Podcasts about Circulation

(0:00) Zolak & Bertrand, with Matt McCarthy in for Beetle, start the second hour by discussing whether the Celtics should break-up Jayson Tatum and Jaylen Brown, as callers offer up their thoughts. (9:51) We dive into how the Patriots offense should operate against the Bills, before going back and forth on Josh Allen's circulation problems. (21:26) The guys decipher how much you'd have to pay them to attend Patriots-Bills on Saturday, as ticket prices for the game continue to go down.  (30:31) Patriots linebacker Josh Uche calls into the show to discuss practicing in the cold, facing the Bills for a third time this season, and what Chase Winovich has in his locker.

Susan Burrell loves supporting women in their inner growth toward finding their true empowerment. And she shares how we can truly discover our true selves in this episode.For Susan, empowerment is about having the courage to live your life according to what you truly desire. It's about making decisions free from influences such as fears or doubt but rather being driven by a real sense of purpose and passion.Susan also talks about how to tap into your intuitive side -- in which she states people are afraid of their inner wisdom due to its psychic nature. She relates this to her own experience as she went through a long, contentious divorce after 28 years of marriage.Susan is an Intuitive Healer and Spiritual Guide at the crossroads of life with more than 25 years of experience counseling and supporting people in transforming from the inside out.Susan is living a life that is wholehearted. After living through many of life's challenges she made the choice (like our girl Tina Turner) to own her life and use her intuition to make powerful changes. What is wholehearted living? Simply put, it means living and loving with your whole heart. According to Brené Brown, wholehearted living “is about engaging in our lives from a place of worthiness.” It's understanding that yes, you are imperfect, vulnerable, and afraid, but you are also brave and worthy of love and belonging.What You Will Learn From This Episode:01:14 - What Susan Burrell is Obsessed With 03:03 - Getting Through Divorce and Discovering Her True Self07:50 - Tapping Into Your Intuitive Side15:01 - The Law of Circulation vs. The Law of Attraction 20:02 - Activating Your Light Leaders 21:51 - Chaos as Precursors for Amazing Changes25:35 - Giving Back to Oneself and OthersResources Mentioned:Tapping Into Wealth by Margaret Lynch Raniere - https://margaretlynchraniere.com/ The Tapping Solution by Nick Ortner - https://www.thetappingsolution.com Emotional Freedom Technique by Dr. Dawson Church - https://www.eftuniverse.com/ Learn More About Susan Burrell:Website: https://www.susanburrell.com/Podcast: https://podcasts.apple.com/us/podcast/empowering-chats-with-susan-burrell/id1450867973Facebook: https://web.facebook.com/susanburrellpageInstagram: https://www.instagram.com/liveyourempoweredlife/Twitter: https://twitter.com/LYILSusanSee What Your Obsessed Girls Are Doing and Send Us Feedback!CROWN AND COMPASS | Linktree - https://linktr.ee/crownandcompassgirls

In this episode, we are going to talk about how to reduce stress. We are going to offer some tips and also talk about how oatmeal and tea might help you reduce stress. Stress is your mental and physical reaction to pressure from a certain situation. But remember not all stress is bad, certain stress helps you and gives you the strength to do more. Negative or harmful stress is referred to as distress and on the flip side, positive or good stress is referred to as eustress. Feeling stressed out? Join us as we tackle more about this topic and how you can handle it.   Cup of Nurses: https://fanlink.to/CONsite Frontline Warriors: https://fanlink.to/FWsite Youtube https://fanlink.to/CONYT Apple https://fanlink.to/Applepodcast Spotify https://fanlink.to/Spotifypodcast Cup of Nurses Store https://fanlink.to/CONshop Frontline Warriors store https://fanlink.to/FWshop Interested in Travel Nursing? https://fanlink.to/TravelNurseNow Free Travel Nursing Guide  https://fanlink.to/Travelnursingchecklist Nclex Guide https://fanlink.to/NCLEXguide Cup of Nurses FB Group https://www.facebook.com/groups/cupofnurses Frontline Warriors FB group https://fanlink.to/FWFBgroup   0:00 Introduction 0:45 Cup of Nurses Introduction 2:28 Episode Introduction 2:45 The Stress Response 16:33 Negative effects of stress 16:46 Effects of Stress in Digestion 19:02 Effects of Stress in Circulation 20:49 Effects of Stress in Immunity 27:12 Effects of Stress in Reproduction 33:00 2 Foods that Decrease Stress 33:25 Foods that decrease stress: Oatmeal 35:23 Foods that decrease stress: Tea

The Stew Peters Show: Jan 3, 2022: Guests: RFK, Jr. Publisher Tony Lyons, Kash Patel, Dr. Jane Ruby, Krystal Tini BREAKING: Still, it's a dangerous world out there, and the enemies of the American people will be just as committed to destroying you in 2022 as they were in 2021. And that means more masking, more restrictions, and more vaccine mandates. Doctor Jane Ruby joins us for her first segment of the year. She says she has the receipts to show that vaccine toxicity varies by batch, and it's possible to find out if the vaccine you're being pressured to take is from one of the tainted batches. Ghislaine Maxwell was convicted on five of six counts last month, and with that begins the desperate campaign to make everyone forget about the entire Epstein saga as quickly as possible. Already, Epstein's infamous black book of friends and contacts has been ordered sealed, to protect the names listed within it. Kash Patel served in the Trump administration and has been our top commentator on all the major trials recently. He joins us. We live in an age of censorship, and if you're willing to say anything that our elite rulers don't like, it's just a matter of time before you get censored. This isn't about “facts” or “misinformation.” It's about political power and control. Robert F. Kennedy Jr.'s book The Real Dr. Fauci has been a massive bestseller this fall, but there's been a near-media blackout of the book. Do not criticize your God Dr. Fauci. That's the narrative and they will defend it to the bitter end. Tony Lyons is RFK Jr.'s publisher. H's publicly challenging critics to find factual errors in the book. He joins us. Get Dr. Zelenko's Anti-Shedding Treatment, NOW AVAILABLE FOR KIDS: http://zStackProtocol.com Go Ad-Free, Get Exclusive Content, Become a Premium user: https://redvoicemedia.com/premium Follow Stew on social media: http://evrl.ink/StewPeters See all of Stew's content at https://StewPeters.TV Watch full episodes here: https://redvoicemedia.net/stew-full-shows Check out Stew's store: http://StewPeters.shop Support our efforts to keep truth alive: https://www.redvoicemedia.com/support-red-voice-media/ Advertise with Red Voice Media: https://redvoicemedia.net/ads

Please join author George Dangas and Associate Editor Brendan Everett as they discuss the article “Colchicine in Cardiovascular Disease.” 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: Welcome, everyone, to 2022. I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, oh, we're starting off the year with a twist on the feature article. It's a review article on colchicine and cardiovascular disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Dr. Carolyn Lam: Absolutely. The new year is starting off with a bonanza issue. This first topic is so important. We know that various non-invasive, intermittent rhythm monitoring strategies have been used to assess arrhythmia recurrences in atrial fibrillation ablation trials. But the question is, what is the frequency and duration of non-invasive rhythm monitoring that accurately detects arrhythmia recurrences and approximates the atrial fibrillation burden derived from continuous monitoring using the gold standard, implantable cardiac monitor? Now to answer this question, investigators Jason Andrade and colleagues from the Montreal Heart Institute, who looked at the rhythm history in 346 patients enrolled in the CIRCA-DOSE trial. They reconstructed the rhythm history using computer simulations and evaluated event-free survivals, sensitivity, negative predictive value, and AF burden in a range of non-invasive monitoring strategies including those used in contemporary AF ablation trials. Dr. Greg Hundley: Ah, very interesting, Carolyn. So what did they find? Dr. Carolyn Lam: Detection of arrhythmia recurrence following ablation was highly sensitive to the monitoring strategy employed between trial discrepancies and outcomes, in fact, may reflect these different monitoring protocols. Binary efficacy outcomes, such as time to AF recurrence, appeared to underestimate the true impact of catheter ablation on the burden of atrial arrhythmia. The most commonly performed intermittent rhythm monitoring techniques, like short duration 24- or 48-hour ambulatory Holter, they do miss a substantial proportion of arrhythmia recurrences and significantly overestimate the true AF burden in patients with recurrences. So based on measures of agreement, serial long-term, that is four seven-day or two 14-day intermittent monitors accumulating at least 28 days of annual monitoring provide estimates of AF burden that are comparable with the implantable cardiac monitor. However, implantable cardiac monitors outperform intermittent monitoring for arrhythmias and should be considered the gold standard for clinical trials. Dr. Greg Hundley: Very nice, Carolyn. It sounds like a lot of clarification on monitoring of AF burden. Well, my first paper comes to us from Dr. Prabhakara Nagareddy from The Ohio State University, The Wexner Medical Center. Carolyn, acute myocardial infarction results in an overzealous production and infiltration of neutrophils in the ischemic heart, and this is mediated in part by granulopoiesis induced by the S100A8/A9 NLRP3, IL-1 beta signaling axis in injury-exposed neutrophils. In this study, Carolyn, the investigators evaluated a hypothesis as to whether IL-1 beta is released locally within the bone marrow by inflammasome prime and reverse migrating neutrophils. Dr. Carolyn Lam: Ah, okay. So what did they find, Greg? Dr. Greg Hundley: Okay, Carolyn. In response to myocardial infarction, the NLRP3 inflammasome prime neutrophils upregulated CXCR4 and reverse migrated to the bone marrow, where they adhered to adhesion molecules like P-selectin on the bone marrow endothelial cells. Second, Carolyn, in the bone marrow, the inflammasome prime neutrophils released IL-1 beta through gasdermin-dependent conduit pores without undergoing the mandatory pyroptosis. Third, genetic and/or pharmacological strategies aimed at limiting reverse migration of inflammasome prime neutrophils to the bone marrow or release of IL-1 beta, both suppressed granulopoiesis and improved cardiac function in mouse models of myocardial infarction. So Carolyn, therefore, strategies aimed at targeting specific signaling pathways within the neutrophils or reducing retention of the inflammasome prime neutrophils in the bone marrow may provide novel avenues to regulate inflammation and improve cardiac outcomes. Dr. Carolyn Lam: Wow, neat, Greg. Thanks for explaining that so nicely. Well, the next paper deals with my favorite topic, heart failure with preserved ejection fraction of HFpEF, and this time looks at mechanisms of sinoatrial node dysfunction. The investigators, led by Dr. Cingolani from Smidt Heart Institute at Cedars-Sinai Medical Center, sought to investigate the role of the intrinsic pacemaker on chronotropic incompetence in HFpEF. They performed extensive sinoatrial node phenotyping, both at baseline and after stress in the well-characterized Dahl salt-sensitive rat model of HFpEF. These rats exhibited limited chronotropic response associated with intrinsic sinoatrial node dysfunction, including impaired beta-adrenergic responsiveness and an alternating leading pacemaker within the sinoatrial node. Prolonged sinoatrial node recovery time and reduced sinoatrial node sensitivity to isoproterenol were confirmed in the two hit mouse model. Adenosine challenge unmasked conduction blocks within the sinoatrial node, which were associated with structural remodeling. Finally, single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the membrane clock or iron channels and the calcium clock of the spontaneous calcium release events. Dr. Greg Hundley: Wow, Carolyn, lot of really interesting data here. So what were the clinical implications? Dr. Carolyn Lam: Yeah, it's a really great study. Two models of HFpEF-consistent result in an important topic. Basically, here at the take-home messages. Provocative testing can be valuable to elicit functional abnormalities to facilitate HFpEF diagnosis and considering the exceptionally high clinical and epidemiologic convergence between AFib and HFpEF, sinoatrial node dysfunction may underlie the development of abnormal atrial rhythms in HFpEF. Dr. Greg Hundley: Very nice, Carolyn. More information on HFpEF, again, one of your favorite subjects. Next, we're going to turn to a paper from Dr. Jian Li from the Peking Union Medical College Hospital. Carolyn, doxycycline has previously been demonstrated in a retrospective study to be associated with greater survival in patients with light chain AL amyloidosis. Therefore, Carolyn, this group prospectively compared the efficacy of bortezomib, cyclophosphamide, dexamethasone, or cyclophosphamide B or D, and cyclophosphamide B or D combined with doxycycline for cardiac amyloidosis. Dr. Carolyn Lam: Cool. So what did they find, Greg? Dr. Greg Hundley: Carolyn, this was a multi-center, open-label, randomized controlled trial, and 140 patients underwent randomization. The primary outcome was two-year progression-free survival. Progression-free survival was defined as the time from randomization to death, hematologic progression or organ progression, and that's the heart, the kidney, or the liver. And so Carolyn, these investigators in this trial demonstrated that doxycycline combined with cyclophosphamide B or D failed to prolong progression-free survival or cardiac progression-free survival compared with cyclophosphamide B or D alone in patients with cardiac AL amyloidosis. So Carolyn, a negative study that's quite informative and a very nice editorial that accompanies this article pertaining to future directions for management of AL cardiac amyloid. Dr. Carolyn Lam: Indeed important. Thank you. And there are other important papers in today's issue. There's a Research Letter by Dr. Pfeffer on the impact of sacubitril/valsartan versus ramipril on total heart failure events in the PARADISE-MI trial. Dr. Greg Hundley: Great, Carolyn. In the nail bag, boy, I've got a big list today. First, Dr. Churchwell has an AHA update on the need for policy change to improve maternal cardiovascular health. Next, Dr. Piazza has a Perspective piece on expanding the role of coronary CT angiography in interventional cardiology. There's an ECG challenge from Dr. Yarmohammadi entitled “Dancing Bundles with Stable Sinus Rhythm.” And next, we have our own Darren McGuire who, in this issue for all of 2021, is really recognizing our outstanding reviewers. And we want to thank all the listeners and everyone that reviews for us in this journal. Such an important feature and aspect to the publication of the wonderful articles that we receive. And then finally, there are some highlights from the circulation family of journals. Well, Carolyn, how about we get on to that feature discussion and learn more about colchicine and its use in cardiovascular disease. Dr. Carolyn Lam: Let's go and a Happy New Year, again, everyone. Dr. Greg Hundley: Welcome listeners to this January 4th feature discussion. This week, we're deviating a little bit because we are going to have an author discuss one of our in-depth reviews. As you know, we select those occasionally where they're is a topic that's very relevant in cardiovascular medicine and an investigator or team of investigators or authors will put together a very nice review of a topic. This week, we're going to talk about colchicine, and we have with us Dr. George Dangas from the Icahn School of Medicine at Mount Sinai and our associate editor, Dr. Brendan Everett, who manages this paper and he is from Brigham and Women's Hospital. Welcome, gentlemen. George, we'll start with you. George, why colchicine? Can you tell us a little bit about mechanism of action? Tolerability? Why would we want to use this particular agent in patients with cardiovascular disease? Dr. George Dangas: Thank you very much for the opportunity to join this interesting podcast. Colchicine is indeed an interesting drug. It's been around for centuries, in all honesty. In general, I would say it's a mild anti-inflammatory and in general, it's rather well tolerated. We'll go into those perhaps a little bit later. The precise mechanism is actually interestingly not quite defined. It may have a few ways to act by blocking perhaps the chemotaxis of the leukocytes or the adhesion of the leukocytes or the ability to release their granules, et cetera, but there isn't a specific major one that is targeting. Perhaps, it's targeting more than one mechanism in a mild way, and I think that goes into each utility, as well as the absence of the major side effect that might limit it. Dr. Greg Hundley: Very nice. So you started to mention the word utility, so maybe let's go through some clinical indications, or clinical uses perhaps rather than indications, can you tell us a little bit about its use in individuals with pericarditis? Dr. George Dangas: I think this is where it started to enter the cardiovascular field because we all recognize that pericarditis is an inflammatory disease and inflammation of the pericardium of different reasons perhaps. And anti-inflammatory drug is rather fitted to treat an inflammatory disease and besides, it's not like we had any other drug, in all honesty. Clearly, recurrent pericarditis might be treated with steroids for example, but steroids is not something any cardiologist would jump as a first line and give high doses and all that. Colchicine made its way to pericarditis like acute or recurrent pericarditis, post-cardiac cardiology syndrome, restless syndrome or the specific post-cardiac surgery, major inflammation. And indeed has a daily dosage perhaps with some loading dose or double the daily dosage or something initially and then we give it for a prolonged period of time in order to suppress. I would say this is a reasonable choice rather than jumping to the steroid. And of course, you reserve the steroid for the, I would say, more severe or more recurrent cases. I think everybody understands this type of activity. There've been quite a few clinical studies in this aspect. Again, in the absence of a competitor, I think it's a winner in this area. Dr. Greg Hundley: Very nice. And then, how about atrial fibrillation? Are there uses of this colchicine in patients with atrial fibrillation? Dr. George Dangas: Well, again, it's very interesting that a lot of atrial fibrillation, it may be in some ways inflammatory in origin. And quite frankly, we had an interesting [inaudible 00:14:50] clinical trial in American Heart Association in 2021. I'd like to point out here, the study that postoperative atrial fibrillation was mitigated when, during cardiac surgery, there was a slicing of the posterior pericardial. This allowing the inflammation in some ways that's related there. To me, that was a very interesting observation, though I related to colchicine because it validates the fact that there is something inflammatory in pericardial that related with the postoperative atrial fibrillation. So along these lines, let's go back to colchicine, Afib, and postop Afib, and post-ablation I would say patients. Again, there are risks of some inflammation and that's where the theory of a mild, rather well-tolerated, anti-inflammatory might come in. And there's been few studies, not a large definitive study, but several studies that are the, I would say, component with interesting results with colchicine in these patients. Dr. Greg Hundley: Very good. Another area of cardiovascular disease that's emerging literally with some demonstrable results using colchicine is the realm of ischemic heart disease. Can you walk us through some of the utility myocardial infarction or maybe even post-percutaneous coronary artery intervention? Dr. George Dangas: Again, the hallmark in this type of diseases, cardiovascular disease or coronary heart disease, is the hallmark of role of inflammation in this disease. And we know very well from the studies of the C-reactive protein, importance is a marker of inflammation. Very, very important in the CAD as well as in even the treatment with the antibody canakinumab a little bit earlier in the CANTOS trial a few years earlier at the very high level inhibited inflammation had a benefit and colchicine comes in maybe a milder anti-inflammatory about this agent, but at the same time with significantly less cause and significantly better recognition among the clinicians and a lot less, I would say, tolerability problems or issues are less unknowns. And I think that's where it comes in. The difficulty has been that whenever you go to cardiovascular, the cardiovascular, I would say coronary artery disease specifically, ACS and all that, the level evidence required for the doctors to believe in a therapy is very different than the areas we discussed before where there's little bit of a pericardial disease, for example, not that many drugs, all of a sudden, coronary artery disease, the bar is so high, and that's where the difficulty has been. There've been several studies. They've been interesting results with some benefits, particularly due to the decrease in inflammation and the secondary prevention, one can say. That is really the hallmark of where it aims to benefit in the secondary prevention, but there hasn't been one massive study with clearly superb results. I would say adequately powered single study that is missing in some ways. But several studies have been, again, very, very encouraging, but we learned that there's no much point if loading a lot of doses of high doses of colchicine, and it's a little bit better, again, when you aim with a daily dose towards reduced recurrences, particularly if you started early after an acute event. Dr. Greg Hundley: Very nice. Well, listeners, we're going to now turn to our associate editor, Dr. Brendan Everett, from Brigham and Women's Hospital. Brendan, you have a lot of papers come across your desk. First and foremost, what attracted you to this particular article? Dr. Brendan Everett: Well, thanks, Greg. And kudos to George and his team for putting together a really nice paper. It's great to have this kind of paper come into my inbox. That's specifically because colchicine, I think, has exploded as a really important novel therapy even though the therapy itself is perhaps hundreds of years old, as you heard George say a moment ago, but its role in treating cardiovascular diseases has really begun to emerge rapidly. I think there's a tremendous amount of enthusiasm for other ways to treat our patients who have really a recalcitrant cardiovascular disease, whether that's pericarditis, atrial fibrillation or I think, importantly, ischemic heart disease, because that's such a common disease and something where we're always looking for new ways to help patients live longer with fewer recurrent events. And so this paper I thought did a really good job of capturing the existing evidence for these conditions and some others and giving us a sense of where the strengths of that evidence lay and where the weaknesses were. I thought particular strength was in the tables where the authors laid out each of the trials and the results of the trial, their endpoints, where the benefit was potentially. And also importantly, where risks were seen because I think that's one of the really important questions that remains open with respect to colchicine therapy when we begin to talk about using it in a vast population of people with stable ischemic heart disease or post-myocardial infarction ischemic heart disease. Dr. Greg Hundley: Brendan, tell us a little bit about those risks. Dr. Brendan Everett: I'd be happy to do that. I want to emphasize before I dive in that I think the benefits that George has laid out are important, and I don't want to overshadow what the major trials have seen. But I think the thing that it is at least a little bit of the fly in the ointment, if you will, for colchicine in ischemic heart disease is that a couple of the large trials have shown an increased risk of non cardiovascular mortality or bad non-cardiovascular outcomes. And that's of concern, I think, as we saw in the CANTOS trial, which was the monoclonal antibody trial for canakinumab that George mentioned earlier, there was an increase in infection-related mortality. And so whenever you use an anti-inflammatory drug, you're worried about whether or not you're blunting other compensatory mechanisms that the body has to protect against infection and other diseases. I think it's likely that these findings are the play of chance, but we don't know for sure. For example, in the COLCOT trial, which I think is probably the largest and most interesting trial, which was designed and run in Canada, there was a slightly higher level of pneumonia in patients who got active therapy as compared to placebo. And then, two of the trials that were published more recently including LoDoCo2, which was a trial of about 5,000 patients run in the Netherlands and Australia. There was actually a marginally increased risk of non-cardiovascular mortality. That didn't reach statistical significance, but it was awfully close, and I think it gave people some concern. And then, there was also the COPS trial. Again, all these are really outlined in wonderful detail in the manuscript where there was a slight increase of total death and non-cardiovascular death. These events are few, but they're in a direction in two trials, and so they make people a little bit worried. I think the other thing that I noticed was the high prevalence of myalgia as a side effect. I think, Greg, you're always interested in the clinical implications and yesterday I was in clinic and saw a young patient who had had pericarditis. He had been prescribed colchicine by his primary care physician, and he literally couldn't stand and walk up straight because of the amount of abdominal pain he had, which was unusual. To be honest, I've given colchicine to a hundred patients at least, and none of them have had that profound of a side effect, but it's at least worth considering that some patients will not tolerate the therapy because of adverse effects. Dr. Greg Hundley: Very good. Well, in just 30 seconds or so, for each of you, first George and then Brendan. George, balancing some of the efficacy and then some of the concerns, what do you see is the next studies to be performed really in this sphere of research? Dr. George Dangas: This is a great question. And indeed, the concerns one can say or the issues, I would say, regarding this drug, are indeed real because any drug that suppresses inflammation has this risk. There are two ways one can address those. One is with term administration. You don't prescribe it as an annuity forever, but you prescribe it in a three- to six-month or one-month or try to control the time. I think this is done in clinical practice, in all honesty. I don't think that people are prescribing colchicine for life. Same way when we prescribe statins, for example. On the other hand or from investigational point of view, I think the two sets of information we need and, in all honesty, when you investigate issues regarding mortality or these are rare events, there's only one. You need a very large trial or a very large register. A very large trial preferably and colchicine being an often genetic drug, funding sources are rather limited, but we have NIH chipping in with some funding periodically and that might really be needed. So I want to outline that in the last table of our very large, I would say large table of our manuscript but were very happily outlined many ongoing trials. There are, in atrial fibrillation, three coronary artery disease. One in PCI and two in stroke. Something we didn't touch up again. But again, there's the question of inflammation in stroke. I think there's a lot of work ongoing. Perhaps you can see some meta-analysis, again, in order to get a handle of those risks, but at a rather low rate. It's just a difficult thing to come around. Dr. Greg Hundley: Very good. Brendan, anything to add? Dr. Brendan Everett: I would just add I agree a hundred percent with George just said. I think the only missing piece there is heart failure, which I think is and many have shown that there's an inflammatory component to heart failure, whether it's heart failure with reduced ejection fraction or preserved ejection fraction. And the timing of when that intervention might be, whether it might be before the development of symptoms or because there's a lot of trials out there that have struggled with this question and have unfortunately failed to show any benefit, I would just encourage the listeners of the podcast to look at this paper because it's a really marvelous compilation of the evidence for what is a really hot topic in cardiovascular medicine, a really important topic for a lot of the reasons that George mentioned. It's just very well done and comprehensive. Again, kudos to the authors for making such a great effort at putting something together that has a lot of clinical relevance, I think, and also points the way forward for research as you ask, Greg. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. George Dangas from Icahn School of Medicine in Mount Sinai and our own associate editor, Dr. Brendan Everett from Brigham and Women's Hospital for bringing us this data pertaining to colchicine benefits, as we know in acute and recurrent pericarditis, but also emerging indications related to post-procedural atrial fibrillation or coronary artery disease. And really, colchicine's targeting of cardiovascular inflammation is being helpful in those alleviating those processes. Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the run. Dr. Greg Hundley: This program, this 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.

MindMatters is back! On this New Year's episode, we discuss the work of Michael McConkey on the managerial revolution in the West, its relevance for ponerology, and McConkey's new substack "The Circulation of Elites," which discusses all these topics. Tune in for insights on the "new class", why it provides the perfect cover for political psychopaths, the fundamental (but fixable) weaknesses inherent in liberalism, and more.

Despite the ongoing challenges of the COVID-19 pandemic, 2021 brought us many more significant developments in type 2 diabetes research. In our final episode of the year, join Dr Kevin Fernando to hear his highlights from 2021 and thoughts about the year ahead. Dr Fernando is a GP partner with a special interest in diabetes, and is Scottish Lead for the UK Primary Care Diabetes Society. For more free CME, go to diabetes.knowledgeintopractice.com, where you can see all past episodes of the podcast as well as other free CME resources. Follow us on Twitter (@dkipractice) or connect on LinkedIn. References: Butler J, et al. Empagliflozin, Health Status, and Quality of Life in Patients with Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial. Circulation. 2021 Nov 15. doi: 10.1161/CIRCULATIONAHA.121.057812. Epub ahead of print. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10. Taylor R, et al. Intra-organ fat content during weight loss-induced remission of type 2 diabetes in people with normal or raised BMI. Abstract 110 presented at the 57th Annual Meeting of the European Association for the Study of Diabetes, 27 September – 1 October 2021, virtual. Diabetologia. 2021 Sep 64:1–380. Disclosures: Dr Kevin Fernando has no relevant disclosures to report at this time. This independent educational activity is supported by an educational grant from Novo Nordisk A/S. The educational content has been developed by Liberum IME in conjunction with an independent steering committee; Novo Nordisk A/S has had no influence on the content of this education.

MindMatters is back! On this New Year's episode, we discuss the work of Michael McConkey on the managerial revolution in the West, its relevance for ponerology, and McConkey's new substack "The Circulation of Elites," which discusses all these topics. Tune in for insights on the "new class", why it provides the perfect cover for political psychopaths, the fundamental (but fixable) weaknesses inherent in liberalism, and more. Running Time: 01:12:43 Download: MP3 — 99.9 MB

Figures from the Central Bank of Nigeria shows that the currency in circulation rose from N2.97tn at the end of October to N3.15tn in November.The CBN data showed that the currency in circulation increased to N2.84tn in September from N2.78tn in August.The Currency Operations Department of the CBN says in its 2020 annual report that it sustained banknotes disposal operations in 2020 to ensure the circulation of clean banknotes.The apex bank says in furtherance of this objective, it deployed 11 banknote destruction systems and three currency disintegrating systems for currency disposal activities in the period under review.

