Podcast appearances and mentions of scott solomon

JACC: Associate Editor Michelle M. Kittleson, MD, PhD, FACC, talks with authors Scott Solomon, MD, FACC and. Marianna Fontana, MD, about their study published in JACC and presented at AHA. Outpatient worsening heart failure (HF) (oral diuretic intensification or initiation) is simple to assess and has been shown to be prognostic of mortality in patients with ATTR-CM. In this pre-specified analysis of a contemporary ATTR-CM population, patients with outpatient worsening HF had an increased risk of all-cause mortality and CV events and all-cause mortality, as well as greater deterioration in assessments of functional capacity, health status, and quality of life. Vutrisiran significantly reduced the risk of outpatient worsening HF and the composite of outpatient worsening HF, all-cause mortality, and recurrent CV events compared with placebo.

Are humans done evolving – or could settling on an alien world with an environment unlike Earth's take us on a different evolutionary trajectory? Host Tom Hale is joined by Scott Solomon, author and professor of bioscience at Rice University, to discuss the myriad ways Homo sapiens may continue to evolve on Earth, and how future human settlements on Mars might influence our species' evolution.   

Insects have superpowers and unique ways of communicating with each other, without the use of cell phones. They have ways of settling disputes, no United Nations required. If you don't believe this, listen as Dr. Scott Solomon, provides the details in this edition of Mothering Earth. Dr. Solomon is a professor of ecology and evolutionary biology at Rice University, and author of one The Great Courses offerings, on insects.

Insects, bugs, pests, whatever you may call them, and whether you love or hate them, they are vital to our planet and by extension to us humans. They provide important ecosystem services by recycling dead things, by pollinating our food crops, by planting seeds, and even just by being food for other creatures, like birds. In this program, we take a deep dive into the remarkable world of insects, to learn about their history, what they do and the pretty amazing ways in which they do it. Our guest is Dr. Scott Solomon, professor of ecology and evolutionary biology at Rice University.

How can artififcial intelligence enhance and augment clinical trials? In what ways can it be used responsibly to increase trial efficiency? Host Chris O'Connor invites Martin Cowie, JoAnn Lindenfeld, Scott Solomon, Jon Cunningham, Mona Fiuzat, and Mitch Psotka to discuss the role of AI in clinical trials.

In this episode, Longitude fellow Keegan Leibrock speaks with Scott Solomon, a specialist in evolutionary biology and science communication, and a professor of Biosciences at Rice University.See transcript at https://longitude.site/communicating-science/We hope you enjoy our episodes and share them with friends.This podcast is a production of Longitude.site, a 501(c)3 charitable organization, enabling cross-generational conversations that bring scientific and creative endeavors to broad audiences. College students are engaged in leading informational interviews and presenting highlights in our episodes. If you would like to explore a partnership for our programming, contact us at podcast@longitude.site.Support the show

Host Dr. Christopher O'Connor invites Drs. Scott Solomon, William Abraham, JoAnn Lindenfeld, Brian Claggett, Mona Fiuzat, and Mitchell Psotka to continue discussion of the importance of subgroups in heart failure clinical trials. How can we analyze subgroups and determine the differences between subgroups and special populations?

Yes, wasps look scary and our first instinct is to kill them, but Rice biology professor Scott Solomon is here to change your mind on wasps. Lead producer Dina Kesbeh talks to professor Solomon about why we need wasps around our houses, the different types of wasps around the city, and so much more! Read the latest from Scott Solomon Monkey on the loose Looking for more Houston news? Then sign up for our morning newsletter Hey Houston  Follow us on Instagram  @CityCastHouston Don't have social media? Then leave us a voicemail or text us at +1 713-489-6972 with your thoughts! Have feedback or a show idea? Let us know!  Interested in advertising with City Cast? Let's Talk! Learn more about your ad choices. Visit megaphone.fm/adchoices

Welcome to the award-winning FCPA Compliance Report, the longest-running podcast in compliance. Join Tom Fox on the FCPA Compliance Report as he discusses with Scott Solomon, the CEO of Operational Security Solutions (OSS), how they manage compliance and ethical considerations around cash management, particularly for high-risk customers. In this episode, they talk about the importance of compliance in the financial industry and how OSS helps financial institutions manage their portfolio through best practices. The podcast also touches on the challenges faced by legal cannabis businesses and the gaming industry regarding compliance and cash operations. Listeners will get insights into boutique cash and transit providers' role in navigating licensing and permitting requirements for cannabis-related cash operations. This informative podcast concludes with contact information and an eagerness to continue the conversation. Don't miss out on the insights shared in this episode. Tune in now to FCPA Compliance Report with Tom Fox and Scott Solomon.  Key Highlights: Challenges of Compliance in Handling Cash Transactions Challenges of Compliance in Regulated Industries Cash delivery in the legal cannabis industry Risk Management for Financial Businesses Notable Quotes: “Our primary customer or partner is a financial institution. So when you look at secure cash management and logistics, it boils down to our specialty is moving cash, and we have the ability in the compliance background to help financial institutions support their high-risk customers.” “OSS was founded around compliance. A group of former law enforcement personnel, special military operators, and federal regulators got together and saw an opportunity to initially start by consulting.” “We work with the customer. It doesn't help us, and it doesn't help the bank if the customer goes off the rails and becomes non-compliant. So, we want to educate them.” “I come out of the anti-corruption compliance space; we've always looked to the casino world as one of the leaders around AML work simply because it was in their business interest to do.” Resources Scott Solomon on LinkedIn Operational Security Solutions Tom Fox Instagram Facebook YouTube Twitter LinkedIn Learn more about your ad choices. Visit megaphone.fm/adchoices

The invasive hammerhead flatworm is being spotted all around Houston so we had to bring in Scott Solomon, biology professor at Rice University and City Cast Houston nature contributor, to help breakdown if these worms are dangerous to humans, how they arrived to Houston, and what we need to do when we spot one.   Useful links: Listen to Wild World with Scott Solomon here.  Learn more about the hammerhead flatworm Scott's video of a hammerhead flatworm Meow Wolf is opening in Houston Interested in advertising with City Cast? Let's Talk! We're doing a survey to learn more about our listeners, so we can make City Cast Houston an even better, more useful podcast for you. We'd be grateful if you took the survey at citycast.fm/survey—it's only 5 minutes long. You'll be doing us a big favor. Plus, anyone who takes the survey will be eligible to win a $250 Visa gift card. Looking for more Houston news? Then sign up for our morning newsletter Hey Houston  Follow us on Twitter and Instagram  Have feedback or a show idea? Let us know! or leave us a voicemail/text us at +1 713-489-6972 with your thoughts, we love hearing from you! Learn more about your ad choices. Visit megaphone.fm/adchoices

Although Houston isn't normally seen as a place for nature, the wildlife here is actually more unique than you think! All kinds of birds sore in our city, including one that is arguably one of the best fishing creatures on the planet! Producer AK AL-Moumen sits down with Cin-Ty Lee, author of Field Guide to North American Flycatchers and Scott Solomon, biology professor at Rice University, to find out more about the art of birding in Houston.  What to learn more? Check out Cin-Ty's book Field Guide to North American Flycatchers: Empidonax and Pewees You can also listen to Scott's podcast Wild World ! Looking for more Houston news? Then sign up for our morning newsletter Hey Houston  Follow us on Twitter and Instagram  @CityCastHouston Don't have social media? Then leave us a voicemail or text us at +1 713-489-6972 with your thoughts! Have feedback or a show idea? Let us know!  Interested in advertising with City Cast? Let's Talk! Learn more about your ad choices. Visit megaphone.fm/adchoices

The Buffalo Bayou is a 52-mile river that flows through the heart of our city. It's home to some of the most beautiful parks. It seems these days, we're also learning more about the different species of fish that live between the murky waters of our Bayou. But one fish in particular seems to be in the headlines more often these days; the Alligator Gar. Today, contributor Scott Solomon and Kory Evans, assistant professor of BioSciences at Rice University, join lead producer Dina Kesbeh to talk about the different species that live in the Bayou and the evolution of their body shapes. Click here to listen to Wild World More on the Alligator Gar here Interested in being the new host of City Cast Houston? Click here to apply! Looking for more Houston news? Then sign up for our morning newsletter Hey Houston  Follow us on Twitter and Instagram  Have feedback or a show idea? Let us know! or leave us a voicemail/text us at +1 713-489-6972 with your thoughts, we love hearing from you! Learn more about your ad choices. Visit megaphone.fm/adchoices

Scarlet macaws are icons of the tropical rainforests of Central and South America. But in the Central American country of Belize, scarlet macaws are disappearing as poachers steal their chicks for the international pet trade.Scott Solomon speaks with Dr. Boris Arevalo, a biologist with the Wildlife Conservation Society, who is working to protect these spectacular birds by any means possible, including camping at the base of the trees where they nest and rearing chicks until they're large enough to be safe from poachers. A native Belizean, Dr. Arevalo became a conservation biologist after learning about the threats facing the species he grew up with, including scarlet macaws, and noticing how few of the researchers working in the rainforests near his home were from Belize.Thanks to the efforts of Dr. Arevalo and his team, poaching rates have plummeted and every chick that the team has reared over the last six years has been successfully reintroduced into the wild.This episode of Wild World features music from Belizean musical group The Garifuna Collective: https://www.garifunacollective.com/ Wildlife Conservation Society - Belizehttps://belize.wcs.org Friends for Conservation and Development, a Belizean NGO working to manage and protect Belize's Chiquibul Foresthttps://www.fcdbelize.org More about Belize's scarlet macaws:https://belizebirdconservancy.org/scarlet-macaw-project Mentioned in this episode:Lindblad ExpeditionsLindblad ExpeditionsThe Rice Alumni Traveling Owls program offers exciting intellectual itineraries to destinations across the globe. Traveling Owls trips serve as a catalyst for lifelong learning and strengthen bonds between Rice University alumni and friends. You don't have to be a Rice alum to participate in Traveling Owls programs. Visit alumni.rice.edu/travelingowls to see a list of upcoming trips. Rice Traveling OwlsWildWorldS1E2 promo

We're taking a break from WCS Wild Audio this week to share a new podcast, "Wild World with Scott Solomon," hosted by field biologist and science communicator Scott Solomon. The show explores the natural wonders of our planet through the voices of the people who explore, study, and protect them.In today's episode, you'll join Scott as he speaks with WCS's own Dr Boris Arevalo, who is working to protect the spectacular scarlet macaw in his home country of Belize. Dr Arevalo's efforts to study this beautiful bird and reintroduce hand-reared chicks back into the wild have contributed to a resurgence in scarlet macaw populations in the region.If you like what you hear, follow "Wild World with Scott Solomon" on Apple Podcasts or your favorite podcast app. We'll be back next week with a new episode of WCS Wild Audio.https://www.wildworldshow.com/

Wild World with Scott Solomon' is a new podcast that explores the natural wonders of our planet through the voices of the people who explore, study, and protect them. Each episode features a new location, from the forests of Madagascar to the underwater world beneath the Galapagos Islands and the icy shores of Antarctica. Hosted by a renowned field biologist and science communicator, you'll hear directly from the people on the ground (or in the water) to understand what drives them to work in such remote, and often dangerous, locations. Featuring diverse voices, guests share their stories of adventure and discovery, from epic triumphs to dismal failures. Experience the wildest places on Earth and beyond and come away with a new sense of wonder and awe about the natural world and the people who help us understand it. Scott Solomon teaches ecology, evolutionary biology, and scientific communication at Rice University in Houston and is a Research Associate at the Smithsonian Institution's National Museum of Natural History. He has a Ph.D. in Ecology, Evolution, and Behavior from the University of Texas at Austin where his research examined the evolutionary basis of biological diversity in the Amazon Basin. Dr. Solomon is a correspondent for the CityCast Houston podcast and has appeared on numerous other podcasts and radio broadcasts, as well streaming series such as Life 2.0, and Becoming Martian. He is the host of What Darwin Didn't Know: The Modern Science of Evolution and Why Insects Matter: Earth's Most Essential Species, available through Wondrium/The Great Courses.

Join Drs. Christopher O'Connor, JoAnn Lindenfeld, Mitchell Psotka, Scott Solomon, Mona Fiuzat, Bill Abraham, and Peter Carson as they introduce a novel concept known as the Heart Failure Collaboratory (HFC) and discuss how it can contribute to the field of heart failure research.

In the Houston area, winter is the best season to be outdoors. But if you want to immerse yourself in nature, where do you go? Consider the Big Thicket, a national preserve that's less than two hours from Houston. Rice University biologist and City Cast contributor Scott Solomon explains. Learn more about the Big Thicket National Preserve. Our morning newsletter Hey Houston brings updates on local news to you daily. Sign up here. Make sure you stay connected to us by following us on Twitter and Instagram @CityCastHouston Or leave us a voicemail/text us at +1 713-489-6972 with your thoughts! We love hearing from you! Learn more about your ad choices. Visit megaphone.fm/adchoices

CME credits: 1.00 Valid until: 19-12-2023 Claim your CME credit at https://reachmd.com/programs/cme/when-to-start-using-sglt2i-in-hfref-initiating-guideline-recommended-treatment-options/14735/ What are the benefits of SGLT2 inhibitors (SGLT2i) in heart failure? What clinical challenges can physicians face when initiating guideline recommended therapy in heart failure? And what unanswered questions with SGLT2i in heart failure remain? Three speakers present the guidelines, evidence of studies and tell us what we can expect in the near future with regard to SGLT2i in heart failure. This course consists of the following: The clinical challenges of initiating guideline recommended therapy in HF - Prof. John McMurray, MD - Glasgow, UK Benefits and evolving insights on SGLT2i in the spectrum of LVEF - Prof. Carolyn Lam, MD, PhD - Singapore Expanding evidence on SGLT2i: Where are we now and what can we expect? - Prof. Scott Solomon, MD - Boston, MA, USA

Operational Security Solutions (OSS) offers its “Full-Spectrum” risk management solutions founded upon proven security protocols, practices and standards designed to anticipate and mitigate the widest scope of potential threats which could result in loss of any kind.Episode 1081 The #TalkingHedge chats with Scott Solomon, CEO, Operational Security Solutions...https://youtu.be/n2yx8t-p1bA

Host: Javed Butler, MD, MBA, MPH Guest: Scott Solomon, MD Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction (DELIVER trial) is a study designed to assess the effectiveness of SGLT2 inhibitors in patients with higher left ventricular ejection fraction. To help lead the discussion on the results of this study, Dr. Javed Butler is joined by Dr. Scott Solomon, lead study author and Director of the Clinical Trials Outcomes Center and the Edward D. Frohlich Distinguished Chair at Harvard Medical School.

