Podcasts about lvads

In this episode of the Better Edge podcast, Anjan Tibrewala, MD, discusses his paper published in Circulation: Heart Failure, “Impact of Heart Transplant Allocation Change on Waitlist Mortality and Posttransplant Mortality in Patients With Left Ventricular Assist Devices.”The study's results found that despite the 2018 heart transplant allocation change deprioritizing patients with LVADs, patients with LVADs are living longer on the heart transplant waitlist. Interestingly, the study also demonstrated that patients with LVADs have slightly higher mortality after heart transplant following the allocation change. Dr. Tibrewala discusses recent advances in LVAD technology and what's next in advanced heart failure care.

On the second November episode of JHLT: The Podcast, the Digital Media Editors continue MCS-month with a paper from the November issue of JHLT, entitled “Aortic insufficiency in the patient on contemporary durable left ventricular assist device support: A state-of-the-art review on perioperative and postoperative assessment and management.”  First author Diyar Saeed, MD, PhD, of the Heart Center Niderrhein, and senior author Jennifer Cowger, MD, MS, of Henry Ford Hospitals both join the podcast. You'll hear about: Why LVAD patients develop new and progressive aortic regurgitation—and how contemporary devices may differ Associated hemodynamic events Intraoperative surgical techniques Slowing the progression of the condition and monitoring it post-op Early interventions For the latest studies from JHLT, visit www.jhltonline.org/current, or, if you're an ISHLT member, access your Journal membership at www.ishlt.org/jhlt. If you haven't yet tuned in for the first November episode of the podcast, MCS enthusiasts will be happy to know the paper discusses temporary MCS devices in acute RV failure. Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.  

On this episode of JHLT: The Podcast, the Digital Media Editors have three expert guests to discuss their paper, “Pragmatic approach to temporary mechanical circulatory support in acute right ventricular failure.” You'll hear from first author Anthony Carnicelli, MD, from the Medical University of South Carolina; Alexander Bernhardt, MD, from the University Hospital Hamburg-Eppendorf; and senior author Manreet Kanwar, MD, of the Cardiovascular Institute at Allegheny Health Network. The episode explores: Parameters that influence deciding when to escalate RV support Determining which device is right for each patient Evaluating a patient for the correct anticoagulants Device-related complications and solutions What's next in research for tMCS and acute RV failure For the latest studies from JHLT, visit www.jhltonline.org/current, or, if you're an ISHLT member, access your Journal membership at www.ishlt.org/jhlt. Join us again later this month for another MCS study, exploring aortic insufficiency in patients with durable LVADs. Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.

In this episode recorded at the Emerald Coast Conference, we interview Dr. Jaron Raper about two of his topics that both involve the chest, a pulmonary embolism update and the managing LVAD issues in the community ED.

LVADs can extend the lives of people living with advanced heart failure. We hear what it's like relying on a machine to help your heart pump blood.

Phage therapy has gained a lot of traction but the challenges created by this approach have not been properly assessed at a big scale. We often read about therapy successes on isolated cases but, rarely, we read or hear about failures. AAC recently published a case series of patients who failed phage therapy. Today, we will discuss this topic with the principal investigator on the research. Topics discussed: Phage therapy as an approach for MDR bacteria. The challenges of phage therapies. Issues that can influence the success of phage therapy Guest: Saima Aslam, MBBS. Director, Solid Organ Transplant Infectious Diseases Service, Professor of Medicine, University of California, San Diego. Article: Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases https://journals.asm.org/doi/10.1128/aac.01728-23 Questions Answered: How are we doing with phage therapy at this point? What are the challenges to deploy phage therapy in clinical settings? The 5 cases of failure of phage therapy in patients with LVADs summarized What factors did Dr. Aslam identify that were related with the failure? How do you develop neutralization against phages and how can you prevent it?   Bacterial isolates with varying phage susceptibility, how can this be detected? What did Dr. Aslam learn? Future research This episode is brought to you by the Antimicrobial Agents and Chemotherapy journal available at aac.asm.org. If you plan to publish in AAC, ASM Members get up to 50% off publishing fees. Visit asm.org/membership to sign up. Visit journals.asm.org/journal/aac to browse issues and/or submit a manuscript.

Editor's Summary by Kristin Walter, MD, MS, Senior Editor of JAMA, the Journal of the American Medical Association, for the December 12, 2023, issue. Related Content: Audio Highlights

Host Sarah Lorenzini and Christian Guzman APRN are back to conclude this three-part heart failure series by examining the use of mechanical circulatory support for cardiogenic shock. This episode expands on the topics covered in previous parts, focusing on the application of mechanical circulatory support methods like the intra-aortic balloon pump, Impella, CentriMag, LVADs, and ECMO.Christian and Sarah review the risks and benefits of each device, when to use them, and the key factors that impact these decisions. They also address the ethical challenges of ECMO, including the clinical judgment involved when determining who's a good candidate and when to escalate care.By the end of this episode, you'll understand how these devices function, their critical role in managing cardiogenic shock in heart failure patients, and the value nurses bring to a multidisciplinary team.Tune in for a knowledge-packed finale of this comprehensive heart failure series!Topics discussed in this episode:The role of mechanical circulatory support devicesBenefits and risks of the intra-aortic balloon pump and Impella deviceHow to properly use Impella devicesCentriMag and Left Ventricular Assist Devices (LVADs)The evolution of permanent LVADsExtracorporeal Membrane Oxygenation (ECMO) for cardiac supportChallenges and ethical considerations of ECMOThe importance of nursing knowledge and confidenceConnect with Christian Guzman APRN on Instagram:https://www.instagram.com/thenerdynursepractitioner/Watch this episode on The Rapid Response RN YouTube Channel! https://www.youtube.com/@therapidresponsern/videosMentioned in this episode:Coming Soon! Rapid Response Academy: The Heart and Science of Caring for the SickClick here to learn more about the community that Sarah is building: https://www.rapidresponseandrescue.com/coming-soon-rapid-response-academy Rapid Response and Rescue Intro CourseCONNECT

This week's topics include aspirin and LVADs, semaglutide and cardiovascular events in people without diabetes, sodium and blood pressure, and live shingles vaccine and waning immunity.

Drs Michelle Kittleson and James Fang cap off the podcast series by discussing difficult cardiac transplantation decision points, including LVADs and the latest innovations in cardiac transplantation. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/982166). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources Heart Failure https://emedicine.medscape.com/article/163062-overview Heart Transplantation https://emedicine.medscape.com/article/429816-overview Lynne Warner Stevenson, MD, FHFSA https://hfsa.org/lynne-warner-stevenson-md-fhfsa Risk Prediction Models for Survival After Heart Transplantation: A Systematic Review https://pubmed.ncbi.nlm.nih.gov/31733026/ Evaluation for Heart Transplantation and LVAD Implantation https://njadvancedheartfailure.com/wp-content/uploads/2022/04/Zucker-Heart-Transplantation-and-LVAD-Indications.pdf Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association https://pubmed.ncbi.nlm.nih.gov/30852913/ Left Ventricular Assist Devices https://www.ncbi.nlm.nih.gov/books/NBK499841/ The Burden of Haemocompatibility With Left Ventricular Assist Systems: A Complex Weave https://pubmed.ncbi.nlm.nih.gov/28329374/ Guidance and Policy Clarifications Addressing Adult Heart Allocation Policy https://optn.transplant.hrsa.gov/media/3931/guidance_policy_clarifications_address_adult_heart_allocation_policy.pdf Heart Transplantation From Donation After Circulatory Determined Death https://pubmed.ncbi.nlm.nih.gov/29492385/ Destination Therapy With Left Ventricular Assist Devices in Non-Transplant Centres: The Time Is Right https://pubmed.ncbi.nlm.nih.gov/32419850/ Frailty and the Selection of Patients for Destination Therapy Left Ventricular Assist Device https://pubmed.ncbi.nlm.nih.gov/22438521/ Heart Transplant Advances: Ex Vivo Organ-Preservation Systems https://pubmed.ncbi.nlm.nih.gov/36004090/ First Clinical Experience With the Novel Cold Storage Sherpapak™ System for Donor Heart Transportation https://pubmed.ncbi.nlm.nih.gov/33447411/ Is the Organ Care System (OCS) Still the First Choice With Emerging New Strategies for Donation After Circulatory Death (DCD) in Heart Transplant? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229932/

The JHLT Digital Media Editors explore two manuscripts from the October issue of The Journal of Heart and Lung Transplantation—the first on lung transplantation in patients with stacked risks, and the second on bacterial pathogens found at driveline exit sites in patients with ventricular assist devices. Digital Media Editor Marty Tam, MD, assistant professor in the division of cardiovascular medicine at the University of Michigan, hosts this episode.   First, hear from senior author Edward Cantu, MD, MSCE, on his team's study “Transplanting candidates with stacked risks negatively affects outcomes.”   Lung transplant centers are increasingly evaluating patients with multiple risk factors for adverse post-transplant outcomes, yet there is little data of the effects of these risks as they stack. The authors of the study used the UNOS registry data linked to the National Inpatient Sample (NIS) to create a national encounter-level sample of healthcare data in the United States, then applied a probabilistic matching algorithm using 7 variables and determined associations between mortality, length of stay, total charges, and disposition with the number of comorbidities.   For details on what the study found about how these risks affected patient success—based on factors like mortality, length of stay, duration of mechanical ventilation, need for ECMO-salvage, total charges, and discharge to a skilled nursing facility—listen to the discussion in the episode.   Next, the editors explored the study “Dynamics of bacterial pathogens at the driveline exit site in patients with ventricular assist devices: A prospective, observational, single-center cohort study.” While the authors weren't able to join the episode, editors corresponded with senior author Monika Fürholz, MD, from the Bern University Hospital in Switzerland, before recording, and shared some of her insights.   Driveline exit site infections commonly occur in patients with LVADs, and can be a source of recurrent or deeper infections. Bacterial colonization of driveline exit sites has not been well studied, and transition from colonization to infection is also not well understood. The authors of this paper sought to address this by conducting a prospective, observational, single-center cohort study which included systematic and routine collection of driveline exit site skin swabs being taken between June 2019 and December 2021, even in the absence of suspected driveline infection. Bacteria were identified and a subset of the samples underwent whole-genome sequencing.   For details on what the study found, including a discussion of how the study findings might impact current practice, check out the episode.   Follow along at www.jhltonline.org/current, or, if you're an ISHLT member, log in at ishlt.org/journal-of-heart-lung-transplantation.  Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.org.    

Clinical research has been around for over 300 years. Todd Nicklas explains why it still isn't perfect but still offers benefits for patients and healthcare providers to Jim Cagliostro.    Episode Introduction  Todd explains the history of clinical research through Paul Offit's You Bet Your Life, asks the big question of ‘'replacement or supplement'', and explains why patients are always their own biggest advocates. He also explains the need for monitoring the ‘'gray line'', and why the key focus in all clinical trials is failing early.   Show Topics   Clinical research isn't always the answer for patients  Supplement or replace? The big question for balance Handling complexities in replacing medication  The high cost of getting drugs to market  Focus on failing early  Patient benefits: a case study with Camzyos Teamwork helps the growth process   03:35 Clinical research isn't always the answer for patients  Todd highlighted the importance of a balanced view in clinical research, highlighting ‘'You Bet Your Life'' by Paul Offit.  ‘'So I kind of wanted to start out with that sometimes it is the answer, clinical research for a patient, or sometimes it's not the answer.. I appreciate reading a book by Paul Offit called You Bet Your Life. And ..he went through the past few hundred years in some of the early medical interventions in development and when they were very early starting off, the first blood transfusions that were tried or first types of anesthesia. And when he would dive into those stories, I mean, Jim, there were dangerous approaches. We look back today, really wild, crazy ideas or people died or people had maimed arms and legs from radiology exposure and such, but it leads us to where we are today with radiology procedures and blood donation and transfusions and anesthesia. Just a few examples. He did a few others…So his approach was, there's a point, and maybe we'll get to this later, where you can kind of know where the risks are worked out, but you can't just write it off and throw the baby out with the bath water. There might be something still good here that we need to learn. And so sometimes it could be the answer like, look where anesthesia and blood donation is today. But sometimes it's not the answer. You can look back for the past few hundred years and health authority figures or people at various companies thought that lobotomies were a good idea or sterilizing the mentally ill or bloodletting. You can look at some of these things that today we'd say, yeah, they were dangerous or inappropriate or not what they were intending to. So people can be wrong and people can be right. And so you have to understand that balance first and foremost. I kind of wanted to stress that upfront.''   06:01 Supplement or replace? The big question for balance Todd explained why this question is essential to balance in patient trials.  ‘'But I think the two questions you have to ask when you're trying to balance it is first, does the present, shall I say medication or intervention, does it supplement what is presently trying to treat or help my disease or does it replace the present? And the reason I wanted to lead with that or categorize that is because when I was a research nurse for many years in the hospital, you're working with sometimes doctors that really love the research that you're doing and are an investigator with that research. Some doctors could care less and tell you to go away and say, "Don't bother me. Really, you're going to bother me with this research?" Some doctors might have no clue because they're not even connected with your hospital system. And so how do you interact with doctors A, B, and C that I just gave as examples because you're going to have to approach them differently? I think that's probably self-evident. So you have to say, "Well, listen, it's meant to supplement and here's how it could work already with the present medical regimen that these patients are getting or it's meant to replace the treatment and this is why and this is how you should manage them." So I guess first, does it supplement the present treatment? This is I guess a question that research has to answer: how does the present treatment alone that they're already on affect a certain lab level or a MRI scan or a vital sign that might be concerned about your blood pressure or what have you, versus how much does it affect that measurable point with the two together or the research medication or intervention? We get a lot of time to dive into that, but I just want to leave that hanging out there to think about that.''   10:08 Handling complexities in replacing medication  Todd emphasized the need for clarity with patients, hospitals and in documentation in ‘'replacement'' trials.  ‘'When you're intending to replace the present treatment, well, then the doctors will say, "Well, wait a minute. When does that happen? Is there a washout period? What's the half-life of the drug that they're presently taking and the one that you want them to take in the research study? How quickly can it come on board and give a therapeutic benefit?" These questions, like I said before with the previous point, you need to be very careful in how you convey that to the patient, to the doctors, to the nurse practitioners, how it's in the documentation. Things can get forgotten, as you know. So it has to be clear in the documentation as well. You and I worked with LVADs, which are the heart pump devices. Could it replace their heart failure meds across the board? Maybe. If they have a really great response, maybe you can get rid of a good bit of them. And then the doctor would say, "Well, when would that occur? And how do we do that in the hospital?" So there are tough questions to ask and you might say... Oh, sorry, I forgot to mention this to you with the supplement. These studies are often with supplements, placebo controlled. Well, how do I handle... If I'm not supposed to know if they're on placebo or not, but it could supplement and have some impact, what do I watch for? What blood levels do I keep an eye on? But with replacement, that doesn't typically happen because they need a therapy, they need to be treated for something. So you have to either be getting the old medication or the research medication. It's not as much. So I wanted to mention that real briefly too, but that is another point I wanted to get across.''   15:10 The high cost of getting drugs to market  ‘'Jim, let's say you have a compound, an asset, a drug for your company, and it looks like it could affect a therapeutic area or a disease process that could pull in two million in sales and another avenue that might pull in two billion in sales. Some people might be more led to the two billion regardless of everything else. So I respect that. However, you have to keep in mind, so I've acknowledged that there is some negative approaches to things that are not good and can be shady, but at the same time, research, if you're not in the space, it takes so much money to get a drug approved in the United States with the FDA because the FDA is very careful with understanding all the components that need to be in place and the data that needs to be understood to say this medication should be on the market….. the typical cost to develop a drug is $2 billion on average. And the average time it takes from saying, "Here's our asset in preclinical," which is kind of working with animals and such, to the time it gets approved is about 13 and a half or 14 years.''   19:34 Focus on failing early Todd said that failing early would save costs further down the line.  ‘'Because the big focus today, and I think I might've mentioned the last podcast, is to fail early. So what a lot of companies like to do is to do a lot of high throughput, testing thousands of different compounds and various disease processes and targets in the body to understand where they might fail down the road, and there's amazing technology to figure that out, so they can hopefully pick the right one to go down that rabbit hole, shall we say, and hopefully get an approval because we know-it's such a big investment. And, oh, I didn't say this, but I think a compound, once it first gets found to get FDA approved through all the phase ones, twos and threes, it's like 5% or 10%, something really low. Even if things sound really appealing, the amount of drugs that actually get approved after all these things, we talked $2 billion, 13 and a half years, is still pretty small. Because the FDA is trying to be careful, they want to make sure something's safe and effective, that's the big thing. And it is great that we have both of those things that are important. You don't want something that's just one of those things, I mean safe but not effective, or effective but not safe. I mean both of those don't sound appealing to the modern consumer.''   31:35 Patient benefits: a case study with Camzyos Todd provided an example of how individuals can benefit from research.  ‘'This is probably six, seven years ago now. I did a study with what's now Camzyos, or mavacamten, a BMS drug, and it helps patients that have hypertrophic cardiomyopathy, apologies if I used this last time, but I don't think I did, where it is an overdevelopment of the muscles of the heart to the point that it's typically pushing into the left ventricular outflow tract, which is the exiting tunnel, shall we say, out to the aorta, which goes to the rest of your body and provides blood to the rest of your body. So the muscle as it pushes into that area, it makes the opening smaller and smaller so less blood can go out to the rest of your body to provide blood to your tissues and organs. And at the point that we were doing the study, the only fixes or treatment were either surgery to cut down that muscle or beta blockers and things to reduce the blood pressure that maybe reduces pressure in that area, but those are difficult to really target long-term or even midterm. It does affect the small muscle fibers and you actually see a reduction in that muscle area. So the reason I say this is because I had a patient that did this and it was a very involved, I think it was early Phase 1b or 2a, pretty early on study where he had to come in weekly for 12 weeks and do echoes and MRIs and a lot of blood work. And some of the visits I remember with him, he was in his 20s, were maybe three, four or five hours long, very busy visits for sure. So the question is, I mean, he's a young kid, does he want to have this burden on his life to do all this? He had a good relationship with the physicians there that saw him, and I think that he really thought this could help him prevent downstream problems or give him a few years before that muscle was impacting enough that he might need surgery or what have you. So it was certainly his decision and it was inconvenient, like I said, those visits and such. But he had good results and I was able to, I believe it was actually open label, so I kind of got to see how things were going from his echoes and data and such. But even within the first week or two, we saw really impressive results from him.''   36:41 Teamwork helps the growth process Todd said delegation prevents people from working in silos.  ‘'And I think that what I'm getting at is good delegation is not a negative thing and it doesn't reflect like you don't know what you're doing. I think we as human beings feel like, "Oh, I'm delegating so I clearly don't want to learn that, or I'm not good enough versus someone else." But no, what I found is, and especially now in larger pharmaceutical companies where there's a lot of team members, it's really beneficial to say, "Hey, you're really good at X, you're really good at Y. I should know them a little bit, and I do, and I oversee that, whatever, but I'm not going to jump in. I'm going to let you do it. Can you get back to me in a certain timeframe? Can you help me with this? Can you help me with that?"' It's very beneficial because not only do you kind of know the lines in the sand where people are working and not working, you're respecting your skillset and theirs, and you're working together as a team rather than like, I'm in my own silo. I'm not going to look both ways. I am my own person. I found that to be really, really helpful, and you can learn a lot at the same time. It really helps you learn a lot more than just saying, "I'll do my own thing." I mean, yeah, you might be baptized by fire and learn it kind of, but you might learn it a wrong way, actually. So I think that's probably what I would say and what I've really appreciated in my growth process.''   Connect with Lisa Miller on LinkedIn Connect with Jim Cagliostro on LinkedIn Connect with Todd Nicklas on LinkedIn Check out VIE Healthcare and SpendMend    You'll also hear:    The longevity of clinical research, starting with James Lind in 1747. ‘'We can't avoid research. We've been using the clinical research approach for the past 300 or so years….and then there were some studies that you can go back to even in the 1500s, that people would try various things to see what worked better than others.''   Patients don't live in a health vacuum: ‘'…..every patient you have is not going to be in a vacuum and have one disease and have nothing else. They're going to be 80 years old, they're going to have 10 other medications they're taking or four other disease processes that are going on. You need to know what's on board, what's working, what's not working.''   Why the patient is the biggest advocate: ‘'..the thing I really appreciated most was telling the patients the nitty-gritty and really driving home the educational points because then they are there with doctors B and C that might not know or want to be involved in the study and they can say, "Wait, wait, hold up. Don't do this. Or maybe talk to Todd first because this might affect that."    Monitoring the ‘'gray line'' in patient trials: ‘'Because some cancer patients do very early phase one and twos because they have to because of the development process or because of their cancer diagnosis or what have you, you might have to do early on. But are we past that line? Are we not? And what might that line look like? And that's why consent forms nowadays are extremely long because patients have to read all the safety data.''   What To Do Next:   Subscribe to The Economics of Healthcare and receive a special report on 15 Effective Cost Savings Strategies.   There are three ways to work with VIE Healthcare:   Benchmark a vendor contract – either an existing contract or a new agreement. We can support your team with their cost savings initiatives to add resources and expertise. We set a bold cost savings goal and work together to achieve it.  VIE can perform a cost savings opportunity assessment. We dig deep into all of your spend and uncover unique areas of cost savings.  If you are interested in learning more, the quickest way to get your questions answered is to speak with Lisa Miller at lmiller@spendmend.com or directly at 732-319-5700.  

Cabrera, Daniel. (Nov 2, 2014). A Basic Approach to the LVAD Patient in the Emergency Department. Available: https://emblog.mayo.edu/2014/11/02/a-basic-approach-to-the-lvad-patient-in-the-emergency-department/ Tchantchaleishvili V, Sagebin F, Ross RE, Hallinan W, Schwarz KQ, Massey HT. Evaluation and treatment of pump thrombosis and hemolysis. Ann Cardiothorac Surg. 2014 Sep;3(5):490-5. doi: 10.3978/j.issn.2225-319X.2014.09.01. PMID: 25452909; PMCID: PMC4229473.

Each month, EMedHome.com presents EMCast, the 90-minute podcast hosted by Dr. Amal Mattu, the premier educator in Emergency Medicine.  Subscribe to EMedHome.com for an array of clinical content that will impact every shift.  This month's EMCast covers:(1) LVADs(2) AMA Discharge(3) Neck Trauma

The partnership between Nuwellis and DaVita to launch an ultrafiltration therapy pilot program is an exciting development in the field of renal care. The agreement enables Nuwellis — formerly CHF Solutions — to pilot its Aquadex ultrafiltration therapy within selected U.S. markets. Fast Five hosts Sean Whooley and Danielle Kirsh discuss the partnership in detail and what executives say about it. CorWave's successful fundraising of $64 million is a significant milestone for the company as it prepares to manufacture its left ventricular assist device (LVAD). LVADs play a critical role in supporting patients with advanced heart failure, and CorWave's technology has the potential to improve patient outcomes and enhance their quality of life. Learn more about the company's technology and other developments in today's episode. Avanos Medical's decision to acquire Diros Technology is a strategic move demonstrating the company's commitment to expanding its portfolio and addressing unmet needs in the medical device market. Diros Technology makes radiofrequency products that are used to treat chronic pain conditions. Whooley explains how the acquisition will support Avanos' offerings and when the transaction will be completed. The FDA approval of Surmodics' SurVeil drug-coated balloon highlights the continued advancements in interventional cardiology and the increasing availability of innovative treatment options for patients with peripheral arterial disease (PAD). Hear how the technology stacks up against other devices in the market and how the company overcame being "unapprovable" earlier this year. BD's decision to sell its surgical instrumentation assets to Steris for $540 million marks a strategic move to streamline its portfolio and focus on core areas of expertise. This transaction enables BD to allocate resources more effectively and invest in research and development efforts that align with its long-term growth strategy. Whooley and Kirsh explain how BD will expand and how the acquisition will affect Steris' bottom line. Check out the show notes and links to the stories we discussed today at MassDevice.com/podcast.

Episode 137: Heart Transplant and LVADFuture Doctor My explains two treatments for advanced heart failure, heart transplant and Left Ventricle Assist Device (LAVD). Dr. Arreaza adds historical information about the first artificial heart implant and the first LAVD.  Written by My Chau Nguyen, MSIV, American University of the Caribbean School of Medicine. Comments by Hector Arreaza, MD.  You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.Introduction: Advanced heart failure is a major concern in the United States. Heart failure has a high 1-year mortality average of 33%. Although medical therapies have improved survival rates, some patients with progressive and advanced heart failure may still require heart transplantation or mechanical support such as left ventricular assist devices (LVADs) to prolong survival and improve quality of life.It is estimated that 23 million people in the world have heart failure, and many of them are in end-stage heart failure. When it comes to treating severe heart failure, there are two main options: heart transplantation and left ventricular assist devices (LVADs). Heart transplant: The operation to perform a heart transplant typically lasts between five to six hours but may take longer in patients who have undergone previous open-heart surgery or have an LVAD in place. However, because donors' hearts are a scarce resource, not all patients are eligible for transplantation. The following are absolute indications for referral for Heart Transplant listing:Cardiogenic shock requiring continuous intravenous inotropic therapy (i.e., dobutamine, milrinone, etc.) or circulatory support with intra-aortic balloon pump counterpulsation devices or left ventricular assist device (LVAD) to maintain adequate organ perfusion.Peak oxygen consumption VO2 (VO2max) less than 10 mL/kg per minute.New York Heart Association NYHA class III or IV despite maximized medical and resynchronization therapy.Recurrent life-threatening arrhythmias unresponsive to medical therapy such as an implantable cardiac defibrillator, medical therapy, or catheter ablation.End-stage congenital heart failure with no evidence of pulmonary hypertension.Refractory severe angina without potential medical or surgical therapeutic options.Selected patients with restrictive and hypertrophic cardiomyopathies.My experience with a heart transplant: I consider myself extremely fortunate for witnessing the whole complex procedure involved in lung and heart transplantation at Jackson Memorial Hospital in Miami, FL. It was an incredible experience to join the transplant team in retrieving a donor organ. Timing plays a critical role in heart transplants. When a suitable donor becomes available, every second counts. We must quickly arrange transport and secure an operating room. It is essential that the distance between the donor and the hospital is within our designated region. For example, we are in Region 5, including Arizona, California, Nevada, New Mexico, and Utah. Once everything is in order, we divide into two teams. One team sets off to retrieve the donor while the other prepares the patient in the operating room. It is a race against time, as hearts and lungs must be transplanted within approximately four hours of removal from the donor. It was remarkable to see how everything was so precisely scheduled, from the arrival and departure of the teams to the transplantation of the organs. It is an inspiring experience to witness these life-saving procedures in action.History of the artificial heart.Arreaza: It is great to hear about your experience, but we know that not everyone can have a heart transplant. So, let us talk about other options. For example, an artificial heart. I lived in Utah for several years and I heard something about the first artificial heart being implanted there, so here is the information. William DeVries was the surgeon who led the implantation of the first artificial heart, the Jarvik-7, at the University of Utah on December 1, 1982. The patient was a retired dentist, Barney Bailey Clark, who survived 112 days connected to the device. Today, the modern version of the Jarvik-7 is known as the SynCardia temporary Total Artificial Heart. It has been implanted in more than 1,350 people as a bridge to transplantation.Left Ventricular Assist Device (LVAD):In recent years, LVADs have become increasingly popular as a viable alternative to transplantation, as they have demonstrated improved durability by using wear-free components, greatly improving mortality rates in heart failure patients. Arreaza: The first left ventricular assist device (LVAD) system was created by Domingo Liotta at Baylor College of Medicine in Houston, Texas, in 1962. It is basically a pump that is used for patients who are on end-stage heart failure. The LVAD is surgically implanted, it is a battery-operated pump that helps the left ventricle pump blood to the rest of the body. LVADs can be used as a temporary treatment while patients are waiting for a transplant. It is called a “bridge-to-transplant therapy”. In some cases, an LVAD may restore a failing heart and eliminate the need for a transplant. An LAVD may also be used as a “destination therapy” in patients who are not candidates for heart transplants. LVAD can prolong and improve patients' quality of life.My: The purpose of an LVAD is to support patients with heart failure by increasing perfusion and reducing filling pressures in the heart. It is important to note, however, that LVADs only partially assist the pumping action of the diseased ventricle and cannot fully replace the function of the heart. Therefore, the decision to have an LVAD or heart transplant must be taken after careful discussion between the patient and the cardiologist to determine which option is best to reach the patient's goals of care.Example of an LVAD:Recently, The Berlin Heart Ventricular Assist Device (VAD) has been a game-changer in saving children with severe heart conditions. As you may guess from the name, it is developed in Germany. It is recently approved by US FDA in 2011. This type of LVAD has been used in approximately 1,000 children worldwide, including 12 cases in the United States. The Berlin Heart is a simple air-driven pump that takes over the work of one or both sides of a child's own heart. It pumps blood around the body to keep the brain and other organs healthy, allowing the child to grow and get stronger. The use of this device is required until the child is transplanted, or for a small number of children until their own heart recovers. I once again had the privilege of witnessing the procedure performed by one of the inventors, my preceptor, Dr. Loebe in the NICU at Jackson Memorial Hospital.Conclusion: Now we conclude episode number 137, “Heart Transplant and LVAD.” My explained two options for the treatment of advanced heart failure: Heart transplant and Left Ventricular Assist Device, or LVAD. She shared her recent experience in her surgery rotation at Jackson Memorial Hospital. Dr. Arreaza added the history of the first artificial heart implanted in Utah and the first LAVD. We hope you enjoyed it.This week we thank Hector Arreaza, and future doctor My Chau Nguyen. Audio editing by Adrianne Silva.Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! _____________________Sources:Theochari CA, Michalopoulos G, Oikonomou EK, Giannopoulos S, Doulamis IP, Villela MA, Kokkinidis DG. Heart transplantation versus left ventricular assist devices as destination therapy or bridge to transplantation for 1-year mortality: a systematic review and meta-analysis. Ann Cardiothorac Surg. 2018 Jan;7(1):3-11. doi: 10.21037/acs.2017.09.18. PMID: 29492379; PMCID: PMC5827119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827119/.Alraies MC, Eckman P. Adult heart transplant: indications and outcomes. J Thorac Dis. 2014 Aug;6(8):1120-8. doi: 10.3978/j.issn.2072-1439.2014.06.44. PMID: 25132979; PMCID: PMC4133547. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133547/.Birks, E. J., & Mancini, D. (2022, November 9). Treatment of advanced heart failure with a durable mechanical circulatory support device. UpToDate. Retrieved April 21, 2023. https://www.uptodate.com/contents/treatment-of-advanced-heart-failure-with-a-durable-mechanical-circulatory-support-device.Drews T, Loebe M, Hennig E, Kaufmann F, Müller J, Hetzer R. The ‘Berlin Heart' assist device. Perfusion. 2000;15(4):387-396. doi:10.1177/026765910001500417.Middleton, J. (2021, August 26). What is the time frame for transplanting organs? Donor Alliance. Retrieved April 21, 2023, from https://www.donoralliance.org/newsroom/donation-essentials/what-is-the-time-frame-for-transplanting-organs/.The Bridge to Transplant Team, The Child and Family Information Group. (2017, July). Berlin Heart Mechanical Heart Assist. NHS choices. Retrieved April 21, 2023, from https://www.gosh.nhs.uk/conditions-and-treatments/procedures-and-treatments/berlin-heart-mechanical-heart-assist/.Royalty-free music used for this episode: "Tempting Tango." Downloaded on October 13, 2022, from https://www.videvo.net/