In this week's edition of Circulation on the Run, Dr. Amit Khera introduces the new Social Media Editors to our Circulation listeners. Please welcome Dr. Vanessa Blumer, Dr. Pishoy Gouda, Dr. Xiaoming (Ming) Jia, Dr. Peder Langeland Myhre, and Dr. Sonia Shah to Circulation. Dr. Amit Khera: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Amit Khera, Associate Editor from UT Southwestern Medical Center in Dallas, and Digital Strategies' Editor for Circulation. And today I have the privilege of sitting in for your usual host, Dr. Carolyn Lam, and Dr. Greg Hundley. Well, two times a year, we really have a special issue, there's no print issue for Circulation in the summer and here in that holiday time. So, fortunately, we get to use this for really whatever we want to do. Dr. Amit Khera: And today we have a very special issue. A few months ago, we transitioned over from a prior social media editor team that was Jainy Savla Dan Ambinder, and Jeffrey Hsu. We were able to recruit a fantastic group of new social media editors. You probably have seen their work behind the scenes, but you've not gotten to meet them personally. So, today I have the privilege of introducing you to our new social media editors. This group of five, that's been working for several months and we get to know them a little bit. Get to hear a little bit about their perspective on social media from fellows in training, and also what they've learned so far in their few months in working with Circulation. So, I'm going to go one by one and introduce you. And first I want to introduce you to Dr. Vanessa Blumer. Vanessa, tell us a little bit about yourself. Dr. Vanessa Blumer: Thank you so much, Dr. Khera, it is such an honor to be here. And I've had so much fun the months that I've been working for Circulation, it's truly just a privilege to work alongside this talented group. So I'm Vanessa Blumer. I am originally from Caracas, Venezuela, born and raised there, did all of my medical training back home. That included medical school, a year of rural service, or rural medicine. Then I actually did residency training in Venezuela as well. It wasn't really in my plans straight away to come to the US, but a little bit due to the political situation that we all know that Venezuela's going or suffering, I decided to come to the US. Dr. Vanessa Blumer: I did residency in the University of Miami, Jackson Memorial hospital, which I loved. Stayed there for a chief year. And then after that came to Duke University to do cardiology fellowship. I'm currently a third year cardiology fellow at Duke, doing a year of research at the DCRI, which I am enjoying a lot, and will be doing heart failure next year. I will be going to Cleveland Clinic for a year of advanced heart failure. Dr. Amit Khera: Well, you've had quite a journey, Vanessa, and congratulations, I think your match was relatively recently. So, we're excited to see where your career takes you from here and appreciate your contribution so far. Now I'm going to introduce you to Pishoy Gouda. Pishoy Tell us a little bit about yourself.     Dr. Pishoy Gouda: Morning, Dr. Khera. My name is Pishoy. I have had the privilege of doing my medical trading all over the world. I was born here in Toronto and moved to Edmonton where I mostly grew up. Since then, I traveled to Galway Ireland where I spent six years to do my undergraduate medical training. Hopped over a short flight and did my Masters in Clinical Trials in the London School of Hygiene and Tropical Medicine before returning to Canada to start my residency training. Got to work with some amazing people in Calgary while I completed my internal medicine training, and then finally returned home to Edmonton where I am in the last few months of my adult cardiology training. Dr. Pishoy Gouda: Next year, I'm really excited to start my interventional cardiology training, which is going to be really exciting. Some of my interests, working with social media, wearable technology so working with this great group has been really awesome. Dr. Amit Khera: Thank you Pishoy. Obviously lots of travels from you as well, and we definitely appreciate your expertise and interest in social media and in technology. It's been very valuable. Next someone who's closer to my backyard. Ming Jia. Ming, welcome. Dr. Xiaoming (Ming) Jia: Hello from Houston, and thank you Dr. Khera. So, it's been a great opportunity to be involved as a social media editor for Circulation. So I'm a current cardiology fellow at Baylor College of medicine in Houston, Texas. Was originally born in China, and grew up in sunny Florida. I did my medical training in Florida as well, and then moved over to Houston, Texas for residency, and now wrapping up my last year in general fellowship. Next year, I'll be staying in Houston at Baylor for interventional fellowship. Then, hopefully after that career in interventional cardiology, but as well as preventional cardiology as well, I tended to actually interest in both interventional and preventional cardiology. Dr. Amit Khera: Very cool. I know you and I were talking about this right beforehand, how that nexus of the two fields and just some of your interest in a lot of the research you've done so far. So again, offering a unique and different perspective, which we appreciate so, welcome, Ming. Next, Peder Myhre. Peder, welcome. Dr. Peder Langeland Myhre: Thank you so much, Dr. Khera. This is Peder Myhre from Norway, all the way across the pond. And it's such a great honor to be part of this podcast, which I've been a big fan since it started a couple years ago and where Carolyn Lam has been doing with it, it's been really amazing. And I've actually been promoting it to everyone I know with any kind of interest in cardiology. My position in training right now is that I'm in the last year of cardiology training and I'm also doing a 50% post-doc at the University of Oslo with Professor Torbjørn Omland as a mentor. And as a part of my training, I was one year at Harvard University at Brigham Women's Hospital to do research with Professor Scott Solomon's group a couple of years ago. Dr. Amit Khera: Well, we appreciate your affinity and now you get to be on the podcast. That's pretty exciting as well. I should say, each of you is linked to an outstanding Associate Editor at your home institution. And so we're glad you have that mentorship as well there too. And speaking of someone at home institution, someone who I've known for a very long time, Dr. Sonia Shah. Sonya, introduce yourself, please.   Dr. Sonia Shah: Thank you, Dr. Khera. No, just to echo what everyone has said already, it truly has been an honor and a privilege to work with this awesome team. And it's been a lot of fun along the way. So I'm Sonia Shah. I'm a third year cardiology fellow at UT Southwestern in Dallas, Texas. Originally from Central Florida, actually. And then did my undergrad medical school training in Chicago and then went out to the West Coast for my residency training was out at Stanford and now I'm loving being in Dallas. So it's been a lot of fun. So I particularly have an interest in women's cardiovascular health and advanced imaging. And so currently looking for jobs now. Dr. Amit Khera: Well, I can say you've been a star fellow and have a really incredible and unique skillset. And, so we look forward to seeing what your career brings and certainly you've brought a lot to our podcast. And we'll talk more about that in just a bit, since you are longest standing social media editor currently. Well, I want to now dig in a little bit and you all again, I want to thank you for what you've done for the last several months. I certainly have learned a lot from you. We've had some discussions as a group about, thoughts about social media and how social media works. Dr. Amit Khera: And so maybe we'll start with the sort of existential question about, why social media? What is the value for journals, if you think about Circulation, but really any journal. What does social media bring? And again, you all have a unique perspective as largely fellows in training and Vanessa, maybe I'll go back to you a little bit about, why social media? What's the point of relevance about all this work that you're doing? Dr. Vanessa Blumer: Yeah. Thank you so much, Dr. Khera. I think that's a great question. And I do think that that's a question that we ask ourselves every day as we're doing this. I think the way that the medical literature has been evolving, it's been evolving in a way of social media and people are consuming more and more social media daily. I think in my own daily life, I discover articles that I'm interested in through social media a lot more than I used to before. And I also discover that I'm interested in particular articles, the way that they are transmitted in social media or the way that they're presented in social media. Dr. Vanessa Blumer: So I think we're reinventing ourselves and reinventing the way that we present to the public, the articles that we have in Circulation, so that people want to read our articles or want to read the articles that authors are doing such a great job at putting together. So I think, we are coming up with creative ideas every day and it's part of what we discuss as a group of how do we present this so that people want to read the articles and discover all the hard work that authors are putting together through different social media platforms. Because we know that people consume not just one social media platform, but several. So I think there's huge potential in social media if we use it in the right way. Dr. Amit Khera: Yeah. I think your points well taken. I know we're going to talk a lot about Twitter today, but as you pointed out, there are other media as well. That's just in the sort of main, I guess, currency and in the medical and cardiovascular literature. And you mentioned value to authors and one thing you mentioned, which I'll transition a little is about the way things are presented, help you get interested in them. And so that gets to the art of the tweet. Something we've talked about a little bit and, there's a little bit of on the job training, if you will. And we've talked about is there a gold standard in terms of what makes a good frankly, a medical journal tweet. Well, Ming, what do you think? You've been toiling over this for a few months now and tell us what you think is helpful in a medical journal tweet in terms of achieving the goals that Vanessa mentioned. Getting an audience interested in reading these articles is really doing justice for the authors to transmit their research. Dr. Xiaoming (Ming) Jia: Great question, Dr. Khera, and this is something that, as a social media editor, I'm still learning. So for me, writing a concise tweet is very important. Trying to get that essence of a entire study into a very limited number of characters. Obviously having a great figure that highlights the key findings of a study is also very important as well. Now at the same time, I think the most effective posts though, are those that serve as a hook for the paper. So, while we want are tweet to stand on their own. I think the most effective tweets helped to entice the audience to want to read a little bit more and go and read the entire manuscript. So certainly there is a art and skillset in terms of writing these effective posts. Dr. Amit Khera: Yeah. You certainly bring up some key points, right? So being concise, one by definition and but two is, there are tweets that sometimes can go on and on and that comes into using some interesting hashtags and some shortcuts. But I think your point about innuendo, enticing, not giving away the whole story, but just enough to get people to want to read more. And I think that that is an art. Dr. Amit Khera: And I've certainly seen as you all have done this more and more about how your own writing and tweets have evolved. Pishoy, we've talked a little bit about, all of you are researchers, you've all done some great research, about thinking about social media, sort of a research area. Again, since there's no gold standard about what's a great tweet, just thinking about it more of a discipline as we do any other area that we want to explore scientifically. What are your thoughts about, how do we figure out more, learn more about what makes a great tweet? Dr. Pishoy Gouda: Yeah. Evidence based tweeting is something that I've been interested in. Everything that we do, we want to make sure that we do it well and that we do it effectively and the same goes with social media posts. So what works, what raises interactions with our content. And that's something that other disciplines and advertising have been doing all the time and we should be doing the same as well. If our goal is to increase interactions with our content, then we want to make sure that we are doing it in the most evidence based way. And we've learned a few things. We know that cardiologists and individuals in medicine in general have been using Twitter much more frequently as a way to consume in both your medical and research content. Dr. Pishoy Gouda: So what makes a post great and what increases its interaction and the bottom line is we don't really know. We have a few studies and a few small randomized controlled trials that have been done that give us some insight. We know that vigor, that tweets that include images might pull readers to them a little bit more. But you know what exactly works. We have a lot of observational data, but we don't have a lot of high quality data that gives us the answer to this question. So what we've learned so far is use images, use links. If you can use graphical abstracts, that seems to help as well. But, it's something that we're continuously looking at and we're really excited to put together some new evidence coming up soon in the future. Dr. Amit Khera: Evidence based tweeting. I like it. As you and I have discussed, my predecessor Carolyn Fox had a randomized trail called Intention-to-Tweet using Circulation and then a follow-up study to that. So we hope to do also some good high quality research about social media and what works. Well, that gets to who's your audience, right? I always like to think about when you start something, who's your audience. And there could be lots of people. I think probably our strike zone is researchers, scientists, clinicians, of course, there's lots of lay individuals too, that are paying attention on social media. One thing that's different about Circulation than some other journals is this melding of basic science and clinical science. Some journals are all basic science and all clinical science and Circulation's both. Dr. Amit Khera: And I mean, frankly, that's posed an interesting challenge for this group. None of you are, including myself, are card carrying basic scientists, if you will. So we've had to translate those articles. And I would consider that both a challenge, but also an opportunity because, if we're speaking to a basic science audience, of course we may have one tone we use, but we want this basic science. I think that's the purpose of Circulation is basic science applicable to the clinician and clinical researchers. So, translating that's been a real opportunity. And Peta, maybe I can ask you about that opportunity of translating basic science for clinical researchers and clinicians. Dr. Peder Langeland Myhre: Yes. I completely agree. And I've learned so much from this job as a social media editor to really try to get the essence out of a basic science paper and the translational outlook for clinicians. Because all of the papers that are basic science that at least I came across in Circulation also have a clinical implication and a translational side of it. And I think when we read these papers and try to sum it up in one tweet, we want to keep the most important essentials of the basic science, but also extend it to clinicians so that they understand in what setting and what this can potentially mean in the future. So for me, that's the biggest challenge when we review basic science papers, but it's also perhaps the part of this job that I learn the most. Dr. Amit Khera: Yeah. I agree. I think we're all learning a lot. I've certainly learned a lot by delving in deeper into the basic science papers and figuring out how to translate them appropriately. And I think this really highlights, as you mentioned, what Dr. Hill our Editor in Chief, his feeling is basic science papers in Circulation all have to have important clinical implications. That's the benchmark, if you will. So I think we've seen that shew in terms of what papers have come across for you all. Dr. Amit Khera: Well, I'm looking now at our longest standing social media editor, Sonya Shaw, she started a few months before as sort of a transition because we certainly wanted someone in place that could help bridge between the old and the new. And Sonya, you've had a decent amount of experience now with two editorial teams. Tell us what you've learned so far by working as a social media editor at Circulation. What are some of the observations you've had and some of the things you've learned in this space? Dr. Sonia Shah: Yeah, certainly. So I think a couple things. I think my ability to accurately and concisely convey the important key points from each journal has definitely improved. But I think the other unique thing, unique perspective that we gain as social media editors is getting to actually see the behind the scenes workings of how the journal works and how papers are put together and accepted. And so I think it's been interesting to see how papers are being analyzed and the teamwork that's required by the Associate Editors and the Editors and making sure to do each paper justice and properly evaluate it. So I think that's been a really cool experience. It certainly has improved my ability to write when I try to think of, what are the key points I want to include. And how to convey information in a way that will be appealing to journals. Dr. Amit Khera: Well, thank you for that. We take this job very seriously, as you all have in that point about doing each paper justice, because you've seen, one, from the author's perspective about how much work they put in and you've been an author before and want to make sure that we appropriately appreciate that. And then also the Associate Editors, there are hours and hours of work for each paper. So even though it comes out, maybe in a few characters in a tweet, we appreciate all that's going behind it. And I'm glad you've gotten to see that process through. Ming, maybe I can come back to you. What have you learned so far by working in Circulation for the last few months? Dr. Xiaoming (Ming) Jia: I do want to echo what Sonya just said in terms of really getting a glimpse of the behind the scenes work is quite amazing. The amount of work and coordination it takes to get a paper from publication to promotion. And, we don't really get that exposure as a author for a manuscript or even as a peer reviewer. So, that part has definitely been a great learning experience. On the other side, I do find it interesting that ever since taking on this role as a social media editor, my way of writing has changed as well. So, trying to be more efficient, getting key points across and really being concise and focused in my manuscript writing. So that's been very helpful from a personal level as well. Dr. Amit Khera: We're very thankful for that. I think we always want this to be bidirectional where you all are contributing in meaningful ways. But that the goal here with fellows in training in this role, social media editors. But for you all to be learning something as well. So I'm glad that that has occurred. And we'll talk more about that in just a few minutes. Dr. Amit Khera: Well, we have a couple of international social media editors and this is my intention. We want to make sure we have a diverse group of social media editors. By background, by thought, by location. And, one way that the beauty of that is again, we get different perspectives. I guess the downside is time zones. We were just joking before, as we were starting this podcast about some of us are very early in the morning and one of our social media editors unfortunately is always late at night when we have our meetings. Peta, tell us a bit about unique observations from an international perspective. You said you've been following Circ for a while, but tell us, from your perspective in Europe, the social media process and how you see it. Dr. Peder Langeland Myhre: Thank you so much. And it's actually been a really transformation for me from before I spent my year in Boston to after. Because I really learned the potential of using social media and especially Twitter to stay updated and get the latest papers and thoughts from experts in the field. And I remember before I went there, I was often very frustrated that it was so inconvenient to get across important papers that was within my field of interest. Because all the journals were not longer sent in paper to our hospital and the websites were confusing. Dr. Peder Langeland Myhre: So when Dr. Vaduganathan at the Brigham & Women's Hospital introduced me to Twitter, that really was an eye opener for me. And, ever since that, 90% of the papers that I read I first see on Twitter. Because that's the first place, the people that are within my field, publish it or tweet it. And also I'm able to, you follow a certain amount of scientists and physicians and they have the same interest as you. So it's also, most of it is relevant for what I want to read. So it's really been a revolution for me to start to use Twitter and social media for medical and scientific purposes. And not only for friends and family. Dr. Amit Khera: Yeah. I think it's some great points. One, is even simplistically just be able to access articles, which we don't always appreciate, from people from around the world. And then obviously what many can, is follow people that have similar interests and amazing to see sort of how different people consume the literature. And for you Twitter being your entry point, I guess, for how you do that, which is I'm sure many, many people do the same. And we have another international editor you met earlier. Pishoy, tell us your perspective. And obviously you're in Canada now and have moved many places. What's your perspective from an international perspective, looking at social media? Dr. Pishoy Gouda: Coming to work at Circulation, I expected a very niche editorial board, but what I'm really finding out is boy, does it take a village. And it is people from all over the world. And it really hits home that collaboration and research has become a global phenomenon. And to be able to do art well and to appropriately represent researchers from across the world. We have an editorial board and team that is global and it really does take a village to take a paper from submission all the way through the publication team, starting from the authors to the peer reviewers, editors. But then the entire post-production team, which is behind the scenes and don't get a lot of glory, but they do a lot of the heavy lifting to make sure that, the research that's submitted gets in front of readers. And that's something that I hadn't really thought of before. And it's been really interesting to see how that process unfolds. So that's definitely been eye opening for me. Dr. Amit Khera: Well, I appreciate what you said about, when it takes a village and I would be remiss if I don't always call out Augie Rivera, who is the engine and mastermind behind Circulation, who's helping us do this podcast today and every week. But the other part is the international workings I think many may not appreciate. We have editorial board meetings every other week at very different time zones on purpose because we have people in Europe and in Asia and in Africa. And as you know, Dr. Lam who's the main podcast editor is in Singapore. Dr. Amit Khera: So, this is by intention. It really gives us a wonderful international perspective. And so we're so glad to have you two as part of our international team. Well, I think that's a great transition, a little bit to just talking about fellows in training and involvement in journals for Circulation perspective, and from the AHA, I should say, getting fellows in training involved in cardiovascular research, the editorial process, this is something that's really important to us and something we continually strive to find new ways to do. So, Vanessa, I'm going to come back to you. I know, not just at Circulation, but I know at other journals you've had some responsibilities. Tell us a little bit of what you tell other fellows in training about getting involved in journal activities. How to, and what's the benefit. Dr. Vanessa Blumer: Thank you so much Dr. Khera. I think this is such an important question. First my recommendation is, get involved in one way or another. I think there's different ways of getting involved as simple as just start reviewing articles. And the reason I say this is as I aspire to become an academic, a well-rounded academic cardiologist, I think my involvement with journals has just made me a much better researcher, a much better academic cardiologist. It's made me, I think, Sonya said this so well, it's made her a better author. It's made me a better writer. So I think it compliments what you do just so much better. I think you're better at what you do when you see the behind the scenes and you understand what happens in scholarly publishing. So I think there's different ways of getting involved. I know that Circulation has many and then probably a good way is to reach out. Dr. Vanessa Blumer: I know that people can reach out to us and we can probably guide them along the way, but different journals have different ways of getting involved. But I think if you want to start, one way is start reviewing. You learn a lot through the review process in itself on how an article is structured. And there's some journal that have a little bit more of a mentorship approach towards reviewing. And, that's also a good way starting out. When we start off as residents, we get some papers get in our inbox to review and we really don't necessarily know how to approach it. So maybe a mentorship approach to it is a good way to start. But overall, I would just say, start getting involved. I think it's a great experience. Personally, I have learned so much from it and I think I'm just a better academic cardiologist because of it. Dr. Amit Khera: Thank you for that. And I think your point about just find ways to get involved. And I think our challenge is to continue to facilitate ways for trainees, fellows in training and others to get involved. But I think that that first step in finding maybe a mentor of your institution that could help guide you would be important. And I'm going to finish with Sonya. I'm going to come back to you. You've not only had the social media editor window for quite some time. Being at Circulation, you get to see behind the curtain perhaps more than others because, Circulation is such a big part of what we do at UT Southwestern. And, we've had this Fellow Reviewer Program where you've been able to participate in reviews and things like that. From your perspective, maybe telling the fellows in training, listening out there about getting involved in journal activities, the value that you've seen and how to do so. Dr. Sonia Shah: Yeah, I think that's a really important question. At the end of the day, the ability to read and interpret and take away the major conclusions and properly interpret a study is a skill. And so I think the more you do it, certainly the better you get at it. And being part of a journal being on the reviewer end, being on the end where you're creating social media posts is really an opportunity to develop and refine that skill. And so to all the fellows out there who are interested, regardless of whether you want to do academic cardiology or not, it is an important skill, even in the future, to be able to read and properly interpret studies. So I highly recommend it. I find for me, I've definitely learned a lot through the process and have certainly improved. Dr. Amit Khera: Well, there you have it, our five social media editors. First, I want to thank you all for your contributions to Circulation. You're an incredibly bright group as everyone learned about. I have future leaders in cardiology. And we're very fortunate to have you contributing to Circulation and to our authors and readers. So thankful to have you as part of Circulation and look forward to working with you and innovating and coming up with some creative, new ways to think about social media and ways to transmit research for journal. Dr. Amit Khera: Well, I think there you have it. Again, I'm Amit Khera. I'm associate editor and standing in this week for Carolyn Lam and Greg Huntley, who will join you again next week. So thank you for joining us for Circulation on the Run. 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.

durée : 00:58:40 - Les Chemins de la philosophie - par : Géraldine Mosna-Savoye, Adèle Van Reeth - Avez-vous déjà eu cette impression paradoxale, au volant, d'être tout à fait vous, fluide, rapide, en connexion avec les autres, mais en même temps de pouvoir devenir le pire de vous-même, et même ne pas vous reconnaître, colérique, tout-puissant, imprudent ? Si oui, cette émission est pour vous. - invités : Matthew Crawford chercheur, Senior Fellow à l'Institut des hautes études culturelles à l'université de Virginie

Amanda Pierce from the Teen Zone and Ben Sargent from Circulation join Marty for a roundtable discussion of the holliest and not so jolliest holiday movies, tackling the eternal debate: Is Die Hard a Christmas movie? Plus, there's bourbon balls, fruitcake, and Reese's Christmas trees. Holiday book recommendations: Amanda--The Polar Express by Chris Van Allsburg Ben--A Christmas Carol by Charles Dickens Marty--Mr. Ives' Christmas by Oscar Hijuelos

Please join Guest Host and Associate Editor Mercedes Carnethon and author Christine Albert as they discuss the article "Effect of Long-Term Marine ω-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. We are 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, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, today's feature paper is such an important question clinically. It's something I've asked myself and so I cannot wait to discuss it in greater detail. It refers to the effect of long-term marine omega-3 fatty acid supplementation, and the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. So it talks about a systematic review and meta-analysis published in this week's issue. Dr. Carolyn Lam: All right. Okay. You got to wait in suspense, as do I, and let's discuss other papers, very important papers in today's issue too. I'd like to start with a bit of a quiz. So Greg, for converting atrial fibrillation, is the anterior-lateral or anterior posterior electrode position better? What's your guess? Dr. Greg Hundley: Oh, wow, Carolyn. That's interesting. We put these pads on and we kind of just follow the directions on whatever the particular device says. Interesting question. It's a guess, Carolyn, it's a guess. Antro-lateral? Dr. Carolyn Lam: Smarty pants. Well, let's see. Frankly I didn't know the answer. It's just such an elegant question, isn't it? To answer in a study. And this is exactly what Professor Løfgren from Randers University Hospital and Denmark and colleagues did. They performed a multi-center investigator initiated open label trial, where they randomly assigned 468 patients with atrial fibrillation scheduled for elective cardioversion to anterior-lateral versus anterior-posterior electrode position. Dr. Carolyn Lam: The primary outcome was the proportion of patients in sinus rhythm after the first shock. And so drum roll. The primary outcome occurred in 54% assigned to an anterior-lateral electrode position. And in 33% assigned to an anterior-posterior electrode position, a significant risk difference of 22% in favor of the anterior-lateral electrode position. Dr. Carolyn Lam: Cheers, Greg. There were no significant differences between groups in any safety outcomes and the superiority of the anterior-lateral electrode position was statistically significant both after the initial low energy shock and after a final high energy shock. So this study really suggests a practice change in the standard approach to electrode positioning for cardioversion in favor of anterior-lateral electrode position. Dr. Greg Hundley: Very nice, Carolyn. Very nice. Well, I'm going to come at you using your heart failure expertise and ask you a quiz here in just a second. But first I want to introduce this paper from Dr. Javier Barallobre-Barreiro from King's College London. Okay, Carolyn, here's your quiz. Do you think that the extracellular matrix fibrosis contributes to LV dysfunction in heart failure patients? Dr. Carolyn Lam: Absolutely. Dr. Greg Hundley: Very nice. I think, of course, you are correct. So Carolyn, remodeling of the extracellular matrix is a hallmark of heart failure and this team's previous analysis of the secretome of mirroring cardiac fibroblast returned ADAMTS5, a disintegrin and metalloproteinase with thrombospondin motifs 5 as one of the most abundant proteases. So ADAMTS5 cleaves chondroitin sulfate proteoglycans such as Versican. The contribution of ADAMTS5 and its substrate Versican to heart failure is unknown. Dr. Carolyn Lam: Ah, so what did the authors find, Greg? Dr. Greg Hundley: Well, first Carolyn, there was a methodologic advance here. Left ventricular tissues from 86 heart failure patients and non-failing controls were analyzed by quantitative mass spectrometry, constituting the largest proteomics analysis on human heart failure today. And so what did they find? Accumulation of proteoglycan Versican was regulated by ADAMTS5, that disintegrin and metalloproteinase with thrombospondin motifs 5, and was associated with the reduction in proteins involved in intercellular communication. And Carolyn, interestingly, proteoglycan accumulation in ischemic heart failure was attenuated by beta blocker administration. Dr. Carolyn Lam: Oh, that's very interesting. Could you put that all together for us? What's the clinical implications, Greg? Dr. Greg Hundley: You bet, Carolyn. So proteoglycan secretion by cardiac fibroblast constitutes an important component of cardiac fibrosis after ischemic heart failure, just like you stated at the beginning with your quiz answer. This contributes to impaired cardiac function and besides their negative chronotropic and inotropic effects, beta blockers may modulate extracellular matrix remodeling. Dr. Carolyn Lam: Wow, nice, Greg, thank you for that. I've got another original paper and it deals with the very important topic of endothelial to mesenchymal transition. Now it has been reported that cardiac endothelial cells contribute to a substantial proportion of myofibroblast through this process called endothelial to mesenchymal transition. Lineage tracing studies have demonstrated that myofibroblasts are derived from expansion of resident fibroblasts rather than from transdifferentiation from endothelial cells. Dr. Carolyn Lam: However, it remains unknown whether endothelial cells can transdifferentiate into myofibroblast reversibly or would these endothelial to mesenchymal transition genes just transiently activated in endothelial cells during cardiac fibrosis? So these authors, corresponding authors, Dr. Sun from Shanghai Jiao Tong University School of Medicine, Dr. Lui from Price of Wales Hospital and Chinese University of Hong Kong, as well as Dr. Zhou from the University of Chinese Academy of Sciences in Shanghai and their colleagues. Dr. Carolyn Lam: What they did is they used the dual recombination technology to generate a genetic lineage tracing system for tracking endothelial to mesenchymal transition in cardiac endothelial cells and their genetic fate mapping results basically showed that although mesenchymal gene expression was activated in cardiac endothelial cells throughout the endothelial to mesenchymal transition in the developing heart, the endothelial cells do not transdifferentiate into myofibroblasts, nor do they transiently express some known mesenchymal genes during homeostasis or fibrosis in the adult heart. Resident fibroblasts that are converted to myofibroblast by activating mesenchymal gene expressions are in fact the major contributors to cardiac fibrosis. Dr. Greg Hundley: Ah, Carolyn, very interesting. So can you put this together? What are the clinical implications? Dr. Carolyn Lam: So what it really says is that it's the resident fibroblasts that are converted to myofibroblast by activating mesenchymal genes. These are the ones that represent a major therapeutic target and really unraveling these mechanisms, driving endothelial to mesenchymal transition in such a detailed way, provided new insights into therapeutic development to target cardiac fibrosis. Dr. Greg Hundley: Wow, Carolyn. You know, two really good preclinical science articles speaking to us about myocardial fibrosis. Dr. Carolyn Lam: Well, there are other papers in today's issue too. There's a Perspective piece by Dr. Christopher Lamb on “Liver Cirrhosis and Hepatocellular Carcinoma After the Fontan Operation: Reaching Clarity in the Face of Uncertainty. And this is paired with a Research Letter by Dr. Toshio Nakanishi on incidents and expected probability of liver cirrhosis and hepatocellular carcinoma after the Fontan operation. Dr. Greg Hundley: Very nice, Carolyn, and I've got an “In the News” piece from Bridget Kuehn entitled “Centering Equity in Cardiovascular Care as Michelle Albert Lays Out a Roadmap for our Profession.” Well, Carolyn, how about we learn a little more about those long term marine omega-3 fatty acid supplementations and the risk of atrial fibrillation? Dr. Christine Albert: Oh, I can't wait. Let's go, Greg. Dr. Mercedes Carnethon: Thank you so much for joining us for today's episode of Circulation on the Run. My Lame is Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and Associate Editor at Circulation. And I have the great pleasure today of having a conversation with a long time friend, Dr. Christine Albert from the Department of Cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles. Dr. Mercedes Carnethon: And today I've got the great pleasure of hearing directly from Christine about a wonderful original research piece that is being featured in Circulation about the effect of long term marine omega-3 fatty acid supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes. And the exciting innovation of this piece that we'll dig into is what we're learning from the systematic review and meta-analysis that Dr. Albert and her team carried out. So, thank you so much for joining us today, Christine. Dr. Christine Albert: Well, thank you, Mercedes. It's really great to be here. Dr. Mercedes Carnethon: Great. Well, I'd just like to launch with you telling us a little bit about the study, what you found, why you decided to conduct this meta-analysis and review. Dr. Christine Albert: Yeah. Great. So my first author, Dr. Baris Gencer and I decided to do this because we actually had participated in a randomized trial called the Vital Rhythm Trial, where we actually randomized people to omega-3 fatty acids and atrial fibrillation, and found a slightly elevated risk, but it wasn't significant. And at that time, a number of other articles came out saying that there really was an increased risk of atrial fibrillation. Dr. Christine Albert: So we wanted to put together the data to see what the combined data, our data, that's been published before, on this sort of long term treatment with omega-3 fatty acids and atrial fibrillation. As you may know, there have been studies that have looked at short term treatment, and specifically for atrial fibrillation, and did not find benefit. So this is why we went ahead and did this study. And what we did is we were able to find seven randomized trials that collected data on atrial fibrillation that had randomized people to omega-3 fatty acids over an average of about five years of follow up between all the different trials. And we found that when you combine all these trials together, you actually see that there is a slightly elevated risk of atrial fibrillation in the participants that were randomized to the omega-3 fatty acids. Dr. Mercedes Carnethon: Thank you so much for that summary, Christine. I think the findings themselves surprised me. This is not my primary area of work, but we hear so much about supplements and their benefits that I thought it was really telling to actually have these data coming from a large number of studies, and particularly large studies that suggest that there is a risk to benefit ratio that we need to consider. How would you recommend that clinicians weigh this evidence that you've generated today? Dr. Christine Albert: So I think that it's got to be individualized. There are benefit, as you said, of these omega-3 fatty acids. And I think it's just awareness, awareness that this potentially is a risk. If you have a patient on omega-3 fatty acids and they start to have atrial fibrillation, there could be a link. Also when you talk about it with patients, I think it's reasonable, especially with the higher doses, we can just discuss that this is a potential side effect. Does it prevent you from using it? I don't think so. I think you have to look at what is, again, as you said, the risk benefit ratio for the individual patient. And as I alluded to, we did do a dose analysis and we found that the risk was primarily seen, and it was higher, in those that were given more than a gram of omega-3 fatty acid a day. Dr. Christine Albert: However, I will say that the trials are very different when you take a meta-analysis, it's really hard to say, "What is the cause of the differences between trials?" You know, these trials that had the higher dose, the reduce it trial that used just a purified EPA was very different than the dose of the medication that was used in vital, different than the type of medication that was used in strength. And as you know, there's the whole debate about the placebo and reduce it versus strength. And so there are other differences, but one thing that is pretty consistent is that most of the point estimates are on the side of harm. So there is the thought that I think this is potentially very real and we should be considering it when we use these supplements. Dr. Mercedes Carnethon: You know, that's a really nice summary which really launches me into two subsequent questions. The first would give you the opportunity to speculate beyond the findings in your particular study, and this is one of the benefits to me of this Circ on the Run podcast, because you, of course, produced excellent science and weighed all of your findings based on what you found. But can you tell me, based on your experience, could you speculate about what you think the mechanism of elevated risk of atrial fibrillation is, particularly with those higher doses? Dr. Christine Albert: Yeah, no, it's interesting. You know, if you look at the epidemiology for this, Mercedes, it was totally inconsistent. When I postulated doing the vital rhythm trial, I actually have to be honest with you, I thought that there might be an increased risk, because when you look at some of the data of what these omega-3 fatty acids do, they increase vegal tone, they lower heart rate. They can actually slow conduction. So potentially those electrophysiologic actions might, might allow atrial fibrillation to emerge in people who are susceptible. Dr. Christine Albert: On the flip side, all of those things might be good for ventricular arrhythmias. So you see, if you look at the literature, there's benefits for…sudden death and epidemiologic studies and in some of the randomized trials, but then when you look at atrial fibrillation, at least the short terms, really didn't show a benefit. And again, that point estimate was more towards harm. Dr. Christine Albert: And then when you look at epidemiologic studies, looking at fish consumption, there's actually a lot of studies that suggest that people who eat more fish get more AFib. So it is really paradoxical. And we know as electrophysiologist that atrial arrhythmias and ventricular arrhythmias are not the same, we give drugs to prevent atrial arrhythmias that then cause ventricular arrhythmias. So it is interesting. And I think it's something that hopefully some of our translational scientists will help us to figure out. Dr. Mercedes Carnethon: All those contradictions are so challenging, but you were certainly speaking my language in describing the hypothesized mechanisms. It calls to mind, back in the day, in your early research on sudden cardiac death that I was citing as part of my dissertation work in epidemiology. So thank you for that. Dr. Christine Albert: Yeah. Dr. Mercedes Carnethon: You know, the second question that builds off of that is I thought that the figure where you display the heterogeneity by the dosage of omega-3's really underscores the argument that you were just presenting. What I was wondering is, did you happen to study heterogeneity by any other characteristics, particularly sex or age? Dr. Christine Albert: That would be fantastic to be able to do, unfortunately, because it's a summary level meta-analysis, we really can't do that. And that's one of the things that we'd love to do in collaboration with some of these authors if they would like to do that, is to really get that sort of paid participant level data, so we could do those kinds of analysis. Dr. Christine Albert: But what we did do is sort of separate out studies that had like confirmed AF, studies that had incident AF versus recurrent AF, so things where the studies were completely different, we were able to look for heterogeneity and we didn't find anything that suggested that there was heterogeneity on that basis. But there's a number of things that I would love to look at and age is definitely one of them, and also sex. And actually looking at, which would be really interesting, is to look at the omega-3 or EPA and DHA levels in these individuals. And again, I think each study has sort of tried to do it on their own and you can't because there's just not enough data. So putting all this data together would be great to have a better understanding of what's going on. Dr. Mercedes Carnethon: Oh, it sounds speaks to a number really thoughtful future directions for this work. One of the benefits of me being able to speak with you today in my role as a guest podcast host, but I was also the Associate Editor for the piece and was really excited when it came in. The discussions that we had amongst the editors about this were really very stimulating and raised a number of questions that led to you responding and making some modifications and explaining certain things. Could you tell our audience, why did you select trials over a certain size? You know, quite often we do meta-analyses in order to pull together smaller studies, but why did you choose larger studies? Dr. Christine Albert: I think it was so that, there were two criterias, one was larger and one was long term, because we felt that the smaller studies had been merged together previously and we wanted to have at least some data on atrial fibrillation. One of the problems I think that I think I want to emphasize a little bit here about research in general in cardiovascular disease is that until now, most studies hadn't really measured atrial fibrillation, and I think it's really important. And I think you can see, you can find off target effects of some of the agents that we use for cardiovascular disease on atrial fibrillation. So for instance, the Statin Trials, everybody said, "Oh, well statins might lower atrial fibrillation," but then nobody measured atrial fibrillation, so we never knew. And then people went back and tried to measure it as a side effect or something that has all kinds of biases to it. Dr. Christine Albert: So I think that what is exciting about this work is that both reduce it and strength and vital, pre-specified that they were going to look at atrial fibrillation. And so if we do that, we may actually find other agents that are beneficial, not just harm, but beneficial, like the SGLT2 inhibitors, there's lots of hypotheses. So the reason that we did pick the bigger trials was that we wanted to find trials that really kind of looked at atrial fibrillation, had enough power to look at atrial fibrillation and then over a long term, a follow up to gather enough events. Dr. Mercedes Carnethon: Again, it has been such a pleasure to hear directly from you. I really hope that our listeners today and our readers of The Journal will dig into this in the same way that we have as editors and really appreciate the thoughtfulness with which you've presented this outstanding work. So I want to thank you so much, Dr. Albert for joining us today. Dr. Christine Albert: Thank you for having me. Dr. Mercedes Carnethon: I guess I will sign off now. This is Mercedes Carnethon from the Northwestern University Feinberg School of Medicine and Associate Editor for Circulation. Disclaimer: 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.

