Podcasts about Endothelium

In this episode, I sit down with Mark Young, CEO of Zona Health, for a conversation that bridges the worlds of health tech, personal growth, and taking radical ownership of your wellbeing.With a career spanning multiple startups and a passion for education, Mark shares how his mission at Zona is not just about product innovation—but empowering people to make informed, sovereign choices about their health. We explore how the Zona Plus supports cardiovascular function, nervous system regulation, and vagal tone in just minutes a day—without medication. Mark also unpacks why so many people outsource their health to insurance companies and governments, and why reclaiming personal responsibility is the real path to vitality.This is a deep dive into the psychology of behavior change, the myth of "rulers" coming to save us, and how micro-decisions shape your long-term outcomes. If you're looking for an honest conversation about sovereignty, science, and self-reliance, this one's for you. Visit zona.com/lukestorey and use code LUKE100 to save $100 off Zona Plus.DISCLAIMER: This podcast is for educational purposes only and not intended for diagnosing or treating illnesses. The hosts disclaim responsibility for any adverse effects from using the information presented. Consult your healthcare provider before using referenced products. This podcast may include paid endorsements.THIS SHOW IS BROUGHT TO YOU BY:LIMITLESS LIVING MD | Book your free consultation today at limitlesslivingmd.com/luke and use code LUKE for 12% off your first order.SUNLIGHTEN | Save up to $600 when you go to lukestorey.com/sunlighten and use code LUKESTOREY in the pricing form.LEELA QUANTUM TECH | Go to lukestorey.com/leelaq and use code LUKE10 for 10% off their product line.NUCALM | Go to nucalm.com and use code LUKE for 15% off!MORE ABOUT THIS EPISODE:(00:00:00) Redefining Radical Generosity(00:05:29) The Physiology of Generosity & the Power of Identity(00:22:21) Identity, Recovery, & the Power of Words(00:31:23) Heart Health, Zona, & Preventative Wake-Up Calls(00:48:04) Zona Demo, Fighter Pilots, & the Real Science Behind Isometric Training(01:07:50) Resetting Your Blood Pressure: Potassium, Endothelium, & the Real Fix(01:30:50) Salt, Science, & Questioning the Narrative(01:40:37) No One's Coming to Save You: Personal Sovereignty & Health Ownership(01:49:55) Zona Protocols, Nervous System Benefits, & the Bona Zona RevelationResources:Website: zona.comWebsite: ryzeagency.comInstagram: instagram.com/themarkyoungInstagram: instagram.com/zonahealthFacebook:

Statistically speaking, cardiovascular disease is the most likely thing both to kill you and to make you stop living before you die.  Knowing the most likely thing to cause the the thing that is most likely to kill you can help you decide what to deliberately put on autopilot in your daily life to drastically decrease your chances of becoming a statistic so you're more able to help the people who need you most as you get older rather than the other way around.Free list of supplement brands I trustsend me a message: healthcouragecollective@gmail.comMy Website

Send us a Text Message.Join Skool HereRichard and Stephen discuss various questions about issues some people may have when following a carnivorous diet. One question addresses whether or not it is okay to consume protein and fat immediately after working out, or if it is better to wait until later in the day. Richard explains that waiting a few hours after working out allows for multiple mTOR responses, which are important for muscle growth. They also discuss the importance of balancing AMPK and mTOR responses. Another question asks about whether there are any health: A question was asked about whether eating red meat can increase the growth of polyps in the colon. The answer was no, as red meat is not inflammatory and can even have anti-inflammatory effects. Other factors, such as processed foods, can contribute to inflammation. Another question was about how to maintain or gain weight on a carnivore diet. The answer suggested being intuitive with eating and not worrying about calorie intake. Advice was also given on incorporating resistance training and adjusting protein and fat intake to achieve.A low-carb, high-fat carnivore diet may help with weight loss, but everyone is different and may need different amounts of food to maintain their weight. The specific types of food, such as chicken, eggs, and pork, may not be harmful unless they are oxidized. High triglycerides may not necessarily be a problem, and factors such as reducing carbohydrate intake, increasing fish consumption, and overall good health should be taken into consideration when looking at triglyceride levels. Thank you so much for listening to my podcast. I hope you enjoyed it. Your support means the absolute world to me. And if you're enjoying the show, I've got a small favor to ask you. I'd be incredibly grateful if you would consider becoming a supporter and make a small monthly donation. Your contribution will really help to improve the show. It's a small monthly contribution. You can cancel at any time, and the link is in the show notes. Support the Show.All my links in 1 easy list, including booking and personal training workout plans at LINKTREE You can now download the carnivore experience appApple direct link for apple devices Google play store direct link to app for Android Coach Stephen's Instagram Book me for coaching My growing UK carnivore YouTube channel I have set up a community that is all about eating low-carb and specifically carnivore. CLICK HERE Support my podcast from just £3 per monthBECOME A SUPPORTER Success stories Optimal Health 5 Star reviews All my facebook and other reviews are here Thanks to www.audionautix.com for any music included. Ple...

Steven Lome, M.D., discusses the profound impact of adopting a plant-based diet on heart health. Drawing from historical anecdotes, scientific studies, and real-life transformations, Dr. Lome emphasizes how dietary changes can not only prevent but also reverse heart disease, America's number one killer. He champions a shift from "pills to plants," underscoring the multi-dimensional benefits of a plant-based diet – from personal health to ethical and environmental considerations. Highlighting pioneers like Nathan Pritikin and Dr. Dean Ornish, this segment serves as a compelling testament to the profound healing power of food. #PlantBasedHeartHealth, #FromPillsToPlants, #DietaryReversal  

Join me on the Flex Diet Podcast as I sit down with the esteemed cardiologist Dr. Michael Twyman to tackle the vital subject of cardiovascular health and the power of early risk detection. We discuss the significance of functional testing and specific scans that could revolutionize your approach to heart disease prevention. Listen in as Dr. Twyman shares his transformation from invasive to preventative cardiology and learn about the essential tests he recommends for gaining invaluable insights into your heart health.For Dr. Twyman's top 4 takeaways, go to https://miketnelson.com/flex4. Special thanks to Flex Diet Podcast sponsor LMNT. Choose LMNT for all your hydration needs. Check out https://drinklmnt.com/mikenelson.Episode Chapters:(0:00:00) - Cardiovascular Health and Early Detection(0:06:22) - Cardiovascular Risk and Plaque Development(0:12:37) - Understanding Heart Health and Cholesterol(0:19:13) - Understanding Lipoproteins and Cardiovascular Health(0:27:54) - Functional Testing for Arterial Health(0:36:32) - Nitric Oxide and Arterial Health(0:44:18) - Understanding the Calcium Score Test(0:50:34) - The Importance of Circadian Rhythms(1:00:47) - Optimal Red Light Therapy Parameters Connect with Dr. Twyman:InstagramWebsite 

Dr Paul Batman is a university academic and is recognised as one of the world's leading exercise physiologists. As co-founder of Fitness Institute Australia (FIA) and a university lecturer, Paul has trained thousands of people to become accredited in the fields of Exercise Science, Sports Coaching and Personal Training. He is a vocational educator, researcher, author, and avid fitness tragic. “For over 40 years I had been participating in and prescribing moderate to high intensity exercise to increase fitness, improve wellbeing and lose weight. Two weeks away from climbing Mount Killimanjaro at age 65 years, my Cardiologist told me I was close to having a fatal heart attack, with one of my coronary arteries 90% blocked. I had been aware of many well-trained athletes for no apparent reason suffering a heart attack against, but I thought it would never happen to me. This diagnosis tipped my approach to exercise programming upside down.” Listen to Paul explain chronic cardio syndrome and the loss in elasticity of endothelial lines, why Orcas in captivity suffer a floppy dorsal fin, how MET (metabolic equivalent of tasks) is transforming fitness programming and Andrew (nervously) asks Paul to assess the guidelines he and Dr Tom Buckley have just released for Level 1 Physiology Building Blocks and Level 2 Longevity and Performance.In this podcast Andrew and Dr Paul discuss:2:25 The change in fitness methods from 15 years ago to now3:45 Dr Paul's own heart attack scare and how he was in disbelief6:15 Shifting the narrative on wellbeing and exercise programming to align with his new research7:20 Endothelium lines and 'the widowmaker'12:00 Exercising too much and METs (Metabolic Equivalent of Tasks)15:00 The wrong messages about exercise going out to the public and how outsourcing your life can eventually kill you18:00 How Dr Paul trains for treks doing housework and vacuuming (this part of the podcast should be sponsored by Dyson vacuum cleaners)21:15 Being sedentary vs being inactive23:30 Getting your 10,000 steps daily and why this is so important27:15 Floppy dorsal fin syndrome and Andrew's analogy of how this plays out for unfit, inflamed middle-aged men31:30 The problem with having too much information about exercise (over-analysis leads to paralysis)34:00 How much sitting is too much and looking at opportunities to move37:30 The best way to exercise during the week 42:30 Creating a tribe of active non-exercisers44:30 Why the World Health Organisation doesn't really work well with the fitness industry47:30 What drives Dr Paul and longevity49:15 Getting kids active.52:30 Dr Paul's thoughts on Andrew's Level 1 Physiology Building Blocks.56:00 Intermittent fasting throughout history and using temperature contrast therapy59:00 Andrew's Level 2 Longevity and Performance, and the importance of lifting heavy weights1:03:20 Sarcopenia and ageing To find the resources mentioned in this episode go to: https://www.andrewmay.com/performance-intelligence-with-andrew-may/ Find Dr Paul at his LinkedIn: https://www.linkedin.com/in/dr-paul-batman-9092a052/Or at his Website: https://www.drpaulbatman.com.au/ Find out more about Andrew's Keynotes : https://www.andrewmay.com/keynotes/Follow Andrew May: https://www.instagram.com/andrewmay/Follow StriveStronger: https://www.instagram.com/strive.stronger/If you enjoy the podcast, we would really appreciate you leaving a short review on Apple Podcasts, Spotify or Google Play. It takes less than 60 seconds and really helps us build our audience and continue to provide high quality guests.

