we provide these reports in the program to hospitals so that they can measure their success against other institutions. Dr Carolyn Lam:                That's such a good idea. And, you know, I practice here in Asia and there aren't these very massive programs that are accepted in many places. So, what do you think is the generalizability of something like this? Dr Jonathan Piccini:         That's such a critical question because a limitation is that these are hospitals that are saying voluntarily, "We want to commit to the program because we think quality care for atrial fibrillation patients is important." And so, you could argue that, well, these results really don't generalize to your run of the mill hospital in different parts of the world. And I think while that's a limitation, it's also a call for what the next steps are. So, having visited many of these hospitals, these are real hospitals of brick and mortar that face many of the same challenges other health systems and hospitals across the world do and I think the key message is that a hospital that implements these types of interventions is very likely to see the same improvement with their patients. And so, I think that's a very important message and a very positive message for patients all over the US and all over the world. Dr William Lewis:             I agree. I think it's, not turn-key, it's much more generalizable than we had ever expected. So, community hospitals do this. The American Heart Association is using other Get With the Guidelines programs in China. I think that there is a lot that has to do with the support that's provided by the program and the tools that are made available to them to be able to make it so that you can recreate it in a hospital. I agree, it is more difficult in some hospitals than others. Dr Carolyn Lam:                John, before we end, what are the take-home messages for clinicians listening out there? Dr Jonathan Piccini:         I'd have two messages. The first message is that this study shows that with some assistance any healthcare system or hospital can achieve optimal adherence to these medications for their patients and thus in so doing achieve a significant benefit for the public health. And the second message I would have, which isn't necessarily specifically related to the paper, but I think it's equally important, that this is just the beginning for the American Heart Association and the Heart Rhythm Society Get With the Guidelines A-fib registry. Though stroke prevention is obviously just one of many different aspects of quality care for atrial fibrillation and so keep an eye out 'cause you'll be seeing a lot of studies coming out about how Get With the Guidelines A-fib is better informing care and treatment for atrial fibrillation across many different therapy domains, including catheter ablation and rate control and other interventions for rhythm control. And again, on behalf of all the co-authors and the American Heart Association, the Heart Rhythm Society sponsors, we really appreciate to have the opportunity to talk about the program. Dr Carolyn Lam:                Thank you so much for sharing that with us.                                                 Audience, you heard it right here on Circulation on the Run. Don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019.  

Transformation and Change is critical in order to succeed in the current landscape of continuing education. All of us as CE providers are required to think “Out of the Box” and innovate, create solutions that are highly impactful and can be sustained. This session will discuss innovative ways in which providers can think creatively to design, develop and deliver CE programs that achieve the goals and expectations. Strategies and tactics that align the CE unit within an organization to the overall QI goals of the system will be discussed. Case studies and success stories will also be shared.Chitra Subramaniam, Ph.D, Asst. Dean and Director, Continuing Medical Education, Asst Director, Center for Educational Excellence, Duke Clinical Research Institute

Transformation and Change is critical in order to succeed in the current landscape of continuing education. All of us as CE providers are required to think “Out of the Box” and innovate, create solutions that are highly impactful and can be sustained. This session will discuss innovative ways in which providers can think creatively to design, develop and deliver CE programs that achieve the goals and expectations. Strategies and tactics that align the CE unit within an organization to the overall QI goals of the system will be discussed. Case studies and success stories will also be shared.Chitra Subramaniam, Ph.D, Asst. Dean and Director, Continuing Medical Education, Asst Director, Center for Educational Excellence, Duke Clinical Research Institute

This is one of my favorite guests, Anang Chokshi, DPT and Chief Clinical Officer at Reflexion Health (bio - http://reflexionhealth.com/anang-chokshi ) Rob and Anang discussed the recently released 2 year study from Reflexion Health and Duke Clinical Research Institute (found here - http://reflexionhealth.com/virtual-physical-therapy-news/veritas-study-results-announcement ) as well as many upcoming topics about the future of Telehealth and medicine and PT. This one goes deep on specific topics in the 47-minute episode! Looking forward to having Anang back in the future to discuss a variety of recent trends and topics. Happy Thanksgiving! Video of this podcast can be found on YouTube at: https://youtu.be/KFM4auG0Xwo *Intro music from @rodgmusic *Episode music from @home-2001

This is an episode featuring Dr Paul Wischmeyer (@Paul_wischmeyer) who is a doctor at the Department of Anesthesiology and Duke Clinical Research Institute, Duke University Medical Center. I noticed he had tweeted about a presentation (Surviving the ICU-The Patient Experience: What Patients Need Their Doctors to Know) he gave which was available on YouTube and […]

This is an episode featuring Dr Paul Wischmeyer (@Paul_wischmeyer) who is a doctor at the Department of Anesthesiology and Duke Clinical Research Institute, Duke University Medical Center. I noticed he had tweeted about a presentation (Surviving the ICU-The Patient Experience: What Patients Need Their Doctors to Know) he gave which was available on YouTube and […] The post CCP Podcast 059: Surviving the ICU-The Patient Experience appeared first on Critical Care Practitioner.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. Will artificial intelligence replace the human echocardiographer? Aha, well to find out the answer, you have to wait for the incredibly exciting discussion of today's feature paper coming right up after these summaries.                                                 The clinical benefits of the cholesterol ester transfer protein, or CETP inhibitor dalcetrapib depends on adenylate cyclase type 9, or ADCY9 genotype. However, what are the underlying mechanism responsible for the interactions between ADCY9 and CETP activity? In the first paper from today's journal first author Dr Rautureau, corresponding author Dr Tardif from Montreal Heart Institute, and colleagues used a mouse atherosclerosis model inactivated for ADCY9 and demonstrated that loss of ADCY9 protected from atherosclerosis and was associated with improved endothelial function, but only in the absence of CETP. ADCY9 in activation increased weight gain, adipose tissue volume, and feed efficiency, but only in the absence of CETP.                                                 This mouse model reproduced the interactions between ADCY9 and CETP activity observed in patients, and offers new mechanistic insights for the importance of ADCY9 in determining the responses to CETP inhibition. For example, the dal-GenE clinical trial is currently testing prospectively whether patients with coronary disease and the favorable ADCY9 genotype will benefit from dalcetrapib.                                                 The next study addresses the controversy around the cardioprotective effects of Omega-3 polyunsaturated fatty acids, and uncovers signaling pathways associated with eicosapentaenoic acid, or EPA supplementation that may mediate protective effects in atherosclerosis. First author Dr Laguna-Fernandez, corresponding author Dr Bäck from Karolinska Institute, and their colleagues showed that EPA supplementation significantly attenuated atherosclerotic lesion growth. They performed a systematic plasma lipidomic analysis and identified that 18 monohydroxy eicosapentaenoic acid was a central molecule formed during EPA supplementation. 18 monohydroxy eicosapentaenoic acid was a precursor for the plural resolving lipid mediator called resolvent E1.                                                 In the present study, a resolve in E1 was shown to regulate critical atherosclerosis related functions in macrophages through its downstream signaling receptor to transfuse protective effects in atherosclerosis.                                                 Are there racial differences and long-term outcomes among survivors of in-hospital cardiac arrest? In the next paper first and corresponding officer Dr Chen from University of Michigan and her colleagues performed a longitudinal study of patients more than 65 years of age who had an in-hospital cardiac arrest and survived until hospital discharge between 2000 and 2011 from the National Get With The Guidelines Resuscitation Registry whose data could be linked to Medicare claims data. They found that compared with white survivors of in-hospital cardiac arrest, black survivors had a more than 10% lower absolute rate of long-term survival after hospital discharge. This translated to a 28% lower relative likelihood of living to one year, and a 33% lower relative likelihood of living to five years after hospital discharge for black versus white survivors.                                                 Nearly one-third of the racial difference in one-year survival was dependent on measured patient factors. Only a small proportion was explained by racial differences in hospital care, and approximately one-half was the result of differences in care after discharge, or unmeasured confounding. Thus, further investigation is warranted to understand to what degree unmeasured, but modifiable factors, such as post-discharge care may account for the unexplained disparities.                                                 The next study provides insights into a novel mechanism of atherogenesis that involves protease-activated receptor 2, a major receptor of activated factor 10, which is expressed in both vascular cells and leukocytes. Co-first authors Dr Hara and Phuong, corresponding author Dr Fukuda from Tokushima University Graduate School of Biomedical Sciences, and their colleagues showed that in ApoE-Deficient deficient mice, protease-activated receptor 2 signaling activated macrophages and promoted vascular inflammation, increasing atherosclerosis.                                                 Furthermore, they showed that in humans, plasma-activated factor 10 levels positively correlated with the severity of coronary artery disease, suggesting that the signaling pathway may also participate in atherogenesis in humans. Thus, the protease-activated receptor 2 signaling pathway may provide a novel mechanism of atherogenesis and serve as a potential therapeutic target in atherosclerosis.                                                 The next paper tells us that biomarkers may help to predict specific causes of death in patients with atrial fibrillation. First and corresponding author Dr Sharma and colleagues from Duke Clinical Research Institute evaluated the role of biomarkers in prognosticating specific causes of death among patients with atrial fibrillation and cardiovascular risk factors in the ARISTOTLE trial.                                                 They looked at the following biomarkers: high sensitivity troponin T, growth differentiating factor 15, N-terminal pro-B-type natriuretic peptide, and interleukin 6. They found that sudden cardiac death was the most commonly adjudicated cause of cardiovascular death, followed by heart failure and stroke or systemic embolism deaths. Biomarkers were some of the strongest predictors of cause-specific death, and may improve the ability to discriminate among patients' risks for different causes of death.                                                 How do the complement and coagulation systems interact in cardiovascular disease? Well in the final original paper this week, first author Dr Sauter, corresponding author Dr Langer from Eberhard Karls University Tübingen, and their colleagues used several in vitro, ex vivo, and in vivo approaches as well as different genetic mouse models to identify the anaphylatoxin receptor C3AR and its corresponding ligand C3A as platelet activators that acted via intra -platelet signaling, and resulted in activated platelet fibrinogen receptor GP2B3A. This in turn mediated intravascular thrombosis, stroke, and myocardial infarction. This paper, therefore, identifies a novel point of intersection between the innate immunity and thrombosis with relevance for the thrombolic disease of stroke and myocardial infarction.                                                 That wraps up with week's summary. Now for our featured discussion.                                                 Can we teach a machine to read echocardiograms? Well today's feature paper is going to be all about that. I am so excited to have with us the corresponding author of an amazing, and I think, landmark paper, Dr Rahul Deo from the One Brave Idea Science Innovation Center and Brigham and Women's Hospital in Boston, as well as our associate editor Dr Victoria Delgado from Leiden University Medical Center in The Netherlands. Now let me set the scene here. We know that echocardiography is one of the most common investigations that we do in cardiology, and in fact even outside of cardiology, and it is hands down the most accessible, convenient tool to image the heart.                                                 Now let's set this up by remembering that echocardiograms are performed with machines, but led by echocardiologists like me. Now this is really scary Rahul because I think your paper is trying to say ... Are you trying to put people like me out of business? Dr Rahul Deo:                    Definitely not. I think what I'm hoping to do is actually two things. One of them is, despite the fact that it's an accessible and safe tool, because it needs people like us, it's probably not used as often as ideally it could be. So part of our hope was to democratize echocardiography by being able to take out some of the expenses from the process so that we can hopefully get more simpler studies done at an earlier stage in the disease process. Because in many ways, at least from my experiences being an attending, it feels like if we could just have gotten to these patients earlier we may have been able to start therapy that could've changed the disease course, but our system can't really afford to do huge numbers of echoes on asymptomatic patients. Really we were trying to find some way of facilitating this by at least helping out on trying to quantify some of the simple things that we do with echocardiography. Dr Carolyn Lam:                I love that phrase, democratizing echo. And you're absolutely right, if we could put it in the hands of non-experts and help them interpret them, we could really lead to detecting disease earlier, and so on and so forth. Wow. But everyone's wondering, how in the world do you go about doing that? Dr Rahul Deo:                    One of the things that's really been amazing in these last five years or so is that the field of computer vision, so the field by which computers are trained to mimic humans in terms of visualizing, recognizing, identifying images, has really advanced, and incredibly rapidly. And one of the reasons for that is that the video game type of computing system, the same things that go into Playstations and such, have resulted in much, much more rapid computing. And that's allowed us to train more complex models.                                                 So that's one of the things that's changed, and also, it's just much easier to get our hands-on training data. So machines can be trained to do things, but they need lots of examples. And the harder the task, the more examples they need. So the widespread availability of digital data has made that easier, though I would say that it wasn't that easy to get our hands on enough echocardiography data to be able to train. But in general, almost any task where there's enough data has been solved on the computer vision side. So this has really been an exciting advance in these last few years. So we thought we could very well just used these same technologies on a clinical problem. Dr Carolyn Lam:                Okay, but Rahul what are you talking about here? Like the machine's actually going to recognize different views, or make automated measurements? That's the cool thing, frankly, that you've written about because we know that the machines can already kind of do EF, ejection fraction, but you're talking about something way bigger. So tell us about that. Dr Rahul Deo:                    Yeah, so there are many cute examples in the popular press about machines being able to recognize the differences between cats and dogs, or some breeds of dogs. And so if you think about things that way, it really shouldn't be that much more difficult to imagine recognizing between different views, which probably are much more dramatically different than different breeds of dogs. So you could really just take the same models, or the same approaches, give enough examples, label them, and then say figure out what the differences are.                                                 And I think one of the challenges with these systems is they're often black boxes. They can't tell us exactly what it is that they're using, but when it comes to something like recognizing whether something is an apical four chamber view or a parasternal long axis view, we actually don't care that much as to how it is that the computer gets there. We just wanted them to do it accurately, and that's one of the places for some of these computer vision models. It's a field broadly called deep learning, and it's just great at achieving complex tasks.                                                 So, once you recognize views, then the other thing that computers have been shown to be able to do is recognize specific objects within an image. For example, you could give an entire football field and you could find a single player within it. You could recognize where the players are, where the ball is, where the grass is. So computers can distinguish all those things too. And then once you know where something is, you can trace it and you can measure it. So in that sense it's very similar to what a human reader would do, it's just broken down into individual steps, and each one of those needs to be trained. Dr Carolyn Lam:                You put that so simply so that everyone could understand that. That's so cool. You mentioned, though, accuracy. I could imagine that a machine would likely interpret one image the same way again and again, and that addresses something that we really struggle with in echo doesn't it? Because, frankly, one reader against another, we always know. Ejection fraction has got a plus minus seven or something, and then even within the same reader you could read the same thing and say something one day, and say something the other. So this is more than just automating it, is it? Dr Rahul Deo:                    Yeah, so it's certainly making it more consistent, and the other thing that we were able to do, I mean once you can teach it to identify and traces the contours of the heart in one image you can have it do it in every single image within the video, and every single video within the study. So now, I mean it's quite painful. I know this from my own experience in terms of tracing these things, so a typical reader can't trace 150, 200, 300, 500 different hearts, that's not going to happen. So instead, they'll sort of sift through manually, pick one or two, and if there's variability from one part of the study to the other, that really won't be captured.                                                 And in this case, the computer will very happily do exactly what you ask it to do, which is to repeat the same thing again and again and again, and then be able to average over that, capture variability. So that's one of the tasks that is much more easy to imagine, setting a computer who won't talk back to you and won't resist and won't refuse to actually taking on the mundane aspect of just getting many, many, many more measurements. And that could happen not only in a single study, but also could happen more frequently. So you could imagine that, again, there's just not that resistance that's coming from having to have an individual do these things. Dr Carolyn Lam:                Oh, my goodness, and not only does he not ... well he, machine, not say no, I mean they don't need to take time off or weekends off. We could get immediate reports directly. Oh my goodness. Victoria I have to bring you in on this. We knew as editors when we found this paper that this is something we just have to publish in Circulation that's going to be groundbreaking. Could you tell us a little bit more about what you think the implications of this is? Victoria Delgado:              I think that this is a very important paper because it's a very large study and it's sets, I would say, three important questions that we deal every day in clinical practice. One is how to reduce burden in very busy echo labs by facilitating the reporting of the echoes and the interpretation of the echoes. Second: to have an accurate measurement and quantification of the images that we are acquiring, and third: this is recognition of the pattern.                                                 And I think that this very important, particularly in primary care because, for example in Europe here, echocardiography is not really in the primary care and the patients are being referred to secondary level hospitals or third level hospitals. That means that the waiting days sometimes is too long. If we train the general practitioners, for example, to do simple echocardiograms with the handheld systems which are also the technologies that are coming and are really available in your iPhone, for example, on your phone, you can get an echocardiographic evaluation of a patient that comes to a general practitioner.                                                 And if you don't have too much knowledge on interpretation, these tools that can have recognition of the pattern of the disease can trace a red flag and say, okay this patient may have this disease or may have this problem, you should consider sending or referring this patient to us at Leiden Hospital where he's going to have a regular check-up and a complete echocardiogram. That could lead to less burden in very busy labs and only refer the patients in a timely manner to the centers when they have to be referred, when the others can wait of can be referred much later.                                                 I think that that's important, and next two technologies that are coming now and it will be very important, some groundbreaking technologies. One is the handheld systems, the ones that you can have in your phone, the ones that you can have in your tablet for example. And the other one is going to be the artificial intelligence to, if not diagnose completely, at least to recognize the pattern that there is a pathology where we need to focus, and we need to act earlier. Dr Rahul Deo:                    I think that one place we would like to see this used is in a primary care setting where you have individuals who have risk factors that we know would be risk factors, for example, for let's say heart failure with preserved ejection fraction. But really, my experience in that phase of clinical practice is there's a lot of resistance from patients to get on the medications. So hypertension is, at that point, often, I just got worked up because I had a hard time finding parking, and so on, and so on, where there's just a natural resistance.                                                 So if you could imagine having objective measures describing, let's say how their left atrium is doing at that point, how it looks the next year, what the change in therapy is doing, all these things, you actually can bring in that quantification at a low enough cost that makes it actually practical, then that would be one place we could imagine motivating or intensifying therapies on the basis of something like this.                                                 And I think one area we have to admit we didn't solve is we haven't solved the ability to facilitate getting the data in the first place. We do know that there are these focused workshops around trying to get some simple views, and more and more of our internal medicine residents are able to get some of these, but we can't dismiss that this is still an important challenge in terms of being able to get the images. What we want to do is say, well you can get some images and we can help you interpret them and quantify in an effort to try to motivate therapies being initiated or intensified in a way that's sometimes difficult to do in the current system. Dr Carolyn Lam:                So, Rahul and Victoria, you both mentioned that one of the key aspects is the acquisition of the echo. Not just the machine that does it, but also who takes the images that will then be automatically analyzed. So, Rahul, do you think that sometimes you're going to invent something that will replace even the acquisition, or maybe even simplify it so that we may not need Doppler anymore? Dr Rahul Deo:                    One of the things that we thought about was, we wanted to limit ourselves to views that might be easier to acquire, in part because we wanted to reduce the complexity of the study and yet still try to capture as much information as possible. And getting back to the first part of your question, you could imagine that recognizing a view is not that different from recognizing that a view is 10 degrees off from where it should be. You could imagine training a computer to do just that very same thing too. It could recognize a slightly off axis apical four chamber view and guide you into correctly positioning the probe, and you could even imagine a robotic system that does this and just takes the person out of it all together. In part because a very skilled sonographer can quickly look at something and say, oh I just need to tilt my wrist this way and move it this way. I was always humbled by that because I never could quite do that myself.                                                 But in the same way, and in the way, that's happening is that an image is recognized, and then the reference image is held in one's brain, and then they just know from experience what needs to be done to turn one into the other. But that very well-oiled machine could very well be taught to do that exact same thing too. Dr Carolyn Lam:                Oh wow. That is just totally amazing. I know the listeners are being blown away by this just as I am. Let me just end by asking for any last words, Victoria and Rahul, of the clinical application of this. When are we going to have this primetime? What do you think? Victoria Delgado:              I think that this is coming. This is one, for example, of the first studies showing the feasibility of this technology. In terms of accuracy, probably we need improvement, but that depends very much on the quality of the echocardiographic data that we obtain. And in the future, I think that we are going to rely more and more on this technology, and we will have the expert view for those cases that are ambiguous or where the technology has limitations. But in terms of accuracy, for example, I can imagine one of the clinical scenarios that we face in everyday clinical practice is the evaluation of the effect of the treatment in heart failure patients for ejection fraction, and in patients, for example, treated with chemotherapy to see changes in ejection fraction.                                                 That, if we do it manually as we do now, we know that we have limitations in terms of the own viability of the observer. If you leave it for artificial intelligence, maybe that viability may be reduced, and you may be better in terms of adjusting the medication if needed. Because you removed completely what would be the individual viability. So these are the fields that probably I see more and more application of this technology in order to improve the reproducibility of the measurements and accuracy. But yeah, for that we need probably very good image quality, and I see in echocardiography we always tend to say, yeah the image quality is not that good. I'm sure that echocardiography can give you much more than just using through the echocardiography. You can use contrast, you can use many other techniques in order to improve the image quality. And artificial intelligence, the better the image quality is, probably the better it's going to be as well, the accuracy of the measurements and the recognition of disease. Dr Carolyn Lam:                Wow, and Rahul? Dr Rahul Deo:                    I completely agree with Victoria. I think that we're going to have to be clever about where we incorporate something like this into the current clinical workflow. You have to choose your problem carefully, you have to understand it. Any system like this is going to make some mistakes. To figure out how to minimize the impact of those mistakes, and at the same time add benefit and potentially enable things that wouldn't even be done. So I think that the fun stuff is yet to come here in terms of really incorporating this in a way that can really change clinical practice.                                                 I want to add one thing that I really haven't mentioned. And we, at this point, really just focused on trying to mimic the stuff that we're already doing. Part of the motivation of this work is to try to potentially see things that we can't even see right now and try to potentially predict onset of disease or early latent forms of something that would really be difficult to detect by the human eye. And we've seen examples of that in some of the other fields around radiology, and I think that's going to be a place that would be augmenting beyond what we're even doing currently.                                                 But of course, the challenge is that the system has to be interpretable enough that we understand what it is that it's seeing, because otherwise I'm sure we'll be reluctant to embrace something clinically that we don't understand. Dr Carolyn Lam:                You've been listening to Circulation on the Run. Don't forget to tune in again next week.  