This week, please join author Sunil Rao and Guest Editor and Editorialist Gregory Lip as they discuss the article "A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction" and the editorial "Factor XIa Inhibition: Is It a Novel Alternative Antithrombotic Strategy for High-Risk ACS Patients?" 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. Dr. Carolyn Lam: Greg, today's feature paper is about the factor XI inhibitor asundexian. It's the trial that we've been waiting for the PACIFIC-AMI trial. You really have to listen to it because these factor XI inhibitors are super interesting. What? We're going to tell you about the other papers in today's issue first. Aren't we, Greg? Do you want to go first? Dr. Greg Hundley: You bet, Carolyn. Thank you so much. Carolyn, did you ever consider the genetic underpinnings of venous thromboembolism? Well, as you know, venous thromboembolism is a complex disease with environmental and genetic determinants. And in this study, this large investigative team represented by Dr. Nicholas Smith from the University of Washington in Seattle, and their colleagues present new cross-ancestry meta-analyzed genome-wide association study results from 30 studies with replication of novel loci and their characterization through in silicone genomic interrogations. Dr. Carolyn Lam: Wow. Sounds like a really large effort, Greg. What did they find? Dr. Greg Hundley: Right, Carolyn. In the author's initial genetic discovery effort that included 55,330 participants with venous thromboembolism: 47,000 were European, 6,000 African, and a little over 1000 Hispanic ancestry. They identified 48 novel associations of which 34 are replicated after correction for multiple testing. In their combined discovery replication analysis, so that's 81,669 venous thromboembolism participants and ancestry stratified meta-analyses from the European, African and Hispanic ethnic groups. They identified another 44 novel associations, which are new candidate venous thromboembolism associated loci requiring replication. And many of the replicated loci were outside of known or currently hypothesized pathways to thrombosis. Carolyn, in summary, these findings from this very large GWAS analysis highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of anti-thrombosis treatments with reducing the risk of bleed. Dr. Carolyn Lam: Wow. Super interesting and very related to that feature paper that we just discuss. But nonetheless, this next paper I love as well, if I may say so myself. It deals with frailty and as we know, frailty is increasing in prevalence. And because frail patients are often perceived to have a less favorable benefit risk profile, they may be less likely to receive new pharmacological treatments. And so, we and led by Professor John McMurray from the University of Glasgow, decided to investigate the efficacy and tolerability of dapagliflozin according to frailty status in the DELIVER trial. Dr. Greg Hundley: The DELIVER trial. Carolyn, tell us about the DELIVER trial? Dr. Carolyn Lam: Sure. In deliver dapagliflozin compared to placebo, reduced the risk of worsening heart failure events or cardiovascular death and improved symptoms in more than 6,000 patients with heart failure and mildly reduced and preserved ejection fraction, so ejection fraction above 40%. Now in this pre-specified analysis, we examine the efficacy and safety of dapagliflozin according to frailty status. That was determined using the Rockwood cumulative deficit approach. And so, what we found was that greater frailty was associated with more impairment of health status and worse clinical outcomes in patients with heart failure and ejection fraction of 40%. The beneficial effects of dapagliflozin compared to placebo on clinical outcomes were consistent regardless of frailty class. But interestingly, the improvement in symptoms, physical function and quality of life were larger in the frailest patients. Adverse events were not more common in individuals randomized to receive dapagliflozin compared to placebo irrespective of frailty class. And so, the take home message is the benefit risk balance related to frailty in patients with heart failure with mildly reduced and preserved ejection fraction is favorable for dapagliflozin. And so, these findings should challenge any clinical reluctance to introduce dapagliflozin in patients perceived to be frail. Dr. Greg Hundley: Wow. Carolyn, really interesting. You could see with the diuretic effect in someone that's frail, the potential hesitancy, but very interesting study results in this world of frailty and the use of dapagliflozin. Well, Carolyn, this next study is very interesting and it comes to us from the world of preclinical science that takes a very interesting approach to a scientific question. Now, as you may know, RNA-binding proteins or RBPs are master orchestrators of genetic expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs, thus characterizing RBPs targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RBP targets, thereby limiting our understanding of their function. Carolyn, these investigators led by Dr. Grégoire Ruffenach from UCLA were interested in assessing pulmonary arterial hypertension and they turned to the world of cancer research. Carolyn, in cancer, the RNA-binding protein hnRNPA2B1, and we're going to abbreviate that as A2B1, promotes a pro proliferative anti-apoptotic phenotype. The same phenotype is present in pulmonary arterial smooth muscle cells and is responsible for the development of pulmonary arterial hypertension. However, the A2B1 function that's never really been investigated in pulmonary arterial hypertension. Dr. Carolyn Lam: Oh, Greg, that's not only fascinating, but so beautifully described. Thank you. What did they find? Dr. Greg Hundley: Right, Carolyn. These authors found that A2B1 expression and it's nuclear localization are increased in human pulmonary arterial hypertension, pulmonary arterial smooth muscle cells. Using bioinformatics, they identified three known motifs of A2B1 and all mRNAs carrying them and demonstrated the complimentary non-redundant function of A2B1 motifs as all motifs are implicated in different aspects of the cell cycle. In addition, they showed that pulmonary arterial smooth muscle cells and A2B1 promote the expression of its targets. Additionally, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats. And so, Carolyn, through the integration of computational and experimental biology, this team study revealed the role of A2B1 as a master orchestrator of pulmonary arterial smooth muscle cells in pulmonary hypertension and that phenotype and its relevance as a therapeutic target in pulmonary arterial hypertension. Dr. Carolyn Lam: Wow, that's super, Greg. Thanks. Shall we go through what else is in today's issue? Dr. Greg Hundley: You bet, Carolyn. There's a Research Letter from Professor Mustroph entitled, “Empagliflozin Inhibits Cardiac Late Sodium Current versus Calcium Calmodulin‐dependent Kinase II.” Dr. Carolyn Lam: There's also an exchange of letters between Doctors Omarjee and Diederichsen regarding vitamin K2 and D in patients with aortic valve calcification: [an] absence of evidence might not be evidence of absence? And finally, there's an On My Mind paper by me and Scott Solomon and it's entitled, “Delivering Therapeutic Efficacy Across the Ejection Fraction Spectrum of Heart Failure.” But let's go on now to talk about the Factor XI inhibitor, shall we, Greg? Dr. Greg Hundley: You bet. Well, listeners, welcome to this feature discussion on October 18th at a very special article today. And we have with us the lead author, Dr. Sunil Rao from NYU in New York City and also our associate guest editor as well as editorialist, Dr. Gregory Lip from Liverpool. Welcome, gentlemen. Sunil, we'll start with you. Can you describe for us some of the background information that went into the preparation of your study and what was the hypothesis that you wanted to address? Dr. Sunil Rao: Yeah, great. Thanks so much, Greg. It's a real pleasure to be here with you. The background of the PACIFIC-AMI study is really rooted in the fact that patients who have acute myocardial infarction are really at risk for recurrent thrombotic events, even after their event. And this risk continues despite the fact that we have evidence based therapies that are really around targeting the platelet as well as aspects of the coagulation cascade. There have been studies that have looked at the use of dual antiplatelet therapy plus an anticoagulant or single antiplatelet therapy plus an anticoagulant. And those studies have shown a benefit. However, their clinical use is limited because of the bleeding risk. Factor XI is an interesting target, because factor XI is likely involved in the amplification of thrombin generation after plaque rupture. But it really doesn't play much of a role in hemostasis. And so, as a target in reducing events after acute coronary syndrome, activated factor XI is a very attractive one. And so, the hypothesis of this study was that a highly bioavailable oral, direct, selective activated factor XI inhibitor called asundexian would be safe and effective in the treatment of patients who experience acute coronary syndrome at reducing adverse events. Now, this is a phase two study, so it really wasn't powered for clinical events. It was really a dose-finding study, so it was really looking at adverse events and sort of bleeding complications. Dr. Greg Hundley: Very nice. Asundexian, a new factor XI inhibitor. And Sunil, can you describe for us your study design and then maybe a little bit more about the study population, how many subjects? Dr. Sunil Rao: Sure. Again, this is a phase two study. It was a randomized, double-blind, parallel-group design where patients, who were admitted with acute coronary syndrome were randomized to three different doses of asundexian and or placebo in a one-to-one to one-to-one fashion. Patients who met criteria for enrollment were: patients who were admitted with a diagnosis of acute MI; if they were older than or equal to 45 years of age; they were hospitalized in acute coronary syndrome that did not occur in the context of revascularization, so it was not a type 4 event; and they were planned to be treated with dual antiplatelet therapy after hospital discharge. Dr. Greg Hundley: Sunil, thank you for describing this very interesting study design. Now, how many subjects did you include and could you just describe for us the study population? Dr. Sunil Rao: We had a total of 1,601 patients that were randomized at 157 centers in 14 countries between June 2020 and July 2021. And in order to be eligible for enrollment into the study: patients had to be admitted with a diagnosis of acute MI, they had to be greater than or equal to 45 years of age, and be hospitalized with that acute MI that did not occur in the context of revascularization, so type 4 MIs were excluded. The other inclusion criteria was that they had to be planned to be treated with dual antiplatelet therapy after hospital discharge. Now, we allowed randomization up to five days after hospital admission and randomization occurred after patients were clinically stabilized and any planned PCI was performed. We included both patients with STEMI as well as non-ST segmental elevation ACS, but we capped the number of patients with STEMI that were included to no more than 50%. Now, the main exclusion criteria were things that you would expect for a phase two trial. Obviously, hemodynamic instability at the time of randomization, active bleeding or bleeding dialysis, severe renal dysfunction, planned use of full-dose anticoagulation. Dr. Greg Hundley: Very nice. And so, we have several doses of this new factor XI inhibitor. Describe for us your study results? Dr. Sunil Rao: Again, this was a phase two trial that was really looking at safety and adverse events as you would expect. The study groups were pretty balanced across all of the dosing arms. When we looked at the pharmacokinetic and pharmacodynamic data, we found something really interesting, which was that there was a dose relationship between the dose of asundexian and the factor XIa activity. Factor XIa is activated factor XI. The higher the dose, the more suppression of factor XI activity. In fact, the highest dose nearly eliminated factor XI activity. The drug clearly works in the way that it was intended. Now again, the clinical data, it wasn't powered for clinical data. But when we look at the bleeding results, we found that there was in fact an increase in bleeding as the dose of asundexian increased. The overall rate of bleeding in the highest dose of asundexian was in 50 milligrams was 10.5% with type 2 or 3 or 5 BARC bleeding, a placebo is about 9.02%. Again, the efficacy outcomes, very, very low rates of overall events. Again, not powered to show a difference. Essentially, very similar across all the arms. Dr. Greg Hundley: And did you find the same results for the men and the women? And what about older individuals and younger individuals? Dr. Sunil Rao: Yeah. We did look at some subgroups. And you had to be a little bit cautious because again, the trial itself is relatively small. I mean, we didn't notice any significant patterns across these subgroups. And the overall interaction p-values were really non-significant. But I think what this does show is like a phase two trial that the drug works as in the way that it's intended. Overall, safety was as expected. And I think it really sets up data for a larger study. Dr. Greg Hundley: Well, listeners, what a fantastic presentation. And now, we're going to turn to our guest editor and editorialist, Dr. Gregory Lip from Liverpool. Greg, I know working for circulation, you have many papers come across your desk. What attracted you to this particular paper? And then maybe secondly, can you help us put the results of this study in the context of other studies that have been evaluating these factor XI therapies? Dr. Gregory Lip: Thanks, Greg. Well, I think this is an important paper, because it is a phase two trial with a novel, orally bioavailable inhibitor factor XI. And this is intriguing because factor XI efficiency in humans and experimentally in animals is associated with a reduced risk of thrombotic events like stroke or venous thromboembolism. But spontaneous bleeding is rare and also bleeding in response to trauma or surgery is much milder. Really it's the holy grail of trying to get an anticoagulant that reduces thrombosis but doesn't cause an excess of bleeding. Now, this was the quest with different anticoagulants. And I think it was very exciting to see this particular paper in the patients who've had an acute coronary syndrome, because there was a lot of interest in the use of anticoagulants, particularly in combination with antiplatelet therapy from trials such as ATLAS and COMPASS, where there was certainly a reduction in adverse cardiovascular events. But a downside with those drugs and when using combination, was an excess of bleeding by the combination of the available anticoagulants now plus antiplatelets. The factor XIs agents offered the possibilities we might have combination therapy to reduce cardiovascular events but not causing an excess of bleeding. Dr. Greg Hundley: Well, listeners, what a wonderful discussion that we've had here. Let's circle back with both individuals. Sunil, we'll start with you. What do you see as the next study to really be performed in this sphere of research? Dr. Sunil Rao: I think that factor XI is a very attractive target in patients with acute coronary syndrome. Again, the rationale for why we did this phase two trial was to show that inhibition of activated factor XI should result in a low rate of ischemic events without a significant increase in bleeding. This phase two trial was really to try and decide which doses result in potent inhibition of factor XIa and potentially which doses should be carried forward into a larger study. What we found in the PACIFIC-AMI trial was that the doses of asundexian and the factor XIa inhibitor were very, very well tolerated with a low rate of adverse events. It resulted in a dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. I think, again, it's a very attractive target in patients with ACS and this really provides support for a larger adequately powered clinical trial in patients with acute coronary syndrome that is really looking at clinical events such as MACE as well as bleeding. Dr. Greg Hundley: And Greg as an editorialist, what did you see with this paper? Maybe some unanswered questions that we'd like to pursue further? Dr. Gregory Lip: Well, I think this does raise a lot of questions in the sense that it'll be interesting because as a phase two trial, it's a relatively moderate sized trial. It's not like a phase three large outcome trial and phase two trials also testing different doses of the novel agent. We need to see the definitive phase three trial and to look at the magnitude of benefit versus potential for bleeding if in the large phase three trial and obviously, the net clinical benefit and importantly are some of the subgroups: ST elevation, myocardial infarction, undergoing primary PCI, for example, those with renal impairment. And I think particularly intriguing would be looking at the patients in this scenario who get the new antiplatelet drugs such as ticagrelor and prasugrel. And the reason I say that is what we have with warfarin or Coumadin and from the current DOACs or NOACs, depending on the risk side upon. We refer to them, that's the direct oral anticoagulants or non-vitamin K antagonist or anticoagulants. Well, if you give a more potent antiplatelet like prasugrel or ticagrelor, the risk of bleeding not surprisingly is higher. Hence, the guidelines recommend that if you use an anticoagulant or a DOAC, you use it with a P2Y 12 inhibitor clopidogrel as opposed to the more potent ones. If this new class of drugs, the factor XI inhibitors can work well in combination with one of the more potent antiplatelets without causing an excessive bleeding, again, this is going to be a substantial advance. Well, with these new class of anticoagulants, will be really interesting to see the phase three trials when applied to other chronic conditions. For example, stroke prevention and atrial fibrillation. And the other category of patients would be those who've had an embolic stroke of uncertain source or ESUS or in old terminology cryptogenic stroke. With the ESUS group of patients, they're currently treated with aspirin because the trials which tried a NOAC or DOAC, they were not showing a positive result. They'll be interesting again with the factor XI inhibitors, whether we are going to see this benefit with the reduction in recurrence stroke with no excessive bleeding. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Sunil Rao from NYU in New York City and Dr. Gregory Lip from the University of Liverpool for bringing us this study highlighting that in patients with recent acute myocardial infarction, three doses of asundexian when added to aspirin plus a P2Y 12 inhibitor resulted in dose-dependent near complete inhibition of factor XIa activity without a significant increase in bleeding and a low rate of ischemic events. And certainly, the data from this study support the investigation of asundexian at a dose of 50 milligrams daily in an adequately powered clinical trial of patients following acute myocardial infection. 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. 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.

Who doesn't have more tasks than there are hours in the day to get them completed? Or more emails than you can possibly read and respond to? Or double and triple booked meetings? How do you get control of your time and focus on what matters most and be efficient? Tune in for tips from a leader who has put the concept into practice.

Who doesn't have more tasks than there are hours in the day to get them completed? Or more emails than you can possibly read and respond to? Or double and triple booked meetings? How do you get control of your time and focus on what matters most and be efficient? Tune in for tips from a leader who has put the concept into practice.

Who doesn't have more tasks than there are hours in the day to get them completed? Or more emails than you can possibly read and respond to? Or double and triple booked meetings? How do you get control of your time and focus on what matters most and be efficient? Tune in for tips from a leader who has put the concept into practice.

American alligators, the kind that live in the Houston area came off the endangered species list in the 1990s. But now they're facing a whole new round of threats. Today, host Lisa Gray is joined by City Cast contributor Scott Solomon, biology professor at Rice University and alligator expert Cord Eversole to explain how you study an alligator next and what risks face the alligator population at Brazos Bend Park. Looking for more Houston news? Then sign up for our morning newsletter here. Follow us on Twitter and Instagram  Don't have social media? Then leave us a voicemail or text us at +1 713-489-6972 with your thoughts! Learn more about your ad choices. Visit megaphone.fm/adchoices Learn more about your ad choices. Visit megaphone.fm/adchoices

In this episode, guest host Deepak Bhatt, MD, MPH, FACC, offers a preview of some of the most important and clinically transformative studies being presented at the ESC 2022 Conference, August 26-29. Day One includes: more data from the EMPEROR trial on the mechanisms and clinical benefits of SGLT2i in heart failure, the TAILOR-PCI randomized trial on genotype-guided oral P2Y12 inhibitor therapy, phase 2 data from the ENTRIGUE study on pegozafermin for the treatment of severe hypertriglyceridemia, and the results of the TIME trial on the timing of morning versus evening medication. Also on Day One, Dr. Valentine Fuster will present the results of the SECURE trial, a polypill strategy in secondary prevention. There will also be a presentation of the ASCEND study on the effects of aspirin and omega−3 fatty acid supplements on heart failure. Dr. Bhatt will present data from the REDUCE-IT trial on the significant reduction in ST-Elevation MI with icosapent ethyl. Day One will also cover the EXHAUSTION project, investigating air temperature and cardiovascular disease, as well as the ADDICT-ICCU study on carbon monoxide and acute cardiac events. Day Two will include: a presentation by Davada Perera on REVIVED, investigating percutaneous revascularization for ischemic ventricular dysfunction, ALL-HEART data on allopurinol and cardiovascular outcomes in ischemic heart disease, and a major presentation by Scott Solomon on the DELIVER trial, examining dapagliflozin in heart failure with mildly reduced and preserved ejection fraction. There will also be a number of pooled analyses on Day Two, including one looking at DAPA-HF and DELIVER, and a pre-specified meta-analysis of DELIVER and EMPEROR-Preserved. Together these studies will firmly cement the concept of the SGLT-2 inhibitors class as a heart failure medication.  Day Three opens with an important presentation on INVICTUS, exploring rivaroxaban versus VKA for rheumatic atrial fibrillation. There will also be a group of presentations on some modest but significant Phase 2 trials on factor XIa inhibitor asundexian. Additionally, Renalto Lopes will present data on the APOLLO trial exploring apixaban for prophylaxis of thromboembolic outcomes in COVID-19, and the five-year data from the MOMENTUM 3 study on LVAD Therapy will be presented.   On the fourth and final day, presentations include the clinical outcomes at 5 years of follow-up in the ISCHEMIA-CKD EXTEND trial, the review of the MASTERDAPT trial data at 15 months, the primary results of FOURIER-OLE, and data from the PANTHER Trial on P2Y12 inhibitor versus aspirin monotherapy in patients with coronary artery disease. ESC 2022 promises to be a rich and rewarding experience for those who can attend in person or participate virtually.