Focus On The LDL, Don't Smoke, Eat Healthy, Exercise, And Protect Your Endothelium At All Costs Steven Lome • https://www.HeartStrong.com #StevenLome#CardiovascularDisease#PlantBasedDiets#ReverseChronicDisease Steven Lome is a doctor of osteopathic medicine, concentrating in Cardiovascular Disease and Lifestyle Medicine. He is currently the medical director at Montage Cardiology and Community Hospital of the Monterey Peninsula. Dr. Lome is the founder/author of HeartStrong.com, a free website to teach people the power of plant based diets and lifestyle changes to prevent and reverse chronic diseases. Read Dr. Lome's Forks Over Knives article detailing how he fell into two traps: The standard American Diet (SAD) and practicing standard western medicine ignoring diet and lifestyle. He successfully lost 100 pounds making many mistakes along the way. He now has a strong commitment to helping others overcome their unhealthy lifestyle habits seeing the power of lifestyle medicine personally and within his family. Hear his powerful story straight from Dr. Lome him during this interview on the Ian Cramer Podcast. Dr. Lome holds board certifications in Internal Medicine, Cardiovascular Disease, Cardiac CT, Nuclear Cardiology, Echocardiography, Vascular Medicine, he is a registered vascular technologist (R.V.T.) and a registered physicain in vascular interpretation (R.P.V.I.). As a member of the Physician's Committee for Responsible Medicine, Dr. Lome has stood along slide Dr. Neal Barnard helping to change legislation and policies to improve nutrition in America. He is the founder of the Chicagoland Plant Based Nutrition Movement and continues to show a never ending passion to fight chronic diseases with plants. Dr. Lome enjoys running, swimming and his family. His wife Helen is a dedicated plant based family physician and together they have 6 plant based children. To Contact Dr Steve Lome go to YouTube: YouTube.com/StevenLomeWebsites: Founder PBNM.org , HeartStrong.com , LearnTheHeart.com Disclaimer:Medical and Health information changes constantly. Therefore, the information provided in this podcast should not be considered current, complete, or exhaustive. Reliance on any information provided in this podcast is solely at your own risk. The Real Truth About Health does not recommend or endorse any specific tests, products, procedures, or opinions referenced in the following podcasts, nor does it exercise any authority or editorial control over that material. The Real Truth About Health provides a forum for discussion of public health issues. The views and opinions of our panelists do not necessarily reflect those of The Real Truth About Health and are provided by those panelists in their individual capacities. The Real Truth About Health has not reviewed or evaluated those statements or claims. 