If you want to sell your home for a high price, improving your home's air circulation can make all the difference. Can it impact your selling price? Absolutely! ABOUT THE PODCAST: This podcast is an audio feed of the website, CadeHildreth.com where you'll learn what you SHOULD'VE been taught in school. As an LGBTQ + entrepreneur, real estate investor, former USA Rugby Player, and fitness enthusiast, Cade will teach you what your parents and teachers should have taught you but didn't know themselves. You'll learn how to increase your income, negotiate a raise, buy real estate, invest for cash flow, lose 10 lbs fast, reveal 6-pack abs, and so much more. CONNECT WITH CADE: Website: CadeHildreth.com Instagram: Instagram.com/CadeHildreth Twitter: Twitter/CadeHildreth Facebook: Facebook.com/CadeHildreth Pinterest: Pinterest.com/CadeHildreth

Welcome to Dive Into Reiki With... an interview series that explores the journeys of high-profile Reiki teachers & practitioners. Hosted by Nathalie Jaspar. You can support the mission of spreading Reiki education through my Patreon for less than the cost of a cup of coffee, or for free by rating this podcast on your app!EPISODE 16—DR. JUSTIN STEIN Dr. Justin Stein (Ph.D.) is an instructor in Asian Studies at Kwantlen Polytechnic University. His research program focuses on how exchanges within transnational networks have shaped spiritual/religious practices and ideas in the North Pacific region. His work on Reiki, including original translations of historical materials, has been published in three languages. His upcoming book, Alternate Currents: Reiki Healing, North Pacific Networks, and the Circulation of Transnational Spiritual Therapies, focuses on the life work of Hawayo Takata, whose cultural translation turned Reiki from an obscure Japanese practice into a source of healing and spiritual transformation for thousands of Americans and Canadians. Justin is also a Reiki practitioner. You can contact Dr. Justin Stein through his website, FaceBook page, or directly via email.   or via email at: steinjustin@gmail.com.Nathalie Jaspar, founder of Dive Into Reiki,  is a Reiki master with over a decade of experience. She's a graduate teacher from the International House of Reiki, led by world-renowned Reiki master Frans Stiene. She also trained with the Center for True Health, and the International Center for Reiki. To gain an even deeper understanding of Reiki practice, Nathalie went to Japan to practice Zen Buddhism at the Chokai-san International Zendo. She is the author of Reiki as a Spiritual Practice: an Illustrated Guide, and the Reiki Healing Handbook (Rockridge Press). She offers continuing Reiki education via her Patreon platform. Support the show (https://www.patreon.com/diveintoreiki) Support the show (https://www.patreon.com/diveintoreiki)

Mission encre noire Tome 32 Chapitre 372. Jusqu'au dernier cri de Martin Michaud, une enquête de Victor Lessard, parue en 2021 aux éditions Libre expression. Au milieu d'une violente tempête, le sergent détective Victor Lessard, enfourche une Honda CR250M Elsinore, il passe en première et actionne le levier d'embrayage pour une course poursuite des plus mémorable au cœur des paysages sauvages englobant la route de la Baie-James. Car voilà, suite à l'assassinat de trois membres d'un puissant cartel de trafiquants d'opium, un précieux colis a été dérobé aux trafiquants qui n'entendent pas à plaisanter. L'enquête déraille rapidement, lorsqu'un homme en fuite, prend huit personnes en otage dans une mine de Matagani. Alors qu'il accompagne Jacinthe Taillon dans la salle d'attente d'un hôpital, à la demande de la GRC, Victor est le seul individu à qui le criminel veut s'adresser. Les deux enquêteurs du SPVM se retrouvent précipités dans une chasse à l'homme haletante, sur les traces de l'auteur du triple meurtre. Embarquez dès ce soir avec moi vers le Nord-du-Québec, histoire de renouer avec les deux inséparables enquêteurs Lessard et Taillon, de croiser Yogi Berra, Scotty Bowman, Victor Hugo, Christopher Walken, Fellini, et bien d'autres, sans oublier bien sûr la montre Hamilton héritée de son mentor Ted, un gant de baseball fétiche et le So what de Miles Davis. J'accueille ce soir, à Mission encre noire, le maître du thriller québécois, Martin Michaud. Extrait:« Victor sentit un craquement sous les semelles de ses bottes élimées. Il s'arrêta et en identifia la cause: il venait de marcher sur des éclats de verre. Il comprit alors pourquoi il n'apercevait toujours pas le haut de l'escalier: des ampoules avaient été sciemment brisées pour plonger l'endroit dans la pénombre. Alors que Victor reprenait son avancée, une certitude s'imposa à son esprit: Le déclencheur de ses pensées négatives avait été la simple mention de son frère, qui le ramenait en arrière, au coeur de son passé, et lui nouait l'estomac. Victor tourna brusquement la tête vers sa droite, là où un grondement bientôt assourdissant secoua la tour, faisant frémir les murs: un hélicoptère survola le site avec fracas, puis le bruit s'amenuisa jusqu'à s'éteindre. Il montait les dernières marches quand une des portes doubles en haut de l'escalier s'ouvrit lentement vers l'intérieur, sans un bruit. Le sergent-détective inspira à fond de nouveau et franchit l'encadrement avec circonspection ; il avança à tâtons dans l'obscurité de la pièce, dont il distinguait vaguement les contours. La porte se referma brutalement dans son dos, une silhouette apparut dans sa vison périphérique et une voix tonna.»   Les gouffres du Karst, une enquête d'Alexandre Jobin par André Jacques, parue en 2021 aux éditions Druide. En 2005, rien n'empêche Alexandre Jobin de voyager en Italie ou en Croatie, du moins pas encore. Le retraité de l'armée canadienne, antiquaire à ses heures perdues, est appelé à la rescousse par le service canadien du renseignement de sécurité (SCRS) alors qu'un meurtre perpétué dans une zone industrielle proche du parc Jarry dévoile une sombre affaire de trafic d'armes et d'œuvres d'art. L'opération visant à démanteler le réseau criminel a mal tourné. La découverte de l'identité du mort, un ancien camarade d'unité lors de deux déploiement dans les Balkans, achève de convaincre Alexandre Jobin. De Montréal en passant par Trieste et Dubrovnic, le personnage fétiche de l'auteur s'immerge de nouveau dans un passé à l'odeur infecte, qui le mènera les yeux remplis d'effroi aux bords des gouffres du Karst. Il y retrouvera fatalement une vieille connaissance, qui, jusque là, hantait seulement ses cauchemars. Au son lointain du chant du Muezzin, et de quelques détonations, la sulfureuse Pavie, l'assistante toute dévouée de Jobin, Isabelle Ménard, Le vieux Sam Wronski, l'ignoble Dragomir Broz et bien sûr la charmante Chrysanthy Orowitzn marquent de leur présence le studio, ce soir. André jacques est invité à Mission encre noire. Extrait:« La pluie a repris. La nuit est tombée. Circulation moins dense sur Van Horne. Presque aucun piéton. Alexandre n'a pas mis l'éclairage, n'a pas installé le trépied ni l'appareil photo. Simplement écarté un peu le rideau. Depuis trois heures, il observe le Zadar, les allées et venues des clients habituels qu'il commence à reconnaître: le vieux avec sa canne, les deux colosses aux allures de débardeurs. Le jeune Josip ne s'est pas pointé. Bien! Il a compris. Ni Petar Horvat d'ailleurs. Moins bien! Mais Baldo Broz est arrivé, seul, il y a environ une heure. À moins qu'il n'ait emprunté la sortie du bureau à l'arrière, il devrait être encore à l'intérieur. Deux clients, les débardeurs, sortent. Un peu chancelants. On commence à éteindre l'éclairage dans le bar. Si Baldo doit sortir ce sera dans les minutes qui viennent. Alexandre referme le rideau, met son blouson et la casquette des Expos. Vérifie de la main gauche si l'arme est toujours bien en place, coincée dans son dos par la ceinture de son pantalon. Puis, il dévale l'escalier, ouvre la porte de derrière, court vers l'avant par la ruelle. se blottit dans l'ombre au coin de l'immeuble et attend de nouveau.»

In this podcast, I continue my discussion on the Circulation of Ideas and why you should execute on every business idea you get. Are you ready to take the next step in your life? Sign up for a free 30-minute consultation about your goals! Schedule a discovery call https://calendly.com/95media/30min Pre-order my new course: https://gum.co/XVCfZo Follow me on Twitter - https://twitter.com/mwthecoach Follow me on IG - https://www.instagram.com/mwthecoach/ Like my page on Facebook - https://www.facebook.com/resyncmartin Subscribe to my YouTube channel https://www.youtube.com/channel/UCGYV_6zNUe-SdYgXXD3S8cQ

Please join Guest Host Mercedes Carnethon, author Jason Roberts, and Associate Editor Vlad Zaha as they discuss the article "Epigenetic Age and the Risk of Incident Atrial Fibrillation." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-host, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature we're going to learn more about the risk of incident atrial fibrillation, but as that pertains to epigenetics. But before we get to that feature, how about we grab a cup of coffee and get started on some of the other articles in the issue. Would you like to go first? Dr. Carolyn Lam: I would love to. And the first paper I want to highlight asks the question, are social economic variables associated with 30 day survival after out of hospital cardiac arrest. And this comes from Dr. Jonsson from Karolinska Institute in Stockholm, Sweden, and colleagues. They linked data from the Swedish Registry of Cardiopulmonary Resuscitation with individual level data on social economic factors. In other words, educational level and disposable income, all from statistics, Sweden. And what they found was that both higher disposable income and higher educational level independently associated with better 30 day survival following out of hospital cardiac arrest. The relationship between disposable income and 30 day survival was more robust for mediating factors compared to educational level. Dr. Greg Hundley: Oh, wow Carolyn. Really interesting in a very, what I would call hot topic these days. So what are the clinical implications of this particular study? Dr. Carolyn Lam: Well, the results really highlight the importance of preventive efforts aimed at patients with lower social economic status. And these preventive actions could include both early recognition and warning signs and for example, CPR and AED training. So very lovely paper there. Dr. Greg Hundley: Absolutely. Very nice Carolyn. Well, my first paper comes to us from Dr. Nan Wang from Columbia University Medical Center. And Carolyn this paper focuses on a common genetic variant called link RS 3184504, and it is associated with increased platelet and neutrophil counts, coronary artery disease, thrombotic stroke, and autoimmune diseases. And so this research group previously has shown that hematopoietic link deficiency synergizes with hyperlipidemia to promote platelet production and activation, neutrophilia, platelet neutrophil aggregates, atherosclerosis and arterial thrombosis, all of those things. So platelet activation and platelet neutrophil interactions have been shown to promote neutrophil extracellular traps or net formations. So nets are formed when neutrophils release their contents leading to the formation web-like structures made of DNA, myeloperoxidase, citrullinated histone and proteases that entrap and kill bacteria. Now, while nets may help to suppress infection, the formation of nets called NETosis in blood vessels can promote atherosclerosis and thrombosis. And so this study was undertaken to investigate the hypothesis that linked deficiency might promote NETosis leading to formation of unstable atherosclerotic plaques, and arterial thrombosis. Dr. Carolyn Lam: Wow. What a really neat hypothesis and NETosis. I learn new things all the time. So what do they find? Dr. Greg Hundley: Right Carolyn. First of all, hypercholesterolemic mice with hematopoietic link deficiency displayed accelerated arterial thrombosis with nets in thrombi and these changes were reversed by PAD4 deficiency or OxPL antibodies. Second, linked deficient platelet from hyperlipidemic mice expose and release increased OxPL when activated promoting NETosis, when incubated with link deficient neutrophils. Third, an AntiOxPL antibody reduced OxPL levels, NETosis and arterial thrombosis specifically in link deficient mice, and finally Carolyn targeting atherothrombotic risk using OxPL antibodies might be particularly effective in genetically defined populations with reduced link function or increased JAK-STAT signaling. Dr. Carolyn Lam: Wow. Okay. So they proved their hypothesis. Could you sum it up for us, Greg? Dr. Greg Hundley: You bet Carolyn. So this foundational work suggests that perhaps future studies targeting NETosis and OxPL in patients carrying the common link loss of function variant, could reduce atherothrombotic risk. Dr. Carolyn Lam: Wow. Thanks, Greg. My next paper is super interesting in its approach. Listen up. Now the assessment of the relationship between myocardial ATP production and cardiac workload. We know is important for better understand disease development and choice of nutritional or pharmacological treatment strategies. So what Dr. Berndt from Charity University and colleagues did, was they developed a comprehensive physiology based mathematical model of cardiac energy metabolism. And this model is called cardiokine one. And what it does is it recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and in vivo studies with humans. The model encompassed all pathways along, which the possible energy delivering substrates like glucose, long chain fatty acids, keto bodies, acetate, branch chain, amino acids are utilized. Dr. Carolyn Lam: They use the proteomic space, the abundance of metabolic enzymes and cardiac tissue to generate individualized metabolic models of cardiac energy metabolism. And so to prove their case, they further applied this approach to the left ventricles of controls in patients with mitral insufficiency and aortic stenosis, and showed that despite overall preserved systolic function, the ATP producing capacity of these left ventricles of patients with valvular dysfunction was generally diminished and correlated positively with mechanical energy demand and cardiac output. Dr. Greg Hundley: So Carolyn really interesting findings. Sort of linking metabolism them with ventricular dysfunction in those with valvular heart disease. So what were the clinical implications here? What's the take home? Dr. Carolyn Lam: Well, this methodology is just awesome, but what they also found I think is a very important physiological principle. And that is, while metabolic capacity have a significant correlation with biomechanical properties like myocardial power and cardiac output, they can also vary considerably between individual patients and therefore help us to understand in future perhaps why some patients develop heart failure over time while others with similar hemodynamic conditions do not. So just interesting. I think it just opens the space to a lot more. Dr. Greg Hundley: Absolutely beautiful summary there Carolyn. Well, in the rest of the mailbag for this issue, we have an exchange of letters between Professors Hu and Trifon on the previously published paper, entitled “Short Term Treatment with Aspirin plus Clopidogrel Compared to Monotherapy of Aspirin May Not Significantly Decrease the Risk of Stroke Recurrence.” Also, there's a Research Letter from Professor Catalucci entitled, “Nano miR-133A Replacement Therapy, Blunts Pressure Overloaded Induced Heart Failure.” And then finally Carolyn, there's an In-Depth article from Professor Aengevaeren entitled, “Exercise-Induced Cardiac Troponin Elevations From Underlying Mechanisms to Clinical Science.” Well Carolyn, how about we get onto that feature discussion and learn more about incident atrial fibrillation and the age of epigenetics. Dr. Carolyn Lam: Let's go. Dr. Mercedes Carnethon: Welcome to this episode of Circulation on the Run, where we're going to have a very exciting discussion about a paper on epigenetic age and the risk of incident atrial fibrillation. We're extremely excited to have the lead author here with us, Dr. Jason Roberts from the Population Health Research Institute, McMaster University and Hamilton Health Sciences in Ontario Canada. And I am really excited to host this episode alongside the handling editor. My name is Mercedes Carnethon and I'm the professor and vice chair of Preventive Medicine at the Northwestern University School of Medicine. And I'm pleased to be hosting this with Dr. Vlad Zaha from UT Southwestern Medical School, who was the associate editor who handled the piece. So I'm really excited to jump right into this because I think there's a lot that we can all learn from this. So welcome Jason, and thank you so much, Vlad. Dr. Jason Roberts: Thank you so much for having me, it's a delight to be here. Dr. Mercedes Carnethon: So Jason, tell us a little bit about the rationale for this study, what you found and what it means. Dr. Jason Roberts: Absolutely. So as a cardiac arrhythmia specialist, I see a lot of patients with atrial fibrillation. And in 2021, our understanding of its underlying pathophysiology still remains modest. Our treatment strategies for the condition are also somewhat modest, although catheter ablation and antiarrhythmic drugs can potentially be very effective. In the context of these limitations, they're also exacerbated to some extent by the prevalence of atrial fibrillation, increasing dramatically in developed countries. Part of this is related to the obesity epidemic. Things like hypertension increasing becoming more common, but because atrial fibrillation is age dependent and because of our aging populations in developed countries, this is felt to have a major contribution to the growing prevalence of atrial fibrillation. Unlike obesity and hypertension and other risk factors, which are potentially modifiable, chronological aging is viewed as non-modifiable. It's not something that we can tackle. That said, we know within the population and just from personal experience that people age at different rates. There are some people that are 65 who behave more like they're 50, other people that are 50 who behave more like they're 65. Dr. Jason Roberts: And in that context, biological aging, we wondered whether or not, does biological aging independent of chronological aging potentially impacts the risk of atrial fibrillation. If that was the case, because there are gradually accumulating to suggest that biological aging is potentially modifiable, that could potentially open up the possibility of tackling aging as a respective for atrial fibrillation. So that drove us to ask this question. In terms of what we found in the approach that we used. So we used our biological marker of aging, was something called an epigenetic clock. So it's been found that modifications to DNA, specifically methylation at CpG at dinucleotides, they correlate with aging. This has been appreciated for a few decades. It was initially felt that with aging, methylation levels gradually reduced over time. But with more careful interrogation, it's shown that there's patterns. Some methylation areas increase, other methylation areas there's decreases. Dr. Jason Roberts: And Steve Horvath, who is a scientist at UCLA has found that using mathematical algorithms, you're able to very accurately ascertain chronological age based on the patterns of DNA methylation, he's called these things epigenetic o'clock. That said, even though they very accurately ascertain chronological age, they aren't perfect in each individual in terms of matching up to their chronological age, but that's actually turned out to be a good thing. So when people, their epigenetic age is older than their chronological age, they're said to have positive epigenetic age acceleration. They may be biologically older than their actual chronological age. And then the reverse also holds. So using this concept of epigenetic age acceleration, we ask whether or not do people that are older biologically on the basis of their epigenetic age, do they have an increased risk of atrial fibrillation? And then we tackle that using a few different core works that I'm certainly happy to elaborate on in terms of what we found. Dr. Jason Roberts: So we used three population based cohorts from the United States, the well known Framingham Heart Study, the Cardiovascular Health Study and Eric as well. There were approximately just under 6,000 people from those studies that had undergone genome wide methylation analysis that in the enabled us to calculate their epigenetic ages. The follow period for these people was just under 13 years. And then we look to see whether or not these epigenetic clocks associated with instant atrial fibrillation. In these cohorts, we look at five different clocks. So there's the Horvath Clock and the Hannum clock that were designed to predict chronological aging. The more recent clocks, things like DNAm PhenoAge and DNAm GrimAge are more designed to predict aspects of clinical phenotype and also mortality. We found that in unadjusted analyses, all of these clocks were associated with atrial fibrillation. When we then adjusted for multiple different clinical variables, we found that the DNAm PhenoAge clock and the DNAm GrimAge clock continued to exhibit statistically significant associations with atrial fibrillation. Dr. Jason Roberts: Interestingly, the multi-variable adjustment, one concern is, do these clinical factors, are they confounders where we should be adjusting, or are they potentially mediators. If we adjust for mediators that potentially masks the effect of the clock. But regardless of how we treat them both DNAm PhenoAge and DNAm GrimAge, we're associated with increased risks of incident atrial fibrillation. Alluding to the possibility that biological aging independent of chronological aging is important in terms of determining risk for atrial fibrillation. And it may be that if we're able to modify biological aging, we could potentially reduce the risk of atrial fibrillation. So that's the study in a nutshell. Dr. Mercedes Carnethon: No, that is really exciting. You said something early on about chronological age being immutable. And I would have to say, both Vlad and I are not aging. And in fact, we are going in the opposite direction. If only this were not just an audio podcast, you would see that I steadily gotten younger and younger and I'm suddenly about 25 now. But no, these are really important findings. I really like the innovation of using multiple different strategies to characterize epigenetic age and genetic aging. So tell me Vlad, I want to turn to you. When this came across your desk, what excited you about this particular piece and why did you think that it would be of great interest to our readership? Dr. Vlad Zaha: Good morning Merci and Jason. This is a great question. And as in associate editor at Circulation for the bridging discipline section, it was fascinating to see this topic coming on my desk, thinking about all the genome wide association studies in nature of fibrillation and predisposition to atrial fibrillation, that in that case would not be changed by interventions because of different loci that would be determined. This was coming as a completely new perspective that was opening some new potentials. And it was very interesting to see some of the findings. Dr. Mercedes Carnethon: Certainly. So Jason, I have a question. So what surprised you about the findings of this particular study? Jason Roberts: Yeah, that's a great question. So we had hoped that biological aging would be associated with atrial fibrillation. I think the concept of being able to tackle biological aging is exciting. In terms of what surprised us, I guess we were hoping for these results, I guess. Dr. Mercedes Carnethon: Yeah. Dr. Jason Roberts: But we were…Yeah. So I guess we were pleasantly surprised that our hypothesis was born out. It's important to note that the epigenetic clocks don't tell the full story with chronological aging. So after we insert the clock into the model, chronological age continues to remain associated with instant atrial fibrillation. So this measure biological aging is just part of the story. So I think that's very important. I had wondered whether or not inserting the epigenetic clocks would that potentially eliminate the subsequent association of chronological aging. So that finding suggests it's part of the story. Dr. Jason Roberts: I think that in terms of the overall concept, the idea of this being reversible really excites me. In terms of the approach of how to reverse biological aging. Right now healthy lifestyle seems to be very important. I think it provides more evidence to suggest to patients with atrial fibrillation, living healthy from a diet perspective, from exercise, keeping your weight under control, all of these things that seem to impact epigenetic aging and biological aging can be helpful for preventing atrial fibrillation. So I think that can help reinforce this message to our patients. Dr. Jason Roberts: I think ultimately in terms of where we'll be at in 15 to 20 years, it's possible that new therapies in the future are developed that are able to more powerfully address biological aging. As you alluded to, will it be possible to reverse biological aging as you and Vlad are experiencing that? Dr. Mercedes Carnethon: Most definitely. Yes. Dr. Jason Roberts: I think it may be possible. This is an intense area of investigation that's being pursued and it's still in its relative infancy. But I think that could it be small molecules? Could it be potentially gene editing that can help adjust biological aging and not only increase lifespan, but also health span? I think those concepts are really exciting. Dr. Mercedes Carnethon: I completely agree. There's a lot of richness in this paper and I think our readership is going to really enjoy digging in. Part of the richness is the use of three different cohorts and the use of multiple measures of epigenetic age. And I think you provided a really nice description of the unique information that each of these markers of epigenetic age provide. One thing I note are differences in the strength of association across the different measures of epigenetic age, which I think makes sense, because you said they characterize different aspects of the phenomenon, but I also see what looks like some variability across the cohorts with Framingham in particular seeming to stand out. And that being the only cohort that is 100% one race. It's white. Versus both the cardiovascular health study and the Eric study, which have more diverse study populations. I'm wondering what your hypothesis is about the differential strength of association that it seems Framingham is demonstrating and what you think is possibly the source of those differences. Dr. Jason Roberts: Yeah. I think those are great questions for all of genetics. The question is, does it apply to all races? For example, polygenic risk scores. It seems like when a polygenic risk scores develop for one race, it may not perfectly translate over to other races. So how relevant is that for epigenetic age acceleration. In this study, I think it's difficult to make definitive conclusions about it. We needed the three cohorts to have adequate statistical power in terms of being able to determine a differential effect of race. I think it would really be primarily hypothesis generating. We weren't really powered to look at the different races. So it's difficult for me to comment. Dr. Jason Roberts: I think ultimately and I want to believe anyways, that epigenetic age acceleration is relevant to all races, but in terms of, was it race that drove the differential impacts that we saw to some extent in terms of the magnitude of the hazard ratios, it's difficult to know in terms of tests for interaction and were these actually truly statistically different. We weren't adequately powered to address that hypothesis. So it's difficult for me to comment in a definitive matter I'd say. And sorry to cop out on… Dr. Mercedes Carnethon: No, not at all. I mean, I think there are a lot of things where there is no firm answer and that was just one of my hypotheses when I saw what was going on differently across the cohorts. I think that's a perfectly reasonable answer that sets us on a course for thinking about how we set up future studies. So I wanted to turn to you Vlad for the closing frame around this. As the editor, how do you hope that our readership will use these findings? Dr. Vlad Zaha: That is an excellent question. I was going to follow on this excellent unpacking of the core messages of the manuscript by Jason here to get his perspective as an electrophysiologist into what these type of work may represent for the everyday life of an electrophysiologist in the connecting with the patients and how would this type of approach influence, and maybe now, maybe later when our treatment for atrial fibrillation. Dr. Jason Roberts: Yeah. So that's a great question. I think, as I alluded to some extent before, as far as reinforcing healthy lifestyle, I think this provides more evidence in that respect. So we know that things like excessive alcohol consumption, being excessively obese, poor diets, not engaging in enough exercise, all of those things seem to accelerate your epigenetic age. And those are all things that we think or feel that are important with atrial fibrillation in terms of driving the path of physiology and people progressing. So I think this gives more data to us to reinforce the patients that in addition to the treatments that we're offering in terms of catheter ablation and antiarrhythmic drugs, the concern is that the substrate can continue you to progress. And that's likely driven by to some extent these modifiable risk factors. So keeping all of these under best control as possible, and hence trying to slow your biological aging as much as possible. Dr. Jason Roberts: I think that this will provide us more motivation to push these messages to our patients. A lot of patients can sometimes be like, "Let's just get on with a catheter ablation and I want to get on with my life…" but it really I think, provides more data to suggest that modifying these very important risk factors that can lead to accelerated biological agents, is very important. And in terms of the future as mentioned, so chronological aging, as people get older, people view it as, "Well, there's nothing I can do, and I'm just going to get gradually more and more unhealthy." I think, and this is somewhat futuristic, but to what extent can we slow biological aging? Can we potentially reverse it in the future? There's certainly lots of very compelling and interesting animal work and people are starting to delve into this in a big way. Dr. Jason Roberts: And not only to increase lifespan, will we some day live until we're 200. Who knows? But the concept of prolonging your health span as well. So the number of healthy years that you have before your body starts to gradually give way, I guess to some extent. Hopefully in the future will have therapies that will help keep us healthy. And if we do that increased health span, I think this data suggests that atrial fibrillation will be one thing that benefits from this. So hopefully in the future, maybe in terms of curbing the AFib pandemic, being able to address biological aging will help push things in the right direction. Dr. Mercedes Carnethon: Well, thank you so much Jason. And thank you so much Vlad for your thoughtful questions. I really like that the final bottom line leans towards my area as an epidemiologist, which is maintaining and promoting healthy lifestyles as a way to hopefully help prevent some of the difficulties of atrial fibrillation and its long-term outcomes. Really pleased to have you on this episode of Circulation on the Run, Jason, and thank you again Vlad, and I hope everyone enjoys this episode of the journal and has an opportunity to really dig into this piece. This is Mercedes Carnethon from Northwestern University Feinberg School of Medicine, saying thanks for listening today. 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 Bretagne dans les Côtes d'Armor, une commune a décidé de couper une route pour des raisons environnementales. Une initiative inédite en France, et je vais vous expliquer pourquoi. Voir Acast.com/privacy pour les informations sur la vie privée et l'opt-out.

If you're experiencing pain or cramps in your legs, there's a chance you are having issues with circulation to your legs. The good news is that there are nutrients that can help. Take advantage of an exclusive podcast offer today by visiting http://www.invitehealth.com/podcast. For more information on the products or studies mentioned in this episode, click here. 