Rice University biologists Scott Egan and Scott Solomon describe the gorgeous, disgusting, and supremely weird lives of insects that grow inside oak galls. Looking for more Houston news? Then sign up for our morning newsletter here. Follow us on Twitter and Instagram  Don't have social media? Then leave us a voicemail or text us at +1 713-489-6972 with your thoughts! Learn more about your ad choices. Visit megaphone.fm/adchoices Learn more about your ad choices. Visit megaphone.fm/adchoices

Summer is upon us! So you know what that means: constantly swatting at mosquitos, declaring war on fire ants, and slamming doors to keep all the flies out. It's true: Bugs can be a nuisance! But, on today's episode, Scott Solomon - Biology professor at Rice University - attempts to convince lead producer Dina Kesbeh that we should embrace insects, because we really, really need them. Check out Scott's page at Rice, @ him on Twitter, he's super active and is constantly teaching what he loves, illuminating biological mysteries all around us: Scott Solomon. Can't identify an insect? Here's a helpful guide! Also, you can "Ask an entomologist" - Here! City Cast Newsletter is great - get in on all that chatter! It's here! We're on Twitter! Follow us at @CityCastHouston Think social media is for the birds? Leave us a voicemail or text us at +1 713-489-6972 with your thoughts! Learn more about your ad choices. Visit megaphone.fm/adchoices

Operational Security Solutions with CEO Scott Solomon today on Blunt Business with Jorge Hermida only on The Cannabis Radio. During our MJBiz conference coverage, you may remember we were introduced to a company called Operational Security Solutions there a premier provider of full-spectrum Risk Management Services with a specialization in Secure management cash management and logistics compliance services security Consulting and facility hardening for high-risk Industries such as cannabis. Scott Solomon, MBA, MSE, is the Chief Executive Officer and Director of Compliance for Operational Security Solutions (OSS) and OSS East. In this role, Mr. Solomon leads corporate operations, staff and contractors, and the establishment of new OSS franchises throughout the country. Mr. Solomon coordinates the efforts of the C-Suite staff to achieve the strategic direction established by the OSS Board of Directors. Previously, he was Chief Operating Officer with a specific focus on compliance operations that included a comprehensive internal AML/BSA program, field audit support for financial institutions, and other programs to maximize compliance operations across their portfolio of clients while aligning staff and capital resources to best support market expansion.Support this podcast at — https://redcircle.com/blunt-business1131/donationsAdvertising Inquiries: https://redcircle.com/brandsPrivacy & Opt-Out: https://redcircle.com/privacy

Correctly managing security is one of the best way to ensure that cannabis companies remain sustainable.   Cannabis companies will have continue to have limited banking options until federal laws are changed.  Abundance of cash created a very dangerous environment for both customers and employees.   Scott Solomon the CEO of Operational Security Solutions (OSS) joins Dan Humiston to talk about being uniquely positioned to assess, manage and mitigate risks that threaten the sustainability of businesses across the industry supply chain.   He explains how OSS solutions and services address the full spectrum of risks that these businesses must manage.Produced by PodConx MJBulls - https://podconx.com/podcasts/raising-cannabis-capitalDan Humiston - https://podconx.com/guests/dan-humistonScott Solomon - https://podconx.com/guests/scott-solomonOperational Security Solutions (OSS) - https://opsecsolutions.us/

We're approaching the peak of birds' spring migration, which means that soon, thousands of birds will pass over your head each night. Scientists know remarkably little about how birds manage these epic journeys. On today's podcast, Rice University professor Cin-Ty Lee joins City Cast contributor Scott Solomon to describe to Lisa Gray a fascinating project. In 2020, when the pandemic quieted the city, Lee set up a recorder on a Rice soccer field to catch the sound of birds as they flew overhead. He's recorded eagles and peregrine falcons, and added roughly 30 species to the number of birds ever identified on the campus. Plus, he has a greater appreciation of just how thousands of birds migrate over us all here in Houston. Cin-Ty's website includes his field notes, his paintings of birds, and a “Sounds of Nature” section. Scott Solomon will talk about how scientists at Rice University use the campus as a living lab to study biodiversity, April 20th. You can register here. City Cast Houston's Website is where you can sign up for the pod *and* the newsletter! It'll make you a way better Houstonian. We have a number - text us! Call us! It's 713-489-6972. We're on Twitter! Check us out: @CityCastHouston.

Would Houstonians ever eat insects, not just as a fear factor kind of dare, but because they are delicious? Chef Hugo Ortega, best known for Hugo's and Xochi, and Dr. Scott Solomon, entomologist at Rice University and City Cast Houston contributor, join us today to tell us the benefits of eating bugs. Today's episode will either leave you salivating for a cricket, or make you run for the hills. Do you want the juiciest Houston news delivered straight to your inbox? Then subscribe to our morning newsletter here. We're also on Twitter, only tweeting when we're fully caffeinated. Follow us @CityCastHouston

Usually, when Houstonians talk about insects, it's about the ones that we want to kill. Mosquitoes, fleas, fire ants, but today one of the insects' biggest fans is joining bug-hating producer Dina Kesbeh. City Cast contributor, Scott Solomon studies ants. He's a Rice University entomologist, and he's just released a lecture series on why insects matter. Scott is going to make the case that yes, even in Houston, we need those creepy crawlies. If you want to go down a rabbit hole of insect learning check these links out: Here's your guide to all things bugs! Here's your guide to common insects in Texas! Here's where you can ask all your insect questions! Battle of the burgers: are you a Whataburger fan or have switched to the In-n-Out fanbase. We want to know! Leave us a voicemail sharing which side you're on and why! Call us at 713-489-6972. Keep up with all your Htown news, subscribe to our newsletter! We're also out here Tweeting!

Scott Solomon - biologist, professor, and science communicator – takes producer Ferrill Gibbs to a portion of the shallow, muddy Brazos (just north of College Station) where certain historical rocks and their peculiar characteristics offer coordinates to one of life's greatest mysteries. Check out Scott's new show on Wondrium, which is his greatest passion... insects! The show is called "Why Insects Matter" - and you can find it here! Also, you should sign up for the City Cast Houston newsletter. It's hand-crafted each day by the most curious Houstonian around: Lisa Gray. Go here!

This week, we have a special podcast: the interviewers become the guests! Join Digital Strategies Editor Amit Khera as he interviews Carolyn Lam, Greg Hundley, and Managing Editor David "Augie" Rivera as they provide a behind-the-scenes look at how Circulation on the Run comes to you each and every week. Come meet your favorite podcast hosts! Dr. Amit Khera: Hi, this is Amit Khera. I'm digital strategies editor for Circulation, and boy, do I have a treat today? I get to step in for Carolyn Lam and Greg Hundley, but wait, I actually get to interview Carolyn Lam and Greg Hundley today. So we have a very special Circulation on the run. Well, the interviewer becomes the interviewee. These two you get to hear every week and hear this amazing back and forth and deep insight into Science and Circulation. But, who are these folks behind the Circulation on the Run podcast? And boy, what interesting life stories they have and how they work through this. And wait, we also have a third joining us today, and that is Augie Rivera, who is the managing editor of Circulation. So we get to see the mastermind behind how all this runs. Well, Carolyn, Greg, Augie, welcome you three. Dr. Carolyn Lam: Thanks, Amit. Feels weird. Dr. Amit Khera: Good. Then mission accomplished this week. Well, first let me start with you, Carolyn. I know you and I started this long ago, with help from so many folks. People hear you every week and I'm sure many people know you quite well. I will say you have one of the most interesting backgrounds, incredible scientific and personal accomplishments, professional accomplishments. So we're very fortunate to have you as leading this podcast in the beginning, but a lot of people may not know your background story about sort of your training and your day job, because you do have a day job outside of podcasting. So tell us a little bit about yourself, about how you got here in life. Dr. Carolyn Lam: Oh my gosh. Amit, I'm humbled by your question. My goodness. I feel just very lucky to be part of the Circulation editors. And I humbly did my med school in Singapore, and did cardiology here, and traveled and lived overseas for the first time. Guess where, in Rochester, Minnesota. Tropical Singapore island to refrigerator state. Other than that, it was absolutely the most pivotal moment of my life. Met my first female mentor and Dr. Margaret Redfield. Really, really just came into my own and got involved in population-based research. And then hopped on over to Boston where actually I was working at the Framingham Heart Study. So continuing sort of the epidemiologic work, but then I think another mentor I really have to call out too is Dr. Scott Solomon, who kind of took me under his wing a little bit and showed me a little bit of the world of clinical trials. And boy, all I can say is I haven't looked back. And so here I am. Dr. Amit Khera: I think you took a detour in the Netherlands too. Am I right to say that? Dr. Carolyn Lam: Oh yes, but that was quite a late detour in life. I was really, really fortunate meet Dr. Adrian Voris who supervised my own PhD. That was a really interesting thing because I come from a family of a pediatrician in my mom, and a scientist, a biologist really, specialized in fish, in my father. And I'm saying this because my father told me never ever follow his footsteps and do a PhD. Make sure I follow my mom's footsteps and be a clinician, and go into private practice. Dr. Amit Khera: Well, it looks like you followed both of their footsteps, maybe the best of both, so they're very proud of you for that. We recently had the privilege of having you give us grand rounds and get to hear your impressive work in clinical trials. And I have to say, the work you're doing in half half and really with some great clinical trial and cohort data involving Asian populations was quite inspiring and impressive. How did you sort of get things going? You've traveled around and moved back and how did you start getting your career going and the momentum you've had so far, incredible success? Dr. Carolyn Lam: Oh goodness. Thanks for letting me share. Amit, honestly, I don't know. And I can only look back and be on my knees and be grateful for being at the right place at the right time. I think it's a combination of taking what I had learned in Olmsted County and Framingham. Coming back to Singapore and realizing that there was a need for similar epidemiologic studies. I firmly believe if I didn't do it, someone else would. I'm not that brilliant. I just get things done. And so that's what I did. I started that. And one thing led to another. It's having really friends as well. And so I really, really want to say big thanks to my mentors who have become my friends and colleagues. And to people listening. This is really, really from the heart. You don't plan these things. You just go the next step that you see, and you go with all your heart. And you make sure that you've got your eyes open to see the next opportunity, and have the energy to seize that one when it comes by as well. I think that's how it all happened. Dr. Amit Khera: Well, that is a good pivot because one of the next opportunities that came up in Circulation on the Run after you'd done it for a while, was to bring in this gentleman, Greg Hundley. And so we're so glad that you two partnered. Now, Greg, you and I have a little bit of a shared background. You were at UT Southwestern for a period of time, where I am currently. Well, tell us your story, Greg. Tell us a little bit about your background and training and where you are currently. Dr. Greg Hundley: Sure. Thanks so much, Amit. Again, I think like Carolyn, we really feel this is an incredible opportunity. The journal is a wonderful blend of collecting impactful science, both clinically and pre-clinically. And trying to bring that to the forefront. It's just been a fantastic opportunity to participate on the editorial side, but then after that, share with the rest of the world, the findings that we really develop each week. And it is truly a team effort. All the way from identifying impactful science, discussing it, preparing it, and then sharing it. And so I think like Carolyn, I just feel very privileged to have this opportunity. Now, my path, listening to Carolyn, and for listeners, you kind of move with it a little bit, and follow along seeking, I don't know, new opportunities, but also being very humble. And as they approach you, and doing kind of the best that you can in the situation. Dr. Greg Hundley: So my career path started at what was Medical College of Virginia, but is now VCU in Richmond, Virginia, and medical school there. And then, at Southwestern, did my internship, residency, and cardiology fellowship. And I would say, probably my first strong mentors was really a mentor team. There was expertise there. Jim Willerson had brought Ron P Shock and Craig Malloy on the magnetic resonance imaging side. So for those that are listening, I'm more of an imager in cardiovascular medicine. But also a key fundamental pivotal figure or figures were David Hillis, and Rick Lang in the cath lab. And at the time, magnetic resonance imaging, we were trying to figure out, well, could this noninvasive methodology help us understand problems related to cardiovascular disease that came along maybe before, or we needed to go to an interventional situation, or how they would relate to an interventional situation. Dr. Greg Hundley: And then was briefly a faculty member at Southwestern, and then recruited back to the East Coast to Wake Forest. Another really pivotal figure for me was Dr. Bill Little at Wake Forest. Now, he's passed away, but bill had again, that great insight and excellence in science, and performing research and investigations, but also clinical expertise and emphasize the world... We haven't talked a lot about this, but education. How we take the information that we gather and educate others. Began working with the American Heart Association, with the American College of Cardiology in that realm. Then after 22 or three years, another opportunity came up actually to return back to VCU, and be the director of the heart center. And so now have that position here in Richmond, Virginia. Again, very excited to be working here with Circulation on the Run. Dr. Amit Khera: Well, I hear some amazing themes from both of you about mentoring and people along the way. It's a great story obviously for our younger listeners that are thinking about life and careers and opportunity sort of finding where life takes you. I think those are great themes for both of you. Now, we won't have as much time for this story, but Greg, you and I spoke recently. You told me this most amazing story of how you were going to be an interventional cardiologist, walked over to drop off something. A patient had an MRI machine and saw this MRI and fell in love. Dr. Amit Khera: I'll paraphrase about staying up all night, drinking soda and coding zeros and ones since that's the technology back then, but what an amazing story. We'll have to do that for our next podcast. All right. I'm going to bring in Augie Rivera. Now, he is the managing editor of Circulation. Meaning he really keeps everything going, and is the engine and brains behind the operation. And one of the many things he does, is the podcast. And we'll talk more about the logistics of that. But Augie, people never get to hear your voice. So tell us a little bit about how you got into this medical publishing and circulation in the pacific, sort of your background. David “Augie” Rivera: Well, thanks, Amit. Also thanks to Carolyn and Greg for inviting me as well to participate. This is going to be shocking and maybe scary, but I only have a couple of years of scientific journal publishing experience, and that's with the Circulation family. My background for my entire career has been in educational school publishing, specifically in mathematics. And mainly grade K to 12 mathematics. So making the jump over to scientific publishing seemed a bit daunting, but after like 20 plus years, I was looking to do something else. And I was grateful that I saw something on LinkedIn. I interviewed for the position and I was very fortunate the American Heart Association that ended up hiring me. In a sense I always say, "Taking a chance on the long shot." And so that's what brought me here. So a lot of this has been very, very new to me, but at the same time, all the Circulation editors have been so helpful, as well as my staff that I work with. They've been so beneficial to me in learning the side effects. So, that's a little bit about me. Dr. Amit Khera: We're very glad that the DHA found you, Augie, and you've been obviously this incredible resource for us. I'm glad you brought up the staff because there's so many people on Circulation that make it run and we're very grateful for all their efforts, including those who help us put on this podcast. Well, I want to dig into the podcast. Carolyn, we haven't told the story in a long, long time. I think you told it on the very first podcast, but Circulation on the Run. For those that missed in earlier days, remind us how you came up with that name. Dr. Carolyn Lam: Okay, very quickly. I'm a runner, and I know a lot of us are. It's just on one of my runs that I realized, "My goodness, wouldn't it be great to be able to just feed my mind at the time?" I was on a treadmill actually, and I was trying to read, and it occurred to me, "It is impossible. I'm getting a serious headache to try to read while you're trying to run." And so I thought, "Wow, wouldn't it be great if somebody just read that to me, so I could just read the journal while I was running?" Yeah, you can join the dots. So that was exactly the idea. That, "No, I'll do that for someone. I'll give them the nuts and bolts of that issue." Dr. Carolyn Lam: At least the main papers. The way it's grown since then, it's frankly thanks to Greg. I need to make a plug here. Greg has admitted that he's humble. And in fact, that's why I need to drag this out of him. I did not realize until I interviewed him on one of the podcasts, that he is totally gifted at interviewing. And then he tells me just, by the way, in the usual Greg way, he has a history and thick experience in this. He had done the interviews like... Greg, you have to tell me, but he had done several of these. He had a show, he had ideas. He used to do it. And I was like, "Why are you hiding all this? You got to come do this with me." But he hides it. So Greg, now you have to fess up. Dr. Greg Hundley: Oh gosh. And now Carolyn, she's too kind. So Carolyn, listeners as you can tell, just has a very warm, inviting personality. And she so couples that with just brilliance and interest in science. I mean, I can't take credit for the things, but she's also open to listening. And I think one of the really exciting things, this sort of team of three with Augie and Carolyn, we have great discussions behind the scenes on how we can bring the information in the journal to you as listeners, in a way that is inviting, engaging, and educational. It's really being part of a team, that has that common goal in mind and in thought. Carolyn and Augie, I just treasure the opportunities that we get to work together every several weeks and putting together the most exciting science that our journal really brings forth. So it's a team effort for the listeners. And just to maybe anticipate the next question, how do we do that? Dr. Greg Hundley: We do get the joy of reading the journal every week, and we spend some time each of us, on our weekends and late at nights reading thoroughly the journal. And Carolyn and I kind of divide up the articles. Both of us taking and becoming enthralled with areas of expertise that we may have. Again, we've talked about Carolyn in heart failure expertise and maybe me a little bit more on the imaging side and cardio oncology and the like. And then in any way we divide up the articles, we read them thoroughly, and then we produce a script. So one of the fun parts of this is working with Augie. We're producers as well as editors, as well as the spokespersons. Dr. Greg Hundley: So it's kind of all done in one shop and put together, and interactive, if you will. And then we are able to record that in sessions with Augie, coordinating them, and involving some of our authors, editorial experts. And then other experts that we gather from around the world that are also involved in the science. And the goal is to create discussions in addition to presenting the information that's in the journal, but to create meaningful, thoughtful discussions regarding this impactful science, so that we can actually take it in as practitioners or other researchers and scientists in the field quickly. And that's sort of the general concept. Dr. Amit Khera: You jumped right in there, Greg. And that's exactly what we want to dive into, which is sort of the behind the scenes, the mechanics about the why. Now, you two have an incredible chemistry. I will say since you two have been doing this together, it's really been a joy listening to you two. Carolyn, just maybe the dovetail on what Greg just talked about, about sort of the chemistry. That back and forth that you two do, the preparation behind that. Tell us a little bit about how that works out. Dr. Greg Hundley: Oh, absolutely. I've been dying to share. You should hear the bloopers. It's hilarious. So after a while, we just totally like... We have the fun doing this. And we realize it's very serious science that we're talking about. We're so solidly proud of circulation, but it's okay to have fun. It's okay by the way, to mispronounce some of these basic science words and to call Joe Hill, which I've done by the way, literally called him to ask him how to pronounce certain things. And you know what? And have fun at the same time. And so Greg starts these quizzes. Now, that is all Greg, okay. This Carolyn quizzes and... So after a while, we started to try to hide little quizzes inside our script with the answers given just in case. But it sometimes catches us unaware, and it's just really hilarious. Dr. Greg Hundley: And once or twice, I think Greg and I have tried to quiz Augie as well. But Augie never allows us to do that. So it's really great when we're having fun. And that is exactly what I'm so grateful for Greg to showing me that. He's the one who had the experience with the back and forth and gave us the idea. He's the one who push to say, "Look beyond the original articles, I really like as a listener, to have an overview of every single article." That was Greg. He's the one who initiated the sort of forum type discussions and double bill discussions, because he got feedback and acted on it, that people really, really enjoy listening to the authors too. And finally, we're really trying to make it even more useful for the audience based on feedback by seeing if we can get CME accreditation, seeing if we can be more responsive. I just want to let people know, even if we don't manage to achieve it, that we're listening, and we're trying, and we're constantly trying to improve. And that's what I really, really thank both Greg and Augie for. Dr. Amit Khera: Thanks for that. Listen, I want to just pick up on many things that you just said. First, I think what people may not appreciate is how much work goes into this. You read all of the articles and prepare with the featured articles. You create a script, and you have fun doing it, which is the most important thing. You record and have to coordinate. Takes a lot of time. I've seen this too, then people don't realize afterwards, you listen to the entire thing and edited again. This is impressive. And it shows, because it's a fantastic product. I want to talk a little bit about some of the deeper features. So you two obviously summarized in the beginning, the original research and we talked a little bit about the back and forth. I want to talk about the featured articles and the interviews of these different folks. Tell me a little bit about that and how that goes. What do you enjoy about the interview part of that. Greg, you want to start? Dr. Greg Hundley: Well, I thoroughly enjoy what we call the feature discussions, where we bring together the authors of the paper, editorial experts that... With Circulation, there's a team of associate editors that process the papers. And actually, when you as a listener submit an article, we review these in a discussion format. And one of the associate editors is leading that through a discussion group. And so we bring in that expert. And then oftentimes, we have an editorialist, or an expert from the world, and bringing together a discussion and focusing on the content, not only in that article, but how that article pertains to the world's literature, and then where we really want to go next with research. Dr. Greg Hundley: And I think that's sort of our objective, is to bring a living discussion for us as listeners, with authors, the active researchers, with the editorial team and the experts. Why of all the papers you get did this impactful science really come to the forefront for you? And then from the editorialists, how do we take this information and put it in the context of the world's research that's going on in cardiovascular medicine? So those are sort of the main insights and as listeners, just as Carolyn said, we really enjoy receiving feedback from you, and how we can perfect that further. One of the things we've started thinking about is, if we have a basic paper and a clinical paper on the same topic, is really having even a broader discussion, a forum discussion, where we talk about several papers at one time and really embrace a topic. And I love what Carolyn said about providing not only continuing medical education credits, but for those in the United States or maybe North America in particular, maintenance of certification credit, and something we're actively looking at, trying to work through right now. Dr. Amit Khera: Thank you for that. And Carolyn, do an add to the features and the interviewing these folks and some of the... what it is that's most interesting to you in doing that process and what you've learned. Dr. Carolyn Lam: Yeah. I certainly want to add, but probably in an angle you would not expect. And here, I really, really want to point out the tremendous work of coordinating this, that Augie takes care of. It is incredible. When we have an editor in Europe, a author in California, a me in Singapore, himself in another part of the US. I do not know how Augie does it. And not only does he do it super well, it's always with a smile. Augie, you truly are amazing. Your positivity has honestly kept me going many times, when I just came on the recording half dead. Kudos to you, truly. Dr. Amit Khera: Thank you, Carolyn, because I wanted to bring in Augie back again now. Augie, it must be amazing for you. I mean, first, the logistics. Maybe you can tell us about coordinating people from all over the world, different time zones, every single week and obviously people that are quite busy and show what a hard thing to do. And then maybe seeing the process. Boy, from seeing these papers come through our meeting, to the selection, to coordinating, to seeing the final product at the end, it must be a pretty satisfying process for you. Tell us a little bit about the mechanics and what this is from your vantage point. David “Augie” Rivera: Well, indeed, it is very interesting. It's something that I did a little bit of production back in college when I did college radio, way back in the day, but I never do. I would end up doing this again, but I think as far as the logistics are concerned, I'm not by myself in this at all. I mean, a big shout out to Sarah O'Brien who trained me when I took on this job because she was covering Circulation on the Run while there was a search for a managing editor. So she was the one who taught me all the tricks of the trade, on how to make some of this happen. But also it's the two assistants for Carolyn and Greg, Afshaan and Angela, who I contact and I go, "Please let me know what their availability is, when, and what can we fit here? And what can we fit there? And can we try to move a meeting?" David “Augie” Rivera: In fact, I get to tell Greg that we were successful in moving a meeting for tomorrow, and we have another one scheduled. So we made it work. So really Afshaan and Angela really help out with those logistics as well. We also have to thank you Ishara and her team over at Learner's Digest. They're the masters who put together all of our raw audio files, and cut them all together, to make the final product of the podcast. And not only does her team do that flawlessly, but it also coordinates with having those reviewed and approved by the editors as well. So there is no way that we would ever be able to get any of our podcasts out and delivered without their awesome help and support. So a big shout out to Ishara and team. And most importantly, and the viewers can't see this, but also to the authors and associate editors, editorialists. Augie Rivera: First of all, we're grateful that they've sent and submitted their articles to circulation for peer review, and then eventual publication, but their flexibility, because I know that they are very busy during their time too, and trying to make things work. I have had an author say, "Oh yeah, 12:30 in the morning, past midnight? Oh totally. I can totally do that. No problem." Or an associate editor who says, "Yeah, I can probably do that for 5:00 AM in the morning." So the flexibility of the authors, the editorialists and the associate editors is also what makes the logistics and everything work out. So it's not me, but it's completely a team effort. And it's also thanks to Carolyn and Greg for finding those pockets of time while they're doing their day job, to also take the time to be prepped and interview our authors and editorialists. So on that end, like I said, it's not me, it's a team of all of us that put this together. Dr. Amit Khera: Well, I appreciate everyone's humility, including yours, Augie. And you are right, there's a broader team and I appreciate you calling them out, but we certainly acknowledge you're at the center of that, and appreciate all your work to make this come to fruition. Well, we're winding down. I have maybe one last question for you two, Carolyn and Greg. Tell us about the future of Circulation on the Run. Where do we go from here? What's the future of this specifically? Or maybe podcasting and Circulation in general. Dr. Carolyn Lam: Well, what I can say is, it is continuously going to improve. You've heard us commit to that. We will and promise to try to make it as short and snappy as we can. So for those of you listening, who kind of don't get to the end, please hang in there with us. We're continuously getting better. Dr. Greg Hundley: Yeah. I would just want to echo that. If listeners have suggestions and there's a pathway to gather that information from you, we are all ears. We're listeners, and we would love to shape and mold this further based on your suggestions, because really, your suggestions have shaped a lot of where we are today. Dr. Carolyn Lam: And Amit, if I could, because the podcast is only one cog in the whole wheel of what you do as overall strategy for us, digital strategy. Could I ask you to give us that last word? I have to be the interviewer again. Dr. Amit Khera: You can't get it out of your system. This one is not about me. I'll give two seconds on my role specifically, but I have a neat role. We purposefully chose the term, digital strategies, because we appreciate there's so many different things behind getting medical literature out there, including website, working with traditional media, social media, podcast, and whatever else comes in the future. Dr. Amit Khera: So I'm very lucky because I get to work with you all plus a ton of other folks to really bring this material to life. And the coolest part is, you all are so easy to work with and so creative, and have done so many amazing things with this podcast. And it's been real privilege just to watch this grow and develop. What I love that you both said, and I hope the listeners heard this, that have hung on with this, you're appreciated for feedback and you always have been. Have made tweaks along the way to make this better and better. And so if anybody has any, feel free to email any one of us, and we welcome that feedback to make this even better. Listen, I want to say what a treat this has been to interview the interviewers. Amazing, and certainly did not disappoint learning about your backgrounds and a little bit more about all of you, and about what makes Circulation on the Run come to life. Dr. Amit Khera: So that's it. There's another rap. I'm Amit Khera, stepping in and interviewing Carolyn Lam and Greg Hundley, who will join you again next week. Thank you. 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.  