We are coming to a point where nothing matters in America, only the rhetoric. Indeed, it is easy to show that virtually everything they told us about Covid or its treatment was a lie. But to make matters worse, people are dying because of these lies and still it doesn't matter. Yet, how can we call our selves Christians or the church if we divorce ourselves from truth or even murder?  Join us on this episode of the Supernatural Junkies as we expose the lies and morn the dead. They Did Everything Wrong 92% of Covid Deaths Are ‘Fully Vaccinated,' Government Study Finds https://slaynews.com/news/covid-deaths-fully-vaccinated-government-study-finds/ Groundbreaking Testimony Changes Everything: Florida County RETURNS CDC Funds After Confirming Vaxx is a Bioweapon https://rumble.com/v2aecme-florida-county-returns-cdc-funds-after-confirming-vaxx-is-a-bioweapon.html New Intel Prompts Energy Dept To Assess COVID Likely Leaked From Wuhan Lab: Report https://www.dailywire.com/news/new-intel-prompts-energy-dept-to-assess-covid-likely-leaked-from-wuhan-lab-report Pfizer Covered up Deaths during Covid Shot Clinical Trials https://thinkcivics.com/pfizer-covered-up-deaths-during-covid-shot-clinical-trials/ AMA quietly reverses position, admits hydroxychloroquine works https://www.audacy.com/971talk/news/local/ama-quietly-reverses-position-admits-hydroxychloroquine-works Lies & Cooking Books BREAKING: NHS Director confirms Hospitals lied about Cause of Death to create illusion of COVID Pandemic Before Covid, four types of pneumonia added together were the highest cause of death in the UK.  In a newly implemented Medical Examiner System to certify deaths, the Medical Examiner was certifying all types of pneumonia deaths as covid-19 deaths, a former Director of End-of-Life Care has said. On Saturday, Sai, a former NHS Director of End-of-Life Care, wrote “When four different diseases [are] grouped and now being called covid-19, you will inevitably see covid-19 with a huge death rate.  “Patients being admitted and dying with very common conditions such as old age, myocardial infarctions, end-stage kidney failure, haemorrhages, strokes, COPD and cancer etc. were all now being certified as covid-19 via the Medical Examiner System. “Hospitals were switching to and from the Medical Examiner System and the pre-pandemic system as [and] when they pleased. When covid-19 deaths needed to be increased, the hospital would switch to the Medical Examiner System.” https://expose-news.com/2023/01/17/how-uk-hospitals-manipulated-cause-of-death/ Vax Health Risks Scott Adams - @ScottAdamsSays The anti-vaxxers won. I lost. Episode 1995 EXCERPT - AntiVaxxers Win https://youtu.be/C41GCgyG4mI via @YouTube BREAKING BBC News:  Cardiologist says likely contributory factor to excess cardiovascular deaths is covid mRNA vaccine and roll out should be suspended pending an inquiry. https://twitter.com/DrAseemMalhotra/status/1613837487796850688 U.S. FDA, CDC see early signal of possible Pfizer bivalent COVID shot link to stroke https://www.reuters.com/business/healthcare-pharmaceuticals/us-says-pfizers-bivalent-covid-shot-may-be-linked-stroke-older-adults-2023-01-13/ CDC, FDA Find Possible Link Between Pfizer's Bivalent COVID Shot and Strokes The U.S. Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) said last week that they are investigating a possible link between Pfizer/BioNTech's bivalent messenger RNA (mRNA) Comirnaty COVID biologic and an increased risk of a type of ischemic stroke among people 65 years of age and older. Data from the CDC's Vaccine Safety Datalink (VSD) uncovered a “safety signal” suggesting that those in this age range are more likely to suffer an ischemic stroke 21 days after getting the bivalent Comirnaty than they are 22-44 days post-vaccination.1 2 3 4 5 6 7 8 https://thevaccinereaction.org/2023/01/cdc-fda-find-possible-link-between-pfizers-bivalent-covid-shot-and-strokes/ Pilot group: Elites secretly demanding UNVAXXED pilots, flight crews Report cites many officers who have collapsed after taking shots https://www.wnd.com/2023/01/pilot-group-elites-now-demanding-flight-crews-unvaxxed/ Booster Shots May Trigger Stroke Incidents, According to CDC and FDA An Overview of Risk and Prevention In addition to cardiac events, another life-threatening side effect has been associated with the Pfizer-BioNTech vaccine. When is the risk period? Does the flu shot play any role in these events? What actions should we take to better protect ourselves? Summary of Key Facts An increased risk ofstroke events has been identified with the Pfizer COVID-19 bivalent vaccine, according to a joint statement from the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). The onset time in people aged 65 years and older was 1–21 days after the booster, with a significant cluster of events observed 11–21 days after the booster. Sixty-four percent had received the flu vaccine on the same day as the COVID-19 booster. The bivalent booster contains the code of the spike protein, contributing to the increased risk of blood clots. High-risk people should avoid the boosters. Solution:Remember the five “suddens” of stroke warning signs. Advice on preventing other risk factors of stroke is also provided in this paper. Seeing Is Believing: What the Data Reveal About Deaths Following COVID Vaccine Rollouts Around the World Why would so many countries big and small, rich and poor, in different parts of the world, some with congested cities, some sparsely populated, cold weather or hot weather, tropical or desert, high altitude or low altitude, small islands or landlocked — why would they all see increases in COVID-19 deaths after mass vaccination? https://childrenshealthdefense.org/defender/covid-vaccine-deaths-cause-unknown/ URGENT/BREAKING: UPDATED SUMMATION: The Spike Protein of SARS-CoV-2 is “Delivered” to All Organs via the Endothelium and Induces Systemic Nonsense mRNA Translations Resulting in Hyperaccelerated Aging The Spike Protein, in Essence, Acts as a Progeria Drug https://wmcresearch.substack.com/p/urgentbreaking-updated-summation MIT Expert Calls for Immediate Stop of mRNA COVID Jabs: Evidence Shows ‘Unprecedented Level of Harm' https://www.theepochtimes.com/health/mit-expert-calls-for-immediate-stop-of-mrna-covid-jab-evidence-shows-unprecedented-level-of-harm_5020151.html Heart & Myocarditis McCulllagh has said that there are now over 100 peer reviewed test indicating myocarditis Vermont had DOUBLE the Number of Fatal Cardiac Arrests in 2022 Compared to the Pre-Pandemic Average https://ashmedai.substack.com/p/vermont-had-double-the-number-of Cancer Top oncologist: Cancer in patients exploding after COVID shots https://forum.demed.com/COVID/posts/J30qO6Y6IgxgFO1rT3VR Cancer Rates Spike After Jab: Stew Peters Show 12/30/22 Mikovits & Kingston EXPOSE Premeditated Depopulation Agenda https://rumble.com/v237jm4-stew-peters-show-123022-mikovits-and-kingston-expose-premeditated-depopulat.html Dr Tess Lawrie - Vax cause inflame in every tissue  and organ https://www.theepochtimes.com/mkt_app/dr-tess-lawrie-covid-19-vaccines-cause-inflammation-in-every-organ-and-tissue-of-the-body_4902588.html COVID-19 Vaccines Causing An Alarming Uptick in Cancers | Dr. Ryan Cole by The Epoch Times https://thevaccinereaction.org/2023/02/covid-19-vaccines-causing-an-alarming-uptick-in-cancers-dr-ryan-cole/ Strokes Relationship between blood clots and COVID-19 vaccines: A literature review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9055170/   Wait, WHAT?!?!  "The last time we were here in Davos it was January 2020...and you were talking about how you were working on a vaccine for COVID." https://twitter.com/realstewpeters/status/1615907210088906752?s=42&t=I_HrX5Osbsjjf78ar430cA CDC Issues New COVID-19 Guidance After FDA Makes Change U.S. Health Officials Renew Call for Annual Coronavirus Booster Shots 1/23/23 Health officials announced Monday they want to make coronavirus booster vaccinations an annual event in America, renewing a call first made by President Joe Biden. https://www.breitbart.com/health/2023/01/24/u-s-health-officials-renew-call-for-annual-coronavirus-booster-shots/   Pfizer's Shots Aren't Safe and Were Never Shown to Be Germans Unleash Spike Protein Bombshell https://www.theepochtimes.com/mkt_app/health/pfizers-shots-arent-safe-and-were-never-shown-to-be_4947190.html Boosted Worse Off Than Vaccinated in Many States, Data Show https://www.theepochtimes.com/mkt_app/health/boosted-worse-off-than-vaccinated-in-many-states-data-show_4920614.html COVID ‘Opened the Floodgates' for New Wave of mRNA Vaccines for Livestock Several new government- and industry-funded studies are underway to develop mRNA vaccines for livestock, but “we need to be sure that no abnormal cellular or molecular changes to the animal could be induced by this type of vaccine,” one scientist told The Defender. https://childrenshealthdefense.org/defender/mrna-vaccines-livestock-big-pharma/ Week 13 : England/Wales Excess Deaths hit 20.9% Deaths registered weekly in England and Wales, provisional: week ending 31 March 2023.  Provisional number of deaths registered in England and Wales, including deaths involving coronavirus (COVID-19), in the latest weeks. https://www.reddit.com/r/unvaccinated/comments/12lh9ry/excess_deaths_up_209/?utm_source=share&utm_medium=ios_app&utm_name=ioscss&utm_content=1&utm_term=4 Analysis: COVID Vaccines Caused 300,000 Excess Deaths in 2022 Alone https://www.theepochtimes.com/health/analysis-covid-vaccines-caused-300000-excess-deaths-in-2022-alone_5163264.html?utm_source=News&src_src=News&utm_campaign=breaking-2023-04-01-2&src_cmp=breaking-2023-04-01-2&utm_medium=email&est=pnLh6sH2P2MRVJft7gRVKGwWpCt3Ug8HuuyqBBjgvwSjIeSDhnF%2FHa8%2BLseTdtDYhg%3D%3D Rand Paul On Rising: Moderna PRIVATELY Admitted The TRUTH About Myocarditis And Vaccines https://www.youtube.com/watch?v=k9D-Dz_-RpE Rhoda Wilson, BREAKING: NHS Director confirms Hospitals lied about Cause of Death to create illusion of COVID Pandemic https://jameshfetzer.org/2023/01/rhoda-wilson-breaking-nhs-director-confirms-hospitals-lied-about-cause-of-death-to-create-illusion-of-covid-pandemic/ Post COVID Vaccine Heart-Related Deaths Sharply Increase, Especially in Young Males https://thevaccinereaction.org/2023/03/post-covid-vaccine-heart-related-deaths-sharply-increase-especially-in-young-males/ Booster Shots May Trigger Stroke Incidents, According to CDC and FDA https://www.theepochtimes.com/health/booster-shots-may-trigger-stroke-incidents-according-to-cdc-and-fda_5021604.html?utm_source=Morningbrief&src_src=Morningbrief&utm_campaign=mb-2023-02-13&src_cmp=mb-2023-02-13&utm_medium=email&est=ZrfK9dxy6XKdeTWVwHAoNtjSwWfR%2FP%2Bb8h5raj0ojEenXB0CofkiUqSBApVeJULksA%3D%3D Link to a YouTube about Lockstep:https://youtu.be/HLemQHmHn3M About Dr. Dozier Pastor Thomas L. Dozier, Ph.D. Attended Life Christian University: Ph.D. Theology; Master of Arts in Pastoral Counseling; Bachelor of Arts in Theology; Faith Theological Seminary & Bible College: Diploma in Theology; Morris Brown College Undergraduate Studies. Dr. Thomas L. Dozier was a part of the LCU faculty for eleven years.  Dr. Dozier served as Academic Dean in addition to Professor of Theology and Christian Counseling.  Over the years, Dr. Dozier has been instrumental in developing various Theological and Christian Counseling courses.  Dr.  Dozier is the Senior Pastor of The Word of Grace and Truth Ministries, the President of Grace and Truth Christian University as well as the Academic Dean of Theology and Christian Counseling. check out Pastor Dozier's website and other media platforms here:  https://www.wogatministries.com/our-pastor.html YouTube: https://youtu.be/ZWa9pKcj8Eg FB: https://m.facebook.com/sharer.php?sid=117277231685999&referrer=pages_feed  Keep up with Supernatural Junkies please subscribe to our newsletter on our website: http://supernaturaljunkies.com/podcast/ By signing up for our newsletter you will be the first to know about any special events we have planned, live streaming Q&A's and we will also have links to any articles or statistical data we talk about on the show, and get some awesome Supernatural Junkies Gear! Dr Kevan's New book The Covid Beast is out on Kindle, get it here: https://read.amazon.com/kp/embed?asin=B09NMTW7GF&preview=newtab&linkCode=kpe&ref_=cm_sw_r_kb_dp_ARERGN8PMPP7FF9KK87P&tag=drkdkruse%40hotmail.com  You can the paperback version of The Covid Beast https://supernaturaljunkies.com/covid19book/ get it  NEW from our website for less $ than even AMAZON!!  Please subscribe and follow us on IG @supernatjunkies https://www.instagram.com/supernatjunkies