CardioNerds (Dr. Amit Goyal), Dr. Sonu Abraham (CardioNerds Ambassador from Lahey Hospital and Medical Center, Burlington, MA) discuss left ventricular assist devices (LVAD) and the implications of renal dysfunction with Dr. Brian Houston and Dr. Nisha Bansal. This episode will focus on the intersection of left ventricular assist devices and renal dysfunction. Patients with a combination of heart failure and renal dysfunction overall have a guarded prognosis and their management poses unique challenges to the clinician. We initially discuss the basics of an LVAD and general approach to LVAD candidacy evaluation. We then discuss specific implications of acute kidney injury, presence of preexisting CKD, and end stage renal disease in patients with/being considered for an LVAD. Risk factor identification and prognostication allows for appropriate selection of the right candidates for an LVAD in the context of renal disease. Dr. Brian Houston is the Director of the Mechanical Circulatory Support program at Medical University of South Carolina. Dr. Nisha Bansal is an Associate Professor and the Arthur Stach Family Endowed Professor in the Division of Nephrology, an investigator at the Kidney Research Institute, the Director of Nephrology Clinical and Research Education, and the Director of the Kidney-Heart Service at the University of Washington. Notes were drafted by Dr. Sonu Abraham and episode audio was edited by student Dr. Chelsea Amo-Tweneboah. Check out the CardioNerds Failure Heart Success Series Page for more heart success episodes and content! CardioNerds Heart Success Series PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - Left Ventricular Assist Devices and Renal Dysfunction End stage renal disease (CKD on dialysis) is considered an absolute contraindication for LVAD implantation. Select young patients who are being considered for heart-kidney transplantation in the near future may be candidates for an LVAD as a bridge to heart-kidney transplantation. LVAD implantation can improve kidney function in the short term in patients with AKI primarily caused by cardio-renal syndrome. Patients with pre-existing CKD (not dialysis dependent) have a greater risk of developing AKI after LVAD implantation.   Several dialysis modalities including in-center hemodialysis, home hemodialysis, and peritoneal dialysis are available for LVAD patients. However, there are several challenges associated with each modality. An AV graft is a useful vascular access option in LVAD patients undergoing hemodialysis due to a lower risk of infection and ease of immediate use. Causes for anemia in patients with an LVAD and renal dysfunction include anemia of chronic disease, gastrointestinal bleeding, and pump thrombosis leading to hemolysis. Show notes - Left Ventricular Assist Devices and Renal Dysfunction Notes: (drafted by Dr. Sonu Abraham) What is a left ventricular assist device (LVAD) and what are its components? An LVAD supports circulation by unloading the left ventricle and providing increased cardiac output to help support organ perfusion. Use in properly selected patients is associated with improved quality of life and increased survival. The current iteration of LVADs offer continuous flow, as opposed to the older versions which employed pulsatile flow. Components of the LVAD: Inflow cannula (sucks blood from the LV) Pump Outflow cannula (dumps blood into the aorta) Percutaneous driveline Electrical controller How is a patient evaluated for LVAD candidacy? The 2 main questions to be answered during the evaluation of a patient for an LVAD are:             1. Are they sick enough? Do they have end stage heart failure?             2. Do we expect the benefits of an LVAD to outweigh the risks? ...

Go Red for Women's footprint, CMS coverage for LVADs, rising violence against cardiologists, and more.

What do you do if your heart starts failing, but you're not able to get a transplant right away? Many patients are relying on a small device called LVAD to keep them alive. You'll learn more about tiny machines that pump blood for your heart and the promising new research about LVADs.

Lecture audio here, you can access video version of lecture and supplemental content at: https://www.icuedu.org/lvads

This month on Episode 41 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the September 30 and October 14 issues of Circulation Research. This episode also features an interview with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, to discuss their study, Transcriptional and Immune Landscape of Cardiac Sarcoidosis.   Article highlights:   Tian, et al. EV-Mediated Heart Brain Communication in CHF   Wleklinski, et al.  Impaired Dynamic SR Ca Buffering Causes AD-CPVT2   Masson, et al. Orai1 Inhibition as a Treatment for PAH   Li, et al. F. Prausnitzii Ameliorates Chronic Kidney Disease   Cindy St. Hilaire:        Hi, and welcome to Discover Circ Res, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cynthia St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I'm going to highlight articles from our September 30th and October 14th issues of Circulation Research.                                           I'm also going to have a chat with Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to discuss their study Transcriptional and Immune Landscape of Cardiac Sarcoidosis. But before I get to the interview, I'm going to highlight a few articles.   Cindy St. Hilaire: The first article I'm going to share is Extracellular Vesicles Regulate Sympathoexcitation by Nrf2 in Heart Failure. The first author of this study is Changhai Tian, and the corresponding author is Irving Zucker, and they are at University of Nebraska. After a myocardial infarction, increased oxidative stress in the heart can contribute to adverse cardiac remodeling, and ultimately, heart failure. Nrf2 is a master activator of antioxidant genes, suggesting a protective role, but studies in rats have shown its expression to be suppressed after MI, likely due to upregulation of Nrf2-targeting microRNAs. These microRNAs can also be packaged into vesicles and released from stressed heart cells.   Now, this group has shown that rats and humans with chronic heart failure have an abundance of these microRNA-containing EVs in their blood. In the rats with chronic heart failure, these extracellular vesicles were found to be taken up by neurons of the rostral ventrolateral medulla, RVLM, wherein the microRNA suppressed Nrf2 expression. The RVLM is a brain region that controls the sympathetic nervous system, and in the presence of EVs, it is ramped up by sympathetic excitation. Because such elevated sympathetic activity can induce the fight or flight response, including increased heart rate and blood pressure, this would likely worsen heart failure progression. The team, however, found that inhibiting microRNAs in the extracellular vesicles prevented Nrf2 suppression in the RVLM and sympathetic activation, suggesting the pathway could be targeted therapeutically.   Cindy St. Hilaire:        The next article I want to highlight is titled, Impaired Dynamic Sarcoplasmic Reticulum Calcium Buffering in Autosomal Dominant CPVT2. The first author of this study is Matthew Wleklinski, and the corresponding author is Bjӧrn Knollmann, and they are at Vanderbilt University.   Exercise or emotional stress can prompt the release of catecholamine hormones, which induce a fast heart rate, increased blood pressure, and other features of the fight or flight response. For people with catecholaminergic polymorphic ventricular tachycardia, or CPVT, physical activity or stress can cause potentially lethal arrhythmias. Mutations of calsequestrin-2, or CASQ2, which is a sarcoplasmic reticulum calcium-binding protein, is a major cause of CPVT, and can be recessive or dominant in nature.   For many recessive mutations, disease occurs due to loss of CASQ2 protein. This group investigated a dominant lysine to arginine mutation in this protein, and found by contrast, protein levels remain normal. In mice carrying the mutation, not only was the level of CASQ2 comparable to that in control animals, but so, too, was the protein's subcellular localization. The mutation instead interfered with CASQ2's calcium binding or buffering capability within the sarcoplasmic reticulum. The result was that upon catecholamine injection or exercise, the unbound calcium released prematurely from the sarcoplasmic reticulum, triggering spontaneous cell contractions. In uncovering this novel molecular etiology of CPVT, the work provides a basis for studying the consequences of other dominant CASQ2 mutations.   Cindy St. Hilaire:        The next article I want to highlight is from our October 14th issue of Circulation Research, and the title of the article is ORAI1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension. The first author is Bastien Masson, and the corresponding author is Fabrice Antigny, and they're from Inserm in France. In pulmonary arterial hypertension, the arteries of the lungs become progressively obstructed, making it harder for the heart to pump blood through them, ultimately leading to right ventricular hypertrophy and heart failure. A contributing factor in the molecular pathology of pulmonary arterial hypertension is abnormal calcium handling within the pulmonary artery smooth muscle cells. Indeed, excess calcium signaling causes these cells to proliferate, migrate, and become resistant to apoptotic death, thus leading to narrowing of the vessel.   This group now identified the calcium channel ORAI1 as a major culprit behind this excess signaling. Samples of lung tissue from pulmonary arterial hypertension patients and a pulmonary arterial hypertension rat model had significantly upregulated expression of this channel compared with controls. And in patient pulmonary arterial smooth muscle cells, the high ORAI1 levels resulted in heightened calcium influx, heightened proliferation, heightened migration and reduced apoptosis. Inhibition of ORAI1 reversed these effects. Furthermore, in pulmonary hypertension model rats, ORAI1 inhibition reduced right ventricle systolic pressure and attenuated right ventricle hypertrophy when compared with untreated controls. This study indicates that ORAI1 inhibitors could be a new potential target for treating this incurable condition.   Cindy St. Hilaire:        The last article I want to share is titled Faecalibacterium Prausnitzii Attenuates CKD via Butyrate-Renal GPR43 Axis. The first author of this study is Hong-Bao Li, and the corresponding author is Tao Yang, and they are from the University of Toledo.   Progressive renal inflammation and fibrosis accompanied by hypertension are hallmarks of chronic kidney disease, which is an incurable condition affecting a significant chunk of the world's population. Studies indicate that chronic kidney disease is linked to gut dysbiosis. Specifically, depletion of lactobacillus bifidobacterium and faecalibacterium, prompting investigations into the use of probiotics. While supplements including lactobacillus and bifidobacterium have shown little effectiveness in chronic kidney disease, supplementations with F. prausnitzii have not been investigated.   Now, this group has shown in a mouse model of chronic kidney disease that oral administration of F. prausnitzii has beneficial effects on renal function, reducing renal fibrosis and inflammation. This bacterial supplementation also produced the short chain fatty acid butyrate, which was found to be at unusually low levels in the blood samples from the CKD model mice and from chronic kidney disease patients. Oral supplementation with this bacterium boosted butyrate levels in the mice, and in fact, oral administration of butyrate itself mimicked the effects of the bacteria. These findings suggest that supplementation with F. prausnitzii or, indeed, butyrate could be worth investigating as a treatment for chronic kidney disease.   Cindy St. Hilaire:        Today I have with me Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis, and we're going to talk about their paper, Transcriptional and Immune Landscape of Cardiac Sarcoidosis. This is in our September 30th issue of Circulation Research. Welcome, and thank you for taking the time to speak with me today.   Chieh-Yu Lin:             Thank you for inviting us. It's a great honor to be here today.   Kory Lavine:               Thank you.   Cindy St. Hilaire:        Really great paper, ton of data, and hopefully, we can pick some of it apart. But before we get into it, I actually want to just talk about sarcoidosis generally. I know it's a systemic inflammatory disease that has this kind of aggregation of immune cells as its culprit, and it can happen in a bunch of different organs. It's mostly in the lung, but it's also, like you're studying, in the heart. Can you just give us a little bit of background? What is sarcoidosis, and how common is cardiac sarcoidosis?   Chieh-Yu Lin:             Well, this is actually a great question, and I'll try to answer it. You actually capture one of the most important kind of features for sarcoidosis. It happens in all kind of organ system, mostly commonly in lung, in lymph nodes, but also in heart, spleen, even in brain, or even orbit, like eyes. It's really a truly multisystemic disease that has been characterized by this aggregate of macrophages, or myeloid cells, with scattered multinucleated giant cells, as the name implies, have multiple nuclear big, chunky, cells that form an aggregate. That's kind of like a pathognomonic feature for sarcoidosis, whether it's happening in lung, in the heart. When any organ system, a lot of studies has been done, but as of now, a very clear pathogenesis or mechanism has been, I would say, still pretty elusive, or still remain quite unclear, despite all the great effort has been made in this field. The other thing is that a lot of the studies actually focusing on pulmonary sarcoidosis for good reasons. Actually, that's one of the most common manifestations. For cardiac sarcoidosis, although it's only effect in probably, I would say depends on the data, 20% to 30% of the outpatient that with sarcoidosis, with or without lung involvement. It's actually carry a very significant clinical implications as of matter that the presentation of cardiac sarcoidosis can be devastating and sometimes actually fatal. Some of the study actually show that cardiac sarcoidosis actually higher, up to 80%, just because the first presentation's actually, unfortunately, sudden cardiac death. That's why Kory and I, we teamed up. I'm a cardiothoracic pathologist, so in my clinical practice I see specimens and samples from human body, from patient suffer from sarcoidosis, both in lung, lymph node, and heart. Kory is an outstanding heart failure, heart transplant cardiologist, see the other end, which is the patient care. This disease, specifically in heart, its presentation and its pathogens in heart, really attracts our attention.   Cindy St. Hilaire:        Do we know any or some of the potential causes? Why it would start, maybe in a different patient population, but also in the heart versus the lung? Do we know anything about that process?   Kory Lavine:              We know nothing about it. Sarcoid has no known etiology. There's been thoughts in the past that it may be driven by infection, the typical pathogens or autoimmune ideologies, but really, there's little data out there to support those possibilities. Right now, the field's wide open. The other challenge is we don't really have a good way to treat this disease, so a lot of the therapies available are things like steroids, which can have some effect on the disease but carry a lot of risk of complications. The other agents that we sometimes use to lower the doses of steroids, things like methotrexate and azathioprine, are only modestly effective.   These are really the motivation for Chieh-Yu and myself to pursue this. We don't really know what causes the disease, and we don't really have very good treatments. We really wanted to take the first step, that's to study the real disease, and understand what are the pathologic cell types that are present within the granuloma, which is these aggregation of immune cells that Chieh-Yu was speaking about.   Cindy St. Hilaire:        What is actually happening at the beginning of this disease? These granulomas form, and then what is the pathological progression in the heart? What goes on there?   Chieh-Yu Lin:             This is actually another great question that I will say there's not much that has been discovered because, especially in human tissue, every time we have a sample, it's actually a kind of time point. We cannot do a longitudinal study. But in general speaking, very little is known about how it's initiated because it will need to accumulate to a certain disease burden for this to have a clinical symptom sign and be manifested, and then being clinically studied. We do know that in both heart and lung after treatment of progressions, it's usually in, a general speaking, going through a phase from a more proliferative means that it's creating more granulomas, more  inflammatory cell aggregate, to a more fibrotic phase. Means that sometimes you actually see the granuloma start to disappear or dissipate, and then showing this kind of dense collagen and fibrosis. That has been commonly documented in both lung and heart sarcoidosis. The other things is that very difficult to study this disease that we do not have a great animal model, so we cannot use animal model to try to approximate or really study the disease pathogenesis. There are several animal models they try to use microbacteria or infectious agents, and these infectious agents can create morphologically similar granuloma, per se, but just like in human body. For instance, patients suffer from TB in their lung, biopsy will show this. But clinically, these are two very distinct disease entities, even though they look alike. Even in the heart, one of the conditions that we study in our paper is giant cell myocarditis, as the name implying having multinucleated giant cells granuloma. It looks really alike under microscopy for pathologists like me, but their clinical course in response to treatment is drastically different. This type of barriers and in the current limitations of our study tool makes, as Kory just said, this is really a wide open. We just know so little despite all the effort.   Cindy St. Hilaire:        Yeah. I'm guessing based on this granuloma information, to start with, the obvious question you went after is going after the immune cell populations that possibly contribute to sarcoidosis. To do this, because you have the human tissue, you went for single cell transcriptional profiling, which is a great use of the technology. But what biological sources did you use, and how did you go about choosing patient? Because the great thing about single cell is you can do just that, you can look at however many thousands of cells in one patient. But how do you make sure or check that that is broadly seen versus just a co-founding observation in that patient?   Kory Lavine:               We use explanted hearts and heart tissue from patients that underwent either heart transplantation or implementation of LVADs. It's a pretty big hunk of myocardium, and we're lucky to work with outstanding pathologists both at WashU, JU, as well as our collaborators at Duke. Between the two institutions, we're able to pull together a collection of tissues where we knew there were granulomas within that piece of tissue we analyzed. You bring up an important challenge. You need to make sure the disease and cause of the disease is present in the tissue that you're analyzing, otherwise you'll not come up with the data that really is informative.   Chieh-Yu Lin:             Kory beautifully answered the question, but I just wanted to add one little thing, and that's also why we use various different modalities. Some of them is more inside you, like the NanoString Technologies' spatial transcriptomic. You can visualize and confirm that we are studying the phenomenon that has been described for sarcoidosis, and then using multichannel immunofluorescence to validate our sequencing data, to complement such limitations of certain technology.   Cindy St. Hilaire:        Especially, I feel like with this diseased tissue that it's such a large tissue, there's so much information, it's really hard to dig in and figure out where the signal is. This was a wonderful paper for kind of highlighting, integrating all these new technologies with also just classical staining. Makes for great pictures as well. How does this cellular landscape of cardiac sarcoidosis compare to a normal heart? What'd you find?   Chieh-Yu Lin:             This is a great question. Compared to normal heart, we have been talking about this accumulation of macrophages with scattered multinucleated giant cells. For the similar landscape, first and foremost, you do not see those type of accumulations in brain microscopy or by myeloid markers in the heart. Although, indeed, in even normal heart tissue we have rest and macrophages. It just doesn't form such morphological alterations. But then we dive deep into it, and then we found that from a different cell type perspective, we realized that the granuloma is composed by several different type of inflammatory cells, with most of the T cells and NKT cells kind of adding periphery. The myeloid cells, including the multinucleated giant cells also, are kind of in the center of the granuloma of the sarcoidosis. Then, we further dive in and realize that there are at least six different subtype of myeloid cells that is contributing to the formation of this very eye-catching distinctive granular malformations, and to just never feel first off and foremost, of course, is those multinucleated giant cells that is really distinct, even on the line microscopy] routine change stand.   And then we have a typical monocyte that's more like a precursor being recently recruited to the heart, and we finally sent the other four different type of myeloid cell that carry different markers, and then improving the resident macrophages. Especially for me as a pathologist, I'm using my eye and looking at stand every day, is actually these six type of cells, myeloid cells, actually form a very beautiful special kind of distribution with the connections or special arrangement with all different type, kind of like multinucleated giant cell in the middle, flanked by HLA-DR positive epithelioid macrophages, kind of scatter, and then with dendritic cells and a typical monocyte at the peripheral, and then resident macrophage kind of like in the mix of the seas of granuloma information. All these are distinct from normal heart tissues that does carry a certain amount of macrophages, but just don't form this orchestrated architectural distinct structure that's composed of this very complicated landscape.   Cindy St. Hilaire:        Those images, I think it was figure six, it's just gorgeous to look at, the model you made. One of the questions I was thinking is there must be a significance between these cells that are on the periphery and those that are in the center of this granuloma. Do you have an idea or can we speculate as to are some more cause and some more consequence of the granuloma? Were you able to capture any more information about maybe the initiating steps of these from your study?   Kory Lavine:              That's a great question, and a question the field has had for a long time. Now, we know there's different populations of cells. The single cell data allows us to understand what are the transcriptional differences and distinctions between them to gain some insights. One thing that we do know from the field is that disease activity correlates with mTOR activity within these granulomas. We took advantage of phospho-S6 kinase staining as a downstream marker of mTOR activity, and Ki-67 is a marker of self proliferation.   Which of these populations within the granuloma might be most active with respect to mTOR and respect to proliferation? If you ask most people in the field, they would jump up and say, "It's the giant cell in the middle." We found that that's not actually the case at all. It's the macrophages that surround the giant cell, the ones that are HLA-DR positive, the epithelioid macrophages, and the ones that are SYLT-3 positive that are scattered around them. That's really interesting and could make a lot of sense, and leads to hypothesis that perhaps activation mTOR signaling within certain parts of the granuloma might be sufficient to set up the rest of the architecture. That's something that we can explore in animal models, and are doing so to try to create a cause and effect relationship. Cindy St. Hilaire:        Yeah, and I was actually thinking about this, too, in relation to kind of the resident macrophages versus infiltrating macrophages or even just infiltrating immune cells. Do you know the original source of the cells that make up the granuloma? Is it mostly resident immune, or are they recruited in?   Kory Lavine:               We can make predictions from the single cell data where you can use trajectory analysis to make strong predictions about what the origin of different populations might be. What those analyses predicted is that the giant cells and the cells that surround the giant cells, the HLA-DR positive and SYLT-3 positive macrophages, come from monocytes. That's the prediction, and, of course, resident macrophages do not. However, that prediction has to be tested, and that's the beauty and importance of developing animal models. The wonderful thing today is we now have genetic tools to do that. We can ask that question.   Cindy St. Hilaire:        I don't know. Maybe you don't want to spoil the lead of the next paper, but what kind of mouse model are you thinking about trying?   Kory Lavine:               Yeah. First of all, let me talk about the tools that are available, because they're published in Circulation Research, of course. We have a nice tool to specifically mark, track and delete in tissue resident macrophages using a CX3CR1 ERT pre-mouse, and taking advantage of the concept that tissue macrophages don't turn over from monocytes and turn over from themselves. We can give tamoxifen to label all monocytes macrophages in Dcs with that CRE, and then wait a period of time where only the resident macrophages remain labeled. We can use that trick to modulate mTOR signaling as a first step, and ask whether mTOR signaling is required in that population. We've now developed a new genetic tool to do the same thing in just recruited macrophages.   Cindy St. Hilaire:        What was the most challenging aspect of this study? There's a lot of moving parts. I'm sure probably the data analysis alone is challenging, but what would you say is the most challenging?   Kory Lavine:               I think you alluded to this early on, but the most challenging thing is collecting the right tissues to analyze, and that's not a small feat or a small effort here. All the technologies are a lot of fun, and everything works so well today compared to many years ago when we trained, so it's an exciting time to do science. The most challenging and time-consuming component was assembling a group of tissues that we could do single-cell sequencing on between our group and our colleagues at Duke, and then creating validation cohorts that we did across several different institutions, including our own as well as Stanford. That team effort in building that team is the most important, challenging, and honestly, enjoyable part of this.   Chieh-Yu Lin:             I cannot agree more what Kory just said. I think that that's the challenging and the fun part, and that we're very fortunate to really have a great team to tackle this questions in multiple from multiple institute. I just want to add one more thing that, particularly for me as a cardiopathologist, one of the hardest things is I've known how to look or diagnose sarcoidosis for years, but seeing the data emerging that is so complicated and then beyond my reliable eyes in understanding, it's kind of mentally very challenging but very fun to really open and broaden the vision. It's not just how it looks like just giant cells in macrophages.   Cindy St. Hilaire:        What do you think about in terms of diagnostics or even potential therapies? How do you think this data that you have now can be leveraged towards those objectives, whether it's screening for new cell types that are really key to this granuloma formation versus therapeutically targeting them?   Kory Lavine:              This study opens new doors, and right now, diagnosis of sarcoids islimited by trying to biopsy, which, in the heart, is limited by sample bias. You certainly can biopsy the wrong area because you don't know whether a granuloma is in the area or not. We do do some cardiac and other imaging studies like FDG-PET scans, which are helpful but are not perfect, and each of them has their individual limitations. One of the beauties of our study is it identifies new markers of macrophage populations that live within the granuloma, many of which are unique to this disease.   That suggests that there's maybe an opportunity to develop imaging tracers that can identify those populations more specifically than our current PET imaging studies do, which rely simply on glucose uptake. It also opens up the possibility that we may able to take blood samples and identify some of these cell types within the blood, and have more simple testing for our patients. I think in terms of therapy, you alluded to it earlier, these concepts about mTOR signaling, that could be a new therapeutic avenue that needs to be rigorously explored in preclinical models. We're lucky already to have very good mTOR inhibitors available in clinical practice today.   Cindy St. Hilaire:        Obviously, opening new doors is amazing because it's more information, but often a good study leads to even more questions to be asked. What question, or maybe what questions, are you guys going to go after next?   Chieh-Yu Lin:             Well, that list is very long, and then that's actually the exciting thing about doing this research. There's no bad questions, in some sense. All the way from diagnosis, management, monitoring, therapeutic, how we predict where the patient can respond, that's the whole clinical side. Even the basic science side, we still haven't really answered the question, although our data suggests where that multinucleated giant cells coming from. It's very eye catching. How do they form, even though our data suggests it's from the recruited macrophages. But that's still a long way from the recruited macrophage,  monocyte to that gigantic bag of nuclei in the very fluffy cytoplasm.   And then, how the granuloma, as we discussed earlier in this discussion, really initially from a relatively normal background myocardium to form this disease process. There are just so many questions that we can ask. There are, of course, several fronts that we would like to focus on. Kory already nicely listed some of them. First and foremost is actually to establish animal model to enable us to do more details in mechanistic studies, because human tissue, as good as it is, it's kind of like a snapshot, just one time point, and it really limits our ability to test our hypothesis. Animal model, certainly, is one of the major directions that we are going forward, but also the other side, like more clinical science also to develop novel noninvasive methodologies to diagnose and to hopefully monitor this patient population in a better way.       Cindy St. Hilaire:        Well, it's beautiful work. I was actually reading this paper this weekend at a brunch place just next door to my house, and the guy sitting next to me happened to see over my shoulder the title and said that his father had passed away from it. This is hopefully going to help lots of people in the future, and really help to make the models that we need to ask, "What's happening in this disease?" Thank you so much for taking the time to speak with me, and congratulations on what seems to be a landmark study in understanding what's going on in this disease.   Chieh-Yu Lin:             Thank you so much. It's a pleasure.   Cindy St. Hilaire:        That's it for our highlights from the September 30th and October 14th issues of Circulation Research. Thank you so much for listening. Please check out the Circ Res Facebook page, and follow us on Twitter and Instagram with the handle @CircRes, and hashtag Discover Circ Res. Thank you so much to our guests, Dr Kory Lavine and Dr Chieh-Yu Lin from Washington University St. Louis. This podcast is produced by Ashara Retniyaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy texts for highlighted articles was provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover Circ Res, your on-the-go source for the most exciting discoveries in basic cardiovascular research. 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 of the American Heart Association. For more information, please visit ahajournals.org.  

