Podcasts about American Heart Association

PRE-RECORDED INTERVIEW 2022 Stroke Awareness Month- Stroke is a leading cause of death in the United States and is a major cause of serious disability for adults. It is also preventable and treatable. ***Dr. Rani Whitfield-I have been in Private Practice and living in my home town of Baton Rouge since 2000. My specialty in Sports Medicine has allowed me to grow my outreach to youth in the Baton Rouge area and across the nation. I speak frequently for the American Heart/American Stroke Association and have been featured on CNN- House Call with Sanjay Gupta, the Michael Baisden Show, The Tom Joyner Morning Show, traveled with Tavis Smiley and his Road to Health Tour, and have recently been featured in Ebony, Jet, and Essence. I have developed a comic book series to educate youth on health issues (www.legionofhealth.com) and several music CD's with the same goals in mind. ***Hyvelle Ferguson--Davis-Stroke, Hewart Attack and Diabetes survivor- She is 48 and now motivating others, especially African Americans. Hypertension, a leading cause of stroke and heart attack, affects more than half of African American adults. Last year, Ferguson-Davis became an ambassador for Know Diabetes by Heart, a joint health and education initiative of the American Heart Association and the American Diabetes Association. She also recently started her own group for African American women called Heart Sistas, where members, including her sister Judy Ferguson-Missick, share heart-healthy information and motivation. One of their sisters recently died from a stroke, Ferguson-Davis said.

info@podcastone.com21fbcbfd-3abe-47f7-b08a-47a363e30dcbTue, 17 May 2022 14:59:06 PDT00:13:15The South Florida Sunday Podcast

This week, please join author Andrew Stokes as he and Greg Hundley discuss the Research Letter "E-Cigarette Use and Risk of Cardiovascular Disease: A Longitudinal Analysis of the PATH Study (2013–2019)." Dr. Greg Hundley: Well, listeners, welcome to this May 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, associate editor, director of the poly heart center at VCU Health in Richmond, Virginia. And this week, Carolyn is away out on vacation and we are going to go through the summaries together. We have a great feature today on e-cigarette use and the risk of 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? And the first one comes to us from the world of clinical science and Dr. Jiaqi Huang from the National Cancer Institute. Listeners, the objective of this study was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption through the prospective analysis of 27,000 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention or ATBC Study, and also a systematic review and meta-analysis of several other cohort studies. Dr. Greg Hundley: So, what did the investigators find? Well, first, based on 482,000 person-years of follow-up, the authors identified 22,000 deaths, including 9,110 deaths from cardiovascular disease. Now, greater dietary cholesterol and egg consumption were associated with increased risk of overall and cardiovascular disease mortality. Now, second, from the meta-analysis component of the study, overall consumption of one additional 50-gram egg per day was associated with an increased cardiovascular disease risk with a pooled relative risk of 1.04 with a higher risk of cardiovascular disease among those from us cohorts where their pooled relative risk ratio was 1.88, a borderline higher cardiovascular disease risk in European cohorts with a pooled relative risk of 1.05, but not an increased cardiovascular disease risk in the Asian cohorts. So, the results from this study, which includes an updated meta-analysis, suggest that there is support for restricted consumption of dietary cholesterol as really a means to improve long-term health and longevity. Dr. Greg Hundley: Well, let's go to our next article. So, in this next study, we are going to move from cholesterol risk now to salt substitution. And this article comes to us from Professor Maoyi Tian from the Harbin Medical University. Listeners, the Salt Substitute and Stroke Study, or SSaSS is a five-year cluster randomized controlled trial and demonstrated that replacing regular salt with a reduced sodium added or potassium salt substitute reduced the risk of stroke, major cardiovascular events, and premature death among individuals with prior stroke or uncontrolled high blood pressure that lived in rural China. So, this particular study, a substudy, assessed the cost-effectiveness profile of this particular intervention. Dr. Greg Hundley: So, listeners, what did the study find? Well, there was a mean follow-up of 20,995 participants that was conducted a little over four years, and over the period, replacing regular salt with salt substitute reduced the risk of stroke by 14% and the salt substitute group had on average 0.054 more quality-adjusted life years per person. The average costs were lower in the salt substitute group, and this intervention was dominant. That is better outcomes at a lower cost for prevention of stroke as well as for quality-adjusted life-years gained. Now, interestingly sensitivity analyses showed that these conclusions were robust except when the price of the salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95% probability of being cost-saving and a greater than 99.9% probability of being cost-effective. A really interesting article. Dr. Greg Hundley: Well, now, let's turn our attention to the world of population science. And in this study, these authors led by Dr. Steven Lubitz from Massachusetts General Hospital performed a Genome-Wide Association Study or GWAS of the QT corrected interval among 84,630 United Kingdom Biobank participants. And they created a polygenic risk score. Now, among 26,976 participants with whole-genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine or TOPMed program, they identified 160 carriers of punitive pathogenic, rare variants in 10 genes known to be associated with the QT interval. Dr. Greg Hundley: So, the authors here examined the QTC corrected associations with the polygenic risk score and with rare variants from the TOPMed cohort. So, what did they find? They found 54 independent loci by GWAS in the UK Biobank. 21 loci were novel of which 12 were replicated in TOPMed. The polygenic risk score comprising over a million common variants was significantly associated with the QTC in TOPMed, and carriers of punitive pathogenic rare variants had longer QTC intervals than non-carriers. Now, 23.7% of individuals with a QT corrected of greater than 480 milliseconds carried either a monogenic rare variant or had a polygenic risk score in the top decile. 3.4% for monogenic and 21% for the top decile of the polygenic risk score. Dr. Greg Hundley: So, listeners, the findings of this study indicate that the QTC duration in the population is influenced by both rare variants in genes, underlying cardiac repolarization and polygenic risk, with a sizeable additional contribution from polygenic risk. And therefore, comprehensive assessment of the genetic determinants of QTC prolongation should include incorporation of both polygenic and monogenic risk. Dr. Greg Hundley: Well, listeners, let's turn our attention to the world of preclinical science. And this next article comes to us from Professor Junbo Ge from the Department of Cardiology in Zhongshan Hospital in Fudan University. Well, listeners, after myocardial infarction, cardiac resident macrophages, which are self-maintaining in that they originate from embryonic hematopoiesis are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes. And that process is called efferocytosis. Now, efferocytosis is required for inflammation resolution and tissue repair. However, the underlying molecular mechanisms of this process really remain unknown. Dr. Greg Hundley: So, as such, listeners, these authors sought to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. Well, what did Dr. Ge and colleagues find? Several things. First, they identified legumine as a gene specifically expressed by cardiac resident macrophages, and legumine deficiency resulted in a considerable exacerbation in cardiac function, accompanied with the accumulation of apoptotic cardiomyocytes and a reduced index of in-vivo efferocytosis in the border area of infarcts. Furthermore, the formation of LC3 to dependent phagosome around secondary encountered apoptotic cardiomyocytes was disabled. In addition, legumine deficiency increased infiltration of MHC to high CCR2+ macrophages, and the enhancement of recruitment of MHC to low CCR2+ monocytes with downregulation of anti-inflammatory mediators, such as IL10 and TGF-beta, and upregulation of pro-inflammatory mediators, including interleukin-1-beta, Tumor Necrosis Factor alpha, IL6, and IFN-gamma. Dr. Greg Hundley: So, listeners, in summary, the results of this study directly link efferocytosis to wound healing in the heart and identify legumine as a significant link between acute inflammation resolution and cardiac function after infarction. Well, listeners, also in this issue, we have a wonderful On My Mind feature from Professor Camlet entitled “A Role for the Vascular Endothelium in Post-Acute COVID-19.” Well, next, we're going to head to our feature article on e-cigarette use and the risk of cardiovascular disease. Dr. Greg Hundley: Well, listeners, welcome to our feature discussion today. A very interesting topic. E-cigarette use and the risk of cardiovascular disease. And we have with us today the senior author of this particular manuscript, Dr. Andrew Stokes from the Boston University School of Public Health in Boston, Massachusetts. Welcome, Andrew. Andrew, to get started, can you describe some of the background information pertaining to your study and what was the hypothesis that you wanted to address? Dr. Andrew Stokes: Absolutely, and thank you for having me on the podcast. Despite the increasing popularity of electronic cigarettes, the long-term health effects of habitual e-cigarette use remain unclear. Most of the studies that have been conducted to date are either cross-sectional or they pertain to small clinical samples. The goal of the present study was to develop a longitudinal design to see if e-cigarette use at a point in time was linked to cardiovascular events over a multi-year follow-up period. Dr. Greg Hundley: Very nice. So, your specific hypothesis really pertained to e-cigarette use, correct? Dr. Andrew Stokes: That's right. As a novel product, information on e-cigarette use and its health effects is lacking, and so our goal was to see if e-cigarette use was associated with the incidence of clinical events. Dr. Greg Hundley: And so, can you describe for us your study population and your study design? Dr. Andrew Stokes: Absolutely. Data come from the Population Assessment of Tobacco and Health Study or the PATH Study, which is a nationally representative cohort study of the non-institutionalized population containing five annual waves of self-reported data collected between 2013 and 2019. The initial sample included over 30,000 US adults ages 18 years and older with oversampling of tobacco users. We excluded respondents who were lost to follow-up or who had a previous diagnosis of CVD or were missing baseline exposure information. Ultimately, we ended up with a sample of just over 20,000 individuals. Dr. Greg Hundley: Very nice. And so, what were your study results? Dr. Andrew Stokes: So, we had several key findings. One key finding was that, compared to people who only smoke cigarettes, people who smoke both traditional cigarettes and used e-cigarettes had no significant reduction in risk for heart attack, heart failure, or stroke, nor any cardiovascular disease outcome. This is significant because many e-cigarette users use both e-cigarettes and cigarettes in combination. Very few move to exclusive e-cigarette use. Additionally, we found that those who do move to e-cigarette use exclusively though, representing a very small fraction of the cohort, had some evidence of reduction in cardiovascular harm. However, these results for exclusive e-cigarette users were not statistically significant, indicating that additional studies with longer follow-up will be required before we can make any definitive conclusions about this group. Dr. Greg Hundley: Very nice. And did you notice any discrepancy in your results between either men versus women or between individuals that were younger in age versus those that may say be 50 years or older? Dr. Andrew Stokes: I think both sources of effect modification will be valuable directions for future research. Unfortunately, samples of e-cigarette users are quite small and incident events over follow-up are quite limited. Therefore, the present study did not pursue or explore these types of stratifications. Dr. Greg Hundley: Very good. So, sounds like more research to come forward. Well, Andrew, how do we put your results really in the context with other studies evaluating the harmful effects of e-cigarettes? Dr. Andrew Stokes: Of course. So, we know from toxicological studies that there are many constituents of e-cigarette aerosols that are concerning and have substantial toxicity. We know that the inhalation of e-cigarette aerosols among young healthy adults induce inflammation and oxidative stress. Population-based studies from cross-sectional data sources also suggest evidence of harm. What's needed are more longitudinal studies with longer follow-up periods and more incidence events so we can really parse this risk and identify the magnitude of these harms. Finally, we also need to understand better whether there's any harm reduction potential associated with e-cigarette use. E-cigarettes are currently not an FDA-approved cessation product. Therefore, we do not recommend their use despite preliminary evidence of potential harm reduction. We'll need further evidence before we can make any such conclusions. Dr. Greg Hundley: And Andrew, describe for us, and you've started to already, what series of studies are needed next to be performed in this sphere of research? Dr. Andrew Stokes: Right. So, it's difficult to really identify definitively the effects of e-cigarette use in the absence of randomized control trials. However, we can use observational data with target trial approaches to emulate the clinical trial that we would like to do if we were able to. So, the next step is really to look at transitions across products between cigarette and e-cigarette use and to associate those who switch products, such as from e-cigarettes to cigarettes or vice versa, to see if those switches are associated with any harm or harm reduction. Dr. Greg Hundley: Very good. Any specific racial or ethnic groups or even social determinants of health that may need to be targeted with some of these future studies? Dr. Andrew Stokes: That's a great question. So, what we know so far from preliminary research is that some groups are more likely to switch to e-cigarettes than other groups. Particularly among current combustible cigarette users, the rates of switching do vary by race and ethnicity. Thus, we need further research to understand why these patterns differ across subgroups and what their implications may be for health. Dr. Greg Hundley: Do you foresee any difficulty in trying to enroll participants from those other groups as you plan these studies moving forward? Dr. Andrew Stokes: The advantage of the current research design is that we're using a large secondary data set of survey participants who are enrolled in the Population Assessment of Tobacco and Health study. Therefore, we are not enrolling patients ourselves and the response rates are quite high in these surveys. Dr. Greg Hundley: Well, Andrew, we hear that some of the inhalants that are mixed with the inhaled nicotine can be flavors and perhaps have been approved by the FDA for consumption in the GI tract where, whatever these additives are, you would think might be broken down by the digestive system. But if they're inhaled and get into the lung tissue and the parenchyma, the alveoli, et cetera, do they perhaps have harmful effects that maybe we're not aware of? Dr. Andrew Stokes: Absolutely. E-cigarettes come in thousands of characterizing flavors including sweet flavors, tobacco flavors, and many other miscellaneous flavors. As we saw with the outbreak of lung injury associated with the use of e-cigarettes in 2019, inhaling flavors can have health effects that are unanticipated based on research in the GI tract, and therefore, as a next step in this research, we really need more work to investigate how different flavors are associated with the incidence of clinical events, whether cardiovascular or pulmonary conditions. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Andrew Stokes from the Boston University School of Health for bringing us this data from the PATH study, suggesting that combining smoking with e-cigarette use does not reduce cardiovascular events and that quitting both products is needed to ensure overall cardiovascular disease risk reduction. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Professor Harvey White is a Cardiologist and Director of the Cardiovascular Research Unit, Auckland City Hospital. He is an Honorary Professor of Medicine University of Auckland and Fellow of the Royal Society of New Zealand.  Harvey trained at Green Lane Hospital, Auckland and Harvard and Brigham and Women's Hospital, Boston. He is the John Neutze Scholar. In recognition of his work on end-systolic volumes as the most important modifiable prognostic factor following myocardial infarction, he was awarded DSc by Otago University. He was awarded the Prince Mahidol Award by the King of Thailand for introducing fibrinolytic therapy in developing countries, including China. He is a Matai (La'uli) in Samoa for services to Samoa, and has a “pou” in the Te Awamutu Walk of Fame recognising his contribution to decreasing heart disease. He is Co-chairman of the Redefinition of Myocardial Infarction Consensus group and defined the 5 types of MIs. He is senior author on the Bleeding Academic Consortium (BARC) to define bleeding.  He has been a member of numerous guideline groups. He is a member of the Cholesterol Treatment Trialists' (CTT) Collaboration and is on 16 editorial Boards. He has over 1000 publications and 77 editorials with an H Score 121.He gave the most prestigious International Society and Federation of Cardiology lecture at the European Society of Cardiology in 1993, and Paul Dudley White lectures at the American Heart Association in 2004 and at American College of Cardiology in 2011. Harvey is recognised in the top 1% of scientists worldwide and No 5 for publication of RCT-related articles in all high-impact-factor medical journals over the past five decades. He was also awarded the highest collaboration index.  He has been NZ Chairman and President of the combined Cardiac Society of Australia and New Zealand. He was awarded the Inaugural Gold Medal at the Cardiac Society of Australia and New Zealand Annual Scientific Meeting 2019 for outstanding contribution to Cardiology.He introduced the 10 year earlier screening for Mᾱori in the absolute risk assessment and has presented this to the Health Committee on doing that for colonic screening; published on  worse outcomes for Mᾱori  after bypass surgery; has a Pou in the Te Awamutu rose gardens; introduced the Mᾱori byline for the New Zealand Medical Association and as chairman of the New Zealand Medical Services Board is responsible for the New Zealand Medical Journal.  He has also had multiple visits to Samoa doing clinics, including a WHO report, attending the 50th annual meeting of the Samoan Medical association, and a matai title La'auli, the highest mountain,  for services to Samoa.In this episode, we discuss his extensive and prolific journey in research, his work in Samoa and Māori health, and his love for cardiology. As always, if you have any feedback or queries, or if you would like to get in touch with the speaker, feel free to get in touch at doctornos@pm.me.Audio credit:Bliss by Luke Bergs https://soundcloud.com/bergscloudCreative Commons — Attribution-ShareAlike 3.0 Unported — CC BY-SA 3.0Free Download / Stream: https://bit.ly/33DJFs9Music promoted by Audio Library https://youtu.be/e9aXhBQDT9YSupport the show

每日英語跟讀 Ep.K363: About health - Screen-Time Before Bed Can Disrupt Sleep   Digital screen time before bed can have a negative impact on the quality of your sleep. A US study found that as little as eight minutes of exposure to blue light keeps you mentally stimulated for over one hour, which tends to throw off the body's circadian rhythm or biological clock. 睡前花時間看數位螢幕會對你的睡眠品質產生負面影響。美國一項研究發現，只要暴露在藍光下短短8分鐘，就能讓你在1個多小時內保持精神興奮，這往往會擾亂身體的晝夜節律或生物時鐘。 Exposure to blue light suppresses the production of melatonin, a hormone that induces sleepiness. Melatonin release in the evening helps you relax before bedtime. Suppression of melatonin can cause you to stay up later and sleep less than you normally would. 暴露在藍光下會抑制褪黑激素的產生，褪黑激素是一種會導致嗜睡的激素。晚間釋放褪黑激素可幫助睡前放鬆。抑制褪黑激素會導致你熬夜，睡眠時間比平時少。 Seeing something right before bed that either makes you upset or happy can trigger a response that prolongs falling sleep, which consequently delays REM (rapid eye movement) sleep. These emotions can leave you staring at the ceiling for hours feeling wide awake. 睡前看到讓你心煩意亂或快樂的事情，會引發延長入睡時間的反應，從而延遲快速眼動（REM）睡眠。這些情緒會讓你盯著天花板看幾個小時，感覺完全清醒。   Next Article   Want to sleep better? Lift some weights 想要睡好點？練些舉重吧   Struggling to sleep? Put some muscle into your efforts by adding resistance training, otherwise known as weight training, to your weekly exercise routine. 難以成眠？將阻力訓練、也就是重量訓練，納入每週例行運動，再多試試看吧。 In fact, resistance training may even beat aerobic exercise in the race for best sleep aid, according to a new preliminary study presented Thursday at the American Heart Association's Epidemiology, Prevention, Lifestyle & Cardiometabolic Health Conference. 事實上，根據週四「美國心臟學會流行病學、預防、生活型態和心臟代謝健康會議」上發表的一份新的初步研究，以最能幫助睡眠來說，阻力訓練或許甚至比有氧運動還好。 "In our study, we found that resistance exercise appeared to go above and beyond aerobics or even a combined aerobic and resistance routine on several different sleep outcomes," said study author Angelique Brellenthin, an assistant professor of kinesiology at Iowa State University in Ames, Iowa. 「我們在研究中發現，在數個不同的睡眠結果上，阻力運動比有氧運動、甚至是有氧加阻力運動的效果還要好」，研究報告作者、愛荷華州立大學人體運動學助理教授布雷倫森說。Source article: https://features.ltn.com.tw/english/article/paper/1509615 ; https://features.ltn.com.tw/english/article/paper/1509987

At the tender age of 9, Kelly Rowland formed a musical group with her friends that in a few year would be known the world-over as "Destiny's Child". That was in 1990, and Kelly is all grown up now with a successful solo career in music, fashion, acting, directing/producing, and recently, writing. Her children's book, "Always With You, Always With Me" was just released.  She's also a loving partner to her husband, a doting mamma of two young boys, and active in numerous causes that aim to make life better for her community and the world. Recently she performed at the American Heart Association's Red Dress Collection Concert. Kelly joins us today to implore women to take their heart health seriously, and we get caught up on all sorts of other things too! ~ Delilah See omnystudio.com/listener for privacy information.

Bryce Fluellen is the Executive Director of Social Equity Franchise at Everytable. They are redefining the fast-food landscape by selling nutritious, fresh, made-from-scratch food at fast-food prices in underserved communities. To that end, they're reducing meal prices to meet the minimum income of each community. Bryce is a master chef who has worked with nationwide restaurants to drive systemic change to benefit underserved populations and communities. In this conversation, he shares how his passion for education and healthy eating serves the company's rapid growth and the democratization of healthy, affordable food where it's needed most. Bryce Fluellen Bryce Fluellen is the Executive Director of Everytable's Social Equity Franchise Program. This model invests directly into marginalized entrepreneurs of color by providing the opportunity to open Everytable stores with zero upfront capital or net worth. Fluellen has fought for food justice and social equity for more than 20 years. He developed and implemented strategic programs at Starbucks, Magic Johnson Enterprises, and the American Heart Association to drive systemic change to benefit underserved communities. As Community Impact Director at the Los Angeles chapter of the American Heart Association, he was instrumental in developing and implementing a multi-year, million-dollar regional campaign with the National Football League Foundation to transform and improve youth physical activity and building an impact blueprint for the League to scale across 30 team markets. Also a Master Chef, he operated a Los Angeles full-service catering company, YAMS Catering, where he created partnerships with health-focused organizations to educate Black and Brown communities about healthy eating.   Resources Learn more about Everytable at https://everytable.com/about Connect with Bryce on LinkedIn: https://www.linkedin.com/in/bryce-fluellen-8307468/ Visit leadwithwe.com to learn more about Simon's new book or search for "Lead With We" on Amazon, Google Books, or Barnes & Noble.