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.21.529379v1?rss=1 Authors: Li, Y., Ding, J., Araki, D., Zou, J., Larochelle, A. Abstract: Several differentiation protocols enable the emergence of hematopoietic stem and progenitor cells (HSPCs) from human induced pluripotent stem cells (iPSCs), yet optimized schemes to promote the development of HSPCs with self-renewal, multilineage differentiation and engraftment potential are lacking. To improve human iPSC differentiation methods, we modulated WNT, Activin/Nodal and MAPK signaling pathways by stage-specific addition of small molecule regulators CHIR99021, SB431542 and LY294002, respectively, and measured the impact on hematoendothelial formation in culture. Manipulation of these pathways provided a synergy sufficient to enhance formation of arterial hemogenic endothelium (HE) relative to control culture conditions. Importantly, this approach significantly increased production of human HSPCs with self-renewal and multilineage differentiation properties, as well as phenotypic and molecular evidence of progressive maturation in culture. Together, these findings provide a stepwise improvement in human iPSC differentiation protocols and offer a framework for manipulating intrinsic cellular cues to enable de novo generation of human HSPCs with functionality in vivo. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.15.520611v1?rss=1 Authors: Marshall, M., Ohman, L., Samasa, B., Papp, T., Parhiz, H., Rompolas, P. Abstract: Loss of vision due to corneal endothelial dysfunction affects millions worldwide and has limited treatment options. Here we present a proof-of-concept for a therapeutic approach that aims to enhance regeneration of the corneal endothelium by inducing proliferation of quiescent cells in vivo, using modified mRNA technology. To test the efficacy of this strategy we developed a mouse model to analyze corneal endothelial regeneration by longitudinal live imaging, using two-photon microscopy. The mouse corneal endothelium displayed complete cellular quiescence and a decline in cell density with aging, consistent with human data. Limited proliferation of corneal endothelial cells was observed during injury repair but was insufficient to restore the tissue to pre-injury levels. Treatment via intracameral injection of five modified mRNAs, encoding for proteins involved in cell cycle activation, induced transient proliferation in corneal endothelial cells in the absence of injury and led to an increase in tissue cell density. This approach may offer a paradigm for enhancing the regenerative response in organs with limited endogenous ability. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.17.516996v1?rss=1 Authors: Wang, Z., Sharda, N., Omtri, R., Li, L., Kandimalla, K. K. Abstract: Blood-brain barrier (BBB) is a critical portal regulating the bidirectional transport of amyloid beta (A{beta}) proteins between blood and brain. Disrupted trafficking at the BBB may not only promote the build-up of A{beta} plaques in the brain parenchyma, but also facilitate A{beta} accumulation within the BBB endothelium, which aggravates BBB dysfunction. Soluble A{beta}42:A{beta}40 ratios in plasma and cerebrospinal fluid have been reported to decrease during Alzheimer's disease (AD) progression. Our previous publications demonstrated that trafficking of A{beta}42 and A{beta}40 at the BBB is distinct and is disrupted under various pathophysiological conditions. However, the intracellular mechanisms that allow BBB endothelium to differentially handle A{beta}40 and A{beta}42 have not been clearly elucidated. In this study, we identified mechanisms of fluorescently labeled A{beta} (F-A{beta}) endocytosis in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers using pharmacological inhibition and siRNA knock-down approaches. Further, intracellular transit of F-A{beta} following endocytosis was tracked using live cell imaging. Our studies demonstrated that both F-A{beta} peptides were internalized by BBB endothelial cells via energy, dynamin and actin dependent endocytosis. Interestingly, endocytosis of F-A{beta}40 is found to be clathrin-mediated, whereas F-A{beta}42 endocytosis is caveolae-mediated. Following endocytosis, both isoforms were sorted by the endo-lysosomal system. While A{beta}42 was shown to accumulate more in the lysosome which could lead to its higher degradation and/or aggregation at lower lysosomal pH, A{beta}40 demonstrated robust accumulation in recycling endosomes which may facilitate its transcytosis across the BBB. These results provide a mechanistic insight into the selective ability of BBB endothelium to transport A{beta}40 versus A{beta}42. This knowledge contributes to the understanding of molecular pathways underlying A{beta} accumulation in the BBB endothelium and associated cerebrovascular dysfunction as well as amyloid deposition in the brain parenchyma which are implicated in AD pathogenesis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.30.514412v1?rss=1 Authors: Fain, C. E., Zheng, J., Jin, F., Ayasoufi, K., Wu, Y., Lilley, M. T., Dropik, A. R., Wolf, D. M., Rodriguez, R. C., Aibaidula, A., Tritz, Z. P., Bouchal, S. M., Pewe, L. L., Urban, S. L., Chen, Y., Chang, S.-Y., Hansen, M. J., Kachergus, J. M., Shi, J., Thompson, A. A., Harty, J. T., Parney, I. F., Sun, J., Wu, L.-J., Johnson, A. J. Abstract: CD8 T cells are implicated in the neuropathology of human cerebral malaria. Using human data as well as the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria (ECM), we sought to define contributions of brain endothelial cell MHC class I antigen (Ag) presentation to CD8 T cells in this pathology. We crossed novel H-2Kb and H-2Db LoxP mice to Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules on endothelium. RNA transcriptomes of brains during PbA infection are differential between H-2Kb and H-2Db expressing mice, highlighting differential regulation of neuropathogenesis. Distinct patterns of disease onset, CD8 T cell infiltration, targeted cell death, and regional BBB disruption and vascular leakage are observed. Strikingly, ablation of H-2Kb or H-2Db from brain endothelial cells resulted in diminished interactions of T cells with brain vasculature and lessened infiltration of activated CD8 T cells, resulting in prevention of blood-brain barrier (BBB) disruption, CNS vascular leakage and death. Overall, endothelium-specific conditional knockout (cKO) mice were protected from development of ECM resulting in survival of the mice. These data show the first in vivo evidence that interactions of CD8 T cells and cognate peptide:MHC on brain endothelium regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