This week on Pharm5: Pharmacists prescribing Paxlovid New oncology payment model from CMS Flu shot updates for ≥65 years old Conflicting mortality and morbidity data for LVADs in heart failure Cardiometabolic trends in the 2000s References: Coronavirus (COVID-19) update: FDA authorizes pharmacists to prescribe paxlovid with certain limitations. U.S. Food and Drug Administration. https://bit.ly/3AuDqbB. Published July 6, 2022. Accessed July 7, 2022. Enhancing oncology model: CMS innovation center. Innovation Center. https://bit.ly/3yq4bLD. Published June 27, 2022. Accessed July 7, 2022. CDC director adopts preference for specific flu vaccines for seniors. Centers for Disease Control and Prevention. https://bit.ly/3ynmotw. Published June 30, 2022. Accessed July 7, 2022. https://bit.ly/3yOSrUE Vidula H, Takeda K, Estep JD, et al. Hospitalization patterns and impact of a magnetically-levitated left ventricular assist device in the momentum 3 trial. JACC. https://bit.ly/3yQVY4R. Published July 1, 2022. Accessed July 7, 2022. Cogswell R, Rogers JG, M.R. M, et al. Residual heart failure on mechanically assisted circulation: A call to action. JACC. https://bit.ly/3yOSrUE. Published July 1, 2022. Accessed July 7, 2022. O'Hearn M, Lauren BN, Wong JB, Kim DD, Mozaffarian D. Trends and disparities in cardiometabolic health among U.S. adults, 1999-2018. Journal of the American College of Cardiology. 2022;80(2):138-151. doi:10.1016/j.jacc.2022.04.046

A Left Ventricular Assist Device (LVAD) is a mechanical pump that is surgically inserted to assist the left ventricle in pumping blood to the body. In this episode you'll learn what an LVAD is, how it works and the basics for caring for patients with ventricular assist devices. A big thank-you to HCA Healthcare for sponsoring this episode. You can learn more about HCA's robust Nurse Residency Program here. Important links: Demo video of obtaining a MAP using a Doppler. Right-Sided vs Left-Sided Heart Failure: Episode 57. UCSF guide about living with a VAD. Read the episode transcript and see references here. For more articles on cardiovascular nursing, check out the collection here. Do you want to start nursing school prepared and ready to conquer? Then check out my nursing school prep course Crucial Concepts Bootcamp.     RATE, REVIEW AND FOLLOW! If this episode helped you, please take a moment to rate and review the show! This helps others find the podcast, which helps me help even more people :-) Click here, scroll to the bottom, then simply tap to rate with 5 stars and select, "write a review." I'd love to hear how the podcast has helped you! If you're not following yet, what are you waiting for? It takes just a quick moment and the episodes show up like magic every Thursday. And, when I release a bonus episode, those show up, too! You'll never miss a thing! In Apple Podcasts, just click on the three little dots in the upper right corner here. Know someone who would also love to study with me? Share the show or share specific episodes with your classmates...when we all work together, we all succeed! On Apple Podcasts, the SHARE link is in the same drop-down as the follow link. Spread the love! Thanks for studying with me! Nurse Mo

This week, join authors Maryjane Farr and Josef Stehlik as they discuss their Perspective article "Heart Xenotransplant: A Door That Is Finally Opening." 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 in 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. Greg Hundley: Well, Carolyn, this week's feature, very interesting, xenotransplantation, where organs from other species are transplanted into humans. And it's a perspective piece. And so, we're going to get a weighted conversation from two different individuals that have a different perspective on the topic. Dr. Greg Hundley: But, before we get to that, how about we grab a cup of coffee, and start with some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: Absolutely, Greg. Although man, that is a big hook you just gave us. Xenotransplantation is seriously, seriously, a hot topic. Can't wait to learn more. Dr. Carolyn Lam: But, for this first paper I want to talk about, well, we know that sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing, can identify carriers of pathogenic, or lightly pathogenic, variants. However, to what extent do these variants associate with clinically meaningful phenotypes, and what do we know about variants of uncertain significance? Dr. Carolyn Lam: So to answer this question, Dr. Dan Roden, from Vanderbilt University, and his colleagues, looked at 10 arrhythmia susceptibility genes, that were sequenced in more are than 20,000 participants without an indication for arrhythmia genetic testing in the eMERGE III study, which is a multi-center prospective cohort. Variants, previously designated pathogenic, or likely pathogenic, were identified in 120 individuals, or 0.6% population. And electronic health records revealed an over-representation of arrhythmia phenotypes. Some variants of uncertain significance were also found in individuals with arrhythmias and patch clamping, confirmed reclassification, to likely pathogenic. Dr. Greg Hundley: Really interesting results from this eMERGE III study, Carolyn. So what's the take home message? Dr. Carolyn Lam: As genetic testing becomes more common, the combination of electronic health records and in vitro testing, will help classify variant pathogenicity. Population screening has the potential to identify patients with undiagnosed Mendelian rhythm disorders. However, we need to consider the pros and cons of such an approach. And this is discussed in an accompanying editorial by doctors, Walsh, and Bezzina, and Wilde, from Amsterdam University Medical Center. Dr. Greg Hundley: Very nice, Carolyn. Well, my first paper comes to us from Professor Karl Heusler from the University of Wurzburg. Carolyn, this study was a pre-specified analysis of the anticoagulation using the direct factor Xa inhibitor, apixaban, during atrial fibrillation catheter ablation comparison to vitamin K antagonist therapy, or the AXAFA–AFNET 5 trial. And it randomized 674 patients with atrial fibrillation, in a one-to-one fashion, to uninterrupted apixaban, or vitamin K antagonist therapy, prior to first time ablation, with a goal to assess the prevalence of magnetic resonance imaging detected ischemic brain lesions, and their association with cognitive function, three months after first time ablation, using the continuous oral anticoagulation in patients with paroxysmal atrial fibrillation. Dr. Carolyn Lam: Huh. Nice. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. They found that brain MRI detected chronic white matter damage, as well as, acute ischemic lesions, were frequently found after first time ablation for paroxysmal atrial fibrillation, using uninterrupted oral anticoagulation. Including, 27.2% of those receiving apixaban, and 24.8% of those receiving the vitamin K antagonists. So Carolyn, no difference there. MRI detected acute ischemic brain lesions were not associated with cognitive function at three months after ablation. And then, Carolyn, the lower Montreal Cognitive Assessment scores, both before and after ablation, were associated with older age only, highlighting the safety of atrial fibrillation ablation on uninterrupted oral anticoagulation. Dr. Carolyn Lam: Oh, thank you, Greg. Well, my next paper talks about basilar artery occlusion, which we know is a devastating condition without definitive evidence to guide treatment. Now, while we do know that faster treatment times with endovascular therapy is associated with better outcomes in the anterior circulation of the brain. What about this relationship for basilar artery occlusion? See? So that's the question that this paper sought to answer, and it's led by Dr. Smith from University of Calgary in Alberta, Canada, and colleagues. They used individual level patient data from the Get With The Guidelines-Stroke nationwide US registry, prospectively collected from January 2015 to December 2019, and identified 3015 patients with basilar artery occlusion treated with endovascular therapy. Dr. Greg Hundley: Ah, Carolyn. And so what did they find here? Dr. Carolyn Lam: So, here are the results. Treatment of basilar artery occlusion with endovascular therapy, within six hours of last known well, is associated with better outcomes, compared to treatment after six hours. Including, lower odds of mortality and higher odds of reperfusion, independence, and discharge home.   Dr. Carolyn Lam: There was a non-linear association between, faster treatment with endovascular therapy for basilar artery occlusion, and better outcomes, with the greatest per hour improvement in outcomes seen within six hours of the last known well. In summary, results indicate that, faster treatment with endovascular therapy may improve outcomes in basilar artery occlusion. Efforts should therefore be made, to optimize workflow, including pre-hospital, inner-hospital, intra-hospital processes, to achieve rapid treatment with endovascular therapy in acute stroke with basilar artery occlusion. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science. And Carolyn, as we know, pulmonary hypertension can be caused by chronic hypoxia, leading to hyperproliferation of pulmonary arterial smooth muscle cells, and apoptosis-resistant pulmonary microvascular endothelial cells. And then, upon re-exposure to normoxia chronic hypoxia induced pulmonary hypertension in mice, is reversible. So in this study, the authors led by Dr. Christine Veith, from Justus Liebig University in Giessen, aimed to identify novel candidate genes involved in pulmonary vascular remodeling, specifically, in the pulmonary vasculature. Dr. Carolyn Lam: Ah, a very interesting and important topic. So what, or how, did they do this, Greg? Dr. Greg Hundley: Right, Carolyn. So following a microarray analysis, the investigative team assessed the role of secreted protein, acidic, and rich in cysteine, or SPARC, using lung tissue from idiopathic pulmonary arterial hypertension patients, as well as from chronic hypoxic mice. In this experiment, the mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent re-exposure to normoxia, at different time points Dr. Carolyn Lam: Okay, so what were the results? Dr. Greg Hundley: Okay, Carolyn, the big drum roll. So the microarray analysis of the pulmonary vascular compartment, after laser micro dissection, identified SPARC as one of the genes down-regulated at all reoxygenation time points that were investigated. Intriguingly, SPARC was vice versa, up-regulated in lungs, during development of hypoxia induced pulmonary hypertension in mice, as well as in idiopathic pulmonary hypertension. Although, SPARC plasma levels were not elevated in pulmonary hypertension. Dr. Greg Hundley: Transforming growth factor, or TGF-beta 1, or hypoxia induced factor to a signaling pathways, induced SPARC expression in human pulmonary arterial smooth muscle cells. In loss of function studies, SPARC silencing enhanced apoptosis, and reduced proliferation. And so Carolyn, in conclusion, these authors provide evidence for the involvement of SPARC in the pathogenesis of human pulmonary hypertension, and chronic hypoxia induced pulmonary hypertension in mice, most probably, by affecting vascular cell function. Dr. Carolyn Lam: Wow. Thanks for that, Greg. Well, let me give a tour of what else there is in today's issue. There's a letter from Dr. Ng on could cardiologists support, improve, the cardiovascular risk of GnRH agonists. There's a Case Series, by Dr. Blumer, on [entitled] Hemophagocytic Lymphohistiocytosis Associated with Endocarditis: A Case Years in the Making.” There's a Perspective piece by Dr. Hillis on [entitled], Is Asymptomatic Severe Aortic Stenosis Still a Waiting Game?” Dr. Greg Hundley: And Carolyn, from the mailbag, we have a Research Letter, from Professor McFadyen entitled, Inherited Thrombophilias are Associated with a Higher Risk of COVID-19 Associated Venous Thromboembolism, a Prospective Population Based Cohort Study. Dr. Greg Hundley: Well, now onto that perspective and discussion from two viewpoints on xenotransplantation. Dr. Carolyn Lam: Xenotransplantation. Cool. Let's go. Dr. Greg Hundley: Well welcome everyone, to this feature discussion. And today, we're taking a little bit of a, different tact, and we are going to discuss a perspective piece. As you know, usually we will discuss an original article, but we have a perspective. And we have with us, the two authors that created this perspective. Dr. Jane Farr from UT Southwestern, in Dallas, Texas, and Dr. Josef Stehlik, from University of Utah. Welcome to you both. Dr. Greg Hundley: And listeners, our discussion today is on cardiac xenotransplantation, taking a heart from another species and implanting it in a human subject. So Josef, we'll start with you. Could you tell us a little bit about the history of cardiac xenotransplantation, and what are some of the obstacles that have to be overcome, if we're considering performing this procedure in a patient? Dr. Josef Stehlik: Greg, thank you for that question. The concept of xenotransplantation has been around for a long time, with the biggest attraction being, a large and ideally safe source of organs for our patients. As far as cardiac xenotransplantation, the first human art xenotransplant was done in 1964, in a man with terminal heart failure, who received a chimpanzee heart at the University of Mississippi. Dr. Josef Stehlik: The patient didn't survive the surgery, and the way it was done back then, brought up a number of ethical issues, and other issues as well. And so, the next xenotransplant was not done until 1984, in a neonate with hypoplastic left heart syndrome, at Loma Linda University. You might have heard the term, Baby Fae, before. And this infant survived about 20 days, and so we couldn't consider it, long term success. However, these two first xenotransplant brought up some important issues that would be studied for years to come. And I think, that the biggest lesson was that, the intra-species immune barriers were a formidable obstacle, and that really, new technologies, and then new medications, would probably have to come into the clinical arena, before we could do it again. Dr. Greg Hundley: Very nice. Well listeners, now we're going to turn to our second author on this particular paper. And Jane, can you describe some of the circumstances pertaining to this most recent cardiac xenotransplantation? What transpired, and what's been the outcome with that individual? Dr. Maryjane Farr: Thanks, Greg. And thanks for having us here on this program today. So the circumstance around this particular groundbreaking transplant was such that, there was a critically ill patient. This man who was in cardiogenic shock. Both sides of his heart were not working. He was on life saving temporary mechanical support with VA ECMO. And he unfortunately, despite his cardiogenic shock, he was not eligible for standard allotransplantation. Dr. Maryjane Farr: Part of that story was really about, not meeting standard criteria for organ transplantation, probably just about anywhere, in terms of a long history of, maybe not taking his meds, or taking care of himself. And there's, certain criteria that he didn't fit into. And he actually had been assessed, as I understand it, by a number of programs, before the University of Maryland approached him with this possibility. Dr. Maryjane Farr: One other option that could have been taken, was a mechanical circulatory assist device. But as I say, both sides of his heart were not working, and so really, total cardiac replacement was really his only option. Dr. Greg Hundley: And so Jane, do we know anything about what happened? How did the surgical procedure go? Do we know anything about the outcomes? Dr. Maryjane Farr: This is of course, patient privacy. So what we know is really, what's in the public arena. And it's actually, there's been a lot of transparency, which has been terrific, by the patient, and the family, and the doctors, because this is such groundbreaking information. But this patient was truly critically ill. There was some paperwork done to try to get FDA approval for emergency experimental surgery, with xenotransplantation. And of course, all the research at University of Maryland, and in many other centers, nationally, and internationally, have been done over the years. And so finally, there was an approval to do this, and it was basically a scheduled surgery. Dr. Maryjane Farr: And as I understand it, it went just like any other transplant surgery. There was obviously, a procurement team for the genetically modified pig. There was cold storage of the device. Transport, at least as far as to the next operating room, or however it went. And then, standard implantation, and release of cross clamp, and perfusion. And at least by what you can read about, the heart started to work almost immediately. And then of course, I think that's the easy part. It was really all the intense and multi blockade immunosuppressive therapy, which is really, the challenge of this type of therapy. Dr. Greg Hundley: Very nice. Well, Josef, Jane's alluded to this a little bit, but who would be a candidate for this therapeutic, this form of therapy? Dr. Josef Stehlik: Greg, so that's an excellent question. And I would like to address it. Before I do that, maybe we should also mention, very briefly, a little bit of the science behind the genetically engineered pig, that Jane mentioned. Dr. Josef Stehlik: There were three main things that have been done, and what enabled that is gene editing. And here, I would like to actually mention Dr. Mario Capecchi, who received a Nobel Prize in 2007, for his groundbreaking work at the University of Utah, by describing mouse gene knockout. That has been part of what has been used for engineering, of course, in newer approaches, like CRISPR. Dr. Josef Stehlik: Some of the things that have been done is that, the highly antigenic carbohydrates that pigs have on their cell surface, have been edited out. There have been genes that have been edited out and in, connected to coagulation and compliment, to prevent clotting and bleeding in the organ and the recipient after transplant. Dr. Josef Stehlik: And of course, one thing that it's very relevant also to our COVID pandemic, there has always, with xenotransplantation, been a question. Could there be trans-species infection? And pigs do have endogenous retroviruses that are parts of their genome, and those have been edited out as well. And so in this way, some of the previous obstacles have been removed. Dr. Josef Stehlik: So to your question, who might be a candidate? And I absolutely agree with Jane, that in the first step, it should really be patients who are not candidates for other clinically approved approaches, like allotransplantation from human donors, or mechanical assist, that can be durable, and those are the characteristics that the patient met. And I think, the next patients that will come now, hopefully, will probably be in the same category. Dr. Josef Stehlik: Now, I believe, and again, this is a little bit of a speculation, that the next step will be patients who are not eligible for transplant, but who may be eligible for durable ventricular assist devices. And our goal will be to show, that survival and quality of life after xenotransplantation can approach survival and quality of life, on LVADs. And of course, LVADs are evolving, as well. Dr. Josef Stehlik: And then, to some degree, it might be the choice of the recommendation of the team, of the multidisciplinary team. What is the best match for the patient? And to some degree, I think patient preference, to really share decision making in patient preference. Dr. Josef Stehlik: And in the next step, I believe, that's what we are hoping for, that at some point, we will achieve is that, xenotransplant will rival the outcomes of human allotransplantation. And so, that will be probably, the next group of patients. How long this will take is to be seen. But I think, that it addresses your question, who could be the candidates for xenotransplant in the future? Dr. Greg Hundley: Very good. And Jane, Josef was touching on a topic here. How do the anti-rejection treatments differ in xenotransplantation, as compared to allograft transplantation? Dr. Maryjane Farr: And so, that's been the thing for all these decades. And so, the first thing is, genetically engineered xenotransplant organs, that can mitigate some of the anticipated xenoantigenic responses. Dr. Maryjane Farr: So first, these carbohydrates that we do not see, so they are foreign to us, so there can be acute fulminant rejection. So that's, one step, and the gene knockout can take care of that mostly, but not completely. And then there's humeral rejection, and then, cellular rejection. Dr. Maryjane Farr: The cocktail that gets put together for a xenotransplant includes, some of the things that we standardly use, like steroids, ATGAM, or antithymocyte globulin, which is a generalized T and B-cell depleting therapy. What's nuanced, and there's also some role for anti-CD20 B-cell therapy, but what it is nuanced in xenotransplant is anti-CD40 monoclonal antibody therapy. And that was specifically developed, and then studied in heterotopics, or non-human primate pig transplant. Because what turns out is that, the robust T-cell responses, by what's called the indirect pathway, really requires significant costimulatory blockade, where anti-CD40 therapy has been critically important, and well studied by these scientists and others at the University of Maryland, and elsewhere. Dr. Maryjane Farr: And as I understand it, anti-CD40 was really, is the basis, the backbone, of this therapy. And then there's one last thing. And that is, temsirolimus, which is a pro drug of proliferation signal inhibitor therapy, that we standardly use in transplant. That's utilized to arrest the further growth of the xenotransplant. So that sounds like it's the cocktail, and there's some published reports, on these scientists using just such cocktail in their non-human primate transplant models. Dr. Greg Hundley: Well, listeners, we've heard a really interesting story here. But now, let's ask these experts, first, Josef, and then, Jane. Josef, moving forward, what are the concerns that you really see in this aspect of research? Dr. Josef Stehlik: Greg, I think, one of the issues that will have to be addressed, are ethical considerations. And we've seen, that after the news of xenotransplant was made public, there has been a lot of discussion among public about ethics of xenotransplant. I think it will be important to really proactively address that. Dr. Josef Stehlik: One aspect from the past is, we knew that primate xenotransplant have not been embraced by the public, just because of the closeness of primates to humans. I think, some of that will be mitigated, now that we are using pigs. But of course, there are many who feel strongly about humane treatment of animals. And so I think, regulation will need to be established that will address that, and that will make both the professionals and the wary public, comfortable with this approach. Dr. Josef Stehlik: And another thing that will need to be addressed, and Jane talked about it a little bit is, what parts of care for xenotransplant will be different from human allotransplant. Right? So how do the assessment of the biopsies differ? Right? We'll probably have a new grading scheme looking at xenotransplant. Should the antimicrobial prophylaxis be different? So we do prevent the possibility of trans-species infections we haven't seen before, et cetera. So there would be a lot of work for the transplant teams to do, as well. Dr. Greg Hundley: And, Jane. Dr. Maryjane Farr: Yes. One thing that's hard, this is amazing science, and this is a huge opportunity to transplant more patients, many of whom die on the wait list every year. But what really needs to be understood also, as we move into this area, and this is where us, as clinicians, get involved in some of these conversations in particular, is that this patient actually wasn't eligible for transplant. And these are very, very difficult decisions that centers are tasked to make. Dr. Maryjane Farr: It can get really tricky, and there's lots of patients who say, "Okay, I'm not a transplant candidate.", because of this or that, or the other reason. And there's, some reasons that are more important than others. They'll say, "Transplant me anyway. Give me a heart that you might turn down. Just give me a chance." And we don't do that. And insurance companies don't pay for that. And we have to actually find a way to be rational in our approach. Dr. Maryjane Farr: But truly, acknowledging that, if we had more resources, we could probably expand transplant even with the organs that we do have, because we turn down about, probably about 40% of organs, and maybe even more, every year, because we want to match the best organs. So it's really important that xenotransplant, in centers that can do this, demonstrate that this therapy works, and it provides a good quality and quantity of life, for at least, to be reasonable. And once you get there, then you can start to talk about, whether you need to think about allocation, and all that. So you can see how the conversation's going to go on for the next 10 years, about how this fits in. Dr. Greg Hundley: You both alluded to the fact, we need more research. And so, incrementally, for maybe each of you in 30 seconds. What do you see as the next research study that needs to be performed in this space? First, Josef, and then again, Jane. Dr. Josef Stehlik: That's a tough question, but I'll try to address it. I think, it will be a little bit in parallel to the first human allotransplant. Now that we've figured out the procedure and the organ that we can use, I think, it will be research focused on the care of the transplant recipient. And the task, number one, will be to identify immunosuppression that will be safe and effective, to protect this heart from dysfunction for many years after transplant. Dr. Greg Hundley: And Jane? Dr. Maryjane Farr: Yeah. You need to do a case series. The handful of centers in this country, and maybe the world, but I only know about this country, that have been studying and working towards this day, should take the lead. University of Maryland has taken the lead, and there are other centers who have been thinking hard about this, and preparing for this time for a long time, and they should lead the way, and try to do this with all the expertise that they've already built. And then as time passes, we can see what their outcomes are, and then we can start to think about, should there be a randomized controlled clinical trial? What should we compare it against? Who should be offered the opportunity? But at first, we need to find that there's safety and efficacy in the patients that are selected, and also, they themselves select, to go through this operation and therapy. Dr. Greg Hundley: Well listeners, we want to thank Dr. Jane Farr and Dr. Josef Stehlik, for providing their perspective on a recent procedure, involving the xenotransplantation of a genetically engineered porcine heart, into a human subject with advanced biventricular heart failure, that was not well suited for human heart allograft transplantation. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run. 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 ahajournals.org.

Left ventricular assist devices (LVADs) can feel incredibly complex and these patients can inspire fear or trepidation in many healthcare providers. In this episode, we talk through the basics of LVADs from taking vital signs, to managing alarms, and evaluating common issues all with the experience and insights of our wonderful guest, Sarah Schettle, PA-C in Cardiovascular Surgery at Mayo Clinic. She is an incredible educator and breaks this topic down into really digestable and applicable pieces.   Check out a summary on the Mayo Clinic EM Blog

CardioNerds (Amit Goyal & Karan Desai)  join Dr. Matthew Delfiner (Cardiology fellow, Temple University Hospital) and Dr. Katie Vanchiere (Internal medicine resident, Temple University Hospital) in the beautiful Fairmount Park in Philadelphia. They discuss a case of a 53-year-old man with an LVAD who presents with progressive dyspnea since LVAD implant due to right-to-left shunting due to a PFO. Dr. Val Rakita (Assistant professor of medicine and advanced heart failure and transplant specialist at Temple University Hospital) provides the E-CPR for this episode. Episode introduction by CardioNerds Clinical Trialist Dr. Anthony Peters (Duke Heart Center). This case has been published by Circulation: Heart failure. See Invasive Hemodynamic Study Unmasks Intracardiac Shunt With Ventricular Assist Device. Claim free CME just for enjoying this episode!  Disclosures: NoneJump to: Pearls - Notes - References CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Case Summary - Dyspnea with an LVAD: A Tale of Hypoxia and Hemodynamics A 53-year-old man with an LVAD placed 3 months prior presents with progressive dyspnea since LVAD implant, though it has acutely worsened over the past 2 weeks. Two weeks ago, he had a hemodynamic and echocardiographic ramp study, where the LVAD speed was increased. By increasing the speed, his LV was more adequately decongested, and flow improved. In the Emergency Department, he was hypoxic on room air, and remained so with escalation ultimately with intubation. Even then he remained severely hypoxic requiring cannulation to veno-venous ECMO. Chest imaging was normal, and LVAD parameters were normal without any alarms. An astute clinician noticed that when the patient became hypertensive, his oxygen saturation improved. A subsequent echocardiogram revealed a patent foramen ovale, with right to left shunting. The patient then went to the cath lab, where simultaneous right atrial and left atrial pressures and oxygen pressures were measured, along with trans-esophageal echocardiography, while adjusting LVAD speed. It became evident that right-to-left shunting occurred only when there was high LVAD speed and low peripheral blood pressure. Essentially, faster LVAD speeds (sucking blood from the LV) and low systemic blood pressure (reducing LV afterload) increased right to left shunting by decreasing the left atrial pressure relative to the right atrial pressure. The PFO was closed at that time, drastically improving oxygenation. He was decannulated and extubated the following day. Invasive Hemodynamic Study Unmasks Intracardiac Shunt With Ventricular Assist Device | Circulation: Heart Failure (ahajournals.org) Episode Teaching -Dyspnea with an LVAD: A Tale of Hypoxia and Hemodynamics Pearls PFOs are present in up to 25% of individuals, including those with LVADs.LV unloading, and therefore LA decompression, depends on both LVAD speed and systemic vascular resistance.Blood pressure dependent hypoxia may be suggestive of a right-to-left intracardiac shunt.Hypoxia refractory to mechanical ventilation should raise suspicion for intracardiac shunt.Patients with LVADs can suffer from the same diseases that anyone can. Notes - Dyspnea with an LVAD: A Tale of Hypoxia and Hemodynamics 1. What factors influence LVAD flow? Factors that influence LVAD flow include pump speed, blood pressure, volume status, RV function, cardiac rhythm, and some other variables. The faster the pump is spinning, the more flow you should provide (to an extent). However, if your LV is underfilled, either from systemic hypovolemia or an RV not providing the needed LV preload, then you have no blood to flow! If you have high systemic vascular resistance, then you will have less forward flow,

Xeno-transplantation, weight loss drugs, DOAC coverage, vitamin D, LAAC and frailty, and recalled LVADs are the topics John Mandrola, MD, discusses in this week's podcast. To read a partial transcript or to comment, visit: https://www.medscape.com/twic I – Xenotransplantation - Pig Heart Successfully Transplanted to Man https://www.medscape.com/viewarticle/966367 - What Does a Pig-to-Human Heart Transplant Mean for Medicine? https://www.medscape.com/viewarticle/966488 II – Weight Loss Drugs - Wegovy Tops Sibling Saxenda for Weight Loss https://www.medscape.com/viewarticle/966376 - Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes https://jamanetwork.com/journals/jama/article-abstract/2787907 III – DOAC Coverage - CVS Caremark Formulary Change Freezes Out Apixaban https://www.medscape.com/viewarticle/966588 IV – Vitamin D - More Vitamin D Not Better for Reducing Cancer or CVD Incidence https://www.medscape.com/viewarticle/966333 - The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality https://doi.org/10.1016/S2213-8587(21)00345-4 - Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial—a randomized controlled trial https://doi.org/10.1093/ajcn/nqab419 - Association between vitamin D supplementation and mortality: systematic review and meta-analysis https://www.bmj.com/content/366/bmj.l4673 V – LAAC and Frailty - Frailty in patients undergoing percutaneous left atrial appendage closure https://doi.org/10.1016/j.hrthm.2022.01.007 - Net Clinical Benefit of Left Atrial Appendage Closure Versus Warfarin in Patients With Atrial Fibrillation: A Pooled Analysis of the Randomized PROTECT-AF and PREVAIL Studies https://pubmed.ncbi.nlm.nih.gov/31752643/ VI – LVAD recall - A High-Risk Medical Device Didn't Meet Federal Standards. The Government Paid Millions for More. https://www.medscape.com/viewarticle/966255 You may also like: Medscape editor-in-chief Eric Topol, MD, and master storyteller and clinician Abraham Verghese, MD, on Medicine and the Machine https://www.medscape.com/features/public/machine The Bob Harrington Show with Stanford University Chair of Medicine, Robert A. Harrington, MD. https://www.medscape.com/author/bob-harrington Questions or feedback, please contact news@medscape.net This podcast is intended for US health professionals only.

LVAD – Who Needs It? Guest: Andrew (Drew) N. Rosenbaum, M.D. (@werDrD) Host: Malcolm R. Bell, M.D. About 6.5 million people over the age of 20 years in the U.S. have heart failure. That number is estimated to grow to about 8 million by 2030. Of those patients, about 300,000 would potentially benefit from left ventricular assist device (LVAD) therapy. Among patients with advanced heart failure, 66% to 75% would have comorbidities that would preclude benefit from LVAD therapy, so approximately 75,000 to 100,000 patients in the U.S. would be potentially eligible for LVAD therapy. Joining us today to discuss LVADs is Andrew (Drew) N. Rosenbaum, M.D., a cardiologist at Mayo Clinic in Rochester, Minnesota. Specific topics discussed: Types of left ventricular assist devices: durable, destination therapy, bridge to transplantation Who benefits from LVAD and why LVAD durability Age limitations for LVAD therapy Inappropriate candidates for LVAD End-stage renal disease, LVAD and dialysis When to consider referral for LVAD therapy Connect with Mayo Clinic's Cardiovascular Continuing Medical Education online at https://cveducation.mayo.edu or on Twitter @MayoClinicCV. No CME credit offered for this episode. Podcast episode transcript found here.