This week, please join Guest Host Mercedes Carnethon and Author Brendon Neuen as they discuss the article "Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data from Randomized, Controlled 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. Dr. Carolyn Lam: Greg, this week's feature paper is on one of my favorite topics, SGLT2 inhibitors. And this time, looking at their association with the risk of hyperkalemia in people with type-two diabetes. Now this is something we've all been waiting to look at. It's a meta-analysis of individual participant data from randomized controlled trials, so a very important, clinically applicable discussion coming right up. But first, I'm actually going to talk to you about text messages. Dr. Greg Hundley: Wow, Carolyn. I can't wait to hear about this article. Dr. Carolyn Lam: Well, specifically the TEXTMEDS randomized clinical trial, which is our first paper today. It is a trial that examined the effectiveness of text-message delivered cardiac education and support on medication adherence following an acute coronary syndrome. Dr. Carolyn Lam: This is from Dr. Clara Chow from University of Sydney and her colleagues, who performed a single blind multi-center randomized controlled trial of post-ACS patients across 18 rural and urban centers and three time zones in Australia. The control group received usual care, and the intervention group additionally received multiple motivational and supportive weekly text messages on medications, and healthy lifestyle, with the opportunity for two-way communication. Dr. Greg Hundley: Wow, Carolyn. So text messaging to facilitate medication adherence. I can't wait to hear. So what did they find? Dr. Carolyn Lam: I think the design, it's such a neat study. However, the study found no significant impact on the primary outcome of medication adherence at six and 12 months, nor on LDL cholesterol or blood pressure. Dr. Carolyn Lam: However, intervention participants were more likely to achieve a normal body mass index and to eat guideline-recommended servings of fruit and vegetables. Qualitative analysis demonstrated a high level of acceptability, utility in being a unified source of information, high program engagement, and emotional support, especially during times of uncertainty. Dr. Greg Hundley: Interesting, Carolyn. Sounds like an impact on diet, so what did we learn from this study? Dr. Carolyn Lam: Well, customized and personalized text message-based prevention programs are indeed a scalable and low-cost means of delivering consistent education and support to patients following hospitalization for ACS. So this study shows it's feasible. The lack of impact, however, on medical adherence, though with better adherence to healthy lifestyle practices, suggests that maybe external factors, such as cost, may strongly influence medical adherence. These need to be addressed, in addition to education programs, to improve medical adherence. But all of this is discussed in a beautiful editorial entitled, "Opportunities and Challenges of Mobile Health Tools to Promote Health Behaviors" by Drs. Sharma and Avram. Dr. Greg Hundley: Very nice. Carolyn, what a great summary. Well, my paper comes to us from Professor Mario Delmar from New York University School of Medicine, and Carolyn, exercise training as well as catecholaminergic stimulation increases the incidence of arrhythmic events in patients affected with arrhythmogenic right ventricular cardiomyopathy or ARVC, and this correlates with plakophilin-2 mutations. Now, Carolyn, separate data show that reduced abundance of plakophilin-2 leads to dysregulation of intracellular calcium homeostasis, and Carolyn, these authors studied the relation between exercise and or catecholaminergic stimulation, intracellular calcium homeostasis, and arrhythmogenesis in plakophilin-2 deficient murine hearts. Dr. Carolyn Lam: Ooh. So what were the effects? Dr. Greg Hundley: Right, Carolyn. For training, the mice underwent 75 minutes of treadmill running once per day, five days each week, for six weeks. And the authors observed that exercise disproportionately affected calcium intracellular homeostasis in plakifilin-2 deficient hearts, in a manner facilitated by stimulation of intracellular, beta-adrenergic receptors or hyper-phosphorylation of phospholamban. Dr. Greg Hundley: Now these cellular changes created a pro-arrhythmogenic state that can be mitigated by plakophilin receptor blockade. Additionally, Carolyn, these authors' data unveiled an arrhythmogenic mechanism for exercise-induced or catecholaminergic life-threatening arrhythmias in the setting of a deficit in plakophilin-2. They suggest that membrane-permeable beta blockers are potentially more efficient for ARVC patients. Dr. Greg Hundley: And also they highlight the potential for ryanodine-receptor channel blockers as treatment for the control of heart rhythm in this population at risk, and propose that plakophilin dependent and phospholamban-dependent, ARVC-related arrhythmias have a common mechanism. Dr. Carolyn Lam: Wow, thanks again, Greg. That was really, really a nice explanation. Well, for this next original paper, it looks at the question of the association between major bleeding and non-major clinically relevant bleeding, with subsequent mortality in hospitalized patients, and authors did this by exploring this relationship in the MAGELLAN and MARINER trials of extended thrombo-prophylaxis in hospitalized medical patients. Dr. Greg Hundley: Wow. Carolyn. I can't quite remember, and maybe for our listeners, remind us of the design of the MAGELLAN and the MARINER trials. Dr. Carolyn Lam: These trials evaluated, whether rivaroxaban compared with enoxaparin or placebo, could prevent venous thromboembolism without increased bleeding. The authors, led by Dr. Spyropoulos from the Feinstein Institute of Medical Research in New York, hypothesized that patients with major bleeding, but not those with non-major clinically relevant bleeding, would be at an increased risk of all-cause mortality. So Greg, would you like to guess what they found? Dr. Greg Hundley: Oh, Carolyn, you've put me on the spot here. I'm not sure. Dr. Carolyn Lam: Maybe just, did the authors get it right or wrong? Just.... Dr. Greg Hundley: I'm saying, they got it right. Dr. Carolyn Lam: Oh, always clever. They found that compared to patients with no bleeding, the risk of all-cause mortality for patient with non-major clinically relevant bleeding was not increased in MARINER, but was increased in MAGELLAN. Major bleeding, however, was associated with a higher incidence of all-cause mortality in both studies, while trivial bleeding was not associated with mortality in either study. These results really inform the risk benefit calculus of extended thromboprophylaxis in medically ill patients. Dr. Greg Hundley: Wow. Carolyn, great presentation. We've got some other articles in this issue. And let me tell you about two that I have. First is a Research Letter from Professor Frankel entitled "Trends in Opioid Use after Cardiac-Implantable Electronic Device Procedures in the United States, between the years of 2004 and 2020." And Tracy Hampton, from the National Association of Science Writers, presents some very recent news in the world of cardiology. Dr. Carolyn Lam: Nice. Well, there's an exchange of letters as well between Drs. Yang and Nagareddy regarding the article "Retention of NLP3 Inflammasome-Primed Neutrophils in the Bone Marrow is Essential for Myocardial Infarction-Induced Granulopoiesis." And finally, in the Editor's Page, a nice piece from Drs. Joe Hill, Darren McGuire, and James de Lemos on “Circulation: Best Papers, 2021.” Gosh, really, really nice issue. Now let's go on, though, to the feature discussion, yeah? Dr. Greg Hundley: You bet. Dr. Mercedes Carnethon: Welcome to this episode of Circulation on the Run podcast. My name is Mercedes Carnethon, one of the associate editors, and I'm a professor of preventive medicine at the Northwestern University Feinberg school of Medicine. I'm really excited today to have a guest with us. Dr. Brendon Neuen, who has shared with us his really outstanding research on SGLT2 inhibitors and the risk of hyperkalemia in people with type-two diabetes, a meta-analysis. So welcome to our podcast today, Brendon. Dr. Brendon Neuen: Thanks very much for having me Mercedes. It's a real pleasure to be here. Dr. Mercedes Carnethon: Well, thank you for joining us. We're really pleased that you chose Circulation to share with us your really important findings. Can you tell us a little bit about the rationale for your study and how you carried out your work? Dr. Brendon Neuen: Yeah, absolutely. So we know that in people with diabetes and people with CKD, hyperkalemia is a common occurrence, and it's a problem for two reasons as you'd be aware. Firstly, it is associated with cardiac dysrhythmias and secondly, perhaps at least as importantly, it limits the optimal use of treatments that reduce kidney disease progression and heart failure events. So that is, agents that block the renin angiotensin aldosterone system. Dr. Brendon Neuen: We now know, and we've got robust evidence from large outcome trials, that SGLT2 inhibitors reduce the risk of heart failure and kidney disease progression in people with and without diabetes, but we haven't really, up and until now, systematically evaluated their effect on potassium outcomes, particularly hyperkalemia. And so we set out to assess whether these agents affect serum potassium levels and alter the risk of hyperkalemia as well as hypokalemia. Dr. Mercedes Carnethon: Thank you. That sounds like a really excellent and well needed study, given how much we've heard within the field about the benefits of SGLT2 inhibitors. It's nice to see a careful evaluation of what some of the considerations are in their use. So tell us a little bit about how you carried out this study and what you ultimately found. Dr. Brendon Neuen: What we did was, we identified clinical trials that enrolled people with type two diabetes at high cardiovascular risk or with chronic kidney disease. And what we did is, we approached the investigators of each of these trials and asked them to collaborate on a large meta-analysis using individual participant data. Dr. Brendon Neuen: What that allowed us to do was, then, standardize across all of the trials of different outcome definitions, and allowed us to assess the effective SGLT2 inhibitors on a primary outcome of time to first serum potassium greater than or equal to six, defined as serious hyperkalemia, as well as hypokalemia, investigator-reported hyperkalemia events, and a range of other potassium-related outcomes in a broad population, including people with chronic kidney disease, people with heart failure, and people using different concomitant medications, such as diuretics and MRAs in the background. Dr. Mercedes Carnethon: So thank you, Brendon, for the explanation of the use of the meta-analytic design and the entry criteria of type-two diabetes and chronic kidney disease. Can you tell us, what were the outcomes across these studies? Dr. Brendon Neuen: The primary outcome we evaluated was time to first serious hyperkalemia, defined as a serum potassium greater than or equal to six, as well as a range of other potassium-related outcomes, including investigator reported hyperkalemia, change in potassium over time, as well as hypokalemia, defined as a serum potassium less than 3.5. Dr. Brendon Neuen: What we found was that overall SGLT2 inhibitors reduce the risk of serious hyperkalemia by about 16%. And that effect was consistent across the agents within the class, and across different subpopulations and trials. This effect was supported by a 20% risk reduction in investigator-reported hyperemia events and importantly, there was no difference in risk of hypokalemia, that is a serum potassium less than 3.5, between SGLT2-treated and placebo-treated participants. Dr. Mercedes Carnethon: Thank you for that summary. You know, one of the very impressive aspects of this clinical trial is certainly the size and the number of participants. Brendon, I was really struck by your description of the consistency of findings across the subgroups. And in particular, when I reviewed the findings in the paper, I noticed that serious hyperkalemia was higher in those with poorer kidney function. Did you find that surprising? Dr. Brendon Neuen: From clinical practice, we know that one of the major determinants of hyperkalemia risk is kidney function. It's a major problem that we run into in people with more advanced CKD. And what that means is that for people with more advanced chronic kidney disease, who are at high risk of hyperkalemia, the absolute benefits of SGLT2 inhibition on hyperkalemia risk are likely greater in these individuals, because they're at high risk of this outcome. Dr. Brendon Neuen: Other patients who might be at increased risk of hyperkalemia include those with heart failure or those taking mineralocorticoid receptor antagonists at baseline. And so you'd expect that if the relative effects are consistent across many subgroups, then the absolute risk reductions are likely to be larger in people taking MRAs or people with more advanced CKD. Dr. Mercedes Carnethon: Thank you so much for summarizing the importance of these findings and what they mean for our clinical audience. It's wonderful to have this sort of information from a meta-analysis because it allows us large sample sizes, where we can do things like you describe, such as describing subgroup effects. Dr. Mercedes Carnethon: It also presents us with very robust evidence that can be taken into clinical practice for our clinical audience to use. Based on what you found, how do you anticipate that these findings can be used by our clinicians? Dr. Brendon Neuen: Well, thanks, Mercedes. I think the reduction in risk of hyperkalemia that is observed in these data suggests that SGLT2 inhibitors might enable better use of other proven therapies that reduce cardio-renal risk in people with chronic kidney disease and people with heart failure. We all know that in treating these high risk patients, hyperkalemia is a problem. And by reducing the risk of hyperkalemia with SGLT2 inhibitors, it might enable better use of renin angiotensin system blockade and mineralocorticoid receptor antagonists in people with chronic kidney disease and heart failure. Dr. Mercedes Carnethon: So you've provided a really excellent overall summary of the impact of these finding for clinical practice and the possible next steps. I wanted to end on a note of asking you what surprised you about these findings that might lead to further future investigations. Dr. Brendon Neuen: Thanks, Mercedes. I think that's a really interesting question. What was somewhat surprising, but also reassuring, was the consistency of the treatment effect on hyperkalemia, regardless of how we defined it, whether that was defined based on investigator-reported hyperkalemia events or central laboratory-measured serum, potassium levels, the treatment effect was very consistent. And I think that gives us some confidence about the robustness of these findings and their application to clinical practice. Dr. Mercedes Carnethon: Well, thank you so much, Brendon. I have really enjoyed this discussion with you today and this really important paper that is describing an important safety outcome for SGLT2 inhibitors in patients with type two diabetes. And again, I really want to thank you for sharing your excellent work with us here at Circulation. I anticipate that our readership, when they leave this podcast and pick up their journals, will be thrilled to read about all of the details about the excellent work that you and your team have carried out. So thank you very much for joining us today. Dr. Brendon Neuen: Thanks very much for having me, Mercedes. It was a real pleasure. Dr. Mercedes Carnethon: Thank you, and thank you again to our audience for joining us for this episode of Circulation on the Run. Speaker 5: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

The entire Fatty Liver community benefits from NASH Patient Advocacy and the work of our advocates, but relatively few of us understand what advocates do or how we benefit from their work. Leading German patient advocate Achim Kautz and Global Liver Institute Vice President of Policy and Public Affairs Andrew Scott discuss how they came to Fatty Liver patient advocacy, their priorities and activities that support our community, and the unique challenges of their fascinating work.This conversation starts with some polite disagreement about whether there is an actual community. At the end of Conversation 23.3, Achim suggested that there is no clear community because of the lack of Fatty Liver focus in specialties and patient groups addressing other metabolic diseases like diabetes, obesity and heart disease. Andrew Scott discusses the work of the Global Liver Institute NASH Council, which focuses on bringing these exact communities into the discussion, at least within the US. The rest of the conversation focuses on using an understanding of metabolic parameters to know which patients should see primary care vs. hepatologists vs. other specialists. It ends with Roger Green asking whether and how politicians, who want solutions that happen quickly and have hard metrics, can get behind this broad an effort.

On this week's show: Full Operational Update. We cover everything in AZ, NM, Colorado, and Texas. National Emergency Declared for New Mexico. President Biden declares Federal funds to New Mexico. What does this include. Forest Service Chief Testifies. Lots of questions answered, many left alone. Huge Study on Firefighter Heart Issues. American Heart Association finished a study on abnormal heart rhythms in firefighters. Colorado Sees Record Year Coming. $20 Million extra funding given to combat this. Plus More. Subscribe monthly to our Substack to support this content and support firefighter donations.