This week, please join authors Paul Ridker and Eric Van Belle, editorialist Robert Harrington, and Guest Editor Allan Jaffe as they discuss the original research articles "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy" and “Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort” and the editorial "Trials and Tribulations of Randomized Clinical 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:             It's double feature time Greg. We've got two totally unique and interesting papers that we'll be discussing. The first, a biomarker substudy from the REDUCE-IT trial, that is looking at the effects of randomized treatment with icosapent ethyl, versus a mineral oil comparator, on inflammatory biomarkers. Now, don't use roll your eyes at me, because I'm telling you, this has results that you may not expect, and very, very important clinical implications, and implications for clinical trials. The second paper, very much up your alley, Greg, is a prospective MRI study of cerebral microbleeds during TAVR. But okay, enough now to whet your appetite, let's now just first grab coffees, and discuss the other papers and the issue, shall we? Dr. Greg Hundley:           You bet, Carolyn. And how about if I go first? Dr. Carolyn Lam:             Please. Dr. Greg Hundley:           So, Carolyn, my first paper comes from a group of investigators led by Dr. Araz Rawshani from the Institute of Medicine, and it included 715,143 patients with diabetes, registered in the Swedish National Diabetes Register, and compared them with over two million match controls, randomly selected from the general population, to determine the role of diabetes in the development of valvular heart disease, and particularly, the relation with risk factor control. Dr. Carolyn Lam:             Huh? Interesting, diabetes and valve disease. All right. What did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. So they found, that individuals with type one and two diabetes, have greater risk for stenotic lesions. Whereas, risk for valvular regurgitation was lower in type two diabetes. Patients with well controlled cardiovascular risk factors, continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control. So Carolyn, diabetes and a link with valvular heart disease. Dr. Carolyn Lam:             Wow. Really interesting, Greg. Thanks. Well, the next paper is a preclinical study with really interesting clinical implications. Now, we know the human heart has limited capacity to regenerate new cardiomyocytes, and that this capacity declines with age. Now, because loss of cardiomyocytes may contribute to heart failure, it is important to explore how stimulating endogenous cardiac regeneration, to favorably shift the balance between loss of cardiomyocytes and birth of new cardiomyocytes, occurs in the aged heart. Now, these authors, Doctors Rosenzweig, from Massachusetts General Hospital, and Dr. Lee from Harvard University and colleagues, previously showed that cardiomyogenesis can be activated by, guess what? Exercise in the young adult mouse heart. However, whether exercise also induces cardiomyogenesis in aged hearts, however, is not yet known. So in today's paper, the authors aim to investigate the effect of exercise on generation of new cardiomyocytes in the aged heart. And here, we're talking about 20 month old mice, who were subjected to an eight week voluntary running protocol, and age matched sedentary animals who served as controls. Dr. Greg Hundley:           Wow, Carolyn. Really interesting evaluation of exercise on cardiomyogenesis. So what did they find? Dr. Carolyn Lam:             Endogenous cardiomyogenesis can be stimulated by exercise in aged hearts. Comparative global transcriptional analysis further revealed, that exercise and age specific changes occurred in gene programs. The regulator of calcineurin RCAN1.4 was specifically found to be induced with exercise in aged hearts, and was accompanied by reduced calcineurin activity. So what's a take-home message? Exercise induced cardiomyogenesis may counter the increased cardiomyocyte loss and reduced cardio myogenic capacity in elderly patients. Dr. Greg Hundley:           Great, Carolyn. Well from the mail bag, there's an exchange of letters to the editor from Professor Zhou and Veith regarding a prior letter to the editor from Professor Jin and associates, pertaining to the previously published article “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.” And also, there's a Perspective piece, from Professor Mentz entitled, “Catastrophic Disruptions in Clinical Trials.” Dr. Carolyn Lam:             There's also a Research Letter by Dr. Kumar on [entitled] “von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis.” There's also this beautiful tour of Cardiology News from the literature, from Tracy Hampton, which ranges from a study linking COVID-19 to higher long term cardiovascular risks, which was published in Nature Med, to uncovering alternative metabolic pathways involving cell fate transitions, published in Nature, to designing an autonomous biohybrid fish, from human stem cell derived cardiac muscle cells, that was published in Science. Wow. Isn't that amazing, Greg? Well, let's get on now though, to our two feature papers. Shall we? Dr. Greg Hundley:           You bet. Welcome listeners, to these two feature discussions on this particular day. And our first feature today, we have with us Dr. Paul Ridker, from Brigham and Women's Hospital in Boston, Massachusetts. Dr. Bob Harrington, from Stanford University in California. And also, Dr. Allan Jaffe, from Rochester, Minnesota. Welcome to you all. And Paul, we're going to start for you. Can you describe for us, the background information that really went into the construct of your study, and what was the hypothesis that you wanted to address? Dr. Paul Ridker: Sure, Greg. So first of all, my thanks to the AHA and the Circulation for publishing this paper, we always want to support the AHA, and we're delighted to be here today for these podcasts. The field of omega-3 fatty acids has been a complicated one for a long time. Epidemiology suggested that, fish consumption would lower cardiovascular risk, and there was a number of trials done. And my friend and colleague here at the Brigham, Deepak Bhatt, was the lead of a very big trial, called REDUCE-IT. Some 8,000 plus patients who received EPA alone, and they got a terrific result. A 25% reduction in their primary endpoint. And this was a New England Journal paper, back in 2019 or so. But another friend of mine, Steve Nicholls, ran another large trial of a combination of eicosapentaenoic acid, or EPA, plus docosahexaenoic acid that's DHA called STRENGTH. And that one showed, really, no benefit. And so, there's been some controversy out there. In any event, when Deepak and his colleagues published their original paper, they said it's interesting, because they got this big risk reduction, but it wasn't apparently due to the triglyceride lowering of the drug. And so, my interest, as many people know, has largely been in inflammation biology. And so we said, well maybe we should just do a test. Well, we said, we'll measure a number of biomarkers that we know were associated with atherosclerosis, some inflammatory, some with coagulation. And so, that was the core hypothesis, was simply to look at some other markers, and see what we might learn. And sometimes, you learn things that you didn't expect. And I think, that goes to the heart of what complicated clinical trials are all about. And I'd also say perhaps, what the roles of surrogate endpoints are, as compared to hard clinical endpoints, and things that make this whole field kind of interesting. Dr. Greg Hundley:           Right. Very nice, Paul. So you mentioned REDUCE-IT, so describe a little bit more for your study. What was the study population, and what was your study design? Dr. Paul Ridker: We were fortunate enough to work with REDUCE-IT investigators, to use their biobank. They had put together, again, it's 8,000 plus patients. I think, it was two thirds secondary prevention, one third primary prevention. And when they received the combination of EPA and DHA, as I said earlier, they had about a 25% reduction in the risk of their primary endpoint, which was cardiovascular death, nonfatal AMI, nonfatal stroke, coronary revascularization, and the like. What we did is, we basically said, "Okay, since the mechanism was uncertain, why don't we go ahead and measure a series of biomarkers?" Things that a lot of us are interested in, homocysteine, LPLa, oxidized LDL, my own interest in inflammation. We measured, IL-1β, we measured, IL-6, we measured CRP. We measured another molecule, Lp-PLA2, that people have been interested in. And the hypothesis, of course, was to see what the drug did, as compared to the comparator did. And the findings were interesting to us, in that, to simplify them, the actual icosapent ethyl arm didn't do much to most of those biomarkers, very little change. But the mineral oil comparator arm had some small to modest effects on all those biomarkers, all of which went up again. Now, some of these effects are pretty small, two to 3% for things homocystine, LPLa. Others were moderate, 10 to 20% increases in oxidized LDL, Lp-PLA2. And the inflammatory markers went up about 25%, sometimes, even a little more. So it's complicated. It's important to point out, that these changes on an absolute scale are relatively small. On a percent scale, they're different. The REDUCE-IT investigators themselves, to their credit, had earlier published that, they saw some increase in LDL cholesterol as well, about 10, 11% in those who had received the mineral oil comparator. So it's not exactly what we thought we were going to find, I guess, is the simplest way to express it. Dr. Greg Hundley:           Very nice. And so, describe for us just a little bit more, any differences in men and women, and what about age? Or for example, premenopausal, postmenopausal women. Dr. Paul Ridker: No, the effects were quite consistent across all various subgroups. It's a very large study. There were, again, 8,000 patients, lots of blood samples been drawn. And I should again, commend the REDUCE-IT investigators, for allowing us to do this work with them. And again, as I point out, sometimes you find things out that weren't what you expected. And the hard part, I was glad this got tossed over with Dr. Harrington, is sort to figure out well, what's it really mean? Because again, as a clinical trial list, I will say, my instincts are to trust the primary endpoint of the trial. That's what they did. They're going to go out and lower heart attacks and strokes. And then, here we are a couple years later, trying to figure out what the mechanism might be, and just came across some puzzling results. Dr. Greg Hundley:           Very nice. Well, next listeners, we're going to turn to the editor that actually processed this manuscript, Dr. Allan Jaffe. Allan, what drew you to this particular article? Dr. Allan Jaffe:   Well, I was asked to be a guest editor this week, by the Journal, because of some conflicts that were intrinsic to the editorial board. And since I have an interest in biomarkers, and had for a long time, it made perfect sense for me to become involved. I was particularly interested in this particular area, because I was aware that there were these two trials that had found different endpoints, and that there were some controversy as to what the mechanisms might be by which these effects could occur. And so I was pleased to get involved. And I think it's a compliment to the REDUCE-IT investigators, and to Dr. Ridker, that they were willing to put the data out there so that everybody could see it. And we could then begin to look. So it was of interest to me. I thought it was important to the field, to get really good reviewers who would be, make sure that the data that would eventually be published was clear, so that readers would understand it. And so that, at the end, we'd be able to at least, come to some conclusions that we could end up having an expert in clinical trials. And I thought about Bob Harrington, right from the beginning, might be able to comment on. Dr. Greg Hundley:           Very nice. Well, Bob he's setting you up here nicely, both Paul and Allan, to really help us put these results in perspective with other studies that have been performed in this space. What are your thoughts? Dr. Robert Harrington:   So first off, Greg, thanks for having me. And Allan, thanks for inviting me to review and comment on the paper. As both Allan and Paul have indicated, that I've spent the last 30 plus years doing clinical trials of all sizes. Very small, where we try to understand mechanisms, and very large, where what we're trying to understand is clinical outcomes. And I've been intrigued in this field, because of the inconsistency of the data across the field. Where in some trials, Paul had indicated this STRENGTH, there seemed to be no effect of omega-3 fatty acids, and in REDUCE-IT, there was quite a pronounced effect of the test agent. And so, when one sees discordance in a field, one tries to understand, well, why might that be? And so in the editorial, I took the position that, well, what are we trying to do in clinical trials? And in outcomes trials, we're trying to figure out what matters to patients. Do they live longer? Do they feel better? Do they avoid bad stuff happening to them? Like having to undergo revascularization procedure. So you're trying to do things that are really clinically meaningful, but that doesn't say that you're also not trying to understand mechanism. And as Allan said, there have been some questions raised. And so, trying to understand mechanism in the edit in trials can be quite useful, not just to understand that trial results, but to really form hypothesis for a field going forward. And so, I took the approach of, we learn things from different trials, and sometimes we learn things in the same trial. Meaning that, there's mechanistic work embedded in the large trial. One of the most famous examples of this, in the GUSTO trial 30 years ago, we learned through the mechanistic substudy, that it was rapid reprofusion TIMI-3 establishment of TIMI-3 flow, that really explained the difference between TPA and streptokinase. So I was very intrigued by how we might use these data to explore the results. And I find the findings fascinating, as Paul said. It is complicated, but it raises a really fundamental issue in clinical trials. There's an assumption in a placebo control trial, that because randomization is allowing you to balance everything, except for the randomized treatment groups, and therefore, that comparison has causal information in it. There's an underlying assumption that's really important. And that is, that the placebo is inert. That it has no biological effect of its own. Well, that assumption was violated here. The placebo is not inert in this clinical trial. Now, the investigators, I think to their credit, have said, "Well, this is small, probably doesn't matter." And that might be right, but it also may be wrong. And you can't just say, well, it doesn't matter, these are small effects. As Paul said, some of the effects are small, some are medium, some are large. So what explains it? And I made a point in the editorial, you could model all of this. If you get 5% of this, and 10% of this, and 20% of this, you could make some assumptions and say, well, the magnitude of the benefit was so great that it couldn't have been overcome by this. But that's just modeling, and there's uncertainty. So for me, as a trialist, and somebody who really believes in using evidence to guide practice and to guide public policy, I think there's uncertainty here. It's likely that the treatment effect is not as large as was observed, but how large is it? And how large is important? And how large might we want to consider to put into our practice guidelines? I think all of those open questions, particularly in a field where there is inconsistency across trials, in terms of the observation of the outcome. So my conclusion is, we need more work. We need another trial, if we really want to understand this. And we need to use an inert placebo, to really understand what the contribution was. I'd like nothing better to see that it didn't matter. But I can't say that it doesn't matter because I don't know. Dr. Greg Hundley:           Well, listeners, boy, we've got kind of some interest here in that an unexpected result. So Paul, it's nice doing an interview like this listeners, because each speaker sets up the next one. Paul, Bob is saying, well, what should we do next to clarify the results here? So maybe we'll go through each of you, and start with Paul. Just describe for us, what do