This podcast was the last episode I published on From the Head of the Bed and originally came out on July 4, 2020.  In August of that year, I launched Anesthesia Guidebook and this episode is being re-released on September 16, 2021.    In this episode, I have the privilege of speaking with Ben Levin, […]

This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Sung-Min Cho and Associate Editor Marc Ruel as they discuss the article "Cerebrovascular Events in Patients with Centrifugal-Flow Left Ventricular Assist Devices: A Propensity Score Matched Analysis from the Intermacs Registry." 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: And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to look at centrifugal flow, left ventricular assist devices and cerebrovascular events. But before we get to the feature, how about we grab a cup of coffee and jump into some of the other articles in the issue? And maybe how about I go first? Dr. Carolyn Lam: All right. I got my coffee. Dr. Greg Hundley: So my first paper comes from Professor Dali Luo from Capital Medical University. And it's pertaining to calsequestrin-1. So calsequestrin-1, and calsequestrin-2 isoforms buffer calcium and regulate its release from the sarcoplasmic reticulum of skeletal and cardiac muscle. Human inherited diseases associated with mutations of calsequestrin-1 or 2 include malignant hyperthermia and environmental heat stroke and catecholamingergic polymorphic ventricular tachycardia. However, patients with hypothermia, environmental heat stroke events often suffer from an arrhythmia for which the underlying mechanism remains unknown. Dr. Carolyn Lam: Wow. Okay. And what did the current paper do and find? Dr. Greg Hundley: Great, Carolyn. So what the authors found, calsequestrin-1, the skeletal isoform of it is indeed expressed in cardiomyocyte sarcoplasmic reticulum for mirroring in human hearts, mostly presenting as a polymeric form and interacting with the ryanodine 2 receptor in ventricles. Second, calsequestrin-1 deficiency cause sinus tachycardia in basal conditions. And this is a novel finding which may be associated with sinus beat regulation and ventricular arrhythmia as an independent arrhythmogenesis if a high concentration of volatile anesthetics are used. Next, these volatile anesthetics and heating to 41 degrees C can directly induce calsequestrin-1 oligomerization, thereby causing enhancement of diastolic calcium leak and premature calcium transience through a reduced regulatory effect of calsequestrin-1 on ryanodine 2 activity. And so Carolyn, this novel mechanism underlying the arrhythmia occurring in patients with malignant hypothermia or environmental heatstroke episodes may provide different strategies for heart disorders as an independent profile in these syndromes. And finally, the finding of calsequestrin-1 confirmational change induced by triggers in those with malignant hyperthermia and environmental heatstroke could lead to novel therapeutic approaches to prevent these types of episodes. And that may also very, very useful in treatment of heatstroke.   Dr. Carolyn Lam: Wow. Thanks Greg. Well, moving from this preclinical world to a very common clinical question of the diagnosis of acute myocardial infarction. Now we know that in patients presenting to the emergency department with symptoms suggestive of an MI, the European Society of Cardiology zero and one hour algorithm is recommended by current ESC NSTEMI guidelines with a class one recommendation. Now, what this does is it combines a very high safety for early rule-out and high accuracy for rule-in allowing a definite triage of about 70 to 75% of patients using the zero in one hour sample. Dr. Carolyn Lam: However, what is the most appropriate management of the 25 to 30% of patients who remain in the gray observed zone? So this is the question that the current paper addresses. Now to answer this, we also need some more background that a single center pilot study previously of patients in the observed zone had derived a cutoff of seven nanograms per liter for a zero and three hour high sensitivity cardiac troponin T change to identify patients also eligible for early rule-out or rule-in of NSTEMI. So the current study that we're talking about in today's issue from Dr. Christian Mueller from Cardiovascular Research Institute in Basil, Switzerland, and colleagues, really aimed to externally validate that previously proposed seven nanogram per liter change cutoff, and if necessary derive and internally as well as externally validate some new criteria for these patients in the observed zone of the ESC zero in one hour algorithm. Dr. Greg Hundley: Wow, Carolyn, so we're learning a lot about cutoff values and also algorithms here with high sensitivity cardiac troponin T. So what did they find here? Very interested to hear. Dr. Carolyn Lam: So in two large prospective multicenter diagnostic studies, they found that the proposed zero and three hour high sensitivity cardiac troponin T change of seven nanogram criteria, unfortunately provided suboptimal safety for ruling out NSTEMI in patients remaining in the observed zone of the ESC zero and one hour algorithm. So this had a sensitivity of only 33% and missed 80 patients with NSTEMI. So they derived their own novel criteria based on zero and three hour samples. And these novel criteria combined a three hour high sensitivity cardiac troponin T concentration of less than 15 nanograms per liter and a zero and three hour absolute change cutoff of four nanograms per liter. Dr. Carolyn Lam: And that combination provided a high safety for ruling out NSTEMI in these patients in the observed zone and with a sensitivity of 99% missing only one patient with NSTEMI. Another further thing they found was at a zero and three hour cardiac troponin T absolute change of greater or equal to six nanograms per liter triage, 63 patients, or 11% towards rule-in thus resulting in a specificity of 98%. So in summary, this novel criteria based on zero and three hour sample seemed to balance safety and efficacy well for the further decision making in patients who are remaining in the observed zone after the zero and one hour cardiac troponin T algorithm. Internal validation of these novel criteria and external validation in an independent international cohort showed robustness of performance metrics and further strengthen its possible clinical use.   Dr. Greg Hundley: Very nice, Carolyn. Lots of data there, and hopefully very important clarification on both the zones as well as the cutoff values for using cardiac troponin T. Well, Carolyn, my next paper again comes from the preclinical science world and it's from Dr. Anne Eichmann at Yale University School of Medicine, and it pertains to activin receptor-like kinase 1. And we're going to call that ALK1.   Dr. Greg Hundley: Kinase 1 and we're going to call that ALK1. And it's an endothelial transmenbrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. And loss of function mutations of the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasias, a devastating disorder that leads to arteriovenous malformations. Dr. Carolyn Lam: Oh, okay. And what did the authors find? Dr. Greg Hundley: Dr. Carolyn Lam, ALK1 mutants displayed defective polarization against the direction of blood flow in capillary and venous endothelium as well as increased integran VEGF receptor 2 mediated P13K activation of YAP/TAZ signaling. Dr Carolyn Lam: Okay, Greg, that was super summarized but what are the clinical implications? Dr. Greg Hundley: Carolyn, pharmacological integrin inhibition using cilengitide or ATN-161, or YAP/TAZ inhibition using verteporfin, prevented AVM malformation in ALK1 mutant mice. And therefore for this study, the authors revealed that integrin and YAP/TAZ were novel affectors of ALK1 signaling in AVM pathogenesis that might be targeted for AVM treatment in patients with hemorrhagic telangiectasias. Dr. Carolyn Lam: Thank you, Greg. Well, let's review what else is in today's issue. There's an exchange of letters between Doctors Amadio and Valentine on cell-free DNA to detect heart allograph acute rejection. There's an AHA Update paper by Dr. Churchwell on preemption, a threat to building healthy, equitable communities. There's a Research Letter by Dr. Merkler on the association between cervical artery dissection and aortic dissection. Dr. Greg Hundley: And Carolyn, I've got a paper from Professor Daniels regarding the Clinical Implications of Basic Research getting inside the engine, the myosin modulation of hypertrophic cardiomyopathy and systolic heart failure. And then finally, there's an In Depth piece from Dr. Viskin entitled, “Polymorphic Ventricular Tachycardia: The Terminology, mechanism, diagnosis and Emergency Therapy.”   Dr. Carolyn Lam: Nice. Well, let's go on to our feature discussion. Can't wait. Dr. Greg Hundley: You bet.   Dr. Mercedes Carnethon: Welcome to this episode of Circulation on the Run, our podcast where we have an opportunity to talk with the authors of some of the top articles within our journal for a given week. And we've chosen today to focus on a set of articles, one of which is led by Dr. Sung-Min Cho from the Johns Hopkins University. And I'm really excited to have you with us today, Dr. Cho and joining us as well as the associate editor, Dr. Marc Ruel who handled the paper. And my name is Mercedes Carnethon from the Northwestern University's Feinberg School of Medicine. I guess without further ado, welcome to you both and we'll just jump right into it. Dr. Mercedes Carnethon: Dr. Cho, I'd love to hear a little bit more about your paper today. What made you choose to pursue this particular topic and what really inspired you? Dr. Sung-Min Cho: Thank you so much for the invitation and opportunity to talk today. During my training as a neuro person, I'm a neurointensivist by training and neurologist. I noticed that we are getting a lot of consults for LVAD associated strokes. When I took a closer look at the ENDURANCE trial, very showed really 29.7% stroke rate at two years and a few years later, we had this MOMENTUM 3 trial, which showed HeartMate 3 device had 10% stroke rate at two years. And we realized that a stroke is a major issue in this population and I wanted to study the incidence respecters and outcome of this strokes in LVAD population. However, despite the many observational studies in the past, we were really interested in looking at device specific stroke risk for current continuous flow LVADs and we wanted to look at the device specific risk and prevalence of these patients balancing co-morbidities each cohort. And that's why we conducted this study. Dr. Mercedes Carnethon: Great, well Sung-Min, it's not often that as an epidemiologist and cardiovascular epidemiologist that I actually get to talk with neurointensivists and get their insights on the importance of their work. Can you tell me a little bit about what you found and whether it surprised you? Dr. Sung-Min Cho: Population, we used the Intermacs registry database. This is well established database as all cardiologists and cardiothoracic surgeons know, and we defined a neurologic adverse event as stroke plus TIA, transient ischemic attack. We used a propensity score matching analysis to assess the association of HVAD with stroke risk, to balance for pre-implant risk factors. And basically after performing propensity score matching, we found that hazard of stroke was higher for patients with HVAD device compared to HeartMate 3. We kind of expected this based on the randomized control trials in the past but there was no head to head comparison between these two cohorts. This study really confirmed our suspicion that HeartMate 3 actually had lower hazard of a stroke compared to HeartMate 3. Dr. Mercedes Carnethon: Well, thank you so much. It's a really great explanation. And for those who haven't had a chance to dig into the issue yet, I really encourage you to read the piece. I found it to be very instructive. And I'm interested as well, Mark in your take about what excited you about this piece. Dr. Marc Ruel: Well, thank you very much Mercedes and Sung-Min it's really a pleasure to have you with us today. As you know, this has been a very impactful paper and you were very kind to share with us the study around your idea as to why you wanted to evaluate this question but even more than your idea and what led to the completion of the paper are the implications of your paper. And I think it would be great if you shared with us a little bit, what has been the path that your paper has led to and including amongst others, very likely a decision by the Medtronic to pull the HVAD out of market. It's interesting that your data, to my knowledge, correct me if I'm wrong, were presented first at the annual meeting of the Society of Thoracic Surgeons in January, 2021. And again, I want to reiterate that Circulation's very thankful that you chose to send your paper to our journal and we feel that it will give it full justice, like many other journals of would have had but we're really excited to have received your paper and give it the fullest consideration. Dr. Marc Ruel: Can you tell us a little bit about the implications and for lack of a better word, the storm that your paper has created in the field and your take on it? Dr. Sung-Min Cho: Right. That's a great question. Thank you for that. Like I said, as a neurologist, we see these patients after complication, patients having stroke and then we see these patients and we always wanted, cardiologists and cardiothoracic surgeons and neurologists, we always wondered which device carried more risk for stroke and TIA. And really our group actually worked on many papers in the past looking at single institutional data and also systematic review meta-analysis looking at this topic, but really HeartMate 3 came along a couple years ago, more recent device so we didn't have a lot of data. Dr. Sung-Min Cho: So intermex registry really helped since we didn't have a lot of data. So, INTERMACS Registry really provided opportunity for us to look at this specific question, really balancing those two chords to look at the risk of stroke in this HeartMate 3 and HVAD. And when we did that two years ago, we submitted a proposal to INTERMACS, and Dr. Kirklin from UAB, he really helped us to look at this data closely with his statistical team. And we had really a thorough statistical method to perform a propensity matching analysis. And we finally finished the analysis and presented in annual STS meeting in January, and it did really trigger a lot of attention to a lot of academic institutions and people who are practicing LVAD, and after that, when we finally submitted this paper to Circulation, we had to have a lot of discussion in between FDA and the Medtronic and discussing this implication of this paper. When it was finally published in Circulation, we are happy that there's a lot of attention and we made it through. Dr. Marc Ruel: Well, thank you, Dr. Cho, and maybe for the listener of this podcast, I would like to reiterate some of the salient points of your paper essentially, and correct me if I'm wrong, over 6,200 patients were included, about roughly 3,000 patients per group comparing the HeartMate 3 versus the HVAD. Dr. Marc Ruel: Now, as you alluded to the HVAD is the more ancient device, if you will. So there's a slightly longer follow-up, around 12 months on median, versus nine months with the HeartMate 3. And there's adjustment that has been made for this. And I think to me, really the key finding is that in the early acute phase around implantation, there is no real difference with regards to the risk adjusted incidents of neuro adverse events. However, once you pass the early implantation acute phase, in the chronic stable phase, there starts being really a signal that is detrimental to the performance of the HVAD versus the HeartMate 3. And I think your hazard ratio, correct me if I'm wrong, it's around 5.7 for neuro adverse events. Dr. Marc Ruel: So this is a very compelling hazard ratio, even coming out of an observational study with all the careful attention that you provided to adjust for residual confounding, et cetera. Dr. Marc Ruel: So obviously this is a very strong finding, but I would like you to perhaps comment on this, the patients are not the same. There's some indication that the HVAD patients may have been a little sicker, more RV dysfunction, more tricuspid regurgitation, higher INTERMACS-1 incidents more often on ECMO prior to an implant. What are your thoughts about this? Dr. Marc Ruel: Obviously, you've been very careful and the reader will note in the paper that many attempts have been made to account for those. But please give us your take around that 5.7 hazard ratio for neuro adverse event that you found. Dr. Sung-Min Cho: Right? In fact, we were really being careful adjusting those compounders. So we did a propensity matching has a primary analysis, but as you pointed out, as a secondary analysis, we wanted to look at multi-variable logistic regression analysis, looking at multi-hazard analytics. And when we did the secondary analysis, as you said, in the beginning early hazard period, the risk was similar, as time went on in the constant hazard period, the hazard ratio was 5.7 for HVAD compared to HeartMate 3, which gives a much higher risk of stroke and TIA for those patients with HVAD compared to HeartMate 3. Dr. Sung-Min Cho: So, that was really convincing to us. Confirming the findings from propensity matching analysis, showing that same findings were consistent throughout the different analysis. As we pointed out, HVAD patients actually were sicker, they had more ECMO, and they had more ventilation requirement or sicker patients INTERMACS level. Those are all carefully balanced in both propensity matching analysis and also multi-hazard analytics. And both of these analysis consistently showed that HVAD carried more risk of TIA and stroke compared to patients with HeartMate 3. Dr. Mercedes Carnethon: Thank you so much Sung-Min. You know what excites me as I think about choosing articles for journal clubs, when we're working with our trainees, the propensity matched approach and comparing it directly with what you're getting from multi-variable regression really provides an excellent methodological strategy to be able to generate results from these real world studies where it's not a randomized trial of who received which device, but we're able to yield practical conclusions that are actionable based on these findings when we have these well done analyses. And Marc alluded earlier to the actions that were taken in response to the findings from your study. Can you expand on those just a little bit more? Sung-Min Cho: Of course. So I guess, I don't know the real backstory, what was going on behind the scene, but I know for sure that STS leadership and INTERMACS leadership, they had a lot of discussion with the company who made HVAD device and also FDA, and I know that this study, the results of this study contributed to the decision they made back in June, pulling up HVAD device from the market. Sung-Min Cho: So I'm glad that this study could contribute to the science and hopefully this will help the patients in the future for device selection. So yeah. Dr. Marc Ruel: Sung-Min, I think it's fair to say that your study is probably, if not the most impactful in the field of ventricular assist devices, and I probably would personally think that it is, if not the single most impactful, certainly one of the two or three that are the most impactful. So congratulations to you and your team. Dr. Marc Ruel: If you still have a minute or two, I had a couple of more secondary questions? Dr. Marc Ruel In your analysis I noted that in the early acute phase, there are some protective predictors, such as performing the LVAD implant by sternotomy, which essentially results in about half of the neuro adverse events that you would otherwise observe. So I was a little intrigued by that. And high volume centers had about 1.8 hazard ratio. I suspect that's probably reflective of baseline risk and more acute illness in those patients coming. But if you have a chance, I'd love to hear your thoughts around this? Dr. Sung-Min Cho: Yeah, that's exactly what we thought actually is, initially we thought, hypothesized that surgical volume, the center volume will be associated with lower risk of stroke, but it was the other way around. But as you said, probably higher volume centers were getting sicker patients, so that's the association probably we were getting in the analysis. And we wanted to adjust for surgical techniques, sternotomy versus thoracotomy, and even after adjusting for that, HVAD remained a significant hazard per stroke, which showed in the table two and three, I think in the manuscript. Dr. Sung-Min Cho: And if I may, I want to say these couple of things. In the raw number, in the 6.4% of patients actually had TIA and strokes, neurological adverse events in HeartMate 3, at one year based on our study. And the risk goes up with a longer follow-up time of course. Moment3 trials had two-year follow-up, about 10% had stroke. And this is still, after HVAD is taken off the market, still there's a significant risk for stroke in these patients and based on autopsy and MRI studies although there is a very small studies--MRI studies, although they're a very small series, studies looking at MRI'd brains after explantation of LVAD. And it shows actually more than 95% of patients have cerebral micro bleeds, which is a marker for small vessel disease in the brain. I think this is an important issue, and although we show that one device had a lower risk of stroke, still question remains, are these patients have a high risk of stroke? And there is a need for improving biomedical engineering aspect, and I'm sure cardiologists and cardiothoracic surgeons know much better than I do regarding hemo-compatibility, especially for stroke. Dr. Sung-Min Cho: There is also a dire need for early detection and intervention for these events to improve the outcome for these patients, because once you have a stroke, the outcome is devastating, right? So I think there needs to be better medical management, neuroprotective agent, as well as neuro- monitoring methods, maybe biomarkers to predict stroke or TIA to come so we can intervene and prevent these really devastating complications. Dr. Marc Ruel: Mercedes, if I'm so allowed, I do have one final comment and question. Dr. Mercedes Carnethon: Most definitely. This has been delightful, so yes. Dr. Marc Ruel: Wonderful. So, first, Sung-Min, I want to thank you for working with us. We at Circulation were interested in your paper. You may recall you and I spoke on the phone offline when the decision to revise was made, and we went carefully over what the editors were anticipating would make your paper even better. And you were very responsive. You and your co-author's team were tremendous. And I think the paper that we have before us is absolutely very, very insightful and very important. And obviously tremendously impactful. So I want to thank you again for that. Dr. Marc Ruel: And my question is probably the very difficult question which is in everybody's mind at this point and I would like your take as a neurointensivist. You have someone who you have to care for who has a well-functioning HVAD, two years post implant. What would you recommend in terms of optimization for the prevention of neural adverse events? I realize we don't have all the information, but you are one of the few experts in the world who can probably provide us with a very valid take on this very difficult question. Dr. Sung-Min Cho: Yeah, it is indeed a difficult question. And that's what I am, including me a lot of neurointensivists, they are very interested in this topic. I think really, as I alluded before, only detection is really important, but it's really tough because either patients, they cannot get MRI. There's no way to know who's going to have stroke or not.   Dr. Sung-Min Cho: We know that a bacteremia is a huge risk factor for these patients. Whenever they have device infection, dry valve infection, bacteremia, their stroke risk goes up quite a bit. We have a lot of data on that. So we can carefully monitor these patients, follow these patients. There is some data that, within six days from infection, their stroke risk goes quite high up for these patients. Dr. Sung-Min Cho: But really, neuro-monitoring and biomarker study, there's so little data on this, but patients who are sick like this, not just LVAD patients but ECMO patients or ICU patients, are close neurologic monitoring and some markers to predict occurrence of a stroke or vascular event. I think that's something we really need to study and look into. Dr. Sung-Min Cho: Of course, we have a lot of biomarkers we can pick up from the brain, brain injury markers that we can study, and that has not been done in this space. And there are a lot of opportunities, I think, to look at that. And there's some signal based on Cleveland Clinic data that Randall Starling actually looked into, use of PDE5 inhibitor in this patient population, some protection against the ischemic stroke, and I think that's something also we should look into for neuroprotective agent. Dr. Mercedes Carnethon: Thank you so much! This has been such a delightful discussion this morning with Sung-Min Cho, the lead author of the study and the Associate Editor, Marc Ruel who handled it. Dr. Mercedes Carnethon: I really appreciate your attention. I hope the listeners enjoyed this episode of Circulation on the Run. Please join us again next time. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. 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, visit ahajournals.org.  

EMS A to Z: Mechanical Circulatory Support Devices Show Notes: From your hosts, Dr. Josh Gaither, Dr. Amber Rice, and Dr. Rachel Munn   There are two types of mechanical circulatory support devices: Left Ventricular Assist Devices (LVAD) and Total Artificial Heart (TAH).    Left Ventricular Assist Device: An LVAD is a Mechanical Circulatory Support (MCS) device designed to restore blood flow and improve survival, functional status, and quality of life for those suffering from advanced heart failure. The device is implanted in parallel with the heart, taking over a majority of its circulatory function. An LVAD is often implanted as a temporary treatment, but is sometimes used as a permanent solution to very low cardiac output.   What are the reasons for VAD implantation?  Bridge to Transplant The patient must meet criteria to be listed for a heart transplant Destination Therapy The patient does not qualify for a heart transplant but meets criteria for Destination Therapy The patient lives the rest of their life with an VAD Bridge to Recovery VAD for a few days or weeks, provides temporary supportto a patient expected to recover native heart function   What are the special considerations for LVAD patients?  Routine assessments such as blood pressure, pulses, and pulse-oximetry may not be unattainable   Chest compressions are usuallynot indicated  The patients carry external equipment: a controller and power sources that operate the implanted pump though a single driveline   How do you assess patients with LVADS?  Attempt to auscultate over the apex of the heart for a “whirling” or “smooth, humming” sound indicating that the VAD is working  A cable exits the abdominal wall that connects the device to power and the control unit Many VAD patients also have an implanted cardiac defibrillator Blood Pressure (BP) - BP taken with a manual cuff;  Automatic BP readings are considered unreliable Pulse - A palpable pulse is variable and clinically insignificant in VAD patients Pulse Oximetry- Can be unreliable Look for physical s/s of ↓ oxygenation EKG is typically unaffected   What types of problems are LVAD patients at risk for?  Bleeding complications due to blood thinner use Arrhythmias VAD flows may be affected Infection (as with any implanted device)   How do you treat arrhythmias in LVAD patients?  Many VAD patients have an ICD / Pacemaker Persistent arrhythmias are treated aftercontacting the VAD coordinator  Okay to defibrillate & cardiovert VAD patients per ACLS protocol Okay to administer anti-arrhythmic medications per ACLS protocol   What are the differences between LVADs and Total artificial hearts?  An ECG is meaningless since there is no heart Pulse oximetry is accurate A regular BP measurement may be obtained Chest compressions are not performed Cardioversion or defibrillation are not performed  

In this 204th episode I welcome Dr. Kia Sedghi to the show to discuss the perioperative management of patients with LVADs coming in for non-cardiac surgery. Advertising Inquiries: https://redcircle.com/brands Privacy & Opt-Out: https://redcircle.com/privacy

In your clinical experience, you may have cared for patients receiving palliative chemotherapy and wondered, hmmm, why is that called “palliative” chemotherapy? We've written about this issue previously here at GeriPal (“a term that should be laid to rest”) as has Pallimed (“an oxymoron”). Well, now we have “palliative” inotropes for people with heart failure.  And we have to ask, is this a fitting term?  And the answer is...complex...more so than you might think.  Recall that in one of our earliest podcasts, we talked with Nate Goldstein who memorably proclaimed “the best palliative care for heart failure is treatment for heart failure.”   To unpack the issue of palliative inotropes, we welcome back Haider Warraich, a cardiologist with a strong interest in palliative care.  We are joined again by Anne Rohlfing, palliative care fellow at UCSF who spent last year as a hospitalist on the heart failure service.  Please tune in to hear more about the role of palliative care in inotrope therapy, inotropes in hospice, Haider's study on palliative needs of patients with heart failure, and a bit about Left Ventricular Assist Devices (including a shout out to Dan Matlock's decision aids) and Haider's Journal of Palliative Medicine paper on top 10 tips for palliative care clinicians on caring for patients with LVADs. -@AlexSmithMD