This week, please join author Guest Host Mercedes Carnethon, Author Brian Bergmark, and Associate Editor Parag Joshi as they discuss the article “Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.” 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, non-high density lipoprotein cholesterol levels in statin treated patients with elevated cholesterol. We're going to hear from the TRANSLATE-TIMI 70 study. But before we get to that, how about we grab a cup of coffee and discuss some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: I would. And by the way, that feature is going to be all exciting. It was discussed at the American College of Cardiology. But okay, how about from cholesterol to vitamins? Let's start with the Greg quiz. Greg, which vitamins have been associated with arterial calcification? Is it A, B, C, D, E? Dr. Greg Hundley: I'm going to pick E and K. Dr. Carolyn Lam: You're smart. Indeed. Vitamin K2, also known as menaquinone-7 is the most effective co-factor for the carboxylation of proteins involved in the inhibition of arterial calcification. Furthermore, combined low vitamin K and low vitamin D have been associated with increased all-cause mortality risk. And so, today's paper is from Dr. Diederichsen from Odense University Hospital in Denmark and colleagues really present the first double-blind, randomized controlled trial to test whether vitamin K2, a drug-targeting processes of calcification in addition to vitamin D, could slow the progression of aortic valve calcification and stenosis. So, in a randomized double-blind multicenter trial, men from the community with an aortic valve calcium score above 300 arbitrary units on cardiac non-contrast CT were randomized to daily treatment with 720 micrograms of vitamin K2 plus 25 micrograms of vitamin D or matching placebo for 24 months. And the primary outcome was the change in aortic valve calcium score. Dr. Greg Hundley: Carolyn, so menaquinone-7 and aortic valve score. So, what were the results? Dr. Carolyn Lam: Menaquinone-7 had no major effect on the progression of aortic valve calcification as assessed by CT or echo. High-dose menaquinone-7 was, however, safe and well tolerated. Now, some limitations is that this external validity is limited to men aged 65 to 74 with aortic valve calcification scores of greater or equals to 300 arbitrary units. Thus, caution is needed if we extrapolate these findings and other pathways need to be explored in order to identify an effective therapy for this unmet clinical need. Dr. Greg Hundley: Wow, very nice Carolyn. Well, my first article comes to us from Dr. Michael Laflamme from the University Health Network. And Carolyn, human pluripotent stem cell-derived cardiomyocytes or hPSC-CMs exhibit promise for application in cardiac regeneration, but their translational potential is limited by an immature phenotype. So Carolyn, this research team hypothesized that large scale manufacturing of mature hPSC-CMs could be achieved via culture on polydimethylsiloxane, and we're going to call that PDMS, lined roller bottles and that the transplantation of these cells would mediate better structural and functional outcomes then with conventional immature hPSC-CMs populations. Dr. Carolyn Lam: Oh, that's neat, Greg. So, what did they find? Dr. Greg Hundley: Right, Carolyn. So, these authors demonstrated the economic generation of greater than one times 10 to the eighth mature hPSC-CMs per PDMS line roller bottle. And compared to their counterparts, PDMS matured hPSC-CMs exhibited increased cardiac gene expression and more mature structural and functional properties in vitro. More importantly, intracardiac graphs formed with PDMS matured myocytes showed greatly enhanced structured alignment, better host graft electromechanical integration, less pro arrhythmic behavior, and greater beneficial effects on contractile function. So in summary, Carolyn, this team describes practical methods for the scale generation of mature human pluripotent stem cell-derived cardiomyocytes and provide the first evidence that the transplantation of more mature cardiomyocytes yields better outcomes in vivo. And there's a wonderful editorial by Professor Murray entitled Flexing Their Muscles: Maturation of Stems Cell-Derived Cardiomyocytes on Elastomeric Substrates to Enhance Cardiac Repair. Dr. Carolyn Lam: Wow! That's really significant. Thank you, Greg. Well, the next paper is the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals. And this is from Dr. Xia Chen from Fudan University and Dr. James Wilson from University of Edinburgh in UK, and their colleagues. And guess what, it focuses on severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID 19. And we know that that enters human cells using the ACE2 protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems. Dr. Greg Hundley: Wow, Carolyn. ACE2, and also a very important topic here with SARS-COVID-2. So, what did they find? Dr. Carolyn Lam: First, the overall heritability of ACE2 level is 16% of which 30% can be explained by 10 protein quantitative trait loci identified in this study. ACE2 level is genetically correlated with both COVID-19 and cardiovascular. Elevated ACE2 levels show a causal relationship with COVID-19 severity, hospitalization and infection as shown by Mendelian randomization analyses. ACE2 regulatory variants are enriched on DNA methylation sites in immune cells. Dr. Greg Hundley: Wow, Carolyn. So, elevated ACE2 and a causal relationship with COVID-19 severity. So tell us, what are the clinical applications of this really nice study? Dr. Carolyn Lam: The causal evidence of ACE2 suggests that pharmacological inhibition of circulating ACE2 may be a promising approach for treating COVID-19 or its comorbidities. Transcription factors that play essential roles in ACE2 generation could provide alternative paths to pharmacological modulation of ACE2 plasma levels. The genetic correlations between ACE2 and both COVID-19 and cardiovascular disease imply that the cardiovascular complications seen in COVID-19 patients may be intrinsic to the disease and mechanically or/and mechanistically-driven by ACE2. Isn't that neat? Dr. Greg Hundley: You bet, Carolyn. Boy, what an exciting issue. And we've got other articles in this issue. Dr. Carolyn Lam: Yeah. Now, let me start this time. There's an exchange of letters between Drs. Duan and Chang regarding the article “Therapeutic Exon Skipping Through a CRISPR-Guided Cytidine Deaminase Rescues Dystrophic Cardiomyopathy in Vivo.” There's a Perspective piece by Dr. Morris, “The Updated Heart Failure Guidelines: Time for a Refresh.” Love that piece! There's an AHA Update piece (AHA President's Page) by Dr. Elkin on The Road to Equity in Brain Health, and ECG challenge by Dr. Kolominsky, Electrical Extremists in a Critically ill Patient, and an On My Mind Paper by Dr. Paulus entitled “Border Disputes Between Heart Failure Phenotypes.” Dr. Greg Hundley: Wow, Carolyn. And I've got two Research Letters. The first from Professor Groeneveld entitled “Prevalence of Short-Coupled Ventricular Fibrillation in a Large Cohort of Dutch Idiopathic Ventricular Fibrillation Patients.” And then a second Research Letter from Professor Yamashita entitled “Single Cell RNA Sequence Reveals a Distinct Immune Landscape of Myeloid Cells in Coronary Culprit Plaques Causing Acute Coronary Syndrome.” Well Carolyn, now, we get to go onto our feature, vupanorsen on non-high-density lipoprotein cholesterol levels and catching up with TIMI 70. Dr. Carolyn Lam: Let's go. Dr. Mercedes Carnethon: So, good morning listeners. I'm really pleased to invite you to this episode of our Circulation on the Run podcast. For those of you who don't hear me often, I'm stepping in as a guest host today. My name is Mercedes Carnahan from the Northwestern University Feinberg School of Medicine. And I'm really excited to be joined today by Dr. Brian Bergmark, and associate editor, Dr. Parag Joshi. And we will have today Dr. Bergmark discussing his new article published with us on the effects of vupanorsen on non-HDL cholesterol levels in the TRANSLATE-TIMI 70 trial. We're really thrilled to have you with us here today, Brian, to talk about the really important findings coming from this trial. So to start us off, just tell us, what did you find? Dr. Brian Bergmark: Great. Thank you so much. It's really a pleasure to be here and I'm grateful for the opportunity. So, in the big picture, despite numerous agents to reduce lipid-mediated cardiovascular risk, obviously, residual risk remains and there are novel targets to address that risk. One of them is angiopoietin-like 3, which is a protein made in the liver. Angiopoietin-like 3 or ANGPTL3 inhibits lipoprotein lipases among other lipases, and thereby interferes with metabolism of triglyceride-rich lipoproteins. And so, the idea here was that if ANGPTL3 could be inhibited that LPL or lipoprotein lipase function could be augmented and metabolism of these lipoproteins could be augmented. And so, what we did is we took patients with an elevated non-HDL cholesterol, at least 100 milligrams per deciliter, and elevated triglycerides, 150 to 500 milligrams per deciliter, and randomized them to placebo or one of seven doses of vupanorsen, which is an antisense oligonucleotide, which inhibits the synthesis of ANGPTL3 in the liver. We then follow them to see what the impact was on their non-HDL cholesterol, as well as other lipid parameters through 24 weeks. Dr. Mercedes Carnethon: Thank you so much. It's a wonderful design, and I'm really excited to hear a little bit more about what you found. Dr. Brian Bergmark: Great. So, the primary endpoint was the change in non-HDL cholesterol from baseline to 24 weeks. And we did find that all vupanorsen regimens reduced non-HDL cholesterol in a statistically significant manner. The magnitude of that effect was up to 27.7% in one of the dose arms or about 28%. We also saw a statistically significant reductions in the target ANGPTL3 up to about a 95% reduction in the highest dose arm, as well as statistically significant reductions in triglycerides at all of the dose regimens. The effect on LDL cholesterol and on apolipoprotein B or apo B was variable across regimens and only statistically significant in a few of the dose arms. We also found several safety signals. One, there appeared to be higher rates of injection site reactions in the skin at higher total monthly doses. We also found higher rates of elevation in liver enzymes, AST and ALT at higher total monthly doses. And we also found significant increases in hepatic fat fraction or the fat content of the liver at higher total monthly doses. Dr. Brian Bergmark: In the end, we found that while statistically significant, the magnitude of the reduction in non-HDL cholesterol was modest as was the reduction in apo B. And so, the goal here was to find a dose that might have a reduction of a magnitude that would be clinically meaningful for cardiovascular risk reduction. We were underwhelmed by the magnitude of that reduction, and then it was paired with these safety signals, which if there's interest, we could get into more detail in our thinking about why those occurred, what the implications are, but suffice it to say that there were medically meaningful safety concerns paired with a modest reduction in non-HDL cholesterol. Dr. Mercedes Carnethon: Thank you for that excellent summary. Before I turn it over to the associate editor, I read this with great interest, and in particular, looking at one of the first figures in the paper, which is demonstrating the adjusted change at 24 weeks across different doses and based on how frequently the doses were given the four week as compared with the two week. And one thing that really stood out to me was the clear dose response with the four week regimens with the higher doses appearing to demonstrate the greatest reductions but a less clear signal with the two week regimens. Do you have any hypotheses about why these patterns appeared so different? Dr. Brian Bergmark: Yeah. It's a great question. So, the responsiveness of this is something of interest here I think. So, if you look at the effect of the drug on its target, ANGPTL3, there is a very clear dose response, so there's no doubt that higher doses were impacting the target ANGPTL3 to a greater extent. So, one of the most direct effects would be on triglycerides, one of the most direct lipid effects, and that appears pretty close to a dose response relationship within each of these frequencies of administration. But once you start getting to non-HDL cholesterol, it starts to break down a bit. And is it simply because of random chance or is there actually something distinct going on with how the lipids are being metabolized? Dr. Brian Bergmark: That is something we are diving into. So, the hope would be that we actually reduce apo B, the number of these actually circulating lipoproteins as has been demonstrated with the monoclonal antibody. It's possible that with this other different mechanism in the antibody, this antisense oligonucleotide, perhaps, we're simply shifting the content of these lipoprotein molecules and decreasing the triglyceride content but not actually meaningfully modifying the amount of apo B, LDL cholesterol. And that might be part of what we're seeing with the more muted relationship between dose and the effect on non-HDL cholesterol. I don't know for certain we are diving into this a bit more with other lipid fractions, et cetera. Dr. Mercedes Carnethon: Oh, well, thank you so much for that explanation. I know that a number of people, this was extremely well received when shared at the recent American College of Cardiology meetings, and so I was really thrilled to find that this was appearing in the journal circulation. So Parag, I'm really interested in hearing your perspectives on why we knew that this was certainly a priority paper for us. Dr. Parag Joshi: Yeah. Let me first start, Brian, congratulations. Fantastic work. And we were excited to receive the paper. I think really hard to pull off trials right now or in the last couple years, so kudos to you. And I echo the sentiments from Mercedes. This is great work. Really important space, the residual risk space I think is very important of course and is critical to moving forward with improving cardiovascular health. So, one of the big picture questions and as we get to this triglyceride-rich lipoprotein lowering space, certainly, there's strong associations with residual risk, but can we impact that risk? And here, we're starting to explore that. And I think when you think of the lipoprotein space, many of us are interested in what is the effect on these lipoproteins as opposed to the cholesterol content or the triglyceride content. And non-HDL cholesterol or apo B, clearly, the better, stronger markers for that risk, so we were really excited to see this paper.   Dr. Parag Joshi: And as Brian mentioned, unfortunately, not the strongest impact here on those measures. And I want to dive into that a little more because I think that carries significant implications for the space, and I'd love to hear your thoughts on that. But overall, really fantastic work. I think my first question really is around the apo B aspect of this and the less than anticipated lowering of those levels. You hinted at this in terms of, is this shuffling cholesterol and triglycerides across particles, or do you think this could be the mechanism by which this happens through ANGPTL3? You do inhibit the levels quite a bit. Did we just miss that... Is this not the right target? What do you think? Dr. Brian Bergmark: Yeah, it's a great question. I do think the target itself holds great promise. Obviously, a monoclonal antibody against this same target results in major reductions in apo B, LDL cholesterol, and the latter through a mechanism that is not really known but is not dependent on the LDL receptor, and therefore has real clinical utility that's approved for people with familial homozygous hypercholesterolemia. Beyond that, of course, in genetic studies, there's a clear association with loss of function in the ANGPTL3 gene and lower levels of all of these lipids, lower rates of coronary artery disease, et cetera. Dr. Brian Bergmark: So, I think it's not that this pathway is not promising and actually already being taken advantage of, I think it's that this particular agent acting through this mechanism was not able to achieve a necessary efficacy with reasonable safety. Some genetic data suggests that there is not actually a dose response between a reduction or loss of function in ANGPTL3 and reduction in apo B or lower levels of apo B and non-HDL cholesterol, but it really requires your complete elimination of ANGPTL3 function, which is probably, likely achieved with the monoclonal antibody. And so, even though we had quite large reductions with the antisense oligonucleotide, perhaps, we just didn't cross that threshold that's needed to modify the lipid panel in the way that would've been clinically meaningful. Dr. Parag Joshi: Yeah. I think that's fantastic as you allude to with evolocumab and the impact that has on apo B levels. I didn't think of it as a threshold effect, but that makes a lot of sense as maybe that just getting to that tipping point is where the issue is here. In terms of the liver signal, what were your thoughts on that? And is that something that we should expect to see in ASOs or do you think it's specific to this compound? Dr. Brian Bergmark: Yeah, I don't know. That was unexpected. Right, there are two liver signals and it's unclear how related they are. One is the inflammation of the liver as indicated by the elevation in enzymes, and then the other is the fat accumulation. So with respect to the fact, if anything, genetic data suggests perhaps loss of function in ANGPTL3 might result in lower rates of hepatic steatosis. In animal models, the antisense oligonucleotide reduces liver fat, and so there's, there was promise going into this that this could actually be beneficial for non-alcoholic fatty liver disease. And additionally, there's not data to suggest that the monoclonal antibody increases liver fat. So, there's not a lot to support this as being an on-target effect that by inhibiting ANGPTL3, by that pathway, the liver fat was increased. So, I think a reasonable person might wonder whether this was an off-target effect of the drug. Dr. Brian Bergmark: By what mechanism that occurred, I don't know, what the implications would be for other related agents, I don't know. And then similarly, the liver enzyme elevations, is that related to this? I'm not exactly sure, but also unexpected and I think off-target. But that sort of intrinsic to this mechanism of hepatic targeting, is this something we need to be worried about for other agents in this class or not? I don't know. Obviously, we can't answer that from this single study. We are going to dive into it a bit more to try to overlay patients with hepatic fat accumulation, liver enzymes, et cetera. Of course, both of those happen more at higher doses. How much we can really parse this? I'm not sure yet. Dr. Parag Joshi: Yeah. That's really fascinating. I think the appeal of this paper to the circulation audience is that you have a really exciting novel target and pathway to explore here but somewhat divergent results from what's existing in this space. And I think that raises a lot of questions, really interesting questions going forward for this space. For the ANGPTL3 pathway, what do you see there coming down the line or what are your thoughts on that going forward for this target and ways to approach risk related to it? Dr. Brian Bergmark: Yeah. Great. Thank you. Yeah. No, so I agree. I think moving into this other end of the spectrum of triglyceride-rich lipoproteins, et cetera, I think this is where we're headed and this is why we do the trial. We weren't expecting these things that's why you do this experiment, and this is what we found. So now, where do we go from here? So there are, of course, other ways beyond the monoclonal antibody of targeting ANGPTL3 specifically. There's siRNA, there is gene therapy being investigated. So, I think all of them hold an great promise. And of course, we will need to see as those therapies move along what the actual trials show. And then there are, of course, other pathways that are of interest, APOC3, for instance. So, I think there's a lot more in this space that's coming down the line. Dr. Parag Joshi: Yeah, absolutely. I think it's a really exciting space, and we're really happy to get this paper as one piece of that whole puzzle. So, thank you. Dr. Mercedes Carnethon: Yes. And I echo that as well. And as a methodologist myself, I'm always really pleased to see such well-designed studies. I think this was sophisticated in many aspects in testing different dosing and different timing of the dosing. And also, I'm really impressed by your inclusion criteria, particularly when I noted that 44% of the participants were female, and that you reported those stratum-specific effects. I just had a final question as we wrap up. You acknowledge a nominally significant interaction by sex and I see, for example, that it appears that the magnitude is larger possibly in the relatively smaller subset of females as compared with males. Is this something to pay attention to or do you think this is just some type of an artifact related to greater variability because the group is smaller? Dr. Brian Bergmark: Yeah, it's a good question. So, this is the burning question. We had no a priority reason to suspect that biologically and we are not adjusting for multiple testing in the key value of 0.04. So just to put my money down, I would say, I would guess it's random chance. We found it. It's worthy of looking into a bit more. There were, of course, the important implications for other drugs, et cetera. So, I think it's worth diving into as we will, but are we likely to uncover some biological difference? I doubt it. I wouldn't guess. There are other subgroups where I think at least upfront, you might expect there could be a difference. So, there are thoughts about insulin's effect on LPL. Could diabetes status have an interaction with the drug? I think though not statistically significant, it's also something worth looking into that group and the subfractions of the lipid panel and all of that stuff. So, I think it's all worth looking into but cautiously with the constraints. Dr. Mercedes Carnethon: Well, thank you so much for that explanation. And I've really enjoyed this discussion with you today, Brian, and you, Parag. I've certainly learned a lot and I'm really excited to see this excellent work coming out in the journal circulation. So, thank you very much for your time this morning and thank you to our listeners. Wrapping up this episode of Circulation on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

The birth of a child is a blend of anxiety and joy, but it can also give rise to a feeling of malaise in mothers that often dissipates in a couple of weeks. A longer-lasting form of this condition is referred to as postpartum depression. Prompt treatment can help moms manage symptoms and bond with a baby, but what if you're a low-income mother in Kansas without access to counseling and health care? The consequences – hypertension, cardiovascular disease, overdose, suicide – can be extreme. The Kansas Legislature and Gov. Laura Kelly have taken a step to alleviate the suffering through legislation extending the state's Medicaid postpartum coverage from two months to 12. Salym Soderholm, a mother of two who experienced postpartum depression; Sapphire Garcia-Lies of the Wichita Birth Justice Society; and Kari Rinker of the American Heart Association join the Reflector Podcast to explain postpartum illness and the benefits of program changes for mothers, babies and families.

Donnetta Watson is known as The Launch Strategist.  She is a seasoned Entrepreneur, Business Professional, Community Activist, and Ex-Government Manager for the US Census Bureau as a Management and Supervisory Statistician overseeing three Medical Research Studies for CDC in 6 states.  She was responsible to guide the data collection efforts through over 200 field and supervisory staff while managing budgets of $1.5mil concurrently.  Donnetta was known for getting results, often placing within the top three in the nation in data quality, production, and budget.  Donnetta has over 38 years of Entrepreneurial experience.  She has a Doctorate in Entrepreneurial Studies, M.S. in Quality Systems Management, is a graduate of Joseph Business School, and a former Administrator, and Adjunct Professor for 13yrs.  She has a B.S. in Human Resource Mgmt and a Minor in Marketing. Donnetta is a top 10 National Finalist in Entrepreneurship and a Top 3 State Finalist in Business.  Former Executive Director of Chapter Development for BlackCEO and former President of the KC Chapter, and Former President of Delta Epsilon Chi.  She completed the 26-1/2 mile Marathon Walk for American Heart Association.  Today, Donnetta can be found guiding The National Black MasterMind Group, The Bridge Builder Coach, and The Business Mastery Institute which she founded in 2015.  The Black MasterMind Group is a 501c(3) educational, coaching, development, and funding initiative which offers The Business Mastery 8-wk BootCamp and The Business Mastery 4-month Train the Trainer, and The Business Mastery Program– a 12 month accelerated intensive business program.  She calls it “The Real Road to Success”.Learn more at https://theblackmastermindgroup.comFree business credit masterclass https://bizcredithelper.comThe Cortez Hustle Show Book Of The Month is "Expert Secrets" by Russell Brunson Get Your Free Copy Here!Text the keyword "Mastermind" to 314-866-4053 to join our private group and get hundreds of dollars in free training & resources weekly. This mastermind is 100% FREE.Support Our Show Partner Bob CraneClick here for FREE Financial Resources: https://bit.ly/tchsbobOpen Arms Wellness - For all of your mental health needs. Take a quick survey to get matched up with the right counselor today: https://bit.ly/h2htherapistmatchOther helpful resources:Dominate Social Media And Build An Attractive, Powerful Profitable, Personal Brand https://personalbranding365.comDesign stunning graphics for your brand try Canva Pro here https://bit.ly/tomcanvaUse Content Study to schedule your social media post to be omnipresent on all platforms: https://tomcontentstudio+++3 TOOLS EVERY ENTREPRENEUR NEEDS TO GROW +++1. Digital Marketing Platform - Create your own websites, sales funnels, digital products, online communities, and more with the Digital Empire System. It's the Premier All-In-One Digital Marketing Platform. Start your 14 Day FREE trial of Go HighLevel by Clicking Here!2. 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Click Here==ABOUT THE CORTEZ HUSTLE SHOW==iTunes: Click HereStitcher: Click HereSpotify: Click HereGoogle Podcast: Click HereAmazon Music: Click Here====================================================Email: hcortez@ThorntonOnlineMarketing.comWebsite https://thorntononlinemarketing.comhttps://www.facebook.com/thorntononlinemarketingllchttp://instagram.com/thorntononlinemarketinghttp://twitter.com/finhealthmentorDISCLAIMER: H Cortez aka Financial Health Mentor is NOT afinancial advisor/planner or CPA. The information shared on this channel is not financial advice but instead examples of actual experiences of H Cortez and the guests of the channel. Also, any mention/reference to income is NOT a guarantee but merely an example of potential income that could be made if one puts in the work required. Always see a certified professional assist you in your financial matters. Finally, the links recommended in most cases pay me a small commission if you were to click through and buy. 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Every now and then, Dr. Martin brings you a knock your socks off moment, and this is one of them. The American Heart Association is now linking non-alcoholic fatty liver to heart disease! Dr. Martin says this is maybe the first time he's seen the connection, at least in mainstream medicine. In the 70's there was cirrhosis of the liver, but never non-alcoholic fatty liver. The study goes on to say that 1 in 4 people, including children, in North America have a fatty liver. Join Dr. Martin in today's episode to understand why the linking of fatty liver and heart disease is so significant!  