you think is the next study that we need to perform? Dr. Paul Ridker: Well, Greg, it's a really interesting issue. We saw it, as authors, to write as neutral a paper as we could possibly write, and sort of do our academic job and say, here are the data. And I think we did it that way because, we don't really know what the interpretation should be. On the one hand, you have a very big beneficial result, which is great for patients. And there's a prior clinical trial called JELIS, which was open label, the same drug, and also got a large benefit. And we were trying to figure out mechanism. That being said, as Bob pointed out, I think what we stumbled into is some level of uncertainty. And the question is, how uncertain would it be, and does it matter in the big picture? Allan was interesting, because the Journal asked us to use the word comparator, rather than placebo. Now this was designed as a placebo controlled trial, but our paper uses the word comparator, because of the possibility, that as Bob Harrington points out, it may not be totally inert. So the writing of this was quite carefully done. I think, at the end of the day, my REDUCE-IT colleagues, who I have great respect for, and really worked terribly hard to do the main trial, understandably feel, that the trial would've showed, and I have a lot of sympathy for that, because it's the hard endpoints we should go with. On the other hand, I have sympathy with the idea that it never hurts to have more data. And if there could be a way to have a second trial, and I might change the population a little bit, maybe I'd do it in true primary prevention. This was one third primary prevention. My colleague, Joanne Manson had done her, she had a trial where they showed some potential benefit in the black populations. Maybe you might over sample some minority groups. But just the pragmatic issues here, make it tough to have a second trial. And so, uncertainty is just part of what we, as physicians, have to learn to live with. Dr. Greg Hundley:           Allan, turning to you. What do you think is a next study to perform in this space? Dr. Allan Jaffe:   Well, I think what Paul has said is correct. That it would be very hard to generate enthusiasm funding for a large trial. But it might not be nearly as difficult to begin to explore the effects of the mineral oil comparator, versus the active agent, versus perhaps, another potential placebo, and see over time what happens in primary prevention patients, as a way of beginning to put some context around what these results might mean. So for example, it could turn out that, the active agent actually kept the values from rising as they normally would've, and mineral oil had no effect at all. Alternatively, mineral oil may well have been a negative. It had a negative effect. And I think, those are the sorts of questions that could be explored reasonably in the short term, without doing another multimillion dollar randomized trial. Dr. Greg Hundley:           And Bob, your thoughts. Dr. Robert Harrington:   Well, and I mentioned this in the editorial, Greg. I didn't make my recommendation lightly. I know that these trials are expensive. I know these trials take a great deal of time, a great deal of energy. And I know that the REDUCE-IT investigators worked enormously hard over the years to get this done. So I don't say tritely, "Oh, just do another trial." But if you think about the magnitude of the public health issue here, there are millions of people to who this kind of therapy might apply globally. And so, shouldn't we be more certain than less certain, if we want to include it, for example, in ACC/AHA guidelines? I would say, the answer to that is yes. And so, I think of it as, okay, let's make some assumptions. Let's assume, that the effect that was observed in JELIS and REDUCE-IT, is the true effect. That's ground truth. Well, there are different study designs one might think about, from an analytic perspective, using Bayesian statistics, as opposed to frequency statistics. One might think about an intense interim analysis plan, to understand where the data are going, and be able to pull in the prior data for evaluation. I would advise getting a smart group of people together, who spend their lives thinking about trials in the atherosclerotic space, and the REDUCE-IT team is pretty darn good, and say, "How could we do this efficiently?" I do think, there's enough uncertainty that it would be ethical, from an equipoise perspective, to include high risk patients in a second evaluation, because we do have uncertainty. And if we really want to nail this down, I think we could look at high risk patients with hypertriglyceridemia, and try to use some interesting design issues, and some interesting analytical issues, to try to reduce the sample size, lot of attention in interim analyses, to try to answer the question. I'd like, as I said, nothing better to say, "Oh look, REDUCE-IT was the truth." This next trial is consistent. That'd be, to me, a terrific outcome of this. On the other hand, if you said to me, "Well, the effect's not 25%, it's more in the 15% range." Well, maybe then we think about how we apply it to our patients a little differently, maybe a little more cautiously. So I don't make the recommendation lightly, as I said, but I do think that there are some conversations that could be had, being respectful of the effort and the expense that goes into these kind of things. To try to answer the question efficiently. Dr. Greg Hundley:           Very nice. Well listeners, we want thank Dr. Paul Ridker, from Brigham and Women's Hospital, Dr. Bob Harrington from Stanford University, Dr. Allan Jaffe, from the Mayo Clinic, for bringing us the results of a substudy of the REDUCE-IT trial, that assessed a variety of serum biomarkers, pertaining to systemic inflammation, and highlighting uncertainty around the mechanism regarding the efficacy of icosapent ethyl, that's been used previously for primary or secondary prevention of cardiovascular events. And next listeners, we are going to move to our second feature discussion and review some data pertaining to microbleeds in the central nervous system, during and after TAVR procedures. Welcome listeners, to our second feature discussion on this August 2nd. And we are going to explore some of the world of TAVR and its potential complications. And we have with us today, Dr. Eric Van Belle, from Lille, France. And also, Dr. Manos Brilakis, from Minneapolis, Minnesota. Welcome gentlemen. And Eric, we'll start with you. Can you describe for us a little, the background information that you use to assemble and construct your study, and describe, or list for us, the hypothesis that you wanted to address? Dr. Eric Van Belle:           Yes. Thanks a lot for the question. So we knew for many years, that some of the complication of the TAVR procedure relate to the brain. And it has been described by many others, that there were some complication in the brain of patient undergoing TAVR. And there was no previous investigation on potential bleeding or microbleeding in this population. And on the other side, there are previous publication on, of course, initially chronic microbleeding, in patient with some of, let's say, disease in the brain, but also, a possibility of acute microbleeding. And especially, in some interesting population relating to the TAVR feed, that is patient with valve disease, patient with endocarditis, or patient with assist device. In this population, microbleedings, acute microbleeding, have been described. And what is interesting, if you look at all these populations, these are population in which the Von Willebrand factor has been impacted and modified, and could be one of the reason of the microbleeding. And one of the similar feature of the patient with aortic stenosis that undergo TAVI, or TAVR, that are patient with indeed also, this kind of Von Willebrand disease. So if we put everything together that is previously, we only looked at antibody complication in those population, and that Von Willebrand disease, which is present in patient with aortic valve stenosis, could promote a bleeding, in particular, bleeding in the brain. We decided to look at the potential appearance of microbleeding, in patient undergoing TAVR procedure. Dr. Greg Hundley:           Very nice. And Eric, can you describe for us, your study design, and who was your study population? Dr. Eric Van Belle:           Yes. So basically, the study population is a basic population of patient undergoing TAVI. Just to make sure that one of the difficulty of this study, was to conduct and perform an MRI, a brain MRI, before the procedure, and as short as possible after the procedure, within three days, which is logistically challenging. And also, to make sure that we keep most of the population to undergo the MRI, we had to exclude patient with a high risk of pacemaker, or patient with pacemaker that could not undergo the MRI. But basically, without this, it's just a regular population. And if we indeed, compare to some of the previous work I was mentioning, about describing the acute MRI, it was important for us to make sure, or to be as sure as we could get, that indeed, this microbleeding, if we observe them, could be related to the procedure. And it means that, the MRI, after the procedure, should be done as short as possible. And also, that an MRI, a baseline MRI, should be performed. Because we know, that in this population, you could have some microbleedings also observed before starting the procedure. Dr. Greg Hundley:           So a cohort study design where MRIs are performed before, and then very soon after, TAVR procedures. So Eric, what did you find? Dr. Eric Van Belle:           So what we observed, the first thing that we confirmed was indeed, that in this population of that age, that is patient around 80 years old, when we do the baseline MRI, you find in about one out of four patients already, some microbleedings. And this was expected, and it is very similar to what is expected in this kind of population. But what was indeed more striking, that when we repeated the MRI after three days, we observed another 23% of patient with a new microbleedings that were observed. This is indeed the most important observation. What was also important that, the patient with microbleedings, and the location of the microbleedings, were not related to the cerebellum brain, because indeed we could observe some cerebellum arise in this population, as it is expected. And there was no relation between the two. So it's also, an important observation, suggesting that this microbleeding are not hemorrhagic transformation of cerebellum brain, for instance. And we also observed that, the risk of microbleeding, or the chance to observe the microbleeding, was increased when the procedure was longer. And also, when the total duration of anticoagulation was longer, we also observed that, when the procedure was, when we used protamine at the end of the procedure, the risk of microbleeding was less. And also, importantly, the status of the Von Willebrand factor, and indeed, an alteration of the multimer of Von Willebrand factor, was also associated with the risk of microbleeding in this population. Dr. Greg Hundley:           Very nice. So in this cohort of 84 individuals, average age around 80, undergoing TAVR procedure, and about 50/50 men and women, you had several factors. Prior history of bleeding, amount of heparin, absence of protamine, all indicating a higher risk of these microbleeds. So very practical information. Well, Manos, you have many papers come across your desk. What attracted you to this particular paper? And then secondly, how do we put these results really, in the context of maybe other complications that can occur during or after TAVR procedures? Dr. Emmanouil Brilakis: Yes, thanks so much, Greg. And also, congratulations Eric, for a wonderful paper, and thanks for sending it to circulation. I think, with increasing the number of targets, as you know, TAVR now is becoming the dominant mode for treating severe aortic stenosis. Safety is of paramount importance. And even though there's been a lot of progress, we still have issues with the safety of the procedure. So understanding how can make it safer is very important. And I think, what was unique in this paper, again, congratulations for creating this study, is that it opens a new frontier. We worry about stroke. We're all very worried about the stroke, and having the patient have a permanent neurologic damage during the procedure. But there may be more to it than the classic embolic stroke. And I think, this study opens actually, a new frontier with the micro cerebral bleeds. Now we don't completely understand, despite the study, we don't understand the functional significance from this. And I think, that's one of the areas that will need further research. But I think, trying to understand what causes them, and preventing those microbleeds, would have a very important role in the future, for making TAVR even safer than it is. Dr. Greg Hundley:           Very nice. Well, Manos, you really lead us into the kind of the next question. So Eric, what do you see as the next study to be performed in this sphere of research? Dr. Eric Van Belle:           Again, to me, and to follow with the comment of Manos, we need to include, I would say, to solve two questions. We have to solve the question of, what could really impact these microbleedings. And what would be the impact of this microbleeding on the long term outcome of this patient? So it's means that we have to set, as part of the studies that we will design, potentially studies on aortic immolation. Or let's say for instance, we could investigate the role of protamine. It has been suggested that protamine could be something interesting, so it could be tested as part of a randomized study. But this means that, as part of such randomized study on the use of protamine, for instance, you would include a last cohort of patients with MRI after the procedure. And also, a long term follow of the neurological complication, which indeed, is the missing part of our current study. We would need to have a much larger cohort of patients, to be able to reconnect the neurological outcome to the MRI outcome, and also to include this. So let's say, for me, one of the studies we would be interested to perform, is to conduct a study on the use of protamine, which is very simple, randomized, yes or no, and includes brain MRI in this population, as a systematic investigation, which is difficult to conduct. You have to know that it's difficult to do, but it will be very important. And then, to look at the long term neurological outcome. Dr. Greg Hundley:           And I see, Eric, you mentioned the long term, because really in the short term, so within six months, you really didn't see any changes in neurological functional outcome or quality of life. So Manos, just coming back to you. What do you see is the next study that should be performed in this space? Dr. Emmanouil Brilakis: Yeah, I agree actually, with Eric. The next step is, this was an 80 patient study. Right? It's a very small preliminary data, all that opens a new system for evaluation, we're still a very small number of patients. So having a larger number of patients, I think for me, the key thing is to understand the connection. Does this actually cause neurologic symptoms? What does it mean having a microbleed? I think right now, we're still confused on the study. There was not really much impact on the neurologic status of the patient. So for me, the number one thing is, to understand how it impacts the patient's quality of life, the neurologic status. Perhaps more sensitive studies, neurocognitive studies, to understand exactly how it impacts. And then after doing that, I agree with Eric, if this is a bad, something really bad, then we can find different ways to prevent them from happening. Protamine is one of them during the procedure time, and not be a very feasible one. Or it could be interesting to see if different valves, for example, have different propensity for causing those microbleeds. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Eric Van Belle, from Lille, France, and also, our own associate editor, Dr. Manos Brilakis, from Minneapolis, Minnesota for bringing this very important study, highlighting that one out of four patients undergoing TAVR has cerebral microbleeds before the procedure. And then, after the procedure, one in four patients develop new cerebral microbleeds. And then, procedural and antithrombotic management, and persistence of acquired Von Willebrand factor defects, were associated with the occurrence of these new cerebral microbleeds. 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.