How did your patient feel that time you took several attempts to place a CVC? What might happen after a dose of haloperidol for delirium?   In this compelling episode, Professor Paul Wischmeyer, shares some of his experiences as a patient in the ICU. Since he was 15 he has endured multiple hospitalizations and ICU stays for his inflammatory bowel disease. This has given him an excellent vantage point to notice what we as ICU professionals do and say to our patients. And from Paul’s perspective we could do much better. Some of the procedures we might think are simple (like placing intravenous or intra-arterial cannulae) can cause significant suffering. And if we treat these procedures as something just to tick off on our list we may diminish the person-centred care we should all be attempting to deliver. Paul’s passion for helping patients recover from illness and surgery arises from his personal experiences as both a doctor and patient in the ICU. As a trained intensivist, anaesthetist, clinical pharmacologist and research scientist, he works predominantly as a Perioperative physician who specializes in enhancing preparation and recovery from surgery and critical care at Duke University. He practices on the Critical Care and Nutrition clinical teams, serves as the Director of Perioperative Research for the Duke Clinical Research Institute, as Associate Vice Chair for Clinical Research in the Department of Anesthesiology and as Director of the Nutrition Support Team. Paul has been awarded significant amounts of funding, won many awards, published over 135 papers and given hundreds of invited presentations. Five days ago Paul tweeted he was back in hospital so I thought it was a good time to bring this interview we did a few months ago. I’m hoping he is much better today and that he’ll be out of hospital and back home very soon. Paul has a lot of valuable things to say in this interview. We also spoke about: How in the early part of his career he loved the physiology and pharmacology but now he loves the family interactions and teaching Learning from people all around the world makes him a better doctor How his personal experiences have helped him to use more sedation in his practice Our need to get away from the concept of keeping a patient quiet with sedatives so we can have a peaceful night in the ICU The effects on his mother of a child psychiatrist asking her about her parenting in the work up of Paul’s illness His reflections on the difference in ward rounds between his current and previous institutions His views on having a close partnership between intensivists and the palliative care team, especially in family meetings The importance of body position and body language in communication How he feels less healthy in a system of 12 hour shifts for intensivists because scheduling self-care can be difficult The anxiety he notices when he doesn’t exercise His views on a good diet and the supplements he takes His need to feel ready to be hospitalised at any time due to his illness The benefit of having a good department chair who helps him say no to too many responsibilities How he deals with feeling overwhelmed The importance of staying well-hydrated during our work His main points about giving a great lecture, including the use of images and developing the skill of inspiring or convincing the audience with emotion Some tips for younger clinicians, including being open minded, keeping up with the literature and focusing on connection to patients My genuine hope with the Mastering Intensive Care podcast is to inspire and empower you to bring your best self to the ICU by listening to the perspectives of such thought-provoking guests as Paul Wischmeyer. I genuinely believe we can all improve, as both professionals and as human beings, so that we can do the absolute best for the people we are privileged to care for as patients. Please help me to spread the message by simply emailing your colleagues, posting on social media or subscribing, rating and reviewing the podcast. To connect, leave a comment on the Facebook “mastering intensive care” page, on the LITFL episode page, on twitter using #masteringintensivecare, or by sending me an email at andrew@masteringintensivecare.com. Thanks for listening. Andrew Davies   -------------------- Show notes (people, organisations, resources and links mentioned in the episode): Paul Wischmeyer profile: https://scholars.duke.edu/person/paul.wischmeyer Paul’s webpage on Duke Clinical Research Institute website: https://dcri.org/our-work/therapeutic-expertise/perioperative-nutrition/ Twitter handle for Paul Wischmeyer: @Paul_Wischmeyer Book: “Presentation Zen Design” (by Garr Reynolds): http://www.presentationzen.com/presentationzen/2010/02/presentation-zen-design-the-book.html Book “In Shock” (by Dr Rana Awdish): https://www.ranaawdishmd.com/book TARGET study: https://clinicaltrials.gov/ct2/show/NCT02306746?term=TARGET+nutrition&type=Intr&cntry=AU&city=Adelaide&rank=1 Mastering Intensive Care podcast: http://masteringintensivecare.libsyn.com Mastering Intensive Care page on Facebook: https://www.facebook.com/masteringintensivecare Mastering Intensive Care at Life In The Fast lane: https://lifeinthefastlane.com/litfl/mastering-intensive-care Twitter handle for Andrew Davies: @andrewdavies66 Instagram handle for Andrew Davies: @andrewdavies66 Email Andrew Davies: andrew@masteringintensivecare.com

"The Importance of Emotional Intelligence and Crisis Management" with Keith Frederick of Duke Clinical Research Institute at Duke University. Contact Frederick at https://www.linkedin.com/in/keithfrederick/.