Commentary by Dr. Valentin Fuster

This week, please join author Vasan Ramachandran and Associate Editor Mercedes Carnethon as they discuss the article "Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I'm so excited about today's feature paper. You see, I trained at the Framingham Heart Study and today's feature paper talks about the temporal trends in the remaining lifetime risk of cardiovascular disease among middle aged adults across six decades in the Framingham Heart Study. Truly a landmark study and a discussion nobody wants to miss. But first, let's talk about the other papers in today's issue, and I understand that you've got one ready. Dr. Greg Hundley: You bet Carolyn. I'll get started first. Thank you. So my first paper comes from Dr. Daniel Mark from Duke University and it refers to the ISCHEMIA trial. Dr. Carolyn Lam: Ooh, could you please first remind us what is the ISCHEMIA trial and are you presenting a substudy, is that correct? Dr. Greg Hundley: Right, Carolyn. So the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, or ISCHEMIA, compared an initial invasive strategy with an initial conservative strategy in 5,179 participants with chronic coronary disease and moderate or severe ischemia. And this sub study of the ischemia research program included a comprehensive quality of life analysis. Dr. Carolyn Lam: So very interesting. What did they find Greg? Dr. Greg Hundley: Right, Carolyn. So this study included 1,819 participants. 907 in the invasive, 912 in the conservative. And collected a battery of disease specific and generic quality of life instruments by structured interviews at baseline. And then at three, 12, 24 and 36 months post randomization, and then finally at study closeout. Now Carolyn, these assessments included an angina related quality of life assessment from the 19 item Seattle Angina Questionnaire, a generic health status assessment, an assessment of depressive symptoms, and for North American patients, cardiac functional status from the Duke Activity Status Index, or DASI. In this study, Carolyn, in terms of results, the median age was 67 years and about 20% were women and about 16% were nonwhite. So Carolyn, getting to the results. The estimated mean difference for the SAQ 19 summary score favored invasive therapy. And remember the SAQ 19 was the Seattle Angina Questionnaire. Dr. Greg Hundley: Next, no differences were observed in patients with rare or absent baseline angina. Next, among patients with more frequent angina baseline, those randomized to invasive had a mean point higher score on the SAQ 19 summary score than the conservative approach, with consistent effects across all of the SAQ subscales including physical limitations, angina frequency and quality of life health perceptions. For the DASI, and remember DASI refers to the Duke Activity Status Index, no difference was estimated overall by treatment. But in patients with baseline marked angina, DASI scores were higher for the interventional arm. Whereas patients with rare or absent baseline angina showed really no treatment related differences. Dr. Carolyn Lam: Oh, okay. So a lot of results. What's the take-home message, Greg? Dr. Greg Hundley: Right, Carolyn. Glad you asked. So in the ISCHEMIA comprehensive quality of life substudy, patients with more frequent baseline angina reported greater improvements in the symptom physical functioning and psychological wellbeing dimensions of quality of life when treated with an invasive strategy. Whereas patients who had rare or absent angina baseline reported no consistent treatment related quality of life differences. Dr. Carolyn Lam: Wow. Thank you, Greg. Very interesting indeed. Now from angina to now cholesterol. Now, cholesterol guidelines typically prioritize primary prevention statin therapy based on 10 year risk of cardiovascular disease. Now the advent of generic pricing may in fact justify expansion of statin eligibility. Moreover, 10 year risk may not be the optimal approach for statin prioritization. So these issues were looked at in this next paper by authors led by Dr. Kohli Lynch from Northwestern University and colleagues who estimated the cost effectiveness of expanding preventive statin eligibility, and evaluated novel approaches to prioritization from a Scottish health sector perspective. A computer simulation model predicted long term health and cost outcomes in Scottish adults, age 40 years or more. Dr. Greg Hundley: So Carolyn, what did they find? Dr. Carolyn Lam: The advent of generic pricing has rendered preventive statin therapy cost effective for many adults. Absolute risk reduction guided statin therapy, which is based on 10 year cardiovascular disease risk and non HDL cholesterol levels, is cost effective and would improve population health. Whereas age stratified risk thresholds were more expensive and less effective than alternative approaches to statin prioritization. So guidelines committees may need to expand statin eligibility and consider new ways to allocate statins based on absolute risk reduction rather than 10 year risk thresholds. Dr. Greg Hundley: Very nice Carolyn. Always important, new information regarding statin therapy. Well Carolyn, my next paper comes to us from the world of preclinical science. And Carolyn, as you know, the regenerative capacity of the heart after myocardial infarction is limited. And these authors led by Dr. Tamer Mohamed from University of Louisville previously showed that ectopic introduction of Cdk1, CyclinB1 and Cdk4, CyclinD1 complexes and we'll refer to those now as 4F, promoted cardiomyocyte proliferation in 15 to 20% of infected cardiomyocytes in vitro and in vivo and improved cardiac function after MI in mice. So Carolyn, in this study using temporal single cell RNA sequencing, the investigative team aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis. And also using rat and pig models of ischemic heart failure, they aim to start the first preclinical testing to introduce 4F gene therapy as a candidate for the treatment of ischemia induced heart failure. Dr. Carolyn Lam: Oh, wow Greg. So what did they find? Dr. Greg Hundley: Several things, Carolyn. First, temporal bulk and single cell RNA sequencing and further biochemical validations of mature HIPS cardiomyocytes treated with either LAcZ or 4F adenoviruses revealed full cell cycle reprogramming in 15% of the cardiomyocyte population at 48 hours post-infection with 4F. Which was mainly associated with sarcomere disassembly and metabolic reprogramming. Second Carolyn, transient overexpression of 4F specifically in cardiomyocytes was achieved using a polycistronic non-integrating lentivirus encoding the 4F with each driven by a TNNT2 promoter entitled TNNT2-4F polycistronic-NIL. Now this TNNT2-4F polycistronic-NIL or control virus was injected intra myocardial one week after MI in rats, so 10 per group, and pigs, six to seven per group. Dr. Greg Hundley: And four weeks post-injection the TNNT2-4F polycistronic-NIL treated animals showed significant improvement in left ventricular injection fraction and scar size compared with the control virus treated animals. And four months after treatment, the rats that received TNNT2-4F polycistronic-NIL still showed a sustained improvement in cardiac function without obvious development of cardiac arrhythmias or systemic tumorigenesis. And so Carolyn this study advances concepts related to myocellular regeneration by providing mechanistic insights into the process of forced cardiomyocyte proliferation and advances the clinical feasibility of this approach by minimizing the oncogenic potential of the cell factors, thanks to the use of a novel transient and cardiomyocyte specific viral construct. Dr. Carolyn Lam: Wow. What a rich study. Thanks so much, Greg. Dr. Greg Hundley: Well, Carolyn, how about if we see what else and what other articles are in this issue. And maybe I'll go first. So there's a research letter from Dr. Wu entitled Modeling Effects of Immunosuppressive Drugs on Human Hearts Using IPSC Derived Cardiac Organoids and Single Cell RNA Sequencing. Carolyn, there's an EKG challenge from Dr. Yarmohammadi, entitled “Fast and Furious, A Case of Group Beating in Cardiomyopathy.” And then finally from Dr. Tulloch, a really nice Perspective entitled “The Social Robots are Coming, Preparing For a New Wave of Virtual Care in Cardiovascular Medicine. Dr. Carolyn Lam: Oh, how interesting. Well, also in the mail back is an exchange of letters of among Drs. Lakkireddy, Dhruva, Natale, and Price regarding Amplatzer Amulet Left Atrial Appendage Occluder versus Watchman Device for stroke prophylaxis, a randomized control trial. All right. Thank you so much, Greg. Shall we go on to our feature discussion now? Dr. Greg Hundley: You bey. Welcome listeners to our feature discussion today. And we're so fortunate we have with us today, Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. Welcome to you both. And Vasan, let's 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. Vasan Ramachandran: Thank you, Greg, first of all for having me. So we know two facts. One is that heart disease and stroke disease death rates and incidents are declining over the last six decades in the United States. Juxtapose against that is also the observation that there is rising incidence of obesity and overweight, and also a rising burden of diabetes. There are a lot of advances in our ability to treat high blood pressure, high cholesterol, as well as high blood sugar. So we wanted to ask the question, given the historic trends in control awareness of risk factors and their control, interrupted by this escalating burden of obesity, overweight, and diabetes, what is the lived experiences of people over time in terms of the risk of developing heart disease or stroke using a metric we call as the remaining lifetime risk of developing heart disease or stroke. Dr. Greg Hundley: The hypothesis you wanted to address? Dr. Vasan Ramachandran: The hypothesis we wanted to address was that perhaps the decline in the incidence of heart disease and stroke may have decreased over time given the escalating burden of overweight, obesity and diabetes. Dr. Greg Hundley: Very nice. And can you describe for us your study population and your study design? Dr. Vasan Ramachandran: Thank you, Greg. So the Framingham Heart Study is one of the oldest running epidemiological studies in the world. We have multiple cohorts. The study began in 1948 with the original cohort, the offspring cohort enrolled in 1971, third generation cohort in 2002, and two minoritized cohorts in the 1990s and 2002. So we have an observation period of different cohorts over a six decade period. So we asked the question, if you were a participant in the Framingham study between 1960 and 1979 and then 1980 to 1999, and then 2000 to 2018, what was your lifetime risk of experiencing a heart disease or stroke in the three different time periods? Is it going down, is it steady or is it going up? Dr. Greg Hundley: Very nice. And so, Vasan, describe your study results. Dr. Vasan Ramachandran: Look, what we found was if you look at the first, the 20 year period from 1960 to 1979, and compare that with the latest, which is 2000 to 2018, in the initial time period, the lifetime risk of developing heart disease or stroke in a man was pretty high. It was about one in two. And that for a woman was about one in three. So when you come to the latest epoch, what we find that the risk of one in two men had dropped to about one in three men in the latest decade. For women, the risk declined from what was one in three in the earlier epoch to one in four. So approximately there was about a 36% reduction in the lifetime probability of developing heart disease or stroke across the six decade period of observation. Dr. Greg Hundley: Very nice. And so help us a little bit, put the context of your results into what that might mean for us today as we are managing patients with atherosclerotic disease. Dr. Vasan Ramachandran: Yes, Greg. What it means is that the permeation of the advances in science in terms of the screening of risk factors, awareness of risk factors, medications to lower these risk factors effectively, the clinical trials that have given us these new medications, they may have translated into a reduction in risk over time. That the lived experience of people in the later decades is better in terms of having a lower risk of heart disease or stroke as the consequence of multiple advances that have happened in heart disease and stroke. Dr. Greg Hundley: Well, thank you so much Vasan. Well listeners, now we're going to turn to our Associate Editor, Mercy Carnethon. And Mercy, you have many papers come across your desk. What attracted you to this particular paper and how do you put these results really in the context of other science pertaining to risk associated with populations that may have atherosclerotic cardiovascular disease? Dr. Mercedes Carnethon: Thanks so much for that question, Greg. And again, Vasan, I really thank you and your team for bringing forth such outstanding research. You know, as cardiovascular disease epidemiologists, we were all raised and taught that what we know about risk factors for cardiovascular disease are based on the Framingham cohort. And so I was really excited to see this very comprehensive piece of work that characterized what the Framingham study has identified and also leverages the unique characteristics of a study that started in 1948. Dr. Mercedes Carnethon: So, you know, we're almost 75 years in and actually has the ability that cross sectional studies don't have to look over longer periods of time at risk. And you know, when we think about papers that excite us, that we really want to feature in circulation, they are papers that teach us something new. And I will say there were aspects of this work that confirmed what I had heard but had not seen using empirical data. Namely that the remaining lifetime risks for developing cardiovascular disease were going down over time, and they were going down secondary to better management and recognition of the risk factors that the Framingham cohort study had really been instrumental in identifying in the first place. Dr. Mercedes Carnethon: There were surprising elements of the paper. The surprising elements being that I think as you brought up earlier, we were concerned that risk factors that were on the rise, such as obesity, were threatening these increases in life expectancy. And it was really nice to see that the findings held, even in the face of rising risk factors. And just to summarize, what I really like about this piece when we situate it within circulation, where we are addressing clinical treatment factors, where we're also featuring clinical trials and even other epidemiologic studies, is that your work identifies for us the overall context in which the clinicians who read the journal are thinking about managing patients and where we're going. It highlights our successes, but it also really brings up what we need to do next. And I look forward to hearing from you about where you think this may be headed. Dr. Greg Hundley: Well, Mercy, you're teeing us up for that next question. Vasan, what do you think is the next study or studies that need to be performed in this space? Dr. Vasan Ramachandran: Thank you, Greg and Mercy, for your kind comments. Like I shared, this is a success story for a predominantly white population in the Northeast. We are very much aware about the heterogeneity and the geographic variation in heart disease burden in our country. So one of the success stories interpretation might be this represents the upper bound. What can happen to a population that is compliant with screening of risk factors, awareness of risk factors, treatment and healthcare access. I think the next set of studies should broaden the study population to bring in additional populations that are more diverse, that are also followed up over a period of time to assess and put the current observations in the appropriate context. Do we see similar findings longitudinally in other cohorts with non-white participants? Is it different, is their lived experience different? If so, why? And that could inform us how we can reach the success story and replicate it across the entirety of our country. Dr. Greg Hundley: And Mercy, do you have anything to add? Dr. Mercedes Carnethon: I do. You know, I really like that focus on broadening to whom these results are applicable. We've undergone a lot of shifts within our country and also around the world. You know, circulation, we have a worldwide readership. I would love to see this sort of work replicated across different countries to the extent that we have the data to do so, recognizing that limitation. But I'd love to see work focus on comparing how these things change in low income countries, middle income and high income countries, so that we can really think about resource allocation and find strategies to try to replicate the successes that we are seeing based on the data from the Framingham heart and offspring studies. Dr. Greg Hundley: Excellent. Well listeners, we really appreciate the opportunity to get together today with Dr. Vasan Ramachandran from Boston University and our own Associate Editor, Dr. Mercedes Carnethon from Northwestern University in Chicago. And really appreciate them for bringing us these epidemiologic data from the Framingham cohort, indicating that over the past decades, mean life expectancy increased and the remaining lifetime risk of atherosclerotic cardiovascular disease decreased across individuals in the cohort, even after accounting for increasing incidences of other cardiovascular risk factors like obesity and smoking. Well on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Dr. Aruni Bhatnagar is the Smith and Lucille Gibson Professor of Medicine, Director of the Christina Lee Brown Envirome Institute, Co-Director of the American Heart Association Tobacco Regulation and Addiction Center, and a Distinguished University Scholar at the University of Louisville. Much of Aruni's work has focused on understanding how the heart and blood vessels work and how they become diseased. He developed a new field called environmental cardiology where he examines how exposure and environmental conditions may impact heart function and heart health. When he's not at work, Aruni enjoys exploring his creativity through art, reading, and writing. He has spent a lot of time painting, and lately, he has been writing songs and poems. He was awarded his PhD in Chemistry from the University of Kanpur in India and he conducted postdoctoral research at the University of Texas Medical Branch at Galveston before joining the faculty at the University of Louisville in 1998. Aruni has received numerous awards and honors over the course of his career, including being named a Fellow of the American Heart Association in 2005. He also received the President's Award for Outstanding Scholarship, Research and Creative Activity from the University of Louisville, the Partner in Healthcare Award, the Outstanding Faculty Mentor of Graduate Students and the Outstanding Mentor Award from the Conference of Southern Graduate Schools, and he was designated Research Exemplar by Washington University in St. Louis. In our interview, Aruni shares more about his life and his science.

This conversation includes part of a more extended discussion that Donna Cryer had with Louise Campbell and Roger Green when she stopped by the virtual SurfingNASH.com studios to discuss her recent work.Donna starts her conversation by saying that she is bringing three pieces of news with her. The first: with support from Novo Nordisk, the National Committee for Quality Assurance has released a white paper titled, "A Rallying Cry: Improving Coordinated Care for People with Nonalcoholic Steatohepatitis." The second: the American Heart Association has released a paper discussing the link between NASH and heart disease. The third is the initiation of GLI's "Liver Health is Public Health" campaign.This episode focuses on all three of these developments, along with the Barcelona conference next month and the reality that socially underserved elements of the population have suffered more during the pandemic than those who are better off economically. The conversation moves too fast and with too many digressions to capture accurately, but it is a great, brief listen.

Dr Patrick Dunn, PhD, MS, MBA, FAHA is the Program Director for Connected Heart Health and the AHA Inside initiative for the American Heart Association's new Center of Excellence for Health Technology and Innovation.  Patrick has a unique blend of knowledge and experience in healthcare, business development, software engineering, quality and research.  Dr. Dunn is a clinical exercise physiologist and health educator with 35 years of experience in cardiac rehabilitation, preventive cardiology and wellness with specific expertise in digital health literacy and digital coaching methods.

Clinical Tests Reveal that Black Cumin Seed (Nigella Sativa) May Treat Hypothyroidism Tabriz University, April 13, 2022 Consuming a few grams of powdered Nigella sativa (NS), more commonly known as black cumin seeds, may improve the autoimmune thyroid condition known as Hashimoto's thyroiditis, according to a study published in the journal BMC Complementary and Alternative Medicine. Hashimoto's thyroiditis is the most common form of thyroid gland inflammation. It is also the most common thyroid disorder in the U.S. In fact, the disease affects 14 million people in the country alone. Data also showed that the condition will affect about five percent of the U.S. population. Hashimoto's thyroiditis was 15 times more prevalent in women compared with men. Women aged between 30 to 60 years had the highest prevalence of the condition. The study also revealed that patients who took the black seed supplement exhibited marked reductions in serum concentrations of thyroid stimulating hormone and anti-thyroid peroxidase antibodies at eight weeks of intervention. In addition, patients in the intervention group showed a notable decline in serum vascular endothelial growth factor levels. Researchers also highlighted a significant increase in triiodothyronine concentration in patients who received powdered black seeds. However, the experts did not observe a similar effect in patients who took a placebo pill. (NEXT) Following a Mediterranean-style diet during pregnancy may reduce the risk of preeclampsia Johns Hopkins University, April 20, 2022 Following a Mediterranean-style diet during pregnancy was associated with a reduced risk of developing preeclampsia, and Black women appeared to have the greatest reduction of risk, according to new research published today in the Journal of the American Heart Association. Preeclampsia, a condition during pregnancy characterized by severe high blood pressure and liver or kidney damage, is a major cause of complications and death for the mother and her unborn child. Preeclampsia also increases a woman's risk of heart diseases, such as high blood pressure, heart attack, stroke or heart failure, by more than two times later in life. Women with preeclampsia have a higher risk of preterm delivery (giving birth before 37 weeks gestation) or low birth weight babies, and children born to mothers with preeclampsia are also at higher risk of developing high blood pressure and heart disease. Researchers created a Mediterranean-style diet score based on participants' responses to food frequency interviews and questionnaires, which were conducted within three days of giving birth. The analysis found: Women who had any form of diabetes before pregnancy and pre-pregnancy obesity were twice as likely to develop preeclampsia compared to women without those conditions. The risk of preeclampsia was more than 20% lower among the women who followed a Mediterranean-style diet during pregnancy. Black women who had the lowest Mediterranean-style diet scores had the highest risk (78%) for preeclampsia compared to all other non-Black women who more closely adhered to the Mediterranean-style diet. (NEXT) Individuals with type 2 diabetes should exercise after dinner University of Missouri, April 18, 2022 Exercise is a popular prescription for individuals suffering from the symptoms of Type 2 diabetes, but little research has explored whether these individuals receive more benefits from working out before or after dinner. Now, researchers at the University of Missouri have found that individuals with Type 2 diabetes can lower their risks of cardiovascular diseases more effectively by exercising after a meal. "This study shows that it is not just the intensity or duration of exercising that is important but also the timing of when it occurs," said Jill Kanaley, professor in the MU Department of Nutrition and Exercise Physiology. "Results from this study show that resistance exercise has its most powerful effect on reducing glucose and fat levels in one's blood when performed after dinner." Kanaley and her colleagues studied a group of obese individuals with Type 2 diabetes. On one occasion, participants performed resistance exercises before eating dinner. During another visit, participants exercised 45 minutes after eating dinner. Participants performed resistance exercises such as leg curls, seated calf raises and abdominal crunches. Compared to levels on a non-exercise day, Kanaley found that the participants who exercised before dinner were able to only reduce the sugar levels in their blood; however, participants who exercised after dinner were able to reduce both sugar and fat levels. Participants consumed a moderate carbohydrate dinner on the evenings of the study. (NEXT) Dietary supplementation with açaí pulps improves cognition attenuates inflammatory signaling in BV-2 microglial cells Tufts University, April 18, 2022 Objectives: The present study was carried out to determine if lyophilized açaí fruit pulp (genus, Euterpe), rich in polyphenols and other bioactive antioxidant and anti-inflammatory phytochemicals, is efficacious in reversing age-related cognitive deficits in aged rats. Methods: The diets of 19-month-old Fischer 344 rats were supplemented for 8 weeks with 2% Euterpe oleracea (EO), Euterpe precatoria (EP), or a control diet. Rats were tested in the Morris water maze and then blood serum from the rats was used to assess inflammatory responses of BV-2 microglial cells. Results: After 8 weeks of dietary supplementation with 2% EO or EP, rats demonstrated improved working memory in the Morris water maze, relative to controls; however, only the EO diet improved reference memory. BV-2 microglial cells treated with blood serum collected from EO-fed rats produced less nitric oxide (NO) than control-fed rats. Serum from both EO- and EP-fed rats reduced tumor necrosis factor-alpha (TNF-α). There is a relationship between performance in the water maze and the production of NO and TNF-α by serum-treated BV-2 cells, such that serum from rats with better performance was more protective against inflammatory signaling.   (SUPERFOOD) Peppers (capsicum): Native American folk medicine, which has so many features we can still learn from, gave a prominent place in its pharmacology to peppers of the capsicum family, which includes bell and chili peppers. Recent work suggests that the nutrient capsaicin, found in these peppers, is a natural analgesic and a neuro-inflammatory blocker that relieves aches and pains to joints and muscles. This is one reason why Native American medicine prescribed a topical application of pepper to painful areas of the body. Capsaicin is particularly deserving of mention in this book because recent, promising research in Canada has explored the uses of capsaicin in the treatment of Type I diabetes. Other work has noted it can benefit sufferers from prostate cancer and leukemia. Some scientists have noted that this much studied nutrient found in peppers helps with weight loss, stimulation of insulin-producing cells, and prevention of LDL cholesterol oxidation. Another benefit recently uncovered is that the nutrient protects from stomach ulcerations and induces apoptosis (cancer cell death) in lung cancer. Setting aside the value of capsaicin, peppers can also be prized because they are rich in the antioxidant vitamins A as well as in vitamins B1, B6, E, and K. They are also high in potassium, magnesium, and iron. Yellow peppers are rich in lutein and zeaxanthin, which protect from eye disease and blindness. Videos: 1. American Who Lived 8 Years in Ukraine Speaks Out on Russia War (Start @ 0:41) 4. Kim Iversen: Noam Chomsky BLASTED By Liberals For Anti-War Stance, EXPOSING The New Pro-War Left 5. How the U.S. Media Betrayed Afghanistan (16:47 long)    