This month on Episode 24 of Discover CircRes, host Cindy St. Hilaire highlights the topics covered in the May 14th Compendium on Heart Failure, as well as discussing two original research articles and a brief overview of the Review Series on Calcific Aortic Valve Disease from the April 30th issue of Circulation Research. This episode also features an in-depth conversation with Dr David Durgan and Huanan Shi from Baylor School of Medicine about their study Restructuring The Gut Microbiota by Intermittent Fasting Lowers Blood Pressure.   Article highlights:   Vacante, et al. CARMN Regulates Atherosclerosis via SMC Modulation   Hanna, et al. Cardiac Neuronal Control of the Sinoatrial Node   Cuevas, et al. Introduction to the Aortic Valve Disease Series   Compendium on Heart Failure   Cindy St. Hilaire:        Hi and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today, I will be highlighting topics presented in our April 30th and May 14th issues of Circ Res. I'll also speak with Dr David Durgan and his graduate student, Huanan Shi, from Baylor School of Medicine about their study Restructuring The Gut Microbiota by Intermittent Fasting Lowers Blood Pressure.   Cindy St. Hilaire:        The first article I want to share comes from the April 30th issue of Circ Res and is titled CARMN Loss Regulates Smooth Muscle Cells and Accelerates Atherosclerosis in Mice. The first author is Francesca Vacante and the corresponding author is Andrew Baker, and they're from the University of Edinburgh. The increased proliferation and migration of local vascular smooth muscle cells is part of the complex pathology of atherosclerotic plaques. These proatherogenic changes to smooth muscle cells are regulated in part via two micro RNAs, miR-143 and miR-145. And these are located together on human chromosome five. In this very same genetic locus is also a gene encoding a long non-coding RNA called cardiac mesoderm enhancer-associated non-coding RNA or CARMN. Cindy St. Hilaire:        This team found that levels of CARMN and miR-143/145 RNAs in mouse and human atherosclerotic plaque decreased as the condition worsened. Mechanistic experiments showed that this decrease drove smooth muscle cell pathology. Knock down of all three RNAs promoted increased proliferation and migration of human artery smooth muscle cells with the loss of CARMN specifically and independently, triggering increased proliferation. The team went on to show that in mice, loss of CARMN accelerated the progression of induced atherosclerosis. Together, the work highlights the interplay between these noncoding RNAs and atherosclerotic disease progression. Cindy St. Hilaire:        The second article I want to share is titled Innervation and Neuronal Control of the Mammalian Sinoatrial Node, a Comprehensive Atlas. The first author is Peter Hanna and the corresponding author is Kalyanam Shivkumar from UCLA. The nervous system regulates cardiac physiology and influences pathophysiological adaptations to disease. Mapping the intrinsic neurocircuitry of the heart is necessary if we are to fully understand how neural circuits function in health and in diseases such as arrhythmia. Neural circuits from outside the heart meet up with those within the heart at ganglionated plexuses on the heart surface. One such plexus is the right atrial ganglionated plexus, RGAP. And RAGP is thought to regulate the signal inputs from the vagus nerve into the sinoatrial node or the SAN, which is the heart's pacemaker. Cindy St. Hilaire:        To develop a detailed description of the connections between the RAGP and the SAN, this group used the pig's heart as it is a close anatomical match to that in a human's. Performing a combination of tissue clearing, immunohistochemistry and 3D fluorescent microscopy, this group showed that approximately 99% of the neurons in RAGP and most of those innervating the SAN, are cholinergic neurons. In spite of this, single cell transcriptomic analysis revealed a great deal of phenotypic diversity among these RAGP neurons. Through electrophysiological and neural ablation studies, the team revealed the extent of RAGPs modulation of the sinoatrial node functions, which characterizes the RAGP as an integrative neural structure and not just a relay station within the intrinsic cardiac nervous system. This work now creates a very detailed reference atlas of the RAGP sinoatrial node conductivity and a framework for mapping other aspects of the intrinsic cardiac nervous system. Cindy St. Hilaire:        The April 30th issue of Circ Res also has a short review series on calcific aortic valve disease. Dr Rolando Cuevas and I write an introduction to this series. Dr Joy Lincoln covers genetic and developmental contributors to aortic stenosis, Dr Jonathan Butcher covers inflammatory and biomechanical drivers of endothelial interstitial interactions in calcific aortic valve disease. Dr Tom Gleason covers current therapeutic options in aortic stenosis and Dr  Elena Aikawa covers multi-ohmic approaches to define calcific aortic valve disease pathogenesis. Cindy St. Hilaire:        The May 14th issue of Circulation Research is the heart failure compendium. This features 10 articles written by the leading experts, who present an update on the state of the field of heart failure research and current therapeutic options. Dr Douglas Mann is the guest editor of this compendium, and in his introduction, he emphasized his vision that the authors of this series, "Focusing on linking disease pathophysiology with the mechanisms action of current therapies, with the hope that past successes would serve as a prologue for the development of future therapies." Together, these Reviews present the recent therapeutic advances in heart failure and is truly representative of the successful transition of bench top research to the bedside of patients. Cindy St. Hilaire:        In the first article in the compendium, Dr Veronique Rogers provides an update on heart failure epidemiology, including a focus on the role of healthcare disparities. Dr Michael Felker, and Dr Mann follow with an overview of the pathophysiology of heart failure with reduced ejection fraction and highlight how several successful heart failure trials fit or do not fit into the current conceptual translational models of heart failure. Dr Walter Paulus and Michael Zile discuss heart failure with preserved ejection fraction, with a focus on the role of systemic inflammation and myocardial stiffness, and relate this pathophysiology to distinct clinical phenotypes and tailored medical therapies. Cindy St. Hilaire:        Drs Joyce Njoroge and John Teerlink discuss what is currently known regarding pathophysiology of acute decompensated heart failure, and present a handful of new therapy developments. Drs Gary Lopaschuk, Qutuba Karwi, Rong Tian, Adam Wende, and Dale Abel discuss cardiac energy metabolism and heart failure and review several promising approaches to beneficially altering metabolism in the failing heart. Highly relevant to the long-term cardiovascular phenotype seen in patients who have had COVID-19, Drs Ray Hershberger, Jason Cowan, Elizabeth Jordan, and Daniel Kinnamon reviewed the genetic basis for dilated cardiomyopathy and discuss what is known regarding the interaction of genetic risk and environmental factors. Cindy St. Hilaire:        Drs Jan Griffin, Hannah Rosenblum and Matthew Maurer discussed cardiac amyloidosis due to light chain or transthyretin amyloidosis and cover current effective therapeutic strategies and active clinical trials. Drs Virginia Hahn, Kathleen Zhang, Lova Sun, Vivek Narayan, Daniel Lenihan, and Bonnie Ky covered the development of heart failure due to targeted cancer therapies and discuss the rationale and evidence supporting different cardiotherapeutic approaches. Cindy St. Hilaire:        The Compendium concludes with an article by Drs Daniel Burkhoff, Veli Topkara, Gabriel Sayer, and Nir Uriel that discusses the current state of left ventricular assist devices or LVADs and the structural, cellular and molecular aspects of LVAD associated reverse left ventricle remodeling. This comprehensive Compendium on Heart Failure is found in the May 14th issue of Circulation Research. Cindy St. Hilaire:        So today, Dr David Durgan and Huanan Shi from Baylor College of Medicine are here with me to discuss their study, Restructuring the Gut Microbiota by Intermittent Fasting Lowers Blood Pressure, which is in our April 30th issue of Circulation Research. So thank you both very much for joining me today. David Durgan              Pleasure to be here. Cindy St. Hilaire:        So this study is bringing together two hot fields, the gut microbiome and intermittent fasting, and it's in the context of high blood pressure, which obviously is a national and global crisis. But before we jump into the details of the paper, could you just define what is meant by gut microbiome and intermittent fasting for the purposes of the discussion? David Durgan:             Sure. So when were you referred to the gut microbiome or the gut microbiome, what we're really referring to there are all the microbes that are residing in the gut. So this can be the complex composition of bacteria, viruses, fungi. However, for the purposes of our studies, we really focus in just on the bacteria. Cindy St. Hilaire:        So how did you even come to this question? What was the premise that existed such that you wanted to ask this question? Microbiome, intermittent fasting, and hypertension? Dr David Durgan:       It really started in terms of understanding the connection between the biome and hypertension. And this actually all started in a separate model of hypertension that we developed here in our lab. And that was a model of obstructive sleep apnea. When we were first developing this and characterizing this, one of the strange observations that we found is that these animals did not have any change in blood pressure, which was contrary to what we see in patients and even what they see in the intermittent hypoxia models. David Durgan:             So when we started thinking about OSA and the patient, we started thinking about all these other co-morbidities, one of them being obesity and poor diet. So at this point we started adding in other morbidities, such as a high-fat diet. And we found that very quickly within one week, actually, when we had the combination of both apnea and high fat diet, that this was then leading to the increase in blood pressure. And really lucky, right place at the right time was that we were thinking about what the high-fat diet was doing. And there was a seminar here on campus about the gut microbiota, which we really had done nothing with up to that point. And after attending that, it quickly became obvious that our high-fat diet was going to be shifting the biota. So this is what really led us to making this connection between changes to the microbiome and blood pressure. Cindy St. Hilaire:        So can you tell me little bit about the design of your study, about the animal systems you use and the diet and the regime that you put them on? David Durgan:             Sure. So we went into this with two overall questions. So we had already shown previously in this model that the biota was disrupted and that was contributing at least to the hypertensive phenotype. So we came into this and wanted to address the questions of, one, what are the mechanisms through which the microbiota is influencing host blood pressure? And then two, is there some type of intervention that we could do to shift the makeup of the microbiota and see how that affected the hypertensive phenotype? David Durgan:             So to address those two components, we took the spontaneously hypertensive stroke prone rat, and it's normotensive parent strain, the WKY, and we put them either on a normal ad libitum food access or every other day fasting, which is just as it sounds, it was a full 24 hours of ad-lib access followed by 24 hours of no food access at all. David Durgan:             And this went on for 10 weeks with constant assessment of food intake, body weight, blood pressure. And then at the end, we isolated fecal content in order to look at the effects on the biome. And that was done with whole genome shotgun sequencing, but we also did a on-targeted metabolomics approach of both the fecal content and the plasma in order to get a real understanding of what are some of the microbial metabolites that could be influencing hosts. Cindy St. Hilaire:        Such an interesting question. And it's such a complex idea, but I thought you did a really great job winnowing it down as your paper progressed. And you did find that the every other day feeding reduced blood pressure in the hypertensive stroke prone rats, and interestingly or maybe not interestingly to you, but I thought it was interesting, is that those every other day fed animals, they certainly ate more on the days when they were allowed to eat. And obviously on the days they weren't, they were eating less. And so their overall food intake was less. And ultimately at the end of your trial period, their weight was less. So are these effects that you see on blood pressure more directly related to the weight loss or to the actual microbiome? And how did you confirm that? Huanan Shi:                So that's actually a very good question. A lot of the intermittent fasting related studies definitely can separate the effects of the fasting itself and the effects of the weight loss as intermittent fasting has been used very frequently as a method for obesity and reduce body weight. So to confirm that the effects is through intermittent fasting, to restructuring the microbiome, a sort of indirect route from the weight loss, so we collected fecal sample of these animals that have been fed either on the intermittent fasting protocol or ad libitum with food access every day. We then transferred the fecal content through our garage into germ-free rats which they do not have an established gut microbiota. Huanan Shi:                So these germ-free animals who'll receive the hypertensive HSR mode] biota with just regular feeding pattern also developed high blood pressure compared to those who received the normotensive microbiota. So interestingly is that the animals that received the microbiota from the hypertensive animal that also was fed on the fasting protocol did not develop a high blood pressure. So this study actually tells us that maybe the weight loss have some effects, but through the microbiota transplant study, we show that majority or the conjoined factors mostly from the changes in microbiota instead of the weight loss. Cindy St. Hilaire:        Yeah. It also makes me wonder how much of the microbiota changes actually influence the weight loss as well. I wonder that's probably a whole another black box to open. You did find that in the feeding regime differences, there was a difference in the actual communities of bacteria. Can you talk maybe about the implications of what that means, and also does that mean this is perhaps something that we could recapitulate with a pill, like with a probiotic pill of some sort? David Durgan:             Yeah. So some of the overall changes that we see, we do see pretty drastic changes in the beta diversity of the community. This being things like richness, evenness, the number of species that are actually present and really pretty interestingly, the way that we saw those shift was that the SHR that were undergoing the fasting protocol, their community structure overall seemed to shift more closely to resemble that of the normotensive WKY. So there were some pretty large shifts. And then when we get down to some of the genera and species levels, we again see that many of these are being normalized to look much more like the communities of the WKY. David Durgan:             In terms of taking a pill or something along that source, somewhat surprisingly, actually we found that in the hypertensive animal, a number of species that are commonly thought of as probiotics. So for instance, bifidobacteria and lactobacillus, which are two of the only FDA approved genera for probiotics, they were actually higher in our SHR control fed animals. So I think there's still a lot of work to be done to understand exactly the contribution of individual species. Maybe what's more important is understanding the functional output from the community as a whole. So what are some of the metabolites that are actually influencing the host? Cindy St. Hilaire:        So it may not be the bacteria itself, but perhaps the products that create. David Durgan:             Right. And the thing that's frustrating, but also exciting about this is that there's so much functional redundancy between different species, meaning that while you could have loss of one species, it may look very significant on paper, but it could be that other species in the community are making up for that. So they're able to make the same metabolites and thereby overcome that deficiency. Cindy St. Hilaire:        Got it. Got it. So it may not really be that big of a shift per se. David Durgan:             Yeah. We can't always go off of just what is the species change and that's why we really moved and thought it was important to move on to looking at the metabolites themselves. Cindy St. Hilaire:        So you did see that these hypertensive rats had more an inflammatory profile in certain sections of the gut. And I was trying to think about this in terms of humans. And I don't know if it's known, but do patients with IBS or with chronic diseases like Crohn's disease or some other gut inflammation phenotype, do they actually have more hypertension or develop it earlier? I guess I'm thinking of this in terms of cause and consequence, the hypertension influence the gut microbiome, or do you think the microbiome perhaps is driving the hypertension? David Durgan:             That's a great question. I've tried to look and see if there's any real conclusive evidence for inflammatory GI disorders and a concrete connection to elevated blood pressure. Personally, I've not found convincing evidence of that at this point in time. Cindy St. Hilaire:        So in terms of the metabolites, I thought it was really interesting that you found, I think it was a reduction in bile acids, and specifically you then explored further choline, that that was at play in this hypertensive state. So can you discuss what it is you exactly found and then what this might mean in terms of hypertension pathogenesis? David Durgan:             Yeah. So from our un-targeted metabolomics data, we performed random forest analysis to try and understand some of the broad pathways that were altered. First of all, just differences between our hypertensive and normotensive control animals, but then also how the fasting affected those metabolites. And there were a number of pathways of interests, which need to be followed up on, but the one that really stood out to us was primary and secondary bile acid metabolism. Now, we followed up on this by doing a targeted approach to look at a specific panel of primary and secondary bile acids. And we were really very surprised at just how different they were. We measured, I believe, 17 different bile acids. And we found that in the plasma, that 12 of these were significantly lower in a hypertensive model. So this was really exciting. David Durgan:             And the more we looked into this, it really all make sense in terms of that if you look at where bile acid receptors are located, they're present in the endothelium and smooth muscle, in brain, on inflammatory cells. So we've really, I think, just started to see the tip of the iceberg in terms of their effects systemically. In a final figure of our paper, we look at their effects on vascular function and show that by giving a TGR5 agonist, which is one of the bile acid receptors that we could improve vascular function in this hypertensive model. I mean, bile acids classically have really been looked at in regards of strictly in the liver and the GI and in the inner hepatic circulation. But just the fact that we see these receptors so widespread systemically really tells us that even though the concentrations may seem low and plasma relative to in the GI tract, that they're very likely having pretty profound effects on overall physiology. Cindy St. Hilaire:        . So do either of you follow an intermittent fasting diet and also, I guess more specifically about IF is these rats, the study, you did every other day feeding. So for humans, obviously I think right now it's Ramadan so a lot of people are almost doing that now. But for humans, that seems like a stretch. I don't think I would really want to do that regularly. So do you think any of these findings could also be similar for different forms of intermittent fasting? I know like that 8/16 hour breakdown is the popular one. What do you think about that? David Durgan:             I personally have not tried it. There have been some grad students that have come through the lab and actually one of the investigators on this paper who worked with me to develop this idea, he was very into ... I think he did the 16/8 that you're referring to. Cindy St. Hilaire:        Okay. Yeah. David Durgan:             But yeah, I mean, that's really kind of been a hindrance almost in the field is that you go to understand clinical studies on intermittent fasting, and there's just so many different protocols out there. Whether it be looking at outcomes or blood pressure or whatever effect on physiology during Ramadan, during a 16/8, during every other day. And it's really muddied the waters in terms of understanding the overall effects, but looking through all of that, it does appear that even in the small clinical studies that are out there, that there does appear to be some benefit. There is a every other day fasting. So very similar to exactly the same as our protocol in a small randomized controlled trial. And it should be said that these were healthy individuals, but even after just four weeks of EODF or every other day fasting, there was about a 5 mm decrease in blood pressure in individuals. David Durgan:             The followup papers from that group really should be very interesting. So these individuals have now gone back on a normal feeding regimen, but they plan, I believe, to look at intervals out to two years to see how long lasting these effects are. Cindy St. Hilaire:        Interesting. The other thing with humans, I mean, obviously your rats, they're eating one meal, the same meal, essentially. Humans eat a variety of things at every meal at every different day. Sometimes they have a bag of candy because it's Easter or whatever, so that doesn't help either. So what was the most challenging part of the study? David Durgan:             This required a lot of legwork by Fred in terms of some of the multi-omics analysis. Huanan Shi:                For me, two part. One part is definitely analyze these data using the machine learning protocol. A lot of things I had to learn from scratch. And eventually, it's a lot of time-consuming troubleshooting, but I'm glad everything went through pretty well. I guess something else will be since these rats are eating and fasting at the same time every day and so you have to come in every day at the same time to change cages,  like food. So, yeah. Cindy St. Hilaire:        Collect poop. Well, it was a beautiful, really well done study. I thought it was super interesting. We talk about what's the next podcast going to be at all of our editorial meetings and this paper, everyone thought it was a great topic. It's just really timely with the intermittent fasting. It was really wonderful. What do you think is next? What are you going to do next on this? David Durgan:             So I think there's a lot to do next. I think that one of the most interesting ideas really I alluded to earlier, and that is the widespread distribution of these bile acid receptors. So while we've taken an initial look at vascular function, I think that there's a lot to do elsewhere. We're really interested in how this could be affecting the neurological component of hypertension. Many of these bile acids signaling pathways have been shown to be anti-inflammatory. So do we see changes in neuro inflammation, in sympathetic output? One we're capable of elevating bile acids, which are capable of passing the blood-brain barrier should be noted. So that's definitely one. And then also just beginning to look at how translational this might be. So do we see changes in bile acids in hypertensive patients as well? Cindy St. Hilaire:        You're talking about the receptors and that last figure paper figure seven where you use, I forget if it was an agonist or antagonist, but you modulated that receptor activity. Do resistance arteries, which have a bigger role in hypertension, do they have higher or different levels of expression than other vascular beds in the body? Or do we not know that yet? David Durgan:             I can think of studies that have shown similar results in terms of bile acids on vascular function, both in aorta and in mesenteric arteries. But whether the distribution is different on these receptors, I'm not really sure that's known. Cindy St. Hilaire:        Well, there's lots of super interesting questions. I mean, I came up with bunches more that I wanted to know based on the study. So I'm sure that will pan out for you, hopefully with lots more great papers like this one and funding and congrats on an excellent graduate student paper. It was a real great story. And thank you both for joining me today. David Durgan:             Thank you very much. Cindy St. Hilaire:        That's it for the highlights from the April 30th and May 14th issues of Circulation Research. Thank you for listening. Please check out the Circ Res Facebook page and follow us on Twitter and on Instagram with the handle @circres and hashtag discovercircres. Thank you to our guests, Dr David Durgan and Huanan Shi. This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire and this is Discover CircRes, your on-the-go source for the most up-to-date and exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2021. The opinions expressed by the speakers in this podcast are their own and not necessarily those of the editors or the American Heart Association. For more information, visit ahajournals.org.  

In this week’s podcast, Derek Herrera explains how a serious battle injury he received while leading Marines in Afghanistan led him to build a career in medtech. Herrera has founded two companies – Spinal Singularity and Habit Camera – to create devices that can improve and save the lives of people who need help the most. Herrera also explains how his military training is serving him so well in medtech and how the medical device industry would benefit from including more veterans in its workforce. We’ll also hear from Kwame Ulmer, principal at Ulmer Ventures and a lecturer at UCLA Anderson’s School of Management, about an effort his helping to lead to update the landmark study compiled by Josh Makower in 2010. The study blasted a regulatory process that it called “unpredictable, inefficient and expensive.” Its finding led to introspection and changes, according to Ulmer who served at the FDA at the time. Now Ulmer is working with UCLA leaders to update the study. He’s hoping to connect with 200 medical device and digital health executives to understand how they’re working with the agency. For more information go to MedtechStudy.com. For more information on the original study go here - https://www.massdevice.com/study-fda-related-activities-cost-24-million-510k/ Meanwhile, Medtech Media Mogul Chris Newmarker, executive editor of life sciences, will unveil his Newmarker’s Newsmakers including reports from Google, Varian, Boston Scientific, Hologic, LumiraDx, and a report detailing racial inequity in how LVADs are implanted. Subscribe to this podcast on all major podcast applications.

"He's more machine than man now" -Obi-Wan Kenobi when talking about LVADs. Do you know what Darth Vader, Randy Travis, and Dick Cheney have in common? They all have LVADs. Its time to stop being afraid of LVADs- let's cover the basic steps fo managing these patients, both for the boards and in life.

On the inaugural episode of JHLT: The Podcast, join Daniel R. Goldstein, MD, Editor-in-Chief of the Journal of Heart and Lung Transplantation, in a round table discussion with the JHLT Digital Media Editors. This companion piece to the January issue of JHLT will give quick insights into some of the most compelling and fascinating studies in transplantation and advanced heart and lung failure from the Journal.   In this episode, Erika Lease, MD, discusses donor ventilation parameters and lung transplantation; while Marty Tam, MD, and Van-Khue Ton, MD, PhD, discuss thrombosis events and LVADs. Follow along in the January issue at www.jhltonline.org/current.   Don't already get the Journal and want to read along? Join the International Society of Heart and Lung Transplantation at www.ishlt.org for a free subscription, or subscribe today at www.jhltonline.com.

Ventricular assist devices can be confusing and scary to manage. Having knowledge can increase your confidence and the care delivered to your patient. I talked with Dillon Wenberg, IA MED critical care instructor and co-author of the NEW IA MED MCAD course/book. We discussed all of the commonly asked questions about LVADs in prehospital settings. MyLVAD.com

This week’s episode features author Emma Birks and Associate Editor Hesham Sadek as they discuss the article " Prospective Multicentre Study of Myocardial Recovery Using Left Ventricular Assist Devices (REmission from Stage D Heart Failure: RESTAGE-HF): Medium Term and Primary Endpoint Results." TRANSCRIPT BELOW: 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, director of the Pauley Heart Center of VCU Health in Richmond, Virginia. Carolyn, our feature article this week, we're going to examine myocardial recovery using left ventricular assist devices, getting some early results from the RESTAGE-HF study. But before we jump to the feature discussion, how about we discuss some of the papers in the issue? Would you like to go first? Dr. Carolyn Lam: Yes I would. Have you thought about what's the benefit of emergent coronary angiography after resuscitation from out of hospital cardiac arrest for patients without ST elevation? It's an important question. Well, the portal study was reported by Dr. Kern from University of Arizona and colleagues, and this was designed to evaluate the efficacy and safety of early coronary angiography and to determine the prevalence of acute coronary occlusion in resuscitated out of hospital cardiac arrest in patients without ST elevation. So adult comatose survivors without ST elevation after resuscitation, were prospectively randomized to early coronary angiography versus no early coronary angiography, where early was defined as less than 120 minutes from arrival at the PCI capable facility. The primary endpoint was a composite of efficacy and safety measures, including efficacy parameters of survival to discharge favorable neurological status at discharge echo measures of left ventricular ejection fraction, more than 50% and a normal regional wall motion score within 24 hours of admission. Dr. Greg Hundley: So, lots of data here. What did they find? Dr. Carolyn Lam: So, unfortunately the study was prematurely terminated before enrolling the target numbers of patients. A total of 99 patients were enrolled from 2015 to 2018 and 49 were randomized to early coronary angiography. The primary endpoint of efficacy and safety was not different between the two groups. Early coronary angiography was not associated with any significant increase in survival or adverse events. And early coronary angiography revealed a culprit vessel in 47% with a total of 14% of patients undergoing early coronary angiography, having an acutely occluded culprit coronary artery. So while this was an underpowered study, when considered together with previous clinical trials, it does not support early coronary angiography, comatose survivors of cardiac arrest without ST elevation, whether early detection of occluded potential culprit arteries leads to interventions that improve outcomes does require additional study. And this is discussed in an editorial by Dr. Lemkes from Amsterdam university medical center. Dr. Greg Hundley: Very nice Carolyn. So at least the study that points us toward the next study that has to be performed and also does with other studies provide a little more clarity. Well, my next paper is from Professor Sanjiv Shah and--oh, wait a minute! And also from you as a co-author. Well, Carolyn, how about we have a little mini feature discussion where I can ask you some questions and then you can tell us all about your paper. Dr. Carolyn Lam: Happy to. Dr. Greg Hundley: Great. So Carolyn, what hypotheses were you testing and what was your study design and who was included in your study population? Dr. Carolyn Lam: Okay. So the question was we wanted to answer was thus a systemic pro-inflammatory state as indicated by proteomic profiling. Does that mediate the association between comorbidities and normal cardiac structure and function in HFpEF. To answer that we studied 228 patients with HFpEF from our multicenter promis HFpEF study. And these patients had 248 unique circulating proteins quantified using the old link multiplex immunoassay. Now I'm going to describe a complex analysis, but we basically had to first perform principal component analysis. And we did this to summarize 47 proteins known a priori to be involved in inflammation, and then used unbiased network analysis of all the 248 proteins to identify clusters of proteins that over-represented inflammatory pathways. We then used a mediation analysis to determine whether and to what extent inflammation mediates the association of comorbidity burdens with abnormal cardiac structure and function. And finally, we externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without HFpEF. Dr. Greg Hundley: Wow Carolyn, such a great design and an app machine learning mediation analyses, and then validation in an independent cohort. So tell us, what did you find? Dr. Carolyn Lam: So first, comorbidity burden was associated with abnormal cardiac function and structure and with these principle components of clusters of inflammation proteins. Second, systemic inflammation was associated with echo indicators of worse hemodynamics, like higher EDE' ratio and worse, right ventricular function. And third, inflammation indeed mediated the association between comorbidity burden and many of these echo parameters with, and I'm going to name a couple of routines. So TNF-R1, uPAR, IGFBP-7 and GDF-15 being the top individual mediating proteins. In the validation cohort inflammation was up-regulated in HFpEF compared to controls and the most prominent inflammation protein cluster identified was also the same one as in PROMIS-HFpEF. Dr. Greg Hundley: Beautiful Carolyn. So with these new proteins identified, what's the take home message here? Dr. Carolyn Lam: Here it is. Proteins involved in inflammation form a conserved network in HFpEF. And this was found across two independent cohorts. This may mediate the association between comorbidity burden and echo indicators of worst hemodynamics and right ventricular dysfunction. In totality, these findings support the comorbidity inflammation paradigm in HFpEF. Dr. Greg Hundley: Great job Carolyn, I liked the mini feature. That was so nice having one of the authors of the study here to explain kind of a two for one here, because we're going to get a feature and a mini feature. Have you got another paper you want to tell us about? Dr. Carolyn Lam: Thanks Greg and that works both ways. This next paper provides insights into the identity origin and function of many cells that make up late stage atherosclerotic lesions. It also identifies the mechanisms by which these control plucks stability. So corresponding author, Dr. Owens from Virginia School of Medicine and colleagues conducted a comprehensive single cell RNA sequencing of advanced human carotid endarterectomy samples, and compared these with murine micro dissected advanced atherosclerotic lesions with smooth muscle cell and endothelial lineage tracing to survey all plaque cell types and to rigorously determine their origins. Dr. Greg Hundley: Carolyn you know, this is another great study where we have both human subjects research and small animals. What were their results? Dr. Carolyn Lam: They provided evidence that smooth muscle cell specific knockout of transcription factors, KLF4 versus Oct-4 showed virtually opposite genomic signatures and their putative target genes played an important role, regulating smooth muscle cells phenotypic changes. They also provided evidence that smooth muscle cell derived cells within advanced mouse and human atherosclerotic lesions exhibited far greater phenotypic plasticity than generally believed, with KLF4 regulating the transition to multiple phenotypes, including LGALS 3 plus osteogenic cells likely to be detrimental for late stage atherosclerosis plaque pathogenesis. So in summary, smooth cell phenotypic switching produces cells that can be beneficial or detrimental to lesion stability and may be an important mechanism controlling the risk of unstable atherosclerotic plaque and myocardial infarction or stroke. Dr. Greg Hundley: Oh, great job, Carolyn. Well, the next paper I have is from Professor Muredach Reilly from Columbia University. And Carolyn smooth muscle cells play significant roles in atherosclerosis via phenotypic switching, a pathological process and with smooth muscle cell D differentiation, migration and trans differentiation into other cell types yet how smooth muscle cells contribute completely to the pathophysiology of atherosclerosis remain somewhat illicit. So the authors sought to reveal the trajectories of smooth muscle cell trans differentiation during atherosclerosis, and to identify molecular targets for disease therapy by combining smooth muscle cell fate mapping and single cell RNA sequencing of both mouse and human atherosclerotic plaques. Dr. Carolyn Lam: Echoing what you said earlier, Greg, both animal and human data. Terrific. So what were the results? Dr. Greg Hundley: The authors found that smooth muscle cells transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. Smooth muscle cell derived intermediate cells termed stem cells were multiphoton and could differentiate into macrophage like and fibro chondrocyte like cells as well as returned towards the smooth muscle cell phenotype. Retinoic acid signaling was identified as a regulator of the transition of smooth muscle cells to stem cells and RA signaling was dysregulated in symptomatic human atherosclerosis. Finally Carolyn, human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene low PSI and correlated between coronary artery disease risk levels and repressed expression of these genes. Now, activation of RA signaling by all trans retinoic acid and the anticancer drug for acute promyelocytic leukemia blocked the smooth muscle cell transition to stem cells, and that also reduced atherosclerotic burden and then promoted fibrous cap stability. So a lot of clarification of the role of smooth muscle cells, trans differentiation and the development of atherosclerotic disease Dr. Carolyn Lam: Indeed and translational implications. Interesting. Now let's review some of the other papers in this issue. Shall we? First as an, on my mind paper by Dr. Kullo on familial hypercholesterolemia, a reportable disorder. There's an exchange of letters between doctors Lazzerini and Li regarding the article autoantibody signature in cardiac arrest. Dr. Greg Hundley: Thanks Carolyn. Well, I've got a couple other papers to tell you about really a series of research letters from the mailbag. So first Daniel Modin has a Research Letter entitled “Acute COVID-19 and the Incidents of Ischemic Stroke and Acute Myocardial Infarction.” Dr. Christian Mueller has a Research Letter entitled “Effect of a Proposed Modification of the Type 1 and Type 2 Myocardial Infarction Definitions on Incidents and Prognosis.” And finally Carolyn a Research letter from Dr. Jizheng Wang involving an East Asian-specific common variant in TNNI3 that appears to predispose to hypertrophic cardiomyopathy. Well, Carolyn, what a great issue and thank you for that many feature, but how about we proceed on next to our feature discussion? Dr. Carolyn Lam: Let's go, Greg. Today's feature paper is one of those that I think is going to change clinical practice. So please listen up. It's about the RESTAGE-HF study. So pleased to have with us the first and corresponding author, Dr. Emma Birks from University of Kentucky Gill Heart and Vascular Institute, as well as our associate editor, Dr. Hesham Sadek from UT Southwestern to discuss this very important paper. Emma, could you please describe the RESTAGE heart failure study? Dr. Emma Birks: Let's say prospective study of patients getting left ventricular assist devices. So patients with very advanced heart failure are receiving left ventricular assist devices as either a bridge to transplant or as destination therapy. And they're seeing them for chronic heart failure because really all other medical therapy has failed and we use the pump to try and recover their own heart. So when the pump's implanted, we optimize the LVAD unloading, the maximum loading, and we give them a very aggressive medical therapy regime, unless they may not have tolerated these medications before because of poor blood pressure and renal dysfunction, we find they do tolerate them. So we give them in very aggressive doses and then we monitor their underlying function at regular intervals and try and promote recovery. So with that, we had done this in England in the past, in a single center study, but it had not yet been reproduced, which was obviously essential to have a bigger impact. Dr. Emma Birks: So we did a prospective study of six big US centers. We found that we've created a primary endpoint that was statistically powered in advance. And the primary endpoint was the number of patients that recovered within an 18 month period, that were explanted and remained off the pump and alive without transplant over for one year. So overall we found that of the 40 patients we recruited in the centers with chronic heart failure, we were able to explore 19. Of those that satisfied the primary endpoint, that was actually 40% of patients, with 52.3% being explanted overall. And importantly, patients were explanted in all six centers, so we found that the protocol was reproducible under the how much higher rate of recovery that you would otherwise see. Normally there is a database in the US that tracks outcomes from bad patients. And generally only 1-2% seemed to recover enough to be explanted generally. So this was a much bigger percentage. Dr. Carolyn Lam: Emma, first of all, congratulations, what an important trial and what stunning results. More than half of patients receiving that protocol were explanted. That's just remarkable. Now, could I just ask, what is it that you did that was different? I noticed you spent a lot of time saying this was an aggressive pharmacological protocol that was along with the LVAD unloading. Could you maybe elaborate on that a little bit more? Dr. Emma Birks: Yeah, I think that was a very important part of it. So generally I think when the LVAD goes in most centers, the patients are very sick, so most of those patients wouldn't then try and recover them or look at underlying functions. I think that was the first thing that was different was to try very hard. And then we had centers, the experience, I had done this before, it was also very helpful, all agreeing to do the same thing. We use a very aggressive regime of ACE inhibitors, Beta blockers, auto serotonin antagonists and ARBs. And that was also an unusual thing. We use the fact that they're supported with the pump to use both an ACE and an ARB together, but the idea that they have better blood flow in the cranial is way more tolerant and we give very high doses. So we use Lisinopril with the target dose of 40 milligrams, Coreg with a target dose of 50 BID, Aldactone 25 milligrams daily. Dr. Emma Birks: And then we add in losartan if they tolerate it and actually aim for 150 milligrams daily, so those doses are very high. And I think not normally given to people on LVADs. So you must've had the LVAD that don't tolerate the medical therapy and stop it. They might just have blood pressure control, etc. There is now also another INTERMACS trial, a sort of big study that's come out that actually shows benefit of neurohormonal antagonists in general. So that goes together with our study to show that they should already be given and then the regular testing. So we had quite thorough testing. So first of all, we do echos on the pump and then we do echos with the LVAD turned down to a speed at which is not contributing. So we do that and we do an echo at five minutes with it down 15 minutes, and then we walk the patient, distress them. Once we show that the hearts come down in size and improved function, then we do an exercise test, right heart cath on an off pump to look at the hemodynamics. Dr. Carolyn Lam: Wow. So tremendous effort and really the protocol is unique in and of itself, not just the pharmacological therapy, also the way this is monitored and decisions are made really, really amazing. Just one last question for me, because it's a humbling reminder of the importance of neurohormonal blockade in these patients. Do you continue that after they're explanted? Dr. Emma Birks: Yes, we do. And we continue aggressively and that's slightly different as well in that normally you wouldn't give a patient a nascent an up of course, but given that they've already tolerated it on the pump in that same patient. So we restart the same drug regime afterwards, and we actually like to get them to quite along that dosage before we discharge them from the XPLAN, we don't want to do that slowly. We get them back on it quite quickly. And then we follow them very carefully because we don't really know the long-term durability. Dr. Carolyn Lam: Wow, thank you. Hesham. I would love your thoughts on this paper. I mean, it really, really is remarkable results. Dr. Hesham Sadek: Yeah. I mean, I was very happy that we received this paper to review, frankly I've been following that work for a long time since the first new England paper that came out and I'd like to congratulate you for an amazing work. I think this will change the field. First, how was this trial different from the first trial, other than the fact that it's multicenter, what would you say are the major changes that you made to the protocol and what you've learned since the first trial? Dr. Emma Birks: Yes, you're absolutely right. We did make some changes. So first of all, it was six sites instead of one site. I think it was very important to reproduce it in the US but we changed the protocol itself as well. The first trial had optimization of the LVAD speed, really just by echo looking at the reduction in the ventricle size. It had the aggressive medical regime was very similar except this time we increased the Losartan dose from 100 to 150 after the Hill's trial came out. The testing was very frequent in the original English Sheffield study, probably a little bit too frequent to be able to be adopted on a wide scale. So we tried to reduce it down a little bit. So we decrease the frequency of the low-speed echos. I think we had them at six weeks, four months, six months, nine months in a year. Dr. Emma Birks: And after that, we saw if they were already improving and started and only did them at a year to 18 months, if they were improving. And then we also cut down the number of exercise tests. So we didn't do the exercise test until the echo was already showing significant improvement. For two reasons, one, we didn't find it very reliable and two, it was just too much testing for the patient. So it was more of a confirmatory test. In fact, it wasn't a requisite for a pump explantation. We didn't do a left heart catheter, which we did before. Previously we tried to measure LVEDP, this time we decided which was enough. So we just did a right heart cath on and off pump. And we did that once the echo was improved as well. So we rationalized that a little bit. And then the other important thing was before in hayfield study, once we saw the ventricular size come down and injection fraction start to improve, we actually added in Clenbuterol, which was a Beta-2 agonist. Dr. Emma Birks: And the idea with that was to cause a kind of physiological hypertrophy so that when you took the pump out, the heart didn't just dilate. We were worried about atrophy at the heart on the pump long-term. So we did that to try and improve the durability of recovery. So the reason we left off this time was really the previous protocol was very good, but was very complicated. So we wanted to see what rate of recovery we could get just with the aggressive reverse remodeling, neurohormonal drugs, plus the aggressive testing and the optimum loading with the idea that later on, we could add on either Clenbuterol or something later to improve the durability of recovery, if the ability of recovery is not good enough, but actually so far it's proven to be pretty good because the study itself takes quite a long time. It was sort of to recruit them. We had an 18 month period than the follow-ups. It was already a multi-year study. So we wanted to establish a regime that many centers could use to try and promote recovery. Dr. Hesham Sadek: I want to follow up on that last point, because as you know, I've looked at some of these Heights as well in our center, and we looked at the results with you and Stavros and others. So the myocytes size is expected to change, decrease with unloading, right with sufficient unloading. So how would you prepare the Myocardium to take on the normal afterload if you are not going to induce by a beta agonist, for example, Dr. Emma Birks: What I would like to do in the future is try using the pump itself actually. Sometimes there's heart recovers, the heart shrinks and actually start opening their own valve and working in the heart. Of course, when you have the HeartMate one, actually, sometimes wasn't synchronous with the heart. So sometimes the heart will beat against the pump anyway. Once you go to the continuous flow pumps, you've got continuous unloading. So I think it'd be very interesting to intermittently turn down the pump speed and load the heart to work it before you take the pump out. So I would really like to do that. I think that might be the next interesting phase of the study to improve your ability to.. So I guess once you've got maximum reverse remodeling and improvement in function, you could just turn the pump speed down to let the valve open. Dr. Hesham Sadek: Do you think perhaps if you do that, you will increase the percentage of patients that can be explanted? Do you think that could be a factor in the percentage of patient that can be explained? Dr. Emma Birks: I think it might be, it might more improve the, to your ability to make sure we have for a long, good echo function afterwards. Dr. Hesham Sadek: That's great. So another question this was limited to not ischemic cardiomyopathy patients. Can you elaborate a bit on why not include, for example, revascularized ischemic cardiomyopathy patients. Dr. Emma Birks: Yeah, so we did that really just because we didn't want to change too much from the original protocol. We also stuck with one device because we thought if you have multiple pumps, multiple diagnosis, it does get hard to analyze in a multicenter trial. So we did that on purpose and we were always trying to simulate the bridge to transplant population in the age group too. But actually interestingly, most of the patients recruited in the trial were destination therapy patients in the end. Dr. Emma Birks: I think this could be done with ischemic cardiomyopathy. I think we don't have enough data on ischemic cardiomyopathy to know whether it does or it doesn't recover. So I don't think our results say that it's only known as ischemics. I think it just means we haven't studied ischemics sufficiently. Logically they might have more scarred. It might be harder to get such a good percentage to recover. I think all of us in our individual centers have seen a few and we've sort of seen the on pump echo improved, and we've tested them and then taken some out. But most of these cases are anecdotal. So I think that is another important study that needs to be done, obviously a large group of patients. Dr. Hesham Sadek: I agree. So given that they're not ischemic cardiomyopathy, do you know how many of them had genetic testing or what is the percentage of monogenic cardiomyopathys or how do you think these patients would respond to this protocol? Dr. Emma Birks: But if you had a familiar history and actually found it didn't make any difference, whether they recovered or not. I think some of us have personally seen actually those were the familial cardiomyopathy tend to recover more actually again, anecdotally. We published a people before looking at the Titin gene saying that that did recover. I think actually only five of these patients, 12% of them had a family history, but some of them recovered Dr. Hesham Sadek: One final question, as you know, I'm a basic scientist. So ultimately the question I'm going to ask, what do you think the mechanism is? Is it that these hearts are just in a vicious cycle of remodeling and validation, increased pressure, and you were sort of giving it a chance for actual structural reverse remodeling where you changed the geometry of the myocardium and perhaps rest of myocardium, allow for improvement of calcium cycling dynamics, or do you think, is something more exciting? Like three-generation for example. Dr. Emma Birks: Yeah, that's very interesting because I think the LVAD doesn't unload, so it shrinks the ventricles. I think it does improve the geometry and the dynamics. And then you use the drugs where they may have felt before you almost put them from class four, heart failure into class three with the bad to give that chance to work again. And then I think various cellular and fibrotic factors have been looked at and it's hard because there was so many factors have been looked at that. You were going to find some that go up and some that go down and what's important. But the impression I get overall is that you do get improvement, the matrix limits, the recovery on the fibrosis and the matrix. Whereas you do get improvements of myocardial function and cellular function. The cells will tend to reverse the dysfunction and it's really whether that happens or not. It's probably limited a lot by the matrix Dr. Carolyn Lam: That is amazing here. Hesham, I'm going to put you on the spot. Do you have your own hypothesis about this Dr. Hesham Sadek: Based on the work that they did initially in the new England paper, we did actually a small pathology study looking at cell cycle of cardiomyocytes from the core samples and from the explanted hearts post-transplant and we saw evidence of increased cardiomyocytes cell cycle in these patients along with decreased DNA damage and some metabolic remodeling as well with mitochondria. So, you can't really tell much from tissue whether you regenerated it or not, but as you know myocytes don't divide and this is the basis for the lack of spontaneous regeneration of the myocardium. So if this in fact removes the block to cardiomyocyte cell cycle, then this might be a regenerative therapy mechanism. Dr. Carolyn Lam: Well, this is amazing. I wish we had all day to discuss this more. I mean, this is the only place you can get a discussion that goes from clinical to basic signs and back to clinical. Thank you so much, Emma and Hesham for sharing today. Thank you audience for joining us today. You've been listening to circulation on the run on behalf of Greg as well. Don't forget to tune in again next week. Speaker 1: Program is copyright the American heart association, 2020.  