En este episodio y con ayuda de Erik Hernández escudriñamos el espacio para aprender en qué se está trabajando, cuáles son las principales compañías que están reimpulsando el sector espacial así como un montón de curiosidades. Nota para los muy curiosos: en realidad, no se trata de hacer al Homo sapiens una especie interplanetaria, se trata de hacer humanos radicalmente nuevos con todo lo que eso conlleva (Scott Solomon). * Puedes encontrar el guión completo en nuestra web: https://pildorasdelconocimiento.com/podcast/exploracionespacial Si quieres seguir aprendiendo -y de paso apoyarnos para seguir adelante- lo puedes hacer aquí: * El pequeño curso de la inversión paciente y racional: https://pildorasdelconocimiento.com/cursos/inversion * Curso completo de inversión en inmuebles: https://pildorasdelconocimiento.com/cursos/inmuebles * Sesgados: https://pildorasdelconocimiento.com/cursos/sesgados *Detectando fraudes contables: https://pildorasdelconocimiento.com/cursos/fraudes * Aprendiendo LaTeX desde cero: https://pildorasdelconocimiento.com/cursos/latex * Aprendiendo Robótica con ROS: https://pildorasdelconocimiento.com/cursos/robotica Si te ha gustado no dudes en dejarnos un comentario y tu "Me gusta" 🙂 🗞 Si quieres estar atento a todas las novedades, síguenos en nuestra NEWSLETTER: http://eepurl.com/g4cfej ✉️ Contacto: pildorasdelconocimiento@pildorasdelconocimiento.com

En este episodio y con ayuda de Erik Hernández escudriñamos el espacio para aprender en qué se está trabajando, cuáles son las principales compañías que están reimpulsando el sector espacial así como un montón de curiosidades. Nota para los curiosos: en realidad, no se trata de hacer al Homo sapiens una especie interplanetaria, se trata de hacer humanos radicalmente nuevos con todo lo que eso conlleva (Scott Solomon). * Puedes encontrar el guión completo en nuestra web: https://pildorasdelconocimiento.com/podcast/exploracionespacial Si te ha gustado no dudes en dejarnos un comentario y tu "Me gusta" 🙂 * Para más información puedes visitar nuestra casa en internet: https://pildorasdelconocimiento.com Escucha el episodio completo en la app de iVoox, o descubre todo el catálogo de iVoox Originals

Scott SolomonMeet the mutant humans of Mars. Professor of evolutionary biology Scott Solomon explains why babies born on the Red Planet will look, function, and behave dramatically different from us Earthlings.Support the show (https://websummit.com/)

In this episode, Scott Solomon, Ankeet Bhatt, and Orly Vardeny are joined by William Schaffner to discuss the importance of influenza vaccination particularly this year in the midst of the coronavirus disease 2019 pandemic.

In this episode, Scott Solomon, Ankeet Bhatt, Orly Vardeny, Mohammad Madjid, and Jay Udell take a step back to dive deeper into the mechanisms behind the association between influenza and acute cardiovascular events. Visit the Taking the Lead: Flu and Cardiovascular Disease hub for more information and resources.