This month on Episode 35 of Discover CircRes, host Cynthia St. Hilaire highlights two original research articles featured in the April 1 issue of Circulation Research, as well as highlights from the Stroke and Neurocognitive Impairment Compendium in the April 15th issue.  This episode also features a conversation with Dr Shubing Chen and Dr Yuling Han from Weill Cornell Medical College to discuss their study, SARS-CoV-2 Infection Induces Ferroptosis of Sinoatrial Node Pacemaker Cells.   Article highlights:   Pabel, et al. Effects of Atrial Fibrillation on the Ventricle   Pattarabanjird, et al. P62-Mediated B1b Cell Atheroprotection   Iadecola, et al. Introduction to the Compendium on Stroke and Neurocognitive Impairment   Cindy St. Hilaire:        Hi and welcome to Discover CircRes, the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. And today I'm going to be highlighting articles from our April issues of Circulation Research.                                     I'll also speak with Dr Shubing Chen and Dr Yuling Han from Weill Cornell Medical College, and they're with me to discuss their study, SARS-CoV-2 infection induces ferroptosis of Sinoatrial node pacemaker cells.   Cindy St. Hilaire:        The first article I want to share is titled, Effects of Atrial Fibrillation on the Human Ventricle. The first author is Steffen Pabel and the corresponding author is Samuel Sossalla and they're from Regensburg University. Atrial fibrillation, or AFib, is the most common form of heart arrhythmia. Patients with AFib may experience shortness of breath, dizziness and weakness. And they're also at risk for more life-threatening complications, such as clot-induced stroke and heart failure. Focusing on heart failure, this study investigated how disruptions to rhythm in the atria might lead to changes in the ventricular myocardium. The team studied ventricular muscle tissue from 24 patients with AFib and 31 without AFib. While the levels of fibrosis were equivalent in ventricular myocytes from both the AFib and the non AFib patients, other cellular features were distinct. For example, patients with AFib had reduced systolic calcium release, prolonged action potential duration and increased oxidative stress, compared with the non AFib patient controls. These differences were largely recapitulated in ventricular myocytes derived from human induced pluripotent stem cells that had been electrically stimulated to either mimic AFib or normal sinus rhythm. The results indicate that AFib affects the ventricles just as well as the atria and might therefore be best studied and treated with the whole heart in mind.   Cindy St. Hilaire:        The second article I want to share is titled B-1b Cells Possess Unique bHLH-Driven P62-Dependent Self-Renewal and Atheroprotection. The first author is Tanyaporn Pattarabanjird and the corresponding author is Colleen McNamara, from the University of Virginia.   Atherosclerosis is a complex and dynamic chronic inflammatory condition. However, not all immune cells exacerbate this disease. Some immune cells are actively dampening the inflammation. B-1 cells are such cells that do this, and they produce IgM antibodies that bind cholesterol, preventing its uptake into macrophages and therefore limiting macrophage driven inflammatory responses. Increased number of B1 cells, therefore, might be atheroprotective. In mice, deletion of the transcription factor ID3 leads to a boost in B-1 cell IgM production.   Cindy St. Hilaire:        In this work the authors investigated the molecular mechanism underlying this effect and found that upon deletion of ID3 in mice B-1b cells, the level of P62 protein was increased. B-1b cell proliferation was found to be dependent on P62 and over expression of P62 in mouse B-1b cells increased cell numbers, raised plasma IgM levels and importantly, ameliorated diet-induced atherosclerosis in animals. The team went on to show that people with an ID3 mutation had an unusually high level of serum IgM and B-1b cell P62. This suggests that results from mice may hold true for humans, and if so, could inform the development of immunomodulatory treatments for atherosclerosis.   Cindy St. Hilaire:        So the April 15th issue of Circulation Research is our Stroke And Neurocognitive Impairment Compendium. The last Circulation Research Compendium on Stroke was published about five years ago. In this year Dr Costantino Iadecola, Dr Mark Fisher and Dr Ralph Sacco focused this update on advances made over the past five years, with a focus on topics that were not addressed in the previous compendium, that best reflect the leading edge of basic in clinical science related to cerebral vascular diseases. Seemant Chaturvedi, Brian Mac Grory and colleagues provide an overview of preventative strategies according to stroke mechanism, including stroke of unknown cause. And the challenges of stroke prevention with antithrombotic therapy and subjects with increased hemorrhage risk are also considered.   Cindy St. Hilaire:        Stéphanie Debette and Hugh Markus provide an account of the most recent developments in the genetics of cerebrovascular diseases. The gut microbiota is another factor that has recently been linked to stroke risk and Pedram Honarpisheh, Louise McCullough and colleagues provide a comprehensive overview of the microbiology and the microbiota, and the influence that stroke risk factors exert on its composition and homeostatic relationship with mucosal surfaces. Karin Hochrainer and Wei Yang provide a systematic review of the large amount of data and stroke proteomic from animal models and human patients. Matthias Endres and colleagues cover the dramatic effect that innate and adaptive immunity exert on stroke risk and on acute brain damage and post stroke sequelae, such as post-stroke cognitive impairment and depression.                                     Cindy St. Hilaire:        Manuela De Michele, Alexander Merkler and colleagues discuss the cerebral vascular diseases that have emerged as a frequent manifestation of the maladaptive immune response to severe SARS-CoV-2 infection. Jessica Magid-Bernstein and Lauren Sansing review the current concepts on epidemiology, risk factors in etiology, clinical features, as well as the medical and surgical interventions for cerebral hemorrhage. Yunyun Xiong and Marc Fisher cover the progress that has been achieved in the treatment of acute ischemic stroke and Natalie Rost and Martin Dichgans and colleagues address the long term impact of stroke on cognitive function, which is becoming a significant healthcare challenge in the world's aging population.   Cindy St. Hilaire:        So today I have Dr Shubing Chen and Yuling Han from Weill Cornell Medical College. And they're with me to discuss their study SARS-CoV-2 infection induces ferroptosis of Sinoatrial node pacemaker cells. And this article is in our April 1st issue of Circulation Research. So thank you both for joining me today.   Shubing Chen:             Thank you. It's really nice to join the program, and it's really a great honor.   Cindy St. Hilaire:        It's a really great article. I'm so excited to talk about. So there's a lot of research happening regarding SARS-CoV-2 virus and the patients who are infected and have COVID-19. And this paper is focusing on the impact of viral infection on the heart and specifically on the sinoatrial node, which is the primary cardiac pacemaker that keeps our hearts beating. So I was wondering if you could tell us what led you to focus on this particular aspect of COVID-19 symptoms, and also how early in the pandemic did you start this?   Shubing Chen:             Yeah, so we started working on SARS-CoV-2 through back to early 2020 when very unfortunately, New York City was a pandemic center and we had a lot of patients in the hospital unit, and also postdoc students working very hard in the lab. So that's the time we start working on SARS-CoV-2. And I was trained as a stem cell biologist. And what we're really interest is to set up a platform to basically understand which type of cells can be infected by SARS-CoV-2 and if they can, how they respond to SARS-CoV-2 infection. Not only for SARS-CoV-2, we sent it as like a viral infection platform, but SARS-CoV-2 is one of the virus we study now. And it's kind of very surprising. We have a pretty broad platform. We have a lung organoid, we have colon organoids, we have pancreas, we have cardiomyocytes, pacemaker cells. And as expected, we see lung can be infected like colon and because patient had GI tract, liver can be infected, but very surprisingly we see very high cardiomyocytes infection as well as pacemakers.                                       So as we'll know that still big controversy in the field, whether we can detect SARS-CoV-2 like viral protein or viral RA in the heart, in particular, cardiomyocytes. But I think now everyone agree that the cardiomyocytes really can be very well infected actually. Because it's very difficult to get the pacemaker tissue and the sinoatrial tissue from the COVID patient. So we collaborate with Dr Ben Andora's lab at NYU to get this hamster model. So we basically take SA tissue from hamster and then other colleagues basically did the section imaging, and we confirm that the hC4 polymerase cells can be infected by SARS-CoV-2. And at that time we start to learn a more clinical studies they report the COVID patient, they develop arrhythmia, or some other problem, not only with cardiomyocyte, as well as the conduction system. So at that time, that's the time that we say maybe we should do something on the pacemaker and focus on that. So that's how the project was developed.   Cindy St. Hilaire:        That is so interesting. And so I know humans infected, like you just said with SARS-CoV-2, they can develop arrhythmias. What's that timeframe? Is there a common timeframe that this happens? Does it normally happen very close to the infection or only in later stage? What's that window of when these arrhythmias are happening?   Shubing Chen:             At least based on the clinical study we show right now, actually the patient can develop acute arrhythmia. So it can be very soon after they developed symptom for COVID.   Cindy St. Hilaire:        Wow. That's amazing. So you mentioned this, your study utilized a hamster model, which you actually don't see a lot of. Most studies use a lot of rats or most studies I'm familiar with, especially in Circulation Research, they use more rats or more mouse models. So what advantages does that hamster model have and why were you interested in using it?   Shubing Chen:             Yeah, that's actually really specific for SARS-CoV-2. As SARS-CoV-2 mainly use ACE2 as a key entry factor to enter the cells. Of course, there's additional receptor, like neutrophils is one. Like all this enzyme involved, but human and mouse ACE2, they have very different structure. So the SARS-CoV-2 virus combine with human ACE2 very well but not mouse ACE2. So from the beginning, the rat and mouse was not used as a very good model to study SARS-CoV-2 infection. Of course there are other models, like knockin human ACE2 in the mouse and also like ACE2 transgenic mice. That's how different mouse model use. But hamster you don't need any modification, but they are very promising to SARS-CoV-2 infection. And so that's a reason we decide to use that as an animal model to basically run in parallel with our human stem cell model.   Cindy St. Hilaire:        We joke in my lab, mice are not little humans, but it's really true in a lot of cases, they're beautiful models in so many ways, but then when they don't work, they really don't work.   Shubing Chen:             Yeah. Before COVID every time when we try to talk about our human stem cell, derived cells, organoids as a disease model. People always ask, why do you want to work on human organoids? Right? It's that we have all these beautiful animal models like as you mentioned, mouse or rats, that's very broadly used. And we have to find different reasons. And now when we start working on SARS-CoV-2, which is very clear example, that mouse are not identical to human. Yeah.   Cindy St. Hilaire:        Yeah. That's great. I love finding additional models to use that are the best one for the question. So in order to investigate, I guess kind of the mechanism of how this was happening in the SAN cells, the sinoatrial node cells, you had to develop a new differentiation protocol that took the human embryonic stem cells, I think it was the H9 line you used, and essentially differentiate that cell line into a sinoatrial node-like cell. So I was wondering if you could tell us a little bit about A) how did you figure out that protocol and B) how does it work?   Shubing Chen:             So it's actually a long story to cell line.   Cindy St. Hilaire:        We can condense it. Let's get-   Shubing Chen:             At least based on the clinical study we show right now, actually the patient can. Let's condense it. But it's as you can imagine, we did not develop this cell line only for this particular project. Actually, we start working on this cell line back to maybe six, seven years ago. The first postdoc we have who basically knockin the mCherry, Myh6. Which basically label the atrial cardiomyocytes. And another postdoc, Zanir, he basically put a GFP in the SARS2 locus. So now we have this duel reporter line we can visualize the SA nodal cells. And we really spend a lot of time on that because we think that unfortunately in our hand, there is not really no good antibody for SARS2. We think it's very, very important that you can see these cells. So after developing these lines and because my lab run a lot of chemical screening, where we run Zanir, we run several chemical screening to develop the protocol.                                       And Jialing Zhu, another postdoc in the lab, also pick up the project to further develop the protocol. And there is several years' work. We do have this good protocol to make pretty efficiently to make the cells. And it's not only our work. I want to say that. For example, Dr Sean Wu from Stanford, they did this beautiful study on the single cell RNC mouse conduction system and Dr Gordon Keller and many other labs also basically published protocol in the field. We are very excited about this duel reporter line. I think they gave us a lot of new opportunity and we are very happy to share this line. Yeah. So if anyone in the field are interested in that, just contact us.   Cindy St. Hilaire:        Yeah. Anyone listening. That's great. So were you surprised to find the entry factors that SARS-CoV-2 uses to get into a cell, were you surprised to find them on these sinoatrial node cells? And I guess in the context of comparing these particular cells to other cells in the heart, are those entry factors higher in the sinoatrial node cells?   Shubing Chen:             So it can be either surprised or not surprised let's say this way. So because one, we see the cardiomyocytes that can be infected, we were kind of surprised. And then we find actually several type of cells in the heart can be infected, like endothelial cells. I will say that the ACE2 expression of like ACE2 aminophenol in pacemaker cell, it's not significantly higher than cardiomyocytes. So we are not really saying, or seeing that SA nodal cells are more permissive to SARS-CoV-2 infections compared to cardiomyocytes, even in the petri dish, but they can be infected.   Cindy St. Hilaire:        So you found SARS-CoV-2 infection in these sinoatrial nodal cells induces a process called ferroptosis. So Yuling, I was wondering if you could tell us what is ferroptosis and what is it doing in these pacemaker cells?   Yuling Han:                 For the ferroptosis, they was surprised so far that its by the RA sequencing of the SARS-CoV-2 infection make our cells. And the first process is mainly caused by the-   Shubing Chen:             Error in iron.   Yuling Han:                 Yes. So more intake of the iron error and induced the RA's pathway and caused the cell deaths. So by our RA sequencing, we found the key factor involved in ferroptosis pathway is the GPS score was checked after the SARS-CoV-2 infection. So we focused on the ferroptosis pathway and found other key factors or checked after the infection makes in the pacemaker cells.   Cindy St. Hilaire:        What is the ferroptosis doing that disrupts the SNA cells?   Shubing Chen:             Ferroptosis is a type of cell death mechanism. So eventually it will cause cell death. And we think something that is really surprising, but we think it's very interesting, is we only see ferroptosis in the SARS-CoV-2 infected general atrial cells. So SA cells, we actually, as Yuling mentioned, when we develop this platform, we see different type of cell can be affected. And we are very curious what happened. So we see that we run a sequence on each individual cells we can see infection and along, we can see cell death like apoptosis in cardiomyocytes. We see apoptosis and only in SA nodal cells, we actually see the ferroptosis pathway as we come up.   Cindy St. Hilaire:        Why do you think that is in that cell type versus in another? Do you have any ideas about why?   Shubing Chen:             No, we don't have any idea yet to be honest, but we are working on that. But at least I think that it gave us some clue that we really need to use different type of whole cells to study the whole cell response. Because traditionally when we study viral infection and when we see lung, we always say, oh, the cell died. It's fairly simple. But now if we really study the details and we think it's maybe over simplified way to think about how cells can respond to viral infection, not only to SARS-CoV-2 infection. So it gives us the motivation, very strong motivation to now really study how different host tissues response to viral infection.   Cindy St. Hilaire:        I thought that was really interesting, not all cell death is the same.   Shubing Chen:             Yeah. And another thing is kind of a little bit surprising is we actually did a very careful comparison between the SA nodal cells and the cardiomyocyte. We only see ferroptosis come up as SA nodal cell, but not cardiomyocyte. Again, we don't understand why as maybe some host factor that is specific, we're working on that.   Cindy St. Hilaire:        So in addition to working out this mechanism of what is going wrong when these cells are infected with the virus, you also used this embryonic stem cell like tool for a drug screen. So can you walk us through that process in terms of what you did to do that? Did you focus in on one specific type of drugs or was it just kind of an unbiased screen?   Yuling Han:                 For the sinoatrial pacemaker cells, we focus on the antiviral drugs screening. And we also did several other projects, like lot of night or some neuron cells. For the [they did drug screening to find some drugs to inhibit the SARS-CoV-2 entry. And for the dominic neuron, we found SARS-CoV-2 infection can cause neuro cells synapses. So we focus on the synapses associated drug screening, but for the pacemaker cells, they only did the antiviral drug screen.   Cindy St. Hilaire:        And you came up with two drugs that you wrote about in the paper, deferoxamine and imatinib. So what are the mechanisms of action of those drugs? Are they targeting the same thing or are they targeting slightly different things?   Yuling Han:                 For the imatinib, we also found this drug inhibit SARS-CoV-2 entry and we did several other screenings, like the lung organoids and neuro cells. We also found this drugs. And the six drug, the mechanism is kept and the spec protein of SARS-CoV-2. And this was found by several other groups and published some paper this year. And we found this in 2020 maybe. And we published this paper before and we found this mechanism. And for another drug, we checked the RA sequencing data of SARS-CoV-2 affect the peacemaker cells. And we did several run of RA sequencing. And we compared the key factors, involved in SARS-CoV-2 entry. Several key factors like CTSL and like TMPS2 and among several run of RA sequencing. We only found the drug can decrease the expression of CTSL. So we also did PTR immunostaining, and then we found the drug decrease the expression level of CTSL.   Shubing Chen:             Yeah. So actually the other drug, it's also an antiferroptosis drug. So we did the mechanism study and it's very nice to see, we also identify the drug from an unbiased chemical screen. And for the chemical screening, we actually have a pretty large platform and we have around 1200 FDA approved drugs. We have like a 2000 anatrofin amino acid that signal pathway regulators for most of the SARS-CoV-2 screening, as you did mention, we have multiple screening platform. We focus on FDA approved drug. So it's more like for the drug repurposing and for other screening we also write larger skills.   Cindy St. Hilaire:        So we got a mechanism, we got a super specific cell type and we now have some drugs. So what are the translational implications of these findings? And I guess I'm thinking about that in terms of the time course of when a patient gets infected, has symptoms, has arrhythmia, like where could you possibly target this ferroptosis pathway? Meaning if someone already is exhibiting AFib as a result of the infection, is that actually too late? Or can you start to treat it to reverse it or prevent it from getting worse? Like what do you see as a therapeutic potential for using these drugs?   Shubing Chen:             That's a very good question. I will say this way, I think when we identify all these drugs, it's very, very exciting. But for antiviral drug development perspective, we definitely want a drug that show broader spectrum. So for COVID patient, of course we want to protect their heart, but we also want to protect their lungs.   Cindy St. Hilaire:        Exactly. Protect everything.   Shubing Chen:             Exactly. Exactly. So for the real drug that can clinical use, I think the lack of broad spectrum antiviral drug, I think that will be the way to go for drug development and for the cardioprotective respective. So if the patient do have very severe cardio symptom, particularly like arrhythmia symptom, I think that can be considered. But I don't want to really say this is the drug to treat the COVID patient. I don't think that's a way to go, particularly for ferroptosis is a cell type. This is a phenotype, very specific for the pacemaker. And I think for us, as a basic scientist, is very, very important that we understand the biology and we can identify these normal chemical tools that we can manipulate the system that can facilitate the future drug development.   Cindy St. Hilaire:        So do you think your findings and I mean findings at multiple levels, that a viral infection can induce apoptosis in one cell, but ferroptosis in another cell, but also the findings of viral infection in general, sufficient enough to drives sinoatrial node cell dysfunction. Do you think this is specific to SARS-CoV-2 and corona viruses or do you think this is something that is more broad with other viruses that maybe we just haven't recognized possibly because we don't have the tools yet?   Shubing Chen:            That's a great question. I will say some other type of virus can also infect heart, at least cardiomyocyte, like a Coxsackie virus, regular virus three. And there's actually a lot of study on the viral infection on the cardiomyocytes. And for us, the most exciting part is we really have now in serious, limited starting materials to get these pacemaker cells. Like I SA nodal cells. So we can use this as a platform to study how other virus infect, how the viral infection in general cause cell dysfunction. Because in the study we also do the calcium blocks assay, we can monitor their beating and then we can do RN-seq to monitor their transcription changes. Because this we have this still reporting system, we can purify cells, we can even run larger scale, like epigenetic level, how they change. So that's a very useful tool to study how cell responds to viral infection. I'm very excited about that.   Cindy St. Hilaire:        That's great. Well, Dr Chen and Dr Han, thank you so much for joining me today. Congratulations on a beautiful story. And I look forward to hearing more out all these different organoid and cell models you have.   Shubing Chen:            Cindy, thank you. Thank you for so much for having us.   Cindy St. Hilaire:        That's it for the highlights from the April issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Shubing Chen and Dr Yuling Han. This podcast was produced by Ishara Rantikac edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles was provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on the go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American heart Association. For more our information visit ahajournals.org.  