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.                                                 Do we finally now have a simple, evidence-based way to make a diagnosis of heart failure with preserved ejection fraction? Well, today's feature paper certainly brings us closer to that goal and you must listen to the discussion coming right up after these summaries.                                                 Bleeding is commonly cited as a reason for stopping oral anti-coagulants. However, what is the prognostic significance of minor bleeding events, or so called nuisance bleeding, in patients with atrial fibrillation on oral anti-coagulants?                                                 First and corresponding author, Dr O'Brien from Duke Clinical Research Institute and her colleagues, identified 6771 patients with atrial fibrillation in the Orbit AF Prospective Outpatient Registry. They ascertained nuisance bleeding from medical records defined as minor bleeding that did not require medical attention. Overall, 20% had documented nuisance bleeding giving an incidence rate of 14.8 events per hundred person years. Nuisance bleeding was not associated with a higher risk of major bleeding, or a stroke and systemic embolism over the next six months.                                                 These findings therefore suggest that the occurrence of nuisance bleeding or minor bleeding should not lead to changes in anti-coagulant treatment strategies in patients treated with anti-coagulants.                                                 The next study sheds new light on mechanisms linking NLRP3 inflammasome activation to atherogenesis. Dr Westerterp from Columbia University, New York and colleagues studied mice with myeloid deficiency of ATP binding cassette transporters A1 and G1 and concomitant deficiency of the inflammasome components NLRP3 or caspase-111.                                                 They showed that cholesterol accumulation in myeloid cells activated the NLRP3 inflammasome. NLRP3 inflammasome activation enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques thus accelerating atherogenesis.                                                 Patients with Tangier's disease, who had ATP binding at transporter A1 loss of function, had increased myeloid cholesterol content and showed markers of inflammasome activation. Thus, inflammasome activation may underline cardiovascular disease in these patients.                                                 The next study identifies TPX20 as a novel transcription factor regulating angiogenesis. TPX20 is a crucial transcription factor for embryonic development and its deficiency is associated with congenital heart disease. However, its role in angiogenesis has been not been previously described. At least until today's paper from co-first authors Dr Meng and Dr Gu and co-corresponding authors Dr Cooke and Dr Fang from Houston Methodist Research Institute.                                                 These authors use loss and gain function approaches to explore the role of TPX20 in angiogenesis both in vitro and in vivo. They showed that with VEGF stimulation, the transcription factor TPX20 upregulated PROK2 with is secreted from endothelial cells and gauges its receptor PROKR1 and thereby promotes angiogenesis in autocrine manner.                                                 This novel signaling pathway appeared to be highly conserved as it functioned in zebra fish vascular development and the angiogenic response to ischemia in a mouse model of peripheral disease. The authors furthered showed the selective role of TPX20 in endothelial migration but not proliferation. Furthermore, treatment with recombinant PROK2 the critical effector of TPX20, improved blood profusion and functional recovery in the mouse peripheral artery disease model. Thus, these data highlight the therapeutic potential of PROK2 in augmenting functional angiogenesis for diseases associated with this regulated angiogenesis.                                                 In patients with atrial fibrillation, left atrial appendage closure with the Watchman device, is known to prevent thromboembolism from the left atrial appendage. However, thrombus may still form on the left atrial face of the device, which then may potentially embolize. This next paper provides important data on the incidents, predictors, and clinical outcomes of device-related thrombus after left atrial appendage closure.                                                 First author, Dr Dukkipati and corresponding author Dr Reddy from Icahn School of Medicine at Mount Sinai, New York and their colleagues studied the device arms of 4 prospective FDA trials of patients undergoing the Watchman implantation. These were the PROTECT AF, PREVAIL, CAP, and CAP2 trials.                                                 They found that following percutaneous left atrial appendage closure with the watchman device, the incidence of device-related thrombus was 3.7% and this was associated with a more threefold higher risk of stroke and systemic embolism. Predictors of device-related thrombus were a history of trans- ischemic attack or stroke, permanent atrial fibrillation, vascular disease, a larger left atrial appendage diameter, and a lower left ventricular ejection fraction.                                                 Device-related thrombus was not associated with an increased risk of cardiovascular or all-cause mortality. Nearly 75% of patients that developed device-related thrombus did not experience a stroke. And ischemic strokes occurring in patients with device-related thrombus accounted for approximately 10% of all ischemic strokes, following left atrial appendage closure. Thus, given the ramifications of device-related thrombus, a judicious surveillance strategy using periodic transesophageal echo cardiography may be considered particularly when risk factors for device-related thrombus are present.                                                 Well, that wraps it up for our summaries. Now for our feature discussion.                                                 Heart failure with preserved ejection fraction or HFpEF, notoriously difficult diagnosis to make, but do we finally have a validated diagnostic algorithm for HFpEF? Oh, you have to listen to our conversation today. I am so proud and pleased and thrilled frankly to have with me today the corresponding author of the feature paper, and that's Dr Barry Borlaugug from Mayo Clinic in Rochester, Minnesota as well as editorialist Dr Walter Paulusus from VU University Medical Center in Amsterdam.                                                 Thank you so much both of you for making it here. I want to dive straight into it. So, Walter, maybe could you please paint the background to this because you wrote I think the most highly cited diagnostic guidelines of HFpEF, but that was in 2007. Tell us how does today's paper take us forward? Dr Walter Paulus:             Thank you very much, Carolyn. It's quite an honor for me to give you comments about this paper, which I think is going to be a landmark event. Over the years we have seen multiple algorithms being proposed usually by professional societies like V and C or the American Society of Echocardiography for the diagnosis of HFpEF. The major drawback of all these algorithms is that they have never been validated in clinical practice. And the reason they have never been validated was that it was extremely difficult to establish a gold standard for HFpEF.                                                 And Barry was so clever to already invest in an establishing a gold standard for HFpEF ten years ago, and he very vigorously subjected all his patients in whom he suspected HFpEF to an invasive stress test and could establish the diagonals of HFpEF using this as a gold standard. And then he used all these consecutive patients with subsequently used to devise some form of an algorithm that was immediately validated against a gold standard. I think this has been a giant leap forwards. And again, I want to congratulate him with this unique endeavor. Dr Carolyn Lam:                Barry, I want to echo Walter's words and congratulate you. Now, has it really been ten years in the making? Tell us about this, Barry. Dr Barry Borlaug:              It has. In fact, it was 12 years ago when we started doing this, in 2006. But, yeah, these patients were examined in our laboratory between 2006 when I joined the staff at the Mayo Clinic to 2016. And really just doing this work up, we kind of started out doing it on a few patients and then we realized how powerful the methodology was. We did the invasive exercise testing with hemodynamics and a larger number of patients and just through accumulating a large number, as Walter points out, with a gold standard assessment this allowed us to then determine which less invasive attributes could be used to identify the likelihood that heart failure was the diagnosis. Dr Carolyn Lam:                That's so great. But you know beyond just that it is such a precious data set and so on, your paper is just so beautifully written and so clinically applicable. You've got this HFpEF score now for diagnosis. Everybody's going to be talking about it. So tell us about it. What does HFpEF score? What makes you think it'll work? How do you apply it clinically? Dr Barry Borlaug:              Thinking about diagnosis a lot, you really have to go back to [00:19:19] thinking, estimating the probability of disease, and when you're able to do that then you can find people where you need to perform really more invasive testing like the exercise testing. So really, we started like we need to have a better way to define who needs that more expensive and invasive evaluation. So we have this large cohort of patients, over 500 patients, 414 in the initial cohort, and then another 100 in the validation cohort. And they had all undergone this work up, they'd all undergone very detailed clinical evaluation and pheno typing. And we hypothesized which characteristics we thought would be most relevant. And then we did logistic regression to identify all the predictors.                                                 There were many things that are associated that you would expect with HFpEF, but there were only 6 factors in the end in a multi-variable model that were all independently associated. That provided the most parsimonious sort of model or score that we could develop. We included these six different variables. So there's two for letter H- heavy and hypertensive, and by heavy we define that as a body mass index above 30. Hypertensive is defined as two or more antihypertensive medicines. The F in the H2 HFpEF score is atrial fibrillation, either paroxysmal or persistence a. Fib. The P is for pulmonary hypertension as estimated by echo with an estimated PA systolic pressure on echocardiography of 35. We wanted all of these to be noninvasive criteria for this score. E is for elder. I specifically didn't call it elderly because that can be a pejorative term and its only 60 years which is not that old. So E is elder. And F is for filling pressures, again estimated by echo doppler cardiography as an EE prime ratio greater than 9.                                                 All of the scores are not one point each. They were arranged based on the strength of correlation in the logistic model. So being obese, having a BMI above 30 was awarded two points because it has a strong correlation. Being in atrial fibrillation or having a history of atrial fibrillation was even stronger at three points. If you tally these up, the score can range from 0-9, and based on that score you can then estimate a probability that HFpEF is present, if you're evaluating a patient that meets the entry criteria of the study, which is basically normal ejection fraction, and exertional breathlessness. Dr Carolyn Lam:                Nice. Okay, Walter, I think I can safely say that you have been thinking about this syndrome longer than either Barry or I. So I'd love your perspectives on how do you think this will be put into practice clinically perhaps, and where is the key area that it will change practice compared to perhaps the old diagnostic algorithms were like? Dr Walter Paulus:             I think this is a very important point, Carolyn. I think this score is so easy to handle and it is so well validated that we can now go to general practitioners and cause a general awareness for the disease. What vies me is that many patients are still unreported. The reason is that general practitioners and even general internal medicine people do not realize the [00:19:19] heart failure with preserved ejection fraction. Now with this score at hand, we can convince them that there needs to be an awareness when they see people that have value higher than six on the score, that they should be suspicious of heart failure being part of the symptomatology. I think this score mainly has its usefulness for general practitioners and general internal medicine.                                                 Apart from the score, and it's more up to Barry to comment on this, but I want to highlight also, that he did not only develop the score, but he also had these very beautiful nomograms which is more of a find than a score, where he treated the variables in a continuous way. I think this is fairly useful for cardiologists and especially for people who want to have acute patients into trials because here we now have a very refined scale that goes from 0-160 and that allows you again to see what type of population you are addressing, what type of patients you are seeing that eventually what type of patients you are recruiting. I think for me the HFpEF score is of importance for general practitioners, general internal medicine, and especially I think we should also promote the nomogram. The nomogram, I think, are so refined that it would be useful tool, I think an excellent tool, for includement into trials. Dr Carolyn Lam:                Oh wonderful. Both of the simplicity and the cleverness, if I may, of this paper are precious to generalists and cardiologists. But Barry, I do have a couple of questions for you. Both you derivation and validation were in Olmsted if I'm not wrong. Now how am I supposed to apply it to my skinny HFpEF patients in Asia or elsewhere? Dr Barry Borlaug:              That's an important point, Carolyn. And it's a limitation of the paper. The people in Olmsted County, MN are not the same as they are in other parts of the United States or other parts of the world. I think that additional evaluation and other cohorts are important. We did the best we could with what we had. We did look at the patients carefully at Mayo Clinic. People think of it as quaternary referral center, but a pretty substantial number of the patients are from the local area, I think about 2/3 of them were. And when we looked in a subset in a sensitivity analysis of the people that were more local practice rather than coming from large academic medical centers, the HFpEF score, or as Walter pointed out, the continuous HFpEF model performed equally well. When we looked at people with so-called advanced HFpEF so high hemopressures at rest versus people at so called early stage HFpEF the people that have normal hemodynamics at rest but elevation during exercise. The model also worked well in that cohort.                                                 But, like most studies that come out of where I work in southeastern Minnesota, it is mostly Caucasian people, the mean BMI was in the low 30s. So we need to look at other populations to make sure this works elsewhere as well. Dr Carolyn Lam:                Barry, let it go on record that I am your biggest fan. So thank you so much for this. I was just thinking even in other populations where the mean BMI may be lower for example here in Asia, we still definitely see an association with a higher BMI albeit at a lower cutoff with the presence of HFpEF. So it does raise this issue of do we need to maybe calibrate the score differently in different geographies or ethnicities. But that's not by any way take away from the tremendous input that you've made.                                                 One other question is also the strength of atrial fibrillation in impacting the score. What are your thoughts on the possibility of misdiagnosis for example atrial fibrillation as HFpEF or the similar situation since they share symptomatology? Dr Barry Borlaug:              This is a great point, Carolyn. People still sort of argue about this. Somebody has breathlessness and effort intolerance and atrial fibrillation. Some doctors say they have symptomatic atrial fibrillation, but when we put catheters when we take these patients to the so-called table of truth and put catheters in and exercise them, we see hemodynamic arrangements that are diagnostic of heart failure. This led us to believe that this isn't just symptomatic a fib. It's really HFpEF. And that's why they have a fib. We published a paper earlier this year in circulation, more of a brief report, on the association between atrial fibrillation and HFpEF where we first reported this. That if you have normal EF, and especially permanent atrial fibrillation, you can pretty much take it to the bank that the patient probably does have heart failure with preserved ejection fraction, at least in the way that we have sort of defined it and the way that [00:19:19] initially defined it as an inability of the heart to pump blood adequately at normal filling pressures.                                                 These patients almost all have that criteria for cardiac failure. I think that it is a really strong indicator and we probably are really just like in the general clinics, under recognizing HFpEF. I think probably in other clinics where people have atrial fibrillation and effort intolerance, we're again really under recognizing HFpEF in these people. Dr Carolyn Lam:                Indeed, and it's actually very consistent with Walter, your recommendations where atrial fibrillation played a big part too. Do you have any thoughts or advice? Dr Walter Paulus:             My idea is that atrial fibrillation and HFpEF are both manifestations of the same underlying process, which is systemic inflammation because of a metabolic disturbance. We used to think of atrial fibrillation as a consequence of left atrial dilatation, which itself was caused by the high filling pressures. I think that this does not hold, there is more to it. I think the atrium is as sick as the left ventricle and it undergoes similar pathological changes. That's why the presence of a fib becomes such a strong determinant of the presence of HFpEF in Barry's H of HFpEF score. All of this makes a lot of sense to me.                                                 I just want to add something else. You spoke about the Asian population having less BMI and already having HFpEF. I think if you look at Barry's variables in uni-variant analysis, there's one which was presence of diabetes or prediabetes which did not make it in the multi-variant analysis on 0.06. It's my belief that if you got to the Asian population, that probably the BMI could be replaced with the presence of prediabetes and diabetes. Usually the insulin tolerance or insulin resistance is presence and the BMI is still low. I think there is need for some fine tuning, maybe in Asian populations, and I think this should be a challenge to go ahead with it. In fact, I'm leaving for Japan the day after tomorrow and I'm going to show the slides of Barry's paper. I'm going to try to set something up to also validate the score in Japanese populations. Dr Carolyn Lam:                We've got our work cut out for us, Barry! Let's get on to this too in southeast Asia. Dr Barry Borlaug:              I totally agree with Walter. I think that's great. And Carolyn, you, in a lot of papers, point this out, that the metabolic, cardio-metabolic associated with excess body mass, the way we define it with BMI, is shifted way down in southeast Asian population, and south Asian population, so I would agree with Walter's hypothesis that diabetes, prediabetes maybe that's the better way to go when we look at this in other patient populations. Dr Carolyn Lam:                You both absolutely made my day with this discussion today. Thank you so much. What a thrill to be on the same podcast with the people I admire most.                                                 Listeners, I know you enjoyed this as much as I did. Don't forget to tune in again next week.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associated editor from the National Heart Center and Duke National University of Singapore. This week's feature paper reports results of the SWAP-4 study, which is the first study to evaluate the pharmacodynamic impact of the timing and dosing of clopidogrel administration when de-escalating from ticagrelor therapy. Extremely important take-home messages for clinicians looking after patients with coronary artery disease and a must listen to. Coming up right after these summaries.                                                 In the first original paper this week, chondroitin sulfate, well known in the context of the monogenic disease mucopolysaccharidosis type 6 may actually represent a novel therapeutic approach for the treatment of general heart failure. First author Dr Zhao, corresponding author Dr Foo, from Genome Institute of Singapore studied changes in myocardial chondroitin sulfate in non-mucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling. They found that failing human hearts display an abundant accumulation of chondroitin sulfate proteoglycans in the extracellular matrix largely localized to fibrotic regions.                                                 The main component of chondroitin sulfate glycosaminoglycan chains in human hearts was chondroitin 4 sulfate. TNF alpha was a direct binding partner of glycosaminoglycan chains rich in chondroitin 4 sulfate. Modification of the chondroitin sulfate chain with the recombinant human arylsulfatase B, which is an FDA-approved treatment for mucopolysaccharidosis type 6 that targets chondroitin 4 sulfate, actually ended up reducing myocardial inflammation and overall fibrosis in vivo. In two independent rodent models of pathological cardiac remodeling, this recombinant human arylsulfatase B treatment prevented cardiac deterioration and improved functional recovery. Thus, targeting extracellular matrix chondroitin sulfate represents a novel therapeutic approach for the treatment of heart failure.                                                 The next paper focuses on the subcutaneous ICD, which is an entirely subcutaneous system that does not require intra-procedural vascular access or endovascular defibrillator leads or coils. Now the subcutaneous ICD has a novel mechanism of defibrillation and is associated with an increased energy requirement for defibrillation when compared to traditional transvenous ICDs. Thus, ventricular fibrillation or VF conversion testing at the time of subcutaneous ICD implantation is a class 1 recommendation.                                                 Yet, what is the current adherence to this recommendation? Well, today's paper addresses this question from first and corresponding author Dr. Friedman from Duke Clinical Research Institute. He and his co-authors studied first time subcutaneous ICD recipients between 2012 and 2016 in the National Cardiovascular Database Registry ICD Registry to determine the predictors of use of conversion testing, predictors of an insufficient safety margin during testing and in-hospital outcomes associated with the use of conversion testing.                                                 Results show that use versus non-use of VF conversion testing after subcutaneous ICD implantation in the US was more related to physician preference than patient characteristics. The study also identified several patient characteristics associated with an insufficient defibrillation safety margin. That included increased body mass index, severely decreased ejection fraction, white race, and ventricular pacing on the pre-implantation ECG. Use of VF conversion testing after subcutaneous ICD implantation was not associated with a composite of in hospital complications or death. These data may inform ICD system selection and a targeted approach to conversion testing.                                                 We know that elderly patients are at elevated risk of both ischemic and bleeding complications after an acute coronary syndrome and display higher on clopidogrel platelet reactivity as compared to younger patients. Does prasugrel at five milligrams compared to clopidogrel reduce ischemic events without increasing bleeding in the elderly? Today's paper addresses this question from corresponding from corresponding author Dr Savonitto from Manzoni Hospital Italy and his colleagues.                                                 These authors performed a multicenter randomized open label blinded end point trial comparing a once daily maintenance dose of prasugrel five milligrams with the standard clopidogrel 75 milligrams in patients more than 74 years old with acute coronary syndrome undergoing percutaneous coronary intervention. The primary end point was a composite of mortality, myocardial infarction, disabling stroke and re-hospitalization for cardiovascular causes or bleeding within one year. Enrollment was interrupted due to futility for efficacy according to pre-specified criteria after a planned interim analysis when 1,443 patients had been enrolled with a median follow-up of 12 months.                                                 At this point of interruption, there was no difference in the primary end point between reduced dose prasugrel and standard dose clopidogrel. The results of this Elderly ACS 2 study therefore could not show overall clinical benefit of prasugrel five milligrams versus clopidogrel in elderly ACS patients undergoing early PCI.                                                 The final study is the first to define the cellular and molecular mechanisms of cardiac valve inflammation and fibrosis occurring in the setting of systemic inflammatory disease. First author Dr. Meier, corresponding author Dr Binstadt from University of Minnesota used T-cell receptor transgenic mice which spontaneously developed systemic auto antibody associated autoimmunity leading to fibro inflammatory mitral valve disease and arthritis.                                                 They identified a critical population of CD301b/MGL2 expressing mononuclear phagocytes that orchestrated mitral valve inflammation and fibrosis in this mouse model. They further demonstrated an analogous cell population was present in human inflammatory cardiac valve disease. Finally, they defined key inflammation molecules that drove mitral valve disease in this model, thus providing multiple potential therapeutic targets that are required for mitral valve inflammation and fibrosis. Dr Carolyn Lam:                That wraps it up for your summaries. Now for our feature discussion.                                                 Searching between different classes of P2Y12 inhibitors including de-escalation from ticagrelor to clopidogrel commonly occurs in clinical practice. However, what are the pharmacodynamic profiles of this strategy? Well, today's feature paper is going to provide a lot of insights. I am so pleased to have the corresponding author of the SWAP-4 study, Dr. Dominick Angiolillo from University of Florida College of Medicine Jacksonville, as well as our associate editor Dr. Gabriel Steg from Hôpital Bichat in Paris, France. Dominick, now this is SWAP-4. That means there was a SWAP 1, 2, 3. Could you just paint the background and rationale for SWAP-4 and tell us what you found? Dr Dominick Angiolillo:   We performed this study on the background of a line of research that we've been conducting over the past number of years of switching antiplatelet therapies. There's so many different types of switches that can occur and one of them is that which is defined as a de-escalation which is that from a more potent P2Y12 inhibitor to a less potent and one of those that occur frequently in clinical practice is the switching from a ticagrelor to clopidogrel and this was essentially the rationale for conducting the SWAP-4 study.                                                 Now I want to start off with saying that the reason for doing this study is not to advocate switching because we always recommend that individuals follow guideline recommendations but we performed this study because we wanted to provide clinicians with some additional insights that if you're going to switch particularly from ticagrelor to clopidogrel, which would be the modality which is associated with, put it this way, with the smoothest transition one drug to another.                                                 This is the rationale. What we did was do a pharmacodynamic, conduct a pharmacodynamic study taking patients who were on standard treatment with dual antiplatelet therapy aspirin and clopidogrel and they had a run-in phase with ticagrelor. And the reason why we took patients on the back part of aspirin and clopidogrel is because we then wanted to look at the effects after switching to compare it with a baseline. There have been some discussions about drug-drug interactions. And patients were randomized to either continue with treatment with ticagrelor to switch with a loading dose of clopidogrel, 600 milligrams 12 hours after last dose of ticagrelor. 24 hours after last dose of ticagrelor or directly switch with a maintenance dose. So, the randomization was into four groups.                                                 Essentially to keep a long story short, what we observed was that when de-escalating from ticagrelor to clopidogrel we did see an increase in platelet activity obviously as expected. But the use of a loading was not able to mitigate this increase but there were no differences according to timing of administration of the loading dose clopidogrel 12 or 24 hours. We had anticipated in our study design that with the administration of the loading dose 24 hours after last maintenance dose we could have achieved a smoother transition, but this was not the case.                                                 Nevertheless, the overall conclusions of our study are supported by the pharmacodynamic data in terms of you still achieve a better transition when you give a loading dose than without a loading dose. I was also want a little bit cautious and I think during the review process of the journal and feedback from the editors we kind of phrased in a very cautious way the suggestion for a drug-drug interaction, in fact we suggested because there are other ways to look into this phenomenon in more detailed manner. For example, doing some specific pharmacodynamic analysis which was not done in this study. Nevertheless, the take-home message from a clinical perspective remains unchanged. Dr Carolyn Lam:                Thanks so much, Dominick. That was a very important framing of the paper that you gave us at the start that this trial was not designed to try to say who should be de-escalated or not and that should be in line with the guideline recommendations and yet such an important just take-home message that if there is a need that the 600-milligram loading dose of clopidogrel should be used. You know, Gabriel, you've thought a lot about this and especially the drug-drug interaction question. What are your thoughts there? Dr Gabriel Steg:                Yeah, well first of I think this is an extraordinary, important study even though it's a pharmacodynamic study, which many clinicians might look at and then quickly read the abstract and turn the page I think this is actually one of the most interesting papers we've published in recent months. The reason for this is this is tackling a very common clinical scenario, which is having or desiring or wanting to de-escalate the intensity of platelet therapy after a PCI or ACS from a potent agent such as ticagrelor to a less potent agent such a clopidogrel. And as nicely explained in the paper, there are multiple reasons why this can occur.                                                 A common clinical scenario is that cost is a major issue. Because of the cost patients or physicians may want to switch to clopidogrel, a generic drug as opposed to a branded drug. Another scenario which is fairly common is side effects. Either nuisance bleeding or maybe dyspnea with ticagrelor may prompt some physicians and patients to want to deescalate to clopidogrel. To a less intensive therapy which may not have dyspnea or may not cause as much nuisance bleeding. And finally, sometimes it's done on purpose because some believe that within a few weeks or months following PCI or ACS the benefits of more intensive patient therapy is less, the risk remains the same and therefore maybe we could proposedly de-escalate therapy to clopidogrel and get away with it and there have been a number of randomized studies and observational studies that suggested that this might be feasible although these studies have weaknesses. They're often open label. They're often fairly small and somewhat underpowered.                                                 So, we don't have a definitive answer. Nevertheless, this happens on an everyday basis in most large clinical centers and we don't know exactly how to do it and what the best way to do it and I really want to credit Dominick's team for doing a rigorous series of investigations, including this one, which is the latest one but not the only one in trying to really map out how exactly we should as clinicians manipulate these agents to achieve the best safety and efficacy for our patients. And I think the message here is very clear. Yes, you can de-escalate but you have to be careful on how you do it. And I think you really need to use a loading dose, a 600-milligram loading dose of clopidogrel if you're going to deescalate from ticagrelor to clopidogrel to avoid a gap in protection that might be deleterious to patients.                                                 That does not address all of the questions that are raised by de-escalation and as I pointed out I think outcome trial data are really of paramount importance here, but I think this really important because it has major practical implications for clinicians worldwide on how to do this. So, I think this is a great study. I really want to congratulate Dominick. Dr Dominick Angiolillo:   Thank you. Dr Carolyn Lam:                You looked at the genetic status as well. Could you tell us about your findings there? Dr Dominick Angiolillo:   We in the spirit of trying to perform the most comprehensive possible assessment we have also looked at the genetic background of our patients and in particular looking whether the presence of a loss of function allele for CYP2C19, which is involved with clopidogrel metabolism, could have affected the outcomes. And the reason why we did this there've been a lot of studies clearly showing that if you have a loss of function allele for CYP2C19 you do have higher levels of platelet reactivity. Therefore, we want to see if those carriers would have had even a greater increase in platelet reactivity. And again, we did all this in the spirit of really trying to define again this from a pharmacodynamic standpoint, if there could be any potential safety hazards with such an increase in platelet reactivity with the de-escalation.                                                 When we did our analysis, we did not find any impact of a CYP2C19 on our data. However, I think it's important to underscore that we did not have too many patients with a loss of function allele so clearly the study was not designed or nearly closely powered to look into this assessment. So, I think that aspect does need to be interpreted with caution. Dr Carolyn Lam:                Thanks so much, Dominick. Were there perhaps caveats that clinicians listening in should pay attention to? For example, this study was conducted in stable patients with coronary artery disease. What about patients with recent acute coronary syndrome? Dr Dominick Angiolillo:   That's a great point. The reason why we conducted this study in a more stable setting was largely driven by two aspects. Well first of all, we wanted to have a run-in phase of patients switching from clopidogrel to ticagrelor to have some sort of baseline to reference to after the switch. And this would have been mostly ACS patients that would be less likely to be on clopidogrel. The second is purely a safety issue. We know that patients with acute coronary syndromes are associated with higher levels of platelet reactivity and in the context of a study where we do not know the pharmacodynamic profiles associated with de-escalation or better off we don't know the details.                                                 And so, there was a safety consideration there which is why we did it in stable patients. But what we can say is tied with Gabriel's comment before in all the studies out there are not powered or do not have the rigor of a mega trial. Although we give our suggestions and recommendations, practical recommendations on how to switch, there is an increase in platelet reactivity and we stress in our manuscript that if you are going to switch, please try to delay this as much as possible because those increases in platelet reactivity for example, in a patient with an ACS for example, immediately after PCI, something that we probably would not want for our patients. I'm very happy actually that we conducted the study in the more stable cohort because we had less confounders. This is kind of the reason behind all this. Dr Gabriel Steg:                The last question maybe I would ask Dominick is whether he believe that results would be different if we had the patients on a maintenance therapy for longer with clopidogrel, do you believe that the risk of rebound or drug-drug interaction are the same early on after institution of therapy or later on? Is there any reason to expect a difference? Dr Dominick Angiolillo:   That's a great question. My personal opinion would be that with longer duration the platelet reactivity would have gone back down to baseline. We actually continue to study out up to around 10 days following the switch which we thought would have been sufficient time to get back to baseline and it was not the case particularly in the patients whose switch was a 75 milligram. The answer's probably yes. Probably yes. To redesign the trial again maybe having that 30-day time point as well would have been obviously of added value. Dr Carolyn Lam:                Thank you so much, Gabriel and Dominick. This has been extremely insightful. Fun as always.                                                 You've been to Circulation on the Run. Don't forget to tune in again next week.  