This week’s episode includes author Finnian Mc Causland and Associate Editor Justin Ezekowitz as they discuss angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction. 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 Greg Hundley Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, we're going to be talking about RNEs and renal outcomes in HFpEF. Oh, you got to hold me back this is going to be such an interesting discussion. But maybe let's grab our coffees. Are you ready to talk about some of the papers in today's issue? Dr Greg Hundley: You bet. Dr Carolyn Lam: Well the first paper I have really represents a novel gene therapy approach to atrial fibrillation. So doctors led by Dr Arora from Northwestern University Feinberg School of Medicine and colleagues used a novel gene therapy approach in a canine rapid atrial pacing model of atrial fibrillation to demonstrate that NADPH oxidase-2 or NOX2 generated oxidative injury by causing upregulation of a constitutively active form of acetylcholine-dependent potassium current, or IKH is an important mechanism underlying electrical remodeling in the fibrillating atrium. Dr Greg Hundley: Wow, Carolyn, very interesting. Tell us a little bit more about this gene therapy approach. Dr Carolyn Lam: They performed targeted expression of anti-NOX2 short hairpin RNA in the intact atria of the dogs, and then subjected those animals to rapid atrial pacing for a period of several weeks to months. The novel atrial gene therapy approach prevented the development of electrical remodeling and sustained atrial fibrillation thus demonstrating for the first time a clearer causative role for NOX2 generated oxidative injury in the creation, as well as the maintenance of electrical remodeling in atrial fibrillation. Furthermore, they demonstrate that a likely cellular and molecular mechanism by which oxidative injury created a vulnerable substrate for atrial fibrillation, the results of this study yield therefore valuable mechanistic insights into the pathogenesis of atrial fibrillation and have important therapeutic implications for this clinical management. Dr Greg Hundley: Very nice, Carolyn. We need more therapies for AFib. Boy, that's so informative. Well, the next paper that I have sort of merges the world of electrophysiology with the world of imaging and it comes to us from Dr Michela Casella from Centro Cardiologico Monzino. Among 162 consecutive patients, this study evaluated the combined utility of electroanatomic voltage mapping coupled with cardiovascular magnetic resonance imaging to guide endomyocardial biopsies. Dr Carolyn Lam: Oh, so interesting. A combined noninvasive and invasive electrical guide to perform cardiac biopsies, wow. So what did they find Greg? Dr Greg Hundley: So they found that the sensitivity of pooled electroanatomic voltage mapping and cardiovascular magnetic resonance was as high as 95%. EVM and CMR together conferred an endomyocardial biopsy positive predictive value of 89%. Endomyocardial biopsy analysis allowed to reach a new diagnosis different from the suspected diagnosis in 39% of patients, complication rates were low, mostly vascular access related, with no patients requiring urgent management. Most impressive for this manuscript are the illustrative figures that are provided. It's really a great article for those performing biopsies, doing imaging, or the EP procedures that guide the biopsy process. Dr Carolyn Lam: Really nice, Greg, thanks. Now for the last paper, have you ever thought about atherosclerosis as an autoimmune disease? Dr Greg Hundley: Well, I wonder, we're learning so much about our immune systems these days, perhaps. Dr Carolyn Lam: Indeed, throughout the inflammatory response that accompanies atherosclerosis auto-reactive CD4 positive T helper cells do accumulate in the atherosclerotic plaque. Apolipoprotein B-100 or Apo B is the core protein of LDL really serves as the auto antigen that drives the generation of pathogenic T helper one cells with pro inflammatory cytokine secretion. Yet there may also exist Apo B specific CD4 positive T cells with an athero protective regulatory T cell phenotype in healthy individuals. And that relationship between the protective Apo B reactive T regulatory cells and the pathogenic T helper one cells really has remained unknown until today's paper. And this is from Dr Ley from the La Jolla Institute for Immunology and colleagues is really the first report to characterize CD4 positive T cells recognizing Apo B in the mouse with a combination of a novel MHC II tetramer and single cell transcriptomics immuno receptor sequencing and functional evaluation, and their results demonstrated an unexpected mixed phenotype of Apo B reactive auto-immune T cells in atherosclerosis and suggest an initially protective auto immune response against Apo B with a progressive derangement in clinical disease. These findings really identify Apo B auto-reactive T regulatory cells as a novel cellular target in atherosclerosis. Dr Greg Hundley: Very nice Carolyn, boy that was a beautiful summary. I've got in the mail bag just a couple of things to talk about before you get to the discussion of some research letters. There's an ECG challenge from Dr Gunaseelan involving a young patient with chest pain. And then Theresa Wang has a very nice case series involving pulmonary hypertension, entitled Pressures at an All Time High. Dr Carolyn Lam: There's also an On My Mind piece by Dr Perman on overcoming fears to save lives. So COVID-19 and the threat to bystanders CPR in out-of-hospital cardiac arrest. There's a research letter by Dr Myhre on cardiovascular hospitalizations, influenza activity, and COVID-19 measures, another by Dr Gurbel on the first inhuman experience with inhaled acetylsalicylic acid for immediate platelet inhibition, the comparison with chewed and swallowed acetylsalicylic acid. A final research letter by Dr Zurek rounds us up regarding neuregulin one inducing cardiac hypertrophy and impaired cardiac performance in post myocardial infarction rats, very surprising because we thought this was protected. So there you have it for this issue, Greg, shall we go on to our future discussion? Dr Greg Hundley: Absolutely. Dr Carolyn Lam: In patients with heart failure, chronic kidney disease is really common and associated with a higher risk of renal events than in patients without chronic kidney disease. In fact, these renal events are really increasing in prominence in the heart failure literature. And so I'm really welcoming the discussion of today's feature paper, which looks at the renal effects of angiotensin neprilysin inhibition in patients with heart failure with preserved ejection fraction in the PARAGON trial. I'm so pleased to have with us the first and corresponding author of this paper, Dr Finnian Mc Causland from Brigham and Women's hospital, as well as our associate editor Dr Justin Ezekowitz from University of Alberta. Finnian, congratulations on this beautiful paper. Could you please tell us a little bit about the overview? What motivated it, what you found? Dr Finnian Mc Causland: It's long been a passion of mine to look at this interaction or intersection between cardiology and renal events. And if the truth be told, I had a moment in my life where I thought about being a cardiologist but I was swayed in other directions during my training in Ireland. Well, I've always been very much interested in this intersection, like I said, and so I've had the opportunity to work very closely with Scott Solomon and others at the Brigham who lead many of the heart failure trials that you are all aware of much more than I have been. And this particular subset of patients with heart failure with preserved ejection fraction is a very unique population that were studied in the PARAGON-HF trial. And we thought it was a unique opportunity to look at some of the pre-specified secondary end points, which were the renal outcomes in terms of trying to figure out what the effect of this was compared to valsartan therapy in this patient population. So I think looking at this intersection between heart failure and preserved ejection fraction and the deterioration of kidney function was the primary driver to look at this in the PARAGON heart failure trial, and to really look at the comparison between sacubitril-valsartan with valsartan in this patient population. Dr Carolyn Lam: Indeed, thanks so much Finnian, and here's a confession too. I really liked nephrology during my training. (laughs) I thought it was really cool and with all the interventions, and so I really admire the many things you think about, especially in these patients, who've got multisystem disease, but okay. Moving on with PARAGON, I know that the secondary outcomes were reported and it was really a striking effect on the renal events. And so glad that you're shedding more light in it. Could you tell us what this paper added? Dr Finnian Mc Causland: Yeah, so here we really got into I suppose the depths of the renal composite outcome and just to remind everybody that was a composite of a 50% or greater decline in eGFR, the development of end stage renal disease, or death from renal causes, so this was the composite outcome that was examined. We really evaluated this in a lot more detailed breaking our composite down into its individual components, as well as looking at it in totality. And I think the big take away point was that we found there was an almost 50% reduction in this primary renal composite outcome for patients on sacubitril-valsartan compared with valsartan. Dr Carolyn Lam: And what about the components and the sort of further analyses? Dr Finnian Mc Causland: Yeah, so getting into the, I suppose the details in a little bit more granularity, the major driver of those events will be 50% or greater decline in eGFR. And that's where the majority of these events really came from over the follow-up of PARAGON. And so this was assessed that various study business throughout the course of the few years that the patients followed up with PARAGON. And I think if we look at this slope and this was clarified in terms of the overall slope analyses of the eGFR. And we thought this relatively early separation in favor of sacubitril-valsartan so that there was less decline in eGFR over time compared with valsartan. So I think this was a supportive finding from the slope analysis that really got to this 50% threshold and that many people have examined in greater detail than they had the cardiovascular literature. So it takes a fair degree of kidney function decline to really reach that threshold of 50%. And so I think this was a very repulsed finding supported by the slope analyses. Dr Carolyn Lam: Yeah, and to the audience that's listening, you have to grab hold of figure three of this paper, and that shows the eGFR slopes, which is something that's I think really important in current heart failure literature, the concept of the eGFR decline. So really nice work. Congratulations again, Finnian. Justin, could you put these findings in context for us? Dr Justin Ezekowitz: Finnian once again, congratulations on getting this analysis. Pretty complex area to try to analyze and analyze properly, given that there's an expansive renal literature out there about looking at eGFR and how you look at it. So I think there's a couple of questions that come to mind when we think about the PARAGON trial overall. When we think about the protection of the kidneys over three, four, five years, my sense was from your analysis and perhaps you could expand on it is there seems to be very few events in those people with pretty preserved eGFR, but a greater number of events in those less than 60 mils per minute, and I'm wondering if you think that there's more of a unique place for medications such as sacubitril-valsartan and that cohort and if so is it really, that's where all the action is, but there's no real difference? Or do you think there's an interaction there that we should explore? Dr Finnian Mc Causland: Thinking back to the entry criteria for PARAGON-HF, one had to have an eGFR more than 30 mils per minute at baseline. And you had to go through this kind of complex running period where you didn't have elevations of creatinine or potassium that went inside the pre-specified ranges. So after you took that element of what many people would consider hemodynamic changes, acute hemodynamic changes out of it, you were left with participants who entered the double blind randomized period. And there, I think that's where again, we started to kind of see most of the end points in terms of follow-up, which again were mostly the eGFR decline. If you go to table two of the paper, you'll see the composite, the components of the renal composite broken out into those with eGFRs of less than 60 or 60 or greater at baseline. And even in both groups, I think you'll find that again they were both driven by the 50% decline, but you only really saw the end stage renal disease events or very few deaths from renal causes in those with eGFR of less than 60 mils per minute of baseline. And I think really what that speaks to is that these are the patients with quote unquote, chronic kidney disease at baseline are the ones who have that detrimenting kidney function to begin with. And so we're more likely to progress as we know than those with more preserved kidney function. And so if you followed patients both for really good kidney function over time, it's going to take a long time before they get that really severe decline due to the compensating mechanisms that the kidney has to preserve eGFR in the face of decline. So I think once you get into the more advanced disease, you really start to see the deterioration where there's very little renal functional reserve to cope with any additional damage or hemodynamic changes. So to me, it wasn't particularly surprising that that's where the action was. To answer your second point of should we be focusing therapy here? If you look at the median eGFR in the PARAGON heart failure study was around 63 mils per minute. So about half of these patients I suppose could be classified as having impaired kidney function. If you look at it by CKD criteria it's eGFR of less than 60. And so I think there's a huge opportunity there to really think about this population in terms of trying to look for interventional studies and potentially protect patients as we've seen with this molecule, and but also with others such as SGLT-2 inhibitors, what I'm really intrigued about is if this was persistent at eGFRs below 30, because of course, one of the most devastating icons for patients with kidney disease that we deal with is the development of end stage renal disease and those who go on to hemodialysis. So if there was some mechanism to prevent those even higher risk patients from progressing, I think that would be a huge opportunity for further research in this area. Dr Justin Ezekowitz: Thanks for that very complete and thorough answer Finnian, and that actually maybe leads to putting this in context for the majority of people who will read Circulation and the audience will most likely be cardiovascular specialists and understand a lot of what you said, but could you put this in context with other studies that really are nearby to this trial, such as CREDENCE where the eGFR slope might be slightly different, or even the UK HARP-III trial where the same molecule was used, but in a different population, I wonder if you could give us some context for these findings. Dr Finnian Mc Causland: Sure, yeah. I mean, I think the UK HARP-III trial maybe is the first one to discuss since this was a comparison of sacubitril-valsartan versus irbesartan. This was a study performed in the United Kingdom and they recruited patients with chronic kidney disease, a small proportion of those patients had heart failure, but this was not any of the pre-specified entry criteria for this study. And their primary outcome was the change in measured glomerular filtration rate after 12 months. And really they found that there was no significant difference at the 12 month mark between sacubitril-valsartan versus irbesartan. And so we were asked a similar question when we presented this study in abstract form at the American Society of Nephrology meeting in Washington last year. And I think a lot of the differences potentially relate to the difference in entry criteria for the patients. But also one might argue that 12 months of follow-up may not have been enough to see these differences in eGFR slope, which tend to occur, I suppose, rather later in the course of progressive kidney disease and heart failure. And so that may be part of the reason that we didn't see the differences with UK HARP-III. In terms of CREDENCE, obviously it's a different molecule. And if you look at our main eGFR decline over time in PARAGON-HF, it was around 0.7 mils per minute, per 1.7, three meters squared per year. And so this compares with the about 1.5 mils per minute in CREDENCE, remember CREDENCE recruited patients with chronic kidney disease. PARAGON-HF recruited patients with heart failure and preserved ejection fraction. So differences in terms of the inclusion criteria right off the bat. I think other big differences where the CREDENCE compared, and it kind of flows in versus placebo, there was an active comparator in PARAGON-HF in terms of it was sacubitril-valsartan versus valsartan. So we saw differences in eGFR slope, despite an active comparator, I think was also quite telling and that there appears to be some additional renal benefit in the additional sacubitril versus blast inhibition alone. And so I think the mechanisms is a whole other area, right? For research, I don't think we're entirely clear of the underlying mechanisms of this potential renal benefit, but I think we're pretty excited in the kidney community. Where now we have several molecules that may have potential to slow kidney functional decline, SGLT-2 inhibitors being one class potentially sacubitril-valsartan in another, and the top line results from their number are just out as well. And so there's ongoing trials that are looking at kidney function outcomes there. So we're getting pretty excited and we're not quite as jealous of the cardiology community as we used to be. Dr Carolyn Lam: I couldn't think of a better way to summarize those findings and to put it into context of other very hopeful medications for the cardio renal outcomes. Thank you so much Finnian for joining us today and for publishing such a great paper with us at Circulation. And thank you, Justin, for your perspectives. Dr Justin Ezekowitz: Thanks Carolyn, and Finnian congrats to your team as well. This has been a terrific paper to be able to handle and read and look at figure three, and it tells a lot of the story of what you saw. Dr Finnian Mc Causland: Thank you very much again for the opportunity and a big shout out to everybody that worked in PARAGON-HF and especially to the support from Scott Solomon and John McMurray for getting me involved. It's a pleasure to be part of this. Dr Carolyn Lam: Thank you so much from Greg and I for joining us today, tune in again, next week. Dr Greg Hundley: This program is copyright of the American Heart Association 2020.

In this episode, Scott Solomon, Ankeet Bhatt, and Orly Vardeny discuss the intersection of influenza and cardiology and why cardiovascular practitioners should be concerned about influenza, particularly in the era of coronavirus disease 2019. Visit the Taking the Lead: Flu and Cardiovascular Disease hub for more information and resources.

Chime in to listen to a conversation with Dr. Scott Solomon, Evolutionary Biologist at Rice University, about our beliefs on the evolution of homo sapiens and biology on Mars. In this episode we discuss the following topics: Physiological challenges and mutations for long-term missions on Mars Tendencies and preferences of early settlers Biological Implications for cosmonauts and policymaking Significance of Digitalized Genomes, CRISPR/Cas9 Epigenetic Engineering, Quantum Tunneling, Medical wearables, Fitbits, and Brain-Machine Interfaces on Mars Settlement and Exploration Guest: Dr. Scott Solomon, Evolutionary Biologist and Professor at Rice University https://solomon.rice.edu/ TEDx Talk on Evolutionary Biology on Mars Evolutionary Biology on Mars | Scott Solomon | TEDxUniversityofHouston 60 Seconds on Space/Mars ESA: Human Urine to Make Concrete on the Moon Plan to Build One Starship a Week Fruitfly-sized Nano cardboard could monitor resources on Mars Elon Musk and SpaceX to Launch Next Gen of deep space telescopes --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/frontierspace/support

Are we still evolving? If we are evolving what factors do you look at in people to determine if we are still evolving? What historical trends are likely to continue? Why can single-celled organisms evolve so much quicker or mutate at least? Is a mutation an evolution?Scott Solomon is a biologist, professor, and science communicator. He teaches ecology, evolutionary biology, and scientific communication as an Associate Teaching Professor at Rice University in Houston. He has a Ph.D. in Ecology, Evolution, and Behavior from the University of Texas at Austin where his research examined the evolutionary basis of biological diversity in the Amazon Basin. He has taught field biology at Rocky Mountain Biological Laboratory in Gothic, Colorado and developed a complete digital lecture series on the modern science of evolution with The Great Courses. Before coming to Rice, he worked as a visiting researcher with the Smithsonian Institution in Washington, DC and São Paulo State University in Rio Claro, Brazil. His current research examines the interactions between native and non-native ants, the impacts of extreme flooding on ant communities, ant foraging behavior, and the co-evolution between ants and microbes. He is currently a member of the Editorial Board of the Journal of Tropical Ecology. Dr. Solomon often speaks and writes about science at schools, museums, churches, science cafés, TEDx events, and other venues and has appeared on radio broadcasts on NPR and the BBC World Service and television series such as NASA's Unexplained Files and Life 2.0. His writing and photography have appeared in publications such as NBC News, Slate, Aeon, Nautilus, and Wired and his first book, Future Humans: Inside the Science of Our Continuing Evolution was published by Yale University Press and was included on the 2017 Best Book List by the American Association for the Advancement of Science (AAAS).Of course, our conversation was heavily oriented around COVID-19. Because COVID-19 is a virus it is a unique parasite that can only be combated with a vaccine. YES A VACCINE! Scott brings a wealth of knowledge to the show and we explore the evolution of viruses, humans and why we humans are a prime target for these diseases.The Evolution of Viruses and Infectious DiseasesConnect with ScottTwitterWebsiteWatch his TedTalkGet Your Bus Merch HereSupport us on PatreonWe offer tons (yes tons!) of extra content for as little as $2 - including an extra ad-free podcast each month. Your support keeps us going and growingGet the Patreon Benefits!I created The Bus Driver Experience as a way to gain a new perspective from the unique lives of other people - Olympic athletes, monks, porn stars - to not just learn, but EXPERIENCE what it's like to be in their shoes for a day.And do it in a way unlike how every other travel/interview show does it. Most other shows merely talk with these individuals.But talking with these people isn't enough for me.I want to live their unique story. To understand not only what they go through in their day to day, but also why they're doing it. Follow me on YouTube for videos of the experiences with my guests, and other content.For media and collaboration inquiries, or more on the show, contact me by email or visit my website. Our GDPR privacy policy was updated on August 8, 2022. Visit acast.com/privacy for more information.