Please join Guest Host Mercedes Carnethon along with first author Connie Hess and Guest Editor Gregory Lip as they discuss the article "Reduction in Acute Limb Ischemia With Rivaroxaban Versus Placebo in Peripheral Artery Disease After Lower Extremity Revascularization: Insights From VOYAGER PAD." 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 Poly Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, our feature discussion is on a really important topic, peripheral artery disease. So important, so rampant, not talked about enough. And it's really insights from the VOYAGER-PAD trial telling us about the reduction in acute limb ischemia with Rivaroxaban versus placebo in peripheral artery disease after lower extremity revascularization. But before we get into all that, I want you to get your coffee while I tell you about my picks of today's issue. Should I start? Dr. Greg Hundley: Very good. Dr. Carolyn Lam: Okay. So the first paper deals with the residual ischemic risk following coronary artery bypass grafting surgery. We know that despite advances, patients following CABG still have significant risk. So this paper refers to a subgroup of patients from the REDUCE-IT trial with a history of CABG, which was analyzed to evaluate the efficacy of icosapent ethyl treatment in the reduction of cardiovascular events in this high risk patient population. Now, as a reminder, the REDUCE-IT trial was a multicenter, placebo controlled, double blind trial, where statin treated patients with controlled LDL cholesterol and mild to moderate hypertriglyceridemia were randomized to four grams daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy endpoint, which was cardiovascular death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Now the current report tells us about the subgroup of patients from the trial with a history of CABG. Dr. Greg Hundley: Ah, Carolyn. So what did they find in this subgroup of patients? Dr. Carolyn Lam: So of the 8,179 patients randomized in REDUCE-IT, 22.5% had a history of CABG with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between the treatment groups and randomization to icosapent ethyl was associated with a significant reduction in the primary endpoint, as well as in key secondary endpoint and in total ischemic events compared to placebo. This yielded an absolute risk reduction of 6.2% in first events with a number needed to treat of 16 over a median follow up time of 4.8 years. So, Greg, I think you'll agree, icosapent ethyl may be an important pharmaco-therapeutic option to consider in eligible patients with a history of coronary artery bypass grafting surgery. Dr. Greg Hundley: Very nice, Carolyn. What an excellent summary. So Carolyn, for my first paper... And this study comes to us from Professor Judith Haendeler from the Leibniz Research Institute for Environmental Medicine. So Carolyn, this is a new type of quiz question. And as you listen to the presentation, help us predict the clinical implications. Okay, here we go. Dr. Greg Hundley: All right. So Carolyn, telomerase, also called terminal transferase, is a ribonuclear protein that adds a species dependent telomere repeat sequence to the three prime end of telomeres. And Carolyn, just to refresh our memories, a telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. And telomerase was discovered interestingly by Carol Greider and Elizabeth Blackburn in 1984. And together with some others, including Jack Szostak, they were awarded the 2009 Nobel Prize in physiology and medicine for discovery. Dr. Greg Hundley: So Carolyn, telomerase is active in gamuts and most cancer cells, but is normally absent from or at very low levels in most somatic cells. And the catalytic subunit of telomerase called telomerase reverse transcriptase or trt has protective functions in the cardiovascular system, particularly in regard to ischemia reperfusion injury. And interestingly trt or telomerase reverse transcriptase is not present in the nucleus, but also in mitochondria. However, for us in cardiovascular medicine, it is unclear whether nuclear or mitochondrial trt is responsible for the observed protection. Dr. Carolyn Lam: Wow, fascinating. So what did today's paper find? Dr. Greg Hundley: Right, Carolyn. So it was mitochondrial, but not nuclear telomerase reverse transcriptase that was found critical for mitochondrial respiration during ischemia reperfusion injury. And mitochondrial telomerase reverse transcriptase improves complex 1 subunit composition. And trt is present in human heart mitochondria and remote ischemic preconditioning increases its level in these organelles. Also, Carolyn TA65 was found to have comparable effects ex vivo and improved migratory capacity of endothelial cells and myofibroblast differentiation. So Carolyn, with this summary, can you help speculate on the clinical implications of this paper? Dr. Carolyn Lam: Oh, Greg. You set it up so nicely. So I would speculate that the clinical implications are that an increase in the mitochondrial telomerase reverse transcriptase or trt would be able to help with cardioprotection in ischaemic reperfusion injury, or at least that's what we hope and that's where we should be going with this. Am I right? Dr. Greg Hundley: Absolutely, Carolyn. So in the future, this research showing that trt and cardioprotection... Maybe we increase this and it could serve as a therapeutic strategy. Excellent job, Carolyn. Dr. Carolyn Lam: Thank you, Greg. All right. My next paper is a preclinical paper. I will spare you of difficult quizzes and maybe... This is just so neat. Let me tell you about it. So the study really provides novel insights into the mechanisms underlying smooth muscle cell phenotypic modulation that contributes to the development of vascular diseases like renal atherosclerosis and restenosis after angioplasty. So very important. Dr. Jiliang Zhou from Medical College of Georgia and colleagues basically used an in silico approach to probe unbiased, proprietary, and diverse, publicly available bulk RNA-Seq and scRNA-Seq datasets to search for smooth muscle cell specific long non-coding RNAs or lncRNAs. Dr. Carolyn Lam: The search ended up identifying CARMN, which stands for cardiac mesoderm enhancer-associated non-coding RNA, CARMN. As a highly abundant, highly conserved smooth muscle cell specific lncRNA, CARMN was recently reported to play roles in cardiac differentiation and was initially annotated as a host lncRNA for the microRNA, the MIR143145 cluster, which is the best characterized microRNAs in regulating smooth muscle cell differentiation and phenotypical modulation. Dr. Carolyn Lam: But in the current study, the authors confirmed the expression specificity of CARMN using a novel GFP knock-in reporter mouse model, and discovered that CARMN is downregulated in various vascular diseases. They further found that CARMN is critical for maintaining vascular smooth muscle cell contractile phenotype, both in vitro and in vivo by directly binding to the smooth muscle cell specific transcriptional cofactor known as myocardit. Dr. Greg Hundley: Okay. Carolyn, what a beautiful summary here. So what's the take home message here? Dr. Carolyn Lam: So these findings collectively suggest that CARMN is a key regulator of vascular smooth muscle cell phenotype, and therefore represents a potential therapeutic target for the treatment of smooth muscle cell related proliferative diseases. Dr. Carolyn Lam: Well, Greg, thanks for letting me to tell you about that one. But let me tell you also about other papers in today's issue. There's an exchange of letters between Dr's Lee and Chew on high rates of coronary events in the rapid troponin T0 one hour protocol. Is it a reality or illusion? There's an ECG Challenge by Dr. Liu on “Acute Inferior Wall Myocardial Infarction. What is the Culprit Artery? In Cardiology News, Bridget Kuehn writes on persistent heart effects of COVID-19 and how that emphasizes the need for prevention. Dr. Greg Hundley: Very nice, Carolyn. Well, I've got a Research Letter to tell you about from Professor Huang, entitled “High Prevalence of Unrecognized Congenital Heart Disease in School-Age Children in Rural China: A Population-Based Echocardiographic Screening Study.” Well, Carolyn, what a fantastic issue. And how about we get onto that feature discussion now and learn more out lower extremity revascularization and insights from the VOYAGER-PAD study? Dr. Carolyn Lam: Let's go, Greg. Dr. Mercedes Carnethon: Good morning, everyone. Welcome to this episode of Circulation on the Run podcast. I'm Mercedes Carnethon, Professor and Vice Chair of Preventive Medicine at the Northwestern University Feinberg School of Medicine and associate editor of the journal. Really excited today to hear from one of our authors of a particularly interesting piece that we'd like to discuss today about peripheral artery disease after lower extremity revascularization. Dr. Mercedes Carnethon: And we have with us today, the lead author, Dr. Connie Hess from the division of cardiology at the University of Colorado School of Medicine in Aurora. And we have Dr. Gregory Lip with us. So welcome to the both of you. Professor Gregory Lip: Hello there. Dr. Connie Hess: Thank you for having me. Dr. Mercedes Carnethon: Thank you both for joining us. This is really exciting. I know that when I read this piece, I was really excited to think about the implications that these study findings from this clinical trial will have for a very important clinical problem of peripheral arterial disease and those complications. So, Connie, would you be willing to start by telling us a little bit about what you found in this study? Dr. Connie Hess: Yeah, absolutely. I think maybe a good place to start first is, if that's okay, is just a little bit of the background and why we looked at this and thought to look at this. I think as you're both probably aware, peripheral artery disease is a very highly prevalent condition. It affects a lot of people, but there's not a lot of awareness about it. It's in some ways the forgotten manifestation of atherosclerosis. And so acute limb ischemia in particular is a very feared complication of peripheral artery disease. And unlike things like ST elevation, myocardial infarction, and stroke about which patients and providers have a lot of knowledge and understanding, many people don't know about acute limb ischemia. And in particular ALI, acute limb ischemia, is a complication of peripheral revascularization that many of us as proceduralists are very concerned about. Dr. Connie Hess: And so what we wanted to do was use this very unique clinical trial and dataset to look at acute limb ischemia, to describe it, to better understand it, especially after a peripheral revascularization. And then also to look at the effect of Rivaroxaban plus aspirin versus aspirin alone on this feared outcome. We're lacking therapies to effectively prevent ALI. Dr. Connie Hess: And so if I just briefly review the trial, VOYAGER-PAD randomized 6,564 patients undergoing peripheral revascularization, both surgical or endovascular to Rivaroxaban, 2.5 milligrams twice daily versus placebo on top of aspirin. And then providers could use prochidagril for up to six months per their discretion. Now, the primary outcome for VOYAGER-PAD was very unique. This was a five point composite that looked at acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. Dr. Connie Hess: And so in this trial in the primary results, Rivaroxaban plus aspirin versus aspirin alone was highly effective in reducing the primary endpoint, that five point composite I just described. And so we were excited to look specifically at the effect of this combination therapy on acute limb ischemia alone. What we found to begin with, I think in terms of describing acute limb ischemia is important. So the three year cumulative incidence in the patients assigned a placebo was about 8% for ALI. So this is not an uncommon problem. And in fact, we found that there was incidents of ALI occurring quite early after the procedure and that the risk persisted, even three years out. Dr. Connie Hess: And Rivaroxaban plus aspirin versus aspirin alone was very effective in reducing ALI by about 33%. Beyond that, we also looked at ALI in terms of severity of these complications. And we found that about a third of patients had a very severe ALI event that we defined as ALI followed by death, major amputation, or requiring a prolonged hospitalization with time in the intensive care unit. And for those patients, Rivaroxaban plus aspirin was even more effective with almost a 55% reduction. Dr. Connie Hess: Lastly, I think we also looked at just the patients who are at risk for ALI after peripheral revascularization. And we did identify some patient and procedural factors that might help us identify these patients. For example, having a prior lower extremity revascularization, having more severe PAD as indicated by a low ankle brachial index, undergoing surgical revascularization, and having longer target lesions. So I think we were able to describe ALI in a way that some other trials and datasets have not been able to do. And then also beyond that to provide some evidence for effective therapy to prevent this complication. Dr. Mercedes Carnethon: All of that is so exciting. And for somebody coming to this outside of the initial field, I can certainly see a lot of innovations that you describe in what you've done and the importance to the population of people who experience this very debilitating illness. So it's really wonderful to see this in print. So tell me, Greg, what excited you as the editor about this particular paper? So what made it really stand out in your mind? Professor Gregory Lip: Thanks, Mercedes. And firstly, congratulations to Dr. Hess for a really nice paper. And I think that it's really important because many cardiologists tend to neglect looking at and managing peripheral artery disease, especially with the medical therapies. And I think VOYAGER-PAD was an important advancement of how we can have... You could say, dual blockade, both with low dose anticoagulation plus antiplatelets should improve the outcomes. Professor Gregory Lip: So I think it really brings to the forefront how we should optimize medical therapy and peripheral disease. It's not simply a matter of surgery or just intervention with stenting. And I think maybe the other important aspects in regard to this study, this trial is when you combine an antiplatelet with an anticoagulant, it's worth flagging up the potential for added risk of bleeding. And it's therefore the fact that your analysis included to identify the patients at high risk of acute limb ischemia, then we will actually facilitate risk stratification so that we can perhaps target the very high risk patients where that balance in terms of the net benefit for the combination therapy compared to aspirin alone would be there because you're balancing the thrombotic and limb ischemic outcome versus the potential for bleeding. Professor Gregory Lip: We are also using of course, in VOYAGER-PAD low dose Rivaroxaban, which is not the stroke prevention dose of Rivaroxaban in everyday clinical practice. And that's worth emphasizing. So we translate peripheral disease dosages or regimes versus what we see in other prothrombotic situations like atrial fibrillation, which leads to stroke. And that's probably worth emphasizing. And I think really what is most important is that we can hopefully identify the high risk subset of patients with peripheral artery disease at risk of acute limb ischemia, where they're going to particularly benefit from combination therapy. So an important advance for medical therapy for peripheral disease. So congratulations on this paper as well. Dr. Mercedes Carnethon: Yeah. I really echo that. One of the things that when we write original research papers, we are always encouraged not to speculate beyond the data that we're presenting. But one of the values of this podcast is that we get a chance to really needle the authors and challenge them to speculate about what does this mean? What does this mean for the field? And Connie in particular, what do you think the next steps are for patients and providers based on what you found today in this excellent study? Dr. Connie Hess: Mercedes, that's a great question. Certainly we always want to know what next? What are the implications of these findings? And so to me, I echo both of you. I'm personally very excited as someone in the field. And as a proceduralist, I'm very excited that for the first time, we actually have data to support a medical therapy post intervention. Although there's a lot of use of things like dual antiplatelet therapy and even anticoagulation, there's not a lot of data to support it after peripheral revascularization. So this really is the first large scale, high quality data to support a strategy. And so I do think that this is something that we should adopt. Dr. Connie Hess: I think what I didn't mention before is that actually, when you look at the cumulative incidence curves for ALI in the Rivaroxaban versus placebo groups, not only do you see that there is early risk for ALI after the procedure... And typically we think of this as potentially technical failure that we can't modify, but you saw a very early benefit for Rivaroxaban plus aspirin versus aspirin alone here, suggesting that the sooner you start, the better. Of course, it has to be when it's safe from a bleeding perspective and when the proceduralist feels comfortable with this. But I do think that the implications are that we should... We proceduralists, especially in this population and as professor Lip mentioned the high risk patients in particular, should be starting this therapy as soon as we feel safe. And so I think the data are there. The next step to me is really increasing awareness, in particular among providers who are treating these patients, but even among our other colleagues or cardiovascular colleagues who may not treat these peripheral artery disease patients primarily, but do see them in their clinic. Dr. Connie Hess: A lot of them have cardiovascular disease and other cardiovascular problems, but to increase awareness that this dual pathway inhibition with low dose factor 10, anticoagulation inhibition and low antiplatelet therapy is a viable and favorable combination and to continue this so that when they see this, they're not surprised and not questioning whether to stop it. Dr. Connie Hess: I think also of course now that we are getting more data to understand how morbid and bad ALI is, I do think we also need to educate patients. You both probably recall all the tremendous efforts that were made to increase awareness in the patient population about myocardial infarction and stroke. You have all those campaigns and understanding the importance of timely intervention and reperfusion. I think that actually should be done for acute limb ischemia as well. We need to have providers aware about this complication and understanding emergent treatment. We also need patients to understand it so they can come in sooner so that they're not having delayed presentation for which primary amputation is the only treatment option. So I think there's a lot of work to be done, but certainly very excited that we have a better understanding of ALI as well as preventive therapy. Dr. Mercedes Carnethon: I really appreciate that final word. And I really can't think of a better way to wrap up than the final words that you provided, Connie. Both the context that you provided around this piece and your thoughts as well, Greg, about what makes it innovative and exciting for our readership at Circulation are really invaluable. So I just really want to thank you for joining us as an author and thank you for selecting this, Greg. This is a really great piece. I've learned a good deal. Dr. Mercedes Carnethon: This is me, Mercedes Carnethon, wrapping up this addition of Circulation on the Run, following an outstanding discussion with Dr. Connie Hess from the University of Colorado and Greg Lip, the handling editor for the piece. 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.

Presentación de libros de estudios ibéricos online. Ana Vera (U. Copenhagen) fala com André Rui Graça, Professor convidado na Universidade da Beira Interior e investigador na Universidade de Coimbra, sobre seu novo livro Portuguese Cinema (1960-2010) Consumption, Circulation and Commercei. Moderação: Ana Vera (University of Copenhagen).

This weekend is the final (and possibly the most important) message of our series on the Holy Spirit. The thirteenth chapter of 1 Corinthians is often used to speak into marriages, but it's not really about marriage. It's about life with the Spirit!

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Please join first author Cecilia Bahit and Associate Editor Graeme Hankey as they discuss the article "Predictors of Development of Atrial Fibrillation in Patients With Embolic Stroke Of Undetermined Source: An Analysis of the RE-SPECT ESUS Trial." 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 and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to analyze the RE-SPECT ESUS trial. What does that pertain to? Well, you're going to have to wait and find out, but it relates to atrial fibrillation and embolic stroke. But before we get to that, how about we grab a cup of coffee and go through some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I sure would. Greg, we know that Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease or diabetes. The question is: What are the effects of Icosapent Ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes from the REDUCE-IT trial? Dr. Greg Hundley: Ah, Carolyn, can you remind us what was the REDUCE-IT trial? What did it encompass there? Dr. Carolyn Lam: The REDUCE-IT trial was a multicenter double-blind, placebo-controlled trial that randomized statin treated patients with elevated triglycerides, who had cardiovascular disease or diabetes, and one additional risk factor, two treatment with icosapent ethyl at 4g daily versus placebo. After a median follow up period of 4.9 years, the study drug demonstrated a 25% relative risk reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina. Dr. Greg Hundley: Ah, great summary of the original paper, but now this is sort of a follow-up paper. What did this paper research? Dr. Carolyn Lam: Well first, remember they focused on renal function and the median baseline GFR was 75 ml/min with a range of 17 to 123 mL/min/1.73 m2. Treatment with Icosapent Ethyl led to consistent reduction in both primary and secondary composite endpoints across the baseline GFR categories. Patients with the GFR >60 treated with Icosapent Ethyl had the largest absolute, but similar relative risk reduction for the primary composite endpoint. And while patients with GFR >60 treated with Icosapent Ethyl had the highest numerical rates of atrial fibrillation of flutter and serious bleeding. The hazard ratios for atrial fibrillation flutter and serious bleeding were similar across GFR categories. In summary Icosapent Ethyl reduced cardiovascular events among patients with elevated triglycerides in a well-controlled LDL on statin therapy across a wide range of baseline renal function. Dr. Greg Hundley: Oh, Carolyn. Beautiful presentation. That presentation was so good that I know you are ready for a quiz. We haven't had Carolyn's quiz in a week, so we've got to get right back to that. Dr. Carolyn Lam: No, we don't (laughs). Dr. Greg Hundley: Can you describe the primary sequelae of Hutchinson-Gilford progeria syndrome? Dr. Carolyn Lam: Oh wow. Okay. So this is the syndrome where there's premature aging, there's a lot of vascular stiffening, calcification. I'm going to guess some sort of atherosclerotic consequence (laughs). Dr. Greg Hundley: Very nicely done Carolyn. Oh my goodness. I need to get you to take my ABIM recertification- Dr. Carolyn Lam: (laughing) Dr. Greg Hundley: Beautifully done. So Carolyn, this paper comes to us from Dr. Vicente Andrés from Centro Nacional De Investigaciones Cardiovasculares Carlos III, and Hutchinson-Gilford progeria syndrome is a rare disorder characterized, just like you said, Carolyn by premature aging and death, mainly due to myocardial infarction, stroke or heart failure. The disease is provoked by progerin, a variant of lamin A expressed in most differentiated cells. Carolyn, these patients look healthy at birth and symptoms typically emerge in the first or second year of life. In assessing the reversibility of progerin induced damage, and the relative contribution of specific cell types is critical to determining the potential benefits of late treatment and to developing new therapies. Dr. Carolyn Lam: Wow, you've really, really piqued my interest. So what did these investigators do and what did they find? Dr. Greg Hundley: Oh Carolyn, very clever design. So the authors use CRISPR-Cas9 technology to generate mice engineers to ubiquitously express progerin while lacking lain A and allowing progestin suppression in lain A restoration in a time and cell type specific manner upon CRE recombinase activation. They characterize the phenotype of these engineered mice and cross them with CRE transgenic lines to assess the effects of suppressing progestin and restoring lain A ubiquitously at different disease stages, as well as specifically in vascular smooth muscle cells and cardiomyocytes. So Carolyn, what did they find? Well, number one, like Hutchinson-Milford progenia syndrome patients, their engineered mice appeared healthy at birth, and progressively developed Hutchinson-Milford progenia syndrome symptoms, including failure to thrive, Lipodystrophy, vascular smooth muscle cell loss, vascular fibrosis, electric cardiographic anomalies and early death. Their median lifespan was 15 months versus 26 months in the wild types. Dr. Greg Hundley: Second, ubiquitous progestin suppression in lain A restoration significantly extended lifespan, when induced in six month old, mildly symptomatic mice, and even in severely ill animals aged 13 months, although the benefit was much more pronounced upon the early intervention. And then finally, Carolyn remarkably major vascular alterations were prevented and lifespan normalized in engineered Hutchinson-Milford progenia syndrome mice when progestin suppression and lain A restoration were restricted to: just Vascular smooth muscle cells and Cardiomyocytes. Dr. Carolyn Lam: Wow, just fascinating, but, okay. What is the clinical take home message? Dr. Greg Hundley: Right, Carolyn. So these authors findings suggest that it is never too late to treat Hutchinson-Milford progenia syndrome, although the benefit is much more pronounced when progestin is targeted early in mice with mild symptoms. Also, restricting its suppression to Vascular smooth muscle cells in Cardiomyocytes is sufficient to prevent Vascular disease and normalize lifespan in mice, and therefore these data suggest that strategies to treat Hutchinson-Milford progenia syndrome through gene therapy or RNA therapy should consider targeting Vascular smooth muscle cells and Cardiomyocytes. Dr. Carolyn Lam: Oh wow. Very, very cool. Well, my next paper is a basic science paper that's significant for both its methods and its results. Dr. Greg Hundley: Oh wow, Carolyn, I can't wait. So tell us about this novel methodology. Dr. Carolyn Lam: Well, this paper is from Dr. Chang from Westlake University in Hangzhou, China, and colleagues who use a gene editing approach to efficiently institute Exon Skipping without introducing DNA double-strand breaks. So harnessing a fusion of a nuclease defective Case protein, and a cytidine deaminase, which is, we're going to abbreviate it as Targeted AID-induced mutagenesis (TAM) or base editor three (BE3), their approach precisely edited conserved guanines at splice sites, thus abrogating Exon recognition resulting in a programmable skipping of the targeted Exons. Isn't that neat? Dr. Greg Hundley: Yeah, it really is sophisticated Carolyn, wow. So what did they do using these methods? Dr. Carolyn Lam: A novel mirroring model of Duchenne muscular dystrophy was generated, which recapitulated many cardiac defects observed in the human form of the disease, including dilated cardiomyopathy, reduced left ventricular function and extensive cardiac fibrosis. Using this model, they examined the feasibility of using a cytidine base editor to install Exon Skipping and rescue the dystrophic cardiomyopathy in vivo. A single dose administration of an Adenovirus 9EtAm, instituted over 50% targeted Exon Skipping in the Chengdu muscular dystrophy transcripts and restored up to 90% dystrophin in the heart. And as a result, early ventricular remodeling was prevented and cardiac and skeletal muscle function were improved, leading to an increased lifespan of the mice. Despite gradual decline of the Adenovirus vector and base editor expression, the dystrophin restoration and pathophysiological rescue of muscular dystrophy lasted for at least a year. And so this technique really has the potential to be applied to monogenic human diseases, to modulate Exon Skipping or inclusion. Isn't that cool? Dr. Greg Hundley: Absolutely, Carolyn. Beautifully explained. Dr. Carolyn Lam: Well, let me end by sharing what else is in today's issue. There's a Perspective piece by Dr. Alexander on “Chest Pain Redux: Updated and Patient Centered.” There is an In Depth paper by Dr. Kroemer on NAD plus metabolism in cardiac health, aging and disease. And there's a Research Letter by Dr. Shepherd on sudden death in female athletes, with insights from a large regional registry in the United Kingdom. Dr. Greg Hundley: Very good, Carolyn. What a great issue. Now, how about we get to that feature discussion? Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Welcome listeners to our feature discussion today on this November 30th. And we have with us Dr. Cecilia Bahit from Rosario, Argentina and our own associate editor, Dr. Graeme Hankey from Perth, Australia to talk to us about a paper pertaining to Atrial Fibrillation. Welcome to you both, and Cecilia, we'll start with you. Could you describe for us a little bit of the background information that went into formulating your study, and then what hypothesis did you want to address? Dr. Cecilia Bahit: Thank you for the invitation. So we all know that embolic stroke of undetermined source, which is called ESUS isn't just a subset of cryptogenic stroke, and is associated with stroke recurrence about 3-6% per year. And on the other hand, we know that continuous cardiac monitoring in this patient population shows that atrial fibrillation can be detected between 10% at six months or 30% at three years. So the underlying atrial fibrillation may be a mechanism for the recurrent thromboembolic stroke in this patient population. So we know that prior studies have identified some predictors of atrial fibrillation in these patients. And if we are able to identify which patients could benefit from cardiac monitoring and have a higher yield to detect atrial fibrillation, we could do a better job at treating them. So, that was our idea behind the paper. So using the RE-SPECT ESUS trial, which was a trial that included patient with ESUS stroke and were randomized to the bigger trend versus Aspirin, we look at predictors of atrial fibrillation unassociated regarding stroke. Dr. Greg Hundley: Very nice. And so, now was this a sub-study here and maybe define for us a little bit, your study design and specific study population. Dr. Cecilia Bahit: So this was a secondary analysis of a randomized clinical trial that as mentioned it was not a sub-study, it was a secondary analysis. We thought all along to do it because of the interest of the clinical question. We look at the total patient population was 5,390 patients. And we looked at those patients who developed atrial fibrillation during the 19 months of follow-up. And it was 7.5%, 403 patients developed atrial fibrillation. Dr. Greg Hundley: Very good. And what were your results? Dr. Cecilia Bahit: So, as I mentioned, we saw that 7.5% of our patient population developed atrial fibrillation during the follow-up. And we know those patients were older, were like, have higher morbidities, and we assessed, we did an one variable analysis and then a multi-variable analysis, trying to identify predictors for atrial fibrillation. And for our model, we identified different predictors, older age, hypertension, lack of diabetes, and higher body mass index, were independent predictors of atrial fibrillation. So the patients who have atrial fibrillation have a higher recurrence of stroke, it was 7.2 versus four, compared to those that did not have atrial fibrillation. Dr. Cecilia Bahit: So I think there's an important part, that 20% of the patient population of the overall trial, this is a little more than a thousand patients, had NT-prob measure at baseline. And when we included this biomarker into the model, only older age and NT-prob were independent predictors of atrial fibrillation. In addition, even though this was not the objective of this analysis, we look at the treatment effect of the bigger trend. And even though we saw that there was a statistical benefit of the bigger trend versus Aspirin in the higher group of these in our score, the overall treatment effect was not there. So we couldn't assess the fact that the bigger trend was better compared to Aspirin in patient with atrial fibrillation, but of course the numbers were very small. Dr. Greg Hundley: Very good. Thank you so much for that wonderful description. And Graeae, now we'll turn to you as associate editor for us at Circulation, and also the editorialist on this particular paper. What caught your attention about this particular study and the results from the many papers that really come across your desk. Dr. Graeme Hankey: Thank you, Greg. And congratulations to Cecilia and her RE-SPECT ESUS colleagues. I mean, this is a landmark study, the RE-SPECT ESUS study, and just to go back, embolic stroke of undetermined source is really common. About one in four ischemic strokes, we don't know the cause of, and it's one of the major subtypes of cryptogenic stroke is an embolic ischemic stroke in which the source could have come from the heart or the aortic arch or the carotids. And we're not really sure. And we think that some of these patients have occult atrial fibrillation, but we can't pick it up at the time. So one way is to try and monitor them with prolonged ECG monitoring. And another way is to actually treat them with anticoagulation because we know that, that's more effective in people with cardio embolic stroke. And so RE-SPECT ESUS and NAVIGATE ESUS used the latter strategy and said, let's see if treating people with ESUS with anticoagulation is more effective than antiplatelet therapy. Dr. Graeme Hankey: And both studies were not significant in terms of showing that Dabigatran or Parovarian for NAVIGATE ESUS was more effective than antiplatelet therapy. So we're left now with this default that all patients with ESUS just get Aspirin, but we have a hunch that some of them actually have cardiogenic embolism and are being undertreated with Aspirin and need anticoagulation. So it's a heterogeneous entity, but we're treating it homogeneously with a sort of weak antiplatelet. So we want to try and find out who's going to get AF or who's already got it that is occult. And this study is a really great and prospective study with 5,000 patients as Cecilia said, who of whom 7% did develop AF just through annual ECG reporting and just with symptom reporting. And that's probably an under report. You know, if they'd had monitoring, they probably would've found about 20 or 30% would've developed AF during that time of 19 months follow up. Dr. Graeme Hankey: And it's the first study to really then show that not just the AF people had a higher stroke rate, but in that group who they predicted to be at high risk of AF with older age and the NT-prob, that the high risk group had a significant reduction with Dabigatran versus Aspirin in that high risk group. It's just, when you look for hetero homogeneity or heterogeneity across the risk groups, it wasn't quite significant. And that might be because it's not significant or it might be that study was underpowered to look at those three, across those three risk subgroups. And also it might be a bit confounded because of it, the patients weren't randomized according to their risk status for AF, they were just randomized, whether they had ESUS, so it's further excited us that there might be a subgroup who needs anticoagulation. And that's why the ARCADIA trial is ongoing now, looking at where the people with ESUS who have high risk of AF benefit from a apixaban versus aspirin. Dr. Greg Hundley: Very nice. And so, with these results that we have here, maybe come back to Cecilia, what do you think would be the next series of studies that needs to be performed in this area of research? Dr. Cecilia Bahit: Well, there's one side that's ongoing as Dr. Hankie mentioned, but I think we should be able to identify which patients have a higher risk of atrial fibrillation and those patients who use cardiac monitoring for long term to identify atrial fibrillation and to treat properly. So I think that would be key in this area. Dr. Greg Hundley: Very nice. And Graeae, what are your thoughts? Dr. Graeme Hankey: Yes. Well, one way is to have our ESUS patients have prolonged ECG monitoring by implantable loop recorders, for example, and then those who develop AF randomizing them to anticoagulation versus antiplatelet therapy. Although if they declare themselves with AF they're usually just go straight onto anticoagulation therapy. So the burning question is, in these people with ESUS who haven't declared themselves as AF, but have predictors of AF like those shown in RESPECT ESUS, like older age, high blood pressure, high BMI ,prob, and perhaps echo features, like left atrial size or ECG features like lots of premature atrial contractions or P wave of abnormalities. Dr. Graeme Hankey: Are these, the subgroups or even LV dysfunction, are these subgroups who need to be more specifically targeted in a randomized trial rather than the whole group of ESUS. And also with longer follow up. NAVIGATE ESUS stopped after 11 months. The bigger RESPECT ESUS stopped after a median follow up of 16 months and the curves were diverging. Maybe with five years follow up, a lot of these people would've developed AF and would've benefited from longer term anticoagulation, but the trials were stopped early, because there wasn't a signal of benefit and there was an early risk of bleeding with anticoagulation. Dr. Greg Hundley: Very good. Well listeners, this has been a really interesting study and we want to thank Cecilia and Graeme for sharing results of the RESPECT ESUS study, highlighting that, in patients with embolic stroke of undetermined source, atrial fibrillation occurs and is a possible source of this stroke, and then also older age, and elevation of NT-prob can be associated with development of atrial fibrillation, subsequent to that stroke event. Dr. Greg Hundley: Well listeners, we want to wish you a great week. And on behalf of Carolyn and myself, look forward to catching you next week on The Run. 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.

Gui, Joanne e Kaue debatem sobre o manejo de taquiarritmias. Abordamos alguns conceitos de eletrocardiograma, conversamos sobre o passo a passo da avaliação de taquiarritmias com QRS estreito e largo, além de cardioversão elétrica e as drogas possíveis. Esse episódio foi em parceria com o Whitebook A medfriday vai começar em breve! Acesso o site pra ficar informado! https://medfriday.pebmed.com.br/?utm_source=podcast&utm_medium=cpc&utm_campaign=medfriday-comercial-2021-tdc&utm_content=tdc Referências: Brugada J, Katritsis DG, Arbelo E, et al. 2019 ESC Guidelines for the management of patients with supraventricular tachycardiaThe Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC). Eur Heart J 2020; 41:655. Kalbfleisch SJ, el-Atassi R, Calkins H, et al. Differentiation of paroxysmal narrow QRS complex tachycardias using the 12-lead electrocardiogram. J Am Coll Cardiol 1993; 21:85. Brugada P, Brugada J, Mont L, et al. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation 1991; 83:1649. Vereckei A, Duray G, Szénási G, et al. Application of a new algorithm in the differential diagnosis of wide QRS complex tachycardia. Eur Heart J 2007; 28:589. Kaiser E, Darrieux FC, Barbosa SA, et al. Differential diagnosis of wide QRS tachycardias: comparison of two electrocardiographic algorithms. Europace 2015; 17:1422. Ganz LI, Friedman PL. Supraventricular tachycardia. N Engl J Med 1995; 332:162. Katritsis DG, Josephson ME. Differential diagnosis of regular, narrow-QRS tachycardias. Heart Rhythm 2015; 12:1667. Link MS. Clinical practice. Evaluation and initial treatment of supraventricular tachycardia. N Engl J Med 2012; 367:1438. Smith GD, Dyson K, Taylor D, et al. Effectiveness of the Valsalva Manoeuvre for reversion of supraventricular tachycardia. Cochrane Database Syst Rev 2013; :CD009502. Appelboam A et al. Postural Modification to the Standard Valsalva Manoeuvre for Emergency Treatment of Supraventricular Tachycardias (REVERT): A Randomised Controlled Trial. Lancet 2015.