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.                                                 Our featured discussion today is really a very important message, that hospitals have the capacity to influence a patient's adherence to secondary prevention and thereby potentially impacting long-term patient outcomes. Much more on this important paper coming right up.                                                 Higher physical activity is known to be associated with lower heart failure risk. However, what is the impact of changes in physical activity on heart failure risk? The first paper in this week's journal, by first author Dr. Roberta Florido, corresponding author Dr. Ndumele from Johns Hopkins Hospital, provides us some answers. These authors evaluated more than 11,350 participants of the Atherosclerosis Risk in Communities, or ARIC, study who were followed for a median of 19 years during which there were 1,750 heart failure events.                                                 They found that, while maintaining recommended activity levels was associated with the lowest heart failure risk, initiating and increasing physical activity even in late middle age were also linked to lower heart failure risk. Augmenting physical activity may, therefore, be an important component of strategies to prevent heart failure.                                                 The next paper highlights the importance of bystander automated external defibrillator use. First author Dr. Pollack, corresponding author Dr. Weisfeldt from Johns Hopkins University School of Medicine sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public out-of-hospital cardiac arrests.                                                 From 2011 to 2015, the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharged with near or normal functional status as defined by a modified ranking score of two or less.                                                 The authors found that among 49,555 out-of-hospital cardiac arrests, 8% were observed public out-of-hospital cardiac arrests, of which 61% were shockable. Overall bystanders shocked a remarkable 19% of shockable observed public out-of-hospital cardiac arrests. Bystander automated external defibrillation in shockable observed public out-of-hospital arrest was associated with an increased odds of survival with full or nearly full functional recovery compared to emergency medical services defibrillation.                                                 The benefit of bystander automated external defibrillation use increased as the arrival of emergency medical service was delayed. Thus, efforts to increase the availability and use of automated external defibrillators in public locations are likely the most promising immediate ways to improve survival from out-of-hospital cardiac arrests.                                                 The next paper suggests that the complement pathway may contain the secret to a successful cardiac regeneration. First author Dr. Natarajan, corresponding author Dr. Lee from Harvard University, and their colleagues performed a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration, the axolotl, neonatal mice, and zebrafish, all of which underwent apical resection.                                                 RNA-seq analysis showed that genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors were found to be highly upregulated in all 3 species, particularly the induction of gene expression for complement 5a receptor 1. Inhibition of this particular complement receptor attenuated the cardiomyocyte proliferative response to heart injury in all 3 species.                                                 Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of complement 5a receptor 1. These data, therefore, identified the complement pathway activation as a common pathway for a successful cardiac regeneration.                                                 The final study sheds light on the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes. First author Dr. Roberts, corresponding author Dr. Trzeciak from Cooper University Hospital performed a prospective multicenter protocol directed cohort study that included 280 adult postcardiac arrest patients.                                                 They found that early hyperoxia exposure, defined as a partial pressure of oxygen of above 300 millimeters mercury during the first 6 hours after return of spontaneous circulation, was an independent predictor of poor neurologic function at hospital discharge even after adjusting for a potential baseline and postcardiac arrest confounders.                                                 That brings us to the end of our summaries. Now, for our featured discussion.                                                 Medication nonadherence is a common problem worldwide and, indeed, the very topic of our featured discussion today. Our featured paper is so interesting because it tells us that hospitals may have the capacity to influence a patient's adherence to secondary preventive cardiac medications, thereby, potentially impacting long-term patient outcomes, and there are a lot of implications of that.                                                 I'm so pleased to have with us the first and corresponding author, Dr. Robin Mathews, from Duke Clinical Research Institute, as well as the editorialist for this paper, Dr. Jeptha Curtis from Yale University School of Medicine, and our associate editor, Dr. Sandeep Das from UT Southwestern. Lots to talk about.                                                 Robin, could you perhaps start by telling us what made you look at this issue of nonadherence and what did you find? Dr Robin Mathews:         The issue of medication adherence has been something that I think we've been dealing with in healthcare for some time now and, traditionally, we looked at factors that, on a patient level, you sort of also have an idea that maybe they might provider level factors that contribute to nonadherence, so we started thinking about this, what's the health system's role in adherence and is there a role? Do hospital and do providers have more of a role in promoting adherence than we acknowledged in the past?                                                 We are fortunate to have a lot of great clinical data sources available, and the one that we used for this study is the ACTION-Get With The Guidelines Registry, and this is a quality improvement registry that's been around for some time. It's a great source of research and observational studies that has produced a lot of data over the years.                                                 ACTION is a voluntary registry; there are several hundred hospitals that participate, and it gives us very good data, detailed data on the patient experience in the hospital for patients who come in with acute coronary syndrome, so we looked at patients who were enrolled in ACTION over the course of 3 years, from 2007 to about 2010, and looked at the typical patient level factors, medications that were given on admission, how they were treated and what medications they went home on.                                                 What ACTION doesn't give us is longitudinal data, which is really what we were trying to get at here, so we were able to link this clinical data set using CMS data, which is administrative data, claims data, in order to ascertain longitudinal adherence, so we ended up, after exclusions of about 19,500 patients or so, and this spanned about 347 hospitals, of patients that we followed up to 2 years out, and our objectives of the study were 2-fold, one to assess adherence at 90 days for cardio vascular medication, secondary prevention medications that are typically used, so, in this case, we looked at beta blockers, ACE inhibitors, ARB, phenoperidine, and statins.                                                 We looked at 90-day adherence, and then the question we had specifically was does adherence vary among hospitals? The second thing we wanted to knowledge was, if adherence does vary among hospitals, is there a relationship between hospital adherence and cardiovascular outcomes at 2 years, so we looked at MACE, which is MI, revascularization, readmission, stroke. We also looked at death and all-cause readmission, and also mortality.                                                                                                 What we found is that the adherence actually did markedly vary within the medication classes, but also among hospitals, and once we divided these groups into essentially high adherence hospitals, low adherence hospitals, and moderate adherence hospitals, there were these typical differences in terms of patient characteristics that one would expect in terms of comorbidity, socioeconomic status. Patients who were in the high adherence hospitals were more likely to be from ... to have a less comorbidity burden. They had higher income based on ZIP code, and they were more often represented from non-southern hospitals in the United States.                                                 When we then correlated these two outcomes, what we found is pretty interesting. Patients who were in the low adherence hospitals were more likely to have the outcomes that I mentioned earlier. That's not too surprising, yeah, because I had mentioned that the patient mix in terms of the ... their case mix varied among these hospitals, so the logical question as well, maybe the hospitals that are ... have low adherence have low adherence because the patients are generally just sicker.                                                 We know that there are certain high-risk groups and we know that the patients who are treated at some hospitals might be sicker than others, so we did our best to adjust to these, so we did a multivariable model. We adjusted for various patient differences, and we also looked at hospital-level differences, the best that we can ascertain based on the ACTION Registry. That was sort of where the interesting finding was the rates of major adverse cardiac events and death at readmission were mitigated somewhat closer to the null, but they remained significant. Dr Carolyn Lam:                What a detailed summary. Thanks so much.                                                 Jeptha, I love your editorial that accompanied it. Could you put the study into context a bit for all of us? Why are these finding so impactful? Dr Jeptha Curtis:               It's rare that you get to review and editorialize a paper that has so many implications both from a clinical practice and policy standpoint, so I think they really hit on a understudied area, and really this paper should cause people to reflect on what's going on in their practice and at the institutions that they practice in.                                                 I would say that adherence is just such a challenging problem that, as Robin articulated, has been refractory to change over 15 years. We've been studying this for a long time, and we know that the numbers had not improved over time.                                                 What's different about this paper is that it really suggests a completely different approach to addressing nonadherence among patients, and if this is ... if their findings are true, if nonadherence is really actionable at the hospital level or attributable to the hospital level, it really opens up new avenues both for research as well as for quality measurements.                                                 As I read this paper for the first time, I was really struck by thinking about how invisible adherence is to frontline clinicians. We just don't have the information to tell us are our patients taking their medications on a day-to-day basis, and we know that most of them are not because the research has consistently shown that a large proportion failed to take their medication, and Robin's paper showed that yet again, but I can't say that there's any steps that our hospitals are really doing to address that in a systematic fashion.                                                 All of our efforts for quality improvement have really been towards making sure that patients are prescribed the medication on discharge, and in the setting of readmission and trying to prevent readmission to our hospitals, we are now having follow-up phone calls with patients to assess failures to taking medications and follow-up, but it's really ... That's it. There's really no systematic way that we're trying to ... if an individual patient or a group of patients are adherent to their medications, so this is really a whole new avenue.                                                 What we don't know is how to improve it, right? I think that the first implication of this paper is that there are differences at the hospital level. Some hospitals seem to be doing this better than others. That could be driven by differences in case mix, but it could also be driven by differences in hospital practices, and I think this is a wonderful opportunity for future direction of research perhaps using positive deviance methodologies to go to those hospitals that have high adherence rates in really trying to understand what differentiates their practices from those of other hospitals. Dr Carolyn Lam:                Indeed, Sandeep, I remember some of the conversations we had as editors about this paper. We, too, were struck by the novelty, and you've mentioned before, Sandeep, that the novelty of perhaps nonadherence or adherence as a new performance measurement. Would you like to comment on that? Dr Sandeep Das:               Yeah, first thing, what was kind of interesting about the discussion surrounding this paper, there were some people who read it and just sort of read it as the message being nonadherence associated with worst outcomes, and I thought like that was pretty established, known, but then there were some people like Jeptha and Erica who really got it, who really understood what was novel and interesting about this, and I also congratulate Robin on a fantastic paper.                                                 One thing I think that's really interesting, in my day job, I wear a couple of quality hats. I am the cardiology division quality officer, and health system quality officer for UT Southwestern, so I spend a lot of time thinking about quality, and I'll tell you there's quite a bit of metrics that he ... there's just a lot of things that now you feel they're not particularly substantive and they're very difficult to change, you have, you know, if aspirin on discharge, as Robin mentioned discharge adherence, aspirin on discharge is 99% and getting people to document the last 1% rather than fail to document it, there's not really a fulfilling challenge where you think, "I'm really impacting patient endpoints."                                                 I was really struck by the opportunity here. We know that from studies like MI FREEE that adherence to medications even at a year is probably about a third of patients are not adherence, so it's really kind of interesting to take that as an opportunity. We should fixate on what are these therapeutic option or not therapeutic option can move the needle by a fraction of a percent, but these are medications that are proven to prevent MI and change lives, and there's a massive delta here that we can address. The concept that this is addressable on the hospital level is fascinating, and I'm a big fan of coming up with sort of systems level approaches to addressing problems. Dr Carolyn Lam:                Congratulations once again on this great paper. Just tell us what do you think of the next steps and what would your message be to those of us who practice outside of the US? Dr Robin Mathews:         Jeptha talked about where our focus should be in terms of what we can do on a hospital level. I think the ultimate answer is there's a lot of heterogeneity in terms of what is done, and I think that, expanding on his point about better investigating practices that currently exist, and whether that's surveying things, and we have a lot of great professional societies and registries that we can sort of reach out to these hospitals, find out what they're doing, what makes them different from the hospitals that are not doing those things and then really doing some rigorous testing to figure out if in fact these specific interventions that these hospitals have put in place are with the high likelihood leading to the effects that we've seen, so I think that surveying sort of what's out there, understanding what works in a rigorous way and then being able to systematically apply this or distribute this to other hospitals to share the knowledge and say, "Hey, this is what we think. We've actually done it."                                                 Like Sandeep said, with the inpatient management of patients who come in with acute coronary syndrome, we've done it well. I think it sort of contributed. Our guidelines and adherence to these guidelines and the metrics that we've used have really demonstrated that we've sort of achieved high levels, but we sort of reached I think the ceiling for a lot of that, and you always have to be open to novel metrics and then the idea of focusing in on the transition from hospital to home and what we can do once they leave their door, once they leave the door of the hospital, I think would be useful.                                                 In terms of the rest of the world, I mean, the US has very unique problems based on our payment models and access to care and whatnot, but I think a lot of the themes that we sort of have seen with medication nonadherence when it comes to patient-level factors and provider-level factors are sort of universal.                                                 At the end of the day, patients need to be empowered, and they also need to have the tools to allow them to be successful in my opinion. I think we've for a long time in this space often said, "Well, this is sort of a patient that there's only so much that we can do as providers," but I think that papers like this highlight the possibility that there's probably more that we can do to make these impacts. Dr Sandeep Das:               One of the comments or a question that I had was the controversial thing is to what extent hospitals should be accountable for things that happen well after discharge? I think readmission is one that always comes up. There's factors that are outside our control, so one question is kind of to what extent should we be responsible for stuff that happens forward of 6, 9 months down the road?                                                 The second question that I had or a comment that I had was I do think that there's going to be a generalizability to non-US settings because there's elements of this ... For example, this now would incentivize hospitals and discharging physicians to make sure that patient education is substantive, right? If the metric is, "Did you provide discharge instructions, yes or no?" then that's sort of trivially accomplished by handing them a piece of paper and checking a box, but, now, if we follow a metric like this, we're really going to be accountable for making sure people understand what they're supposed to be taking and have a path to get it and things like that, so it makes some of the transitions of care stuff, and that's a great point, some of the transitions of care stuff much more substantive. Dr Robin Mathews:         Sandeep's point is a very good point, and it's very difficult to come up with a clear answer for that and, like you said, the issue with readmissions and all sort of the factors that are involved from a social level and research level cloud that, so ... and, hence, I think something like readmission is controversial, and I think this sort of question will generate a lot of further questions about whether using medication adherence and holding hospitals responsible.                                                 I will say that when we looked at adherence sort of in the short term at 90 days and we looked at it in the long term at a year, we saw there was sort of a drop off, but it wasn't as substantial it was earlier, so I think a lot of adherence in the short term after hospital discharge continues to decline over time, but it doesn't drop down as precipitously downstream as it does early on, and I think that, just like with readmission, there's been some data to suggest that near term readmission are more likely things that "could be preventable" as opposed to maybe a readmission toward the end of the month.                                                 At the end of the day, it's a very difficult thing and there's a lot more discussion that needs to be had about this topic, but I think that with this, it gives me some hopefulness and I think everybody else on this call that at least we wouldn't then be able to prevent every adverse outcome that happens 2 years down the road, but we might be able to at least affect a substantial portion of them. Dr Carolyn Lam:                Listeners, you heard it. There's lots that we can do. This paper says a lot. Please do pick it up. Read the editorial as well.                                                 Thank you so much for listening today, and don't forget to tune in again next week.

Available On: iTunes  | Google Play  | Stitcher  | Spotify Kristen MacDermott is a consultant and performance coach who has created resilience training programs for some of the highest performing people on the planet, including Naval Special Warfare Command (Navy SEALs) and the Los Angeles Police Department. Kristin’s programs have also been used in more than 20 hospitals across the country, in the Duke Cancer Institute, and in the National Institutes of Health among others. Kristin brings a unique skill set to her executive coaching, leadership training, and corporate consulting work. The resilience training curriculum she created has been validated in four studies with researchers from the Duke Clinical Research Institute, published in peer-reviewed journals and shown to promote clinically significant improvement in key wellness and resilience measures. The cornerstone of Kristin’s resilience training curriculum is emotional intelligence, which is why her expertise lends itself so well to the corporate world. Study after study shows that “the single biggest predictor of professional success is not education, skill set, experience or IQ. It is emotional intelligence.” Kristin’s own research shows that emotional intelligence and resilience can be taught, and these skills improve performance and satisfaction with the workplace, which engenders loyalty to the organization. From Andy: One of the coolest parts of this interview for me was when we talked about how you can hear the same information from two different people – and one will trigger you into anger and upset while the other has no impact at all. In unraveling that, we got to the reason… that on some level, you believe that the person that triggered you is right – you believe them, and that causes you to judge yourself. So the upset is really about self-judgment… and THAT, you can do something about. There’s that… and so much more in this conversation. Check it out – you’ll be glad you did! Enjoy! FORWARD TO A FRIEND - If you enjoy the podcast, please help us spread the word by sharing it. LEAVE A REVIEW - Your written reviews in iTunes go a long way in helping us get the word out. Here's a link to make it easy - bit.ly/breakingordinary. Thanks in advance for your help and support! Connect with Kristin Instagram: kristinmacdermott Website: www.kristinmacdermott.com Facebook: Kristin MacDermott DMFT Blog: Practical Resilience   Twitter: Kristin MacDermott Questions? Feedback? Email - podcast@wholelifechallenge.com Instagram - @andypetranek Facebook - @andypetranek Twitter - @andypetranek REVIEW THE PODCAST ON iTUNES - bit.ly/breakingordinary If you liked this episode, try these: 76: Scott McGee — On Grit, Resilience and Having an Unconquerable Soul 107: Dr. Christopher Neck — The Surprising Benefits of Setbacks  

Dr. Bob Harrington, an interventional cardiologist and Chairman of the Department of Medicine at Stanford University, speaks with Venrock’s Dr. Bob Kocher about his passion for coagulation and thrombosis (seriously, he loves it) and his involvement with Gusto, a clinical trial that changed the way doctors treat heart attack patients. Bob also talks about working with an executive coach to develop new skills, when he found himself managing teams at Duke Clinical Research Institute.

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our featured discussion today centers on new data from the Framingham Heart Study that addresses the question of the prognosis of pre-hypertension among individuals who never progressed to hypertension as well as the role of early versus late onset pre-hypertension in this context. Well, more soon, right after your summary of this week's journal.                                                 The first original paper provides mechanistic insights on the relationship between low and oscillatory wall shear stress, together known as disturbed flow, and atherosclerotic arterial remodeling and stiffness. Co-first authors doctors Kim and Pokutta-Paskaleva, co-corresponding authors Dr. Brewster and Jo from Georgia Institute of Technology in Emory University in Atlanta, Georgia used a novel mirroring model of disturbed blood flow to stimulate arterial stiffening through collagen deposition in young mice. They discovered a critical role for Thrombospondin 1, or TSP1 in activating TGF beta and stimulating arterial stiffening, all of which was significantly attenuated in the TSP1 knockout animal.                                                 Blockade of TSP1 activation of TGF beta decreased the up regulation of pro-fibrotic genes that contributed to arterial stiffening. Furthermore, they show that TSP1 localized to regions of disturbed flow in arteries from patients with peripheral artery disease and these arteries had similar increases in collagen gene expression. Thus, this work links TSP1 up regulation to arterial stiffening and identifies TSP1 as an important promoter of pathologic arterial remodeling in peripheral artery disease.                                                 The next study provides international insights on the degree to which secondary prevention treatment goals are achieved in clinical practice among patients with diabetes and cardiovascular disease. First and corresponding author, Dr. Pagidipati from Duke Clinical Research Institute at Duke University School of Medicine in Durham, North Carolina, looked at 13,616 patients from 38 countries with diabetes and cardiovascular disease in the TECOS trial. They found that only 30 percent of patients met all 5 secondary parameters of aspirin use, lipid control, blood pressure control, angiotensin-converting enzyme-inhibitor, or ARBUs, and non-smoking status.                                                 Only 58 percent of individuals with diabetes and cardiovascular disease attained blood pressure control. Furthermore, the degree to which secondary prevention goals were met in this trial varied by the world region and country. In summary, patients with diabetes and cardiovascular disease are still being undertreated globally with respect to secondary prevention, and especially with regard to blood pressure control. These gaps in care provide clear opportunities for improvement in this high risk population.                                                 The next study is the first to directly compare data from an electronic data research network to a large cardiovascular disease cohort. First author Dr. Ahmed, corresponding author Dr. Allen from Northwestern University in Chicago and colleagues sought to evaluate the degree of agreement of electronic data research networks compared with data collected by standardized research approaches in a cohort study. To achieve this goal, authors linked individual level data from the multi-ethnic study of atherosclerosis, or MESA community based cohort with Healthlink, a 2006 to 2012 database of electronic health records from 6 Chicago health systems.                                                 They identified areas of agreement and disagreement between blood pressure, cardiovascular risk factor diagnosis, and cardiovascular events between the two data sources. The correlation was low for systolic blood pressure, compared with MESA, Healthlink overestimated systolic blood pressure by 6.5mm mercury. Conversely, there was a high correlation between body mass index in MESA and Healthlink. Healthlink underestimated body mass index by 0.3 kilograms per meters square.                                                 Using ICD-9 codes and clinical data, the sensitivity and specificity for Healthlink queries for hypertension were 82.4 percent and 59.4 percent. For obesity these figures were 73 percent for sensitivity and 89.8 percent for specificity and for diabetes they were 79.8 percent for sensitivity and 93.3 percent for specificity.                                                 Finally compared with adjudicated events in MESA, the concordance rates for myocardial infarction, stroke, and heart failure were at 41.7 percent, 61.5 percent, and 62.5 percent, respectively. These findings therefore illustrate the limitations and strengths of electronic data repositories compared with information collected by traditional standardized epidemiologic approaches for the ascertainment of cardiovascular risk factors and events.                                                 The next paper helps physicians and patients to make an informed decision about whether or not to stop low dose aspirin use. First and corresponding author Dr. Sundstrom from Uppsala University in Sweden and colleagues investigated whether long term low dose aspirin discontinuation increased the risk of cardiovascular events in a cohort study of more than 600,000 users of low dose aspirin for primary or secondary prevention in the Swedish prescription register between 2005 and 2009.                                                 They found that patients who discontinued aspirin had a 37 percent higher rate of cardiovascular events than those who continued, corresponding to an additional cardiovascular event observed per year in one out of every 74 patients who discontinued aspirin. The risk increased shortly after discontinuation and did not appear to diminish over time. Thus, in long term users, discontinuation of low dose aspirin in the absence of major surgery or bleeding seemed to be associated with a more than 30 percent increased risk of cardiovascular events, thus adherence to low dose aspirin treatment in the absence of major surgery or bleeding may be an important treatment goal.                                                 The final study raises the possibility of using Histone Methyltransferase Inhibitors for the treatment of heart failure. Dr. Papait from Humanitas Clinical and Research Center in Italy and colleagues focused on G9A, a histone methyltransferase that defines a repressive epigenetic signature. Using normal and stressed cardiomyocytes from a conditional cardiac specific G9A knockout mouse, and a specific G9A inhibitor, they showed that the histone methyltransferase G9A was important in defining the epigenetic landscape that maintained the transcription program of the cardiomyocyte. It was also important for the regulation of gene expression reprogramming during cardiac hypertrophy.                                                 Furthermore, impaired G9A function promoted cardiac dysfunction. Thus, these findings suggest that G9A may represent a therapeutic target for early stages of cardiac hypertrophy.                                                 That wraps it up for your summaries, now for our feature discussion.                                                 For today's feature discussion, we're talking about the very important topic of the prognosis of prehypertension without progression to hypertension. Now, we've always known that mild blood pressure elevations that we call prehypertension are associated with cardiovascular risk. However, this risk could be attributable to the fact that these patients with prehypertension eventually progress to overt hypertension. But, what happens to the patients with prehypertension who do not progress to hypertension, and what is the role of early versus late onset prehypertension?                                                 Well, we have some answers today and I am so pleased to have the first and corresponding author with us, Dr.  Teemu Niiranen, from Boston University's Framingham Heart Study. Welcome, Teemu. Dr. Teemu Niiranen:       Thank you very much, great to be here. Dr. Carolyn Lam:               And to help us along in this discussion, we have a familiar voice. Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back, Wanpen. Dr. Wanpen Vongpatanasin:       Thank you Carolyn. Happy to be here. Dr. Carolyn Lam:               Teemu, you know, I sort of set the background that you so nicely articulated in this research letter, but could you tell us a little bit more of what you were looking at, how you did it, and what you found? Dr. Teemu Niiranaen:     My boss, Dr. Vasan, was also a coauthor in this paper, he already showed some 15 years ago that prehypertension carries greater cardiovascular risk than perfectly normal blood pressure. However, it's pretty much unclear what happens to people who are prehypertension but never go on to develop hypertension because even the name suggests that if you have prehypertension you will get hypertension. We also looked at what effect does the age of developing prehypertension and hypertension have in this context.                                                 We used a case cohort setting in the Framingham Heart Study in the way that we only looked at 5 1/2 thousand decedents. These were people who had already passed away. Then we categorized those decedents into 5 categories, people who never got prehypertension or hypertension, people who developed prehypertension late in life, who never developed hypertension, and people who developed early onset prehypertension but never developed hypertension, and then people who went on to develop late or early onset hypertension. We used a cutoff of 55 years as the definition of early onset versus late onset.                                                 Then, in a case cohort setting, we estimated case versus controls, adjusted case versus control odds ratios, for the 4 prehypertension/hypertension categories versus those who died without ever developing prehypertension. Dr. Carolyn Lam:               Teemu, could I just stop you here before you share the intriguing results. I just wanted to remark that it's so amazing how the Framingham Heart Study really enables analysis like this, simply because of the long follow up and just the great detail and the standardization of blood pressure measurements and so on. I mean, as I said, I worked at the Framingham Heart Center, and we were trained to do this in a standardized fashion.                                                 Define prehypertension and hypertension, just in case, and then please tell us your results. Dr. Teemu Niiranaen:     Prehypertension was 120 to 135 systolic blood pressure, and a diastolic blood pressure of 80 to 89 millimeters mercury, and then hypertension was 140 over 90 millimeters mercury, or antihypertensive medication, and yes, your correct that the Framingham Heart Study provides a very unique setting. Especially for defining early versus late onset hypertension because we can define the age of hypertension or prehypertension or prehypertension onset objectively because these people have been followed up, they have attended so many exams, especially the original cohorts.                                                 But, to the results, so we observed that basically people who develop prehypertension, either early and especially late in life, but did not ever develop hypertension, their risk, or odds of dying of cardiovascular disease versus non-cardiovascular disease was pretty much similar to those who never develop prehypertension or hypertension, while conversely the people who went on to develop either late or especially early onset hypertension, or developed early onset hypertension they had considerably greater risk of cardiovascular death versus those who developed either prehypertension or hypertension. That's our main result. I won't go into conclusions yet. Dr. Carolyn Lam:               Okay, but maybe at this point, I could ask Wanpen to share some thoughts. I mean, this is very striking findings. Curious what you think the clinical implications were, and especially as we discussed among the editors. Dr. Wanpen Vongpatanasin:       It is very important study that, as Teemu outlined it, to look at the fate of people with prehypertension and I think that's the first time we had this kind of data to show whether the earlier versus late prehypertension and even hypertension itself. I don't think people have looked at in the large number in terms of outcome people who have early versus late onset hypertension. I found the result to be fascinating. Dr. Carolyn Lam:               Yeah, what does this mean though when we see a patient with this sort of borderline hypertension, you know, falling in the prehypertension range. We don't know whether they're going to develop hypertension. What do you think the clinical implications are? Teemu? Dr. Teemu Niiranaen:     Unfortunately a lot of the people who develop prehypertension as the name suggests they go on to develop hypertension, but there is still a considerably great part that never develop hypertension, and our study shows basically that if you are able as a doctor or a patient to prevent progression to hypertension you are much better off and this really hasn't been previously shown, so it just should motivate patients and also doctors to strive to, if they see a prehypertensive individual, try to through lifestyle and other interventions try to prevent the progression to hypertension. Dr. Carolyn Lam:               Yeah, I think that was one of the take home messages for sure. Were there any other plans for future work you think that needs to be done? Dr. Teemu Niiranaen:     There's the everlasting problem with observational studies, so definitely it would be great if our results could be taken into clinical trials or anything to test whether interventions, A, that preventing the progression from prehypertension to hypertension could then impact cardiovascular outcomes. Dr. Carolyn Lam:               Indeed, and if I may comment, I've always wondered about ethnic differences when it comes to this. The one thing that Framingham, you know, it's difficult to see from there, is what happens in other ethnicities other than white ethnicities, isn't it? Still, very striking findings. Wanpen did you have any other comments or questions from Teemu? Dr. Wanpen Vongpatanasin:       Well, I think that one thing also that's interesting to me is even the people who had early onset prehypertension, although the number of CHD deaths were not significant, but the odds still 28 percent higher than the control that will never have prehypertension so, I think that that the signal is there but perhaps because the number of people who had prehypertension but never really progress to prehypertension is relatively small. It could be underpowered to see the significance and I think that from this study, it tells me that the exposure to blood pressure to our life, I think is the blood pressure lowered on the cardiovascular system, I think that's the one that really determine the cardiovascular outcome the most. I think that we should not discount that this is not a truly benign phenomenon, I think hopefully they'll be some more data from the Framingham group or other group.                                                 Also, I think that this study also very important to show that early onset hypertension actually have the worst prognosis, and often time when people come to see a doctor when they're 30 and 40 years old, they don't really want to take medicine, and the physician often time are reluctant to prescribe the drug, and I think that this study say that we probably need to be a little bit more serious about it, because they actually have the most cardiovascular events. Dr. Carolyn Lam:               What excellent points, and you know what? At this point I just want to highlight that beautiful figure that you have in your research letter, Teemu. I think it says it all. It highlights that point estimate for the prehypertension groups is not exactly 1. If anything, it is above 1, right? For the odds of poor outcomes, so I do take Wanpen's point as well. Beautiful figures, and I also actually want to use that to ask you a different question Teemu. You have 1 figure, because this is a research letter that only allows 1 figure and 800 words, and you've put so much important information into that space. I'd love for you to share that experience with our listeners too, of a research letter versus a full paper. Why did you choose to submit yours as a research letter, and how was that? Dr. Teemu Niiranaen:     One of the important take home messages from this was the differences between early onset versus late onset hypertension that we'd been also recently publishing on, so we wanted to delve more in depth on this prognosis of prehypertension versus hypertension so we don't have to be repetitive too much. We decided to focus on this very small topic most intensively, therefore we decided that maybe a research letter would be the most effective way so we could communicate all the really novel stuff that we have in just one figure. Well, it has 3 panels, but it still counts as 1 figure.                                                 I just wanted to point out that maybe the early onset prehypertension, yeah the confidence intervals are somewhat wide, but the panels sees for coronary heart disease versus non-cardiovascular disease deaths, so that's maybe a bit more underpowered than the back panel B, so the CHD deaths are part of the CBD deaths, so with CBD deaths, the early onset prehypertension, the odds ration was 1.09, but still of course the confidence intervals reach up to 1.49. Just to clarify the difference between panel B and panel C, so B's better powered. Dr. Carolyn Lam:               It's a very nice figure, and indeed, I think it works very, very well as a research letter, and I think the fact that we're discussing it right now shows that length doesn't dictate importance. Wanpen you had a few comments about that. What do you think of a research letter format? Dr. Wanpen Vongpatanasin:       Yes, I think this research letter is a really important part of articles in Circulation. I think that all the others should be aware that we're trying to enter at submission if it's suitable, just like this one. It actually show up in the pub med exactly like the full article and gets cited as much and sometimes much more than a regular article because it capture the essence of one more focused problem and the figures and table allow to show only one or two at a time, so they really capture the essence or the guts of the article and the reader can go through that quickly and grasp the concept and learn within flipping through a few pages.                                                 I think we should have many more interesting research letter like this. Dr. Carolyn Lam:               Congratulations again Teemu for a beautiful paper, a very important one. Thank you Wanpen for shepherding this one.                                                 And thank you listeners for joining us today. Don't forget to tune in again next week.  