Dr Carolyn Lam: Welcome to Circulation on the Run, Your Weekly Podcast Summary and Backstage Pass to The Journal and its Editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, this issue is full of super interesting papers, many of which were presented as late-breaking presentations at the American Heart Association, like the feature paper that sacubitril/valsartan across the spectrum of ejection fraction in heart failure, where this was really analyzed across the landmark PARADIGM and PARAGON trials. I'm sure everyone's looking forward to hearing about it, but before we talk about that, I want to share some more very interesting results from a very important trial, the REDUCE-IT trial. So, as some background, some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. And this was the reason that there was a pre-specified subgroup analysis of the REDUCE-IT trial, which really is the reduction of cardiovascular events with icosapent ethyl-intervention trial, and this analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. So, Greg, do you remember what the REDUCE-IT trial was about? Dr Greg Hundley: Well, Carolyn, I think REDUCE-IT randomized 8,179 statin-treated patients with triglycerides between 135 and 500 milligrams per deciliter and LDL cholesterol levels between 40 and 100 milligrams per deciliter and a history of atherosclerosis or diabetes to Icosapent Ethyl, four grams per day or placebo. And the primary endpoint, I believe, was cardiovascular death, nonfatal myocardial infarction, non-fatal stroke, coronary revascularization or hospitalization for unstable angina. Hah! Dr Carolyn Lam: Wow, Greg, you pass that quiz, like maybe you had a cheat sheet answer. Dr Greg Hundley: All right, Carolyn, tell us now what did REDUCE-IT USA find? Dr Carolyn Lam: This was from a corresponding author, Dr Deepak Bhatt, from Brigham and Women's Hospital Heart and Vascular Center, and his colleagues and they found that in the United States Icosapent Ethyl at four grams a day produced large and significant reductions in multiple ischemic endpoints including cardiovascular death, myocardial infarction, stroke, coronary revascularization, and hospitalization for unstable angina. Furthermore, REDUCE-IT US demonstrated that Icosapent Ethyl provided a statistically significant 30% relative risk reduction and a 2.6% absolute risk reduction in all-cause mortality. The risk benefit profile of Icosapent Ethyl was highly favorable with an overall safety and tolerability profile virtually identical to placebo. Dr Greg Hundley: Wow, Carolyn. So, this does have important implications for us in the US, very nice. Thank you for that lovely quiz. So, Carolyn, I'm going to switch now and talk about a paper from Roddy Walsh from Amsterdam in the Netherlands. In this study, the investigators defined the frequency of rare variation in 2,538 patients with dilated cardiomyopathy across protein-coding regions of 56 commonly tested genes and compared this to both 912 confirmed healthy controls and a reference population of 60,706 individuals to identify clinically interpretable genes robustly associated with dominant monogenetic dilated cardiomyopathy. Dr Carolyn Lam: Wow, wow. That's a huge study. So what did they find? Dr Greg Hundley: Okay, Carolyn. So overall rare variants in 12 genes potentially explain 17% of cases in the outpatient clinical cohort representing a broad range of adult patients with dilated cardiomyopathy and 26% of cases in the diagnostic referral cohort enriched in familial and early onset dilated cardiomyopathy. And so, practically speaking, by analyzing two dilated cardiomyopathy cohorts with distinctive patient profiles, the authors were able to comprehensively evaluate the genetic basis of dilated cardiomyopathy and identify variant classes that were particularly associated with early-onset disease. By restricting analyses to validated and interpretable genes and variant classes, the authors hoped in this study to increase the accuracy and reduce the uncertainty associated with genetic testing in dilated cardiomyopathy. Dr Carolyn Lam: Very nice, very practical information. Well, my next paper is, I have to admit a super favorite topic of mine, and that is sex differences in heart failure. Now as a reminder to everybody, women represent over half of patients with heart failure with heart failure preserved ejection fraction, and there are multiple effective drug and device therapies for HFrEF, or heart failure reduced ejection fraction, but none approved for HFpEF. Thus, there is a greater so-called failure therapeutic deficit in women compared to men. So, does the recently presented PARAGON trial provide answers? Dr Greg Hundley: Ah, Carolyn, you were involved in the PARAGON trial. Maybe tell us a little bit about that first to help us get oriented. Dr Carolyn Lam: I would love to. So PARAGON compared sacubitril/valsartan with valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes, and the trial overall narrowly missed this primary outcome. However, an intriguing result in PARAGON was a significant sex-by-treatment interaction. And this was explored further in the current pre-specified subgroup analysis of outcomes by sex, which was reported by John McMurray from University of Glasgow and his colleagues. Dr Greg Hundley: Ah, so I'm interested. What was this interaction? Dr Carolyn Lam: Ah, so here is how the interaction work. Now, remember this was multi-variably adjusted significant in a pre-specified large subgroup of PARAGON. And what we found was that as compared with valsartan, sacubitril/valsartan seem to reduce the risk of heart failure hospitalization more in women than in men. Now, while the possible sex-related modification of this effect of treatment has potential explanations, the current study really cannot provide a definitive mechanistic basis for this finding. Dr Greg Hundley: Very interesting. So, perhaps then, in heart failure preserved ejection fraction, sacubitril/valsartan could be very helpful in women. Dr Carolyn Lam: Yes, and perhaps especially those with each ejection fraction in the lower ejection fraction range. And that is coming up in our future discussions, so let's not preempt it. You got another paper, Greg? Dr Greg Hundley: Absolutely, Carolyn. My next paper is from Professor Irene Lang at the Medical University of Vienna, and it's related to microvascular disease and chronic thromboembolic pulmonary hypertension and hemodynamic phenotyping and histomorphometric assessments. So, Carolyn, pulmonary endarterectomy is the gold standard for treatment of patients with operable chronic thromboembolic pulmonary hypertension. However, persistent pulmonary hypertension after PEA or endarterectomy remains a major determinant of poor prognosis. Dr Carolyn Lam: Ah, so are there any possible solutions to this? Dr Greg Hundley: Well, Carolyn, today it is thought that a concomitant small vessel arteriography in addition to major pulmonary artery obstruction may play an important role in the development of persistent pulmonary hypertension and survival after pulmonary endarterectomy. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence severity of small vessel arteriopathy. Dr Carolyn Lam: Huh, that makes a lot of sense. So what did the authors do? What they find? Dr Greg Hundley: Okay. Well, Carolyn, they had 90 patients with 49 of them receiving lung wedge biopsies for validation. So, in analyses incorporating receiver operating characteristic curves, pulmonary vascular resistance measures and larger arterial upstream resistance beds predicted persistent pulmonary hypertension after pulmonary endarterectomy, and certain values identified patients with poor prognosis after endarterectomy. Therefore, perhaps this form of analysis could be helpful in establishing prognosis in these patients and perhaps suitability for future interventions. Dr Carolyn Lam: Wow, very interesting. Well, we were saying this issue's full of very important papers, and that also includes research letters. There's a research letter by Dr Cannon talking about evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with an HbA1c less than 7%. And these are very interesting results from the CREDENCE trial that was also presented at the American Heart Association. There's a research letter by Dr Jackevicius on the population impact of generic valsartan recall in Ontario, Canada, that really highlights the potential burden and risks associated with recalls of chronic oral medications used by large populations. And in Cardiology News, Bridget Kuehn talked about cardiovascular risk biomarkers, high-sensitivity cardiac troponin T and NT-proBNP and talked about how these two biomarkers may help clinicians stratify which patients may benefit the most from therapies for hypertension or diabetes. And this was according to a pair of studies presented, again, at the American Heart Association. Dr Greg Hundley: Well, Carolyn, that's quite a nice review. I've got just a couple more papers to discuss. There's a perspective piece from Dr Ben Levine and colleagues from UT Southwestern that discusses whether a simple physical exam and maneuvers could actually supplant tilt-table testing. He provides arguments as to whether we should continue with tilt-table testing given the high rate of false positives. And then lastly, from the Mailbag, Dr Shuyang Zhang from Peking Union Medical College Hospital and the Chinese Academy of Medical Sciences provides a letter to the editors regarding a prior publication on the clinical applicability of the awareness of androgen-deprivation therapy's effects on ventricular repolarization. And Dr Joe-Eli Salem from Vanderbilt University provides his response. Well, Carolyn, how about onto that feature? Dr Carolyn Lam: Let's go. Our feature discussion today is all about left ventricular ejection fraction. Ah, that measure we both love and hate in the world of heart failure, I think. And this paper is truly remarkable, in my opinion. It is the look at the effect of sacubitril/valsartan across the spectrum of left ventricular ejection fraction in the PARADIGM and PARAGON trials. And I'm just so pleased to have none other than the first and corresponding author, Dr Scott Solomon, from Brigham and Women's Hospital and Harvard Medical School, as well as our Senior Associate Editor, Dr Biykem Bozkurt, from Baylor College of Medicine as well. Scott, could you start by telling us about this analysis and why the opportunity to do such a special analysis in this paper? Dr Scott Solomon: This was a really fantastic opportunity because, as you know, we did these two trials, PARADIGM and PARAGON, not at the same time but essentially in series. PARADIGM was a trial of patients with heart failure reduced ejection fraction, so ejection fraction of 40%, and PARAGON was a study of patients with heart failure with preserved ejection fraction. And the interesting thing is that, with the exception of ejection fraction, the criteria for enrolling patients in these trial was virtually the same. In other words, we enrolled patients with signs and symptoms of heart failure, some elevation in natriuretic peptides, and we followed them. So it's really an extraordinary dataset of 13,195 patients in whom we can look at heart failure across that full spectrum of ejection fraction. We haven't been able to do this really since the CHARM study, which enrolled about 8,000 patients across the spectrum of ejection fraction. And it gave us an opportunity to look at a number of things including the effect of sacubitril/valsartan across that full spectrum of ejection fraction. Dr Carolyn Lam: Great. And, Scott, you want to tell us what you found? Dr Scott Solomon: When we pooled 13,195 patients, and by the way, this was a pre-specified analysis that we had decided to do prior to unblinding PARAGON. We see that if we put them all together, all these patients together, and just treat them as one group, we see that for every endpoint that we looked at, whether heart failure, hospitalization and cardiovascular death, cardiovascular death, all-cause mortality, whether we look at the time to first event endpoints or the total number of heart failure hospitalizations, we see a significant benefit in patients receiving sacubitril/valsartan compared to patients receiving either enalapril in the PARADIGM study or valsartan in the PARAGON study. Now, what we also saw though, and this is probably most important, is that there appears to be an attenuation of the treatment effect as ejection fraction rises. Now we know that patients with higher ejection fractions tend to have a lower frequency of these events such as heart failure, hospitalization and cardiovascular death. But we also see here that as ejection fraction goes up that the benefit of sacubitril/valsartan appears to wane, especially when you get over about 60, an ejection fraction of about 60%. We've looked at this in categorical ways and also looking at a continuous spline analysis throughout the entire spectrum. Dr Carolyn Lam: Yeah, I love that, and I just need to point every listener right now to figures 3 and 4 of your paper. I have a feeling we're going to be seeing these figures in a lot of talks and cited everywhere. Biykem, could I bring you in on this? What are the implications of something like this? Dr Biykem Bozkurt: The interesting findings from the pooled data are, first, support of what we had seen in PARADIGM, meaning the lower the EF, the more the benefit or the higher the benefits. And as we had seen in PARAGON, which did not show an improvement in the combined endpoint with treatment with sacubitril/valsartan in patients with heart failure with preserved ejection fraction. In the pooled analysis as the EF got higher, there didn't seem to be any benefit, but the interesting, perhaps group of patients that the pooled analysis allowed us to have a deeper dive into was heart failure with mid-range EF. And we can crudely perhaps define this as ejection fraction between 40 and 50%. And by certain analyses, which again this is in the post-hoc and also in a continuous analysis and a specific analysis and a cubic spline analysis, it appeared that the benefit extended into those individuals with mid-range ejection fraction. Again, we need to keep several points in consideration. One is ejection fraction can vary over time and is not a very precise measurement. There's definitely inter-reader as well as intra-reader variability and is not a good mayor of contractile performance. And we tend to actually have a significant amount of a specific infiltrative cardiomyopathies in that EF range, which tend to be excluded from usual clinical trials. And with that caveat, having kept this in mind, it's also important to recognize from cohorts and population-based studies, about 10 to 20% of our patients currently reside in that have HeFmrEF or heart failure with mid-range EF status. And thus the findings are intriguing, hypothesis generating and also encouraging that we may see perhaps benefits with RAS antagonism in individuals that do have LV systolic dysfunction. And probably, if this is persistent and a clear reflection of a phenotype that reflects itself as reduced ejection fraction, probably the patient may benefit. Again, these results may need to be supported by future studies, and also we need to keep in mind that infiltrative cardiomyopathies, such as amyloidosis or sarcoidosis or others, were not included in these studies. Dr Carolyn Lam: Thank you, Biykem. Go ahead, Scott. Dr Scott Solomon: Carolyn, I agree with many of Biykem's points. I think that this middle range, and you and I kind of coined that term, heart failure with mid-range injection fraction, a number of years ago. The problem, of course, is knowing where that range exactly is, and I think that some people believe it's 40 to 50%, but we know that these are very arbitrary cutoffs. The data from the pooled analysis in PARAGON, in particular, do suggest that the patients who have evidence of some degree of left ventricular dysfunction seem to benefit from sacubitril/valsartan. Now, this is not a completely novel finding because we saw that in patients who received candesartan in the CHARM study and in patients who received spironolactone in the TOPCAT trial that the greatest benefit was observed in the patients in that middle range of ejection fraction, again, below what we would normally consider the normal range. Normal might be 55% or 55% in men and women. And that gets me to the other thing that I think is really worth mentioning here, which is that we found that the range of benefits does vary by sex, so that women seem to derive greater benefit to a higher ejection fraction than men. We can see that here in figure 4, looking at these two curves that there really does appear to be a difference between men and women. Women overall derive greater benefit in the PARAGON study, it appeared than in men. So I think that the fact that there's biologic plausibility here that patients with cardiac function that is not normal seem to benefit from therapies that we know benefit patients with heart failure with reduced ejection fraction, that patients with ejection fraction that was in this middle range also do appear to benefit from sacubitril/valsartan as we think they did in other studies of other agents that we know work in patients with lower ejection fraction. Dr Carolyn Lam: Indeed, Scott. You've just pointed out my favorite figure of all, that figure 4. You know how I feel about sex differences and pointing them out. I would love to ask for Biykem's thoughts on it. But in the meantime, just to emphasize how important findings like these are because it makes us question the cutoffs that we use to define heart failure groups, makes us question is midrange more mildly reduced ejection fraction like we're also writing about. And I think really makes us question, for example, the 2016 ESC Guidelines that say that mid-range ejection fraction should be treated like preserved ejection fraction. Well, maybe this could be really game changing here in that we actually think now this group should be treated more like reduced ejection fraction. So, really, congrats on this incredible paper. Biykem, what do you think of those sex differences? I have to point out, I love your editorial, which everyone should read. Dr Biykem Bozkurt: It's very intriguing, very interesting point. The benefits from sacubitril/valsartan was interestingly similar for both sexes at lower EF levels. Women's benefit compared to men's benefit for low EF was comparable; they were not different. But women seem to confer a benefit at higher EF ranges and by this continuous analysis all the way up to the 50 to 60% range, which is very, very interesting. And as to what were the phenotypes of the women compared to men at that range, women were older, had more obesity, less CAD, and of course, at all ranges they usually tend to have a higher baseline EF. And, interestingly, even though we may state that maybe women may have more systolic dysfunction at higher EF quantification ranges or may have a different phenotype than men for HFpEF, maybe a more clear or pure heart failure phenotype, heart failure with preserved EF phenotype than men. The interesting things were the NT-proBNP levels were lower for women, though the symptoms were a little bit higher, and the benefit seemed to be higher even though the KCCQ scores were not different. So, even though we did have lesser sort of filling pressures for women and perhaps other surrogates for improvement did not seem to differ, and also biological metabolites, such as urinary cyclic GMP to creatine ratios, were not different in women. So, if we were to think of whether there were biological differences, whether there were differences in NT-proBNP levels or delta changes over time or the urinary cyclic GMP levels, they were not different in women versus men. So, we still have many other substrates for neprilysin. I mean there could be other substrates, such as adrenomedullin or bradykinin or substance P that may be differentially metabolized for women compared to men, and we don't have the data on those. But again, it's very interesting to see this upper scale of EF benefit being higher in women compared to men. So, we don't have any other either biological or other surrogate markers for benefit for women, either for the HFpEF or HFrEF being than different than men. Dr Carolyn Lam: Biykem, I just love the way you so carefully dissected that, and it's so reflected in that editorial that you and Justin Ezekowitz wrote entitled Substance and Substrate. So I'm going to make sure all readers look for it. We could go on forever. I mean I just was struck, that figure 4, also is really similar if we look at what normally ejection fraction is for women versus men with increasing age. We also see that women are supposed to have higher ejection fractions as they age compared to men at any age. So it's just intriguing to me, but you're right. I think hypothesis generating. Scott, I'm going to give you the last word. Dr Scott Solomon: I'm pretty confident that there are biologic differences between men and women. I just don't necessarily know what they are with respect to heart failure, preserved ejection fraction, but I think we're going to be spending a lot of time and effort trying to sort this out. We're pretty confident that the finding of a weighing of benefit with ejection fraction is a real one and that the benefit in this middle range is an important one to pay attention to because I agree with what you said, Carolyn. If we had been thinking about heart failure with reduced ejection fraction as something that went up to a higher level 25 years ago, we would probably have treated a lot more patients with therapies that we now know to benefit patients with heart failure with reduced ejection fraction. So, I think this data helps us rethink how we parse up heart failure and hopefully, ultimately will lead to changes how we treat patients. Dr Carolyn Lam: Well, listeners, you heard it right here on Circulation on the Run. Thank you so much, Scott and Biykem, for joining us, and don't forget to tune in again next week. Dr Greg Hundley: This program is copyright The American Heart Association 2020.  

On today's episode we have our first interview with Scott Solomon who presents his idea on how to initiate and incentivize a global wealth tax. Considering the kind of capital that will be needed to combat climate change, workable solutions for raising that kind of capital could not come at a better time. 