Wow. Absolutely wow. The guys get blown away going behind the scenes with Karen Walker, RN, Cardiac Cath Lab Director at San Jose Regional Medical Center.They discuss so. Much. Stuff. Cardiology, the history of cardiology, stents, ECMO, bypass, ablations, heart failure, quality control, LVADS, transplants and several other completely fascinating rabbit holes regarding the ol' ticker. They waited a bit to dip their toe in the cardiology waters and the wait was completely worth it! It is a great high-level overview, and also goes in-depth at just the right moments. Karen is an incredible guest, and the guys hope you enjoy hearing from her as much as they enjoyed spending time with her in the studio.Email the Off The Box guys @ offtheboxpodcast@gmail.com - they read every email sent to them and appreciate hearing from the fans of the show.Follow us on Instagram and Twitter - a picture is worth 1000 words.Special thanks to:Super Producer: Steve Cooper @ AudiosaurusGraphic Design and Executive Production: Audrey Cooper @ Dodge Design Studios

In this episode, I have the privilege of speaking with Ben Levin, MD on the perioperative management of patients with left ventricular assist devices (LVADs) for non-cardiac surgery. We discuss device function, cardiac physiology, and perioperative management and monitoring of … #69 – LVADs in non-cardiac surgery with Ben Levin, MD Read More »

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: I'm Dr Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue features a very important, but rather somber subject and it talks about suicide attempts among LVAD recipients and the real-life data from the Assist-ICD study. Now we have to get to that and it's a very interesting discussion, but first, let's discuss a couple of papers and I'll start. Now, we know that extracorporeal cardiopulmonary resuscitation using extracorporeal membrane oxygenation or ECMO, for hemodynamic support has been shown to enhance survival for patients with refractory VF or VT out of hospital cardiac arrest. However, what are the effects of prolonged CPR on development of metabolic derangements and neurologically favorable survival in these patients? Well, this was examined by Dr Bartos from University of Minnesota School of Medicine and colleagues who retrospectively evaluated survival in 160 consecutive adults with refractory VF/VT out of hospital cardiac arrest, treated with extracorporeal cardiopulmonary resuscitation, and compared these with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial. They found that extracorporeal CPR was associated with improved neurologically favorable survival compared to standard CPR at all CPR durations less than 60 minutes. However, CPR duration remained a critical determinant of survival with a 25% increase in mortality with every 10 minutes of CPR beyond 30 minutes. The progressive metabolic derangement which developed during prolonged CPR was associated with reduced neurologically favorable survival. Dr Greg Hundley: This mirrors an article that we had maybe about a month ago. What are the clinical implications of this particular study? Dr Carolyn Lam: Well, healthcare systems utilizing extracorporeal CPR for out of hospital cardiac arrest should optimize pre-hospital and in-hospital processes to minimize time to CPR. Further research is needed to identify strategies to increase CPR efficiency, improve profusion, and decrease the metabolic demands such that the progressive metabolic derangement associated with prolonged CPR can be delayed. This is discussed in an editorial by Dr Sonneville and Schmidt.   Dr Greg Hundley: Very nice, Carolyn. Well, my next article is from Roxana Mehran from the Icahn School of Medicine at Mount Sinai. It's really getting at the issue of high-risk implantation of inter-coronary stents and balancing where is that risk. Is it from bleeding or a complication from the procedure? In this study, they had a total of 10,502 patients and they were included from four registries. 3,507 were identified as having high bleeding risk. The authors aimed to evaluate the long-term adverse events in the high bleeding risk patients undergoing PCI with cobalt chromium, everolimus-eluting stent implantation. Dr Carolyn Lam: Ah, Greg. Awesome. I'm a fan of Dr Mehran and looks like I'm going to be a fan of this study. What did they find? Dr Greg Hundley: Well, Carolyn, I love just thinking about coated stents. How about that? Interestingly, those at high bleeding risk had more comorbidities. They had higher lesion complexity and a higher risk of four-year mortality. In fact, four times that of those without those risk factors. The risk of mortality was increased after coronary thrombotic events and after major bleeding. Thus, rather than just being evaluated as a subset of patients in whom the risk of bleeding takes precedence, high bleeding risk patients must be considered a vulnerable population in whom both ischemic as well as bleeding events have a significant impact on their mortality. Dr Carolyn Lam: Nice, Greg, and you said all of that without repeating everolimus. Dr Greg Hundley: Coated, remember, coated stents. Dr Carolyn Lam: These tongue twisters, but hey, my next paper provides novel insights into mechanisms underlying diastolic stiffness in cardiomyocytes and the myocardium. This is from Dr Prosser from Perelman School of Medicine in Philadelphia and colleagues, who interrogated the role of the microtubule network in the diastolic mechanics of human cardiomyocytes and myocardium. They found that stable detyrosinated microtubules contributed viscous forces during diastolic stretch that increased cardiomyocyte stiffness, particularly in patients with heart failure. Depolymerizing microtubules reduced myocardial stiffness over the range of strains and strain rates associated with early rapid filling in tissue from patients with diastolic dysfunction. Dr Greg Hundley: Now, how are we going to take this to patients? Are there any translational insights? Dr Carolyn Lam: Microtubule deep polymerization using colchicine. Colchicine, the stuff we use for gout, this reduced myocardial viscoelasticity with an effect that decreased with increasing strain. Post-hoc subgroup analysis revealed that myocardium from patients with heart failure reduced ejection fraction were more fibrotic and elastic than myocardium from patients with heart failure preserved ejection fraction, which were relatively more viscous. Now, colchicine reduced viscoelasticity in both HFpEF and HFrEF myocardium, but may confer greater benefit in conditions with limited myocardial fibrosis including HFpEF. How's that for translational? Dr Greg Hundley: Oh, very nice, Carolyn. My next paper comes from Dr Lior Zangi from Mount Sinai School of Medicine. Carolyn, in this study, the authors performed transcriptomics sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling after myocardial infarction. They investigated the effect of altering sphingolipid metabolism through a loss of chemical inhibitors or gain modified MRNA and modified RNA of acid ceramidase function post hypoxia or MI. Dr Carolyn Lam: Whoa, so what did they find? Dr Greg Hundley: Well, Carolyn, translationally, the authors found that transiently altering sphingolipid metabolism through acid ceramidase over expression is sufficient and necessary to induce cardio-protection after myocardial infarction. Carolyn, these results highlight a new therapeutic potential of acid ceramidase modified messenger RNA in ischemic heart disease. The basic science is just phenomenal in our journal. Dr Carolyn Lam: It is, and I loved the way you explained that one, Greg, thanks. Now, there's lots of stuff also in the journal. There's an On My Mind by Dr Ray entitled "LDL Cholesterol Lowering Strategies and Population Health: Time to move to accumulative exposure model." We also have a research letter by Dr Chen describing a novel mouse knock-in strategy utilizing a biotin ligase-based system called biotin identification 2, to identify the cardiac diet proteome in vivo. Well, very interesting stuff, especially in terms of this particular novel strategy. Dr Greg Hundley: You know, Carolyn, this week the mailbox is just full, so I've got a research letter emphasizing trends in anti-arrhythmic drug use among US patients between 2004 and 2016 and it's from Dr David Frankel from the Hospital of the University of Pennsylvania. I've also got a letter to the editor regarding the association between the use of primary prevention implantable cardio defibrillators in mortality in patients with heart failure, a prospective propensity matched analysis from the Swedish Heart Failure Registry, and the corresponding author is Professor Laszlo Littman from atrium health at the Carolinas Medical Center in Charlotte, North Carolina. There is also a response to this letter from Dr Gianluigi Savarese from Karolinska Institute. Then finally I have a new another EKG challenge, Carolyn, from Dr Miguel Arias. It's a case of new onset, recurrent syncope triggered by fever. Can you get it right from just looking at the EKG? Well, Carolyn, should we head on to our feature discussion, which this week has a very somber tone? Dr Carolyn Lam: Let's go. Left ventricular assist devices or LVADs are really becoming established therapy for end stage heart failure. Now, we who manage such patients realize there are numerous complications and have seen patients who suffer things like anxiety and depression. Interestingly, until today, there was very little data regarding the suicide risk in this population. I am so pleased to welcome the authors of a very unique and important research letter and they are Vincent Galand as well as Erwan Flécher, both from Ren University Hospital in France, and of course Mark Drazner, our associate editor from UT Southwestern. Vincent, could you start us off by telling us what made you do this important study and what did you find? Dr Vincent Galand: As you know, in the entire population where a lot of tests have thromboses or infection or ventricular arrhythmias, but there is a lack of data about the clarity of life for the secret distress or suicide in this population. I think it's very important to have information about the population. At the beginning is the Assist-ICD study is a study focused on arrhythmias in this population, but we recorded data about suicide in this population. What the objective of this study was to analyze the incidents of suicide in this population and to see if there is some predictor of suicides in this population. Dr Carolyn Lam: What did you find? Dr Vincent Galand: We find that in centers without LVAD nurse coordinator, the incidents of suicide, was higher. It was not significant, but it was a very big trend. Additionally, we found that patient implanted in destination therapy was a bigger risk of suicide compared to patient granted bridge transportation or bridge to recovery. I think there is two factors of suicide. The first one is a lack of LVAD nurse coordinator and the second one is the implementation and destination therapy. Dr Carolyn Lam: Yeah, and the really cool thing is that that first factor is something that I suppose can be addressed in future efforts. Mark, could I just ask you to put these findings and this research that are into context for circulation to publish quite a specialty, if you may, topic, why is this so important?   Dr Mark Drazner: DT vans are really a rapidly emerging therapy for patients with advanced heart failure, with almost exponential growth. As these profound technologies are emerging on the scene, it's important, first, to consider all the ramifications for our patients. I think anyone could imagine having an LVAD implant and how that might have profound influence on your life in totality and the impact on the psychological aspects. While there's been previous studies, there seems to be much avoidance in us really fully understanding the total impact. There have been previous case reports of suicide, but not anything to this magnitude where a systematic series with an estimate of the frequency of as high as 2%, which may not sound high, but, compared to the general population, is increased. We view this as an important look at a critical topic. It's the beginning, there needs to be, as you said, it's a research writer on a case series, but it's a cautionary tale and really is pointing the way for us to proceed with further investigation as potentially important complication related to that. That's essentially why the editorial board found this interesting. Dr Carolyn Lam: Indeed. Could you just remind us how big this study was? Because this is really big for an LVAD study. Dr Erwan Flécher: We collected data from 19 university centers in France over 10 years period and we collected a lot of that especially in the fields of arrhythmia. As Vincent said, we thought it was interesting to take the entire picture, so we collected data about quality of life and how do they live and if they had a lot of risk of suicide, if not, and that's how we succeeded to lead this study. In France, what is important also for you to know is that we do implant a different population of patients than in the US. We do implants in bad patients, in very, very sick patients. Most of them are currently in cardiogenic shock or already under temporary support, ECMO support, IMPELLA support, so it may impact also our results. That's an interesting point to say and the overall thing is that our paper demonstrated, I think, that we need to take care of these patients not only about the device, not only about the anticoagulation, but also, I mean again, the entire picture. The social part, the quality of life, the way they do live is very important. Probably they should be proposed for psychological follow-up also, or any kind of support for the family. This is important in order to decrease the risk of suicide, in my opinion. Dr Carolyn Lam: I liked those take-home messages that are very practical, and you kind of read my mind about that question of generalizability. Mark, did you have any reflection on that? The generalizability to the US population?   Dr Mark Drazner: Yeah, that's an important point. I was struck in the paper that 80% of the patients who committed suicide were followed at centers without LVAD coordinators. That number seems high compared to what we're used to seeing. It would be intriguing how widespread that is, where patients who are getting implanted don't have access to a VAD coordinator in your country. Dr Erwan Flécher: Well, that's an important point also. It is different in France. I mean, we just created...That coordinator did not exist a few years ago in France and I know you are used to work with VAD coordinator in the US, in the UK, even in Netherlands and Germany, but in France it was not like that and all patients were only followed by cardiologist or cardiac surgeons and a few centers started few years ago, five, eight years ago to have a VAD coordinator nurse program. We do believe it is very, very important. That's also plea for a better organization of care in our country. Dr Mark Drazner: Yeah, that's a thinking point. I didn't realize that that was not widespread practice and relatively new implementation. It'll be interesting to see if the rates subsequently fall with that change in practice. Can I ask, let me follow up in terms of your previous comment. It sounds like a lot of these patients were acute presentations and I wonder also whether they may not have had the full time to grasp exactly what they were getting into, for example. I think we've all been there. Someone went into cardiogenic shock, ends up crashing and burning and has to go for a durable VAD. A very different complex in someone who has consolidation has been followed in the center for a while, has a chance to come to understand what all that really is. You think that is a major factor in this experience? Dr Vincent Galand: We think that patients who are granted in case of emergency; it's a bigger risk of surgical distress afterwards the implantation. In fact, that they cannot many information before the implantation, information about the worth life after the LVAD implantation. Of course if they don't the information, they can't be prepared for life after surgery. I think it's a bigger risk, yeah. Dr Erwan Flécher: That's why maybe in your country or maybe elsewhere, I don't know, maybe the findings would have been different. That's, that's an option we should consider, also. In France, as we told you, we do implants. Most of our patients are implanted in emergency. They're already in ICU. Most of them are already under mechanical ventilation, so they just wake up and they learned that they have been implanted. Not all of them, but most of them, the vast majority of them, so of course they are not so well prepared and that may have an impact on the follow-up. We try to talk to the family; we try to talk to the general practitioner. Dr Mark Drazner: Of the 10 patients, it's very interesting that patients are being implanted and not knowing they're being implanted in and say waking up with an LVAD. I don't know if you have the granular detail, but do you know, of these 10 patients, how many of them were in that situation? Dr Vincent Galand: The patients were implanted in cardiogenic shock, so I think it's four patients, but six patients were implanted without cardiogenic shock. They received this kind of information before the LVAD implantation, so it's not a big part of the population, but it's some patients. Dr Mark Drazner: Could you, just for our readers, it's a little goory, I will admit, but in terms of how these patients attempted or actually committed suicide, just to explain in terms of, it was oftentimes related to a mechanism through the LVAD. If you could just summarize that and how they tried to commit suicide or commit suicide. Dr Vincent Galand: That was the case. The suicide was with drive line disconnection or drive line section. In two patients, it was drug suicides, but in most of the patients the drive line is the main way for suicide. Dr Mark Drazner: It's interesting that the mechanism that these patients tried to commit suicide was directly through the LVAD. Dr Erwan Flécher: Of course it's the easiest way to terminate their life and they just cut off it. Just don't plug the battery and they are alone and that was the main way to practice their suicide. Dr Mark Drazner: I know we don't have the initial report, we probably don't have all those, but in terms of you postulating in the paper why patients might get to the state where they would try or commit suicide with the LVAD. If you just want to throw out some of your hypotheses so that our listeners can hear those as well. Dr Erwan Flécher: I've got in mind two or three points in order to improve our results. First of all, we should implant maybe earlier patients in France in order to have a better way to prepare and to invest the VAD implantation. The second point would be to have a better organization of care and I think we should develop that VAD nurse coordinators program like in many countries. We still have some but not in all the hospitals implanting that. The third point would be also to get the better LVADs. I mean, probably the drive line in sections, batteries, the controller, this of course it's much better than it was 10 years ago. There is no noise. It's less big than it was, but still, I think if we can improve the device itself, I think we may observe maybe the decrease in the risk of a system in society, especially the drive line, if there is no drive line, the quality of life should be better. We may suggest that the risk of suicide would decrease. Dr Carolyn Lam: A very somber topic, but those last take home messages, leaving hope for improvement, were really important. Thank you everyone for sharing with us today, and thank you, audience, for joining us today.   Dr Greg Hundley: This program is copyright, the American Heart Association 2020.  

Our population is aging, and heart failure is only going to increase. This will inevitably lead to an increase of patients with left ventricular assist devices. New technology can be intimidating and confusing with complex recent medical histories and unfamiliar terminology surrounding the various LVAD brands. Join the podcast crew as we attempt to simply an EMS approach to the LVAD patient. REFERENCES: 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123099/pdf/wjem-19-834.pdf 2. https://emj.bmj.com/content/34/12/842.long 3. Goebel et al. (2019) An Urban 9-1-1 System’s Experience with Left Ventricular Assist Device Patients, Prehospital Emergency Care, 23:4, 560-565 4. Shinar et al. Chest compressions may be safe in arresting patients with left ventricular assist devices (LVADs). Resuscitation. 2014;85(5):702-704