Dr Carolyn Lam:     Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. And Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University at Singapore.                                 What is the effect of obesity and underweight status on perioperative outcomes of congenital heart operations?                                 Our feature paper this week sheds light from the Society of Thoracic Surgeons Database. More soon, right after these summaries.                                 The first original paper highlights the role of micro RNAs in metabolic remodeling and heart failure. As a reminder, micro RNAs are small, noncoding RNAs important in post transcriptional modification and influencing many cellular processes simultaneously.                                 First author, Dr. Heggermont, corresponding author, Dr. Heymans, and colleagues from Maastricht University in the Netherlands use mice subjected to pressure overload by means of endotension to infusion or transverse aortic constriction. They show that micro RNA 146A was up regulated in whole-heart tissues in these murine pressure overload models, as well in left ventricular biopsies of aortic stenosis patients. Over expression of micro RNA 146A in cardio cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of micro RNA 146A blunted the hypertrophic response and attenuated cardiac dysfunction in Vivo.                                 Mechanistically, micro RNA 146A reduced its target dihydrolipoyl succinyltransferase or DLST, a mitochondrial protein that functions as a TCA cycle transferase. DLST protein levels were reduced in pressure overload mice, while they were partially maintained in micro RNA 146A knockout mice. Furthermore, overexpression of DLST in wild type mice, protected against cardiac hypertrophy and dysfunction in Vivo. Thus, micro RNA 146A and its target DLST are important metabolic players in LV dysfunction. These results also opened the door to novel therapies to treat metabolic disturbances and improve energy efficiency of a failing heart.                                 Program cell death is critically involved in ischemic cardiac injury, pathologic cardiac remodeling, and heart failure progression. Our next paper sheds light on the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure. Using genetic mouse models, first authors Dr. Guo and Yin, corresponding author Dr. Liu, and colleagues from University of Washington in Seattle, identified a critical role for a tumor necrosis factor receptor associated factor 2 or TRAF2 in myocardial survival and homeostasis by suppressing necroptosis.                                 The authors delineated an important TRAF2 mediated NF-KB independent pro-survival pathway in the heart by suppressing necroptotic signaling. They identified novel molecular mechanisms whereby TRAF2 suppressed TNF receptor 1 mediated, receptor interacting protein 3 dependent necroptosis, which is critical for myocardial survival and homeostasis. Thus, this finding suggests that the necroptosis suppressing TRAF2 signaling pathway and its effectors may serve as novel therapeutic targets for pathologic cardiac remodeling and heart failure.                                 Our next paper tells us that cerebral hyperperfusion may be associated with accelerated cognitive decline and an increased risk of dementia in the general population. First author Dr. Walters, corresponding authors Dr. Ikram, and colleagues from Erasmus University Medical Center in Rotterdam, The Netherlands, measured cerebral blood flow by 2D phase contrast MRI in non-demented participants of the population based Rotterdam study. A 4,759 participants with a median age of 61 years, and a median follow up of 6.9 years, 123 participants developed dementia.                                 Lower cerebral perfusion was associated with higher risk of dementia and this risk was even higher with increasing severity of white matter hyperintensities on MRI. At cognitive reexamination after an average of 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition, which was similar after excluding those with incident dementia, and again, most pronounced in individuals with higher volumes of white matter hyperintensities.                                 Thus, lower cerebral perfusion was associated with accelerated cognitive decline and increased risk of dementia in the general population. This association was modified by hypertension and cerebral small vessel disease, possibly reflecting impaired arteriola and capillary function. This paper calls for further long term study and evaluation of optimizing cerebral perfusion as a means to prevent cognitive deterioration, for example, in patients with heart failure or carotid artery stenosis.                                 Well, that wraps it up for our summaries. Now for our feature discussion. For today's feature discussion, we will be looking at data from the Society of Thoracic Surgeons Database. This time looking at the effect of body mass index on perioperative outcomes of congenital heart operations in children, adolescents, and young adults. To discuss this, we have none other than the first and corresponding author, Dr. Michael O'Byrne from Children's National Medical Center in Washington D.C., as well as Dr. Naveed Sattar, Associate Editor from University of Oxford. Welcome gentlemen. Dr Michael O'Byrne:       Good morning. Dr Naveed Sattar:            Good morning. Dr Carolyn Lam:                Michael, we know that extreme body mass indices, very high or very low, has been associated with increased risk of at first, perioperative outcomes in mainly older adults undergoing cardiac surgery. We also know about the obesity paradox in conditions like heart failure, so why was it important to look at this specific group of patients? Congenital heart patients and children, adolescents, and young adults? Dr Michael O'Byrne:       Yeah, I think that as a pediatric cardiologist, a lot of the data that we use to guide our management is extrapolated from adult studies. However, in this particular case, it wasn't clear necessarily that adult data would necessarily be applicable to children and adolescents and young adults. We are aware that there are epidemiologic trends that congenital heart disease population ages and there are also in increasing problems of obesity among children in the United States.                                 The convention wisdom among surgeons in the United States is that obesity would increase perioperative risk and the thought is that some combination of exposure to hypertension and diabetes and peripheral vascular disease might impede wound healing and that body habit as itself might be a risk for the technical approach in wound healing. Acknowledging that there's a lot of evidence both for extreme BMI being a risk in surgical patients and adults, but also the idea that obesity paradox might be important in children because the biological mechanisms might be different.                                 Children themselves are exposed, their sort of dose response or dose exposure is less, they're younger, and so haven't been obese for a prolonged period of time, so that the integrated effect of having diabetes, hypertension, and obesity might be less. At the same time, we also acknowledge that in children with heart disease, we have congenital cardiac disease, the same issues with cachexia and frailty are present. i.e. that children with very low body mass index might be assigned to their own medical frailty, or a part of a heart failure cachexia syndrome.                                 One of the challenges in dealing with children with congenital heart disease, however, as you know is that its rarer than cardiac disease of the aging and additionally, that the population is very heterogenous in terms of the actual defects that are present and the surgeries that are performed. It was relevant to look and see over a wide range of sort of technical complexity surgeries with a wide range of sort of intrinsic preoperative risk of perioperative outcome, whether or not BMI would be associated with an adverse outcome. Either operative mortality in this case, or a composite outcome of mortality, major adverse events, and wound infection. Dr Carolyn Lam:                Wow, that makes a lot of sense and congratulations. This is not just the first, it's huge and really comprehensive. Could you just tell us a little bit more about what you did and what you found? Dr Michael O'Byrne:       I think as this point, I'd have to acknowledge that the challenges that we described in terms of both a sample size and in terms of getting a representative sample, is a constant challenge in our field and we have to give credit to my co-authors Marshall and Jeff Jacobs for their work in developing the collaboration that allowed for the STS Congenital Heart Surgery Database to exist. Also, on top of shepherding the database, their research, along with the people at Duke Clinical Research Institute, they've developed a robust risk stratification model for mortality that we utilize as part of this study. Without that, this would be really be very challenging.                                 What we did is performed an observational cohort study using the STS Congenital Heart Surgery Database to look at the risk of perioperative mortality and composite outcome in patients undergoing surgery in the United States between 2010 and 2015. We looked at both the actual events, the sort of observed events, in terms of mortality and adverse events, and then created multivariate models to adjust for the known covariance.                                 We hypothesized that extreme BMI, either very high or very low, would be associated with increased risk of mortality and increased risk of that composite outcome. What we found that operative mortality and that perioperative adverse events occurred more frequently in obese and severely underweight subjects. However, because they have an unequal distribution of potentially important covariance, we used multivariate modeling to adjust for those covariance.                                 Our multivariate models for death, however, the severely underweight subjects had an odds ratio of 1.4 and obese subjects had an odds ratio of 1.3, but neither was specifically significant in that context. We sort of anticipated that with a possibility given the very low event rate. That's the reason we've used a composite outcome, a higher event rate.                                 For that composite outcome, in both different versions of the multivariate model that we used, the severely underweight subjects had an odds ratio of 1.5, underweight subjects had an odds ratio of 1.3, and obese subjects had an odds ratio of 1.2. An increased risk in all three of those populations of interest relative to normal weight or just overweight subjects. Dr Carolyn Lam:                We're always saying that at circulation we do want to publish papers that have direct and important clinical implications, so Naveed, could you share some thoughts on what this means clinically? Dr Naveed Sattar:            Yeah, I think they went through the review process and I think the paper was very well written. I think Michael and his colleagues clearly understood the strength and the limitations of the data so that you can only ever itself prove associations here and therefore, clinically when we push them on trying to make clinical inferences, I think clearly they recognize that once they find associations between obesity and adverse outcomes and underweight.                                 What they need to do next, now this is a paper that then leads you to think, "Well actually, I need to do some clinical trials to prove that module ..." You're preventing these outcomes or in very under knowledge where they're actually increasing the BMI but improving their nutrition, cannot also improve outcomes following surgery. Now those are tough things to do. Michael, what do you think from some of the clinical inference? My inferences were the associations were there, particularly for the normal [inaudible 00:12:35] outcomes, but actually to prove that, to make a difference, you probably might need to do some intervention trials or is that how you take it as well? Dr Michael O'Byrne:       I agree with you 100%. I think that as an epidemiologist, I think that what we see in an observational study like this is an association. The two next levels of research that are necessary at this point are to see whether or not in this population BMI is a modifiable factor in the short run before surgery, or even in the long run. And the second question to answer is whether those adjustments in BMI, if they are achievable, affect outcome with surgery. Absolutely.                                 It's a tremendous challenge, both logistically in organizing a study, and honestly, in terms of capturing a cohort that would be large enough, given that this is almost 100% of the surgeries that occurred over a six year period in the United States. Dr Naveed Sattar:            I looked at it and thought, "Well, the mortality association once you adjusted were not quite significant but are there any individuals you would not do surgery on based on their BMI based on these results? Dr Michael O'Byrne:       The motivation for the study is exactly to try to begin to shed light on that kind of question. I think that it might be what I would call a tiebreaker potentially, if you have a situation where a patient is near meeting criteria but isn't quite at a place where you need to do surgery at that point. It might dissuade you from proceeding immediately potentially pursuing a course that might adjust their BMI in the correct direction.                                 At the same time also, in a patient who's underweight particularly to evaluate whether their medical regimen has been optimized and if there are other residual lesions that can be addressed in a non-surgical or medical fashion. Dr Naveed Sattar:            I suppose the other trick with this type of research research is always trying to make sure that people understand these are the associations and not trying to attribute causality because it's always physical, isn't it? But I think you and your team did that very well and I'm sure we had a back and forth with review but I think your discussion section, your limitation section, is beautifully written and covers those kinds of caveats, which I think is important as well. Dr Michael O'Byrne:       I thank you for that. That's very complimentary and we certainly strived for that, but I think that you as an editor, and also in terms of the reviewers also, were very helpful in that sort of collaborative process to try to make sure that we're communicating it. It's not always clear in a project that takes months and years to finish when you're writing it necessarily, you may be constantly aware of trying to be clear in your communication but it's also helpful to have a reviewer from the outside carefully read the study. Dr Carolyn Lam:                That's wonderful and Michael, may I just join Naveed in congratulating you on beautiful paper? And maybe just one other little question, did you have any insights into the mechanisms of increased risk for composite events in the extremes of BMI? Dr Michael O'Byrne:       I think it's an important question. There's been a tremendous amount of research in adult cardiac disease about whether it is the BMI as a steady state or BMI changes immediately before and after surgery that are relevant in this case. From this kind of observational study, it's very hard and very challenging to try to make any sort of inferences about the causes. It would be an important part of any study moving forward to include ways to investigate that, and honestly, as an interventional cardiologist and epidemiologist, I probably would defer to Naveed, he might have more cogent and logical ideas about that than I do. Dr Naveed Sattar:            We've had lots of research from a whole variety of researchers. We all understand it's finally serious but recognize it's difficult, so one of the ways moving forward and I think Michael and his colleagues have this is if you have serial BMI data prior to surgery, that could try and inform on reverse causality because of the low BMI, but in terms of the mechanisms, remember these are associations, but I think mechanisms are well covered if you are obese and clearly you have risk factors for death, across the vasculature, across the cardiac functions, across the whole variety of things.                                 We know those mechanisms, question is, to what extent are they actually operating and causing increased risk in the surgical arena and that's a really tough ask. I think people can come up with a multitude of mechanisms. I think the key things, like this particular paper, is that there are potential mechanisms but these are associations ... Look, this is what we found, and clinically now we need to try and address this within the following types of interventions or at least provide some guidance to colleagues and clinicians.                                 Exactly as Michael says, if there is somebody who is approaching surgery whose quite obese, perhaps they should try and intervene to try and lessen their weight for a short period of time prior to [inaudible 00:17:07], you know what happens. It would be nice to do some big trials but I think doing trials in this area is going to be really tough, but with imagination, with good collaboration across centers, trials are not impossible. I think they can be done. Dr Michael O'Byrne:       Naveed, I think, actually articulated what I think is both the difficulty of doing that trial but also the importance of it. I think that looking at ... In these databases, we don't have a serial BMI and I think that's an important missing piece of information that we tried to address in our discussion and I think it's something that would be really valuable moving forward. And certainly testing interventions, whether they're medical, interventional, or surgical, to help these patients who are obese either lose or maintain an appropriate weight is the next step.                                 On the converse side, this research highlighted to me the prevalence of chachectic or underweight patients in our population and it's something that outside of the infant period, we don't necessarily think about tremendously and we don't think about it as a modifiable factor. I think that's another group of patients who also deserve some attention. Dr Carolyn Lam:                Listeners, you've been listening to Circulation on the Run. I'm sure you learned a lot as I did. Don't forget to tune in again next week.  

This is an in depth discussion about the connection between flame retardants and plastics, and thyroid cancer.  These chemicals, also known as endocrine disruptors, have a clear connection to thyroid cancer occurrence. The research is presented by Julie Ann Sosa, MD MA FACS is Chief of Endocrine Surgery at Duke University and leader of the endocrine neoplasia diseases group in the Duke Cancer Institute and the Duke Clinical Research Institute. She is Professor of Surgery and Medicine. Her clinical interest is in endocrine surgery, with a focus in thyroid cancer. She is widely published in outcomes analysis, as well as cost-effectiveness analysis, meta-analysis, and survey-based research, and she is director of health services research.  NOTES: Study Associates Flame Retardants with Papillary Thyroid Cancer Flame retardants used in furniture may increase thyroid cancer risk Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013 How to Buy a Sofa without Toxic Flame Retardants Julie Ann Sosa, MD

Produced in collaboration with the Journal of the American Medical Association (JAMA) Date: March 13, 2014Featuring: Craig W. Robbins, MD, MPH, Medical Director, Center for Clinical Information Services, Kaiser Permanente Care Management Institute Don Goldmann, MD, Chief Medical and Scientific Officer, Institute for Healthcare Improvement Peter Basch, MD, FACP, Medical Director, Ambulatory EHR and Health IT Policy, Medstar Health Eric Peterson, MD, MPH, Director, Duke Clinical Research Institute; Professor of Medicine, Division of Cardiology, Duke University Medical Center   Hypertension is a hot issue, especially in the US, where an expert committee recently recommended that the available evidence does not support initiating treatment (largely medication) for people 60 years or older until their blood pressure climbs to 150 over 90. The decades-long consensus had been to initiate treatment at 140 over 90, which is still the recommendation for adults younger than 60. The reasons for this change are possibly as complicated as the guideline process itself, but one of the chief concerns of the majority on the Eighth Joint National Committee (“JNC 8”) is the risk associated with aggressive treatment of hypertension in older adults. So, can we talk about this? We invite you to listen to this special WIHI produced in collaboration with the Journal of the American Medical Association. The discussion was constructive and forward-looking.  Some experts take exception to the committee’s findings and the process itself. Our guests are going to take all that into consideration, but, with your help, we’ll focus primarily on the best ways to approach changing and often-debated guidelines when working with patients to achieve optimal health. (The new guidelines for determining who should be put on statins to lower cholesterol are another case in point.)