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts of Circulation on the Run and if you don't know what this show is about, well, you have to listen to the previous episodes in January please.                                 I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Greg Hundley:   I'm Greg Hundley from the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: So Greg, before we pick up our coffees and begin discussing a couple of the paper, let's just tell everyone that this feature paper, they have to listen to because it is the results of the cardiac amyloidosis section, or sub-set of the APOLLO study. Have to listen to this one. But how about the other papers in today's issue Greg? Greg Hundley:   Right Carolyn, the first one I'm going to start with is from Alexander Fanaroff at Duke University and the DCRI. And basically, this particular paper was looking at the procedural volume and how that might affect outcomes with those that are performing PCI. So they divided the cohort into those individuals that had less than 50 PCIs per year, 50 to 100 and then greater than 100 PCIs per year. So, this is looking at our national cardiovascular data registry within the United States, and of course, as you know, that's linked to Medicare claims data for those that are over 65 years in age. So they had 723,644 PCIs performed by 8,936 operators. And the surprise in this study was that those low volume operators, less than 50 PCIs per year had a one year rate of 15.9% of MACE as opposed to those that were high volume operators that had 16.9% MACE rates. That was significant at a P value of .004. Dr Carolyn Lam: Wait a minute, this seems different from prior reports. Are you saying that those with low volume operators actually had lower mortality? Greg Hundley:   Yeah, exactly. And you've pointed out something, cause previously what's been shown is that high volume operators have lower 30 day and in-hospital mortality rates. And that was actually confirmed in this study. But out of a year it was really the low volume operators in unadjusted results had lower rates of all MACE.                                 A very nice editorial by Dharam Kumbhani from UT Southwestern points out that high volume operators do tend to take on more serious cases, those with higher numbers of cardiovascular risk factors. And so, when they did adjustments and accounted for all those risk factors, actually the event rates were the same. Still though, they're the same. And so what could be going on? And the editorialist and also the authors of the paper point out, "Hey, maybe we shouldn't just be focusing on PCI volume per operator, but other quality metrics to look at outcomes. And so this really builds in to the whole quality discussion. Adherence to therapy with the patients in your health care system. What about operator longevity? An operator that may have been doing this for 10 years but has a lower volume, maybe that could come into play. So future studies I think, certainly all over the world in this field, this paper's going to direct us to focus more on other quality issues and not just procedural volume. Dr Carolyn Lam: So, quality versus quantity. Interesting.                                 Well switching gears to a paper that I thought was nice, it is from Dr Lubitz from Massachusetts General Hospital in Boston and colleagues, and they sought to answer the question of whether refining a phenotypic classification of heart failure would facilitate genetic discovery. So, to do that, they defined all cause heart failure among almost 500,000 participants in the UK bio-bank and performed a GWAS study and then later refined the heart failure phenotype by classifying individuals with left ventricular dysfunction but without coronary artery disease as having nonischemic cardiomyopathy and then repeated the GWAS. And basically they found that the GWAS in the all cause heart failure yielded multiple genetic signals for known heart failure risk factors, such as coronary artery disease and atrial fibrillation.                                 However, after refining the heart failure phenotype to a nonischemic cardiomyopathy sub-set, this enhanced the detection of genetic loci associated with dilated cardiomyopathy, which appeared to operate independent of the traditional heart failure risk factors. So that was pretty interesting. Greg Hundley:   So where do we go from here with that Carolyn? I mean, what is this telling us and how are we going to move forward with this information? Dr Carolyn Lam: I think the clinical implications are first that common genetic variants associated with both clinical and sub-clinical heart failure, because they looked at left ventricular dysfunction, these genetic variants may be leveraged to improve heart failure risk prediction and prevention. But obviously future studies are warranted to investigate the prognostic and therapeutic implications of these findings. Greg Hundley:   Very good. Well I'm going to take us back into the cath lab again and we're going to address fractional flow reserve. And remember, typically, we get fractional flow reserve measures using guide wires, and that's kind of a tough thing to do sometimes in terms of adding links to the procedure, etc. So what these investigators did, they had 10 centers in the United States, Europe and Israel. And this was William Fearon from Stanford University who did this study. And they looked at 301 subjects and they had 319 evaluable vessels. Now what did they compare? They looked at guide wire derived fractional flow reserve versus angiographic derived. Simply, just when you're doing the injections, looking at how quickly that contrast flows down the coronary arteries.                                 And so, in this study the mean fractional flow reserve value was 0.81 and 43% of the vessels they studied had an FFR less than or equal to that magic number of 0.8. Interestingly, the angiographic obtained FFR measures were 94% sensitive and 91% specific for identifying the guide wire derived FFR. That's really incredible. And importantly, the accuracy of this contrast measure was 87% for FFR values between 0.75 and 0.85, that magical threshold. Dr Carolyn Lam: Well that is impressive, suggesting that we don't need guide wires. I mean, is that true for all patients? All vessels? Greg Hundley:   Right, so that's sort of the kick here, this is really interesting new data but let's look at the patients that they studied. First of all, they were relatively stable I would say. They had either angina or maybe even unstable angina and non-ST elevation MIs. But no ST elevation MIs. The average stenosis by angiography that they looked at was about 63% and then, very importantly, you have to look at the exclusion criteria. So things that, other conditions within the heart that are going to impact FFR were excluded. So, all their patients had an EF greater than 45%. Nobody had a CABG. Nobody had a chronic total occlusion. Nobody had a heart transplant, aortic stenosis, no heart valve surgery, no left main. It couldn't have had a recent stent within 12 months. It couldn't have had severe diffused disease, no collaterals, no in-stent thrombosis or stenosis. So this technique I think could be useful when you've got that patient perhaps with stable angina, single vessel disease, stenosis severity of 50 to 60% and none of these other conditions, preserved EF etc. But for many of the patients that we send to the cath lab, this technique, we still need a little bit more development. We don't know its utility. You've got another paper? Dr Carolyn Lam: I've got another few papers because I'm going to drag you out of the cath lab right now and into the ICU. And we're talking about cardiogenic shock and it's really nice that we have these three papers in today's issue. One's an original paper and two are On my Mind articles. Now the original paper talks about the randomized shock cool trial. This is from Dr Thiele from the heart center Leipzig in University Hospital in Germany. And it is an un-blinded, randomized trial of 40 patients with cardiogenic shock undergoing primary percutaneous coronary intervention. And without a classical indication from mild therapeutic hypothermia, but randomized one-to-one to mild therapeutic hypothermia for 24 hours versus control. And basically the mild therapeutic hypothermia did not show a substantial beneficial effect on the primary outcome of cardiac power index at 24 hours or on any other of the hemodynamic parameters. And there was also no difference in the short and long term outcomes. So a neutral trial.                                 But taking a step back and just talking about these patients with cardiogenic shock and all the different ways that we have now to keep them alive, I really want to highlight these two On My Mind papers. One is by Drs Gill, Grunau and MacRedmond from University of British Columbia. And they really talk about the need to define limits for extracorporeal cardiopulmonary resuscitation. In a very similar vein, Drs Mulaikal, Nakagawa and Prager from Columbia University also wrote a beautiful piece on ECMO, ECMO as a bridge to no recovery. And when is enough enough? So really, really interesting conversations and discussions regarding what is death, when do we have to put a time limit perhaps to these therapies? And yet not limit the potential life-saving effects of these. I really strongly encourage our listeners to read these papers and also to stay tuned because coming right up, a very important paper on the APOLLO study in our feature discussion.                                 For today's feature paper we're discussing the results of a sub-study of the APOLLO study. Now this deals with cardiac amyloidosis, a super, super hot subject. And we have super, super hot guests today on the show. The first our corresponding author, doctor Scott Solomon from Brigham and Women's Hospital as well as our associate editor doctor Justin Ezekowitz. Welcome both, and let's just plunge straight into it. So Scott, tell us, tell us about this APOLLO sub-study. Scott Solomon: APOLLO is a study of patients with hereditary transthyretin amyloidosis and, as you know, that hereditary transthyretin amyloidosis is an inherited disease caused by mutations of the transthyretin gene and these mutations cause the transthyretin protein to misfold and then accumulate as amyloid fibrils which go to the nerves and go to the heart. And we know that this can cause severe polyneuropathy and cardiomyopathy, partly depending on which mutation the patients have. And we, as cardiologists, are aware that when amyloid infiltrates the heart it can increase cardiac wall thickness, it can cause increase in chamber stiffness, it can result in severe diastolic dysfunction and these patients, often with cardiac involvement of amyloid, have a really markedly reduced life-span and really poor quality of life.                                 The APOLLO study was a study of a new agent that is designed to reduce transthyretin, it's a transthyretin knock-down agent. It's basically an RNAi therapeutic, it basically is a small, interfering RNA that basically blocks the production of transthyretin and this is one of several approaches that are currently being considered for amyloid disease. And APOLLO is primarily designed as a study to look at neuropathy. The primary end-point was a neurologic scale to look at neuropathy, but it was also designed to secondarily look at some cardiac end-points, especially in the patients who were felt to have cardiac involvement. Dr Carolyn Lam: Cool. And so your current paper deals with that cardiac amyloidosis sub-set, but it was pre-specified, it was planned, right? Scott Solomon: Yeah, it was a pre-specified sub-group. In fact, what we did is we actually did echocardiograms on everybody in the study and then defined a pre-specified cardiac sub-population that was comprised of patients who had a very high likelihood of having cardiac amyloid involvement, and so this was patients who had a baseline left ventricular wall thickness of 13mm or greater and no history of either aortic valve disease or hypertension. And so this was a group that we thought most likely had evidence of cardiac involvement. And just so it's clear, we did echocardiography on everybody in the study and in this paper we reported in both everybody and in the pre-specified cardiac sub-population. So we looked a number of things in these patients including various measures of cardiac structure function including wall thickness, left ventricular mass, ejection fraction, cardiac output, atrial size, volumes and myocardial strain which, as you know, has been particularly useful in assessment of patients with amyloidosis. And we also looked at reduction or improvement in Anti-proBNP which, as you know, is a very good measure of the severity of heart failure in patients.                                 And so, of the 225 patients who enrolled overall in the APOLLO study, 126 were part of this pre-specified cardiac sub-population. And in this group of patients, we've observed a reduction in left ventricular wall thickness of about a millimeter. And this was statistically significant in the patients who were treated with patisiran compared with placebo. We also saw an improvement in global longitudinal strain and improvement of cardiac output and an increase of left ventricular end-diastolic volume. In this case an increase in end-diastolic volume is actually a good thing because these patients often start out with smaller end-diastolic volumes because of the increased wall thickness. Those improvements in echocardiography were really paralleled by dramatic improvements in Anti-proBNP and we started out with patients with abnormal Anti-proBNPs in the range of about 800. These were significantly reduced, highly significantly reduced with a P value of about seven times 10 to minus eighth at both nine and 18 months, so pretty dramatic relative reduction in Anti-proBNP in the patisiran group compared to placebo. Dr Carolyn Lam: Super exciting, and it really adds to mounting evidence isn't it? That we're sort of reaching a really effective treatment for these patients and who knows how common they are. But Justin, you've been thinking a lot about this, what are your thoughts? Justin Ezekowitz: This is a terrific paper, and this is a groundbreaking therapy. Scott, this really has something for everybody, for example functional Anti-proBNP and echocardiographic measures of improvement and also less deterioration which I think is also holding it in its tracks. The question is, if you have 126 patients in the cardiac sub-group, whether or not this is really prime for clinical integration, as to start using this therapy broadly or do we need to really broaden the scope and do larger outcome studies with this therapy for these patients, recognizing some of the gaps in any clinical trial design and implementation. So what are your thoughts on that? Scott Solomon: First of all, it's important to remember that the APOLLO study was designed primarily to look at the neurologic outcomes, not the cardiac outcomes. The cardiac outcomes were technically considered exploratory and, in fact, although really pretty impressive in this group, this wasn't really how the study was designed. And so the current indication for this particular therapy. Patisiran is for the improvement in the neurologic outcomes, not for the cardiac. So I think that there will need to be additional studies that will look more specifically at the cardiac effects, although I think these are among the most impressive findings we've seen with any agent that is interfering with transthyretin. And just to put this in context, there are a variety of ways in which amyloid can be affected and one of the other approaches to this disease has been not to reduce the production of transthyretin but to stabilize transthyretin.                                 And you may be aware of the ATTRACT trial which was presented at ESC and published in the New England Journal, which was actually an outcomes trial in patients with cardiomyopathy secondary amyloid and they used a drug which is a TTR stabilizer and showed a significant reduction in cardiac events and mortality. And I think that in the context of that study, this is extremely exciting as well because it says that there are multiple potential approaches to affecting transthyretin and potentially improving outcomes in patients with cardiac amyloidosis. There are other approaches that also are being tested. In fact, another therapy that works in a similar way to patisiran is atersin which is an agulo nucleotide anti-sense molecule. And so, I think that it's such an exciting time now in this field because there almost certainly will be several different approaches to transthyretin amyloidosis.                                 So, I think, Justin, to succinctly answer your question I don't think we're quite ready yet with patisiran but stay tuned because there will be more trials for sure. The other thing that we have to realize is that this study was done in mutant or hereditary amyloidosis but there's a very broad group of patients out there with wild type amyloidosis and there's no reason to think that a therapy like this won't work there as well. So that has to be tested too. Justin Ezekowitz: I think, Scott, that's a true way to put it. I think one of the other questions is the substantial difference between the trials and sub-groups of the trial between the three major therapies you just described about wild type versus hereditary. It does make you wonder if either one individual therapy or a combination of the therapies might give the right way to precisely manage these individuals according to their phenotype, neurologic status or cardiac status. So, I maybe just want to draw you on one other point which is that you used global longitudinal strain as one of your outcomes and it sounds like, and from all the data we've seen, it looks like GLS will be the way to go for earlier phase two and other types of studies. What are your thoughts based on experience? Scott Solomon: Well in general I'm a big fan of global longitudinal strain because I think it is, in many respects, more robust than our standard measures of cardiac function like ejection fraction, it's not volume dependent the way ejection fraction is. In particular in amyloid heart disease, as you know, global longitudinal strain can be quite abnormal and, interestingly, it can be quite abnormal in a very specific pattern. And patients with amyloid is typically sparing at the apex, so the apical strain is relatively normal compared to the strain at the base of the heart. And this is kind of interesting and we've certainly been looking at this as well in amyloid heart disease but I agree that this global longitudinal strain as a measure of potential benefit for a therapy has a lot of potential. Dr Carolyn Lam: You know, that's just so amazing. I just have one last question for both of you. Where do you think the field is going? Do you think it's going to be a race to treatment or a race to diagnosis? I shudder to think of the number of cases we're missing, what do you think Justin? Justin Ezekowitz: Carolyn you just brought up a great point which is, one is our diagnostics need to improve and be broadly applicable and implementable in any health care system, so I think that race has to speed up and become more cost-effective and efficient to know who indeed we need to screen closer. That's point number one but number two is the therapies ... the race has to be focused around what will be the best way to treat patients rather than the cost-effectiveness initially, but then once we identify the three or four different agents that work with different groups and how you can combine them, then the consideration has to be how we can apply these more broadly to the groups that really haven't had a therapy that has had a meaningful impact trajectory. Dr Carolyn Lam: Scott, what do you think? Scott Solomon: Well I would add that one of the most exciting things I think in this area, Carolyn, and this is going to interest you I think because of your own interests, is that there's probably a lot of amyloid out there that we don't know about. Especially in these patients that we're currently calling heart failure with preserved ejection fraction. There's some data from Mayo clinic and from groups in Europe suggesting that 15 to 20% of patients with HFpEF, might actually have wild type transthyretin amyloid. And that means that we've got to get better at making this diagnosis, especially where our suspicions are high. Because we might all of sudden have a targeted therapy for some of these patients, so I think that's one area where things are really exciting. And then with respect to which of these therapies is going to be beneficial, I mean I think that we're still in the early stages, it's very possible as Justin said that even a combination of TTR stabilizers and knock-down agents are going to provide the best benefit. But I think we're going to see a lot of very interesting studies in the next several years in this field. It's really great to have a potential molecular target, and targeted therapy for a type of cardiomyopathy and I think this is one of the really few areas where we have that as this point. So I'm extremely excited. Dr Carolyn Lam: Thank you so much for publishing your paper with us in Circulation.                                 Well audience you heard it right here on Circulation on the Run. Don't forget to tune in again next week.                                 This program is copyright American Heart Association 2019.  

Scott and I talk about how he became an ant biologist, why he's so fascinated by evolution, and ways humans are guiding our own evolution – for example, through online dating, IVF, having children later, and more. Scott outlines the main arguments against the idea that humans are done evolving, and points out that we're not as special as we might think when it comes to avoiding evolution. Get full show notes and more information here: https://bit.ly/2FBrKre