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. We're your cohosts, I'm Dr Carolyn Lam, associate editor from National Heart Center and Duke National University of Singapore Dr Gregory Hundley:       And I'm Greg Hundley, associate editor from the Pauley Heart Center in Richmond, Virginia at VCU Health. Our feature article today really invokes thought regarding LVAD bridging to heart transplantation. I really look forward to the conversation with Dr Veli Topkara from Columbia University, the corresponding author and our associate editor, Dr Mark Drazner from UT Southwestern. And it's regarding the outcomes from their study, evaluating patients waiting for transplant that are bridged with an LVAD versus not. But before we get to that, let's dive into some of our other original articles with our little coffee chat. Do you have an article that you'd like to discuss? Dr Carolyn Lam:                You bet I do Greg and I have my coffee here. Have you ever wondered, does microvascular disease, in any location in the body, increase the risk of lower limb amputation? Well, this was looked at in the paper that I chose first today. It's from Dr Beckman from Vanderbilt University Medical Center in Tennessee and his colleagues, and they basically examined 125,674 participants in the Veterans Aging Cohort Study from 2003 to 2014 and analyzed the effect of prevalent microvascular disease defined as retinopathy, neuropathy and nephropathy and peripheral artery disease status on the risk of incident amputation events, of which there were 1,185 amputations over a median of 9.3 years. Dr Gregory Hundley:       Wow, Carolyn. What did this study find? What did Josh and his colleagues find? Dr Carolyn Lam:                They found that the presence of microvascular disease increases the risk of amputation significantly in the absence of peripheral artery disease. As many as one in six below knee amputations may result from microvascular disease, even without peripheral artery disease. Microvascular disease also potentiates the amputation risk in persons with peripheral artery disease to more than 20-fold, compared to persons with neither peripheral artery disease nor microvascular disease. Further research is really needed to understand the mechanisms by which this occurs. And in the meantime, clinicians should bear this increased risk in mind when screening for and managing lower extremity disease. Dr Gregory Hundley:       Ah. Well Carolyn, my first paper is somewhat related because we're going to talk about triglycerides. And this paper is from Zahid Ahmad from UT Southwestern Medical Center. He's the corresponding author. And can you imagine Carolyn an antibody that could correct elevations in serum triglycerides? Dr Carolyn Lam:                Tell us about it, Greg. Dr Gregory Hundley:       Well, I'm going to give you a little background first. Low levels of triglycerides and other lipids are observed in individuals with loss of function mutations in angiopoietin-like protein 3 which inhibits lipoprotein lipase activity, increasing triglycerides and other lipids, and providing a rationale for development of a monoclonal antibody therapy. Dr Carolyn Lam:                Interesting. What did this study do Greg? Dr Gregory Hundley:       It evaluated evinacumab. They looked at the safety of this. This is a fully human angiopoietin-like protein 3 antibody, and it was compared with placebo, with no serious treatment emergent adverse events, no events related to death or treatment discontinuation was reported. They did two phase one studies evaluating single and multiple ascending doses. In addition, substantial and sustained percent reductions from baseline versus placebo were observed and triglycerides with absolute levels reaching about 50 milligrams per deciliter for several of the evinacumab doses at specific time points in both studies. And therefore, the data from these two phase one studies in this one paper support further clinical evaluation of this new antibody in larger studies of hypertriglyceridemic individuals. Dr Carolyn Lam:                Definitely a space to look out for. Well Greg, my next paper is a basic paper. Genome wide association studies have identified chromosome 14 Q32 as a locus for coronary artery disease. The disease associated variants fall in a hitherto uncharacterized gene called Hedgehog Interacting Protein Like 1, or HHIPL1. the function of this gene and its role in atherosclerosis has previously been unknown, well, until today's paper. But Greg, here's your quiz. What do you know about the hedgehog proteins? Dr Gregory Hundley:       Well, I know hedgehogs are friendly little animals and I know they must have great proteins because they're so friendly. Dr Carolyn Lam:                Why did I expect that? Oh, let me tell you a little bit about them. The mammalian hedgehog proteins like sonic hedgehog, desert hedgehog, and Indian hedgehog are secreted molecules that exert a concentration and time dependent effect on target cells following binding and complex signal transduction pathways. They induce the transcription of target genes, primarily involved in cell proliferation, survival, and fate specification.                                                 Now in adults, the hedgehog signaling is involved in the maintenance of adult vasculature and ischemia induced neovascularization, including after myocardial infarction. Today's authors, however, including Tom Webb from University of Leicester and colleagues, report the first experimental investigation of HHIPL1 and the present evidence that it is a secreted proatherogenic protein that regulates smooth muscle cell proliferation and migration. So, that's novel.                                                 Through a series of experiments involving coronary artery disease, relevant human cells and mouse models, they showed that HHIPL1 is a secreted protein that interacts with sonic hedgehog and is a positive regulator of hedgehog signaling. In murine models, HHIPL1 deficiency attenuates the development of atherosclerosis by reducing smooth muscle cell proliferation and migration. The clinical implications are two-fold. First, this study supports HHIPL1 as the causal gene at that 14 Q32 coronary artery disease locus that we did not really understand previously. And secondly, HHIPL1 is a promising therapeutic target that affects a pathogenic mechanism not addressed by current mechanisms for coronary artery disease. Room for novel development. Dr Gregory Hundley:       Very interesting Carolyn. Well, I've got another basic science paper, and this is from Dr Kenneth Walsh at University of Virginia and it's going to look at the role of neutrophils, not necessarily macrophages but neutrophils and their role in pressure overload induced cardiac dysfunction. While the complex roles of macrophages in myocardial injury is widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. This study examined the regulation and function of neutrophils in pressure overload induced cardiac hypertrophy as mice underwent treatment with Ly6G antibody to deplete neutrophils and then subjected them to transverse aortic constriction or TAC. Dr Carolyn Lam:                Huh? What did they find? Dr Gregory Hundley        Caroline, the study revealed that neutrophils played a critical role in the hypertrophy of the left ventricle that results from pressure overload in this murine model of heart failure and identified that a non-canonical Wnt protein is essential for the recruitment of neutrophils to the injured myocardium. Dr Carolyn Lam:                Hmm. What do you think are the clinical implications of this? Dr Gregory Hundley        This study demonstrates how neutrophils contribute to the hypertrophy of the left ventricle under conditions that do not involve ischemia or myocardial necrosis. Also, since cardiac hypertrophy is a risk factor for the development of heart failure, this study implicates WnT5a mediated neutrophil infiltration as an early step in the progression of this disease. Dr Carolyn Lam:                Wow, thanks Greg. That was so cool. But let's hurry on to our feature discussion, shall we? Dr Gregory Hundley        You Bet. Dr Carolyn Lam:                Bridge to transplant with left ventricular assist devices is a mainstay of therapy for heart failure in patients awaiting heart transplantation. The criteria for heart transplantation listing does not differ between patients medically managed versus mechanically bridged to heart transplant. However, are there differences in post-transplant outcomes between medically managed and mechanically bridged patients? Well, today's paper provides important data to address this question. So pleased to have with us the corresponding author, Dr Veli Topkara from Columbia University Medical Center, New York Presbyterian as well as Dr Mark Drazner, associate editor from UT Southwestern. Welcome gentleman. Veli, this is an important question. Could you please tell us how you addressed it and what you found? Dr Veli Topkara:                We decided to visit an old question of whether bridging with LVAD confers at risk for post-transplant mortality. Because the field and pump technology has been rapidly changing. There has been a significant increase in utilization of devices nationwide to the extent that more than 50% of patients already have an LVAD in place by the time they receive a heart transplant. And patients also wait much longer on these pumps before they could get a heart.                                                 Currently, available devices provide continuous flow and patients essentially live without a pulse for many months to years waiting for a heart. And with this unique physiology, they also have unique complications such as RV failure and there has also been pre-survey reports including one from our center suggesting an increase in the primary graft failure rates after heart transplant. And mostly seen in patients who were bridge to transplant with an LVAD.                                                 To address some of these questions, we took advantage of the UNOS database, which is the largest prospective transplant data registry in the United States. We were able to identify more than 14,000 patients who are either medically or mechanically bridged to transplant. We then derived a cohort from patients who were LVAD baseline by propensity score and we looked at their outcomes.                                                 And what we found was that patients who were mechanically bridged to transplant with an LVAD, had 9.5% mortality at one year, compared to 7.2% in patients who were medically bridged. And this is more than 30% increase in relative risk of death for LVAD patients. When we looked at the specific cause of death at one year, LVAD patients had a higher number of cardiovascular death secondary to primary graft failure, confirming findings of the recent studies at a larger scale.                                                 Next, we looked at whether mortality risk factors were similar in the mechanical versus medical bridged patients. And this is a very important question clinically because the criteria for transplant listing do not distinguish between the two patient cohorts. For example, at my center age cutoff transplant listing is less than 72 years of age and that is whether or not patients are on VAD support. And same applies for example, GFR cutoff for renal function or PVR cutoff for pulmonary hypertension. And all the cutoffs that are utilized are essentially identical for transplant candidates irrespective of the bridging strategy.                                                 But what we found in this paper, however, what's quite different that if we apply the same thresholds for mechanical versus medical bridged patients, for some of these risk factors, you end up having outcomes that are remarkably different. For example, for patients with a normal renal function, the mortality risk is similar going into transplant with or without an LVAD, but for patients with borderline renal function observed mortality has more than doubled for those going into transplant with an LVAD, as opposed to medical therapy.                                                 And we also observed similar trends for recipient age, BMI and PVR, in which numerical increase in these factors would translate to high risk of mortality in LVAD patients going into heart transplant. Despite the limitations of this large registry analysis, I think these findings suggest that we may need to think of it differently when it comes to listing or transplanting patients who are on LVAD. And there seems to be a group of patients who are perhaps maybe better served by staying on an LVAD as opposed to moving on to heart transplant and we need to better identify who these patients are. Dr Carolyn Lam:                Oh Wow. Veli, thank you. First, congratulations on a very important paper and also how you beautifully summarized. Mechanically bridging patients associated with a higher risk of early post-transplant mortality and even providing data on the cause and risk factors associated with that mortality. Mark, could I bring you in here? Not just as AE (associate editor), but as a doc[tor] who manages many of these patients. What were your perspectives? Dr Mark Drazner:             As I step back and as Veli said, there's an increasing number of patients who are being bridged with a VAD, so the question clearly is important, and we don't really have any randomized data available to us in terms of how the bridging strategy may impact outcomes. When you look at the groups of patients who are supported with VADs or not, they're very different and so you need to do some statistical manipulation which here they did propensity matching, to try to come up with equal groups as you look at their outcomes. That was nicely done.                                                 And then theoretically I think you could argue there may be reasons why patients bridged with VADs may do better or they may do worse. They may do better because you may restore their functionality, you may improve renal function and, but they may do worse because they have coagulopathies, the VAD itself may lead to complications and so it's a question you can't really answer just logically. You really need some data which is I think the best study that's been brought forward so far as the one we're discussing today. Veli, let me ask you because the obvious question then is why do you think the outcomes are worse among the patients who are bridged? Dr Veli Topkara:                I think they are doing worse for multiple different reasons. Having an LVAD is clearly an additional surgery which technically makes the second transplant surgery more complicated. But when we looked at the risk factors for primary graft failure at our institutions, the predictors of primary graft failure in LVAD patients were also very similar to factors we identified in this nationwide analysis which included renal failure, RV dysfunction, as well as trans-transplant and increased time on device support. I think it's clear that some subset of LVAD patients who have these risk factors are at higher risk for increased post-transplant mortality for some of the mechanistic reasons are unclear at this point. Dr Mark Drazner:             Do you think their continuous flow exposure is part of it? Dr Veli Topkara:                That's clearly one of the hypotheses that we have been talking about because as we discussed, these patients are exposed to continuous flow for a long time and one of the concerns is whether they lose their peripheral arterial venous-reactivity over time. And this could potentially also be the reason why patients who are on pump support for longer times are at higher risk for PGF. That's a possible underlying mechanism. But in this data set, we didn't have fair data with regards to pulse pressure and pulsatility, which could have helped answering this question. Dr Mark Drazner:             And just for clarification for the listeners, this was pre-HeartMate 3 data, is that correct? Dr Veli Topkara:                Yes. This analysis doesn't include any HeartMate 3 patients. Dr Carolyn Lam:                And Mark, if you don't mind, could you also clarify for the listeners why you specifically pointed out HeartMate 3 in the setting of the pulsatility? Dr Mark Drazner:             There is some degree of pulsatility reintroduced with the HeartMate 3, whether that has any physiological consequences is not yet known. Certainly, in terms of the impact of transplants. But as Veli said, the dataset available didn't yet include the HeartMate 3 so that's, remains an unanswered question for us currently, but certainly an important one. Dr Veli Topkara:                We would probably be able to do this analysis now that we have accumulated more patients with HeartMate 3. At the time of the study we didn't have any HeartMate 3 patients in the registry. In terms of primary graft failure, we have implanted over 160 patients with HeartMate 3 at my center, but we still see primary graft failure in HeartMate 3 patients going into heart transplant, but that would clearly be an interesting follow up project. Dr Mark Drazner:             Yeah, for sure. Another point that people, as they looked at your paper and asked me, is in terms of the impact of the VAD complications, whether the patients who are doing worse or those who, because they are patients who had VAD who have had complications and then went on a transplant and the impact of that, in terms of your findings. I know you did some analyses on that. Could you just clarify that for our listeners as well? Dr Veli Topkara:                Sure, so we wanted to look at for the LVAD patients, if there were any VAD related factors that would impact the posttransplant mortality and one of the things that we looked at was, their specific complications on LVAD support and were able to pull that data by looking at their reason for 1A upgrade status which clarifies the complication pipe. And when we looked at, based on complication type, we didn't see any impact of complication on the post LVAD mortality. In other words, the other patients who are transplanted with an infection or they were transplanted because of device thrombosis, they did not have any difference in terms of their posttransplant mortality.                                                 We also compared patients who were supported by axial flow devices versus centrifugal flow devices and again, there was no significant difference in terms of posttransplant mortality. One factor that we found that was significant was the duration of the LVAD support and patients who stayed on the LVAD for longer times clearly had increased higher risk of posttransplant mortality. And this is also something that we had found in our institutional data. Dr Mark Drazner:             And Veli that would potentially speak to the impact of the continuous flow if duration of VAD is a risk factor. Dr Veli Topkara:                That's our hypothesis Mark. And I think we all tend to think that continuous flow is not natural, and we have pulse style flow for a reason. Now it's possible that if our bodies and end organs and vessels are exposed to continuous flow for a long time, that may be potentially a reason for, increased risk of PGF or raise of PGF after heart transplant. But I don't think we have enough data yet. Dr Mark Drazner:             Veli, one of the other interesting findings was the lack of impact on long-term outcomes. I'd be interested in your thoughts about that, why there was an impact on the first year but not long term. Dr Veli Topkara:                Absolutely. And that was a critical part of the findings and when we looked at our survival, when we visually looked at the curve, it seemed like the curves really separated early on and they sort of remain parallel to each other after one year. And for that reason, we did a conditional survival analysis starting from one year and then we compared starting for one year. There was actually no difference between the LVAD versus medical group. Again, confirming that the adverse impact of survival was really early, within the first year after transplant and I think that really has to do with primary graft failure as well as vasoplegia which are, typically seen early posttransplant. And I think the reason the VAD support is increasing mortality is most likely through increasing risk of PGF as well as vasoplegia. Now that's my read on the early risk rather than the late impact. Dr Mark Drazner:             Do you think that speaks to maybe not as big an impact on the immunological milieu of VADs as one might anticipate? Dr Veli Topkara:                Certainly, I mean the immunology, one thing we know is that LVAD patients have higher HLA sensitization going into transplant. However, primary graft failure is typically very early after transplant. And in general, we don't find, obviously we don't see any rejection in these patients. The mechanism is not related to HLA mediated rejection. Dr Mark Drazner:             That's interesting. Dr Carolyn Lam:                Well Mark and Veli, thanks so much. This is such an important and interesting discussion. Could I wrap it up now by asking each of you, you've already covered possibly the important areas for future research including the pulsatile devices, but what should clinicians take home right now? Veli, if I could start with you, because you had already said earlier that perhaps these patients need to be more carefully considered. What do you mean by that? What's the take home for now? Dr Veli Topkara:                I think the question is whether we should be listing or transplanting LVAD patients who are high-risk, and I think the research should focus on developing tools to better identify LVAD patients who are too high-risk for transplant. In this project, we only worked with a limited number of variables that were available in the UNOS registry, but there may be more specific clinical risk factors or even biomarkers predicting outcome in this unique cohort of LVAD patients potentially transitioning into transplant. I think that's an important question to figure out.                                                 And another important question is whether we should be using identical cutoffs for listing patients with or without LVAD and if not, what would be the ideal cutoff for each one of these risk factors? Because what I read from this paper is that, a creatinine level of 1.8 may signal a different risk in an LVAD patient versus another patient on a minor trump. That's another important question.                                                 And also, since October of last year, the new heart allocation policy has been in place, which now defines LVAD patients to appear status three or four based on their complication profile. And it will be interesting to see how the new allocation system would impact patients are on LVAD support waiting for an organ. And it's possible that these patients may end up waiting longer compared to patients who are with cardiogenic shock and are assigned to higher tier status. And if LVAD patients wait longer as we see from this data, they will have worse posttransplant outcomes. It's going to be very interesting to see how the new allocation policy impacts.                                                 Another point I want to make is that with the recent MOMENTUM-3 trial patients receiving HeartMate 3 LVADs, had a 13.4% mortality risk at one year and this is actually lower than 17.6% mortality at one year in high risk LVAD patients in our study. Again, questioning transitioning from LVAD to transplant in high risk patients. Dr Mark Drazner:             I might take a step back even further. It's an important, it touches on a critical question in my mind, which is if you have a patient who needs to go into transplant and they're not crashing and burning. I'm assuming if they're crashing and burning, you need to go onto an LVAD, the following comments won't apply to that group. If you're a patient who's relatively stable, is it a better strategy to try and get them to transplant directly? Or is it better to go through and VAD and then transplant them? And ultimately that strategy question I think would require randomization to really answer that. But the data that we have discussed today, I think are opening that question and touch upon that in terms of the strategy of the impact of bridging people with VADs itself, which is why I think this is such an important question. Dr Carolyn Lam:                Thanks again, Mark and Veli. That was an amazing discussion.                                                 Thank you, audience, for joining us. 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.  

Podcast summary of articles from the June 2019 edition of the Journal of Emergency Medicine from the American Academy of Emergency Medicine.  Topics include pediatric fever, vancomycin dosing, seatbelt sign in trauma, REBOA, ECMO in a community ED, and board review on LVADs.  Guest speaker is Dr. Colin Crowe.

Dr. Adam Gottula interviews Paige Barger and Liz Powell, MD on the basics of LVADs and how to troubleshoot them prehospital and in the ED

Dr. Jeffrey A. Morgan, a cardiac surgeon and Chief Medical Officer for BIOLIFE4D, provides an overview on surgical therapies currently used to treat patients with heart failure and overviews the current and future direction of bioprinted hearts.   In this episode, Dr. Morgan explains what causes heart failure, the physiology of a healthy and diseased heart, and outlines the most common surgical therapies currently available to patients with heart failure. He explores the benefits and drawbacks of current surgical therapies such as the total artificial heart (TAH) and left ventricular assist devices (LVADs). Dr. Morgan also discusses the current challenges with heart transplants, which leads us to a discussion on bioprinted hearts as a therapy currently undergoing development.   Dr. Morgan provides insight on why using bioprinted hearts would be superior to traditional heart transplants and explains what challenges scientists currently face in developing these technologies. His insight as a practicing surgeon and as a figure in the biomedical technology industry offers a unique perspective on how bioprinted hearts can be useful in every stage of treating heart failure – from drug research and development to clinical use. Tune in to discover how this technology has the potential to save thousands of lives.

Steven Nissen, MD talks with Jerry Estep, MD, Section Head, Heart Failure and Transplantation and Edward Soltesz, MD, Surgical Director of the Kaufman Center for Heart Failure and Recovery about what a diagnosis of heart failure means, what medications help improve survival and quality of life, when a patient should seek a second opinion about advanced heart failure therapies such as left ventricular assist device (LVAD) or heart transplant, and what LVADs do and how they work.

Join the EMGuideWire Team as they discuss a simple approach to the very complex and complicated patients with a Left Ventricular Assist Device (LVAD). "LVAD" is for "Look & Listen, Ventricle, Anticoagulation, and Driveline."

Dr Carolyn Lam:                We start today's podcast with a few words from our Editor-in-Chief, Dr Joe Hill. Dr Joe Hill:                           I speak with you today with a heavy heart as we recently lost an esteemed and beloved colleague, Professor Bongani Mayosi. Bongani was a pioneering leader, a renowned investigator, Dean of the Medical School at the University of Cape Town, and an important member of our Circulation editorial leadership team.                                                 Bongani had an abiding passion for the under-served, especially those in his native Africa. He died tragically and suddenly at the early age of 51, just 10 days after recording the podcast you're about to hear.                                                 We mourn the loss of this colleague and our hearts go out to his family. It is a very poignant moment, as we hear his voice once again. We grieve deeply, and are reminded of Bongani's towering achievements and contributions to the betterment of our world. 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.                                                 CD4-positive T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Today's paper describes the first study to detect apolipoprotein B peptide 18 specific CD4 T cells in mice and humans. First author Dr Kimura, corresponding author Dr Ley from La Jolla Institute of Allergy and Immunology and their colleagues constructed novel P18 tetramers to detect human and mouse APOB-specific T cells and assayed their phenotypes by flow cytometry. They found that these P18 specific T cells were mainly anti-inflammatory regulatory T cells in healthy donors, but co-expressed other CD4 lineage transcription factors in patients with sub-clinical cardiovascular disease.                                                 Immunization with P18 reduced atherosclerotic burden in APOE deficient mice and induced antigen specific T regulatory cells. This study therefore, identifies APOB peptide 18 as the first T regulatory APOtope in human atherosclerosis.                                                 The next study suggests that testing intracellular calcium handling in circulating B lymphocytes may be a novel biomarker for monitoring patients with heart failure. During [inaudible 00:02:47] intracellular calcium is released from sarcoplasmic reticulum into the cytoplasm through Type II ryanodine receptor calcium release channels. In heart failure chronically elevated, circulating catecholamine levels cause pathologic remodeling of these Type II receptors, resulting in diastolic sarcoplasmic reticulum calcium leak, thus decreasing myocardial contract [inaudible 00:03:09]. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum calcium release and this occurs through Type I ryanodine receptors. Chronically elevated catecholamine levels in heart failure cause Type I mediated sarcoplasmic reticulum calcium leak, thus contributing to skeletal myopathy and weakness.                                                 In today's paper, first author Dr Kushner. Co-corresponding authors Dr Kitsis from Albert Einstein College of Medicine and Dr Marx from Columbia University, New York hypothesized, that since circulating B lymphocytes express Type I ryanodine receptors, they may be a potential surrogate for defects in intracellular calcium handling due to leaky ryanodine channels in heart failure. Indeed, they found that circulating B lymphocytes from humans and mice with heart failure exhibited remodeled Type I ryanodine receptors and decreased endoplasmic reticulum calcium stores, consistent with chronic intracellular calcium leak. This calcium leak correlated with circulating catecholamine levels. The intracellular calcium leak was significantly reduced in mice treated with S107, which is a drug that specifically reduces ryanodine receptor calcium leak.                                                 Furthermore, heart failure patients treated with LVADs exhibited a heterogenous response. Thus, Type I ryanodine receptor mediated calcium leak in B lymphocytes assessed using flow cytometry may provide a surrogate measure of intracellular calcium handling and systemic sympathetic burden and therefore represent a novel biomarker strategy for monitoring the responses in heart failure therapy.                                                 Hypouricemia and gout are known to be associated with increased risk of cardiovascular disease. And xanthine oxidize inhibitors such as allopurinol and febuxostat are the mainstay of urate lowering treatment of gout, but do they have different effects on cardiovascular risk? First author, Dr Jong, corresponding author, Dr Min from Brigham and Women's Hospital Harvard Medical School in Boston, Massachusetts, studied a cohort of almost 100,000 older Medicare patients with gout and found that there was, overall, no difference in the risk of MI, stroke, new onset heart failure, coronary revascularization are all cause mortality between patients initiating febuxostat compared to those initiating allopurinol. However, there did seem to be a trend toward an increased opiate not statistically significant risk for all-cause mortality in patients who use febuxostat for over three years compared to allopurinol use for over three years. The risk of heart failure exasperation was slightly lower in febuxostat initiators.                                                 The final original paper this week provides important contemporary data on the clinical characteristics in hospital management and long-term outcomes of patients with acute myocarditis. Co-corresponding authors, Dr Ammirati and Kamichi, both from Milan, Italy and their colleagues screened 684 patients with suspected acute myocarditis and recent onset of symptoms within 30 days between May 2001 and February 2017 and included 443 patients with acute myocarditis diagnosed either by endomyocardial biopsy or by increased troponin and edema and late gadolinium enhancement on cardiac magnetic resonance imaging. They showed that among these 443 patients, 118 patients or 26.6% had either left ventricular ejection fraction less than 50% sustained ventricular arrhythmias or a low cardiac output syndrome. While, the 73.4% had no such complications.                                                 Cardiac mortality and heart transplantation at five years was 4.1%, but went up to 14.7% in the patients with complicated presentation and contrast down to zero percent in the uncomplicated cases. Similarly, major acute myocarditis related cardiac events after the acute phase, such as post discharge death and transplantation, sustained ventricular arrhythmias, symptomatic heart failure needing device implantation all occurred in 2.8% at five years, but was much higher in patients with a complicated presentations at 10.8% versus zero percent in the uncomplicated presentations. Thus, the authors concluded that patients with acute myocarditis can be effectively stratified based on their initial clinical presentation. Patients with left ventricular ejection fraction less than 50% at the first echo. Those with sustained ventricular arrhythmias or those with low cardiac output syndrome are at higher risk of cardiac events compared to those without these manifestations.                                                 And that brings us to the end of our summaries. Now, for our feature discussion.                                                 With advances in therapy most deaths in people with HIV are now due to noncommunicable diseases, especially cardiovascular disease. What does the global burden of HIV associated cardiovascular disease really look like? Well we're going to get some answers in today's feature paper. I have with us today the first and corresponding author of the paper, Dr Anubshaw from University of Edinburgh, as well as our associate editor, Dr Bongani Mayosi from University of Cape Town in South Africa. Dr Carolyn Lam:                Welcome to you both. And Anub, what an important question to examine. Could you tell us how you looked into this question and what you found? Dr Anubshaw:                   Sure. So, this is a very interesting question from our end and we had in short idea looking at the risk of cardiovascular disease in patients with HIV. And there are many studies of it, varying results. I'm looking at the risk of heart disease and stroke in patients with HIV. So, what we did was a big systematic review to extract all the data out there looking at the risk of heart disease in patients with HIV, we then developed a model that looked at what the overall risk was and then tried to calculate the actual burden of cardiovascular disease attributable to patients with HIV. In some of the work we found, well, primarily we found that the majority of the burden, as expected in Sub-Saharan Africa and that is primarily the cause, in prevalence of HIV is the highest in Sub-Saharan Africa, accounting for about two thirds of all people living with HIV. Dr Anubshaw:                   The risk of cardiovascular disease with patients with HIV is twofold higher compared to patients not infected by virus. And there was not [inaudible 00:10:12] variations in the actual burden. The majority of the burden in Sub-Saharan Africa and Southeast Asia. Dr Carolyn Lam:                Wow, Sub-Saharan Africa and Asia Pacific, isn't it? Oh my goodness, Bongani, your views please on these standing results from Africa. Dr Bongani Mayosi:         Yes. I think these results are actually very important in the Sub-Saharan African region, reaching the, at the center of the HIV/AIDs epidemic in the world. And particularly important now that we are finding people and are on treatment and that they are growing older and there's a thriving proportion of people above the age of 60, they are on HIV infection and therefore the whole question of cardiovascular disease in these patients has become very important and clearly now these data suggest that HIV [inaudible 00:11:08] for cardiovascular disease, but what is more important [inaudible 00:11:14] they are important [inaudible 00:11:17] for cardiovascular disease, but also a [inaudible 00:11:22]. [inaudible 00:11:23] such as another vascular condition, which is pulmonary hypertension associated with HIV detection. [inaudible 00:11:35] with the increase of the number of people on treatment, these particular conditions are becoming [inaudible 00:11:43] in the context of how to [inaudible 00:11:48], but is an important condition in the African continent. So that the overall burden of cardiovascular disease is likely to be greater than is estimated here because the study is only estimating atherosclerotic cardiovascular disease. Dr Anubshaw:                   That brings up a very intriguing question, Anub. Could you at all distinguish between atherosclerotic risk factors and the role that played versus more HIV specific risk factors, such as the medication, the degree of HIV control, level of inflammation, for example? Now, of course in a meta-analysis this may be difficult, but just your thought.                                                 You're absolutely right from a meta-analysis point of view it's very difficult for a couple of reasons. Firstly, we do not have individual patient level data, so we couldn't really see a [inaudible 00:12:45] level which patients are on [inaudible 00:12:47] therapy and what their personalized risk factors are. Varying schools of thought estimated around the candidates that they need, which kind of portrays a risk of heart disease in the [inaudible 00:12:59] artery in patients with HIV. And what we think may be happening there, one that HIV represents a degree of sub-clinical inflammation that leads to vascular inflammation, which then leads to accelerated atherosclerosis and there's some fantastic mechanistic evidence looking at this where, workers have looked at vascular inflammation in the arteries in patient HIV can go through control and you do get much more vascular inflammation. There is some evidence about the fact that the [inaudible 00:13:31] therapy itself can cause [inaudible 00:13:34] and therefore increase the risk of atherosclerotic heart disease.                                                 And finally, some risky behavior is probably much more, have a look at HIV for example, smoking entered the [inaudible 00:13:46] etc., etc. and there may be a degree of overlap in terms of or correlation in terms of risk factors being much more common in HIV patients, which are more conditional for atherosclerotic heart disease. I think a combination of all those three things probably explain the increase risk of atherosclerotic heart disease and strokes in these patients. Dr Carolyn Lam:                Indeed. Your paper is so important to raise awareness of that very risk. I mean, if I could please re-iterate, you show very clearly that people with HIV are the two fold increase risks of cardiovascular disease and that that global burden had tripled over the last two decades. I think that your paper really shines a bright light in this area, that we have to study further because the clinical implications are enormous aren't they? Because we're using guidelines developed in non-HIV patients to perhaps treat these cardiovascular diseases in HIV patients and there may be other pathophysiologic mechanisms like you just mentioned. What do you think are the main clinical implications of your paper? Dr Anubshaw:                   The clinical implication is quite important because what the burden estimate show is that the majority of burden is in no or little information and therefore the resource of those innovations are quite limited, but there's one condition that has been treated so well in these countries. One of the main success stories of medicine, over the last two or three decades and how they've tackled HIV, who runs PEP for has made intrical virals available so widely in the Sub-Saharan African regions, while there's other highly prevalent regions. And they set up logistically clinics to deliver and scare for persons with HIV and if you and I will see that the survival in these patients [inaudible 00:15:39] just mentioned. Then, these patients are at more high risk of other among AIDs related conditions, such as strokes and heart disease. What you now have in these poor resource countries or limited resource countries, where clinics and the logistical support is only set up to deliver cardiovascular risk prevention strategies and therapy. Which is not expensive in terms of antihypertensives, in terms of [inaudible 00:16:06] and in terms of lifestyle factors.                                                 So, I think there is [inaudible 00:16:10] here that the region has to further reduce the cardiovascular burden in this population. Dr Carolyn Lam:                Bongani, you too recognize the very important clinical implications and in fact invited the editorial by Priscilla Sue and David Waters from San Francisco General Hospital. I love the title of it. Is it time to recognize HIV as a major cardiovascular risk factor? Bongani, what are your thoughts? Dr Bongani Mayosi:         I think it is time we should be considering the HIV as a risk factor for cardiovascular disease. You know these data arriving from this [inaudible 00:16:48] are quite compelling and when you look, for example at that this is a hot study [inaudible 00:16:55] in the editorial and conferred by HIV, it is almost the same as the other [inaudible 00:17:02]. I mean if you go into it now that in fact the European Society of Cardiology it is already [inaudible 00:17:12] in HIV infected individuals with [inaudible 00:17:19]. So, if now may be entering their [inaudible 00:17:27] of practice, they consider HIV as a significant risk factor for cardiovascular disease and maybe contribute to bring a drug that will modify outcome. I do think though that because of the mechanism of cardiovascular disease it [inaudible 00:17:45] HIV it is not common on the basis of atherosclerotic disease. In Africa as an example, we know very well that the patient tend to [inaudible 00:17:55] with not a lot of traditional risk factors of cardiovascular disease, in fact, atherosclerotic diseases such as [inaudible 00:18:07] still have a relatively low level of [inaudible 00:18:10].                                                 So, we still, I think need to discover what are the other [inaudible 00:18:14] mechanisms that are involved, I mean they do that very much more targeted drug [inaudible 00:18:21] where it needs to be tested, that don't know our traditional interventions for reducing risk and preventing cardiovascular disease. So, there is need for further research here and the mechanisms and specific intervention. That is the important in this large HIV infected populations because at the moment there at least 27 million people in the world, living with HIV who already facing a major public health issue on a global scale. Dr Carolyn Lam:                Exactly and all these new research efforts, paying attention to this, making sure that we don't underestimate cardiovascular risk and HIV based on traditional risk calculators. All of this starts with awareness and with important papers such as yours, Anub. Thank you so much for publishing that with us at Circulation.                                                 Well, listeners you know how important this is globally, so please share this podcast with your colleagues and don't forget to tune in next week.  

Survival in patients with advanced heart failure (AHF) has improved over the last 2 decades. An increasing number of patients however, are dying with progressive heart failure over the same duration. Optimal utilization of medical therapies and devices like implantable defibrillators and biventricular pacemakers are the likely reasons patients are surviving longer albeit with progressive HF.   Evolution in mechanical circulatory support (MCS) devices has occurred over the same period, such that they can now be rapidly instituted providing support for pump failure, often percutaneously, with timely restitution of physiologic and metabolic derangements with fewer complications.    MCS devices can be classified as Short term and Long term. Short term devices such as Intraaortic balloon pumps (IABP), Impella ®, TandemHeart® or Venoarterial extracorporeal membrane oxygenation (VA – ECMO) using a Cardiohelp® device, are usually employed as ‘Bridge to Recovery’(BTR) or Bridge to Decision’(BTD), usually in acute settings. Long term devices such as implantable left ventricular assist devices (LVADs) e.g. Heartmate II® & 3®, Heart ware HVAD® are implanted as ‘Bridge to transplant’ (BTT) or ‘Destination therapy’ (DT) usually in patients ‘sliding’ on inotropes when they are transplant eligible (BTT) or ineligible (DT) respectively.     Ventricular assist devices have traditionally been developed for left ventricular support in case of severe left heart or biventricular dysfunction. Historically, right ventricular (RV) dysfunction following LVAD implantation or as a component of biventricular dysfunction was managed with either medical therapy, temporary VADs (i.e. ECMO configuration with continuous flow centrifugal pumps like CentriMag®, Rotaflow ®) or occasionally with LVADs placed on the right side. Recently the Impella RP® and ProtekDuo®, percutaneously placed pumps with inflow in the inferior vena cava & right atrium respectively and outflow in pulmonary artery, have become available as less invasive options, for short term RV support.    The Syncardia® is the only approved total artificial heart system currently in use; however various biventricular, total heart systems (e.g. BiVACOR®) in development show promise.     Mechanical circulatory devices provide attractive, viable, physiologically plausible ventricular support options that can be used effectively in carefully selected patients. 