Guto Montezano discusses the role of endothelial inflammation and ACE2 biology in COVID-19 infections and the resulting long-term effects.

Guto Montezano discusses the role of endothelial inflammation and ACE2 biology in COVID-19 infections and the resulting long-term effects.

In honor of Father's Day, we're thrilled to welcome Dr. Caldwell B. Esselstyn Jr. back on the podcast to answer YOUR questions. He answers questions related to cholesterol, exercise, sodium, fat, atrial fibrillation, the best diagnostic tests, and – of course – how to build an ENDOTHELIUM FORTRESS. The best Father's Day gift is sharing the wisdom and knowledge of this pioneer so let's get right to it. Episode Timestamps 4:50 It's Showtime! 5:55 I'm 100% plant-based, but have high cholesterol. Do I still need statins? 8:30 What is the best diagnostic test to see if my arteries are clogged? 9:52 Question about sodium consumption. The data is so confusing! 12:50 What are the best heart health tests I should take at 50? 14:15 LPa - What is it, and how can I improve it? 16:00 How do I build an endothelial fortress and lower my triglycerides? 18:15 Atrial fibrillation - Can it be reversed via diet? 21:45 Could I potentially have familial hypercholesterolemia? 26:39 Talk about the role of fats in a plant-based diet. Aren't some fats healthy? 31:30 What is your opinion on meds for clotting and atrial fibrillation? 33:30 Could I impact familial hypercholesterolemia with a whole foods plant-based diet? 34:14 Opinions on cardio exercise? Can too much be bad? 37:00 Can my HDL be too high? 44:05 How can I best treat mild atherosclerosis? Episode Resources Watch the Episode on YouTube Order Prevent and Reverse Heart Disease by Dr. Caldwell B. Esselstyn, Jr. Dr. Esselstyn's Prevent and Reverse Heart Disease Program Website PLANTSTRONG Foods - shop our official unsalted broths- and our growing assortment of other delicious products made without oil, added sugar, or excessive sodium. PLANTSTRONG Sedona Retreat - October 10th-15th, 2022 - Dr. Doug Lisle - the esteemed evolutionary psychologist and co-author of The Pleasure Trap - is attending our upcoming Sedona Retreat to give three of his paradigm-shifting lectures that help us understand all the forces working against us in our quest to live plantstrong. Once you SEE the system we live in - you can't UNSEE it. And Dr. Lisle is a master in giving us language and tools to set ourselves on a permanent path to success. And great news! Our Sedona retreat has been approved for 21.5 CME credits for physicians and physician assistants. And 21.5 Nursing Contact Hours for nurses…. And 2.2 CEUs for other healthcare professionals as part of the registration fee for our PLANTSTRONG Retreat. PLANTSTRONG Meal Planner - Save $10 off the annual membership with the code: PLANTSTRONG Visit plantstrong.com for all PLANTSTRONG Resources, including books, recipes, foods, and the PLANTSTRONG Coaching Programs Join the Free PLANTSTRONG Community with over 26,000 members Theme Music for Episode Promo Music: Your Love by Atch License: Creative Commons License - Attribution 3.0

Dr Alec Schmaier, a cardiology and vascular specialist, has studied the impact that COVID-19 has on the endothelium.  This week we called on his knowledge of the vascular system and coagulation issues to talk us through the potential role of the endothelium in Long Covid.  We wanted to take a step back and look at why clotting might be playing a role in our Long Covid symptoms, and discuss what drives it.  Schmaier offers us that and more in a discussion that includes anticoagulant drugs, the stiffening of arteries and comparisons with endothelial damage in conditions such as sepsis.