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.                                                 Can proteomic biomarkers distinguish between subtypes of aortic stenosis even years before surgery? Well, to find out more, stay tuned. That's coming right up after these summaries.                                                 The first original paper this week adds to the evidence that smoke-free policies are associated with a lower risk of cardiovascular disease. First and corresponding author, Dr Mayne from Northwestern University Feinberg School of Medicine, and her colleagues linked smoke-free policies to participants of the Coronary Artery Risk Development in Young Adults, or CARDIA study, which has a follow-up of up to 20 years. They found that smoke-free policies in workplaces were associated with significantly lower risk of incident cardiovascular disease after controlling for a wide range of covariants. Results were weaker for bar and restaurant bans, but in the same direction.                                                 Preventive fractions range from an impressive 24 to 46%. Thus, smoke-free policies may improve cardiovascular health through reducing population exposure to tobacco smoke. However, we should remember that much of the US population remains unprotected by smoke-free policies. Thus, taken together with prior ecological work, these results support the continued expansion of smoke-free policies in indoor public places.                                                 Most phase-3 randomized control trials feature time-to-first event end points for their primary analysis. In chronic diseases, however, a clinical event can occur more than once and recurrent event methods have been proposed to more fully capture the disease burden, as well as to improve statistical precision and power.                                                 However, is this really the case? This question was examined by first author, Dr Brian Claggett, corresponding author, Dr Scott Solomon, from Brigham Women's Hospital in Boston, Massachusetts, and their colleagues, who sought to better characterize factors that influence the statistical properties of recurrent events and time-to-first event methods in the evaluation of randomized therapy.                                                 They performed repeated simulated trials with 1:1 randomization of 4000 patients to active versus control therapy. Through simulation, they varied the degree of between-patient heterogeneity of risk as well as the extent of treatment discontinuation. They then compared their findings with those from the actual randomized control trials.                                                 The authors found that the statistical power of both recurrent events and time-t- first event methods were reduced by increasing heterogeneity of patient risk, a parameter that's not usually included in conventional power and sample size formulae. Furthermore, data from real clinical trials were consistent with the simulation studies, confirming that the greatest statistical gains from the use of recurrent events methods occurred in the presence of high patient heterogeneity and low rates of study drug discontinuation.                                                 The next paper uncovers a novel biomarker and therapeutic target of pulmonary arterial hypertension, and that is selenoprotein P. First author Dr Kikuchi, corresponding author, Dr Shimokawa, from Takaoka University Graduate School of Medicine in Japan and their colleagues performed micro-array analyses using pulmonary arterial hypertension, pulmonary artery smooth muscle cells, and found a 32-fold up regulation of selenoprotein P compared with controls.                                                 Selenoprotein P promotes cell proliferation and apoptosis through increased oxidative stress and mitochondrial dysfunction. Using five strains of genetically modified mice, the authors demonstrated a pathogenic role of selenoprotein P in the development of hypoxia-induced pulmonary hypertension.                                                 Furthermore, sanguinarine, which is an orally active small molecule identified by throughput screening reduced selenoprotein P expression and pulmonary arterial smooth muscle cell proliferation and ameliorated pulmonary hypertension.                                                 In summary, this study shows that selenoprotein P plays a crucial role in the pathogenesis of pulmonary arterial hypertension and may be a useful and novel biomarker and therapeutic target in this disorder.                                                 Familial hypercholesterolemia is known to be associated with a high risk of ischemic heart disease, including myocardial infraction, but what about the risk of ischemic stroke? Well, first author, Dr Beheshti, corresponding author, Dr Nordestgaard, from Copenhagen University Hospital and their colleagues examined the associations of familial hypercholesterolemia and high LDL cholesterol with ischemic stroke in both causal, genetic, and observational analyses using more than 106000 individuals from the Copenhagen General Population Study, and more than 10000 individuals from the Copenhagen City Heart Study.                                                 They used a Mendelian randomization design to test whether high LDL per se had a causal effect on ischemic stroke risk using a combination of the familial hypercholesterolemia causative mutations and common genetic variants associated with high LDL.                                                 The authors found that there was no association between familial hypercholesterolemia mutations and ischemic stroke risk. In the Mendelian randomization analysis, also including common genetic variants, there was also no causal effect of high LDL on the risk of ischemic stroke.                                                 These findings imply that the predominant goal of targeting LDL lowering in those with and without familiar hypercholesterolemia is likely to reduce myocardial infractions, rather than ischemic stroke. Well, that wraps it up for our summaries. Now for our feature discussion.                                                 Circulation publishes numerous papers regarding circulating biomarkers. We talk about biomarkers in the diagnostic, prognostic sense, but what about in a pathophysiologic sense, and especially in a disease as important as aortic stenosis? Well, that's what our featured paper this week is all about and I'm so excited to have with us corresponding author, Dr Stefan Söderberg, from Umeå University in Sweden, as well as our associate editor, Dr Peipei Ping from UCLA. We will be discussing the paper entitled “Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement.” Stefan, could you tell us a bit about what made you look at this very interesting question, and perhaps the unique resources you had in Sweden to look at this? Dr Stefan Söderberg:      I'm a practicing cardiologist, and I have been working a lot with aortic stenosis over the years. It's frustrating that we can't do anything to stop the process. In many cases, the patients are old and frail, and if you could find the means to stop the process long before they need surgery, it will be of great benefit for the human and for the society.                                                 Also, knowing that the interventions on the statins, for example, have been unsuccessful, we thought that there must be better ways or other biomarkers. Furthermore, that many of these studies, the phenotype of aortic stenosis has been very poorly described and there is probably much more behind just aortic stenosis than just, for example, calcium deposits in an X-ray, et cetera, et cetera. Dr Carolyn Lam:                You used some very unique resources in Sweden to therefore look at the proteomic signatures of aortic stenosis. Could you describe that and simplify perhaps the results so we can understand it? Dr Stefan Söderberg:      First of all, I got this idea from other studies done up in northern Sweden. If you have an absolutely unique setting, the combination of huge population-based studies in 30 years back, we have a huge biobank with examples of extraordinary good quality from each of these participants. For example, for each participant, the blood has been spun and put into freezer, deep freezer, within one hour for 30 years, and they are now, as I said, about 100000.                                                 Furthermore, I'm working as a cardiologist at a university, and up here, you do all of the aortic surgery for the whole northern Sweden. That is, we can combine the names of the person undergoing surgery together with these population-based surveys and we can get details from all those who have participated in the surveys long before they did the surgery, and they can go and retrieve samples from cases and match controls from the freezers. It's a unique setup. Then, when we were designing the study, we got the chance to get these analyses done by our friends at the university to get the proteomic analysis via a unique data technique. Dr Carolyn Lam:                Wow. Could you describe your results? Dr Stefan Söderberg:      The results that we found in the first set of 334 patients who underwent surgery is 10 years after their first sampling, we found six proteins. Then, we got the question back from Circulation to establish a validation cohort, and we were able to do so to include all those new cases in the last 2 years, and there we could replicate five of these proteins.                                                 The interesting thing that the pattern is completely different between those having coronary artery disease from those without. That kind of phenotyping has not been done throughout other aortic stenosis studies. Therefore, this study is unique. We have had two papers in the last year in the Journal of American Heart Association from the cohort, as well, showing the thing that happened.                                                 For example, lipoprotein little A is only associated with future aortic stenosis valve replacement only in those with concomitant coronary artery disease. There are many unique things, the prospective design, and the phenotype differentiating those with and without coronary artery disease. Dr Carolyn Lam:                Yeah, and if I may just reiterate that the population base that you work with is just enviable and just so that the audience realizes, these are biomarkers that were collected 11 years before the aortic stenosis surgery, isn't it? You really had a long follow-up.                                                 Also, just to let everyone know, it was a proximity extension assay that you used for the discovery, and the six proteins were growth differentiating factor 15, or GDF15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and PCSK9, so very interesting. Peipei, you have a way of putting things into context so beautifully. Could you tell us your thoughts when you saw this paper? Dr Peipei Ping:                   I thought this is a very high-quality study that actually benefited from the long-term established, well-controlled cohort in northern Sweden, as Dr Söderberg just shared with us. On the other end, it married a technology platform that's very well-established and -validated, and this situation targeted proteomics platforms using multi-proximity extension assays with carefully controlled markers and screened 92 cardiovascular candidate markers.                                                 This is the kind of approach that provides semi-quantitative as well as quantitative outputs and is capable to offer validated screens on large population clinical subsets. A study of such with a high value cohort combined with a validated and well-controlled technology platform offered results that clearly have clinical significance, as well as setting up examples for other studies to follow. The enthusiasm from the editorial boards, as well as the reviewers, have been substantially high and supportive. Dr Stefan Söderberg:      Fantastic. I'm very glad to hear this. Dr Carolyn Lam:                Stefan, you also mentioned that a very unique element was the separation of aortic stenosis with and within coronary artery disease, or at least established or visible coronary artery disease. Could you explain how that provided pathophysiologic insights? Dr Stefan Söderberg:      First, I should say we were very, very strict. Our routine is that everyone was 100% undergoing, aortic valve replacement, they undergo a coronary angiogram before. If we saw any sign of atheromatosis, it was not enough that they had the significant stenosis, but any signs, they were put into the group of coronary artery disease. Those without, we couldn't see anything there. Radiograph here reported absolutely clean coronary arteries. Of course, we cannot exclude if there were aortic changes within them all, of course.                                                 We believe that this is a very important message that in order to further study aortic stenosis, we should be very careful in phenotyping the disease. We hope the growing cohort will be able to do this further. For example, cuspid versus tricuspid valves, women versus men, et cetera.                                                 My answer in short is phenotype. Let me take one example which I found very, very exciting. That is the finding of PCSK9, which is closely related not only to cholesterol symptoms, but also to lipoprotein little A emphasis. As you know, the first strong finding in aortic stenosis was the LP little A. This is related to that genetic finding, and that was in the huge study from Canada. They did not have the same phenotyping, so we had information to his important findings. That's one example.                                                 Another example is the transferring receptor, where data has shown that bleeding acutely in the valvular tissue causes damage, and this relates iron metabolism to the formation of the aortic valve. Obviously, it seems that the process in the aortic valve is very much similar to the vessel arteriosclerosis. It seems to be different. This is the indication that when we formulate new studies or new drugs on aortic stenosis, we must be very careful to use the right drug for the right type of valvular disease. Dr Carolyn Lam:                Those are great points. Peipei, do you think that's the main clinical take-home message, beyond that great comment you made earlier that this paper's just a great example of the use of tools, modern tools, that we have in proteomic characterization like the proximity extension assay to provide pathophysiologic insights when you have a really well-phenotyped cohort? What's the critical take-home message, though? Is there one now? Dr Peipei Ping:                   The take-home message is marriage of amazing high value cohort's data sets with that of the well-controlled clinical study using target proteomics approaches. In this particular study, one main critical innovation is the study is capable of providing insights regarding molecular signatures that have predicted values. As stated in the manuscript, the circulating proteins that found critically important, their alterations took place years before the surgery were associated with aortic stenosis. That is of value, clinical value, to many other clinical studies to follow. Dr Carolyn Lam:                Wow. That's wonderful. Thank you so much for putting these findings in context for us. Thank you, listeners, for joining us today. Don't forget to tune in again next week.  

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our feature paper this week contains novel data from the TOPCAT trial, this time relating physical activity to prognosis in patients with heart failure and preserved ejection fraction. A great discussion coming right up after this weeks' summaries.                                                 Our first paper tells us that pericarditis may be a marker of occult cancer and augurs increased mortality following the cancer diagnosis. Authors, Dr. Sogaard and colleagues from our host university hospital in Denmark used the Danish medical databases to conduct a nationwide cohort study of all patients with a first-time diagnosis of pericarditis from 1994 to 2013. Among 13,759 patients with acute pericarditis, 1,550 subsequently were diagnosed with cancer during followup.                                                 Patients with newly-diagnosed pericarditis had higher risks than age and sex match members of the general population of being diagnosed with lung cancer, Non-Hodgkin lymphoma, and myeloid leukemia during the first three months following a pericarditis diagnosis, but increased risks for lung cancer and Non-Hodgkin lymphoma and bladder cancer persisted beyond one year following a pericarditis diagnosis. The increased cancer risk was not restricted to patients with pericardial effusion.                                                 Furthermore, pericarditis was a prognostic factor for survival after lung cancer, breast cancer, and bladder cancer. Thus, the clinical take-home message is that patients with pericarditis, particularly when complicated by pericardial effusion, may need to be considered for workup targeted at diagnosing or ruling out cancer.   The next paper provides insights into mechanistic processes leading to stent thrombosis in the largest contemporarily available series of patients undergoing optimal coherence tomography, or OCT imaging, during stent thrombosis presentation. The first author, Dr. Adriaenssens, corresponding author, Dr. Byrne from Munich, Germany, and colleagues of Prestige Consortium, performed a prospective multicenter study to evaluate OCT findings in consecutive patients presenting with stent thrombosis enrolled in a registry that was using a centralized registration system.                                                 In 231 patients with stent thrombosis undergoing OCT, uncovered and malapposed struts were frequently observed, with the incidents of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to the time intervals from index stenting. Uncovered struts and stent underexpansion were the most common observations in acute or subacute stent thrombosis, whereas neoatherosclerosis and uncovered struts were the most common findings in late or very late stent thrombosis. The impact of dedicated clinical strategies for the prevention and treatment of mechanisms underlying stent thrombosis should be investigated in future clinical studies.                                                 The next study identifies a new type of capillary malformation, arteriovenous malformation. Now, we know that most arteriovenous malformations are localized and occur sporadically. However, they also can be multifocal in autosomal dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation arteriovenous malformation or CMAVM. RASA1 mutations have been identified in 50% of patients with CMAVM.                                                 In the current study, first author, Dr. Amyere, corresponding author, Dr. Vikkula from Brussels, Belgium and colleagues studied non-RASA1 patients and found that EphB4 mutations occurred in patients with multifocal capillary malformations associated with arteriovenous malformations. This phenotype named CMAVM2 mimicked RASA1-related CMAVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120-RasGAP was a direct effector of EphB4. Furthermore, the study implicated EphB4-RAS-ERK signaling pathway as a major cause of arteriovenous malformations. Thus, patients with multifocal capillary malformations need to be screened, not only for an inherited RASA1 mutation, but also for EphB4.                                                 The final study identifies a novel potential therapeutic target in the treatment of atherosclerosis, and that is Dickkopf-related protein 3, or DKK3, a secreted protein previously known for its involvement in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but very little studied in atherosclerosis. In the current study, first author is Dr. U.N. [inaudible 00:05:51], corresponding authors, Dr. Qu from Capital Medical University in Beijing, and Xu from Kings College London used both epidemiological and experimental approaches to test the hypothesis that DKK3 was atheroprotective.                                                 In the prospective population-based Bruneck study, they found that the level of plasma DKK3 was inversely related to carotid artery intimal medial thickness and five-year progression of carotid atherosclerosis independently from standard risk factors for atherosclerosis. Experimentally, they demonstrated that DKK3 promoted re-endothelialization in murine models of atherosclerosis and wire-induced femoral artery injury, thus revealing its atheroprotective role.                                                 They further explored the mechanism of DKK3-induced endothelial cell migration, which was via noncanonical Wnt signaling pathways.  The study, therefore, provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair with potential therapeutic implications.                                                 That wraps it up for our summaries. Now for our feature discussion.                                                 For today's feature discussion, we are talking about physical activity and prognosis in heart failure with preserved ejection fraction, or HFPEF. To discuss this paper, which contains really neat results from the TOPCAT trial, we have none other than the first author, Dr. Sheila Hegde, corresponding author, Dr. Scott Soloman, both from Brigham and Women's Hospital, as well as Dr. Jarett Berry from U.T. Southwestern, who was the editorialist on this paper. Welcome, everyone. Dr. Scott Solomon:          Thanks, Carolyn. Dr. Sheila Hegde:             Thank you. Dr. Jarett Berry:                Thank you, Carolyn. Dr. Carolyn Lam:               Hey, Scott. Could you set the background a little bit and let us know what was the rationale of looking at physical activity in TOPCAT? Dr. Scott Solomon:          As you well know, heart failure with preserved ejection fraction is a disorder in which we don't currently have a therapy, or for which we currently don't have a therapy, and we know that people would also have a lot of comorbidities. Sheila has been extremely interested in the role of physical activity in heart failure and patients with heart failure, has studied this in the atherosclerosis risk in community studies, and we thought TOPCAT would be a great overall trial dataset to understand the importance of physical activity in HFPEF patients and the relationship with outcomes.                                                 As you know, TOPCAT is a study that was funded by the NIH in patients with heart failure, preserved ejection fraction. Patients were randomized to spironolactone or placebo and then followed for outcomes, and it was a very rich dataset for which we have a lot of physical activity information. Dr. Carolyn Lam:               Indeed, and I wasn't even aware of the extent of the physical activity information in TOPCAT. Sheila, could you explain a bit how physical activity was captured and graded, and tell us about your findings? Dr. Sheila Hegde:             Each participant's physical activity was assessed by self report. Subjects were asked about the amount of heavy, medium, and light exercise in the preceding two weeks. They were given some examples of what those might be and what we did was, we converted these to AHA, American Heart Association categories of poor, intermediate, and ideal activity. As you know, the ideal activity category corresponds to 150 minutes of moderate intensity activity per week or 75 minutes of vigorous activity per week. What we found, using these categories, was that the majority of subjects actually met criteria for poor activity, so at least 75%. Also, a majority were New York Heart Association Class II heart failure.                                                 Those with poor activity were more likely to be women, have diabetes, chronic kidney disease, and a previous history of heart failure hospitalization. Interestingly, there was no significant difference in history of myocardial infarction, stroke, atrial fibrillation, or COPD. The median follow-up time for this group was 2.4 years, and we did sort of focus on the first two years because there was an interaction with times and randomization and, using Cox regression models, we found that those with poor or intermediate activity had approximately a two-fold higher risk of a primary composite outcome, which was heart failure hospitalization, cardiovascular mortality, or aborted cardiac arrest. Dr. Carolyn Lam:               Wow! You know what the question is? Chicken or egg? Does this mean those who were exercising had better outcomes or they were just better and, therefore, they could exercise? Dr. Sheila Hegde:             That's a very good question. This is a post hoc analysis, so it will be difficult to say, but we did sort of look at excluding those with a history of stroke or MI and found that the same two-fold increased risk of outcomes existed for those with poor intermediate activity. Dr. Scott Solomon:          This is always the problem, as you know, Carolyn, with observational data. We don't know if the patients who are exercising more are doing better because they're exercising more or is it that the people who feel better can exercise more? You try to adjust as much as you can, but I don't know that there's any way to determine that for sure without doing a randomized trial of exercise in patients with HFPEF. Dr. Carolyn Lam:               Certainly and, in fact, I thought that was one of the good messages, that it's time that we do a proper trial of that, don't you think? Jarett, would you have some questions for Sheila and Scott, too? Dr. Jarett Berry:                I was really interested in your figure 3, this dose response analysis. In figure 3, you divided the exposure into deciles. You don't begin to see a decremented risk until you begin to see the ninth and tenth decile of exercise. If you look at other observational data, you really see this different pattern where just getting off the couch seems to be beneficial in other observational data for preventing coronary disease events but, both in our work and also in this paper here, particularly your figure 3, you see that this higher dose of physical activity was required to see a reduction in risk. I don't know if you could comment a little bit on that. Dr. Sheila Hegde:             I agree that there is a difference in what appears to be a dose response at lower levels of activity. In this analysis, we actually included amount of light intensity of activity since the majority of people had no moderate or vigorous intensity activity to account for. In that sense, there's even sort of a higher threshold, perhaps, required to achieve benefit and reduction of risk, and it may be that heart failure has a different mechanism for physical activity in terms of achieving those benefits. Dr. Jarett Berry:                I'm wondering, I guess getting back to Carolyn's original point there about, and Scott's comments, as well, about the need for a trial. If you look back at HF-ACTION where we saw some relatively modest benefit for exercise training and heart failure with reduced ejection fraction. Some of our prior work would suggest that, actually, the benefit of exercise is much more apparent in HFPEF patients. When you train HFPEF patients, they tend to improve much more dramatically with regard to VO2 peak, compared to heart failure with reduced ejection fraction. I'm just wondering what your thoughts were about the next steps. It seems like a trial of some type would be of great interest. What are your thoughts about that? Dr. Scott Solomon:          I agree with you 100%. It would be a great idea for a trial. There have been small trials, as you know. Dalane Kitzman did a trial and Frank Edelmann and Burkert Pieske did a trial, and I think they're actually even doing another one now. The relatively small numbers of patients do show improvement in myocardial oxygen uptake, improvement in quality of life, and some improvement in some measures of echocardiographic measures of diastolic function, as well, with exercise training which is, frankly, more than we've gotten with drug therapies, so I agree 100%.                                                 It's also important to note that it's actually hard to get our patients with HFPEF in the United States into cardiac rehab because it's currently not paid for by Medicare, and I'm hoping that will change, as well. Dr. Carolyn Lam:               You know, that's so well put, Scott. I've got a question, though. Every time you think TOPCAT, you think regional variation, right? How did this look in the different regions, in the U.S. versus elsewhere? Dr. Scott Solomon:          First of all, let me just tell the audience that TOPCAT was a study in which we enrolled patients both in the Americas, which was the U.S., Canada, Argentina and Brazil, and in Russia and the Republic of Georgia. As you know, when we unblinded the trial, we found that the event rates in Russia and the Republic of Georgia were considerably lower, about five-fold lower than they were in the Americas. We believe that many of these patients may not have had heart failure.                                                 We've also recently found that many of these patients probably weren't taking spironolactone, as well. For many of our TOPCAT analyses now, including this one, we excluded the patients in Russia and Georgia and just focused on the Americas. Sheila, did you happen to look at the results in Russia and Georgia, just as a tweak? Dr. Carolyn Lam:               I can tell you that the majority of patients were active, so very much different than our majority in active patients in the Americas region. Dr. Jarett Berry:                This is an amazing study that really puts forward an important hypothesis that needs to be tested. Before, I know we've discussed that a couple of times already, but I really believe that we are exercising the wrong heart failure patients. As the Director of Cardiac Rehab here at Southwestern, we are including a lot of heart failure with reduced ejection fraction but, as Scott points out, there aren't currently funding available or billing is not allowable for patients who have heart failure with preserved ejection fraction.                                                 I think it's only studies like this that are going to move the field for it and how we can begin to think about caring for these patients and treating their comorbidities and treating their disease process through what we believe is probably one of the most important therapeutic strategies we have that we're not using, and that would be the exercise training, so I think this is a fantastic study and a wonderful contribution as we begin to think more about the future of treatment for patients with HFPEF. Dr. Carolyn Lam:               Thank you so much, everyone. Listeners, I'm sure you enjoyed that conversation as much as I did. Don't forget to tune in again next week.  

How have humans evolved and what drives this evolution? Evolutionary biologist Scott Solomon, author of Future Humans, discusses the science of human evolution.

How have humans evolved and what drives this evolution? Evolutionary biologist Scott Solomon, author of Future Humans, discusses the science of human evolution.