Please join first author Yuan Lu and Guest Editor Jan Staessen as they discuss the article "National Trends and Disparities in Hospitalization for Acute Hypertension Among Medicare Beneficiaries (1999-2019)." Dr. Carolyn Lam: Welcome to Circulation on the Run: your weekly podcast, summary and backstage pass to the journal and it's editors. We're your co-hosts. I'm 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, and director of Pauley Heart Center at VCU health in Richmond, Virginia. Dr. Carolyn Lam: Greg, today's feature discussion is about the national trends and disparities and hospitalizations for hypertensive emergencies among Medicare beneficiaries. Isn't that interesting? We're going to just dig deep into this issue, but not before we discuss the other papers in today's issue. I'm going to let you go first today while I get a coffee and listen. Dr. Greg Hundley: Oh, thanks so much, Carolyn. My first paper comes to us from the world of preclinical science and it's from professor Christoff Maack from University Clinic Wursburg. Carolyn, I don't have a quiz for you, so I'm going to give a little break this week, but this particular paper is about Barth syndrome. Barth syndrome is caused by mutations of the gene encoding taffazin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Now beyond the first months of life, Barth syndrome cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, one of your favorites, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced Barth syndrome cardiomyopathy to mitochondrial formation of reactive oxygen species. Since mitochondrial function and reactive oxygen species formation are regulated by excitation contraction coupling, these authors wanted to use integrated analysis of mechano-energetic coupling to delineate the pathomechanisms of Barth syndrome cardiomyopathy. Dr. Carolyn Lam: Oh, I love the way you explained that so clearly, Greg. Thanks. So what did they find? Dr. Greg Hundley: Right, Carolyn. Well, first defective mitochondrial calcium uptake prevented Krebs cycle activation during beta adrenergic stimulation, abolishing NADH regeneration for ATP production and lowering antioxidative NADPH. Second, Carolyn, mitochondrial calcium deficiency provided the substrate for ventricular arrhythmias and contributed to blunted inotropic reserve during beta adrenergic stimulation. And finally, these changes occurred without any increase of reactive oxygen species formation in or omission from mitochondria. So Carolyn what's the take home here? Well, first beyond the first months of life, when systolic dysfunction dominates, Barth syndrome cardiomyopathy is reminiscent of heart failure with preserved rather than reduced ejection fraction presenting with progressive diastolic and moderate systolic dysfunction without relevant left ventricular dilation. Next, defective mitochondrial calcium uptake contributes to inability of Barth syndrome patients to increase stroke volume during exertion and their vulnerability to ventricular arrhythmias. Lastly, treatment with cardiac glycosides, which could favor mechano-energetic uncoupling should be discouraged in patients with Barth syndrome and left ventricular ejection fractions greater than 40%. Dr. Carolyn Lam: Oh, how interesting. I need to chew over that one a bit more. Wow, thanks. But you know, I've got a paper too. It's also talking about energetic basis in the presence of heart failure with preserved ejection fraction, but this time looking at transient pulmonary congestion during exercise, which is recognized as an emerging and important determinant of reduced exercise capacity in HFpEF. These authors, led by Dr. Lewis from University of Oxford center for clinical magnetic resonance research sought to determine if an abnormal cardiac energetic state underpins this process of transient problem congestion in HFpEF. Dr. Carolyn Lam: To investigate this, they designed and conducted a basket trial covering the physiological spectrum of HFpEF severity. They non-invasively assess cardiac energetics in this cohort using phosphorous magnetic resonance spectroscopy and combined real time free breathing volumetric assessment of whole heart mechanics, as well as a novel pulmonary proton density, magnetic resonance imaging sequence to detect lung congestion, both at rest and during submaximal exercise. Now, Greg, I know you had a look at this paper and magnetic resonance imaging, and spectroscopy is your expertise. So no quiz here, but could you maybe just share a little bit about how novel this approach is that they took? Dr. Greg Hundley: You bet. Carolyn, thanks so much for the intro on that and so beautifully described. What's novel here is they were able to combine imaging in real time, so the heart contracting and relaxing, and then simultaneously obtain the metabolic information by bringing in the spectroscopy component. So really just splashing, as they might say in Oxford, just wonderful presentation, and I cannot wait to hear what they found. Dr. Carolyn Lam: Well, they recruited patients across the spectrum of diastolic dysfunction and HFpEF, meaning they had controls. They had nine patients with type two diabetes, 14 patients with HFpEF and nine patients with severe diastolic dysfunction due to cardiac amyloidosis. What they found was that a gradient of myocardial energetic deficit existed across the spectrum of HFpEF. Even at low workload, the energetic deficit was related to a markedly abnormal exercise response in all four cardiac chambers, which was associated with detectable pulmonary congestion. The findings really support an energetic basis for transient pulmonary congestion in HFpEF with the implication that manipulating myocardial energy metabolism may be a promising strategy to improve cardiac function and reduce pulmonary congestion in HFpEF. This is discussed in a beautiful editorial by Drs. Jennifer Hole, Christopher Nguyen and Greg Lewis. Dr. Greg Hundley: Great presentation, Carolyn, and obviously love that MRI/MRS combo. Carolyn, these investigators in this next paper led by Dr. Sara Ranjbarvaziri from Stanford University School of Medicine performed a comprehensive multi-omics profile of the molecular. So transcripts metabolites, complex lipids and ultra structural and functional components of hypertrophic cardiomyopathy energetics using myocardial samples from 27 hypertrophic cardiomyopathy patients and 13 controls really is the donor heart. Dr. Carolyn Lam: Wow, it's really all about energetics today, isn't it? So what did they see, Greg? Dr. Greg Hundley: Right, Carolyn. So hypertrophic cardiomyopathy hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic arrangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced crystal density coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, the hypertrophic cardiomyopathy hearts failed to up-regulate mitophagic clearance. Dr. Greg Hundley: So Carolyn, in summary, the findings of this study suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with hypertrophic cardiomyopathy, and these results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing myocardial injury. Dr. Carolyn Lam: Wow, what an interesting issue of our journal. There's even more. There's an exchange of letters between Drs. Naeije and Claessen about determinants of exercise capacity in chronic thromboembolic pulmonary hypertension. There's a "Pathways to Discovery" paper: a beautiful interview with Dr. Heinrich Taegtmeyer entitled,"A foot soldier in cardiac metabolism." Dr. Greg Hundley: Right, Carolyn, and I've got a research letter from Professor Marston entitled "The cardiovascular benefit of lowering LDL cholesterol to below 40 milligrams per deciliter." Well, what a great issue, very metabolic, and how about we get onto that feature discussion? Dr. Carolyn Lam: Let's go, Greg. Dr. Greg Hundley: Welcome listeners to our feature discussion today. We have a paper that is going to address some issues pertaining to high blood pressure, or hypertension. With us, we have Dr. Yuan Lu from Yale University in New Haven, Connecticut. We also have a guest editor to help us review this paper, Dr. Jan Staessen from University Louvain in Belgium. Welcome to you both and Yuan, will start with you. Could you describe for us some of the background that went into formulating your hypothesis and then state for us the hypothesis that you wanted to address with this research? Dr. Yuan Lu: Sure. Thank you, Greg. We conducted this study because we see that recent data show hypertension control in the US population has not improved in the last decades, and there are widening disparities. Also last year, the surgeon general issued a call to action to make hypertension control a national priority. So, we wanted to better understand whether the country has made any progress in preventing hospitalization for acute hypertension. That is including hypertension emergency, hypertension urgency, and hypertension crisis, which also refers to acute blood pressure elevation that is often associated with target organ damage and requires urgent intervention. We have the data from the Center for Medicare/Medicaid, which allow us to look at the trends of hospitalization for acute hypertension over the last 20 years and we hypothesize we may also see some reverse progress in hospitalization rate for acute hypertension, and there may differences by population subgroups like age, sex, race, and dual eligible status. Dr. Greg Hundley: Very nice. So you've described for us a little bit about perhaps the study population, but maybe clarify a little further: What was the study population and then what was your study design? Dr. Yuan Lu: Yeah, sure. The study population includes all Medicare fee-for-service beneficiaries 65 years and older enrolled in the fee-for-service plan for at least one month from January 1999 to December 2019 using the Medicare denominator files. We also study population subgroups by age, sex, race and ethnicity and dual eligible status. Specifically the racial and ethnic subgroups include Asian, blacks, Hispanics, North American native, white, and others. Dual eligible refers to beneficiary eligible for both Medicare and Medicaid. This study design is a serial cross sectional analysis of these Medicare beneficiaries between 1999 and 2019 over the last 20 years. Dr. Greg Hundley: Excellent. Yuan, what did you find? Dr. Yuan Lu: We actually have three major findings. First, we found that in Medicare beneficiaries 65 years and older, hospitalization rate for acute hypertension increased more than double in the last 20 years. Second, we found that there are widening disparities. When we look at all the population subgroups, we found black adults having the highest hospitalization rate in 2019 across age, sex, race, and dual eligible subgroup. And finally, when we look at the outcome among people hospitalized, we found that during the same period, the rate of 30 day and 90 day mortality and readmission among hospitalized beneficiaries improved and decreased significantly. So this is the main findings, and we can also talk about implications of that later. Dr. Greg Hundley: Very nice. And did you find any differences between men and women? Dr. Yuan Lu: Yes. We also looked at the difference between men and women, and we found that actually the hospitalization rate is higher among females compared to men. So more hospitalizations for acute hypertension among women than men. Dr. Greg Hundley: Given this relatively large Medicare/Medicaid database and cross-sectional design, were you able to investigate any relationships between these hospitalizations and perhaps social determinants of health? Dr. Yuan Lu: For this one, we haven't looked into that detail. This is just showing the overall picture, like how the hospitalization rate changed over time in the overall population and by different population subgroups. What you mentioned is an important issue and should definitely be a future study to look at whether social determine have moderated the relationship between the hospitalization. Speaker 3: Excellent. Well, listeners, now we're going to turn to our guest editor and you'll hear us talk a little bit sometimes about associate editors. We have a team that will review many papers, but when we receive a paper that might contain an associate editor or an associate editors institution, we actually at Circulation turn to someone completely outside of the realm of the associate editors and the editor in chief. These are called guest editors. With us today, we have Dr. Jan Staessen from Belgium who served as the guest editor. He's been working in this task for several years. Jan, often you are referred papers from the American Heart Association. What attracted you to this particular paper and how do you put Yuan's results in the context with other studies that have focused on high blood pressure research? Dr. Jan Staessen: Well, I've almost 40 years of research in clinical medicine and in population science, and some of my work has been done in Sub-Saharan Africa. So when I read the summary of the paper, I was immediately struck by the bad results, so to speak, for black people. This triggered my attention and I really thought this message must be made public on a much larger scale because there is a lot of possibility for prevention. Hypertension is a chronic disease, and if you wait until you have an emergency or until you have target organ damage, you have gone in too late. So really this paper cries for better prevention in the US. And I was really also amazed when I compared this US data with what happens in our country. We don't see any, almost no hospitalizations for acute hypertension or for hypertensive emergencies. So there is quite a difference. Dr. Jan Staessen: Going further on that, I was wondering whether there should not be more research on access to primary care in the US because people go to the emergency room, but that's not a place where you treat or manage hypertension. It should be managed in primary care with making people aware of the problem. It's still the silent killer, the main cause of cardiovascular disease, 8 million deaths each year. So this really triggered my attention and I really wanted this paper to be published. Dr. Greg Hundley: Very nice. Jan, I heard you mention the word awareness. How have you observed perhaps differences in healthcare delivery in Belgium that might heighten awareness? You mentioned primary care, but are there any other mechanisms in place that heighten awareness or the importance? Dr. Jan Staessen: I think people in Belgium, the general public, knows that hypertension is a dangerous condition. That it should be well treated. We have a very well built primary care network, so every person can go to a primary care physician. Part of the normal examination in the office of a primary care physician is a blood pressure measurement. That's almost routine in Belgium. And then of course not all patients are treated to go. Certainly keeping in mind the new US guidelines that aim for lower targets, now recently confirmed in the Chinese study, you have to sprint three cells. And then the recent Chinese study that have been published to the New England. So these are issues to be considered. I also have colleagues working in Texas close to the Mexican border at the university place there, and she's telling me how primary care is default in that area. Dr. Jan Staessen: I think this is perhaps part of the social divide in the US. This might have to be addressed. It's not only a problem in the US, it's also a problem in other countries. There is always a social divide and those who have less money, less income. These are the people who fell out in the beginning and then they don't see primary care physicians. Dr. Jan Staessen: Belgium, for instance, all medicines are almost free. Because hypertension is a chronic condition prevention should not only start at age 65. Hypertension prevention should really start at a young age, middle age, whenever this diagnosis of high blood pressure diagnosis is confirmed. Use blood pressure monitoring, which is not so popular in the US, but you can also use home blood pressure monitoring. Then you have to start first telling your patients how to improve their lifestyle. When that is not sufficient, you have to start anti hypertensive drug treatment. We have a wide array of anti hypertensive drugs that can be easily combined. If you find the right combination, then you go to combination tablets because fewer tablets means better patient adherence. Dr. Greg Hundley: Yuan we will turn back to you. In the last minutes here, could you describe some of your thoughts regarding what you think is the next research study that needs to be performed in this sphere of hypertension investigation? Dr. Yuan Lu: Sure. Greg, in order to answer your question, let me step back a little bit, just to talk about the implication of the main message from this paper, and then we can tie it to the next following study. We found that the marked increase in hospitalization rate for acute hypertension actually represented many more people suffering a potential catastrophic event that should be preventable. I truly agree with what Dr. Staessen said, hypertension should be mostly treated in outpatient setting rather than in the hospital. We also find the lack of progress in reducing racial disparity in hospitalization. These findings highlight needs for new approaches to address both the medical and non-medical factors, including the social determinants in health, system racism that can contribute to this disparity. When we look at the outcome, we found the outcome for mortality and remission improved over time. Dr. Yuan Lu: This means progress has been made in improving outcomes once people are hospitalized for an acute illness. The issue is more about prevention of hospitalization. Based on this implication, I think in a future study we need better evidence to understand how we can do a better job in the prevention of acute hypertension admissions. For example, we need the study to understand who is at risk for acute hypertensive admissions, and how can this event be preempted. If we could better understand who these people are, phenotype this patient better and predict their risk of hospitalization for acute hypertension, we may do a better job in preventing this event from happening. Dr. Greg Hundley: Very nice. And Jan, do you have anything to add? Dr. Jan Staessen: Yes. I think every effort should go to prevention in most countries. I looked at the statistics, and more than 90% of the healthcare budget is spent in treating established disease, often irreversible disease like MI or chronic kidney dysfunction. I think then you come in too late. So of the healthcare budget in my mind, much more should go to the preventive issues and probably rolling out an effective primary care because that's the place where hypertension has to be diagnosed and hypertension treatment has to be started. Dr. Greg Hundley: Excellent. Well, listeners, we've heard a wonderful discussion today regarding some of the issues pertaining to hypertension and abrupt admission to emergency rooms for conditions pertaining to hypertension, really getting almost out of control. We want to thank Dr. Yuan Lu from Yale New Haven and also our guest editor, Dr. Jan Staessen from Louvain in Belgium. 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, 2021. The opinions express by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association for more visit aha journals.org.

If you've followed the NBT podcast for a while you probably heard Dr. Malcolm Kendrick talking about the tenuous connection between cholesterol levels and cardiovascular disease. Malcolm has published with The International Network of Cholesterol Skeptics on this topic, including a recent review paper entitled LDL-C does not cause cardiovascular disease. In the paper, they include both total cholesterol and LDL-C in their discussions, and if you look at epidemiological data, I think they make a good point. For instance, total cholesterol had almost no effect on mortality in the HUNT-2 study in Norway, and higher levels were associated with lower mortality risk in women. Or the ESCARVAL-RISK study, where higher LDL-C is associated with lower all-cause mortality until it's well above 200 mg/dl. Or the In-Chianti study, where people over 64 had the lowest mortality rates if they had an LDL-C greater than 130mg/dl. The question then becomes, if not cholesterol, then what? To answer that we must resist monomania and acknowledge the very notion of causation in a complex system is suspicious. Ask not what but how. Malcolm argues in his new book The Clot Thickens that if you maintain metabolic health, manage stress, and mind your endothelial function, cholesterol levels become largely irrelevant. Simple enough, but as you'll discover in this interview, the devil is in the details. Here's the outline of this episode with Malcolm Kendrick: [00:00:24] Previous NBT podcasts with Malcolm Kendrick: Why Cholesterol Levels Have No Effect on Cardiovascular Disease (And Things to Think About Instead) and A Statin Nation: Damaging Millions in a Brave New Post-health World. [00:00:42] Book: The Clot Thickens: The enduring mystery of heart disease, by Malcolm Kendrick. [00:03:04] 5-part series with lipidologist Thomas Dayspring (Part 1, 2, 3, 4, 5);  2-hour interview with Ron Krauss on The Drive Podcast. [00:04:23] Book: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. [00:06:12] LDL Cholesterol - challenging mainstream thought. [00:17:16] Fatty streaks never become atherosclerotic plaques; Review: Velican, C., M. Anghelescu, and D. Velican. "Preliminary study on the natural history of cerebral atherosclerosis." Medicine interne 19.2 (1981): 137-145. [00:18:54] Genetic influences; familial hypercholesterolemia (FH) and high clotting factors; Case study of patient with untreated FH but no presence of atherosclerosis: Johnson, Kipp W., Joel T. Dudley, and Jason R. Bobe. "A 72-year-old patient with longstanding, untreated familial hypercholesterolemia but no coronary artery calcification: a case report." Cureus 10.4 (2018). [00:21:22] Clotting factors more important than high LDL; Paper: Ravnskov, Uffe, et al. "Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia." Medical hypotheses 121 (2018): 60-63. [00:25:03] UK Biobank Study: Mora, Samia, Seth S. Martin, and Salim S. Virani. "Cholesterol Insights and Controversies From the UK Biobank Study: Three Take-Home Messages for the Busy Clinician." (2019): 553-555. [00:25:51] Machine learning used to predict cardiovascular disease; Study: Weng, Stephen F., et al. "Can machine-learning improve cardiovascular risk prediction using routine clinical data?." PloS one 12.4 (2017): e0174944. [00:30:54] FOURIER PCSK9-inhibitor study: More deaths in the treatment group; Study: Sabatine, Marc S., et al. "Evolocumab and clinical outcomes in patients with cardiovascular disease." New England Journal of Medicine 376.18 (2017): 1713-1722. [00:31:26] Evolocumab also reduces Lp(a); Study: O'Donoghue, Michelle L., et al. "Lipoprotein (a), PCSK9 inhibition, and cardiovascular risk: insights from the FOURIER trial." Circulation 139.12 (2019): 1483-1492. [00:34:02] APOA-1 Milano and HDL cholesterol. [00:38:45] Lp(a) and Vitamin C, plasminogen and clotting. [00:47:02] Rudolf Virchow, the father of the cholesterol hypothesis. [00:48:42] So what causes CVD? [00:49:53] Biomechanical stress; High blood pressure. [00:52:16] Endothelial and glycocalyx damage. [01:02:19] Steroids, immunosuppressants. [01:03:52] Avastin (bevacizumab) increases the risk of CVD; Study: Totzeck, Matthias, Raluca Ileana Mincu, and Tienush Rassaf. "Cardiovascular adverse events in patients with cancer treated with bevacizumab: a meta‐analysis of more than 20 000 patients." Journal of the American Heart Association 6.8 (2017): e006278. [01:06:07] Clotting disorders. [01:10:41] Sickle cell anemia - 50,000% increased risk of CVD. [01:11:36] Case study of 14-year old boy: Study: Elsharawy, M. A., and K. M. Moghazy. "Peripheral arterial lesions in patient with sickle cell disease." EJVES Extra 14.2 (2007): 15-18. [01:13:25] Air pollution, smoking, lead. [01:15:57] Biggest risk factors for CVD. [01:20:09] Supplements that strengthen the glycocalyx; Chondroitin Sulfate. [01:22:12] Malcolm's blog.

Natto, or fermented soybean, has been studied for its ability to support heart health. Natto provides nattokinase, a powerful enzyme that can be taken as a supplement to promote the health of the entire cardiovascular system. Take advantage of an exclusive podcast offer today by visiting http://www.invitehealth.com/podcast. For more information on the products or studies mentioned in this episode, click here. 

Les films RoboCop ont ancré dans notre imaginaire ce personnage mi-homme, mi-machine, 100% police, qui  affronte un robot policier 100% machine, devenu incontrôlable et destructeur.  Malgré les avertissements bien clairs de ces scénarios de science-fiction, des robots policiers sont actuellement testés à Singapour et à New York. Qu'est-ce qui pourrait mal tourner? Avec Baptiste Zapirain et Charles Trahan  Pour de l'information concernant l'utilisation de vos données personnelles - https://omnystudio.com/policies/listener/fr

Dr Steven McVea talking about Return of Spontaneous Circulation Care. This talk is part of the Paediatric Emergencies 2021 event. To get your CME certificate for listening to the podcast please visit https://www.paediatricemergencies.com/conference/paediatric-emergencies-2021/

Global warming is, obviously, a world-wide phenomenon.  When the concept of a 2 degrees Celsius temperature rise is discussed, it refers to the average global temperature and the effects that would have on such things as sea level rise and weather patterns.  But the effects of the changing climate are not homogeneous.  Very different things […]

Please join authors Babken Asatryan and Anwar Chahal, and Associate Editor Ntobeko Ntusi as they discuss the Primer article "Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review." 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 at Richmond, Virginia. Well, Carolyn this week, our feature discussion, we're not going to go with one of our original articles, but we are going to feature a primer and a primer is a state of the art review article. The topic is going to be on arrhythmogenic cardiomyopathy and we'll be looking at the role of inflammation and the immune response in arrhythmogenic cardiomyopathy. But before we get to that feature, how about we grab a cup of coffee and talk about some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I would, because guess what? I'm going to be talking about prescription opioids. We know these are a major contributor to the ongoing epidemic of persistent opioid use. What do you think is the incidence after cardiac implantable electronic device procedures? Greg, let's start with a Greg Hundley quiz. I'll give you multiple choice, how about that? Do you think it is 1%, 10%, 25%. 50%? Dr. Greg Hundley: All right, Carolyn, I'm going to guess here. I'm going to go 10%. Dr. Carolyn Lam: Smart. Well, guess what? Today's paper actually gives us insight into that question, it's from Dr. Frankel from the hospital of the university of Pennsylvania and his colleagues, and these authors performed a retrospective cohort study using data from a national Administrative Claims Database from 2004 to 2018 of patients undergoing cardiac implantable electronic device procedures. Adult patients were included if they were opioid naive during the 180 day period before the procedure and did not undergo another procedure with anesthesia in the following 180 days. Dr. Carolyn Lam: Persistent opioid use, which is what we're interested in, was defined by filling an additional opioid prescription more than 30 days following the procedure. So, here's your answer. Of the more than 143,000 patients meeting these inclusion criteria, 11%, so you were right Greg, 11% filled an opioid prescription within 14 days of surgery. Among these patients, persistent opioid use occurred in 12.4% of patients, 30 to 180 days after surgery. The likelihood for developing persistent opioid use was increased for patients who had a history of drug abuse, pre-operative muscle relaxant or benzodiazepine use or opioid use in the prior five years. Also, patients who have prescribed more than 135 milligrams of oral morphine equivalence had a significantly increased risk of persistent opioid use. Dr. Carolyn Lam: Now, this is important because all physicians who perform cardiac implantable electronic device procedures and care for these patients should be aware of the risk of persistent opioid use. This is discussing in editorial by Dr. Kandil from UT Southwestern. Dr. Greg Hundley: Very interesting Carolyn, so connecting sometimes the prescription use of opioids after cardiac implantable electronic devices. Great presentation. Well, my first paper comes to us from the world of preclinical science and it's from our prior editor in chief Dr. Joseph Loscalzo from Brigham and Women's Hospital and the Harvard Medical School. So Carolyn, interferon gamma, producing CD4 positive and CD8 positive T-lymphocytes, have been identified as the predominant pathological cell subsets in human atherosclerotic plaques. Dr. Greg Hundley: While the immunological consequences of these cells have been extensively evaluated, their interferon gamma mediated metabolic effects on endothelial cells remains unknown. So Carolyn, the purpose of this study was to determine the metabolic consequences of the T-lymphocyte cytokine interferon gamma on human coronary artery endothelial cells. Dr. Carolyn Lam: Interesting. So what did Dr. Loscalzo and colleagues find? Dr. Greg Hundley: Right, Carolyn. So, the authors found that interferon gamma impairs endothelial glucose metabolism via altered tryptophan metabolism while depleting NAD plus, which results in a metabolic shift toward increased fatty acid oxidation, and therefore, Carolyn, this work suggests a novel mechanistic basis for pathologic T-lymphocyte endothelial interactions in atherosclerosis, mediated by interferon gamma, linking endothelial glucose, tryptophan, and fatty acid metabolism with NADH and ATP generation and their adverse endothelial functional consequences. Dr. Carolyn Lam: Oh, very nice, Greg. Thank you. The next paper describes a comprehensive characterization of cardiomyopathy caused by filament C truncating variance. Dr. Greg Hundley: Whoa. Okay, Carolyn. Now what is filamin-C? Dr. Carolyn Lam: I thought you may ask and I wasn't going to quiz you, see Greg? The filamin-C gene can cause a striated muscle protein that crosslinks actin and anchors cell membrane proteins to the cytoskeleton, sarcolemmal and sarcomere Z-disc. So, the co-corresponding authors of today's paper Drs. Mestroni and Taylor from University of Colorado, Denver Anschutz Medical Campus, analyzed longitudinal clinical data from an international multicenter cohort of 85 carriers of this filamin-C truncating variants. And this is what they found. Dr. Carolyn Lam: First, the cardiomyopathy associated with filimin-C truncating variants appeared to be a disease with heterogeneous phenotypic presentation, ranging from typical dilated cardiomyopathy to arrhythmogenic, right ventricular cardiomyopathy, and with frequently overlapping forms. Dr. Carolyn Lam: Number two, left ventricular ejection fraction was associated with the risk of death, either all cause or non-arrhythmic, heart transplantation, or LVAD, but not with the risk of sudden cardiac death or major ventricular arrhythmias, highlighting the need for alternative strategies of stratification of the arrhythmic risk in these patients with the filimin-C truncating variant cardiomyopathy. Dr. Carolyn Lam: And number three, this cardiomyopathy was associated with a high risk of ventricular arrhythmias with frequencies of life-threatening ventricular arrhythmias, not significantly different from things like Lamin and desmoplakin cardiomyopathy. Dr. Greg Hundley: Well, Carolyn, just fantastic. My next paper comes to us from Professor Lena Claesson-Welsh from Uppsala University and Carolyn, palmdelphin belongs to the family of paralemmin proteins implicated in cytoskeletal regulation and single nuclide polymorphisms in the palmdelphin locus that result in reduced expression are strong risk factors for development of calcific aortic valve stenosis, and predict the severity of the disease. Dr. Carolyn Lam: Wow, interesting. Palmdelphin, great. So tell us, what did they find and what are the clinical implications please? Dr. Greg Hundley: Right, Carolyn, great question. So first, calcific aortic valves stenosis patients with the single nucleotide polymorphism RS754 3130 express reduce palmdelphin levels in valve endothelial cells, which shows hallmarks of palmdelphin deficiency, such as loss of cytoplasmic RanGAP1, altered nuclear morphology and nuclear rest of P53 of P21. Carolyn, second, gene-regulatory changes affecting actin reorganization, are detected in seemingly healthy regions of calcifying bowels, in agreement with disturbed actin-dependent processes, being an early event, instigating the calcific process. And so Carolyn, the take home message is that palmdelphin is prominently expressed in endothelial cells and the presence of the palmdelphin single nucleotide polymorphism correlated both with a Barrett endothelium and calcific aortic valve stenosis suggesting that endothelial cell dysfunction is essential in development of calcific aortic valve disease. Dr. Carolyn Lam: Oh, wow, wow. Thank you for translating that into the clinical implication. Thanks Greg. Let's maybe discuss what else is in today's issue. There's a prospective piece by Dr. Kirchof entitled “In Patients With Recently Diagnosed Atrial Fibrillation, Think Anticoagulation And Rhythm Control.” There's an exchange of letters between Drs. Liao and Hakala regarding the article Cardiovascular Risk Factor Trajectory Since Childhood And Cognitive Performance In Midlife, The Cardiovascular Risk In Young Finns, study. Dr. Greg Hundley: And Carolyn, I've got a research letter from Professor Ramin entitled “Association Between Sarcomeric Variants In Hypertrophic Cardiomyopathy In Myocardial Oxygenation, Insights From A Novel Oxygen-Sensitive CMR Approach.” Well, how about now we get onto that primer feature discussion relating to arrhythmogenic cardiomyopathy? Dr. Carolyn Lam: Yay. All right, let's go, Greg. Dr. Greg Hundley: Well, listeners, we are now onto our feature discussion and this week we've got a different aspect to the feature discussions. We're going to work through a review article and what we call as a primer. It's one of our state-of-the-art family of publications, where we take a topic and perform a review on a new evolutionary concept that might be occurring in a particular field. This week, we are going to discuss arrhythmogenic cardiomyopathy and we have with us two of the authors of this primer, Dr. Babken Asatryan from Bern, Switzerland and also Dr. Anwar Chahal from Lancaster, Pennsylvania. And of course, as always, we invite one of our associate editors and we have with us this week Ntobeko Ntusi from South Africa. Welcome gentlemen and Babken, let's start with you. Can you give us just a little bit of review regarding arrhythmogenic cardiomyopathy? We hear that term as opposed to arrhythmogenic right ventricular cardiomyopathy, and then maybe also, what are the underlying fundamental histopathologic and pathophysiologic findings associated with this disease? Dr. Babken Asatryan: Thank you, Greg. It's really an absolute pressure being here and thank you for your invitation again. So arrhythmogenic cardiomyopathic is genetically-determined heart disease and the common cause of sudden cardiac death in individuals younger than 40 years of age, it's characterized pathologically by fibrosis and/or fibro fatty infiltration of the myocardium. This infiltration provides a substrate for electrical and stability and leads to ventricular arrhythmias ranging from isolated premature ventricular contractions to sustain ventricular tachycardia and ventricular fibrillation. Live ventricular arrhythmias are cardio manifestations of the orthogenic cardiomyopathy, and they typically occur at early stages of the disease, preceding pathological and functional abnormalities. We call that a concealed stage of the disease. Dr. Babken Asatryan: The typical form for arrhythmogenic cardiomyopathy, which has been previously termed as arrhythmogenic right ventricular cardiomyopathy, primarily affects the right ventricle and has been recognized for decades. Following implementation of postmortem autopsy, increased use of contrast, enhanced cardiac MRI, and improved understanding of the genotype phenotype correlations, more recently cases with more pronounced left ventricular involvement have been discovered as well as cases with biventricular involvement of the disease. Dr. Babken Asatryan: Nowadays, we believe that around 60% of cases have also left ventricular involvement, even if they're diagnosed based on the 2010 task force criteria for arrhythmogenic cardiomyopathy. Causative variants in desmosomal genes are identified in about 60% of patients with typical arrhythmogenic right ventricular cardiomyopathy. Dr. Babken Asatryan: Recently, there have been studies reporting non-desmosomal gene variants in patients with arrhythmogenic right ventricular cardiomyopathy, as well as in those left ventricular and biventricular forms of the disease. But the left ventricular form is quite new to us, so we are learning a lot every day about this disease. Dr. Babken Asatryan: The pathogenesis of this condition appears to be quite complex. We know that these pathogenic variant in desmosomal genes can initiate several pathways and these could be gene dependent. What we do know, that these eventually lead to fibrosis and fibro fatty infiltration of the myocardium, which is the hallmark feature of arrhythmogenic cardiomyopathy. Dr. Greg Hundley: And patients present generally when, in terms of lifespan? Dr. Babken Asatryan: So, patients present in between 30 to 40 years of age, there's a typical presentation for arrhythmogenic cardiomyopathies but young presentations are also common nowadays, particularly. So, programs in families, they usually present 30 to 40 years of age. But in families, we do discover patients who have typical arrhythmogenic right ventricular cardiomyopathy or left and right ventricular involvement were younger at age, but they still need the criteria. Dr. Greg Hundley: And then when we diagnose this condition, do we also need to think about, at least clinically, looking for other affected individuals within a family? Dr. Babken Asatryan: Absolutely. So most of the arrhythmogenic biventricular cardiomyopathy, arrhythmogenic left ventricular cardiomyopathy cases are autosomal dominant diseases. So, this means if an individual carries a pathogenic variant in one of the genes responsible for the condition, the likelihood that the first degree family members will carry the same variant is about 50%. The disease however, presents with reduced penetrance and variable expressivity. Some of the family members may have just arrhythmias and others may develop arrhythmias and structural heart disease. And some of the individuals who carry pathogen occurrence in desmosomal are the genes responsible for the condition may not show phenotype at all. So, that makes the decision-making in families quite challenging. Dr. Greg Hundley: Very nice. Well, thank you so much Babken and now, we're going to turn to one of your co-authors, Anwar and Anwar, in this primer, you start to present a new sort of theme, that inflammation actually may play a role in this disease, at least in terms of adverse events. Can you describe a little bit what your team was thinking here and what took you in this direction and what are some of the research that you've revered here that supports this new line of thinking?   Dr. Anwar Chahal: Thanks, Greg and Ntobeko, for first, the kind invitation to come on this podcast. I must add that I normally listen to the podcast and very much enjoy it, so it's a great honor and privilege for us. Dr. Anwar Chahal: Let me contextualize it, I think it's important to think about what are problems are when we evaluate cases, whether that's the program or the family members, and try to determine what's actually going on. There's been a number of changes over the last 15 years that really evolve around a better understanding and the availability of multimodality imaging, which has altered the way we evaluate these cases. If you look at the 2010 taskforce criteria, for example, they talk about volumetric changes and injection fractions by echo or MRI, and even ventriculogram synapse on fluoroscopy, which I don't think many people do anymore, but they don't mention gadolinium enhancement, and there is an updated version that will come out and talk about that, and the advantages of MRI and even contrast-enhanced CT, and now 18F-FDG, CT PET imaging. Dr. Anwar Chahal: So, the patient journey and the problem that we face is that actually some people present with very unusual features, chest pain, troponin rise, undergo coronary angiography, normal coronary arteries, or unobstructed coronary arteries. We put them through MRI scanners and we see a little bit of gadolinium enhancement. We follow them over the next five years or so, and it develops into taskforce criteria, positive ARVC. So, that's the sort of clinical angle where we've started to see this. Dr. Anwar Chahal: As we put people through scanners, we see the hearts lights up on PET scanners, pretty reproducibly and reliably, that tells us that there's some inflammation there. We look back into the literature and actually very, very early work that was done, autopsy-based, some of it endomyocardial biopsy-based describing lymphocytic infiltrates. Usually that's dry, as you say, or sterile, but there have been reports of even viral pathogens. Dr. Anwar Chahal: That's where it stirred this debate up for us about whether there's this signal that we're seeing there, what is it? What's actually going on? It raises a question, we recognize the other mechanisms, the fiber fatty replacement, the apoptotic pathways, that contribute to that. But there's such variable expressivity with this disease. It's a difficult disease to pin down and it raises a question. What are these other effect modifiers? Is there something else that we do not recognize? And that's really what's driven this. Dr. Anwar Chahal: Our group of co-authors are leaders in the field. Some of them are colleagues in veterinary medicine, Dr. Anna Geltser, and we work together on boxer dog patients. So, she is a practicing vet and a scientist, and has lots of boxer dogs with arrhythmogenic cardiomyopathy. We've been looking at how we could utilize that as a model to test some of the findings that we have in humans and pioneering work really by Bob Hamilton in Toronto, in this paper where they described anti-DSG2 antibodies, which were found not only in humans, whatever the underlying genotype, but also in boxer dogs with arrhythmogenic cardiomyopathy. And that's been followed up with work from Europe, describing anti-heart antibodies, anti-intercalated disk antibodies. Dr. Anwar Chahal: It doesn't really matter what the genotype is, but we're seeing these antibodies there and we're seeing these positive scans indicating inflammation. So the big question is, is this inflammation of primary insult or is it secondary? Is it that the heart in somebody with a genetic cardiomyopathy is predisposed, maybe the remodeling is affected. Bob Hamilton thinks this is probably the best explanation to explain why, whatever the genotype, that these antibodies were positive, that actually that myocardium becomes exposed. The epitope of DSG is now exposed to the immune system, which mounts an antibody response, and hence you see the rise in these antibodies, but it's possible it could it be primary as well. With COVID, and this is a bit of a stretch, so just bear with me there, with COVID we've been recognizing that there's myocardial injury. Dr. Anwar Chahal: There's not as much myocarditis as we expected, but there's been, with virus SARS-CoV-2, we know regular human coronavirus is a recognized cause of viral myocarditis. So, the question really arose are we going to see a lot more of this myocarditis? In our lab discussion, it was, "Well, do you think we're going to see something similar in that we've seen with arrhythmogenic cardiomyopathy, these genetically predisposed individuals are more likely to get invaded? Now, we haven't really seen that with COVID and I won't delve too much into it, but going back to the classical viral infections that we see with myocarditis, here's a really, really interesting biological link. Most of them invade through the desmosome, so with SARS-CoV-2, we see the ACE2 receptors as the way the virus really invades. But with these regular coxsackie virus, for example, parvovirus, a lot of them invade through the desmosome, and that's where we thought, here's a link. Dr. Greg Hundley: Very nice. Ntobeko, you see a lot of papers come across your desk. What attracted you to this group of investigators and this particular review article? Dr. Ntobeko Ntusi: Thank you very much, Greg. I want to start by congratulating Babken, and Anwar for a really fantastic submission, which as an associate editor, was an absolute pleasure to handle. There really are six things that stood out for me about this article. The first one really relates to the question that you ask Babken, which relates to the nomenclature and people have traditionally thought of this is a disease of the right ventricle. I think it's now timely to consider a clear change in nomenclature, that recognizes not only right ventricular involvement, but also left ventricular involvement. And the common finding of biventricular disease in patients with ACM. Dr. Ntobeko Ntusi: The second really important contribution for me from this primer was that we've always thought of arrhythmogenic cardiomyopathies as a genetic disorder with abnormalities in the genes, encoding components of the desmosome. Many groups recently, including our own group that described novel mutations for arrhythmogenic cardiomyopathy in adhering to poultry and other genes outside of the desmosome are showing that the genetic underpinnings are much wider. But the key contribution here is really the consideration of the centrality of inflammation to the pathogenesis of this disease. Anwar has spoken to some length about that, so I won't rehash those comments, but for me, what is key for future work in this area is really to clarify whether the inflammation, as in with many other forms of cardiovascular disease, is merely an epiphenomenon, or whether it plays a critical role in the causal pathway for the phenotypes that we see. Dr. Ntobeko Ntusi: The next important feature for me was the review of the literature and evidence in the association with myocarditis. So, we've seen lots of case reports and small case series showing young people presenting with myocarditis and meeting either the Dallas criteria histologically, or the Lake Louise criteria on imaging, and then subsequent genetic testing confirming the diagnosis of an arrhythmogenic cardiomyopathy. I thought for the first time with quite a compelling review of the link between these two. Dr. Ntobeko Ntusi: The fourth important contribution relates really to the contribution of imaging modalities, both in diagnostics, but critically in risk stratification for this clinical entity. And for me, the importance of cardiovascular magnetic resonance, either with planimetric mapping or late gadolinium enhancement to really add to our ability to predict future events. Dr. Ntobeko Ntusi: Then there's been quite a number of publications in the last five years that have clarified our understanding of the at risk patient with arrhythmogenic cardiomyopathy who's likely to suffer a sudden cardiac death event. This tends to be somebody who was young, who was male, who has a history of documented non-sustained ventricular tachycardia or a history of syncope and on ECG, quite extensive T wave inversion. So again, this is nicely reviewed, and we think about those as candidates who'll benefit from implantation of an ICD. Dr. Ntobeko Ntusi: Then I thought for me, the last really nice contribution from this piece was the review of advancing our understanding of the hot phase. So in all forms of heart muscle disease, we speak of the presentation of patients with the chest pain syndrome, with a troponin leak, but unobstructed coronaries. On further investigation, we don't really find any other evidence of an inflammatory event. We call this a hot phase. And in some case reports in small case series, endomyocardial biopsy has revealed the association of these, whether in TCM, HCM, or arrhythmogenic cardiomyopathy with lymphocytic infiltration. I thought this was all very nicely reviewed. Dr. Ntobeko Ntusi: So, the question that really left me with having read this review, was whether in the future, we may actually need to consider targeting inflammatory pathways as a therapeutic target in this heart muscle disorder. Thanks Greg. Dr. Greg Hundley: Yes. Thanks so much in Ntobeko. You've really led us to the next question that I'm going to ask both Babken and Anwar, you've discussed where do you feel this field is moving and what is the next study or series of studies we need to perform. Babken, first you, and then Anwar. Babken, what do you think is the next study to be performed in this space? Dr. Babken Asatryan: I so much agree with Ntobeko, that perhaps understanding better what can be targeted in these patients, in order to prevent development of phenotype or least to prevent cardiac events, is perhaps the most important next step. In our first figure, we have summarized this potential mechanisms, involving inflammation leading to with arrhythmogenic cardiomyopathy in these patients. We have also highlighted the potential mechanisms that perhaps in the future can be targeted. This could include both targeting the inflammatory cytokines, as well as the primary agents that cause the myocardial inflammation in patients, depending on the results that we will receive over the next years and perhaps animal models should be the next step to better understand how similar arrhythmogenic cardiomyopathy phenotype, where inflammatory contributors to the phenotype are important. And then we can understand whether this can be the same in humans as well. Dr. Greg Hundley: Very nice. And Anwar, do you have anything to add? Dr. Anwar Chahal: Yes. So, agree with that. I guess I would add what are we doing to try to help decipher this? So some of the work that we're doing, I mentioned earlier with the boxer dog patients, who have arrhythmogenic cardiomyopathy. So some of the aspects that we're actually looking at is taking swab cells to see if we can phenotype as a alternative tender myocardial biopsy. And one of the co-authors, Angeliki Asimaki, really pioneered that as a alternative tool because the desmosis are ubiquitous and this may help us phenotype patients better. But also, we want to look at using that as a tool in the pheno copies of arrhythmogenic cardiomyopathy. So we would advocate, re-phenotyping people as well as possible and trying to use some of these techniques. Dr. Anwar Chahal: The next thing we're really looking at is antibody based tools, either working with collaborators, who've already described these antibodies such as anti-DSG2, anti-heart antibody, and anti-skeletal disc to see if we can develop those and perhaps identify others in both human and ox models. And that will then hopefully open the way for us to develop therapeutics that may be able to target those and address that, and maybe use these antibodies as markers to see disease progression, or halting of disease. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Babken Asatran from Bern, Switzerland, Anwar Chalal from Lancaster, Pennsylvania, and our own associate editor, Ntobeko Ntusi from South Africa, really helping us see this new scientific consideration regarding the potential role of inflammation in causal pathways of adverse manifestations of arrhythmogenic cardiomyopathy. 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, 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.