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.                                                 This week's journal is really special. It is the 2017 cardiovascular surgery-themed issue of "Circulation." To summarize this issue, I am so privileged to have the editors, Dr. Marc Ruel from University of Ottawa Heart Institute, as well as Dr. Timothy Gardner from Christiana Care Health System. Welcome gentleman. Dr. Timothy Gardner:     Hello. Dr. Marc Ruel:                   Hi, Carolyn. Glad to be here. Dr. Carolyn Lam:               Thank you for another beautiful themed issue, Marc. I see that there are four general themes within this theme, if I may. The first of which are a collection of papers on coronary disease and coronary surgery. Could you maybe start by giving us an overview of that? Dr. Marc Ruel:                   One of the main topics that have been looked at in the surgical-themed issue this year is coronary surgery. We all know well that 2016, 2017, the academic year was quite fertile in providing new information around coronary surgery, especially with the release of the ART trial had actually scientific sessions of the American Heart Association the last November with simultaneous publication.                                                 Interestingly, the cardiovascular surgical-themed issue has several coronary papers and one that deals with essentially with graft failure, if you will. There's an in-depth review written by Mario Gaudino, who is well known and does fantastic work at Cornell, who essentially put a team together looking at several aspects of coronary graft failure. I guess we can say that these are looked in quite great depth, and they deal with several aspects of what would lead to a coronary bypass graft to fail.                                                 First and foremost, Mario and the team look at the blood components. Then the artery and the native bed itself. Then they focus a lot on the conduit, not only the nature of the conduit being a venous versus arterial conduit, but also the way of storing the conduit prior to performing the bypass. Also, the technique that's used around the use of that conduit.                                                 Finally, I'd say that the review culminates with the patient bioreactor, for lack of a better term, aspect. Endothelial dysfunction in the patient with diabetes, age, gender, hypertension, dyslipidemia, etc., all these things that do act as a significant substrate for the fate of the conduit vessel.                                                 A very unique, I think, first-time, in-depth review that, certainly, the "Circulation" editorial team and reviewers were very excited about. I think this will be quite impactful and provide very, very detailed information for future research and future improvement and fate of the coronary graft conduits. Dr. Carolyn Lam:               And, Dude, I agree. It's the new look at perhaps a classic, old, central surgery, the cardiovascular surgery. Very nice, indeed. Dr. Marc Ruel:                   Precisely, thank you. We also have a couple of important, seminal original papers within the realm of coronary surgery. In fact, these also deal, to some extent, with the fate of conduits and certainly how they work in the patient population in long ago bypass surgery.                                                 One is a randomized control trial, a single center randomized control trial that was performed in South Manchester. It's called the VICO trial, a study comparing vein integrity and clinical outcomes. Essentially, the study looked at open vein harvesting versus two types of endoscopic vein harvesting for coronary artery bypass grafting.                                                 The study was performed at a single center in England with three sound methods, having three groups of 100 patients who were compared with regards to the vein harvest technique. The primary outcome was with regards to actual vein integrity, looking at muscular damage and endothelial function and integrity on microscopy.                                                 Surprisingly and actually quite reassuredly that there were very few differences between endoscopic vein harvest and open vein harvest. Certainly the investigators also looked, as one of their secondary outcomes, at quality of life. It was quality of life that was gained in patients who had endoscopic vein harvest versus those who had open vein harvest.                                                 Overall, there was no difference in major adverse cardiac events. Therefore, showing at least in an internally valid fashion that these investigators at their center could do endoscopic vein harvesting as well as open vein harvesting. Dr. Carolyn Lam:               I know that there are other original research papers, perhaps. Would you like to highlight any of them? Dr. Marc Ruel:                   Yes, for sure. Carolyn, there's also one more coronary surgery paper, which I wanted to highlight and that is the paper entitled, "Does Use of Bilateral Internal Mammary Artery Grafting Reduce Long-Term Risk of Repeat Coronary Revascularization?"                                                 This is a multi-center analysis with first author is Iribarne from Northern New England. Essentially, seven medical centers got together and took about 20 years of consecutive CABGs with a total number of 50,000 operations, or just shy of 50,000 operations.                                                 The median duration of follow-up was 13 years, and these patients were well matched together using a propensity matching scheme. I think this paper and this research is unique and of high impact. Even though it does have shortcomings of not being a randomized control trial, it is very welcome information, especially in light of the recent ART trial, which, as you know, did not show any difference at five years analysis between single and bilateral internal thoracic artery use.                                                 The particularity of the Iribarne paper is that it is a very large data set up with close to 50,000 patients. It is multi-centered, therefore, it is real life. It is a consecutive series. The patients are extremely well matched, and it is remarkable to hear that the patients, in fact, had no difference in mortality until about five years after the operation.                                                 As opposed to many previous series where single versus bilateral internal mammary grafting shows a mortality difference very early on, which always raises the suspicion of poor matching or confounding by indication, if you will, this paper did not have that.                                                 Finally, the follow-up was quite long and at about six years, there was really a mechanistic signal with regards to repeat revascularization events, which seemed to match the difference in late mortality. There was no difference in early and five-year mortality, but afterwards as repeat revascularization events started to occur more frequently in the single mammary group, this was matched by a difference in mortality, as well.                                                 I think a very useful, large, long follow-up mechanistically-based information that I think adds very significantly to the current information we have about bilateral versus single mammary use. Dr. Carolyn Lam:               Thank you, Marc. Two original papers, highlighted, dealing with really very important modern controversies in this area. Open vein versus endoscopic vein harvesting, single versus bilateral mammary artery bypass. Excellent.                                                 Let's move on now to the next sub-theme, if you will. And that is the collection of papers on "Adult Congenital Heart Conditions," really, really an increasingly important and growing population that we're seeing. Tim, would you like to summarize maybe some of the highlights of the papers there? Dr. Timothy Gardner:     The first paper, as you point out, is focused on adult patients with repaired tetralogy of Fallot. This series came from the UK and it examines the course of almost 60 patients, at a mean age of 35 years following a repair of tetralogy as infants or young children, developed right heart failure and required pulmonary valve replacement.                                                 This is a common scenario that we're seeing, successfully repaired children who appear to do well but as they get into their late 20s and 30s, their pulmonary valve function, which is often inadequate or not even present valve, require an intervention.                                                 The important learning here is that pulmonary valve replacement, either surgically or by catheter technique, was shown to be highly effective in salvaging right ventricular function. That is based on imaging studies as well as hemodynamic studies of right ventricular function. There was an almost, in this group of patients, almost an immediate reverse remodeling of the right ventricle after placement of the valve, that continued to improve over time.                                                 This was, I think, quite reassuring. There, historically, was a bit of a reluctance to operate on these patients as their right heart was failing, despite the fact that without some intervention to take the volume load off of the RV, the patients didn't do well. This is good news for an important group of patients who we are all seeing, who oftentimes present to the adult cardiologist because of this right ventricular failure problem. A nice, reassuring study.                                                 Actually, the other two congenital papers are, again, focused on the infant. They both deal with the infant with hypoplastic left heart syndrome or single ventricle pathology. The first paper seems sort of specialized in terms of its focus, "The Optimal Timing of Stage-2-Palliation for Hypoplastic Left Heart Syndrome." This was a report from the NIH Pediatric Heart Network. They had a single ventricle reconstruction trial.                                                 This network is comprised of about 10 North American centers, both in the U.S. and Canada and has provided excellent data about the management of pediatric heart disease but, in particular, the single ventricle trial has been excellent.                                                 In this particular paper, they look at the optimal timing for stage-2 repair. Just to remind ourselves, the first part of the three-stage treatment for hypoplastic left heart syndrome is the Norwood procedure, which has to be done shortly after birth, as the patent ductus arteriosus closes and converts, essentially, the single right ventricle into the systemic ventricle.                                                 The stage-2 comes along, usually done with a Glenn-type of shunt, increases pulmonary blood flow and stabilizes these infants until they can reach the age for, and the heart function for definitive repair. This has been a particularly difficult problem for the congenital heart surgeons. What is the optimal timing?                                                 This study, which involved over 400 patients, identified optimal timing for the second stage between three and six months after the Norwood. I think this was very reassuring, is reassuring or supportive for the congenital heart community in terms of both patients and also good evidence base that a delay of three to six months does, in fact, produce the best transplant-free survival.                                                 In fact, the other aspect of this observation was that infants who developed the need for another second stage operation sooner than that did not do well, and the reasons for the required earlier surgery could be failure of the initial operation or additional anatomic risk factors. But this, I think, was an important, large series, multi-center study that will prove to be very helpful in sorting out this complex timing of a three-stage repair.                                                 Just to comment, again, for readers who don't deal with infant congenital heart treatments very often, there's been a remarkable amount of success over the last two decades in salvaging and saving these very difficult infants with the hypoplastic left heart syndrome. In fact, an additional paper in this surgery-themed issue, comes from the UK and is, in fact, a report on the findings from the UK-wide audit of the treatment of infants with hypoplastic left heart syndrome.                                                 In fact, their findings, in this sort of real world, not in the Pediatric Heart Network trial group, is very similar. They found that infants who got to the second stage without additional refinement of the initial Norwood procedure and were able to be successfully treated with a Glenn shunt somewhere in the four-to-six-month age range, did well. They actually made the point that the anatomy was more of a determinant than anything else.                                                 I think that this particular review will reinforce what the congenital heart surgeons have learned about optimal timing for this three-stage treatment of what previously were unreconstructable children. Dr. Carolyn Lam:               Thank you so much, Tim. Isn't it wonderful the way papers come in and they're actually complementary and consistent with one another. We're just so lucky to be publishing all of these great, high-quality, impactful papers in "Circulation."                                                 Moving on, the next paper actually reminds us why this is a cardiovascular surgery-themed issue and not just a cardiac surgery-themed issue. Didn't we just say that earlier, Marc? This one is on abdominal aortic aneurysm treatment. A population-based landscape of this. Could you tell us a little bit more about that one? Dr. Marc Ruel:                   Absolutely. Carolyn, you're entirely right. We must remember that "Circulation" is also about peripheral vascular disease, saying this earlier, or cardiovascular surgery and anesthesia consult also when it encompasses vascular surgery. Precisely to that effect, one of the papers in our cardiovascular surgical-themed issue is a landscape population based analysis from Finland that looks at the incidence of abdominal aortic aneurysm between the years of 2000 and 2014.                                                 Finland has a population of about 5.5 million and remarkably has a very circumscribed healthcare system. They do not have an organized system of AAA care as some other countries have shown to have and potentially benefit from, but rather they have a treatment of this condition at several institutions, many of which may not be high volume.                                                 I think the paper is remarkable is that it is very well nested in terms of a population. It provides a comprehensive landscape of where this condition has evolved to over the last few years. Obviously, we see in the results from the authors that the mortality has decreased quite a bit, but also the incidence, probably as a result of better control of risk factors. And also the incidence of rupture outside the hospital.                                                 One thing that came out of this paper, as well, is a potential cohort of the benefits gained from developing an organized system of AAA care, from the reason that the mortality of AAA rupture in Finland was still quite high, despite this being a modern series. In fact, when you include ruptures, before arrival to hospital and at arrival to hospital, the overall mortality was almost 80% for ruptured AAA.                                                 Perhaps one message that comes out of this is that there may be a benefit in having specialized centers dealing with these conditions, especially as they are in the process of rupturing. One last observation was, obviously, the increasingly prevailing role of endoscopic vascular repair in the treatment of this condition, which, in fact, has now surpassed open repair as the dominant method of elective repair.                                                 I think, overall, a very comprehensive, well-nested, country-wide with good follow-up landscape of the AAA condition in a country that has essentially a similar socioeconomic status to much of the western world. Therefore, with external generalized ability to some extent. Dr. Carolyn Lam:               Exactly, and contemporary data. I really enjoyed that you paired those with an excellent editorial, as well. Finally, before we wrap this up, I have to ask Tim to comment on this next paper, and it's on ventricular assist device malfunctions, I love the title, "It's More Than Just The Pump." Of course, as a heart failure physician, this one's very close to my heart. Forgive the pun. But, Tim, could you tell us about that? Dr. Timothy Gardner:     This paper comes from the University of Pittsburgh and their artificial heart program. Robert Kormos is the first author and he's been one of the stalwart leaders in the use of LVADs and other pump devices. He reports on their experience with over 200 both HeartMate and HeartWare ventricular assist devices.                                                 It was interesting when we reviewed this paper by the editors, there was some thought that maybe this was a little too engineering focused and so on, but I think the point of the paper is that, as they say in the very first line in their report, reports of LVAD malfunction had focused on pump thrombosis.                                                 But they point out very appropriately that, in fact, controller failure, battery failure, cable failure and other causes of device failure, which can be critical and life threatening and so on, are engineering issues. It reminds us that when we're managing this difficult group of patients, and we're seeing many more patients today with getting LVADs than 10 or 20 years ago, we need to have the bioengineering abilities and resources available.                                                 Even the surgeon and the critical care physician who is dealing with these patients either has to acquire this kind of knowledge or capacity himself or herself, or needs to have a good bioengineer nearby.                                                 What's interesting, I think, that all of us define that these mechanical failures were more common in this pretty big experience than what we've more clinically worried about, which was thrombosis of the pump. Dr. Carolyn Lam:               Exactly. That's so wonderful. And you know it just leads me to really thank you both, Marc and Tim, for this extraordinarily excellent selection of original research, state-of-the-art and perspective articles and editorials on congenital, coronary, vascular and heart failure surgery. This really appeals not just to the cardiovascular surgeons but really to the vast readership of "Circulation."                                                 Thank you for a wonderful themed issue and thank you for this great podcast. Dr. Timothy Gardner:     Well, thank you. Dr. Marc Ruel:                   Thank you very much, Carolyn. Dr. Carolyn Lam:               Listeners, 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 Center and Duke National University of Singapore. Today's feature discussion centers on the population burden of sudden death associated with hypertrophic cardiomyopathy. These are novel data from the ongoing Oregon sudden unexpected death study, results that may surprise you. Stay tuned and that's coming up right after these summaries.                                              The first original paper in this week's journal tells us that risk reductions from air pollution control yields health benefits comparable to the control of systolic hypertension and smoking in a high risk segment of the urban Chinese population. First author Dr Huong, corresponding author Dr Gu and colleagues from Fu-Wai hospital in Beijing China projected the life years gained if urban China were to reach one of three air quality goals. First, Beijing Olympic games level. Second, China class 2 standard. Third, the WHO standard. They further compared projected air pollution reduction control benefits with the potential benefits of reaching WHO hypertension and tobacco control goals.                                              Now to do this, the authors used the Cardiovascular Disease Policy Model: China, which is a computer simulation state transition mathematical model of coronary heart disease and stroke incidence, prevalence, mortality, non-cardiovascular deaths, and costs of health care in the Chinese population. They found that air quality improvement under the different scenarios could lead to a great health benefit, ranging from 241,000 life years gained to much greater benefits, benefits that were greater to or equal to the combined benefits of a 25% improvement in systolic hypertension control, and a 30% smoking reduction. Thus, the authors called for joint efforts of the whole society for air quality improvement in China.                                              The next study describes six differences and similarities in atrial fibrillation epidemiology, risk factors, and mortality in the community. First author Dr [Magnusson 00:02:42], corresponding author Dr [Schnabel 00:02:44] and colleagues from University Heart Center Hamburg Eppendorf studied 79,793 individuals without atrial fibrillation diagnosis at baseline from 4 community-based European studies, namely, FINRISK, DanMONICA, Molisani, and Northern Sweden, all followed for a medium of 12.6 years. They found that cumulative incidence increased markedly after the age of 50 years in men and after the age of 60 years in women. The lifetime risk was similar in more than 30% for both sexes.                                              Subjects with incident atrial fibrillation had a three and a half fold higher risk of death compared with those without atrial fibrillation. Among the classical risk factors, body mass index explained the largest proportion of atrial fibrillation risk. Six interactions were seen for the risk associations of body mass index and total cholesterol, wherein body mass index was associated with a greater risk increase in men than women, whereas total cholesterol was inversely associated with incident atrial fibrillation with a greater risk reduction in women than men.                                              The next study describes a novel circular RNA as a potential target in diabetic proliferative retinopathy. Circular RNAs are a novel class of non-coding RNAs that regular gene expression and they're characterized by closed loop structures with neither five-prime, nor three-prime polarity nor a polyadenylated tail. In today's study, first author Dr [Shah 00:04:33], corresponding authors Drs. [Yen 00:04:33] and [Zhao 00:04:36] from Shanghai Medical College Fudan University in China characterized the expression and regulation of the circular RNA, circHIPK3 in retinal endothelial cells and diabetic retinal vascular dysfunction.                                              CircHIPK3 expression was significantly up regulated upon high glucose stress in vivo and in vitro and regulated retinal endothelial cell function and vascular dysfunction by acting as an endogenous microRNA 30A-3P sponge that sequestered and inhibited its activity. In summary therefore, the circular RNA circHIPK3 plays a role in diabetic retinopathy by blocking microRNA 30A function, leading to increased endothelial proliferation and vascular dysfunction. These data suggest that the circular RNA may be a potential target for diabetic proliferative retinopathy.                                              The next study identified important new principles of endogenous chromatin structure that have key implications for epigenetic therapy. In this study from first author Dr Rosa-Garrido, corresponding author Dr Vondriska, and colleagues of David Geffen School of Medicine in UCLA, the authors examined changes in chromatin configuration in cardiomyocytes isolated from mouse hearts subjected to transverse aortic constriction or hearts subjected to Tamoxifen inducible cardiac specific excision of CTCF, which is a ubiquitous chromatin structural protein.                                              There was several important findings from this work. Firstly, the authors found that depletion of CTTF was sufficient to induce heart failure in mice and human heart failure patients receiving LVADs also showed increase CTCF abundance. Pressure overload or CTCF depletion selectively altered the boundary strength between topologically associated domains, which are regions of DNA in which physical interactions occur frequently. The authors showed that there were changes in the compartmentalization of active chromatin and inactive chromatin segments, which is a measure of genomic accessability.                                              Heart failure involved decreased stability of chromatin interactions around disease causing genes. In summary, these finding provide a high resolution chromatin architectural resource for cardiac epigenomic investigations and also demonstrate that global structural remodeling of chromatin underpins heart failure.                                              The final study is the first to provide insights into the fluid mechanics of transcatheter valve thrombosis. First author Dr Midha, corresponding author Dr Yoganathan and colleagues from Georgia Institute of Technology and Emory University in Atlanta analyzed post-procedural four dimensional volume rendered CT data of transcatheter aortic valve replacement, or TAVR patients, enrolled in the Resolve trial, excluding patients on anticoagulation. Patients were classified as having transcatheter heart valve thrombosis if there was any evidence of hypoattenuated leaf thickening. The authors studied the flow characteristics within the neo sinus which is formed followed deployment of a transcatheter valve into a native aortic valve.                                              The authors found that post deployment valve geometry and final implant position affected the flow within the neo sinus, which in turn, may affect the predisposition to thrombus formation. The impact of geometry and position varied according to the different valve types. A supra-annular transcatheter heart valve deployment resulted in a nearly seven fold decrease in stagnation zone size when compared to an intro-annular deployment. In addition, the in vitro model indicated that the size of the stagnation zone increased as cardiac output decreased. In summary, deployed transcatheter heart valve geometry may have implication on the occurrence of thrombosis and a supra-annular neo sinus may reduce thrombosis risk due to reduced flow stasis. While additional prospective studies are clearly needed, these results may help identify patients at higher thrombosis risk and aid in the development of the next generation of devices with reduced thrombosis risk.                                              Well, that wraps it up for our summaries. Now for our feature discussion.                                              Sudden death in hypertrophic cardiomyopathy has been and still is a very hot topic in cardiology. Of course it's understandable given all the high profile deaths that have occurred in young athletes ascribed to hypertrophic cardiomyopathy and the fact that these deaths may potentially be preventable with implanted defibrillators. However, we're so proud to have in this week's journal, some of the first data on the population-based burden of sudden death associated with hypertrophic cardiomyopathy. I'm so happy to have with us the corresponding author of this research letter, Dr Sumeet Chugh from Cedar Sinai Medical Center, as well as Dr Mark Link, associate editor from UT Southwestern. Welcome, gentlemen. Dr Sumeet Chugh:            Thank you. Dr Mark Link:                    Thank you. Dr Carolyn Lam:               Sumeet, you know as I said in the introduction, sudden death in hypertrophic cardiomyopathy, we've talked about it a lot. There's been lots published. What makes your data so novel? Dr Sumeet Chugh:            There is indeed a large body of work related to hypertrophic cardiomyopathy but most of it came from registries. Probably what's a bit unique about our work is that it was done in one large, US community over a number of years. Dr Carolyn Lam:               Indeed. So population-based statistics, not just of hypertrophic cardiomyopathy, but of sudden death related to it, isn't it? Dr Sumeet Chugh:            That's correct, Carolyn. Dr Carolyn Lam:               I think the other thing that we were just actually chatting about is the fact that it's contemporary. Could you tell us maybe the period you're looking at and then give us your findings? Dr Chugh:                           Yes. The study was initiated in 2002 and is now in it's 16th year, so this particular analysis was conducted between the time period 2002 and 2015. What we do in the process of this community-based work is that we track prospectively every cardiac arrest that happens in the community centered around Portland, Oregon in the USA. The work in performed in the process of doing a multiple-source ascertainment where we take the help of the first responders or the ambulance personnel, the hospital emergency rooms, as well as the police, and the coroner network. It's a fairly comprehensive way of ascertaining sudden cardiac arrest. Dr Carolyn Lam:               That is a very unique and valuable data set. Could you summarize the top line results, because they were rather surprising? Dr Sumeet Chugh:            We are already learning that over time, with more awareness, education, and modern management of hypertrophic cardiomyopathy, the risk of sudden cardiac arrest and the overall morbidity from hypertrophic cardiomyopathy may be on its way down. What this study is showing is, that actually the risk of sudden cardiac arrest and the burden of sudden cardiac arrest from hypertrophic cardiomyopathy in the community may be quite low. Those are the main findings. Dr Carolyn Lam:               Yeah. In fact, I was just so impressed because first of all, you excluded the individuals in this population and found that hypertrophic cardiomyopathy was responsible for 1 in 30 of the cardiac deaths, but that the incidence of the sudden deaths were 0.2 to 0.3% among these hypertrophic cardiomyopathy patients, perhaps less than others may have expected.                                              Mark could I bring you in on this for a moment? What do you think are the take home messages for something like this, because in a young and middle age population, is any rate really too low? Dr Mark Link:                    I think this is great data because it encompasses an entire population, so it gets us good data on the true incidence of sudden cardiac death. In the study, if you look at the total number of patients that either had an ECHO or had an autopsy, about 5%, a little over 5% of them, had hypertrophic cardiomyopathy. Roughly 5% of the individuals dying suddenly, under age 60 are dying secondary to hypertrophic cardiomyopathy. That's the sort of data that we really didn't have before because we didn't have such a nice population-based study.                                              It was interesting also, they tended to be younger, 10 years younger than the others dying suddenly, so it was a younger cohort. They more often had ventricular fibrillation or ventricular tachycardia than the others dying suddenly. It really does give us some nice data on the true incidence of sudden death due to HCM in the community. Dr Carolyn Lam:               What I thought was also valuable was the fact that the diagnosis of hypertrophic cardiomyopathy was quite often missed prior to the cardiac arrest and I'm trying to wrap my head around about what that implies. Dr Sumeet Chugh:            That's a very important point, Carolyn. These findings also give us the message that our risk classification methodology continues to need more work. The fact remains that a significant proportion of patients with hypertrophic cardiomyopathy are also going to be asymptomatic. Sometimes they just don't come to our attention.                                              Another important point, however, that's related to this work is that there may have been during the course of this time period, at least a few patients in this community who would have received an implantable defibrillator and their sudden cardiac arrest would have been averted, so we're not able to count those individuals who were already found and managed. Dr Mark Link:                    That's a very important point because if a person is found with HCM and has risk factors, they would get a implantable defibrillator. Those individuals would not show up in this database because they wouldn't die. Dr Carolyn Lam:               Mm-hmm (affirmative)-                                              That's a very, very important point. Thank you for highlighting that. I think it goes back to why these data are so important, because they are contemporary as well and we really need such estimates, so congratulations Sumeet and thank you for giving us these valuable data.                                              I'd like to switch tracks a little bit though, and point out this was a research letter, a big data set, important findings, but published as a research letter. Should I even say but? Mark could you comment a little bit about research letters in circulation versus original articles? Dr Mark Link:                    We increasingly are using research letters in circulation for original research that drives home a basic single point. If that basic single point can be made in 1,200 words, we actually like the research letter format. It's a quick read, people remember it, it's cited. It is something that authors that we ask to turn a full length manuscript into a research letter, should be taking that as a positive sign, because that means that we're interested in the topic and would like to see it in print. Dr Carolyn Lam:               I completely agree and in fact, Sumeet, if I could ask you to weigh in. Sometimes it's harder, isn't it, to write a research letter than to write a full length manuscript? How was your experience? Dr Sumeet Chugh:            I have to admit that the first responses as you said, where you feel, "Oh, I've spent a lot of effort in writing this large paper, and now I have to squeeze it into 1,200 words," but the second thought for me was, "The fact is that this is a one bullet message and why not make it shorter and snappier as it is?" I think I've come around in the appropriate situation to appreciating this opportunity of writing a research letter. Dr Mark Link:                    when you read the research letters, they're very succinct. I actually like them. They get the message across quickly and I think it's a great way to produce science and to show what you've done. Dr Carolyn Lam:               Yeah. The thing is that we also restrict to a single figure, or a single table and I cannot tell you how many times I've referred to that single figure because it usually tells the full story and it's beautiful summary.                                              So, listeners, you've heard about the research letters in circulation. Please have a look at them. I'm pretty sure that you will fall in love with the format just like we all have.                                              Thank you so much, Sumeet and Mark for joining me today. I'm afraid our time is up, but I've so enjoyed talking to you. Thank you, listeners, for following us today. Don't forget to tune in again next week.  

Commentary by Dr. Valentin Fuster

According to the CDC, approximately five million adults in the United States suffer from heart failure. Lourdes new program in LVADs offers hope for patients with severely debilitated hearts.LVADs are implantable mechanical pumps that enhance the output of the heart. LVADs help to extend the lives of end-stage heart disease patients, temporarily supplement the pumping capacity of hearts recovering from surgery or support the patient waiting for heart transplantation.Listen as Robert Mohapatra, MD explains how Lourdes new program in LVADs offers hope for patients with severely debilitated hearts.

Ep #36 Advanced GEMS - @NAEMT_ Beta Course #AGEMS   NAEMT’s groundbreaking Geriatric Education for Emergency Medical Services (GEMS) Advanced course builds on the GEMS core course, delving into more complex, realistic scenarios and the unique technology EMS practitioners are likely to encounter when assessing, treating, and transporting older adults. -Highly interactive, immersive educational format focuses on integrating critical thinking into real world application. -Topics covered include caring for and transporting patients on home ventilators, LVADs (left ventricular assist devices), tracheostomies, PICC lines/invasive lines and feeding tubes. -Prepares EMS practitioners for the array of medical, mobility, psychosocial and communications issues found in older patients. -Students are guided through a series of scenarios involving increasingly complex symptoms and situations.   Lance Villers, PhD @LVillers villers@uthscsa.edu Keith Widmeier @MICUParamedic micuparamedic@gmail.com Wayne Burdette @WayneBurdetteJr Wayne.burdette@gwinnettecounty.com Tray Reynolds reynoldsta@juno.com   http://www.naemt.org/ AMSL and GEMS instructors will be eligible to become Advanced GEMS instructors after an online module and training!     Sponsored by the @PerfectCPR app designed to provide High Quality CPR Feedback Apple Watch App with Audio and Haptic Feedback to Optimize Cardiac Arrest Training and Improve Quality of CPR Delivery PerfectCPR.com     Message us on Twitter! www.twitter.com/EMS_Nation Like us on Facebook! www.facebook.com/prehospitalnation   Wishing everyone a safe tour! ~Faizan H. Arshad, MD @emscritcare www.emsnation.org  

In this episode of The FlightBridgeED Podcast, Eric talks with ASTNA President Allen Wolfe.

In this episode of The FlightBridgeED Podcast, Eric talks with ASTNA President Allen Wolfe.See omnystudio.com/listener for privacy information.

Dr. Raja Laskar. The Impact of LVADs on Heart Transplantation. Recorded 2015-04-13.

Commentary by Dr. Valentin Fuster

Dr Priya Nair is a senior intensive care specialist at Sydney's St Vincent's Hospital and an expert in managing patients with cardiac assist devices. In this talk she takes us through the key issues encountered when on managing patients with left ventricular assist devices. As LVADs are becoming more widespread, this inside know-how is invaluable to all of us. They physiology and technology involved with these devices is pretty amazing.

LVADs are complicated especially when the patient starts going downhill. Zack Shinar is going to attempt to make it a bit easier.