Dr. Lam:                               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. In this week's issue, we are discussing if public placement of defibrillators in the community can be improved. First, here's your summary of this week's Journal.                                                 Stroke incidents, prevalence, and risk factors have been changing over the past 50 years so do we need a more contemporaneous revised Framingham Stroke Risk profile to reflect these trends? Well the first paper in our issue looks at this and this is from first author Dr. Dufouil, corresponding author Dr. Seshadri and colleagues from the Boston University School of Medicine.                                                 Let's first recall that the Framingham Stroke Risk profile was originally described in 1991 and integrates the effect of age, sex, and baseline measurements of various vascular risk factors such as systolic blood pressure, use of anti-hypertensive medications, left ventricular hypertrophy on ECG, prevalent cardiovascular disease, current smoking status, atrial fibrillation and diabetes all to describe the 10-year probability of incident stroke.                                                 In the current paper, the authors updated the Framingham Stroke Risk profile using the means of risk factors that reflect current prevalence, the estimate of incident stroke to reflect current rates, and the hazards ratio that reflect current associations. They used the same risk factors identified in the original stroke risk profile with the exception of left ventricular hypertrophy. The authors compared the accuracy of the standard old risk profile with the revised new risk profile in predicting the risk of [alt 00:01:58] and ischemic stroke and validated the new risk profile in two external cohorts, the three cities and regards or reasons for geographic and ethnic differences in stroke studies.                                                 They found that the new stroke risk profile was a better predictor of current stroke risks in all three samples than the original old Framingham Stroke Risk profile. The new stroke risk profile was also a better predictor among whites compared to blacks in the regard study. The authors therefore concluded that a more contemporaneous revised Framingham Stroke Risk profile could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.                                                 The next study provides preclinical proof of principle that an apelin receptor agonist may be of therapeutic use in pulmonary arterial hypertension. And the agonist in this case is  Elabela/Toddler or ELA, first identified as an essential peptide in the development of the heart in Zebrafish, and subsequently proposed as a second endogenous ligand at the G-protien coupled apelin receptor, which works at this receptor despite a lack of sequence similarity to the established ligand, apelin.                                                 In this study from first author Dr. Yang, corresponding author Dr. Davenport and colleagues  from University of Cambridge in the United Kingdom, ELA competed for binding of apelin in human hearts with overlap of the two peptides indicated by encyclical modeling. ELA activated G-protein and β-arrestin dependent pathways and as expression was detectable in human vascular endothelium and plasma. Comparable to apelin, ELA increased cardiac contractility, ejection fraction, cardiac output, and elicited vasodilatation in rats in vivo.                                                  ELA expression was reduced in cardiopulmonary tissues from patients with pulmonary arterial hypertension and in rat models. Finally, ELA treatment significantly attenuated the elevation of right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in monocrotaline exposed rats. Thus, these results suggest that a selective agonist that mimics the action of indulgence ligand apelin or Elabela/Toddler, ELA, may be a promising therapeutic strategy in the treatment of pulmonary arterial hypertension.                                                 The final paper looks at sudden cardiac death after coronary artery bypass grafting, its incidents, timing, and clinical predictors. First author Dr. Rao, corresponding author Dr. Velazquez and colleagues from Duke Clinical Research Institute in Durham, North Carolina, looked at the patients enrolled in the STICH, or Surgical Treatment of Ischemic Heart Failure Trial who underwent coronary artery bypass grafting with or without surgical ventricular reconstruction. They excluded patients with a prior ICD and those randomized only to medical therapy. Over a median followup of 46 months, 113 out of 1,411 patients who received coronary artery bypass surgery, had sudden cardiac death while 311 died of other causes.                                                 The five-year cumulative incidence of sudden cardiac death was 8.5%. In the first 30 days after bypass surgery, sudden cardiac death accounted for 7% of all the deaths. The numerically greatest monthly rate of sudden cardiac death was in the 31 to 90 day time period. In multivariable analysis end-systolic volume index and BNP were the most strongly associated with sudden cardiac death. Thus, this study shows that the monthly risk of sudden cardiac death shortly after bypass surgery among patients with a low ejection fraction is highest between the first and third months, suggesting that risk stratification for sudden cardiac death should occur early in the post-operative period, particularly in patients with an increased preoperative end-systolic volume index and/or an increased BNP.                                                 Well, that wraps it up for you summaries, let's turn to our feature paper.                                                 I love our feature paper this week. You know why? It actually tells us what Tim Hortons, Starbucks, Second Cup and ATMs may have in common and may have to do with sudden cardiac death. Indeed, our feature paper actually tells us that coffee shops and ATMs may be the best spots to place AEDs at, well at least in Toronto. And to discuss this really interesting paper, I have the corresponding author, Dr. Timothy Chan from University of Toronto as well as Dr. Sana Al-Khatib, welcome again Sana, Associate Editor from Duke University, welcome to you both. Dr. Al-Khatib:                     Thank you, my pleasure. Dr. Chan:                             Thank you, very nice to be here. Dr. Lam:                               So Tim, was that an interesting enough lead up? I mean you have to tell us about your study, it is so fascinating. Dr. Chan:                             I'm very pleased that you find it interesting and not just us. So we undertook this study, we started this actually a couple of years ago, and we've been working on this issue of defibrillator location optimization for several years, and we've been talking and we have meetings in coffee shops and we were just wondering one day, what would be the risk or the coverage provided by all these different well-recognized location types around the city, and that was really the motivation that got us started looking at this study. Dr. Lam:                               Tell us what you did and also how it differs from the study you did that was published in 2016 where you also reported on the spatial temporal analysis of registered AEDs in Toronto. The current study clearly extends it, but could you clarify to us all how it does? Dr. Chan:                             Maybe just give a little bit of a background and context with regards to other literature that's similar. There have been studies in the past that looked at what we would call spatial coverage of cardiac arrest, so they looked at different broad location types and they tried to calculate, they basically calculated how many cardiac arrests happened, let's say within 100 meters of those location types. And what we've done here is we've extended that in a couple of directions. The first direction is looking at spatial temporal coverage and so this is not just in the nearby vicinity, IE, 100 meters, but also that cardiac arrests happen when that nearby location that had the AED was open. So if a cardiac arrest happens, but for example, let's say there's a coffee shop that actually has an AED and that coffee shop is closed, it's almost as if that AED is not even there. So one of the major things we made sure to include was this idea of temporal coverage as well, on top of the spatial.                                                 The second major difference I would say would be the fact that we're really looking at more granular location types, so you mentioned a few businesses in your opening such as Tim Hortons and Starbucks and so on, which are coffee shops, and so one of the things that we find is when we look at very broad location types, we tend to aggregate together lots of different types of businesses. For example, if you think about a restaurant, there are many different types of restaurants that get lumped in to this category, and they do have different cardiac arrest coverage associated with them. So by breaking it up into smaller location types, we wanted to get a better idea of the risk at different locations and if you also think about one of the long term goals of this work would be to try and help policy makers identify promising partners to partner with for, let's say public access defibrillation programs, by identifying specific businesses or municipal locations, it might actually give them better targets to try and pursue rather than let's say a group of different businesses. Dr. Lam:                               That makes so much sense and it really just seems like such an important public health message as well. The sensible part being of course, if you have an out of hospital cardiac arrest, you need an AED that's both nearby and available, so that was really clever. Sana, could you give us your take on the public health implications of Tim's findings? Dr. Al-Khatib:                     I think the public health implications of this work can be vast and if you look at what he's done in terms of ascending to out of hospital cardiac arrests a lot of initiatives have been launched to try to improve the outcomes of patients who have the out of hospital cardiac arrests. Unfortunately despite all the work that has been done and all the wonderful initiatives that have been launched, we still have a lot of work to do to improve the survival of those victims. So certainly a crucial step is how we deploy AEDs in a strategic way based on data and evidence such as these data that are provided to us by Tim and his colleagues.                                                 I think this is very clever, I do agree that we have to be more strategic in how we deploy AEDs and having the data such as these will only help us improve and get better of course. Everybody has limited resources, and so if we can be more selective in terms of how we deploy AEDs I think that would help everybody. I realize this was done within Toronto and some of these findings may not be generalizable to other cities, but I think this is definitely a great way to make us reshape our thinking in terms of how we do this, and so a question I have for Tim if I may, are you aware of any similar studies that have been done looking at this in other cities and then if not, how do we encourage other groups to do similar work? Dr. Chan:                             There have been similar studies done that have focused really on the spatial side of things, so doing this 100 meter radius and counting cardiac arrests that have been nearby, there's actually been fairly little work that's been done on the spatial temporal side. And a couple of exceptions that I will note that I think are important to point out is there was a very nice study that was done out of a group in Copenhagen, and they were looking at actually spatial temporal coverage, particularly the loss in coverage that you experience when you go from looking at spatial to spatial temporal. For example if you count all of the cardiac arrests that happen nearby a registered AED based only on 100 meters, and then you count the same number, but you have to now layer on top of that when the building that the AED is in is open, then you tend to get a big loss. They found quite striking numbers, I think they found a 50% loss, when you look at evenings and weekends I believe, in Copenhagen. So basically all the cardiac arrests that happened where you thought there was an AED nearby, there's actually only one in two is actually nearby and accessible when you looked into hours of operation.                                                 And this actually comes back to the earlier question from Carolyn about how our study relates to our previous study in 2016, so we actually replicated that Copenhagen study in Toronto where we measured spatial coverage and we measured spatial temporal coverage and we measured that loss, and we found a similar loss overall, about 20%, so 1 in 5 cardiac arrests happened where there was an AED nearby, but that AED was not available because that location was closed. So that was one of the impetuses for leading us to do this study where we start to examine specifically the different location types and the specific businesses that were involved. Dr. Lam:                               Wow, that's just really inspiring Tim, I mean I'm kind of thinking about the Singapore situation too and I think it's actually applicable and I would love if we had local data similar to yours, so congratulations, I really share what Sana said. Thinking though about the public health and the larger implications of what you're talking about, what do both of you think of the implications for a public commercial partnership in these things if it is coffee stores or banks that seem to be the best locations, perhaps these have implications to how the public and private should collaborate to make these things happen, what do you think? Dr. Chan:                             I completely agree. These types of public private partnerships, specifically for AED deployment are not necessarily new, they already happen in some parts of the world. One of the examples I always like to bring out is if you go to Japan and they have vending machines everywhere in Japan and then you'll often run into vending machines that have an AED right in them, so one of the benefits is that first the vending machines are everywhere and second, if you're a citizen there, you probably know where the vending machines are where you travel in your day to day life and so I would say that would be a very similar thing here in North America, whether it be coffee shops or ATMs, if someone were to put me in a random part of the city and ask me, "Hey Tim, do you know where the nearest AED is?" I'd probably have a lot of trouble, but if they said could you figure out where the nearest ATM is for your bank or where the nearest Starbucks is you know, there's pretty much one on every corner. It would be much easier to identify and find, so I think there are significant benefits to partnering with these companies or these businesses that have very broad name recognition and brand recognition, are geographically well spread and located in populated areas.                                                 I should also mention, I feel like there's a few other benefits for these types of locations, so for example for ATMs, I think there's a lot of secondary benefits, so for example, there's a built in security component, there's a video camera there, that might be able to help make sure that no one's vandalizing or stealing an AED. There's perhaps built in weather protection because there's electricity there already, so in a cold climate like Toronto where you might worry about putting an AED outside, you could have potentially a heating cabinet that would be fed by the electricity for the ATM and so on. So I think there's actually a lot of benefits if we could actually operationalize a system like this. Dr. Lam:                               Sana, do you think there are some more unanswered questions? Dr. Al-Khatib:                     I did want to agree with Tim on what he said, that these public private partnerships have been in place. Unfortunately we haven't been able to make much progress. As I said, I do see the results of this study as being potentially a catalyst to improve the work that we are doing and ensuring stronger partnerships and collaborations to help us achieve what we want to achieve which is basically improve the survival rate of out of hospital cardiac arrests, so I completely agree with that and I loved your idea, Tim, when you talked about now people may not recall where AEDs might be, but if you link them with teller machines or coffee shops, I think that would be much easier to remember.                                                 You know of course there are a lot of questions that remain unanswered unfortunately. Again as was stated by Tim and his colleagues in the paper and on the call, how we can translate these findings to other locations I think is really key and then of course doing the work, meaning let's use these data to deploy more AEDs and then really looking at the impact of that. Ultimately we want to make sure that if we hypothesize that by doing this we can improve outcomes for these victims, we would want to prove that. So I think the next steps would be to see if this can be replicated in other places, but also even within Toronto, if we can accomplish some of this and then examining the impact, I think would be extremely beneficial. Dr. Lam:                               Fabulous, thank you so much Sana, thank you so much Tim for sharing your thoughts today.                                                 Listeners, you heard it right here on Circulation on the Run. Don't forget to tell all your friends about this podcast and tune in next week.                                                                                

Caroline:              Welcome to Circulation On The Run! Your weekly podcast, summary, and backstage pass to The Journal and it's editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore. What does the gut microbiome have to do with Cardiovascular Disease? Well to find out you'll just have to stay tuned for our featured discussion debate. First, here's our summary of this week's journal.                                 The first paper seeks to answer the question "does first trimester screening modify the natural history of Congenital Heart Disease?" To answer this question Doctor Jasinskyl and colleagues from the University Hospital in Masaryk University in the Czech Republic, analyze the spectrum of congenital heart defects and outcomes of 127 fetuses diagnosed with congenital heart defects in the first trimester compared to 344 fetuses diagnosed in the second trimester screening. All of these analyzed between 2007 and 2013.                                 They found that the spectrum of congenital heart defects diagnosed in the first versus second trimesters differed significantly with a greater number of comorbidities, defects with univentricular outcomes, intrauterine deaths, and terminations of pregnancy in those diagnosed in the first compared to second trimester.                                 They further analyze 532 fetuses diagnosed with congenital heart defects in the second trimester but in an earlier period of 1996 to 2001, which is the period before first trimester screening was introduced. In this group they found significantly more cases of defects with univentricular outcomes, intrauterine deaths, and early terminations of pregnancy. In comparison to fetuses also diagnosed with congenital defects in the second trimester but in the later period of 2007 to 2013.                                 Thus, the authors concluded that first trimester screening had a significant impact on the spectrum of congenital heart defects and on the outcomes of pregnancies with defects diagnosed in the second trimester. Early prenatal cardiac ultrasound screening may therefore, in some countries, reduce the number of children born with severe cardiac abnormalities and associated comorbidities.                                 The next study sheds light on the use of intravenous recombinant tissue plasminogen activator, or "RTPA," in patients with acute ischemic stroke also receiving no wax or the newer oral anticoagulants. Doctor Sienne and colleagues from the Duke Clinical Research Institute in Durham, North Carolina use data from the American Heart Association "Get With The Guidelines" stroke registry in 42,887 ischemic stroke patients treated with RTPA at 1,289 hospitals in the United States between 2012 and 2015. They basically found no statistically significant differences in the risk of symptomatic intracranial hemorrhage between patients who were taking Noac, Warfarin, or not taking any anticoagulant before the stroke.                                 This largest clinical experience of stroke thrombolysis in patients receiving Noac before the strokes thus suggest that RTPA is reasonably well tolerated without prohibitive risks for adverse events amongst selected Noac treated patients. However, the authors are quick to say that their observations must be considered as preliminary due to the absence of coagulation parameters, timing of the last Noac intake, and whether or not non-specific reversal strategies may have been applied.                                 The next paper provides experimental evidence of the unique effects of plasminogen activation and Alpha 2 antiplasmin inactivation on the fibrinolytic system in pulmonary embolism. In this paper from Dr Sing, Hong, and Reed from the University of Tennessee Health Sciences Center in Memphis, Tennessee the authors use mouse models of experimental pulmonary emboli to show that monoclonal antibody inactivation of Alpha 2 antiplasmin, which is an endogenous inhibitor of plasmin, effectively dissolved pulmonary emboli with similar potency to high dose RTPA.                                 Alpha 2 antiplasmin inactivation synergize with low dose RTPA to enhance thrombus dissolution. And like RTPA, Alpha 2 antiplasmin inactivation alone or in combination with low dose RTPA, did not cause fibrinogen degradation or increased bleeding. The authors therefore concluded that Alpha 2 anti plasmin is a dominant regulator that prohibits thrombus dissolution in vivo.                                 Therapeutic modulation of Alpha 2 antiplasmin activity may therefore prove an effective strategy to enhance fibrinolysis without significantly increasing the bleeding risk. These results are discussed in an accompanied editorial by Doctor Yurano from Hamamatsu University School of Medicine in Japan.                                 More exciting experimental data in the next paper showing that novel beta arrestin signaling pathways may be viable targets in dilated cardiomyopathy. First author Doctor Reba, corresponding author Dr Solaro, and colleagues from University of Illinois at Chicago treated a dilated cardiomyopathy mouse model expressing a mutant tropomyosin for three months with either a beta-arrestins two biased ligand of the entertance and receptor or losartan and angiotensin receptor blocker as control. Treated mice showed improved cardiac structure and function associated with myofilamins that had significantly improved myofilament calcium responsiveness. Which was depressed in the untreated mice.                                 These functional changes were mediated through beta arrestin which may have a novel role in increasing MLC2V phosphorylation through a previously unrecognized interaction of beta arrestin localized to the sarcamore. Thus, long term beta arrestin 2 biased agnonism of the angiotensin receptor may be a viable approach to the treatment of dilated cardiomyopathy. Not only by preventing maladaptive signaling but also by improving cardiac function by altering the myofilament calcium response via beta-arrestin signaling pathways. The concept of a two in one angiotensin receptor blocker and calcium sensitizer is discussed in accompanying editorial by Doctors Wu, Ju, and Siao from Peking university in China.                                 The final paper asks the question "are three arterial graphs better than two coronary artery bypass grafting?" Doctor Galdino and colleagues from Weill Cornell Medicine in New York performed a meta analysis of eight propensity score matched observational studies on more than 10,000 matched patients comparing the long term outcomes coronary artery bypass grafting with the use of two verses three arterial graphs.                                 They found that the use of a third arterial condo et in bypass grafting is a associated with superia long term survival irrespective of sex and diabetes status and without a higher operative risk. These results therefore support a strategy of the use of a third arterial graph and really deserve confirmation in prospective randomized trials. Well, that's it for the summaries. Let's welcome our guests.                                 Our topic for discussion today is so exciting. In fact, I am going to read from the paper describing it as an exciting, new, and important field of investigation where we start to understand how nutrition, our gut micro-community composition, and our genetics actually all play a part in Cardiovascular Disease. And to discuss this paper I have the first and corresponding author Doctor Wilson Tang from Cleveland Clinic Foundation as well as Doctor Nikhil Munshi, Associate Editor from UT Southwestern. Welcome Wilson and Nik! Nik:                        Thank you. Wilson:                 Thank you. Caroline:              Wilson, please set the stage for us! What does our gut microbiome have to do with cardiovascular disease? I agree it's a hot area but, you know, could you just describe what it actually means. Wilson:                 This has been somewhat of an accidental discovery from our group when we start encountering different types of metabolites that we measure to kind of associate them with Cardiovascular Disease. And unbeknownst to us, some of them are produced by the bacteria that live inside us to which we convert and try to eliminate. So one such metabolite that we identify is, which in many of the foods that we tell our patients, advise our patients that have high risk of Cardiovascular Disease. So all these connections come together to form a scientific basis to which how one of the biggest environmental exposures that we have which is what we eat every day is filtered by trillions of bacteria that live inside us and many of these metabolites become hormones that effect our every day function and activity.                                 And, in many ways, can actually lead to diseases that are so remote from the gut but such as Cardiovascular Disease, Atherosclerosis, and we further identify these process and they impact downstream organ function like heart function and kidney function. So these are all very excited areas and this is just one of several metabolites. There are other metabolites that also impact blood pressure and even brain function and so all these areas become kind of a new avenue for us to look at potential therapeutic targets. Caroline:              Yeah I think it's so completely fascinating that we can actually each experience a given meal differently based on the different types of gut microbial communities in our bodies isn't it? And that that actually can effect things all the way from atheroscleroses, to obesity, insulin resistance, and so on. Could you give us a specific example from your research? Wilson:                 We actually identified a metabolite, a very small molecule called Trimethylamine N-oxide, we abbreviate it as TMAO. And TMAO is actually formed from the bacteria from a precursor called Trigosamine which is, you know, gas. In other words, the bacteria taken substances of nutrients such as choline and connetine which is actually common in many foods but particularly in red meats, in egg yolks, and many other foods that we know are potential contributors to Cardiovascular Disease.                                 And actually converted into this gaseous compound that our liver converted into a neutral compound, that we think is neutral for a long time and nitrogenous waste, except that when we have both animal studies and human studies patients with high levels of this TMAO metabolite has been associated with a high risk of Cardiovascular Disease. And in fact in animal studies we have direct evidence that show its contributing to the mechanistic compartment. Caroline:              Now extrapolating from what you just said so vegetarians, for example, or vegans even more so, would have less TMAO levels then? Wilson:                 Yeah, obviously there are wide variation in these levels actually change almost by the minute because obviously we eat different times of the day and it comes in and out of our bodies. But in general, yes, in other studies that we actually identified a higher level of in carnivores which are meat eaters verses vegans and vegetarians who do not eat meat. Wilson:                 Yeah and we actually use... I sort of labeled choline and connetine to actually directly show that the synthesis of TMA and TMAO by a labeled connetine is higher in meat eaters, carnivores, verses vegetarian or vegans. Caroline:              Oh, I really have to ask both you Wilson and Nik the following question then. What do you think is the, you know, take home message? How do you apply this clinically and even more cheeky, perhaps, how are you applying this in your own life? I mean with this knowledge have you become vegetarian? I'm putting you on the spot here. Wilson:                 I think this is basically a very scientific demonstration of how what we eat does impact our every day bodily function. And I think many cultures have this identification. Obviously many Asian cultures have seen the impact of food. In fact, it actually opens entire insight into how different medicinal food may actively be impacting the gut microbiome that actually creates different effects in the body. But in terms of diet and nutrients, yeah I have totally have eaten less meat in my every day dietary habits.                                 I definitely think it's something that is certainly quite insightful and probably very impactful. That being said, I think different cultures also have different populations of microbiome and I think it's not a one size fits all. In fact I think every individual has his own dynamic ranges and we are still in the very very first early stage of understanding how this impact helps in disease. So there's a lot of excitement and there's a lot of technology that hopefully can help us to unravel this mystery. Caroline:              Exactly, a new and important field just like you said. Nik, what do you think? Nik:                        From my standpoint, I'm actually not a big meat-eater so this was very welcomed news when this all came out. But, you know, from another standpoint it really opens up a lot of new questions. You know, it kind of blurs the line between sort of genetics and environmental factors. You know, so the questions of maybe a family who shares certain genetic traits may also share certain environmental traits. In other words, they share certain gut microbial components and maybe this sort of complicates how we're going to disentangle some of these risk factors going forward. I'm interested to get Wilson's take on this. Wilson:                 Yeah it gives us a lot of insight to the I guess what happens is the microbiome is isolated in the family lineage because the lifestyle exposure are very similar in each household. So, what we thought is inherent is being inherited from both the genomic but also a microbiome perspective. Caroline:              Nik, you manage this paper. I really love, for example, that figure which I think everyone should get ahold of the journal and have a look at. Could you tell us a little bit more about this category of papers? Wilson:                 I'm sort of charged with this task of bringing sort of basic Science across the aisle to clinicians so that we can all sort of talk the same language and perhaps interact on a higher level. And so I was really excited reading some of Wilson's work and you know I really wanted to bring that to some of our broad readership just so that we could sort of appreciate what sort of science was going and I really think that this is a really great example of something that's on the verge of being translated.                                 You know you can imagine that by either effecting certain metabolite compositions or maybe by treating certain subsets of bacteria we may be able to influence long term cardiovascular risks not to mention obesity, diabetes, and some of these other diseases that Wilson is actively working on. So I really read this with a lot of excitement and I wanted to bring this to a broader audience and you know we have a number of other articles that are in the pipeline that I think will serve to bridge this gap and put us on the same field so that we can kind of speak the same language. Caroline:              Wilson, did you have a good time sort of writing something like this its not long. Wilson:                 It's actually very difficult. In fact, its just like writing poetry. You know it's hard to write in simple and short sentences. So it actually was a big challenge for me and I really thank the opportunity to be able to do that but I also want to emphasize I think it was a very insightful experience for me too. Because as a practicing physician and a commissioned scientist don't always merge these too few, these two areas in a way to actually see the importance we like to learn the science and try to explore I think clinicians really need to take charge and learn exciting science that's occurring. I think this is a wonderful avenue and I applaud [inaudible 00:18:10] for setting this radio [inaudible 00:18:11] Caroline:              Well listeners you heard it first here on Circulation On The Run it is poetry by Wilson Tang. So please, please pick up a copy of today's journal and don't forget to tune in again next week!

  Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.                                                 In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.                                                 The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.                                                 They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.                                                 On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence.                                                  In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.                                                 The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.                                                 This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.                                                 All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.                                                 They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.                                                 In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.                                                 In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.                                                 The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.                                                 They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.                                                 Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.                                                 Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.                                                 The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.                                                 The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.                                                 These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.                                                 After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.                                                 These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.                                                 The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.                                                 As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.                                                 The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.                                                 Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.                                                 Those were your highlights. Now, for our featured discussion.                                                 On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.                                                 This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.                                                 Welcome Daniel. Dr. Daniel Singer:             Thank you for having me. Dr. Carolyn Lam:               Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana. Dr. Sana Al-Khatib :         Thank you Dr. Carolyn, I'm happy to be here. Dr. Carolyn Lam:               Daniel, could we start by you letting us know what you sought to do in your study and what you found? Dr. Daniel Singer:             We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.                                                 There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.                                                 While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.                                                 What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper. Dr. Carolyn Lam:               Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation. Dr. Daniel Singer:             We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.                                                 Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.                                                 Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.                                                 If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"                                                 We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores. Dr. Carolyn Lam:               The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static. Dr. Daniel Singer:             Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.                                                 We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.                                                 One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation. Dr. Carolyn Lam:               Daniel, congratulations again for that fascinating and really very sobering findings.                                                 Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts? Dr. Sana Al-Khatib :         Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.                                                 A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.                                                 I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well. Dr. Daniel Singer:             Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.                                                 The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.                                                 We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.                                                 This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.                                                 I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror. Dr. Sana Al-Khatib :         That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.                                                 As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.                                                 If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.                                                 In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that? Dr. Daniel Singer:             I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.                                                 At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.                                                 We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke. Dr. Sana Al-Khatib :         I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.                                                 I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.                                                 One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients. Dr. Carolyn Lam:               Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.                                                 Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings. Dr. Daniel Singer:             I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.                                                 The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.                                                 I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid. Dr. Carolyn Lam:               Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.  

Carolyn: Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. [Carolyn Nam 00:00:08], associate editor from the national heart center and Duke National University of Singapore ...     In just a moment we will be discussing the exciting new results of the [Prague 00:00:21] 18 study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. But first, here's your summary of this week's issue ...     The first study represents the largest published study on the association between PR interval and cardiac resynchronization therapy with defibrillator versus implantable cardioverter defibrillator and real world outcomes. Dr. Friedman and colleagues from Duke Clinical Research Institute studied 26,451 CRT eligible patients from the National Cardiovascular Data Registry ICD Registry. They found that a PR interval at or above 230 milliseconds was associated with increased rates of heart failure, hospitalizations, or death among CRTD but not ICD patients. The real world comparative effectiveness of CRTD versus ICD was significantly less among patients with a PR interval above 230 milliseconds compared to patients with a shorter PR interval.     The authors discuss that these findings may be due to the association between a prolonged PR interval and factors associated with lower rates of CRT response such as non-left bundle branch block morphology, ischemic heart disease, or atrial arrhythmias. It could also be due to the association between delayed AV conduction, disordered diastolic filling, and contemporary CRT reprogramming strategies. The take home message is: in CRT patients with a prolonged PR interval, recognize that they are at high risk for poor outcomes and merit close follow up and consideration of AV optimization ...     The next study is the first adolescent study of serum lipidomics that identifies a new panel of serum glycerophosphocholines that are associated with cardiovascular risk. First author Dr. [Sine 00:02:29], corresponding author Dr. [Palsova 00:02:31], and colleagues from Hospital for Sick Children in University of Toronto recognize that atherogenic dislipidemia is traditionally assessed with high abundance lipids, such as cholesterol and triacylglycerols, which accumulate at millimolar levels in blood. Current advancements in mass spectrometry now allow the discovery and study of new low abundance lipids, which circulate at micro- or nanomolar blood levels. And one such example are the glycerophosphocholine metabolites.     They studied a population based sample of 990 adolescents with age range 12-18 years using liquid chromatography electrospray ionization mass spectrometry. They identify several novel glycerophosphocholines that were associated with multiple cardiovascular disease risk factors. Mediation analysis revealed that these novel glycerophosphocholines mediated their respective relationships between visceral fat and cardiovascular disease risk factors. Furthermore, a particular glycerophosphocholine shown recently to predict incident coronary heart disease in older adults was already associated with several cardiovascular disease risk factors in these adolescents.     The clinical implication is that the development of a lipidomics signature that could facilitate early intervention or treatment of those at high risk of cardiovascular disease or monitor response interventions could help triage limited healthcare resources. Furthermore, future research on glycerophosphocholines might improve biological understanding of disease and identify potential drug targets to impede cardiovascular disease development ...     The next study also describes plasma lipidomic profiles but this time in patients with type 2 diabetes. This study is from first author Dr. [Elchuri 00:04:35], corresponding author Dr. [Meekly 00:04:37], and colleagues from the Baker IDI Heart and Diabetes Institute in Melbourne, Australia. These authors performed a targeted lipidomic analysis using liquid chromatography electrospray ionization tandem mass spectrometry in a case cohort of 3,779 patients with type 2 diabetes and one or more additional cardiovascular risk factors from the advance trial.     They found that sphingolipids, phospholipids, cholesterol esters, and glycerol lipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model of 14 traditional risk factors and medications improved the prediction of cardiovascular events. The prediction of cardiovascular death was also improved with the incorporation of 4 lipid species to the base model. These results were further validated in a subcohort of type 2 diabetes from the lipid trial. In summary, this important study demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes ...     The last study sheds new light on the optimal ablation method for atypical atrioventricular nodal reentrant tachycardia or atypical ARNVT. Dr. [Catrisis 00:06:10] and colleagues from Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts study 2,079 patients with AVNRT subjected to slow pathway ablation. In 113 patients, atypical AVNRT or coexistent atypical and typical AVNRT without other concomitant arrhythmias was diagnosed. Ablation data and outcomes were compared to a group of age and sex matched control patients with typical AVNRT. The authors found that in the atypical group slow pathway ablation was accomplished from the right septum in 110 patients and from the left septum in 3 patients. There was no need for additional ablation lesions at other anatomical sites and no cases of AV block were encountered.     In summary AVNRT, regardless of the type, appears to be successfully ablated by targeting the anatomic area of the slow pathway. When a right septal approach is not successful, the anatopic area of the slow pathway can be ablated from the left septum and so it seems the slow pathway participates in both typical and atypical AVNRT. The take home messages are that catheter ablation at the anatomical area of the slow pathway from the right or left septum may be the treatment of choice for atypical AVNRT. The approach is not associated with an increased risk of inadvertent AV block. The recurrence rate following ablation of atypical AVNRT may not be significantly higher than that seen following the ablation of typical AVNRT.     Those were the highlights from this week's issues. And now for our feature paper ...     We're so pleased to have with us today for our podcast interview first and corresponding author of the Prague 18 study, Dr. [Zuzana Motovska 00:08:12] from Charles University in Prague. Welcome Zuzana.   Zuzana: Thank you for having me.   Carolyn: We're also so lucky to have Dr. [Gabriel Stig 00:08:21], associate editor from Paris, and I understand you're even traveling at the moment. Thank you, Gabriel for making the time.   Gabriel: Yes, hello Carolyn, hello Zuzana.   Carolyn: So let me start by congratulating you Zuzana on this first head-to-head comparison study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. And what a lovely study acronym of course, Prague 18. Could you maybe start by describing, in the Czech Republic before your study, how were clinical decisions being made between prasugrel and ticagrelor in these patients?   Zuzana: The current guidelines prefer newer P2Y12 inhibitors over clopidogrel for patients with acute coronary syndromes. Prasugrel and ticagrelor are being increasingly used in patients [with just 00:09:15] primary PCI in Czech Republic. Analysis of our registry documented that doctors did not view these two drugs as interchangeable and prasugrel is a drug associated with a high risk of bleeding. Our data show that safety in terms of bleeding risk was the most important aspect under consideration when choosing one of new agents for an individual patient. The same observation has been reported from other contemporaries from other countries and according to the published subgroup analysis of [stratum 00:09:54] and other studies we have also perceived prasugrel to be a more effective agent for primary PCI. We prefer this drug in patients with a high thrombotic risk.   Carolyn: Could you, maybe now, clearly describe what you did in this study and what were your findings?   Zuzana: The Prague 18 study truly [inaudible 00:10:19] was designed to test the hypothesis on whether one of the newer drugs, prasugrel or ticagrelor, is more effective and safer than the other one in acute myocardial infarctions, which is the primary [treatment 00:10:36] strategy. We randomized the total 1,230 in 14 participating sites. I highlighted hemodynamic instabilities, was not an [excluding 00:10:52] criterion for study participation. The patients were randomized for prasugrel or ticagrelor immediately on hospital arrival and the recommended dosing regiments were used for both drugs. The prasugrel dose was reduced during the maintenance phase in patients over 75 and [reduced vein 00:11:12] was the [sixth 00:11:14] feature around presence of both these parameters was an exclusion criterion.     So, what we find. Fewer [unsourced 00:11:23] primary endpoint composed of all cause of death or reinfarction show serious bleeding or urgent vessel revascularization within 7 days after randomization or discharge if prior to the seventh day. They did not differ between groups, either for in 4 person prasugrel group and in 4.1 person in ticagrelor group. The appearance of key secondary end point composed of cardiovascular death, nonfatal MI, or nonfatal stroke. Within 30 days did not show any significant difference between prasugrel and ticagrelor, furthermore no significant difference was found in any of the components of the primary and secondary endpoints and also no significant difference was observed in the appearance of definite vein thrombosis [inaudible 00:12:17] days after randomization.     So the study did not show any difference between ticagrelor and prasugrel in the early phase of a mild [treatable 00:12:26] primary PCI. Because of small sample size the confidence for the estimation of the [interval 00:12:35] of either were quite high, however we identify differences, which are very low in absolute numbers and [inaudible 00:12:45]   Carolyn: That was very nicely explained Zuzana, thank you. Now could you share a little bit more about, were you powered for this analysis and the decision to stop early.   Zuzana: Oh yes, the power analysis was computed for primary endpoint difference of 2.5 person and the needed sample size was estimated at 2,500 patients. The interim analysis led to a decision to terminate the study prematurely because of futility. No significant difference in primary endpoint was found between the two study drugs in the course of the entire randomization process, moreover the difference in appearance of the primary endpoint between the compare groups was declining with a growing number of randomized patients and analyzed on the different 0.1% and this was the decision why we stopped the trial prematurely.   Carolyn: Right. Gabriel could you comment a little bit as the associate editor managing this paper, how do you think it's going to impact practice?   Gabriel: First of all, let me start by congratulating Zuzana and the team of the Prague 18 trial for this academic trial. I think it's really important that we have a clinically led effort to investigate optimal treatments in modern cardiology in general and specifically in acute coronary syndromes. We've known for several years now, through large randomized trials, that the novel P2Y12 agents, ticagrelor and prasugrel, are clearly superior to clopidogrel but we don't know which of the two agents to choose and we know that comparison across trials are fraught with major methodological problems. So with evidence that prasugrel is superior to clopidogrel for PCI treated ACS patients, there was evidence that ticagrelor was superior to clopidogrel for ACS patients in general but we didn't have any rational data on which to base a rational selection process between the two agents.     Really, I think it's an important issue and often people state that these are delicate differences between agents, and we shouldn't expect that this is going to impact clinical outcomes. Actually it does impact clinical outcomes because we know that those novel agents have had a roughly 20% reduction in major heart outcomes compared to clopidogrel so this is not a moot point. It's not a minute difference, it's a huge difference and it's an important clinical issue. That's my first point, I think it's an important question and I really want to commend the investigators for launching this trial despite not having the support of industry.     The second point I want to make is I think that the results from the trial are not yet complete because we don't have the one year follow-up and I know that this is planned and the investigators are continuing follow-up of their patient cohort, which I think is going to be important because it's conceivable that differences may emerge over time as was, in fact, the case in some of the previous trials. In [plato 00:15:49] there was a modest difference early on but the curves diverged over time between clopidogrel and ticagrelor so it's conceivable that differences that are absent at 30 days might emerge over time.     In fact, I have a question for Zuzana. One of the interesting features and important issues that needs to be addressed is ... I know that in some sites in the Czech Republic, because of the out of pocket expenses related to the cost of the novel agents, it was allowed for patients to be switched back to clopidogrel after hospital discharge. Do you have any sense of what is the proportion of patients who are scaled back to clopidogrel instead of prasugrel or ticagrelor after initial index submission?   Zuzana: Thank you Gabriel, it's true the study ... a lot of patients who are unable to bear the cost associated with long term treatment with the study medications and switch to clopidogrel. Therefore, a second goal of the study was to assess the rate, the reason, and also the consequences of switching from a study drug to clopidogrel after the acute phase in the course of 12 months follow-up. We are not focusing on the study completion and analysis that are related to the second study. There are, of course, patients who switch from prasugrel or ticagrelor to clopidogrel also in first 30 days and this proportion was about one third of patients.   Gabriel: The other point I want to make really relates to the power issues and Zuzana already pointed out herself this important issue. The paper is actually accompanied by an excellent and very cogent editorial by Steve [Webiok 00:17:31], who discusses explicitly and in great detail the issue of sample size. We know that the relative difference between the novel agents and clopidogrel is in the range of 20% so we might expect that the difference between the two novel agents themselves, when we compare prasugrel and ticagrelor, might be less. Yet the study was powered for actually a greater relative risk reduction than what was seen in the pivotal trials of prasugrel and ticagrelor compared to clopidogrel. So the study is really on the low end of the power spectrum and I think, as you pointed out Zuzana, it's important to keep in mind that the confidence interval for the relative risk between ticagrelor and clopidogrel both act together on prasugrel, both for the primary endpoint, which is a combination of efficacy and safety, as well as for the key secondary endpoint of efficacy.     It's really very wide and we can't rule out a major benefit or a major detrimental effect of one agent versus the other. I think this is important to keep in mind because many people equate a neutral result of a trial, a non-significant result, particularly in the [secondary 00:18:36] trial, with lack of difference or clinical equivalence or non-inferiority and I think it's important to remember the readers that this is not a non-inferiority trial, it's not a clinical equivalence trial, it's superiority trial that is actually with a neutral result. It's really and important issue.     Yet, because it's the first head-to-head comparison, because it's an academic effort independent, and because it's going to report one year outcomes, I think this is a critical effort and the investigators need to be lauded for that. Even if this study isn't powered, it will be able to be pulled in further meta-analysis with other upcoming studies that are similar that also may be underpowered and provide us with a hint of evidence of what might be the best agent to use, which is an every day clinical question. This is a very, very common condition and any unbiased evidence we can get from randomized trials is very valuable ...   Carolyn: Thank you, everyone, for listening to this episode of circulation on the run. Tune in next week ...  

1) Impaired self-agency in functional movement disorders2) What's Trending: Interview with James Sejvar about possible links between Zika virus, microcephaly, and Guillain–Barre syndrome3) Topic of the month: Neurology Today story about where advances are revolutionizing stroke treatmentThis podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Michelle Fullard interviews Dr. Carine Maurer about her paper on impaired self-agency in functional movement disorders Dr. Andy Southerland is interviewing Dr. James Sejvar for our “What's Trending” feature of the week on the topic of possible links between Zika virus, microcephaly, and Guillain–Barre syndrome. Dr. Andy Southerland interviews Dr. Ralph Sacco about a Neurology Today story on the topic of where advances are revolutionizing stroke treatment.DISCLOSURES: Dr. Maurer receives research support from the NINDS Intramural Program.Dr. Southerland serves as Podcast Deputy Editor for Neurology; receives research support from the American Heart Association-American Stroke Association National Clinical Research Program, American Academy of Neurology, American Board of Psychiatry and Neurology, Health Resources Services Administration and the NIH; has a provisional patent application titled: “Method, system and computer readable medium for improving treatment times for rapid evaluation of acute stroke via mobile telemedicine;” and gave legal expert review.Dr. Sacco serves as an editorial board member of Stroke and Neuroepidemiology; serves on the scientific advisory board for DSMB for SOCRATES Trial through UCSF(indirect sponsor Astra Zeneca) and EUCLID trial through Duke Clinical Research Institute (indirect sponsor Astra Zeneca); receives research support from Boehringer Ingelheim, Evelyn McKnight Brain Institute, American Heart Association Burgher Foundation and the NIH.

Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. I am excited to be joined today by 2 guests and we will be discussing the feature paper on phenotype specific treatment of heart failure with preserve ejection fraction but first here are the highlights from 5 original papers in this week's issue. (0:42) The first paper by first author doctor Haas, corresponding author Dr. Bidinger and colleagues from Boston Children's Hospital aim to investigate the role of PCSK9 in nephrotic syndrome associated hypercholesterolemia. The authors did this by first looking at 50 patients with nephrotic syndrome and showing that resolution of nephrotic syndrome was associated with a decrease in their plasma cholesterol, as well as a decrease in their plasma PCSK9 levels. They then looked at two mouse models of nephrotic syndrome. One using nephrotoxic serum to induce immune mediated damage of the kidney podocytes. The second, a model of genetic ablation of the kidney podocyte. In both these models nephrotic syndrome produced hypercholesterolemia and a 7 to 24 fold induction of plasma PCSK9 levels. The authors then went on to look at the effect of knocking out PCSK9 both in the whole body as well as specifically in the liver in these mice. They showed that mice lacking PCSK9 no longer showed the increase in LDL cholesterol with nephrotic syndrome induced by nephrotoxic serum. Thus in summary, podocyte damage triggered mocked inductions in plasma PCSK9 and conversely knocking out PCSK9 in ameliorated this lepodimia in a mouse model of nephrotic syndrome. The cool thing about this data is that they now opened the door to the consideration of PCSK9 inhibitors in patients with nephrotic syndromes associated hypercholesterolemia. (2:45) The second paper by Dr. Fortis and colleagues from Duke Clinical Research Institute aimed to address an important knowledge gap that has not yet been addressed in the pivotal noac trials or large registries. Which is whether outcomes differ among atrial fibrillation papers with worsening renal function compared with those with stable renal function while taking a noac versus warfarin. The authors looked a this by studying more than 12,600 patients who were treated with rivaroxaban compared to warfarin in the ROCKET AF trial. On treatment worsening renal function was defined as a decrease of more than 20% from screening creatinine clearance measurement any time point during the study. The main finding was that among patients with on treatment worsening renal function, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin without an increase in the composite leading end point. This is really encouraging to all of us who treat these patients, knowing that it is possible to safely anti-coagulate patients with worsening renal function without excessive bleeding and to know that rivaroxaban may be an alternative to warfarin in these patients. This paper is accompanied by a beautiful editorial on the multifaceted dilemma of renal function and atrial fibrillation by doctors Hijazi and Wellington. (4:30) The third paper by doctor [inaudible 00:04:32] and colleagues from Massachusetts Journal Hospital describes a randomized controlled trial of an advanced care planing video decision support tool in 246 patients with advanced heart failure. Patients were randomized to an intervention arm which consisted of a six minute video as well as an advanced care planning checklist or to a control arm where patients received only a verbal description of the goals of care. This video began by first introducing to the patient the concept of advanced care planning and then using images to depict the three part goals of care namely, life prolonging care, limited medical care and comfort care. Patients in the intervention arm who were showed the video, were more likely to be informed, to select a focus on comfort and less likely to desire CPR and intubation compared to patients receiving the verbal information only. The clinical application of this finding is that advanced care planning video decision needs can stimulate and supplement patient decision communication. Indeed we need such tools to enhance patients understanding of their goals of care options and to ensure that our patients get care that reflects their well-informed wishes. (6:10) The fourth paper is by first author Dr. [inaudible 00:06:12] and corresponding author Dr. Lloyd Jones and colleagues from the Northwestern University Feinburg school of medicine in Chicago. These authors provided the first prospective evaluation of atherosclerotic cardiovascular disease outcomes in adults with heterozygous familial hypercholesterolemia in the US population. They did this by using individual pool data from 6 epidemiologic cohorts including more than 68,500 baseline person exams and 1.2 million person years of follow up. They confirmed substantially elevated long term, meaning up to 30 year risks of coronary heart disease and total atherosclerotic cardiovascular disease including stroke in US adults with a familial hypercholesterolemia phenotype defined as LDL cholesterol above 190 milligrams per deciliter. This was associated with an acceleration of coronary heart disease risk by up to 20 to 30 years. These findings were independent of other risk factors and were consistent using various definitions of the familial hypercholesterolemia phenotype. What are the clinical implications of these findings? This was discussed by Dr. Rodriguez and Dr. [inaudible 00:07:47] in an editorial, the take home message is that there is likely an important long term burden of atherosclerotic cardiovascular disease in phenotypic but unrecognized familial hypercholesterolemia patients in the United States. Current efforts to identify patterns and gaps in the diagnosis and management are well justified. The findings also have implications for risk communication to patients. (8:20) Finally, the fifth paper is by Dr. [inaudible 00:08:25] and colleagues of the TIMI study group from Brigham and Women's Hospital. These authors looked at the impact of renal function on outcomes with edoxaban and oral factor 10 A inhibitor with 50% renal clearance compared to warfarin in the ENGAGE AF-TIMI 48 trial. In the pre-specified subgroups of granting clearance 30 to 50 and more than 50 ml per minute. The higher dose edoxaban regiment was comparable to warfarin for preventing stroke or systemic embolism and resulted in significantly less major bleeding. In further exploratory analysis, there was a suggestion of lower relative efficacy for prevention of stroke or systemic embolism with the high dose edoxaban regiment, compared to warfarin in the upper range of creatinine clearance beyond 95 ml per minute. Due to lower rates of major bleeding, the net clinical benefit was more favorable with the higher dose edoxaban regiment across the range of creatinine clearance. In summary, edoxaban demonstrated superior safety and comparable efficacy to warfarin for the prevention of thromboembolic events in many patients with atrial fibrillation. However the authors were careful to note that there was insufficient evidence to allow definitive conclusions to be drawn in patients with normal renal clearance above 95 ml per minute. The authors called for further investigation of optimal dosing of edoxaban in the higher range of creatinine clearance. (10:14) Those were our highlights now for our feature paper of the week. Phenotype specific treatment of heart failure with preserved ejection fraction, a multi-organ road map. The first author is Dr. [inaudible 00:10:31] from Northwestern University Feinberg School of Medicine in Chicago and colleagues. To discuss this very special paper today I have two guests, one is a corresponding author, Dr. Walter Paulus from the VU, University medical center in Amsterdam as well as Dr. Jarett Berry, associate editor from UT Southwestern. Welcome Walter and Jarett. Jarett Berry: Thanks Carolyn. Walter Paulus: Thank you very much Carolyn. Carolyn Lam: To start us off this is an in depth review paper and it is a really very special type of paper that it's new to Circulation. Jarett could you tell us a little bit about these reviews and how this paper came to be? Jarett Berry: As we think about the new Circulation and our goals to really make the content of Circulation as clinically relevant as possible, as we think of the different circumstances and clinically challenges faced by practicing physicians, many different topics come to mind and one in particular, therapeutic area heart failure with preserved ejection fraction is one particular type of cardiovascular disorder that has been very difficult to find novel treatments for. As we all know there has been a number of large scale clinical trials that have failed to improve clinical outcomes in these patients, in situations like this what we really need is wisdom and a guide from those with expertise in this area so we can take that wisdom and that perspective and incorporate it into our approach to caring for these patients in a way that can provide a road map moving forward. This particular review addressing heart failure with preserved ejection fraction was timely in that sense and the choice of author, of course, Walter and his colleagues are leaders in the field in terms of the research and our understanding of HFpEF. With that goal, we're really trying to reach out to these types of investigators for these types of reviews to provide us with a framework to help us think about charging our way forward and we couldn't think of a more appropriate choice to lead that effort other than Walter Paulus. Carolyn Lam: Thank you so much Jarett, that's so well put and I couldn't agree more. I mean HFpEF is one of those disease syndromes were guidelines haven't changed in years and basically the first sentence is that we don't have outcome improving treatments available. Walter this must have been particularly challenging and I really congratulate you because one of the central figures that I'm so impressed with in this review is actually a clinical application figure and I'm referring to figure 2. Do you think you could tell the readers a little bit more about this? Walter Paulus: I would like to thank first the editors of Circulation for having given us the opportunity to write this in-depth review. I must admit before answering Carolyn's question that I really enjoy this [inaudible 00:13:37]. We have a very challenging team of co-authors and the most difficult part of the enterprise was to have all the noses directed in the same direction. You have to align very many ideas and it has been a very challenging in-depth but I think it will be teamed out with a, not a compromise but something, a paper where everybody is still happy with its content. This is somehow also reflected in the figure 2 to which Carolyn is alluding. When we start speaking about the phenotypic diversity, it's very difficult to [inaudible 00:14:13] with a conceptual theme on how we're going to organize therapy when there are many different phenotypes around. I think this is what this figure is all about, it tries to organize the phenotypic diversity and come up with a type of personalized medicine for each phenotype in a very comprehensive way. This figure, in fact, orders the phenotypes, presentation phenotypes and pre-disposition phenotypes with presentation phenotypes on the abscissa and the pre-disposition phenotypes on the ordinate. Then you get a matrix configuration, you start out in the matrix in the left hand corner for the most common phenotype which is metabolic risk combined with [inaudible 00:14:59] congestion. Then you go on and you see that you can have [inaudible 00:15:04] hypertension, then you have additional measures that need to be taken. You can go downwards in the graph and then you'll find out that it might be renal dysfunction and then you find specific measures that have to be taken when renal dysfunction is present. By combining the ordinate and the abscissa in the matrix, you find a very personalized type of therapy for the individual phenotype. I think this to me what makes the figure that feeling is that it's structured, it's organized, it's something very complex in something which is easily comprehensible. Carolyn Lam: Walter, I have not seen a figure like this that it's so novel and I know that clinicians will really welcome this because as Jarett so nicely put, it's wisdom and some sort of simplification and yet with in-depth understanding that we so need in the management of this syndrome. Another thing that I thought was very special about your paper is that you tackled head on the divergent results of several recent trials. You described the low nitric oxide, low cyclic guanosine monophosphate cycle that's present in HFpEF but also try to put into context the need trial, the relax trial, top cat and even mention Socrates preserved in all of this. Do you have any quick top line comments, not to give the whole story away because I'm sure readers are now encouraged to look at the paper but on how all of this actually falls into place in your schema. Walter Paulus: I think how everything falls into place is illustrated in the figure 1. Figure 1 shows a very broad perspective on the problems of HFpEF as it shows HFpEF to be the result of systemic inflammatory state but so far we have focused only on the project manifestations of the systemic inflammatory state [inaudible 00:17:08] cardiac manifestations, which is the stiffness of the myocardium, and the [inaudible 00:17:12] of the myocardium. There are also things going in the pulmonary [inaudible 00:17:16], there are things going on in the skeletal muscle and there are things going on in the kidney. I think that if you do not take these other organs into perspective, then the image you will have from the results of your trials is getting blurred. For instance, we have so many trials about look at the exercise [inaudible 00:17:35] in terms of elevation of [inaudible 00:17:37]. It's my feeling that many patients with HFpEF just get treated diabetic. You see them afterwards again in your [inaudible 00:17:46] patient clinic and they have symptoms of nasal fatigue. They no longer being hindered by the elevation of [inaudible 00:17:52] probably because of the administration of the diabetic but they're still highly symptomatic and they have moved over to another board and that limits the [inaudible 00:18:01] mainly the skeletal muscle. It's of course nicely illustrated already for years by the work of Dalane Kitzman which is one of the co-authors, but still these issues, the same goes for the hypertension, a field in which Carolyn has been very active. There are some patients who are persistent [inaudible 00:18:18] hypertension, I'm intrigued by our classification. It's clear that these patients have moved to a [three catalyst 00:18:24] type of hypertension and we should pay attention to this and we should try to treat it in a very specific way. Again [inaudible 00:18:33] the failure of our trials is also comprehensible. He have two, [inaudible 00:18:38] focus on the myocardium and we should try to keep a very broad perspective and look at [inaudible 00:18:43] in major broader way. Just to support this point is the result of the Socrates reserve trial which I was very intrigued by it, just listen to the results couple of days ago at the European Heart Failure Society meeting in Florence. Turns out if you give this very [inaudible 00:19:01] patients that there is no change in nature at [inaudible 00:19:05], no change in left atrial dimension, there's no single argument that something is changing in the myocardium. Nevertheless the effort tolerance of the patients was greatly increased and the question is in quality of life, how that has drastically improved? What I think is going on, is that maybe on the dose of the [inaudible 00:19:23] you are using this very [inaudible 00:19:24]. The main effect might be going on the [inaudible 00:19:27] and you just took the wrong end point, you are again focusing very narrowly on the myocardium. I think most of the patients have entered such a trial are relatively stable. You're not going to put in a trial a patient who is unstable, they must be all be treated with diabetics and you shift symptoms from the myocardium to the other organs. I think that the index review which we provide, I think has 2 main issues, that you should have a broad perspective on HFpEF with inclusion of the other organs and secondly, that we provide a matrix configuration for phenotypes specific treatment. Carolyn Lam: Walter that is beautifully put and Jarett I think I'm speaking on behalf of you too that this paper has really accomplished what our in-depth reviews were aiming to do, which is to provide a clinical perspective and really insightful comments regarding the syndrome. Is there anything else you'd like to add Jarett? Jarett Berry: Yeah, I just wanted to echo your congratulations and just to really highlight the importance of this figure 2. I think it is an important step for us to begin to take the concept of the heterogeneity the phenotype, whether it's something happening centrally or peripherally and take that heterogeneity and try to incorporate that into our practice pattern. I think that's obviously been discussed in length in literature before but has not been put together in a practical way for practicing clinicians. I just want to echo your comments that Walter and his coauthors have done an important service for all of us as we think about how to take care of our patients with HFpEF. Carolyn Lam: That's awesome, I think anyone listening is really going to want to take hold of that journal and have a look at both figures, 1 and 2 and read this beautiful paper. Thank you very much Jarett and Walter for your time, today. Jarett Berry: Thanks Carolyn. Walter Paulus: Thank you very much Carolyn, [good night 00:21:20]. Carolyn Lam: You've been listening to Circulation on the Run, thank you for listening and don't forget to join us next week for more highlights.    

In this episode of the Heart Podcast, Heart Digital Media Editor Dr James Rudd is in conversation with Dr Chris Fordyce from the Duke Clinical Research Institute. His team has just published an Education in Heart paper on "Optimal non-invasive imaging test selection for the diagnosis of ischemic heart disease." In this podcast, they discuss the similarities and differences between the international guidelines on the investigation of chest pain. They also highlight the results of the landmark PROMISE and SCOT-HEART studies and discuss how the results of these trials might influence future guidelines. The paper contains many high-resolution multimedia elements, along with MCQs to test your knowledge in this area.

We are really excited to present the first female guest in our show: Today's guest is Pamela Douglas, MD. She is the Ursula Geller Professor for Research in Cardiovascular Diseases at Duke University and Director of the Duke Clinical Research Institute's Imaging Program. Dr. Douglas is internationally known for her scientific work in noninvasive imaging especially echocardiography. She's the author of over 320 papers and over 30 national guidelines, she has previously served on the faculties of the University of Pennsylvania, Harvard University and the University of Wisconsin. She was chief of cardiovascular medicine at Duke University and the University of Wisconsin as well as President of the American College of Cardiology and the American Society of Echocardiography. In this interview we talk about what makes a good researcher and clinician and she gives advice to all female doctors and scientists on how to be successful. In this short interview (around 30 minutes) we talk about how to be happy and successful as a cardiologist, what makes a great clinician, researcher and overall human being. If you are working in cardiology, you don't want to miss these valuable nuggets of wisdom! For more show-notes, please visit our blog at www.medmastery.com/blog  

Host: Lawrence Sherman, FACEHP, CCMEP Join host Lawrence Sherman at this year's meeting of the Alliance for Continuing Education in the Health Professions (ACEHP), formerly the Alliance for CME, held on January 21-24, 2012 in Orlando, Florida. His two guests are: Dr. Catherine Grichnik, Director of the Center for Educational Excellence at the Duke Clinical Research Institute. She is also Associate Dean for Duke CME and Professor of Anesthesia at Duke University. Dr. Grichnik discusses interdsciplinary learning environments for physicians. Dr. Jack Kues, Vice President of the ACEHP and Associate Dean for Continuous Professional Development at the University of Cincinnati. Dr. Kues discusses the evolution of CME and its impact on practicing healthcare professionals.

Host: Janet Wright, MD Guest: Robert Harrington, MD Recent studies have raised doubts about the efficacy of some common treatments for cardiovascular disease, including: the use of PFO closures (based on the CLOSURE trial); some methods of cardiac resynchronization therapy (or CRT, based on the SMART-AV trial); telemonitoring for patients with congestive heart failure (based on the Tele-HF trial); and doubling the dose of clopidogrel in patients who had a poor response to the drug after percutaneous coronary intervention (based on the GRAVITAS trial). Dr. Robert Harrington, director of the Duke Clinical Research Institute at Duke University Medical Center in Durham, North Carolina, reviews the evidence in each of these trials, and gauges the clinical impact of their findings. Dr. Janet Wright hosts. Produced in Cooperation with

Host: Janet Wright, MD Guest: Robert Harrington, MD Recent studies have raised doubts about the efficacy of some common treatments for cardiovascular disease, including: the use of PFO closures (based on the CLOSURE trial); some methods of cardiac resynchronization therapy (or CRT, based on the SMART-AV trial); telemonitoring for patients with congestive heart failure (based on the Tele-HF trial); and doubling the dose of clopidogrel in patients who had a poor response to the drug after percutaneous coronary intervention (based on the GRAVITAS trial). Dr. Robert Harrington, director of the Duke Clinical Research Institute at Duke University Medical Center in Durham, North Carolina, reviews the evidence in each of these trials, and gauges the clinical impact of their findings. Dr. Janet Wright hosts. Produced in Cooperation with

Guest: Robert Harrington, MD Host: Lawrence Sherman, FACEHP, CCMEP As continuing medical education continues to evolve, assessing quality in the provision of CME is vital. Joining host Lawrence Sherman this week is Dr. Robert Harrington, director of the Duke Clinical Research Institute at Duke University Medical Center, to discuss quality and performance improvement in CME.

Kristin MacDermott is the founder and President of the MacDermott Method, which provides resilience-based resources for individuals and organizations. Kristin's evidence-based method has been validated in four studies (including two randomized-controlled trials) with researchers from the Duke Clinical Research Institute, published in peer-reviewed journals, and proven to improve key resilience and mental health benchmarks, including anxiety, depression, distress, PTSD, and self-efficacy. She has designed resilience training programs for some of the highest performing people on the planet, including Naval Special Warfare Command (Navy SEALs) and the Los Angeles Police Department; more than 20 hospitals across the country, including Duke Cancer Institute and the National Institutes of Health; numerous mentoring programs for at-risk kids in South Central LA; as well as for CEOs, corporate executives, parents, divorcing couples, and teens and young adults with anxiety. Kristin is the author of the book It Takes Two Minutes to Shift Your Mindset and Build Resilience, which contains bite-size resilience skills you can read in two minutes and apply to your life immediately (now available on Amazon). Kristin is a Licensed Marriage and Family Therapist (CA) and a Licensed Professional Counselor (CO). She holds a bachelor of arts from Duke University and a master's in clinical psychology from Antioch University. She has also completed advanced training in Mind-Body Medicine at the Center for Mind-Body Medicine in Washington, D.C. and at the Benson-Henry Institute for Mind-Body Medicine at Massachusetts General Hospital. Kristin is the co-founder of Pathfinders, an Aspen-based nonprofit dedicated to improving the lives of people living with cancer as well as those experiencing grief. She also helped start Zero Hour Expeditions, a nonprofit that helps combat veterans reintegrate into civilian life and overcome the effects of PTSD by experiencing 30- day wilderness trips. She lives between Los Angeles and Palm Beach with her husband of 28 years and her three children ages 22, 18, and 14. Check out this special offer for listners here: https://www.macdermottmethod.com/davepamah Website: https://www.kristinmacdermott.com Support this podcast at — https://redcircle.com/the-dave-pamah-show/donations