On Episode 15 of the Stroke Alert Podcast, host Dr. Negar Asdaghi highlights two articles from the April 2022 issue of Stroke: “Kawasaki Disease May Increase the Risk of Subsequent Cerebrovascular Disease” and “Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage.” She also interviews Dr. François Gros-Louis about his article “Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function.” Dr. Negar Asdaghi:                        1) How would you counsel the parent of a child who has just recovered from Kawasaki disease on their child's future risk of having a stroke? 2) Should we or should we not treat stress hyperglycemia in the setting of acute intracerebral hemorrhage? 3) What is the CRISPR-Cas9 gene editing technology? And why, if you haven't heard of it already, you most definitely should be listening to this podcast? We're back here with the April issue of the Stroke Alert Podcast, and this is the latest in Stroke. Stay with us. Dr. Negar Asdaghi:                        Welcome back to another extremely informative Stroke Alert Podcast. My name is Negar Asdaghi. I'm an Associate Professor of Neurology at the University of Miami Miller School of Medicine, and your host for the monthly Stroke Alert Podcast. The April 2022 issue of Stroke contains a range of really exciting papers and topics. In the paper titled "Vascular Response to Spreading Depolarization Predicts Stroke Outcome," we have a really interesting in vivo mouse model of ischemic stroke, looking at the spreading patterns of cortical depolarization and the subsequent vascular response to this by way of hyperemia. The researchers from Zurich University, led by Dr. Binder and colleagues, walk us through how the patterns of hyperemia can actually predict the severity of subsequent ischemic injury. Dr. Negar Asdaghi:                        In a separate paper in this issue of the journal, we're reminded of how the classic NIH Stroke Scale can underestimate the severity of neurological symptoms and outcomes in patients with posterior circulation infarcts. In the paper led by Dr. Alemseged and colleagues, the investigators from the Royal Melbourne Hospital in Australia evaluate the prognostic accuracy of the Posterior NIH Stroke Scale, which is the modified version of the classic NIH Stroke Scale, in predicting the outcomes of patients with posterior circulation infarcts. Dr. Negar Asdaghi:                        I encourage you to review these papers in addition to listening to our podcast today. Later in the podcast, I have the great pleasure of interviewing Dr. François Gros-Louis from Laval University in Quebec to discuss the latest in gene editing technology and how this technology has helped his team unravel the biological function of RNF213 susceptibility gene in Moyamoya disease. But first with these two articles. Dr. Negar Asdaghi:                        Kawasaki disease, which was first described in 1976, is an acute febrile illness predominantly affecting children younger than five years of age. In addition to fever, other clinical signs of the disease include rash, bilateral conjunctival injection, cervical lymphadenopathy, swelling of the hands and feet, and irritation and inflammation of the mouth, lips, and throat. Now, for those of us like me who are adult neurologists, here is a quick review of the pathophysiology of Kawasaki disease. Dr. Negar Asdaghi:                        This is a medium vessel vasculopathy, most significantly affecting the coronary arteries, a vasculopathy that is characterized by three linked pathological processes, necrotizing arteritis, subacute to chronic vasculitis, and luminal myofibroblastic proliferation. So, simply put, these processes can lead to stenotic lesions in various vascular beds, which are affected by this disease. Dr. Negar Asdaghi:                        And as we mentioned earlier, the most recognized vascular blood vessels affected by Kawasaki disease are the coronary arteries, which can lead to myocardial ischemia, infarction, and sudden death in these cases. However, involvement of other vascular beds, including cerebral vessels, are also increasingly reported as part of Kawasaki disease. Dr. Negar Asdaghi:                        So, in the current issue of the journal, Dr. Chien-Heng Lin from the Division of Pediatric Pulmonology at China Medical University Children's Hospital in Taiwan and colleagues studied the subsequent risk of cerebrovascular events in patients with Kawasaki disease. Using the National Health Insurance Research Database of Taiwan, they collected data on 8467 children with Kawasaki disease from 2000 to 2012. And for each child with Kawasaki, data was also collected on four randomly selected non-Kawasaki disease children who were matched with the Kawasaki cohort for sex, urbanization level of residence, and parental occupation. Dr. Negar Asdaghi:                        So, that gave them a sample size of over 33,000 children for their non-Kawasaki cohort. And then they compared the risk of subsequent stroke in children between the two cohorts. The study period for any given patient would end when the said patient was either diagnosed with a cerebrovascular disease or withdrew from the research database. Dr. Negar Asdaghi:                        So, in terms of their demographics, 61% of patients in the Kawasaki group were boys; 88% of the Kawasaki cohort were younger than five years of age. So, here are the findings. Number one, the incident rate of subsequent cerebrovascular disease was 14.7 per hundred thousand person years in the Kawasaki cohort versus only 4.6 per hundred thousand person years in the non-Kawasaki cohort. That's greater than a threefold higher incidence rate of cerebrovascular disorders for children who had Kawasaki disease before. Dr. Negar Asdaghi:                        This finding was independent of other potential confounders, which they adjusted for in their multivariate analysis. Now, the length of follow up was a median of 9.8 years for the entire cohort. And on the issue of time, they found two important associations. The first finding was that when the follow-up time was stratified by five-year periods, Kawasaki disease cohort patients showed a significantly higher risk of developing a stroke within the first five years after being diagnosed. Dr. Negar Asdaghi:                        And the second important association was that when they looked at the age at the time of diagnosis of Kawasaki, children who were younger than five years at the time of diagnosis were at a significantly higher risk of having a future stroke as compared to those who were older than five at the time of diagnosis. Dr. Negar Asdaghi:                        So, simply put, the risk of subsequent stroke was higher in children who acquired the disease at a younger age, and that risk was higher in the first few years after the diagnosis of Kawasaki disease. The authors discuss a number of putative mechanisms to link Kawasaki with stroke. The most important being a cardiac source of embolism that we already alluded to, but other etiologies, including medium vessel cerebral vasculitis, or hypercoagulability in the setting of increased systemic inflammation, and even Kawasaki disease-associated aneurysmal rupture to cause hemorrhagic forms of stroke, are discussed in the paper and should be considered in the correct setting in children with a prior history of this disease. Dr. Negar Asdaghi:                        So, what we learned from this large population-based pediatric study is that Kawasaki disease does indeed increase the risk of subsequent cerebrovascular disorders, and its influence is stronger in children who are diagnosed with this condition under the age of five, and the time period during which the risk of stroke is the highest is within the first five years after the diagnosis. Dr. Negar Asdaghi:                        In the setting of spontaneous intracerebral hemorrhage, or ICH, much research has focused on the association between hypertension and blood pressure-lowering therapies and hematoma expansion and functional outcomes, but a lot less attention relatively has been given to the impact of hyperglycemia and ICH-related outcomes. Dr. Negar Asdaghi:                        The current guidelines state that serum glucose should be monitored and both hypo- and hyperglycemia should be avoided in the setting of ICH. The older studies have given us inconsistent results as to whether or not hyperglycemia can increase the risk of ICH-related mortality. More recent studies have suggested that perhaps persistent hyperglycemia is indeed a predictor of poor neurological outcomes in ICH, but these results come from smaller single-center studies, which require further confirmation. And this confirmation is exactly what Dr. Adnan Qureshi from Zeenat Qureshi Stroke Institute and the Department of Neurology at University of Missouri and colleagues aim to give us in their study titled "Effect of Moderate and Severe Persistent Hyperglycemia on Outcomes in Patients With Intracerebral Hemorrhage." Dr. Negar Asdaghi:                        So, they use data from the ATACH-2 study, and a quick reminder that ATACH-2 was a multicenter randomized control trial of a thousand patients with acute spontaneous intracerebral hemorrhage enrolled within four and a half hours from symptom onset, and patients were randomized to either the intensive blood pressure control treatment arm to maintain their systolic blood pressure goal of 110 to 139 millimeter of mercury versus standard treatment arm, which was keeping their systolic blood pressure above 140, between 140 to 179 millimeter of mercury, in the first 24 hours after randomization. Dr. Negar Asdaghi:                        You will recall that enrollment of ATACH-2 was stopped early because of futility after pre-specified interim analysis. The main results of the trial was published in 2016 in New England Journal of Medicine, and the primary results did not show a lower rate of death or disability in patients assigned to the intensive treatment group. Dr. Negar Asdaghi:                        So, in the current paper, in this current issue of the journal, the authors looked at the glycemic status of the patients enrolled in the trial. As part of the trial, patients had a complete chemistry panel at baseline, 24, 48, and 72 hours from onset. So, they used the glucose measurement from this panel and defined moderate hyperglycemia as serum glucose level of over 140 and under 180 and severe hyperglycemia as serum glucose levels of equal or greater than 180. Dr. Negar Asdaghi:                        Now, persistent hyperglycemia was if two consecutive serum glucose levels were in the moderate or severe categories. And, very simply, they looked at the effects of hyperglycemia on ICH outcomes. And importantly, they evaluated whether hyperglycemia modified the effects of intensive blood pressure reduction on outcomes of ICH. So, of the thousand participants in ATACH-2, 11% had persistent moderate hyperglycemia, and 17% had severe persistent hyperglycemia. Those in the hyperglycemic group were more likely to be diabetic, not surprisingly, more likely to have a history of hypertension and dyslipidemia as compared to the normal glycemic patients. Dr. Negar Asdaghi:                        And here are the results. Number one, serious adverse events were higher in the hyperglycemic groups, whether we're talking about the moderate or the severe hyperglycemic groups. This is despite the fact that the rate of hematoma expansion and perihematomal edema was not different based on the hyperglycemic status. However, the hyperglycemic patients were more likely to have serious adverse events, which were operationally defined as complications that were not expected to have occurred from the study intervention, in this case, the intensive hypertensive therapy, and resulted in either death or prolonged hospitalization or persistent or significant disabilities. Now, serious renal adverse events, which are, of course, expected as a complication for aggressive blood pressure therapy, were also significantly higher in the hyperglycemic category. Dr. Negar Asdaghi:                        Now, their next important finding was that overall, both moderate and severe hyperglycemia was associated with higher odds of 90 days disability or death post-ICH adjusting for typical variables that could predict these outcomes, such as GCS score, hematoma volume, presence or absence of intraventricular hemorrhage, amongst other factors that they accounted for. Dr. Negar Asdaghi:                        Now, number three, this is perhaps the most important finding of the study. Among patients without a preexisting history of diabetes, both moderate and severe hyperglycemia increased the risk of death and disability at 90 days after adjusting for all the potential confounders, but hyperglycemia was not associated with these poor outcomes in those with a prior history of diabetes. I'm going to pause here to let this information sink in. Let's go over them again, stress hyperglycemia in non-diabetics was associated with poor ICH outcomes, but high sugars in diabetics did not predict the same poor outcomes. And finally, they looked at the possible interactions between the glycemic status and the ATACH-2 intervention, which as we alluded to earlier, which was intensive versus standard blood pressure therapy, and it turns out that the intensive systolic blood pressure reduction was indeed associated with a lower rate of hematoma expansion only in patients with normal glycemia, but not in those with moderate or severe hyperglycemia. Dr. Negar Asdaghi:                        So, this is again food for thought. Simply put, if the sugars are not well controlled, it appears that intensive blood pressure control would not lower the rate of hematoma expansion. Blood pressure lowering works when the sugar levels are controlled. So, overall, here are the two simple messages of this study. Number one, hyperglycemia in the acute setting of intracerebral hemorrhage is associated with poor outcomes or death only in those with stress hyperglycemia, meaning in those who have high sugar levels, but are not diabetic. Dr. Negar Asdaghi:                        Number two, there seems to be an important interaction between the acute glycemic status of the patients and how intensive blood pressure control can prevent hematoma expansion, in that intensive BP control is only effective in prevention of hematoma expansion if the sugar levels are normal. So, a lot of thought-provoking and hypothesis-generating findings, and definitely more to come on this topic. Dr. Negar Asdaghi:                        Moyamoya disease, or MMD, is an idiopathic disorder characterized by progressive stenosis of the supraclinoid internal carotid artery and its main branches in subsequent formation of a network of abnormal lenticulostriate collaterals. First described in Japan, the term "Moyamoya" is a Japanese expression for the puff of smoke and describes the characteristic appearance of the tangled and abnormal collateral vessels that are seen in angiography in various stages of the Moyamoya disease. Dr. Negar Asdaghi:                        Epidemiological studies have revealed several risk factors associated with Moyamoya disease, including Asian ethnicity, female gender, and a family history of the disorder. Given that 15% of MMD patients have a family history of this disease, it's not surprising that genetic factors are suspected to underlie its pathogenesis. Now, a polymorphism in the ring finger protein 213, or RNF213, gene on chromosome 17 has been identified as the strongest genetic susceptibility factor for Moyamoya disease specifically in the East Asian population. Dr. Negar Asdaghi:                        But despite the many advances in understanding the pathophysiology of MMD, as well as advances in animal models and genetic studies, to date, none of the animal models of RNF213 have quite replicated the vascular abnormalities that are typically seen in human Moyamoya disease. Dr. Negar Asdaghi:                        The scientists feel that this is related to how little is known about the exact biological function of RNF213 gene and the protein it encodes. So, in the current issue of the journal, in the study titled "Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function," Dr. François Gros-Louis from CHU de Québec Research Center at Laval University in Québec and colleagues aim to study the biological functions of RNF213 using a novel genome editing technology by the name of CRISPR-Cas9 technology. Dr. Negar Asdaghi:                        Joining me now is Dr. Gros-Louis himself to discuss the findings of this paper. Dr. Gros-Louis is a Professor of Neurosciences at the Department of Surgery at Laval University. He holds the Canada Research Chair in Brain Disease Modeling and is the Director of the Induced Pluripotent Stem Cell Platform research in Québec. Dr. Negar Asdaghi:                        Good morning, François. Welcome to our podcast. And thank you so much for joining us. Dr. François Gros-Louis:               My pleasure. Dr. Negar Asdaghi:                        François, you have to promise to hold my clinician's hand through this interview as obviously these are some foreign subjects for us, but very excited to learn from your study and learn from you on the association between RNF213 and the pathophysiology of what happens in Moyamoya disease. Now, before we talk about your paper, can you please talk to us about some basic concepts? What is the RNF213 protein? Dr. François Gros-Louis:               Yes. The RNF213 gene is thought to be involved in mediating protein, protein interactions. The protein also contains a domain which is associated with an ATPase activity. This gene is a susceptibility gene for Moyamoya disease, as you mentioned in the introduction, vascular disorder of intracranial arteries. It's encoded in ubiquitously expressed protein. The protein is found to be expressed throughout the cytocell with the partial association in the intracellular membrane and cytoskeleton. Its expression varies according to the tested tissue type or location or cellular types. Dr. François Gros-Louis:               Although the function of RNF213 protein is unknown, studies suggest that it plays a role in the proper development of blood vessels, cell proliferation, and inflammation. Recently, RNF213 has been reported to be associated with angiogenesis. However, little is known about its endogenous function or its pathogenic role in Moyamoya disease. Our results are in line with these results and indicate that RNF213 could also be a key regulator of cerebral endothelial integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. Dr. Negar Asdaghi:                        So, just to continue on this, there's quite a bit of research already done on association of the RNF213 gene, that's located, as we noted earlier, on chromosome 17, and basically susceptibility of development of Moyamoya disease. Can you give our listeners a brief overview of this genetic connections and what was known from past research? Dr. François Gros-Louis:               Yeah, there is a couple polymorphism describing this gene, the most frequent, the most prevalent genetic study have identified the variant R4810K, meaning for arginine is replaced by another amino acid at the position of 4810 within the protein. It's a large protein and a large gene and a susceptible gene and a risk factor for developing Moyamoya disease. Dr. François Gros-Louis:               So, people bearing this variant have a higher chance to develop the disease. This is a loss of function variant, also called inactivating mutation, meaning that the mutated gene product have less or no function. So, this variant is found in heterozygous, meaning one copy, or two copy homozygous in Moyamoya disease patients. While patient bearing homozygous mutation develop a more severe disease with earlier age of onset and worse prognosis, patients bearing heterozygous mutation can also develop the disease. Dr. François Gros-Louis:               So, strong evidence suggests that the carrying rate of RNF213 R4810K mutant is closely related and give a higher chance to develop the disease. Interestingly, also with colleagues, we found that there are other variants within this genes leading to what we think is a gain of function mutation have been associated also with other cerebrovascular disease, such as intracranial aneurysms. Dr. Negar Asdaghi:                        So, François, this is very interesting. Let me recap what you mentioned so I know that I understood it. So, this is an interesting gene, this RNF213, and basically evidence shows that mutations in the RNF213, whether it's loss of function or gain of function, both can result in variety of cerebrovascular disorders. And interestingly, the phenotype of the disease when it comes to loss of function of this gene is actually correlated with whether a person is a carrier, homozygous carrier of this gene, loss of function, or heterozygous carrier of the gene. Dr. Negar Asdaghi:                        So, very interesting information for clinicians who treat patients with Moyamoya disease, specifically those who have a family history of Moyamoya disease, so perhaps a higher chance of carrying a genetic susceptibility gene. Now, we want to get to the paper that you published in this issue of the journal, but I think before we talk about your paper, we also have to have a basic understanding of this CRISPR-Cas9 technology, which is the new genome editing technology that you use in your experiments. Can you please give us a little bit of an overview of this technology? Dr. François Gros-Louis:               Yes. CRISPR-Cas9 gene editing is genetic engineering technique in molecular biology by which the genomes of living organisms may be modified. This technology allows genetic material to be added, removed, or altered at particular location in the genome. Several approaches to genome editing have been developed. Recent one is known as CRISPR-Cas9. So, the CRISPR-Cas9 system has generated a lot of excitement in the scientific community because it is faster, cheaper, and more accurate, and also more efficient than other existing genome editing methods. It's clearly revolutionizing the field in research. Dr. Negar Asdaghi:                        So, it's very exciting. It's truly a new chapter in gene targeting research and editing research. So, now we're ready to hear about your study. And I guess the first part of the study was just to look at how various cells in vitro that you used had expressed RNF213. Can you please tell us about the first part of your experiments? Dr. François Gros-Louis:               Yeah. We first wanted to know where the protein is expressed or where the protein is more highly expressed. So, we found by doing immunofluorescence analysis that the RNF213, so we confirmed that it's ubiquitously expressed in the cytoplasm of different cellular types. So, we found that significant difference also in the expression of RNF213 protein levels in several endothelial cells, where we found it's been highly expressed when compared to other endothelial cells isolated from different other body location, meaning outside of the CNS. So, it's highly expressed also when compared to smooth muscle cells or fibroblasts. Dr. Negar Asdaghi:                        Okay. So, just again, to recap for our listeners, this is, this RNF213 protein, is ubiquitously expressed in many different cell types, but you did find a significantly higher expression rates in endothelial cells, specifically those endothelial cells that were derived from cerebrovasculature. So, that's the first exciting part of the experiments that you showed in the study. Now, using the CRISPR-Cas9 technology, you and your team were able to successfully create an in vitro RNF213 knockout model. Can you please tell us about these models and also the main findings of your study? Dr. François Gros-Louis:               Yeah, so taken together, the results we presented in the article indicate that RNF213 could be a key regulator of cerebral, endothelial and tight junctions integrity whose disruption could be an early pathological mechanisms leading to Moyamoya disease. So, we established for the first time an easily reproducible and stable in vitro 3D model generated using the CRISPR-Cas9 gene editing technology. Dr. François Gros-Louis:               This advanced 3D culture approach has emerged as an excellent system to recapitulate histopathological feature reminiscent to disease pathogenesis. So, 3D cell culture approach is different from standard 2D culture, where cells are cultured, monolayered into a Petri dish. And we have results showing that the 3D cell culture system better mimic the in vivo conditions in terms of cell to cell and cell to matrix interaction and lead to histopathological phenotypic feature can be observed in cell culture, in a 3D fashion. Quite interestingly, alongside of providing the first evidence for the role of RNF213, the maintenance of endothelial barrier and the potential implication of this gene in the expression of maturation of tight junctions. So, we define a novel role for PECAM-1 as well in barrier impairment as a part of the disease pathogenic mechanisms. Dr. Negar Asdaghi:                        Okay. And now this is really interesting. So, I wanted to, again, recap some of the important points that you raised here. First of all, your in vitro models are different than the classic in vitro models, where 2D cells were basically grown in a Petri dish. You are trying to, more and more, replicating what happens, for instance, in blood vessels, where you have endothelial cells overlying mesenchymal cells underneath them, so tunica intima and then tunica media, and so you have 3D cells, where various types of cells are overlying each other in a more in vivo representation of what happens in blood vessels, which is truly interesting. Dr. Negar Asdaghi:                        And what you found was, in sort of summary, was that these knockout endothelial cells ended up having abnormal tight junctions and abnormal connectivity, which basically would lead in an in vivo model to abnormal leaky blood brain barrier, if this were truly in the in vivo model. Does that summarize the findings of the paper? Dr. François Gros-Louis:               Yes, perfectly. Dr. Negar Asdaghi:                        Perfect. And so I want to also give us a chance to talk about the important pro-inflammatory aspects of these knockout cells. You did find that a number of cytokines were expressed in excess in those RNF213 deficient cells. Can you please elaborate on those findings? Dr. François Gros-Louis:               So, to further investigate whether inflammation plays an important role in RNF213-associated Moyamoya disease development, we indeed performed experiments to study pro-inflammatory cytokines and analyze the immune secretome profiles of cerebral RNF213 deficient endothelial cells. So, then the cells can secrete different cytokines or different other proteins. So, by analyzing the secretome, we found an end secretion of a few pro-inflammatory cytokines indicating that inflammation may also play a central role in the initiation of the immune response in the pathogenesis of the disease. Dr. Negar Asdaghi:                        So, this is exciting, François. For years, we thought about the pathophysiology of Moyamoya disease as a disorder involving large vessels. And perhaps the initial thought was that it starts with excessive proliferation of smooth muscles within the middle layer of the cerebral blood vessels, in tunica media, and then perhaps subsequently there will be other abnormalities, including the intimal hyperplasia that is classically seen in Moyamoya. Dr. Negar Asdaghi:                        Your study seems to propose a shift in that pathophysiological paradigm, where the problem seems to start from endothelial cells, so inside of the blood vessels and the tunica intima, and then gradually would go out to the middle layers, and, of course, proposes the hyperinflammatory state in the Moyamoya disease as well. So truly interesting. Do you think that that is the new or rather a paradigm shift for pathophysiology of MMD? Dr. François Gros-Louis:               That's a great question. Our results certainly demonstrated that endothelial cells are involving in the disease pathogenesis in Moyamoya disease, but it doesn't exclude the possibility that other cell types might also be involved in the disease pathogenesis. We know, like you mentioned, that a blood vessel is formed by two different cell layers, tunica intima, media, and adventitia, containing, respectively, endothelial cells, smooth muscle cells, and fibroblasts. So which cells are to be blamed in Moyamoya disease is a question of many ongoing results studies over the years. Dr. François Gros-Louis:               So, using tissue-engineered approach to reconstruct small caliber blood vessels, as we developed in my lab, in combination with patient-derived stem cells, in which adult cells isolated from a patient of any individuals can be reprogrammed into stem cells and re-differentiated into different cell types in occurrence, smooth muscle, fibroblasts, or endothelial cells. We would like to generate blood vessels in which each of the different cellular layers will harbor or not, or a combination with RNF213 mutants. So, this will hopefully help us to elucidate this question. Dr. Negar Asdaghi:                        That's perfect. So, François, before we end the interview, I wanted to ask two more questions. So, what should be our top two takeaway messages from your study? Dr. François Gros-Louis:               We believe that the innovative transdisciplinary approach to generate, for the first time, as we describe in the article, an in vitro 3D model recapitulating important diseases features. So, this model could become a unique tool in precision medicine to study Moyamoya disease or other RNF213-associated pathologies. So, our study provides, for the first time, role of RNF213 in the maintenance of blood-brain barrier and the potential implication of RNF213 in the expression and maturation of tight junctions. Taken together, our data define a novel role for PECAM-1 in the blood-brain barrier impairment in Moyamoya disease. Dr. François Gros-Louis:               So, better characterization of each, also this regulated inflammatory molecules, we found taken separately could reveal a crucial information and help elaborate a more precise approach. Hence, this pro-inflammatory signature could be used as a circulatory biomarker for the follow-up of Moyamoya disease patients and to manage an appropriate treatment, according to the pathology progression. Dr. Negar Asdaghi:                        François, this is great. And last, I want to digress a little bit and ask you about the future of gene editing. I think it's important to end our interview with a little bit of a discussion regarding the future of CRISPR-Cas9 technology. In subatomic quantum physics, people talk about the God particles. And I feel that the CRISPR-Cas9 technology is, in a way, like playing God, if you agree. What do you think is the future for gene editing, and how do you see that helping us in terms of treatment of genetic causes of cerebrovascular disorders? Dr. François Gros-Louis:               Yes, gene editing is, like I said, revolutionizing, of course, experimental therapies for genetic disorder and generated excitement for new and improved gene therapies. We can think that it will be possible to correct any gene mutations associated with a disease to reestablish the normal or natural gene function and help treating the targeted diseases. But also, to me, the future of genome editing also resides in optimizing next generation disease models. The use of genome editing, in particular, the CRISPR-Cas9 technology, has extended to potential in generating new personalized model for a number of disorder, not only including Moyamoya disease or other cerebrovascular diseases, but also diseases like Alzheimer's, ALS, or Parkinson's disease, for which obtaining patient sample is difficult. Dr. François Gros-Louis:               No one wants to give up a bit of his brain. So modeling it, this disease, in vitro will be really helpful in combination also gene editing with the stem cells, induced pluripotent stem cells technology, will allow the generation of better model to mimic human disease and reflects the genetic drivers that govern specific pathology. So, the synergy between IPS cell-based model system and gene editing will play a pivotal role in the root of precision medicine and clinical translation in the future. Dr. Negar Asdaghi:                        Dr. François Gros-Louis, it was a pleasure learning from you. And we look forward to the endless possibilities brought by the future of genome editing technology. Dr. François Gros-Louis:               It was a pleasure discussing with you. Dr. Negar Asdaghi:                        Thank you for joining us. Dr. Negar Asdaghi:                        And this concludes our podcast for the April 2022 issue of Stroke. Please be sure to check out this month's table of contents for the full list of publications, including a series of Focused Updates on the topic of blood pressure management in stroke, organized by Dr. Else Sandset. I would also like to draw your attention to two scientific statements from the American Heart Association, which appear in print in the April issue. The first one is titled "Identifying Best Practices to Improve Evaluation and Management of In-Hospital Stroke," and the second one is on the effect of marijuana use on brain health. Dr. Negar Asdaghi:                        And now, to end our podcast, last month, in honor of the 2022 Olympic Games, and to celebrate those with determination to survive and push despite the most difficult of circumstances, we ended our podcast with the story of a refugee Olympic athlete. Dr. Negar Asdaghi:                        Sadly, since our last podcast, the world has seen even darker days of war, mass immigration, displacement, and human suffering. At times like this, we're reminded that although not all of us can help everyone, but at least each of us can do something to help someone, and the comfort in knowing that what we do in the field of medicine, from daily patient care to the scientific work leading to the next medical breakthrough, every action is a step forward in reducing the suffering of another person. And what better way to do this than staying alert with Stroke Alert. Dr. Negar Asdaghi:         This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit AHAjournals.org.