Credits: 0.25 AMA PRA Category 1 Credit™   CME/CE Information and Claim Credit: https://www.pri-med.com/online-education/podcast/frankly-speaking-cme-250   Overview: While the data conflict on how much sodium intake is optimal for preventing cardiovascular disease, it is clear that daily salt intake for most Americans exceeds what is recommended. However, restricting salt intake on an individual or on a public health level has been controversial. An interesting alternative is the use of salt substitutes, which can help to decrease sodium intake while increasing potassium intake, and both have been associated with lowering blood pressure. Join us to hear a discussion on the results of the recently published studies on salt and cardiovascular disease, along with an overview of the Salt Substitute and Stroke Study (SSaSS).   Episode resource links: Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. DOI: 10.1056/NEJMoa2105675 O'Donnell M, Mente A, Alderman MH, et al. Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake, European Heart Journal, Volume 41, Issue 35, 14 September 2020, Pages 3363–3373, https://doi.org/10.1093/eurheartj/ehaa586 Circulation. 2021;143:1542–1567. DOI: 10.1161/CIRCULATIONAHA.120.050371 Guest: Robert A. Baldor MD, FAAFP   Music Credit: Richard Onorato

Credits: 0.25 AMA PRA Category 1 Credit™   CME/CE Information and Claim Credit: https://www.pri-med.com/online-education/podcast/frankly-speaking-cme-250   Overview: While the data conflict on how much sodium intake is optimal for preventing cardiovascular disease, it is clear that daily salt intake for most Americans exceeds what is recommended. However, restricting salt intake on an individual or on a public health level has been controversial. An interesting alternative is the use of salt substitutes, which can help to decrease sodium intake while increasing potassium intake, and both have been associated with lowering blood pressure. Join us to hear a discussion on the results of the recently published studies on salt and cardiovascular disease, along with an overview of the Salt Substitute and Stroke Study (SSaSS).   Episode resource links: Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. DOI: 10.1056/NEJMoa2105675 O'Donnell M, Mente A, Alderman MH, et al. Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake, European Heart Journal, Volume 41, Issue 35, 14 September 2020, Pages 3363–3373, https://doi.org/10.1093/eurheartj/ehaa586 Circulation. 2021;143:1542–1567. DOI: 10.1161/CIRCULATIONAHA.120.050371 Guest: Robert A. Baldor MD, FAAFP   Music Credit: Richard Onorato

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Please join author Maria Nunes and Associate Editor Ntobeko Ntusi as they discuss the article “Incidence and Predictors of Progression to Chaga Cardiomyopathy: Long-Term Follow-Up of Trypanosoma cruzi-Seropositive Individuals.” Dr. Carolyn Lam:             Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley:           And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well Carolyn, this feature this week, we're going to talk about Chagas disease and we have some really important long-term, really for the first time, observational data and a cohort that's been followed in Brazil. And it's just a wonderful discussion from a team that's been working very hard in this area over an extended period of time. But before we get to that, how about we grab a cup of coffee and get started on some of the other articles in this issue? Would you like to go first? Dr. Carolyn Lam:             I would. And with your coffee, I would like to tell you about non-combustible nicotine or tobacco products. Fancy a smoke with your coffee? Well, you know that those are novel forms of nicotine consumption composed of things like nicotine vaping products that vaporize the nicotine-containing fluids and heated tobacco products that really heat the tobacco products without combustion. Now, these have recently gained popularity because they're portrayed as being safer modes of smoking compared with the traditional combustible cigarettes. However, their associations with subsequent cardiovascular disease risks are still unclear. So Greg, here's today's quiz. Gosh, I miss our quizzes. What do you think? Are they safer or are they not? Dr. Greg Hundley:           Oh, Carolyn, you're catching me on this and I never know which way to go, but I'm going to guess not. How about you tell us? Dr. Carolyn Lam:             Well, the paper will tell us, and this is from co-corresponding authors Dr. Lee from Seoul National University Bundang Hospital and Dr. Park from Seoul National University College of Medicine and their colleagues. And they basically studied more than 5,000,000 adult men who underwent health screening examinations during both a first and second phase of health screening periods from the Korean National Health Insurance Service Database spanning 2014 to 2018. Initial combustible cigarette smokers who subsequently quit that cigarette smoking and converted to a non-combustible nicotine or tobacco product use was associated with a lower incident cardiovascular disease risk compared to those who continue the combustible cigarette use. However, compared with combustible cigarette quitting without using these non-combustible substitutes, those who ceased smoking but continued with the non-combustible products was associated with a higher cardiovascular disease risk. So the take home message is although the non-combustible nicotine or tobacco products may be associated with a lower cardiovascular disease risk compared with continued combustible cigarette smoking, those who quit without using these substitutes may benefit the most in reducing the risk of developing future cardiovascular disease events. And this is discussed in a wonderful editorial by Dr. Auer, Diethelm and Berthet. Dr. Greg Hundley:           Very nice, Carolyn. Great presentation and really new information in this space. Well, my paper comes from the world of preclinical science and it involves long noncoding RNAs. And Carolyn, they are important regulators of biological processes involved in vascular tissue homeostasis and cardiovascular disease development. And so, the current study, led by Professor Lars Maegdefessel from Karolinska Institute, assessed the functional contribution of the long noncoding RNAs myocardial infarction associated transcripts and their relationship to atherosclerosis and carotid artery disease. Dr. Carolyn Lam:             Hmm, interesting. They are the rage, these lncRNAs. So what did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. So long noncoding RNAs possess key regulatory functions directly interacting and mediating expression and functionality of proteins, other RNAs, as well as DNA. Next, the long noncoding RNA myocardial infarction associated transcript plays a key role during atherosclerotic plaque development and lesion destabilization. Its expression becomes highly increased in high risk patients with vulnerable plaques. And so, Carolyn, the take home therapeutic targeting of the long noncoding RNA myocardial infarction associated transcript, using antisense oligonucleotides, well that offers novel treatment options for patients with advanced atherosclerosis in the carotid arteries that are at risk of stroke. Dr. Carolyn Lam:             Oh, very interesting. So from the preclinical world back to the clinical world with an important clinical trial. Now, we know that percutaneous closure of the left atrial appendage is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with nonvalvular atrial fibrillation. The Amplatzer Amulet Left Atrial Appendage Occluder IDE trial, called the Amulet IDE trial, was designed to evaluate the safety and effectiveness of the dual seal mechanism of the Amulet left atrial appendage occluder compared with the WATCHMAN device. And here, 1,878 patients with nonvalvular atrial fibrillation at increased risk of stroke were randomly assigned to undergo percutaneous implantation of a left atrial appendage occluder with the Amulet occluder or a WATCHMAN device. And the primary end points included safety, which was a composite of procedure-related complications all cause death or major bleeding at 12 months, and effectiveness, which was a composite of ischemic stroke or systemic embolism at 18 months. They also looked at the rate of left atrial appendage occlusion at 45 days. And this paper is from Dr. Lakkireddy and colleagues from Kansas City Heart Rhythm Institute. Dr. Greg Hundley:           Well Carolyn, these devices, they are really being heavily tested in patients with atrial fibrillation. So what did they find? Dr. Carolyn Lam:             The Amulet occluder was non-inferior with respect to safety and effectiveness compared to the WATCHMAN device, and superior with respect to left atrial appendage occlusion; however, procedure-related complications were higher with the Amulet occluder, largely related, perhaps, to more frequent pericardial effusion and device embolization. And the authors noted that the procedure-related complications decreased with operator experience; however, I think all of this still needs to be further investigated. Well, those were really nice original papers, but let's also discuss what else there is in today's issue. There is an exchange of letters between Drs. Mueller and Allen regarding the article “Diagnostic Performance of High Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite U.S. Cohort.” There's a perspective piece by Dr. Olson, “Toward CRISPR Therapies for Cardiomyopathies.” Dr. Greg Hundley:           And Carolyn, I've got a research letter from Professor Layland entitled “Colchicine in Patients with Acute Coronary Syndromes: Two Year Follow Up of the Australian COPS Randomized Clinical Trial.” Well, what a great set of papers that we've discussed. Now, let's get on to that feature discussion and learn a little bit more about the longitudinal history and progression of cardiovascular disease and patients with Chagas disease. Dr. Carolyn Lam:             Yay. Let's go, Greg. Dr. Greg Hundley:           Well, listeners, we are here for our feature discussion today and a very exciting one we have, pertaining to Chagas disease. And we have with us today Dr. Maria Nunes from Belo Horizonte, Brazil, and also one of our Associate Editors, Dr. Ntobeko Ntusi from Cape Town, South Africa. Welcome to you both. And Maria, we'll start with you. Could you describe for us some of the background information pertaining to your study and what was the hypothesis that you wanted to address? Dr. Maria Nunes:             Yes, thank you for these opportunities. My main hypothesis is that Chagas disease is the major cause of dilated cardiomyopathy in endemic areas. So we selected patients without cardiomyopathy at baseline to see if the Trypanosoma cruzi seropositivity is a predictor of further developing of cardiomyopathy. Dr. Greg Hundley:           Very nice. And so tell us, how did you construct this study? What was your design? And then also, maybe describe for us how you selected the participants for this study. Dr. Maria Nunes:             We selected the participants from two blood donor centers. One in Sao Paulo and one in Montes Claros, which is north of Minas Gerais State. We select blood donors because it's the way that we have Chagas disease's screening tests. And in asymptomatic patients, usually at the hospital, patients comes to us with heart failure or a kind of symptoms related to Chagas disease. Our main goals in this study is to select healthy participants based on the screen test of Trypanosoma cruzi. So the population was blood donors selected from two centers. Dr. Greg Hundley:           Very good. And then again, your study design. So did you follow these two groups of individuals longitudinally over time, and for how long? Dr. Maria Nunes:             Yes, we have different visits of this study with the patients initially was selected at first in 1996 and 2002. At this time, they don't have cardiovascular exams. And our study actually is starting 2008 to 2010, and we select all these patients with all comprehensive cardiovascular evaluation with the clinical examination, echocardiogram and electrocardiogram, and then just the baseline for our patient population. And we follow them 10 years on average until 2018, 2019. Dr. Greg Hundley:           Very nice. So it sounded like from individuals in two regions of Brazil, identified those through screening of the blood, and I guess these were blood donors, and then performed a series of cardiovascular exams 2008 to 2010 and followed them for the next 10 years. And you're going to tell us about the results that occurred 2018 to 2019. And so what were those results? Dr. Maria Nunes:             We found that Trypanosoma cruzi seropositive is a risk factor for developing cardiomyopathy. Nowadays, this is still a risk factor, seropositive without cardiomyopathy at baseline has two times higher risk of developing cardiomyopathy compared to the seronegative controls. And we have also detected that the parasite load or the level of parasite in the blood expressed by antibodies against Trypanosoma cruzi is an important risk factor for disease progression. That means some patients have Chagas disease, but the level of antibodies is not too high. These patients go well. And other hand, the patients with high level antibodies means the parasite load may be higher too. This is the high risk of disease progression to cardiomyopathy or of dying too. Dr. Greg Hundley:           Very nice. And were there any subgroups of patients where you found these relationships to be particularly more striking? So for example, the elderly, or was there a discrepancy based on sex, men versus women? Dr. Maria Nunes:             Yes, other studies has already shown that the male gender is a risk factors in Chagas disease. Usually they progress more, they have more severe clinical presentation, usually die at the age between 30 and 50 years old, the most productive years of the life. That's why Chagas is so important here in Brazil and Argentina, in Latin America countries because people die at early ages. Dr. Greg Hundley:           And your results confirmed what was previously known in that regard. Dr. Maria Nunez:             Yes, patients with developing cardiomyopathy with heart failure has a high mortality rate. And then even patients with cardiomyopathy detected by exams like based on ECG or echo, they asymptomatic, but they progress more for dying or to develop cardiomyopathy compared to seronegative with similar risk effects for cardiovascular disease, such as hypertension, diabetes, smoking. Dr. Greg Hundley:           Very good. Well Ntobeko, you see many papers come across your desk as an Associate Editor for Circulation, and what attracted you to this paper and the results that Maria has described? Dr. Ntobeko Ntusi:          Thank you, Greg. I was attracted to this paper because it's an important natural history study of Chagas disease. But secondly, it's also one of the largest contemporaneous cohorts of Chagas disease which provides important insights and advances in our knowledge with regard to this clinical entity. And for me, there were three things that stood out. The first one was an important description of the outcomes of Chagas cardiomyopathy. The second was the contemporaneous description of the epidemiology in a well-characterized cohort. And the third and novel contribution was the description of the determinants of disease progression. So I thought overall, the really important contribution to the field. Dr. Greg Hundley:           Very good. And for those that might not live in the endemic area, but might occasionally encounter someone with Chagas disease, what results from this paper can we use to help manage patients in this situation? Dr. Ntobeko Ntusi:          Thanks, Greg. So this was a study which had a number of really positives. Firstly, it's a large study, it was non acute [inaudible 00:16:42] design and it used PCR for diagnosis. And unlike many other studies, also ascertained antibody levels and had very good clinical characterization, which included electrocardiographic, echocardiographic assessment, including serum assessment of proBNP and CK-MB. And all really important take home messages are for me. The first one is understanding that the relationship of your antibody levels and baseline LV function to mortality. In other words, are finding that in those with existing LV structural abnormalities, or higher levels of antibody titers, mortality was higher. The second important contribution is a description of the incidence of Trypanosoma cruzi, and this was highest as one would expect in the seropositive donors and much lower in seronegative donors. The third important contribution relates to our improved understanding of the determinants of disease progression, which were related to the Trypanosoma cruzi antibody levels. In other words, the higher your antibody titers, the quicker you progressed to manifest the cardiomyopathic phenotype. And then lastly, the predictors of mortality, which were related to your PCR being positive, as well as your antibody titers. Important is this contribution is there are a number of important caveats. The first is that the study is limited by the huge amount of loss to follow up, which as you can imagine, adds a number of biases to our conclusions. The second is that the observations may of course be confounded by comorbidity in particular because these patients are older and had higher comorbidity. The third is that we assume that the PCR positivity and antibody titers actually correlate with parasite pattern, but in fact, we know that is not always the case. And then lastly, for people who read this paper from non-endemic parts of the world, the result may not be clearly generalizable to those parts of the world. Dr. Greg Hundley:           Very nice. Well, we've had a great discussion, listeners. From Maria and Ntobeko sort of presenting the paper and then what are some of the take home messages. So now I'd like to go back to both of them and Maria, first you and then Ntobeko. Maria, what do you think is the next study to really be performed in this sphere of research? Dr. Maria Nunes:             We may should stratify patients with Chagas disease. Those who have high antibodies titers should refer to a kind of treatment or benznidazole treatment. We should intervene in this subgroup. Dr. Greg Hundley:           Very good. And Ntobeko, anything to add? Dr. Ntobeko Ntusi:          Yes, Greg, I think that there are two important next steps. The first one is that I think we need other large designed prospective studies that will validate the observations by Dr. Nunes and colleagues. And then the second key step for me would be the design of randomized controlled trials to test therapeutic agents with antitrypanosomal activity to demonstrate their ability to retard or completely block disease progression, which would be a nice way to complete the story. Dr. Greg Hundley:           Very nice. Well listeners, we've had a great discussion today and we want to thank Maria Nunes from Brazil and Ntobeko Ntusi from South Africa for bringing these really informative results pertaining to Chagas disease, and highlighting the natural history and showing an association between these high titer values and poor cardiovascular outcomes. 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, 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.

Please join author Ole Fröbert and Associate Editor Dharam Kumbhani as they discuss the article "Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center in Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, associate editor, director of the Poly Heart Center at VCU health in Richmond, Virginia. Well, listeners, this week we've got a really hot feature topic pertaining to flu vaccines, which are coming in the US, North America, South America, coming up soon, and their relationship to myocardial infarction. But before we get to that feature discussion, let's grab a cup of coffee and jump in to some of the other articles in this issue. Oh, wait a minute. Our first article, we've got a co-author here. Carolyn, something about the VICTORIA trial, which you were a part of. Can you tell us a little bit about this? Dr. Carolyn Lam: I would love to, and first of all, I'm doing this on behalf of a big team, and I want to really, really call up first Dr. Paul Armstrong who's the senior author from University of Alberta. But let me tell you first about the VICTORIA study. VICTORIA evaluated vericiguat, a soluble guanylate cyclase stimulator, compared to placebo, in patients with heart failure with reduced ejection fraction with a recent worsening heart failure event and the primary result was actually a significant reduction in the primary composite outcome of cardiovascular death or heart failure hospitalization with vericiguat compared to placebo. Dr. Carolyn Lam: Now, interestingly though, in VICTORIA, we found that anemia occurred more often in patients treated with vericiguat at a rate of about 7.6% compared to placebo, which was 5.7%. Now, although earlier studies of another soluble guanylate cyclase stimulator like riociguat was found to be associated with anemia. The etiology really remains unknown. In the current paper, we explored the relationship between markers of anemia and vericiguat versus placebo in VICTORIA. We further explored the changes in hemoglobin and hematocrit over the course of the trial and their relationships with the primary composite outcome. Dr. Greg Hundley: Carolyn, this is such an important new study heart failure therapy for those with reduced ejection fraction, and again, an important topic related to anemia. What did they find? Dr. Carolyn Lam: Thanks, Greg. First, approximately a third of patients in VICTORIA had anemia at randomization, and this is using the standard sex-based definitions. With a lower hemoglobin indeed predicting a higher risk for cardiovascular death, heart failure hospitalization, all-cause mortality. As I had already mentioned, we found more anemia with vericiguat than with placebo. The interesting thing though is after 16 weeks, no further decline in hemoglobin occurred over the remaining and over 96 weeks of follow up, and the ratio of hemoglobin to hematocrit remained constant. Now, overall, the adverse event of anemia occurred in 7.1% of the patients. Dr. Carolyn Lam: Importantly, the lower hemoglobin was not related to the beneficial effect of vericiguat over placebo on the primary outcome. Now, I know all of that may be more descriptive and reassuring than really understanding the mechanism by which it occurred. Further mechanistic studies are certainly warranted to better understand the basis of the anemia development, and it's of principle importance because as you said, vericiguat I think it's going to be an important new medication that we can consider in high-risk patients with recent worsening heart failure with reduced ejection fraction. Dr. Greg Hundley: Thanks so much, Carolyn, especially the perspective of being an author on this particular study. Well, Carolyn, my next study is going to come to us from Dr. Zhao Wang from University of Texas Southwestern Medical Center, and it's really about the integrated stress response, and that's an evolutionary conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery perfusion is the most effective means to mitigate cardiac damage resulting from myocardial infarction. However, that can cause, as we know, additional reperfusion injury. This study aim to investigate the role of the integrated stress response in myocardial ischemia reperfusion injury. Dr. Carolyn Lam: Oh, very interesting. What were the results? Dr. Greg Hundley: Right, Carolyn. The authors found that the integrated stress response is activated by ischemia reperfusion injury in the heart, and the perk branch of the integrated stress response protects the heart from ischemia reperfusion injury through inhibition of protein synthesis. Also, Carolyn, mitochondrial complex proteins are selectively suppressed and oxidative stress is reduced by the integrated stress response. Carolyn, the takeaway is that this integrated stress response is cardioprotective against cardiac ischemia reperfusion injury. Perhaps pharmacological stimulation of the integrated stress response at reperfusion, well, that may reduce heart damage and improve cardiac outcomes after ischemia reperfusion injury. Dr. Carolyn Lam: Cool. Thanks, Greg. Well, I've got one more paper, and this deals with coronary microcircuitry dysfunction and acute rejection after heart transplantation. Co-corresponding authors, Doctors Lee and Choi from Heart Vascular Stroke Institute in Samsung Medical Center sought to evaluate the prognostic implications of coronary microcircuitry dysfunction assessed by the index of microcircuitry resistance or IMR for the risk of acute cellular rejection after heart transplantation. They did this by prospectively enrolling 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment one month after transplantation.   Dr. Greg Hundley: Very interesting, Carolyn. What did they find here? Dr. Carolyn Lam: IMR measured early after heart transplantation was significantly associated with the risk of acute cellular rejection, and an IMR above or at 15 was highly predictive for the recurrence of acute cellular rejection during two years of follow up following heart transplantation. Adding IMR to the prediction model with clinical variables significantly increase discriminant and reclassification ability for the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, the implications are that early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation, and this is discussed in an editorial by Doctors Fearon and Valentine from Stanford University. Dr. Greg Hundley: Very nice, Carolyn. Dr. Carolyn Lam: Great. Greg, before we go to the exciting feature discussion, let's round it up by just a quick tour of what else there is in today's issue. There is an exchange of letters between Doctors Pappone Leor on atrial fibrillation as a cardiomyopathy, global rounds on United Kingdom by Dr. Cowie, an ECG challenge by Dr. Tsai on grouped beating following acute inferior myocardial infarction, and a research letter by Dr. Salem on electrocardiographic manifestations of immune checkpoint inhibitor myocarditis. Dr. Greg Hundley: Great, Carolyn. Well, I can't wait to get to this next feature discussion and learn a little bit more about the relationship between flu vaccines and future myocardial infarction. Dr. Carolyn Lam: Today's feature discussion was a really hot topic at the ESC 2021, and in fact, a simultaneous publication. It is about influenza vaccination after myocardial infarction, a very important topic and a very novel paper. We are so pleased to have the first and corresponding author, Dr. Ole Fröbert from Orebro University in Sweden to discuss this paper, as well as our associate editor, Dr. Dharam Kumbhani, from UT Southwestern. Welcome, gentlemen. Only if I could start with asking you to describe the rationale for why you did this study, and then perhaps quickly summarize the results. Dr. Ole Fröbert: Yeah, thank you so much, Carolyn. The background of the study was that during influenza epidemics, more people die from cardiovascular causes, and out in the literature, there are numerous observational studies suggesting a protective effect from influenza vaccination on cardiovascular events. There are also three smaller single-center randomized trials supporting these registered findings. Currently influenza vaccination carries a Class I, Level of Evidence B recommendation in both American and European secondary prevention guidelines, but uptake is low and vaccination timing is unclarified. Our aim was to determine whether influenza vaccination improves clinical outcomes in patients with a recent myocardial infarction or with high risk corona artery disease. Dr. Ole Fröbert: The study was international, multi-centers investigator initiated, double-blind randomized control trial, and we enrolled patients at 30 centers across eight countries in both the Northern and the Southern Hemisphere, Sweden, Denmark, Norway, Latvia, Scotland, Czech Republic, Bangladesh and Australia. We enrolled patients between October 2016 and March 2020. We had quite broad inclusion criteria. We included hospitalized patients with STEMI or non-STEMI, or high-risk stable patients over 75 years of age undergoing an angio or PCI. We excluded patients already vaccinated or intending to be vaccinated during the current season. We also included, of course, patients if they had allergy to X or influenza vaccine, if they had infection or if they were immunosuppressed or previously randomized in the trial. Dr. Ole Fröbert: Over these four years of inclusion, we enrolled a total of 2,571 participants. The primary outcome was a composite of all-cause death, MI and stent thrombosis. This outcome occurred in 67 participants assigned influenza vaccine and 91 assigned placebo corresponding to a reduction of the primary endpoint of 28% with a P value of 0.04. Also, rates of all-cause death and of cardiovascular death were reduced and both with a hazard ratio of 0.59 corresponding to a reduction of 41% in all-cause death and cardiovascular death. Based on these results, we think that this trial and what we know from previous smaller trials should be sufficient to establish influenza vaccination as a new standard of care as part of in-hospital treatment after an MI. Dr. Carolyn Lam: Heartfelt congratulations, Ole. What an elegant intervention in a very frankly challenging situation that the trial obviously carried on through COVID as well, multinational. May I just double check? Was it investigator-led? Because- Dr. Ole Fröbert: Yes, this was- Dr. Carolyn Lam: That's amazing. Dr. Ole Fröbert: ... an idea that just popped up, and then yeah, we did it, but it was seven years of work. Dr. Carolyn Lam: Wow. Hard work as I can just imagine. First, heartfelt congratulations. Very impactful results. Dharam, could I invite you to put those results in context and why we single this out? Dr. Dharam Kumbhani: Yeah. No, thank you, Carolyn. Ole, I want to amplify or recapitulate the amazement and wonder that Carolyn just articulated. I think this is a huge endeavor. It's a very important topic. It's "a fairly simple intervention." It's vaccination, and you've just really shown that even in the acute setting, that A, this is as feasible, B, it is safe, and three, it is effective. I think it's potentially ... Given the magnitude of influenza in the world, I think this has tremendous public health ramifications. I really want to congratulate you and your investigators for pursuing this important question and then just executing this, I'm sure despite multiple challenges over a long period of time. Dr. Ole Fröbert: Thank you very much. Dr. Dharam Kumbhani: Yeah, no. I guess you already alluded to the fact that this may influence guidelines. As you mentioned, it's a 1B. Maybe get your thoughts, I suppose this may move the needle towards becoming perhaps a little stronger on the recommendation front, both in the US and the European guidelines? Dr. Ole Fröbert: Yeah. I think what has been the challenge until now is that many places, of course, you commend patients to take a flu jab when treatment is over in the hospital. But then the responsibility is diffused. Who should take care of that? Is that up to the patient or the primary care physician? Who is in charge? One important finding of this study is, as you said, it's safe. There were no differences, adverse events between the two groups. It's safe and it could be given early. I think a take-home factor from the study is that it should be given at the hospital and it's a responsibility of the cardiologist. Dr. Dharam Kumbhani: Yeah, I really like that. Actually, I'm sure this would resonate across the board in the cardiology community. We've taken ownership for starting from statin and now SGLT-2 inhibitors, which kind of ... All of these medications have come from non-cardiology realms, so to say. But now we prescribe those medications. We know they have clear cardiovascular benefits. I suppose you could make a case to say we, the cardiology community, has to adopt this. The implementation gap that exists for a lot of these therapies, that also comes to us and for us to move that forward. It's thought provoking. I certainly felt very strongly after your study. I don't know how you feel about that. We should really be the ones driving this and help with more widespread immunization in these patients. Dr. Ole Fröbert: I think because not just this study, but also the previous studies and what we know from observational findings is that this is safe and it works. What we also saw in our study, and it has been indicated in previous meta analysis, is that the maximum effect is seen in the acute setting. It's the acute coronary syndrome patients, the patients we had in our study, that benefit the most. That's also a case for actually doing this in the hospital and not postponing it. Dr. Carolyn Lam: Wow. That's amazing. Ole, I do have one question. Just for clarification. You were careful to say that you did this during influenza seasons, right? Coming from my part of the world in Singapore where we don't really have influenza seasons, don't have any seasons, frankly, what would you think? What would you advise? Dr. Ole Fröbert: There is influenza seasons in all parts of the world, I'm sorry. Dr. Carolyn Lam: True. Dr. Ole Fröbert: For example, we had Bangladesh on board in our study. It's in the Northern Hemisphere, but influenza-wise, it's in the Southern, and their season is between May and September. But it's not as clearly defined as the Northern Hemisphere season. It's almost always in two waves during that season. One practical challenge with influenza vaccine is that it's produced for the seasons. It's difficult to say, "Yeah, we can just do it all year round," and also we didn't test that. I, of course, feel we should give it all year round, but it's not available, the vaccine. Perhaps it should be tested, but it is probably difficult to find funding for such a study. Dr. Carolyn Lam: Very fair, and thanks for the correction. It's true though. Singapore's on the Equator, so we don't have maybe weather seasons. But yeah, we do get vaccinated for both North and South. It's quite fascinating. But nonetheless, could I now switch topics a little bit and just over the next couple of minutes just ask you, could you please perhaps share with the audience what it was like to work with Circulation, to do this simultaneous publication? You see, our associate editor, Dharam Kumbhani, really leads this effort to get simultaneous a fast-track publication from major conferences, and it means a lot to us that investigators like you chose us. Could you share a bit? Dr. Ole Fröbert: Yeah, thank you very much. Overall, it was a pleasure. Of course, we were ... With every study of this size, you are under stress, you get the results late, and there's a conference coming up, and you would like your paper to come out at the same time across to maximize impact and attention. What I really like with working with Circulation was turnaround time was ultra fast, really extremely fast. Of course, we had a lot of questions to our study, but these were ... Some of them of course were quite difficult, but they were fair. In a way, they were also helpful in a way that made it easier to address the questions in a more, you could say, collaborative way. It was very smooth. No hiccups. Dr. Carolyn Lam: Thank you. Dharam, any final responses to that? Dr. Dharam Kumbhani: No, thank you, Carolyn. Yeah. Well, Ole, it was really a pleasure to work with you on this. I think we all recognize that this was an important study and wanted to make sure that we were able to accomplish the goal of simultaneous publication. Thank you for working with us on that. I just want to put a pitch in, I think this, for Joe, Dr. Hill and the rest of the editorial team, having a robust simultaneous publication program has been very, very important. We are very committed to working with investigators and authors on this. We are really blessed with our team on the backside that works seamlessly with us nights, weekends, just to get these things done. I just want to end with that to say this is very important for us, and we look forward to the opportunity to work with Ole and others on future papers as well.   Dr. Carolyn Lam: I love that. Thank you both for being on this podcast today. Today I want to especially call out David Rivera, a wonderful managing editor who really, really is part of leading this entire group that supports us, but also even this very podcast. You've been listening to Circulation on the Run. Thank you, from both Greg and I, for joining us today, and don't forget to tune in 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.