Arizona Liver Health Institute V.P. of Academic Affairs and Fatty Liver Program Director Naim Alkhouri and Global Liver Institute Founder and CEO Donna Cryer join Louise Campbell and Roger Green to discuss their recent projects and accomplishments. Each of them brings newsworthy stories that lead to thoughtful, stimulating conversations about a range of issues.Naim Alkhouri's news includes two recent academic publications and some exciting, innovative new projects. One of his publications, the EDICT trial, contrasted two sets of T2D patients that were treated with different regimens. One set was treated with a "classic" regimen of metformin, a sulfonylurea and insulin -- agents that are liver-neutral or problematic. The other set was treated with a more friendly regimen of pioglitazone, a GLP-1 and metformin. Not surprisingly, when patients in the two groups were evaluated, the differences were dramatic. The other paper was a collaboration with the Pfizer NASH team, looking at 10,000 NHANES patients who were evaluated using FibroScan to estimate the proportions of NAFLD and NASH in the population. The numbers here were consistent with public health estimates. One interesting point: the CAP threshold the researchers used in this paper was far different from what Louise uses when evaluating patients with Tawazun Health. The difference? Louise chooses lower levels in the belief that lower levels will motivate more patients towards self-care, while Naim's higher levels reflect the score at which physicians are likely to prescribe medications. This led to a conversation on the value of this two-metric approach: one level for self-care and a higher one for medication. As Roger notes, this aligns with the concept of "prehypertension" that has him taking steps to reduce his blood pressure slightly without the aid of medication. Naim goes on to discuss two novel sets of studies he is conducting, one with the diet app Noom and the other with a range of digital therapeutics companies.Donna Cryer begins by announcing she has three pieces of news to report: a recently released paper supported by Novo Nordisk and developed with a group convened by the National Committee for Quality Assurance, titled "A Rallying Cry: Improving Coordinated Care for People with Nonalcoholic Steatohepatitis," a scientific statement from the American Heart Association on the connection between NASH and cardiovascular disease, and the formal launch of GLI's "Liver Health is Public Health" campaign. The NCQA paper and entire idea of liver health as public health launch spirited conversation with emphatic agreement among the three participants. When Roger shares some thoughts from Naim's conversation about the potential for digital heath apps to become personalized and tailored over time, it leads Donna to a fourth announcement about a talk she is giving next week at the University of California Health System on the use of data for the public good. As with Naim, the conversation turns to the use of digital health in its many forms to improve liver care.Combined with the Episode 20 conversation with the three permanent Surfers, this episode connects the many streams of Fatty Liver research into a single package that is part pharmacotherapy, part better diagnostics, part digital health and part public policy.

Dr. Pescatello is Distinguished Professor of Kinesiology at the University of Connecticut (UConn). She holds joint appointments in the Departments of Allied Health Sciences, Nutritional Sciences, and Physiology and Neurobiology at UConn, and the Department of Community Medicine and Health Care at the UConn School of Medicine. Her research focuses on exercise prescription to optimize health benefits — particularly among adults with hypertension and overweight and obesity — and on genetic and clinical determinants of the response of health-related phenotypes to exercise, particularly blood pressure and muscle strength. Dr. Pescatello was an associate editor of the eighth edition of the American College of Sports Medicine (ACSM) Guidelines for Exercise Testing and Prescription, is Senior Editor of the ninth edition of the ACSM's Guidelines for Exercise Testing and Prescription, and recently served as an expert panel and writing team member on an update of the ACSM's exercise pre-participation health screening recommendations. She has authored over 150 manuscripts, 4 books, and 16 book chapters, and has had numerous grants funded by UConn, the American Heart Association, the National Dairy Council, NIH, and USDA. Dr. Pescatello has served in multiple leadership roles for ACSM. Twitter handles of institutions: @UConnCAHNR, @UConnResearch, @UConn --- This podcast episode is sponsored by Fibion Inc. | The New Gold Standard for Sedentary Behaviour and Physical Activity Monitoring Learn more about Fibion: fibion.com/research --- Collect, store and manage SB and PA data easily and remotely - Discover new Fibion SENS Motion: https://sens.fibion.com/

This week, please join author Andrew Chapman and Guest Editor Harvey White as they discuss the article "Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study." 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. Dr. Greg Hundley: Well, Carolyn, this week's feature on April 19th refers to coronary artery and cardiac disease in patients with type two myocardial infarction. And we will have more to learn about that, but how about we grab a cup of coffee and get started with some of the other articles in the issues. Dr. Carolyn Lam: Please? You first. Dr. Greg Hundley: Thanks Carolyn. So Carolyn, this team investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity based proteomic assays to estimate their association with incident heart failure. And so to accomplish this, the team, led by Dr. Thomas Lumbers from University College of London, utilized a fixed effect meta-analysis of four population-based studies comprising a total of 3,000 plus participants with 732 heart failure events. Now, the causal effects of heart failure associated proteins were then investigated by Mendelian randomization using CIS protein, quantitative loci, genetic instruments identified from genome-wide association studies or GWAS and over 30,000 individuals. Dr. Carolyn Lam: Wow! Big study, important stuff. So what did they find? Dr. Greg Hundley: Right Carolyn, several things. So 44 of 90 proteins were positively associated with the risk of incident heart failure. Now, among these eight proteins had evidence of a causal association with heart failure that was robust to multiverse sensitivity analysis. Higher CSF1, Galectin-3 and KIM-1 or kidney injury molecule one were positively associated with the risk of heart failure, whereas higher adrenomedullin chitinase-3 like-protein-1, cathepsin L1, and fibroblast growth factor 23, and matrix metalloproteinase 12 were protective. And so Carolyn in summary, the team identified 44 circulating proteins that were associated with incident heart failure of which eight showed evidence of a causal relationship, and seven were identified as being drugable, including adrenomedullin, which represents a particularly promising drug target. Dr. Greg Hundley: Additionally, Carolyn, this is a really interesting study as the teams approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases. Dr Carolyn Lam: Wow! Super cool. Yeah, indeed the methodology is significant there too. Thanks Greg. Well, this next paper deals with hypertrophic cardiomyopathy and we know that familial hypertrophic cardiomyopathy is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. But how exactly is the dysregulated sarcomeric force production sensed and how does that lead to pathological remodeling? Dr. Carolyn Lam: Well, today's authors and they are Dr. Qyang from Yale University School of Medicine and colleagues gained insights from a severe phenotype of an individual with hypertrophic cardiomyopathy and a second genetic alteration in a sarcomeric mechanosensing protein. They derived cardiomyocytes from patient specific induced pluripotent stem cells and developed robust, engineered heart tissues to study human cardiac mechanobiology at both cellular and tissue levels. They further used computational modeling for muscle contraction and rescue of disease phenotype via gene editing and pharmacological interventions to identify a new mechanotransduction pathway in hypertrophic cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn! Tell us more about this new pathway. Dr. Carolyn Lam: The study presents a novel biomechanical mechanism by which enhanced myofilament contractile force generation due to sarcomeric mutations, destabilize the muscle limb protein Z-disc mechanosensory complex, and this leads to disinhibition of calcineurin nuclear factor of activated T-cells or NFAT signaling and consequently leads to hypertrophy. Normalization of hypercontractile force in proband cardiomyocytes either with gene editing approaches or with ectomyosin crossbridge inhibitor mavacamten, resulted in an increase in Muscle Lim Protein levels, a decrease in that calcineurin and fat activity and a rescue from the hypertrophic cardiomyopathy defects. Dr. Carolyn Lam: The authors provided evidence that the common Muscle Lim Protein W4R variant is an important modifier that worsens the disease severity of hypertrophic cardiomyopathy, but alone does not appear sufficient to cause disease. All in all, these data established a foundation for developing innovative mechanism-based treatments for hypertrophic cardiomyopathy that stabilize the Z-disc Muscle Lim Protein mechanosensory complex. Dr. Greg Hundley: Oh, wow Carolyn! What a really nice mechanistic study and important new information too. Well, Carolyn, my next paper comes to us from Dr. Anthony Rosenzweig, Massachusetts General Hospital at the Harvard Medical School and Carolyn the LV myocardium increases in mass in response to pathological as well as physiological stimuli. The former or pathologic hypertrophy, often proceeds cardiomyocyte loss and heart failure. The latter or physiologic, paradoxically protects the heart enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Now, while long non-encoding RNAs are important in cardiac development and disease associated with pathologic hypertrophy, less is known about their roles in physiologic hypertrophy or cardiomyogenesis. Dr Carolyn Lam: Oh, interesting! So what did these authors find about link RNAs and physiologic hypertrophy? Dr Greg Hundley: Right, Carolyn. So in this study of mice, the authors identified exercise regulated cardiac link RNAs termed lncExACT and lncExACT1 was evolutionarily conserved and decreased in exercised hearts, but increased in experimental heart failure. Cardiac lncExACT1 over expression caused pathological hypertrophy and heart failure while lncExACT1 inhibition induced physiologic hypertrophy and cardiomyogenesis protecting against cardiac fibrosis and dysfunction. Dr. Greg Hundley: Now, lncExACT1 functioned by regulating microRNA 222 calcineurine signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCH2 over expression in zebra fish induced pathological hypertrophy and impaired cardiac regeneration promoting scarring after this injury. In contrast mirroring DCH2 deletion, induced physiological hypertrophy and promoted cardiomyogenesis. Dr. Carolyn Lam: Oh, wow, Greg! Okay. Could you wrap it up for us? What's the take home message? Dr. Greg Hundley: You bet, Carolyn. These studies identify that lncExACT1 DCHS2 is a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1 DCHS2 acts as a master switch, toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the benefits of exercise. Dr Carolyn Lam: Oh, thank you, Greg. Well, also in this issue is an In-Depth paper by Dr. Luesebrink on “Percutaneous Transvalvular Micro Exhale Flow Pump Support in Cardiology.” There's a Research Letter by Dr. Shekhar on “Age and Racial or Ethnic Disparities in Pediatric Out-of-Hospital Cardiac Arrest.” Dr. Greg Hundley: Right, Carolyn. Well, Carolyn from the mailbag, we have a Letter to the Editor from Dr. Gronda entitled “The Failing Heart and SGLT2 inhibitor Renal Effects: Are They Mutually Engaged in Business?” We also have from Dr. Viskin, an ECG challenge entitled “Sinus Node Dysfunction with a Nice Twist.” And finally, Carolyn, there's a Perspective piece from Dr. Schulman entitled “The Price and Quality of the Generic Pharmaceutical Market.” Well, how about at Carolyn we get on our feature discussion involving type two myocardial infarction. Dr. Carolyn Lam: Yay! Let's go. Dr. Greg Hundley: Well, listeners, welcome to our feature discussion on this April 19th and we have with us today, Dr. Andrew Chapman from Edinburg, Scotland and Dr. Harvey White from Auckland, New Zealand. Welcome gentlemen. And we'll start with you, Andrew. First, could you describe for us some of the background information that went into the preparation of your study? Dr Andrew Chapman: Good morning and good evening and thank you very much for the invitation. So type two myocardial infarction is an interesting diagnosis. It was first introduced in around 2007 in recognition that patients could have heart injury when they were in hospital with other problems that led to an imbalance in myocardial oxygen supply, or an unmet need in myocardial oxygen demand, without the presence of atherothrombotic coronary artery disease. We don't know a great deal about these patients. Dr. Andrew Chapman: There have been a number of observational cohort studies, including from ourselves in Scotland, which have demonstrated the outcomes for this patient group are poor. We know only around one-third of patients with type two MI, survive to five years after diagnosis. And we also know, and previously demonstrated from patients in Scotland that those with underlying coronary artery disease actually had the worst outcomes and were at increased risk of future myocardial infarction events due to plaque rupture. So we hypothesized that patients with type two myocardial infarction may have failed a physiological stress test due to another illness and we wanted to investigate what the prevalence of underlying coronary artery disease and/or structural heart disease was, using a panel of different imaging modalities. Dr. Greg Hundley: And so Andrew tell us the hypothesis that you wanted to address? Dr. Andrew Chapman: So we believed that observational evidence suggested that coronary artery disease was important in patients with type two myocardial infarction and we felt that this was increasing their susceptibility to these events. Our primary hypothesis was that the majority of patients with type two myocardial infarction would have underlying coronary artery disease, which was previously quiescent undetected. Dr. Greg Hundley: Tell us a little bit about the study design and the study population that you use to answer this question. Dr. Andrew Chapman: Demand MI is to our knowledge, the first prospective observational cohort study in which patients who were in hospital with evidence of myocardial injury, so a raised cardiac troponin, were screened for the presence of supplier demand imbalance and the clinical diagnosis of type two MI. Now, in those patients that we were able to recruit, we did obviously have important exclusion criteria, but we designed a series of different investigations depending on individual patient risk factors and the appropriateness of such, but the primary goal was to undertake coronary angiography, ideally using an invasive coronary angiogram, which would allow us to undertake additional testing, such as plaque imaging and pressure wire study, to look for the functional consequences of stenosis. In those not fit for an invasive angiogram, we undertook CT coronary angiography. And in all patients we undertook structural imaging and we aimed to do cardiac MRI in all. Due to the coronavirus pandemic and for other reasons, we used echocardiography where MRI was not available. Dr. Greg Hundley: And so the total number of subjects here was how many? Dr. Andrew Chapman: We recruited 100 patients with a clinical diagnosis of type two myocardial infarction. Dr. Greg Hundley: Very good. And so now, Andrew, what were your results? Dr. Andrew Chapman: It's a really fascinating study, obviously, in my opinion. So we recruited 100 patients with a clinical diagnosis of type two myocardial infarction who had evidence of supplier demand and balance, a raised cardiac troponin concentration and evidence of symptoms and/or signs of myocardial ischemia. So in line with the universal definition criteria. Of 100 patients after undertaking coronary imaging, we reclassified the diagnosis in seven. Dr. Andrew Chapman: In five patients, we found that there was evidence of either plaque rupture or a stent thrombosis. And in two patients, we found evidence of myocarditis and stress cardiomyopathy respectively. The first principle finding is that actually despite careful characterization and really detailed screening, we were correct in 93 of 100 patients and we got the diagnosis wrong in seven. The principle hypothesis related to the prevalence of coronary artery disease and this was, as alluded to, undertaking with invasive and noninvasive imaging. But overall, the prevalence of coronary artery disease was 68% of those with type two myocardial infarction and this was obstructive in 30%. Dr. Andrew Chapman: We also undertook structural imaging as mentioned. We observed evidence of left ventricular systolic dysfunction in 34% of patients, of around a third, and perhaps most surprisingly, although we had a clear diagnosis of myocardial infarction in these patients, we only found imaging evidence of in part pattern late gadolinium enhancement, which is considered the gold standard for its diagnosis of myocardial infarction. We only observed that in 42%, which raises some interesting questions. Dr. Andrew Chapman: One of the principle clinical findings of the study is that these underlying conditions of coronary artery disease and left ventricular impairment, both of which are readily treatable with secondary prevention. These conditions were previously unrecognized in 60% of patients and only one-third were on appropriate evidence-based treatment, which gives me some cause for optimism, that there may be a role here for targeted treatment, which could plausibly, plausibly impact on outcomes. Dr. Greg Hundley: And Andrew, just a clarification point, maybe a subgroup analysis, any differences in your findings in regarding men versus women? Dr. Andrew Chapman: Excellent question. And in most studies of type two myocardial infarction, it's thought that this condition is more prevalent in women than men, but undoubtedly in all observational cohorts, there is selection bias as you will only diagnose a type two myocardial infarction if a clinician requests to test troponin in the first place. In our study, interestingly, we recruited more men than women. We had 56% men and we did not find any differences by sex in our analysis. Dr. Greg Hundley: Well listeners, what an excellent description from Dr. Chapman. A very interesting study. And we now want to turn to one of our editors, guest editors, Dr. Harvey White, and Harvey, we want to thank you for your work here with us at the American Heart Association and Circulation, and you receive many articles to review. What attracted you to this particular article and how do we put in context, these results with others that have been published pertaining to type two myocardial infarction? Dr. Harvey White: Thanks, Greg, it's a pleasure to work for Circulation. This paper is very close to my heart because I introduced the typing system in 2007 and it had minimal support and people said, "Why do we need a typing system? We've got killer class and Canadian class and you've done a troponin release system as well". And people stood up and then I laid out the type one plaque rupture. We know the pathophysiology and we know the treatment. Type two, I'd worked on beta blockers, supply and demand and I thought we should define the pathophysiology and define the treatment. That's 2007, which is 15, 16 years ago. And Andrew's paper is really lovely. As I said, it's close to my heart and he inches things forward. I've written an editorial, which I call "Zooming in on the enigmas of type two MI" and enigma means mystery or it's unclear, uncertain. Dr. Harvey White: And that's for sure we don't have full support for the diagnosis. It's become very practical, used in clinical trials and clinically, but we don't know how to manage it and we don't know how to define the groups. Andrew and colleague study is very nice. It's prospective and it has set out to define the coronary artery disease. I've tried for about 10 years to subdivide type two and to those without coronary disease and those with coronary disease. And you could also have a type C, which hasn't been investigated or unknown. And Andrew has answered one of the enigmas and it's really interesting. Large proportion, normal coronary arteries, diagnosis was changed a little bit based on the finding of thrombus. We're challenged with that finding because all MIs have thrombus at PM and really type one should be ruptured plaque. But Andrew changed the diagnosis in a few where one was an OTC, a marvelous case with marvelous pictures, changed the diagnosis. So I like the study and I like the findings. Thanks. Dr. Greg Hundley: Very nice. Well, Andrew, what a perspective and listeners getting just to listen to Dr. White is really quite exciting for me. Andrew, what do you see as the next study to be performed in this sphere of research? Dr. Andrew Chapman: I think we've gone some way to provide some insights into the underlying pathophysiology of this condition and these coexistent conditions of coronary artery disease and left ventricular impairment, which might increase an individual's susceptibility to a type two myocardial infarction. The question is what can we do about it and does targeted treatment with secondary prevention therapies for coronary disease and treatment for heart failure left ventricular impairment, does that improve outcomes? Dr. Andrew Chapman: The next study for me is clear. The next study for me, needs to be a randomized controlled trial, whereby patients with type two myocardial infarction are randomized to current best practice or risk stratification by a cardiologist with an interest in this condition, followed by targeted investigation for coronary disease and LV impairment and thereafter treatment as appropriate. This will be a trial of a complex intervention. I'm very grateful that we've received funding in Scotland already for this pilot phase of this trial, which we've called Targets Type Two and we'll begin recruitment for that trial in August of this year. Dr. Andrew Chapman: I must acknowledge colleagues in this area are looking at coronary disease and type two myocardial infraction. Professor Derek Chew is leading a study called Act Two, which is already recruiting and that will also provide invaluable information as to the prevalence of coronary disease and the potential benefits of treatment of that coronary disease in patients with this condition. Dr. Greg Hundley: And Harvey. How about your, what is your perspective in terms of the next series of studies perhaps that need to be performed in this space? Dr. Harvey White: There's a number and I like very much, Andrew's suggestion. The study that we're doing is randomizing to angiography or not angiography working with Derek Chew. I think all patients with MI should have coronary angiography. It's simple, it takes about 10 minutes. There's obviously some contraindications, but the information as Andrew has pointed out is really so useful. He found dissection, he found an embolus. Normal coronary arteries that in my view changes the management. Whether you should do an angiogram is very important. Randomization to various treatments. That's important. I would like to get more information about the objective evidence of type two MI, the criteria for low hemoglobin, shortness of breath, low blood pressure, high blood pressure, and so forth. There's a lot to do. As Andrew pointed out, the outcome may be worse than type one that's becoming more common and I think these studies will be very, very important. Dr. Greg Hundley: Very nice well listeners. We want to thank Dr Andrew Chapman as lead investigator and Dr Harvey White as guest editor for bringing us this study using advanced imaging of patients with type two myocardial infarction, which identified coronary artery disease in two-thirds and left ventricular dysfunction in one-third, and also highlighting that unrecognized and untreated coronary or cardiac disease occurs in many patients with type two MI and gives us pause for thought on a series of studies that may be performed in the future. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American heart association, 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