CLICK HERE to listen to episode audio (4:53).Sections below are the following: Transcript of Audio Audio Notes and Acknowledgments Image Sources Related Water Radio Episodes For Virginia Teachers (Relevant SOLs, etc.). Unless otherwise noted, all Web addresses mentioned were functional as of 10-29-21. TRANSCRIPT OF AUDIO From the Cumberland Gap to the Atlantic Ocean, this is Virginia Water Radio for Halloween 2021.  Besides focusing on autumn's festival of fun and fright, this episode is part of a series this fall about water connections to the human body and human biology. SOUND – ~9 sec That eerie sound of a tree creaking in October wind sets a seasonal stage for a Halloween challenge: exploring how Halloween, water, and human biology all connect.  Sound like quite a trick?  Well, have a listen to some Halloween music for about 50 seconds, and then we'll treat you to some examples. MUSIC - ~50 sec – instrumental You've been listening to “A Little Fright Music,” by Torrin Hallett, a graduate student at the Yale School of Music.  And here are six matches of Halloween creatures or images with water in the human body. 1.  Skeleton images rattle around everywhere for Halloween, and in living skeletons water is a significant component of bones and cartilage.  2.  Pretend blood covers many-a Halloween costume, and over half of the volume of blood is plasma, which in turn is over 90 percent water, and water is also a major component of blood cells. 3.  A muscular costume is part of pretending to be a super-strong character like Wonder Woman or Superman; and water plays a significant role in muscle structure and function; in turn, muscle is an important water-storage area for the body. 4.  The monster in movie versions of “Frankenstein” was brought to life by electricity, and the cells of our nervous system transmit messages though electrochemical impulses, using sodium and potassium ions in a water-based solution. 5.  If fiery or icy creatures need some temperature regulation, water's the body fluid that does it. And 6.  Flashing and watching from many creatures on Halloween night are eyes, either scary, suspenseful, or super-powered; and eyes have chambers containing aqueous humor and vitreous humour, two fluids that consist mostly of water and that maintain the shape of the eyes. This Halloween, imagine being a creature that's about 60 percent composed of an amazing substance with unique powers to dissolve other substances, absorb and release heat, and withstand being compressed.  What would you be?  Why, the water-based human being that you are! Thanks to Torrin Hallett for composing this week's music for Virginia Water Radio, and we close with another listen to the last few seconds of “A Little Fright Music.” MUSIC - ~13 sec – instrumental SHIP'S BELL Virginia Water Radio is produced by the Virginia Water Resources Research Center, part of Virginia Tech's College of Natural Resources and Environment.  For more Virginia water sounds, music, or information, visit us online at virginiawaterradio.org, or call the Water Center at (540) 231-5624.  Thanks to Ben Cosgrove for his version of “Shenandoah” to open and close the show.  In Blacksburg, I'm Alan Raflo, thanking you for listening, and wishing you health, wisdom, and good water. AUDIO NOTES AND ACKNOWLEDGEMENTS The wind and creaking tree sounds were recorded by Virginia Water Radio in Blacksburg, Va., on October 5, 2014.  “A Little Fright Music” is copyright 2020 by Torrin Hallett, used with permission.  Torrin is a 2018 graduate of Oberlin College and Conservatory in Oberlin, Ohio; a 2020 graduate in Horn Performance from Manhattan School of Music in New York; and a 2021 graduate of the Lamont School of Music at the University of Denver.  He is currently a graduate student at the Yale School of Music.  More information about Torrin is available online at https://www.facebook.com/torrin.hallett.  Thanks very much to Torrin for composing the piece especially for Virginia Water Radio.  This music was previously used in Episode 548, 10-26-20. Following are other music pieces composed by Torrin Hallett for Virginia Water Radio, with episodes featuring the music. “Beetle Ballet” – used in Episode 525, 5-18-20, on aquatic beetles.“Chesapeake Bay Ballad” – used in Episode 537, 8-10-20, on conditions in the Chesapeake Bay.“Corona Cue” – used in Episode 517, 3-23-20, on the coronavirus pandemic.“Flow Stopper – used in Episode 599, 10-28-21, on the “Imagine a Day Without Water” campaign.“Geese Piece” – used most recently in Episode 440, 10-1-18, on E-bird. “Ice Dance” – used in Episode 556, 12-21-20, on how organisms survive freezing temperatures.“Lizard Lied” – used in Episode 514, 3-2-20, on lizards.“New Year's Water” – used in Episode 349, 1-2-17, on the New Year. “Rain Refrain” – used most recently Episode 559, 1-11-21, on record rainfall in 2020.“Runoff” – in Episode 585, 7-12-21 – on middle-school students calling out stormwater-related water words.“Spider Strike” – used in Episode 523, 5-4-20, on fishing spiders.“Tropical Tantrum” – used most recently in Episode 580, 6-7-21, on the 2021 Atlantic tropical storm season preview.“Tundra Swan Song – used in Episode 554, 12-7-20, on Tundra Swans.“Turkey Tune” – used in Episode 343, 11-21-16, on the Wild Turkey.  Click here if you'd like to hear the full version (2 min./22 sec.) of the “Shenandoah” arrangement/performance by Ben Cosgrove that opens and closes this episode.  More information about Mr. Cosgrove is available online at http://www.bencosgrove.com. IMAGE Water uses in the human body.  Illustration from the U.S. Geological Survey, “The Water in You: Water and the Human Body,”  https://www.usgs.gov/special-topic/water-science-school/science/water-you-water-and-human-body?qt-science_center_objects=0#qt-science_center_objects. SOURCES Used for Audio Peter Abrahams, ed., How the Body Works: A Comprehensive, Illustrated Encyclopedia of Anatomy, Metro Books, New York, 2007. American Red Cross, “Blood Components,” online at https://www.redcrossblood.org/donate-blood/how-to-donate/types-of-blood-donations/blood-components.html. Erin Blakemore, “How Twitching Frog Legs Helped Inspire ‘Frankenstein,'” Smithsonian Magazine, December 4, 2015, online at https://www.smithsonianmag.com/smart-news/how-twitching-frog-legs-helped-inspire-frankenstein-180957457/. Fandom, “Monster Wiki/Frankenstein's Monster,” online at https://monster.fandom.com/wiki/Frankenstein%27s_Monster. Mayo Clinic Health System, “Water: Essential to your body,” online at https://www.mayoclinichealthsystem.org/hometown-health/speaking-of-health/water-essential-to-your-body. Science Direct:“Aqueous Humor,” online at https://www.sciencedirect.com/topics/medicine-and-dentistry/aqueous-humor;“Vitreous Humour,” online at https://www.sciencedirect.com/topics/veterinary-science-and-veterinary-medicine/vitreous-humour. University of Michigan Health, “Eye Anatomy and Function,” as of August 31, 2020, online at https://www.uofmhealth.org/health-library/hw121946. U.S. Geological Survey, “The Water in You: Water and the Human Body,” https://www.usgs.gov/special-topic/water-science-school/science/water-you-water-and-human-body?qt-science_center_objects=0#qt-science_center_objects. U.S. National Institutes of Health/National Cancer Institute, SEER Training Modules:“Composition of the Blood,” online at https://training.seer.cancer.gov/leukemia/anatomy/composition.html;“Skeletal System,” online at https://training.seer.cancer.gov/anatomy/skeletal/. For More Information about Human Biology, Including Water Aspects American Society of Hematology, “Blood Basics,” online at https://www.hematology.org/education/patients/blood-basics.Cleveland [Ohio] Clinic:“Heart & Blood Vessels: How Does Blood Travel Through Your Body,” online at https://my.clevelandclinic.org/health/articles/heart-blood-vessels-blood-flow-body;“Lymphatic System,” online at https://my.clevelandclinic.org/health/articles/21199-lymphatic-system. Eric Cudler, “Neuroscience for Kids,” online at https://faculty.washington.edu/chudler/neurok.html. The Franklin Institute of Philadelphia, Penn., “Blood Vessels,” online at https://www.fi.edu/heart/blood-vessels. Isabel Lorenzo et al., “The Role of Water Homeostasis in Muscle Function and Frailty: A Review,” Nutrients, Vol. 11, No. 8 (August 2019, accessed online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723611/(subscription may be required for access). Memorial Sloan Kettering Cancer Center, “Facts About Blood and Blood Cells,” online at https://www.mskcc.org/cancer-care/patient-education/facts-about-blood-and-blood-cells. Science Direct, “Synovial Fluid: Structure and Function,” excerpted from Textbook of Pediatric Rheumatology, 5th Edition, Elsevier, Amsterdam, Netherlands, 2005; accessed online at https://www.sciencedirect.com/topics/medicine-and-dentistry/synovial-fluid(subscription may be required for access). University of Bristol (England), School of Medical Sciences, “Brain Basics: The Fundamentals of Neuroscience,” online at http://www.bris.ac.uk/synaptic/basics/basics-0.html. U.S. National Institutes of Health/National Cancer Institute, SEER Training Modules:“Blood, Heart and Circulation,” online at http://www.nlm.nih.gov/medlineplus/bloodheartandcirculation.html;“Muscular System,” online at https://training.seer.cancer.gov/anatomy/muscular/;“Nervous System,” online at https://training.seer.cancer.gov/anatomy/nervous/. RELATED VIRGINIA WATER RADIO EPISODES All Water Radio episodes are listed by category at the Index link above (http://www.virginiawaterradio.org/p/index.html).  See particularly the “Science” subject category. Following are links to other episodes on connections of water to human biology (much of the information in this week's episode was taken from these previous episodes). Overview of water's roles in the body – Episode 592, 8-30-21.Disease: COVID-19 – Episode 517, 3-23-20 and Episode 519, 4-6-20.Disease: influenza – Episode 393, 11-6-17.Disease: viruses – Episode 600, 10-25-21.Circulatory system connections to water – Episode 593, 9-6-21.Muscular system connections to water – Episode 596, 9-27-21.Neurological system connections to water – Episode 594, 9-13-21.Skeleton system connections to water (with a Halloween theme) – Episode 595, 9-20-21.Water intake and exercise – Episode 466, 4-1-19.Water thermodynamics – Episode 195, 1-6-14. Following are links to other Halloween-themed episodes. Episode 238, 10-31-14 – focusing on the plant Witch-hazel.Episode 548, 10-26-20 – focusing on water-related readings that are supernatural, mysterious, or imaginative. FOR VIRGINIA TEACHERS – RELATED STANDARDS OF LEARNING (SOLs) AND OTHER INFORMATION Following are some Virginia Standards of Learning (SOLs) that may be supported by this episode's audio/transcript, sources, or other information included in this post. 2020 Music SOLs SOLs at various grade levels that call for “examining the relationship of music to the other fine arts and other fields of knowledge.” 2018 Science SOLs Grades K-3 plus 5: MatterK.4 – Water is important in our daily lives and has properties.3.3 – Materials interact with water. Grades K-4: Living Systems and Processes4.2 – Plants and animals h

Overview: This episode reviews the current news updates of this pandemic as well as recently updated guidelines and medical literature. In addition, our moderator, Dr. Krystina Woods, sits down with Dr. Brett Singer of Lawrence Berkeley National Laboratory around venitilation, air circulation, and air quality. They discuss recent research Dr. Singer and his team have done around indoor air and transmission, how to improve ventilation at businesses, schools, hospitals, and the home, and future research in this area for the pandemic and beyond. Speakers: - Brett Singer, PhD - Krystina Woods, MD (moderator) - Chris Crnich, MD, PhD (news update) Sources from the news update: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-takes-additional-actions-use-booster-dose-covid-19-vaccines https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v1.full.pdf https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1028113/Technical_Briefing_26.pdf https://www.nature.com/articles/s41586-021-04130-w What do you think of our podcasts? Do you have topic or speaker suggestions? Let us know at https://learningce.shea-online.org/content/shea-podcast-feedback

In this “Breathe Easy Critical Perspective” podcast, Dr. Dominique Pepper interviews Dr. Lars W Andersen. They discuss Dr. Andersen's recent publication in JAMA about the effect of vasopressin and methylprednisolone on return of spontaneous circulation in in-hospital cardiac arrest. Dr. Lars Andersen is an Associate Professor in Clinical Medicine at Aarhus University Hospital, Denmark.

Please join author Jonathan Newman and Associate Editor Sandeep Das as they discuss the article "Outcomes of Participants With Diabetes in the ISCHEMIA Trials." Dr. Carolyn Lam: Welcome to circulation on the run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts; I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, this week's feature, a couple of weeks ago, we had that feature forum on the ischemia trial. Now we're going to explore some of the outcomes in patients with diabetes, from the ischemia trial in the feature discussion today. But, before we get to that, let's grab a cup of coffee and start in on some of the other articles in this issue. So, how about if I go first, this time? This particular paper, Carolyn, we're going to start on one of your topics. I know you're a fan of diet related interventions. So high intake of added sugar is linked to weight gain and cardio-metabolic risk. And in 2018, the U S National Salt and Sugar Reduction Initiative proposed government supported voluntary national sugar reduction targets. Dr. Greg Hundley: This intervention's potential health and equity impacts and cost effectiveness are unclear. And so Carolyn, these authors, led by Dr. Renata Micha from Tufts University, incorporated a validated micro-simulation model - CVD Predict coded in C++, and used it to estimate incremental changes in type two diabetes, cardiovascular disease, quality adjusted life years, cost and cost effectiveness of this national policy. The model was run at the individual level and the model incorporated national demographic and dietary data from the National Health and Nutrition Examination Survey across three cycles spanning from 2011 to 2016, added sugar related diseases from meta-analysis and policy costs and health-related costs from established sources and a simulated nationally representative us population was created and followed until age 100 years or death with 2019 as the year of intervention start and findings were evaluated over 10 years and a lifetime from healthcare and societal perspectives. Dr. Carolyn Lam: Ooooh, You so got my attention, Greg, a very important topic and so, what did they find? Dr. Greg Hundley: Right, Carolyn. So achieving the NSRI sugar reduction targets could prevent 2.48 million cardiovascular death related events, 0.5 million cardiovascular disease deaths, and three quarters of a million diabetes cases, gain 6.7 million quality adjusted life years, and save $160.8 billion in net cost from a societal perspective over a lifetime. The policy became cost-effective, defined as less than $150,000 for quality adjusted life years at six years and highly cost-effective at seven years with a cost savings noted at nine years. And therefore, Carolyn, implementing and achieving the NSSRI sugar reformation targets could generate substantial health gains, equity gains, and cost savings. Dr. Carolyn Lam: Wow, thanks Greg. So, moving from a very publicly health focused paper to this paper that really focuses on hypoplastic left heart syndrome with very, very scientifically significant findings. Now, first, we know hypoplastic left heart syndrome is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis is unknown, but hemodynamic disturbances are assumed to play a prominent role. Authors led by Doctors Moretti and Laugwitz from Technical University of Munich in Germany, as well as Dr. Gruber from Yale University School of Medicine, and their colleagues combined whole exome sequencing of parent offspring, trios, transcriptome profiling of cardiomyocytes from ventricular biopsies and immuno-pluripotent stem cell derived cardiac progenator or cardiomyocyte models of 2D and 3D cardiogenesis, as well as single cell gene expression analysis to decode the cellular and molecular principles of hypoplastic left heart syndrome phenotypes. Dr. Greg Hundley: Wow, Carolyn, there is a lot of data, very complex preclinical science here. So what did they find? Dr. Carolyn Lam: Indeed, Greg. As I said, scientifically incredible and rigorous, and they found that initial aberrations in the cell cycle unfolded protein response, autophagy hub led to disrupted cardiac progenator lineage commitment, consequently, impaired maturation of ventricular cardiomyocytes limited their ability to respond to growth cues. Resulting in premature cell cycle exit and increase apoptosis under biomechanical stress in 3D heart structures. Together, these studies provide evidence that the hypoplastic left heart syndrome pathogenesis is not exclusively of hemodynamic origin, and they revealed novel potential nodes for rational design of therapeutic intervention. Dr. Greg Hundley: Wow, Carolyn, we really need research in this topic and this is great preclinical science that we're getting here in our journal. Congratulations to the authors and what a great presentation of that by you. Well, Carolyn and my next paper there remain major uncertainties regarding disease activity within the Retain Native Aortic Valve, as well as bioprosthetic valve durability, following transcatheter aortic valve implantation. And these authors led by Doctor Jacek Kwiecinski, from the Institute of Cardiology, aimed in a multi-center cross-sectional observational cohort study to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison to subjects with bioprosthetic surgical aortic valve replacement or SAVR. Dr. Carolyn Lam: Oh, very interesting. And what were the results? Dr. Greg Hundley: An interesting comparison, Carolyn. So in patients with TAVI, native aortic valves demonstrated 18 F sodium fluoride uptake around the outside of the bioprosthesis that showed a modest correlation with the time from TAVI. Next, 18 sodium fluoride uptake in the bias prosthetic leaflets was comparable between SAVR and TAVI groups. Next, the frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echo cardiography 6 and 8% respectively, CT, 15 and 14% respectively, and with PET scanning. Next, baseline 18 F sodium fluoride uptake was associated with subsequent change in peak aortic velocity for both TAVI and SAVR. And on multi-variable analysis, the 18 F sodium fluoride uptake was the only predictor of peak velocity progression. And so Carolyn, therefore, in patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease and across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR suggesting comparable midterm durability. Dr. Carolyn Lam: Very nice, important stuff. Dr. Carolyn Lam: Well, thanks, Greg. Let's tell everyone about the other papers in today's issue. There's an exchange of letters between Doctors Baillon and Blaha regarding the article very high coronary artery, calcium and association with cardiovascular disease events, non-cardiovascular outcomes and mortality from MESA. There's an ECG challenge from Dr. Bell Belhassen on a left bundle branch block, tachycardia following transcatheter aortic valve replacement. And On My Mind paper by Dr. Neeland on cardiovascular outcomes trials for weight loss interventions, another tool for cardiovascular prevention, another Research Letter by Dr. Nakamura on clinical outcomes of Rivaroxaban Mono therapy in heart failure, patients with atrial fibrillation and stable coronary artery disease. So insights from the AFIRE trial, and finally, a Research Letter from Dr. Kumoro three-dimensional visualization of hypoxia induced, pulmonary vascular remodeling in mice. Dr. Greg Hundley: Great, Carolyn, and I've got an in-depth piece from Professor Jia Sani entitled breadth of life, heart disease, linked to developmental hypoxia. Dr. Greg Hundley: Well, Carolyn, how about we get onto that feature discussion and learn more about results from the ischemia trial? Dr. Carolyn Lam: Let's go Greg. Dr. Carolyn Lam: Well, we all know how important diabetes is as a risk factor for atherosclerotic coronary disease. And we know it's a very common comorbidity among patients with chronic coronary disease, but the question is do patients with diabetes and chronic coronary disease on top of guideline directed medical therapy and lifestyle interventions, of course, do they derive incremental benefit from an invasive management strategy of their coronary disease? Well, we are going to try to answer that question today in our feature discussion. Thank you so much for joining us today. The first author and corresponding author of today's feature paper, which tells us about results from the ischemia trials. And that's Dr. Jonathan Newman from New York university Grossman School of Medicine. We also have associate editor Sandeep Das from UT Southwestern. So welcome both of you. And if I could please start with Jonathan reminding us, perhaps, what were the ischemia trials and then what you tried to answer and do in today's paper, Dr. Jonathan Newman: Of course, Carolyn, and thank you so much for having me and for the discussion with Sandeep. It's a pleasure to be here. So sure has a little bit of background, as you indicated, the ischemia trials basically enrolled and for the purposes of this discussion and this analysis, I'm referring to both the main ischemia trial and the ischemia chronic kidney disease trials. So ischemia CKD under the umbrella of the ischemia trials. Ischemia stands for the international study of comparative health effectiveness with medical and invasive approaches. And the purpose of the trial was to test to see whether a routine invasive approach on a background of intensive guideline directed medical therapy for high risk patients with chronic coronary disease and at least moderate ischemia and obstructive coronary disease documented on a blinded CCTA or computed coronary tomography angiography prior to randomization was associated with benefits for a cardiovascular composite. And we looked in this analysis at whether or not there was appreciable heterogeneity of treatment effect or a difference in treatment effect for patients compared without diabetes in the ischemia trials, in ischemia and ischemia CKD. Dr. Carolyn Lam: Great, thanks for lining that up so nicely. So what, Dr. Jonathan Newman: So the results of our analysis really highlighted a couple of things that I think you touched upon initially, the first thing that I would highlight is that diabetes was very common in this high risk cohort with chronic coronary disease, over 40% of participants in the ischemia trials, 43% with obstructive coronary disease and moderate to severe, you may have had diabetes. Perhaps not surprisingly patients with diabetes had higher rates of death or MI than those without diabetes. And the rates were highest among those patients that required insulin, had insulin treated diabetes, but using really robust methods to assess for heterogeneity using a Bassen assessment of heterogeneity of treatment effect accounting for violation of proportional hazards. The fact that there was an upfront hazard and a late benefit, we really saw no difference in death or MI, between the invasive or conservative strategies for patients with, or without diabetes over about three years of follow-up. Dr. Jonathan Newman: And the results importantly were consistent for ischemia and ischemia CKD and provided the rationale for us when we started by looking to see if the distribution of risk and characteristics allowed the trials to be combined. The study really confirms this higher risk of death or a MI for chronic coronary disease patients who have diabetes extends these findings for those patients with moderate or severe ischemia. And I think really notably also adds information about chronic coronary disease patients with diabetes and CKD. That's sort of the overall findings. And I'm happy to talk in more detail about that. Dr. Carolyn Lam: I love the way you explain that Jonathan and especially, going into detail on what was so different about the paper and the really important statistical methods that made these findings robust, very important and impactful findings. If I could ask Sandeep to share your thoughts. Dr. Sandeep Das: Thanks, Carolyn. You know, I am just a big fan of everything that's come out of the ischemia group. One of the things that I really most enjoy as a consumer of the literature is when well done studies give me results that are unexpected. And I know it's become fashionable now to say that everybody knew that all along that this is what going to be the result. But honestly, I think we all sort of are many of us thought that there's going to be a subgroup somewhere that's really going to benefit from an invasive approach in terms of preventing heart outcomes. I think the key here that really jumped out at me was that this is identifying what we typically think of is a very high risk subgroup. You know, patients with diabetes patients with multi-vessel coronary disease patients with insulin dependent diabetes. Dr. Sandeep Das: And we did see the association with mortality across the increased disease severity and the increased severity of diabetes as expected. But really we didn't see a signal that revascularization, routinely revascularizing patients, even the higher risk patients led to clinically relevant heart outcome benefits. So I thought that that was a really interesting top line finding and really that's kind of. I mean, it would have been interesting if it was the other way too, but it was, it really was kind of the hook that got me into the paper. Dr. Sandeep Das: I actually have a question for Jonathan, one of the things that I think we spend a lot of time as an editorial group thinking about and talking about, and we bounce back and forth with the authors a few times was the idea that relatively few of these patients with multi-vessel CAD ended up having CABG. So, you would typically think of diabetes multi-vessel CAD as being a pretty strong signal for patients that may benefit in terms of mortality from having bypass surgery. And here it was a relatively small group about a third, or maybe even less than a third. And I realized up front, they excluded the left main and the patients that had angina had a CTA, et cetera. But what I'd be curious as to your thoughts about, the benefits of bypass surgery and diabetes, which have been established in other trials. Dr. Jonathan Newman: It's a great question. And I think we really appreciated the questions from you and from the editors to try and get at some of the nuance with this issue. As you indicated in the ischemia and ischemia CKD trials overall, and the patients in the invasive treatment arm, it was about 25% or so 26% and 15% were revascularized with CABG. Part of the issue here is that it gets a little tricky with the use of CCTA of pre randomization CTA to define coronary artery severity, which was not required in the CKD population due to impaired renal function. But what we can say is among the patients with diabetes and multi-vessel coronary disease, 29% were revascularized surgically in their combined analysis, which is comparable to the 30% in Bery 2d that were revascularized via bypass surgery, as we've discussed. And as you know, the decision for surgical versus percutaneous revascularization in ischemia, as in Barry 2d was non-randomized though we might want to, we really tried to be very, very cautious in terms of comparing revascularization strategies on outcomes for patients with diabetes and multi-vessel CAD, which has you suggested. Dr. Jonathan Newman: And as we pointed out, the proportion with multi-vessel CAD was more common amongst in patients with diabetes compared with those patients without diabetes. The other thing I would sort of say in the framework of, the revascularization and strategies for revascularization, comparing, let's say ischemia to Barry 2d or to freedom. Basically we have very little data about revascularization approaches for those patients with creatinine with impaired renal function and, patients with the crediting greater than two were excluded from Barry 2d. So while we had about 15% or so that had severe CKD. So in the GFR, less than 30 are on dialysis. And we know that's an extremely high risk group of patients with diabetes and chronic coronary disease. And we don't have great evidence on which strategy for revascularization if at all provides additional benefit. So I think it's a really a tough question to answer, and we tried to be as judicious as possible in our comments about revascularization approaches, given the nature of the trial design. Dr. Carolyn Lam: Gee, thanks so much, Jonathan, for explaining that. So, well, I actually have a related question now, referring to the medical therapy. Can I, sort of ask you about the fact that, these days that the rage is all about GLP one receptor agonist, for example, that are known to reduce the risk of atherosclerotic cardiovascular disease and diabetes. So these ischemic trials, I assume, did not have a high usage of these medications. And what do you think would be the impact, if anything, I suppose even more for guideline directed medical therapy. Huh? Dr. Jonathan Newman: Yeah. So it's a great question, Carolyn. As you know, in strategy trials and clinical trials in general, that take a while it's always a real challenge to keep the trial contemporary with current clinical practice, whether it's revascularization strategies or changes in medical therapy. And as you indicated, the real revolution and glucose lowering therapies with profound cardiovascular benefit for patients with diabetes, we worked hard to try and stay up to date and encourage sites around the world with the use of best SGLT2 inhibitors and GLP ones. The rates were very, very low and we don't actually given the fact that the ischemia trials were conducted a real multinational and is really an international trial is over 330 sites worldwide. So we really had to balance the data that we could get from sites with the reality of collecting and running this trial across the whole world. Dr. Jonathan Newman: So we don't actually know. We know insulin use or non-use or oral medication use or non-use or no medication use or non-use, but not much more than that. From what, as, you know, unfortunately, even after now, six going on seven years of impressive data for the benefit of these agents, uptake remains low for patients with diabetes, whether it's with coronary disease or heart failure. And there was certainly the case with the trial, which started back in 2015, or sorry, before 2015, even before the results of EMPA-REG. So the rates of those agents were low. I would expect as you indicated that if we did have greater use of these beneficial therapies. Medical therapy may have performed even better and potentially given an added boost potentially for our high risk, even higher risk subgroups that we'd looked at that were available in these trials. Dr. Carolyn Lam: Oh, thanks again. I wish we could go on forever, but we've got just a little bit of time left. So I'd like to ask you both for your quick take home messages for the audience. Could I start with Sandeep and then Jonathan? Dr. Sandeep Das: Yeah. You know, I think a key take home from this is that, although it may be naively intuitive that a very aggressive invasive strategy would be superior, especially in high risk patients. You know, the data are very, very convincing that it's not. And so therefore I think in an absolute minimum, you have plenty of time and ability to think about these patients carefully, to select who, if anybody would be a great candidate for revascularization, more aggressive therapy and more invasive therapy, but the most patients will do well with conservative management. Dr. Sandeep Das: And I think that that's the, that's a real key take home here. And I think that the points that Jonathan raised about, you know, poor uptake of GLP one RAs and SGLT 2 inhibitors in the community as they're so far are key, right? So we have great medicines that we just under used, and that to me is the other sort of clarion call here is that if in the context of a nice trial, that you can see similar result for invasive conservative approaches, then lets, let's get our medical therapy where it needs to be to provide our patients the best outcomes we can Speaker 3: Love it, Jonathan. Dr. Jonathan Newman: Yeah. So I'm really glad that Sandeep brought up the issue of medical therapy in the trial. And maybe I can take a minute to sort of frame what San kind of build off of what Sandeep just said, you know, we, in the context of this clinical trial, you know, Dr. Judy Hawkman, the study chair and Dr. David Marin, the co-chair and I, we worked very hard with optimizing medical therapy across the trials, for all participants. So really getting patients on the maximum tolerated doses of high-intensity statins, lowering patient's LDL as aggressively as possible evolving our systolic blood pressure targets. And it was extremely challenging. And at the end of the day, we see that patients with diabetes were more likely than those without to get to our LDL goal. We used a threshold problematic concept that that still may be to some extent, but they were less likely to achieve their systolic blood pressure goals. Dr. Jonathan Newman: And I think Sandeep was exactly right. We have a way to go with implementing existing therapies, existing medical therapy. There may be a benefit for as demonstrated in Dr. S. for patients that remain highly symptomatic to derive symptom benefit with revascularization. The other context I would sort of add with the medical therapy issue is that despite really aggressive medical therapy, and we really did as much as we could, patients with diabetes still had, a 40, 50% greater risk of death or MI than those without diabetes. So there's still this idea of kind of residual risk. And these were patients with diabetes that were very well managed from a medical and glycemic control perspective. So we still have a lot of work to do. And I think understanding ways we can benefit our patients is really that challenge. Speaker 3: Thanks so much, Jonathan, and thank you Sandeep for joining us today. Speaker 3: And thank you audience for listening from Greg and I. This has been "Circulation On The Run", please tune in again. Next week. 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 AHJjournals.org.

Beijing knows it wants to discontinue the country's existing, unsustainable growth model. The latest "Common Prosperity" policy will only shift domestic demand at the margins; a full-fledged rebalancing will require a more radical transformation. A reading, by Emil Kalinowski.----------WHO----------Michael Pettis, Finance Professor at Peking University and Senior Fellow at Carnegie-Tsinghua Center, specializes in Chinese financial markets, economic history, global capital flows and the relationship between different sectors of national economies. Read by Emil Kalinowski. Art by David Parkins. Intro/outro is "Amber Lights" by Chill Cole at Epidemic Sound.----------WHAT----------Will China's Common Prosperity Upgrade Dual Circulation?: https://bit.ly/2Z6CoCr----------WHERE----------Michael's Blog: https://carnegieendowment.org/chinafinancialmarketsMichael's Twitter: https://twitter.com/michaelxpettisEmil's Twitter: https://twitter.com/EmilKalinowskiDavid's Art: https://davidparkins.com/---------HEAR IT----------Vurbl: https://bit.ly/3rq4dPnApple: https://apple.co/3czMcWNDeezer: https://bit.ly/3ndoVPEiHeart: https://ihr.fm/31jq7cITuneIn: http://tun.in/pjT2ZCastro: https://bit.ly/30DMYzaGoogle: https://bit.ly/3e2Z48MReason: https://bit.ly/3lt5NiHSpotify: https://spoti.fi/3arP8mYPandora: https://pdora.co/2GQL3QgBreaker: https://bit.ly/2CpHAFOCastbox: https://bit.ly/3fJR5xQPodbean: https://bit.ly/2QpaDghStitcher: https://bit.ly/2C1M1GBPlayerFM: https://bit.ly/3piLtjVPodchaser: https://bit.ly/3oFCrwNPocketCast: https://pca.st/encarkdtSoundCloud: https://bit.ly/3l0yFfKListenNotes: https://bit.ly/38xY7pbAmazonMusic: https://amzn.to/2UpEk2PPodcastAddict: https://bit.ly/2V39Xjr

Please join author Khurram Nasir and Associate Editor Sandeep Das as they discuss the article "Social Vulnerability and Premature Cardiovascular Mortality Among US Counties, 2014-2018." Dr. Carolyn Lam: Welcome to Circulation on the Run your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke-National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly Heart Center, VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I'm really excited about today's feature discussion. It's really meaningful on so many levels. It discusses social vulnerability. In other words, social determinants of health and its association with premature cardiovascular mortality among US counties. Now, even as an ex-US person I learned a lot, so everyone is going to want to listen in. But now let's start with going through some exciting papers in today's issue, shall we? Dr. Greg Hundley: You bet Carolyn. So, I'm going to grab a cup of coffee and we'll get started with the first article. And really gets into the world of cardiovascular risk and prostate cancer management. Dr. Greg Hundley: So, Carolyn in the light of improved prostate cancer survivorship, and the competing risk of cardiovascular disease, there's an ongoing need for rigorous cardio oncology clinical trials. As you probably know, androgen deprivation therapy is a cornerstone of prostate cancer therapy. Through different pituitary gonadotropin releasing hormone receptor mediated mechanisms both GnRH agonists, as well as antagonists, either indirectly or directly inhibit luteinizing hormone secretion, consequently inhibiting testosterone production. These GnRH agonists are the most commonly prescribed form of androgen deprivation therapy with only 3 to 4% of patients receiving a GnRH antagonist. Dr. Greg Hundley: So, Carolyn the relative cardiovascular safety of gonadotropin releasing hormone antagonists compared with gonadotropin releasing hormone agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains somewhat controversial. And therefore these authors led by Dr. Renato Lopes from both Brazil, as well as the Duke University Medical Center in Durham, conducted an international multicenter, prospective randomized open label trial, and men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomized one to receive gonadotropin releasing hormone, antagonist degarelix or the gonadotropin releasing hormone, agonist leuprolide for 12 months and the primary outcome was time to first educate major adverse cardiovascular event that combined the endpoints of composite death MI and stroke over these 12 months. Dr. Carolyn Lam: Nice Greg, and what did they find? Dr. Greg Hundley: Right Carolyn, due to slower than projected enrollment and fewer than projected primary outcome events enrollment was stopped before the 900 plan participants were accrued from May 3rd, 2016 to April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were really balanced between the two study groups. Now Mace occurred in 5.5% of the patients assigned to degarelix and 4.1% assigned to leuprolide and so in summary, Carolyn, this pronounced study is the first international randomized clinical trial to prospectively compare the cardiovascular safety of a gonadotropin releasing hormone antagonist as well as agonist in patients with prostate cancer. And the study was terminated prematurely due to smaller than planned number of participants and events. And so no difference in mace at one year was noted between the two groups and this pronounced study really provides a model for interdisciplinary collaboration between urologists, oncologists and cardiologist with a sheer goal of evaluating the impact of cancer therapies on cardiovascular outcomes. Dr. Carolyn Lam: That's so cool, Greg. I heard the presentation of these results at the ESC by Dr. Renato Lopes and it's a really cool and important study, but a paper I want to present is an analysis from Emperor preserved on inpatient and outpatient heart failure events. Dr. Greg Hundley: Great. Carolyn, so remind us, what did the Emperor preserved trial show? Dr. Carolyn Lam: Emperor preserved showed that in patients with heart failure and preserved ejection fraction empagliflozin reduce the primary endpoint of cardiovascular death or hospitalization for heart failure, primarily related to a lower risk of hospitalizations for heart failure. Greg you're smiling, because you can see me beaming because we finally have a robustly positive outcomes trial in have pep in this trial. Nonetheless in the current analysis, Dr. Milton Packer from Baylor Heart and Vascular Institute and others used prospectively collected information on inpatient and outpatient events, reflecting worsening heart failure, and pre specified their analysis in individual and composite end points. Dr. Greg Hundley: I've been in suspense here. What did they find? Dr. Carolyn Lam: Empagliflozin reduced the risk of severe hospitalizations as reflected by admissions requiring the use of ionotropic or vasopressor drugs and the need for intensive care. Empagliflozin also reduce the risk of outpatient worsening heart failure events, including the need for urgent care visits, diuretic, intensification, and unfavorable changes in functional class. So, basically benefit across the spectrum. Furthermore, because there's controversy about the effect across the spectrum of ejection fraction. The benefit on total heart failure hospitalizations was found to be similar in patients with an ejection fraction of above 40, but less than 50% and between 50 to 60%, although it was attenuated at the higher ejection fractions and we'll hear a lot of discussions about this.   Dr. Greg Hundley: Wow, Carolyn. Just more information that keeps coming out about SGLT-2 inhibition. My next paper comes from the world of preclinical science and angiogenesis is a dynamic process, involves expansion of a preexisting vascular network that can incur in a number of physiologic and pathologic settings. But despite its importance, the origin of the new angiogenesis vasculature is really poorly defined in particular, the primary subtype of endothelial cells, whether they be capillary, Venus or arterial that might be driving, this process really remains undefined. These authors led by Dr. Michael Simmons at Yale University school of medicine, fate mapped endothelial cells using genetic markers specific to arterial, Venus and capillary cells. Dr. Carolyn Lam: What did they find Greg? Dr. Greg Hundley: This team study results found that Venus endothelial cells were the primary endothelial subtype responsible for the normal expansion of vascular networks, formation of arterial, venous malformation, and pathologic angiogenesis. And these observations highlight the central role of the Venus endothelium in normal development and disease pathogenesis. Dr. Carolyn Lam: Wow. That's really interesting. I don't think I've ever really paid attention to that bit. Venus endothelium. Thank you for that. Now what else is in today's issue? Well, there's an exchange of letters between Doctors Zhang and Liao regarding the article anti hypertrophic memory after regression of exercise induced physiologic, myocardial hypertrophy is mediated by the long noncoding RNA M heart 779, then ECG Challenge by Dr. Ahmed on challenges of interpreting smart watch and implantable loop recorder, tracings. There's cardiology news by Tracy Hampton and Highlights from the Circulation Family of journals by Sara O'Brien. These regular articles are just really worth a read. You learn so much from just these short lovely summaries. There's On My Mind paper by Dr. Meyer on a targeted treatment opportunity for taking advantage of diastolic tone. And there's also a Research Letter by Dr. Brozovich on a rat model of heart failure with preserved ejection fraction changes in contractile proteins, regulating calcium cycling and vascular reactivity. Dr. Greg Hundley: These journal issues, there's so much information. I'm in a close out with an in depth piece from professor entitled antithrombotic therapy in patients undergoing transcatheter interventions for structural heart disease. I really look forward to your feature discussion on the social vulnerability and premature cardiovascular mortality in US countries. Dr. Carolyn Lam: Thanks Greg. It's good. Dr. Carolyn Lam: Today's feature discussion focuses on an extremely important topic of social vulnerability and premature cardiovascular mortality. So pleased to have the corresponding author of the feature paper, Dr. Khurram Nasir from Houston Methodist and Dr. Alana Morris, who is the editorialist for this paper. And she's joining us from Emory University in Atlanta, Georgia. So thank you both of you for joining and Alana if you don't mind, I'm going to borrow some of the words from your really-excellent editorial to bring us into the discussion. You very nicely brought up that early race and ethnic disparities and a death toll from COVID 19 really, laid the foundation for us having Frank conversations about vulnerable populations and has really brought to light social determinant of health and social economic inequality as risk factors. Now that's, COVID 19. And frankly, if we put everything in a global view of what kills most of us, it's still cardiovascular disease, which is why this paper is just so important, but current recognizing I'm not from the US, lots of our audience are not from the US. Could you please walk us through what your paper looked at and what it means? Dr. Khurram Nasir: Sure. Klan, thank you so much for having us today and what a wonderful editorial by Dr. Morris on this. As you pointed out about the COVID challenges, we were all touched by the significant disparities, really in a one of the lifetime crisis, such as COVID. But the reality is that even in times of calm the benefits, for example, cardiovascular disease prevention access have not been shared equally among vulnerable groups. So I'm a preventive cardiologist, and it gives me immense pride that despite being the number one cause of morbidity mortality for so long as a cardiology community, we have made significant strides over the last three decades, cutting into our losses. And if you look at the trends it's appeared and I'm very hopeful that we'll soon be losing the number one killer tag in US. At the same time we are seeing that those cuts are being lost, especially in the young individuals. Dr. Khurram Nasir: And at one point while we celebrate these decline. But the thing that bothers many of us that unfortunately these gains have not been equal, especially for our more vulnerable patients. And apart from the well documented, I think racial disparities that we all know and are becoming more aware. I think health disparities also form across various fourth lines and I believe the deepest and more persistent divides is around income. And you can even go a step further in US, unfortunately for our international group is unfortunate fact that in US, your zip code may hold more sway than your genetic code. And an example was made famous in St. Louis, Missouri Del marble award, which is known as the Delmer divide, a title that was made famous by a four minute BBC documentary that showed, that a sharp dividing line between the poor predominantly African American neighborhoods in the north and more affluent, largely white neighborhood in the south with health falling across this divide. Dr. Khurram Nasir: And in our practice, we see this phenomenon clearly in our own backyard. So, inspired by this sterling. We wanted to determine that a mirror geographical measure, where we can get insights of conditions where people live, learn, work, play, grow, and age, and commonly now known as the social determinants of health. Can that explain some of these rising risks, especially in the premature cardiovascular disease. So to design this study, we reached out to the CDC social vulnerable, the index that has been created that ranks communities and zip codes based on 15 factors across food domains, socioeconomic status, household composition of disability, that in includes single parents, elderly or children, minority status and language and housing type and transportation, all of them are put together and for each census. And then eventually at the county level, you can classify what their social vulnerability is. And as you know, this was really developed in to identify places where in times of disaster and emergencies, you can focus a little bit more, but we thought about how do we connect this to, for example, our data on mortality from CDC wonder. Dr. Khurram Nasir: And once we did that, we found very interesting patterns that across the scale social vulnerability, there is a risk dose dependent fashion and the age adjusted mortality rates for premature cardiovascular disease, which we define as less than 65, went from the least vulnerable and became the worst across the most vulnerable. At the same time, we also found this double jeopardy issues where this association was varied by race, gender, and ruler. And what we found that specifically Non-Hispanic lack individuals were more likely for certain types of cardiovascular, premature, such as stroke and heart failure, mortality, as compared to the rest, even if you were from the least vulnerable to the most women also unfortunately had a twofold higher risk of CBD mortality. And what is becoming clearly this whole ruler urban that a two to five fold risk of CBD mortality was seen among the least vulnerable. So this is in just the motive of our study, what we did and what we found. Dr. Carolyn Lam: That is so wonderful. Thank you for setting the context and then just to reiterate, so this was all within the US. Alana, could you maybe help frame how important these findings are for us? Dr. Alana Morris: Yes. I think that this analysis is so important, particularly within the context of some of the things that we see happening politically in our country and our landscape right now. And I think we tried to touch on some of those issues in the editorial. Again, I think that the COVID 19 pandemic, if you want to put that against this landscape has really brought into the forefront of our minds, this issue of disparities. Of course, there are many of us who have been thinking about researching and writing about disparities for a long time, but the issue of disparities really, came into the public mindset with the COVID 19 pandemic. The question now is how do we address these as we go forward? And what we're seeing politically is this question of how do we address inequalities that have been present for really since the beginning of time and maybe are widening and perhaps threaten many of the advances that we've made in terms of cardiovascular disease, morbidity, and mortality. Dr. Alana Morris: I think we have to think about in the US, universal healthcare coverage, because we have to be able to prevent disease and treat disease. And as current addressed, there are neighborhood zip codes where people not only don't have access to healthcare, but they don't even have access to the ability to promote health. They don't have access to things like parks, where they can exercise. They don't have access to healthy foods or grocery stores and in a country like the United States where there's so much wealth, you need to think about the fact that certain individuals, don't have the ability to access a grocery store, to access healthy food. It's just really striking and mind boggling that we have this, the difference in rural versus urban locations where some of our US residents, unfortunately don't have access to primary care clinicians, certainly not specialty clinicians is really very mind boggling. And we've seen this play out with the pandemic, but hopefully once we get past the COVID 19 pandemic, we still have to come back to a place where again, we're taking care of not only preventives or services to prevent the onset of cardiovascular disease, but certainly once people are diagnosed with cardiovascular disease, we want to get them access to specialty care. So we have to think as a community, how do we prevent disease, but also treat disease once disease is diagnosed within our country.   Dr. Carolyn Lam: What you just said about the zip code being more powerful about, than the genetic code, that's like a quotable code. It's incredible. And for those of us coming outside of the US, we don't even realize how much that plays a role, even just within the US. But now let's get to exact point that Alana pointed out, which is what are the next steps. And could you maybe suggest Khurram, and Alana maybe come first, but what's the one thing you want to get out or the one next thing that should happen after this Dr. Alanna Morris: We put a figure in to the editorial that I think really gets to the heart of the matter, I think that those of us who are in healthcare or those of us who think about public health really would ask the question of, why in a country that has as much wealth as the United States, do we not have universal healthcare, most countries across the world that are in an economic position similar to the United States do have universal healthcare coverage for their residents. And you see much better statistics in terms of longevity for their residents as compared to what we have in the United States. And what you see when you look at the United States is that where there is the most vulnerable residents as per analysis identifies those states are the ones that actually don't have, Medicaid expansion. Dr. Alanna Morris: They don't have a safety net for their residents. And so there's really contrast and this disparity that just does not make sense. It does not make sense where there are residents in the United States, which need the most help and they just don't have it. They just are not able to get access to preventive services as well as diagnostic services. And it really just doesn't make sense what we're doing in the United States, in my humble opinion. And I think in the humble opinion of many of us who want to take care of patients, but just cannot, Kern and I both practice in states where this is an issue. And I think that's one big driver. But again, I think when we also think about the built environment in the US and how we think about promoting health and how we talk to patients, when we talk about individuals in the US, we try to give them advice about therapeutic lifestyle changes, how to exercise, how to eat healthy, to prevent disease. That's easier for certain individuals as compared to others, depending upon where you live, depending upon those five digits that make up your zip code. So if we really want our residents to be healthy, we have to create an environment that enables them to do that. Dr. Carolyn Lam: Wow, thank you very much. And as I let Khurram have the final words even about where you think mixed research should be. I just want to highlight that incredible figure from your editorial Alana. I mean, it is really started, there are three panels to it, everyone. The first one chose the social vulnerability index, the second, the premature cardiovascular disease mortality, and then the third, the status of Medicaid expansion. And you can see the colors are just vivid in, how it all makes sense and goes together. So pick up our journal and have a look, but then finally Khurram? Dr. Khurram Nasir: So, Alana, your figure was fantastic and so much add perspective to our findings. As you were saying, it took me back to 35 years back when, where we are before Medicare disparities, even in access to hospitals were dramatic. So where we practice in the south one third of the hospitals would not admit African Americans even for emergency. Now, this is where the policy comes in and suddenly in 1965 using the carrot of Medicare dollars, the federal government virtually ended the practice of racially segregating patients, doctors, and medical staffs, blood supplies so that is the direction that we need to go from the policy perspective and trying to affect the upstream determinants. Now moving forward, as I think more, and especially as a physician, I think while the census level measures are extremely useful to help refine these policy and focus programs in vulnerable areas. Dr. Khurram Nasir: I also think that there is a parallel need to start focusing on similar efforts at the individual level. The first thing is how do we even identify social determinants at this patient level? Are there three main categories, income, education, possibly healthcare, but I think that we need to broaden this. And in the past we have been challenged because we didn't have a set of consensus of the defined SDUH framework. But thankfully now in 2021, we have the healthy people, 2020. Actually for international community, the WHO there is a WHO framework of identifying SDOH at an individual level and in US a more comprehensive Kaiser family foundation. And not only that, we looked at superficially broadly, but we have to go deeper beyond these components of economic instability, education, housing, social context on healthcare beyond insurance, and even food. Dr. Khurram Nasir: For example, income and employment are predominant pillars of income stability, but it may not capture the full picture. For example, difficulty paying bills out of pocket cost and death related to medical care, same in education, where we captured the highest degree, but issues around health and digital literacy and language proficiency may be even more important. So not only we have to broaden the scope, but we have to go in depth. And thirdly, what I've realized from these kind of studies that we have to go a step further, that social disparities don't occur in silos. And we have to look at the aggregated information. And maybe it's time to potentially learn from advances in genetics, in what we have learned that manifestation of disease, especially cardio metabolic rather than being influenced by few major genes is manifested secondary to multiple interacting genes. So can we create similar to a poly genetic risk score, which is an aggregation of genetic smaller risk to a relevant something similar called poly social risk score. Dr. Khurram Nasir: Now, this is an area that our group has been extensively working. And over the last 12 months, we have tried to construct a comprehensive poly social risk score at an individual level based on almost about 50 sub components of the social determinants. And we have suddenly finding very interesting associations with premature CAD stroke. Almost one in two young individuals with stroke, have the worst poly social risk code at the individual level. I think so the next steps will be definitely validation of this tool, incorporation in practice, whether it's adoption and effective interventions can be tied. But the final thing, what I truly want to say is that I'm hopeful that these efforts, the census level at an individual level, at a societal level and the health system are waking up to the importance of social determinants that we can think outside the box and have strong community partnerships. Multi Pro strategies driven largely by social economic environmental factors. So we can all make a lead towards the mission of achieving social justice and equity that eventually cascades through the health system and beyond. So we had enough time to illuminate the issues and challenges. Now it's the time to act. Dr. Carolyn Lam: Thank you so much Kern for a beautiful paper. We are so proud to be publishing it in circulation. And thank you, Alana lovely, editor that we've said so many times. Thank you audience for joining us today. You've been listening to Circulation on the Run from Greg and I please tune in again. Next week, 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.

Welcome back to another episode of SDG Talks where we highlight change makers and their inspirational work towards the United Nations Sustainable Development Goals (SDGs)! What do you know about climate models? IN THIS EPISODE: Climate scientists need to find ways to make their knowledge meaningful at the local scale. We are used to adjusting the real world to fit our theories, but we need to start adjusting our theories to fit the real world, which is a paradigm shift. Climate modelling and the distinction between certain influences (Thermodynamic ie transfer of heat energy) and uncertain ones (Dynamic - Jet stream, Indian Monsoon etc). Why near-future social tipping points may be as bad as climate tipping points. The missing link between climate science and adaptation planning. Theodore (Ted) Shepherd FRS is Grantham Professor of Climate Science at the University of Reading. He is a specialist in large-scale atmospheric dynamics and circulation and its role in climate change, including extreme events. During the first part of his career at the University of Toronto, he initiated and led, for 20 years, a large university-Environment Canada collaboration on the development and use of the Canadian Middle Atmosphere Model (CMAM). Ted has held leadership roles in international scientific assessments of climate (IPCC) and stratospheric ozone (WMO/UNEP), and in the World Climate Research Programme (WCRP). He co-authored the US National Academy of Sciences report on Extreme Weather Events and Climate Change Attribution (2016), and chaired the Science Review Group of the Met Office Hadley Centre (2017-2021). Since moving to the UK in 2012, Ted has highlighted the large uncertainty in aspects of climate change related to atmospheric circulation, which is in striking contrast to thermodynamic aspects of climate change. Ted's recent research has focused on how to effectively characterize these circulation-related uncertainties, including their impacts. As part of this research he has been pioneering a ‘storyline' approach to representing uncertainty in physical aspects of climate change, including extreme events, and beginning to engage in inter-disciplinary collaborations. The storyline approach, which has influenced the current IPCC WGI report (AR6), asks what would be the consequence of particular choices or actions under different imagined futures. It thereby represents a paradigm shift compared with the traditional probabilistic ‘predict-then-act' approach to climate risk. Ted is currently trying to implement this approach through his co-leadership of the WCRP's new Lighthouse Activity called ‘My Climate Risk'. Resources: “The future cannot be forecast, but it can be explored” (E.F. Schumacher, in Small is Beautiful, 1973) Let's get SDG Talking!! Got a good story or want to collaborate? Send us an email at sdgtalkspodcast@gmail.com and we will get back to you as soon as we can! And don't forget to check out our Virtual Roundtables on our website! Instagram | Facebook | Twitter | LinkedIn

Ross and Carrie try the Shakti Mat, a foam pad studded with ABS plastic discs wielding thousands of sharp, stabby points. Will this modern spin on the classic bed of nails improve sleep, relax muscles, ease recovery from headaches, and increase circulation? And just how long can [Americans!] Ross and Carrie stand on the mat in their bare feet?For pics and videos, follow us on Facebook!

This episode is brought to you by MEDHOST, a Trusted EHR for Healthcare Facilities. To learn more, go to Medhost.com. Dr. Keith Churchwell is the president of Yale New Haven Hospital. A strategic and innovative leader, Dr. Churchwell is leading Yale New Haven into the new era of hospital care with an eye towards equity and diversity. With his roots here in Nashville, Dr. Churchwell shares with us how his family's commitment to excellence shaped his career – he and his two brothers are all hospital system leaders. And we talk about what it takes to make the tough calls in healthcare that take guts but result in true breakthroughs. For more insights from Dr. Churchwell, read the following resources: Call to action in Circulation: structural racism as a major driver of health disparities: https://www.ahajournals.org/doi/10.1161/CIR.0000000000000936 Working towards more equitable communities: https://www.ynhh.org/publications/bulletin/111220/an-interview-with-keith-churchwell-md-president-yale-new-haven-hospital.aspx Fighting Covid-19 vaccine hesitancy: https://www.newhavenindependent.org/index.php/archives/entry/ynhh_naacp_town_hall/ Pushing for diversity in clinical trials: https://www.newhavenindependent.org/index.php/archives/entry/churchwell_interview/

Welcome back to our weekend Cabral HouseCall shows! This is where we answer our community's wellness, weight loss, and anti-aging questions to help people get back on track! Check out today's questions:  Tahlia: Hi Dr. Cabral, Thank you so much for providing such a truly life changing resource! I'm hoping you can help point me in the right direction, I looked through previous podcasts and I don't believe you've ever spoken about idiopathic hypersomnia before. I had to laugh when I asked my sleep specialist who'd just diagnosed me with it what it meant and he said 'excessive daytime sleepiness with no known cause'. He was sure the other specialists I had been referred to would find an underlying chronic condition that would explain this and my other chronic fatigue symptoms but nobody did. Over the years I've managed to improve my symptoms and come off all medications (including modafinil which was specifically prescribed for the hypersomnia, to keep me alert during the day) and I've come a long way but I haven't seen any further improvement for quite some time. I'll never stop learning and growing but my symptoms currently have far too big an impact on how I spend my time and I was wondering if you might have come across this disorder before or have any information to share about it? A huge thank you in advance for taking time out of your life to answer this and all the other questions you get asked! Anonymous: Hello Dr. Cabral! Thank you for answering our questions in your HouseCalls every weekend and for providing the IHP health coaching courses! You have positively changed my life. What causes a person to smell like mothballs? I encountered a man at the grocery store who overwhelmingly smelled like mothballs. I could smell him from 15 feet away. I also noticed one of my older relatives smelled like mothballs when they talked to me at the end of the evening after they had been quietly watching tv and not talking or opening their mouth for an hour.nnI think both people had mothball breath. Is there also mothball body odor and does it have a different cause? Thank you! Anonymous Eve: Hello  I had COVID in February 2021, I had it very very bad after 4 days I lost my sense of smell and taste. Very strange experience. I counted and on my 29th day I started to smell little and taste little but would still be off every other day. Now we are in July 2021 and since July 12th Everything I mean everything I smell is either gasoline, nail polish remover or bleach like. When I step outside to take a breath of fresh air in its like nail polish remover, fresh grass being cut outside is a potent polish remover smell. I can not eat garlic, onions or ginger without vomiting because it tastes like bleach. Cucumbers, spinach, green beans, I can write a list of almost all the veggies and fruits that taste and smell like bleach for me. Toothpaste I have switched to 4 different kinds and it's the worst of it all, makes me nauseous of it all. Even water, I can smell my water now when I shower or wash dishes. I feel like I'm washing my dishes with gasoline like toxic smell water. What do you recommend or believe would help? It's hard to find with to eat and keep my health and nutrition up. I'm 32, female healthy. Thank you Angela: Dear Dr. Cabral, You mention the importance of eating/sleeping with the sun to help with digestion and sleep. However, what do people in Alaska do when the have endless daylight or minimal daylight periods? What about people who work graveyard shifts? Another example of altered schedule is in Europe they tend to eat dinner and sleep much later than Americans. I know many European countries take an afternoon siesta, could that be their secret? They seem much healthier than Americans in general. Mahalo, Angela Evan: How long does H pylori normally take to get rid of when treating naturally? Is it ok to have some gluten and alcohol during treatment? Also do you typically look for h pylori numbers to be low or be zero? Gabriel: Hi Dr. Cabral, I was enjoying your podcast with Organic Olivia when a comment about circulation sparked this question. I am a 25 year old woman who eats clean and exercises a few times a week (though it could be more consistent). In the past few years I've noticed issues with my circulation. For example, lifting an arm away from my body for more than 10 seconds is uncomfortable and if I sit in a certain position for a while my leg will start to tingle. Whenever I get my blood pressure tested the dr comments that it is low but 'healthy' (100/62, 99/61, 90/50 etc.). I have brain fog daily and was diagnosed with ADD a few years back but have had attention issues since I was a child. I do not take ADD medication as the side effects aren't worth it for me. Your comment about bad circulation prohibiting blood from reaching the brain struck me as I have family history of dementia. What can I do to improve my circulation to make my limbs for comfortable and hopefully improve brain function? I appreciate your help and love the podcast! Thank you for tuning into today's Cabral HouseCall and be sure to check back tomorrow where we answer more of our community's questions!  - - - Show Notes & Resources: http://StephenCabral.com/2045 - - - Get Your Question Answered: http://StephenCabral.com/askcabral   - - - Dr. Cabral's New Book, The Rain Barrel Effect https://amzn.to/2H0W7Ge - - - Join the Community & Get Your Questions Answered: http://CabralSupportGroup.com - - -  Dr. Cabral's Most Popular At-Home Lab Tests: > Complete Minerals & Metals Test (Test for mineral imbalances & heavy metal toxicity) - - - > Complete Candida, Metabolic & Vitamins Test (Test for 75 biomarkers including yeast & bacterial gut overgrowth, as well as vitamin levels) - - - > Complete Stress, Mood & Metabolism Test (Discover your complete thyroid, adrenal, hormone, vitamin D & insulin levels) - - - > Complete Stress, Sleep & Hormones Test (Run your adrenal & hormone levels) - - - > Complete Food Sensitivity Test (Find out your hidden food sensitivities) - - - > Complete Omega-3 & Inflammation Test (Discover your levels of inflammation related to your omega-6 to omega-3 levels) - - - > View all Functional Medicine lab tests (View all Functional Medicine lab tests you can do right at home for you and your