RxSafe | Heart Health Panel Discussion Panelists: Sandra Awaida, PharmD Jennifer Marquez, PharmD Dr. Nathan S. Bryan, PhD Brittany R. Messer, PharmD The pharmacist plays an important role in the prevention of cardiovascular diseases, mainly through patient education, counseling, detection, and control of specific risk factors. Join RxSafe as we present experienced pharmacists and experts who will share their knowledge of best practices that have a direct impact on heart health outcomes that community pharmacies can implement in their practices. Dr. Messer is a clinical pharmacy specialist practicing with the cardiology department at Marshall Health. She completed residency at the VA Medical Center in Huntington, West Virginia, where she gained experience with heart failure medication optimization, anticoagulation management and cardiovascular disease state management, such as lipids and hypertension, in both the inpatient and ambulatory settings. Dr. Messer currently works closely with the heart failure clinic and general cardiology at Marshall Cardiology. Dr. Awaida is founder of PreciGenX, a company that helps other physicians and pharmacists grow their businesses by incorporating CCM, RPM, and PGx services in their practices. She utilizes patient monitoring and evidence-based pharmacotherapy and pharmacogenomics to prevent, predict and personalize medication therapy to improve outcomes for her patients. Dr. Marquez is an experienced, residency-trained, oncology board-certified, and PGx-certified pharmacist. She is passionate about helping patients and providers overcome drug therapy challenges. Dr. Bryan was the first to describe nitrite and nitrate as indispensable nutrients required for optimal cardiovascular health. Dr. Bryan has published a number of highly cited papers and authored or edited 5 books. He is an international leader in molecular medicine and nitric oxide biochemistry.  Panel Overview:     Cardiovascular disease is highly prevalent, affecting 4 of every 10 Americans, and its costs are expected to exceed $1.1 trillion by 2035, noted from a study published by the Journal of American Heart Association.    The pharmacist plays a relevant role in primary and secondary prevention of cardiovascular diseases, mainly through patient education and counseling, drug safety management, medication review, monitoring and reconciliation, detection and control of specific cardiovascular risk factors and clinical outcomes.   Pharmacists can be a key source of support for individuals looking to manage their heart health. Many of the conditions that increase the risk of heart disease require medication to treat, and taking those medications as prescribed can help reduce the risk of a cardiovascular event.   This discussion is about the panelists experience and knowledge of heart health best practices, suggested supplements like Nitric Oxide, lowering cholesterol, and many other topics which have a direct impact on heart health education and programs for Community Pharmacies to implement in their practices.    What is the link between cholesterol and heart disease?   Many years of scientific studies have shown a close relationship between cardiovascular disease and cholesterol levels. Your doctor may request a lipid profile—a test that shows the levels of LDL (bad cholesterol), HDL (good cholesterol), and triglycerides in your blood—to assess your risk for developing heart disease.   What about the risk of liver damage from taking statin medications?   The frequency of liver problems with statin therapy is actually quite low. Less than 1 percent of people have to stop taking statins because they develop liver problems. Long-term trials have confirmed the safety of statins—the latest guidelines do not suggest a need to monitor people on statins who have normal liver function. In addition, in some cases where there is evidence of fat deposits in the liver, statin therapy may actually improve liver function tests. Learn more about your ad choices. Visit megaphone.fm/adchoices

RxSafe | Heart Health Panel Discussion Panelists: Sandra Awaida, PharmD Jennifer Marquez, PharmD Dr. Nathan S. Bryan, PhD Brittany R. Messer, PharmD The pharmacist plays an important role in the prevention of cardiovascular diseases, mainly through patient education, counseling, detection, and control of specific risk factors. Join RxSafe as we present experienced pharmacists and experts who will share their knowledge of best practices that have a direct impact on heart health outcomes that community pharmacies can implement in their practices. Dr. Messer is a clinical pharmacy specialist practicing with the cardiology department at Marshall Health. She completed residency at the VA Medical Center in Huntington, West Virginia, where she gained experience with heart failure medication optimization, anticoagulation management and cardiovascular disease state management, such as lipids and hypertension, in both the inpatient and ambulatory settings. Dr. Messer currently works closely with the heart failure clinic and general cardiology at Marshall Cardiology. Dr. Awaida is founder of PreciGenX, a company that helps other physicians and pharmacists grow their businesses by incorporating CCM, RPM, and PGx services in their practices. She utilizes patient monitoring and evidence-based pharmacotherapy and pharmacogenomics to prevent, predict and personalize medication therapy to improve outcomes for her patients. Dr. Marquez is an experienced, residency-trained, oncology board-certified, and PGx-certified pharmacist. She is passionate about helping patients and providers overcome drug therapy challenges. Dr. Bryan was the first to describe nitrite and nitrate as indispensable nutrients required for optimal cardiovascular health. Dr. Bryan has published a number of highly cited papers and authored or edited 5 books. He is an international leader in molecular medicine and nitric oxide biochemistry.  Panel Overview:     Cardiovascular disease is highly prevalent, affecting 4 of every 10 Americans, and its costs are expected to exceed $1.1 trillion by 2035, noted from a study published by the Journal of American Heart Association.    The pharmacist plays a relevant role in primary and secondary prevention of cardiovascular diseases, mainly through patient education and counseling, drug safety management, medication review, monitoring and reconciliation, detection and control of specific cardiovascular risk factors and clinical outcomes.   Pharmacists can be a key source of support for individuals looking to manage their heart health. Many of the conditions that increase the risk of heart disease require medication to treat, and taking those medications as prescribed can help reduce the risk of a cardiovascular event.   This discussion is about the panelists experience and knowledge of heart health best practices, suggested supplements like Nitric Oxide, lowering cholesterol, and many other topics which have a direct impact on heart health education and programs for Community Pharmacies to implement in their practices.    What is the link between cholesterol and heart disease?   Many years of scientific studies have shown a close relationship between cardiovascular disease and cholesterol levels. Your doctor may request a lipid profile—a test that shows the levels of LDL (bad cholesterol), HDL (good cholesterol), and triglycerides in your blood—to assess your risk for developing heart disease.   What about the risk of liver damage from taking statin medications?   The frequency of liver problems with statin therapy is actually quite low. Less than 1 percent of people have to stop taking statins because they develop liver problems. Long-term trials have confirmed the safety of statins—the latest guidelines do not suggest a need to monitor people on statins who have normal liver function. In addition, in some cases where there is evidence of fat deposits in the liver, statin therapy may actually improve liver function tests. Learn more about your ad choices. Visit megaphone.fm/adchoices

See all the Healthcasts at https://www.biobalancehealth.com/healthcast-blog/ I have always told women who are menopausal that giving Estrogen to them after menopause lower's their risk of Alzheimer's, decreases their insulin resistance and helps decrease belly fat.  There are many studies that prove that testosterone decreases the risk of Alzheimer's Disease (AD) and delays the timing of AD by 10 years.  This is what I have always told women to reassure them about taking estrogen and testosterone after their ovaries stop making both hormones.  It is a simple concept that the practice of medicine has made very complex, however this new research article in Nature 3-2022 by Dr Kamoroff, helps support the practice of replacing the hormones that women lose with menopause, estrogen and testosterone, to prevent the diseases of aging including Osteoporosis and Dementia. Let me explain the response of the female body to our ovaries shrinking and essentially dying, which is what women's ovaries do when we become menopausal. The ovaries are the primary source of estradiol (young women's estrogen) and the only secretor of testosterone in women.  Other androgens are produced by the adrenal gland, but they do not provide a woman with the benefits of pure testosterone. At menopause blood levels of estradiol (E2) decrease to nearly zero. Free T (the active form of T), and estradiol also decreases to less than 60 pg/dl from a pre-menopausal range of 60-250 pg/dl.   In response to this radical change in a woman's chemistry, and very low levels of Estradiol and Testosterone, the pituitary raises the FSH and LH production, the hormones that, previous to menopause stimulated the ovaries to make more E2 and T. After menopause the increasing of FSH and LH continues to increase and cause hot flashes and night sweats.  These two hormones are only suppressed by a woman replacing Estrogen and or Testosterone (T). When women get E2 and T, it causes the FSH and LH to “relax” and stop sending out high levels, so hot flashes and night sweats stop.  If E and T are not replaced, LH and FSH continue to be elevated and these symptoms can continue for life! This most recent study by Dr. Kamaroff goes one step farther toward what I already know about ERT (estrogen replacement therapy), and just described. The only way to stop the cause of elevated FSH and LH, and hot flashes and night sweats, is the replacement of estrogen and testosterone. Giving enough estrogen to achieve pre-menopausal blood levels of these two hormones is to give higher doses than the FDA approves of.  It is our goal to prevent AD, dementia and Osteoporosis my dosing adequate Estradiol and Testosterone in the form of subcuticular pellets.  Low dose estradiol is not the way to be healthy after menopause.  Women need adequate hormones to shut down the FSH and LH surges and that is the way to prevent several of the diseases of aging. Simply, this new study links the elevation of FSH and LH to the onset of dementia, Alzheimer's Disease and Osteoporosis (thinning of bones) after menopause. But how does FSH and LH cause dementia and Alzheimer's disease? This study blames the elevation of FSH and LH for causing inflammation and the accumulation of B amyloid on neurons in the brain is a response to inflammation. This accumulation of plaque causes Alzheimer's Disease (AD). It seems that the recommendation of the American College of OBGYN gives to doctors to limit the dose and the time ERT and HT are given is counterproductive to the health of women's brains and bones.  The result is that most women are given too little estrogen, and therefore are still at moderate risk for AD and Osteoporosis.   When we give compounded E2 and T with pellets, the FSH and LH are suppressed to pre-menopausal levels, and therefore it is the best way to prevent hot flashes but also prevent osteoporosis and AD that can develop without a sufficient amount of estrogen.  It is in this way that women without ERT or who have low dose estrogen replacement oral, or patch have a higher risk of the diseases of aging, AD and Osteoporosis than those women who are given an adequate dose that provides pre-menopausal blood levels. A second study reported at the American Heart Association's Epidemiology, Prevention, Lifestyle & Cardiometabolic Health Conference 2022, also reported that the longer a woman is without estrogen, the higher her risk of developing heart disease and dementia. This is consistent with the first study I cited, that links high LH and FSH to these diseases of aging. This study looked at women who go through menopause early, before 40, who therefore have more years of high LH and FSH, and a longer period of time associated with inadequate estradiol and testosterone. The earlier women experience menopause the higher the incidence of Dementia by 1.3 times the rate of women who went through menopause at the normal time, after age 40. The healthier aging without disease occurred in women who had more exposure to Estradiol and Testosterone, and less exposure to elevated FSH and LH. The bottom line for both research studies is that estradiol is one of the keys to healthy aging, pivotal to preventing the devastating diseases of aging like Osteoporosis, Heart Disease, and Dementia. Estradiol is a hormone that should NOT be dosed to achieve a minimal blood level, and when it is replaced after menopause with reasonable doses meant to achieve a normal physiologic blood level , this one hormone brings a woman's body back to homeostasis and can lead to healthy aging without the diseases of aging. March 22, 2022 Follicle-Stimulating Hormone's Role in Alzheimer Disease, in Mice Anthony L. Komaroff, MD, reviewing Xiong J et al. Nature 2022 Mar Blocking FSH in ovariectomized mice protected against cognitive decline. The incidence of Alzheimer disease (AD) is particularly high in older women, as are levels of follicle-stimulating hormone (FSH). This observation led investigators to wonder whether blocking the action of FSH might be beneficial. In mouse models of AD, ovariectomy (with its associated sharp rise in FSH level) promptly increases the degree of deposition of both β-amyloid and tau, which are cardinal pathologic features of AD. Following ovariectomy in mice, the researchers administered a monoclonal antibody that blocked the action of FSH. The antibody reduced deposition of both β-amyloid and tau in the brain and protected against cognitive decline. The mechanism for this effect is that blocking FSH also blocks an enzyme that causes accumulation of both β-amyloid and tau. Further incriminating FSH in AD pathology, deposition of β-amyloid and tau also was reduced by using genetic engineering to knock out receptors for FSH, and deposition was increased by raising levels of FSH. FSH also is produced at low levels in males, and the FSH-blocking antibody also reduced hippocampal and cortical deposition of β-amyloid and tau in males. Experiments showed that two other features of menopause — low estrogen levels and high luteinizing hormone levels — did not explain the AD-like features seen in ovariectomized mice. COMMENT Many, but not all, findings in mouse models of AD have been replicated in humans. Blocking FSH also reduced bone loss and visceral fat in mice. Given all these theoretical benefits, one might surmise that trials of FSH blockade in humans will be undertaken. Study: Early menopause may signal women's dementia risk A preliminary study to be presented at the American Heart Association's Epidemiology, Prevention, Lifestyle & Cardiometabolic Health Conference 2022 found that women who experience menopause before they reach 40 years of age may have a 35% increased risk for dementia later in life. The researchers also found that women who entered menopause before they turned 45 years old were 1.3 times more likely to receive an early dementia diagnosis by the time they reach 65 years of age.

Ahna talks about how she went from working as a nurse practitioner to running her own successful entrepreneurial businesses, Jason and Ahna discuss their shared love of the Brits and why it's critically important for women to ditch the scale and focus on what really matters with your health."The truth is rarely found in the extremes. But somewhere in the middle. Fight hard for that middle ground."Ahna Fulmer is the author and owner of leading DIY healthy lifestyle blog, Hammers N Hugs, where women are inspired to reclaim their hearts and homes by empowering holistic wellness with all-natural recipes, fitness and nutrition advice, DIY tutorials, home decor inspiration, and family fun to redevelop your emotional, mental, physical, spiritual, and social health – one imperfect day at a time.A podcast host, dual-certified nurse practitioner, fitness/nutrition coach, and DIY pro – Ahna has been published by the American Heart Association and featured on major platforms such as iHeart Radio, ABC News, Wayfair, Apartment Therapy, Authority Magazine, Thrive Global, and American Farmhouse Style Magazine.http://www.hammersnhugs.comhttps://www.facebook.com/ahnahammersnhugs/https://instagram.com/ahna_hammersnhugs/Enjoying the podcast? Please tell your friends, give us a shoutout and a follow on social media, and take a moment to leave us a review at https://lovethepodcast.com/talkingtocoolpeople.Find the show at all of the cool spots below.WebsiteFacebookInstagramIf something from this or any episode has sparked your interest and you'd like to connect about it, please email us at podcast@jasonfrazell.com. We love hearing from our listeners!If you are interested in being a guest on the show, please visit jasonfrazell.com/podcasts.