For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources:  ·Jubilee website·PrevMed's website·PrevMed's YouTube channel·PrevMed's Facebook page·PrevMed's Instagram·PrevMed's LinkedIn·PrevMed's Twitter ·PrevMed's Pinterest

The endothelium is a single layer of cells lining the inside of our blood vessels – and other internal organs. Not only is it responsible for signaling the contraction and dilation of vessels, but it controls clotting, inflammation, oxidative stress, and more! When this system breaks down, its effects are wide-reaching. Endothelial dysfunction is often the root cause of subsequent cardiovascular disease, strokes, and many chronic conditions. Because it can sometimes be reversible, understanding what causes it, how to treat it, and what you can do to prevent it becomes vital. In today's episode, we discuss the physiologic role of the endothelium, how it relates to atherosclerosis, and practical strategies to promote cardiovascular health. Today on The Lab Report: 2:55 Defining Terms – What is the Endothelium? 7:10 Oxidative stress, inflammation, and drivers of endothelial dysfunction 11:00 How do we get to atherosclerosis? 14:20 Indirect causes of endothelial dysfunction 15:50 Direct causes and sheering forces 16:45 Sedentary lifestyle and other triggers 18:00 Movement, omega-3 fatty acids, herbal and prescriptive medications Subscribe, Rate, & Review The Lab Report Thanks for tuning in to this week's episode of The Lab Report, presented by Genova Diagnostics, with your hosts Michael Chapman and Patti Devers. If you enjoyed this episode, please hit the subscribe button and give us a rating or leave a review. Don't forget to visit our website, like us on Facebook, follow us on Twitter, Instagram, and LinkedIn. Email Patti and Michael with your most interesting and pressing questions on functional medicine: podcast@gdx.net. And, be sure to share your favorite Lab Report episodes with your friends and colleagues on social media to help others learn more about Genova and all things related to functional medicine and specialty lab testing. Disclaimer: The content and information shared in The Lab Report is for educational purposes only and should not be taken as medical advice. The views and opinions expressed in The Lab Report represent the opinions and views of Michael Chapman and Patti Devers and their guests.     See omnystudio.com/listener for privacy information.

The RSB Show 8-6-21 - DeSantis vs Biden, Los Angeles mandate, Biden federal coercion, Stan Graham, Bryan Ingram, Endothelium targeted

ไนตริกออกไซด์ โมเลกุลส่งสัญญาณที่สำคัญที่สุดในระบบหลอดเลือดหัวใจ (ตอนที่ 2/3) วันนี้ เราจะมาคุยกันต่อว่า 1. มีสาเหตุอะไรบ้าง ที่ทำให้เซลล์บุผนังหลอดเลือดชั้นใน ที่เรียกว่า Endothelium นี้เสียหาย ทำหน้าที่สำคัญในการสร้างไนตริกออกไซด์ได้ไม่สมบูรณ์ 2. ผลกระทบต่อสุขภาพ 4 ประการที่เกิดจาก เซลล์บุผนังหลอดเลือดชั้นในเสียหายคืออะไร เชิญฟังได้เลยค่ะ

Nitric Oxide “Molecule of the year” จากการคัดเลือกของ American Association for the Advancement of Science (AAAS) ในปี พ.ศ.2535

In this week’s podcast, articles “The Cardiac Late Sodium Channel Current is a Molecular Target for the Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin” by Light et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.053350) and “Metabolic effects of empagliflozin in heart failure: A randomized, double-blind, and placebo-controlled trial (Empire HF Metabolic) by Jensen et al (www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.053463) are discussed. 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, it's double feature day. And guess what? Both papers that we're going to talk about are regarding the SGLT2 inhibitors, and really look at the mechanism of action of these amazing compounds, from both a pre-clinical and clinic point of view. That's all I want to say, because we've got to tune in, a very interesting discussion coming right up. Dr. Carolyn Lam: But first I'd like to ask you a question. What do you think is the association between health-related quality of life and mortality in heart failure around the world? Dr. Greg Hundley: Well, Carolyn, I would think that, actually, they might be linked. Dr. Carolyn Lam: That's a really clever answer. Thanks Greg. Well, the authors are actually going to tell you with this next paper. It's from Dr. Salim Yusuf from Population Health Research Institute and McMaster University in Hamilton, Canada, and colleagues, who looked at the global congestive heart failure, or GCHF study, which is the largest study that has systematically examined health-related quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, which is the largest study that has systematically examined health-related quality of life and its association with outcomes in heart failure, across eight major geographic regions, spanning five continents. Dr. Greg Hundley: Wow, Carolyn. So what did they find here? Dr. Carolyn Lam: Health-related quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire, or KCCQ, really differs considerably between geographic regions, with markedly lower quality of life related to heart failure in Africa compared to elsewhere. Health-related quality of life was also a strong predictor of death and heart failure hospitalization in all regions, irrespective of symptoms class, and with both preserved and reduced ejection fraction. Dr. Carolyn Lam: Indeed, this paper really highlighted a great need to address disparities that impact health-related quality of life in patients with heart failure in different regions of the world. Dr. Greg Hundley: Fantastic, Carolyn. Well, I have two studies to discuss, Carolyn, and they're kind of similar, so we're going to do them back to back. The first study reports the results of the Sort Out X Trial, a large scale randomized multi-center, single-blind, two-arm, non-inferiority trial, with registry based follow-up designed to evaluate the Dual Therapy Sirolimus-Eluting, and CD34 positive antibody coated combo stent or DTS versus the Sirolimus-Eluting Orsiro Stent or SES. Dr. Greg Hundley: And the study comes to us from Dr. Lars Jakobson, from Arhus University Hospital. The primary endpoint target lesion failure, or TLF was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, all analyzed using intention to treat. Dr. Carolyn Lam: All right, Greg. So the DTS compared to the SES, what did they find? Dr. Greg Hundley: Thanks, Carolyn. So the DTS did not confirm non-inferiority to the SES stent for target lesion failure at 12 months. The SES was superior to the DTS, mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the two stent groups. Dr. Greg Hundley: Now Carolyn, in this same issue, we have another study evaluating endothelial function and implantation of intercoronary stents. And this second study comes to us from Professor Alexandra Lansky, from the Yale University School of Medicine and Yale Cardiovascular Research Group. And Carolyn, the study evaluated whether implantation of an intercoronary stent that facilitated endothelialization after the four to six weeks smooth muscle anti-proliferative effects post-stent implantation would be non-inferior to traditional drug-eluting stents. Dr. Carolyn Lam: Okay, another interesting study. And so, how did they do that? What did they find? Dr. Greg Hundley: Yeah, so Carolyn, a total of 1,629 patients were randomly assigned in a two to one fashion to the supreme DES stent, so 1,086 patients, or the DPDES stent, which was 543 patients. And there were no significant differences in rates of device success, clinically driven, target lesion revascularization, or stent thrombosis at 12 months. Dr. Greg Hundley: And the safety composite of cardiovascular death and target vessel revascularization or myocardial infarction was 3.5 versus 4.6% with the supreme DES stent compared to the DPDES stent. But target revascularization for this new stent was two and a half fold higher. Dr. Greg Hundley: So Carolyn looking at these two papers, what have we learned? So first, the Jakobsen, et al, tested whether the stainless steel COMBO Sirolimus-Eluting Stent coated luminally with CD34 positive antibody could theoretically capture endothelial progenitor cells and regrow endothelium. Dr. Greg Hundley: And the investigators observed that this stent had higher, not lower or equivalent, target lesion revascularization relative to the current generation Cobalt-Chrome Stent that only eluted sirolimus. Dr. Greg Hundley: In the second study, Lansky and associates examined an approach which was touted as enhancing endothelial recovery, where the early erosion of material and release of drug was thought to allow earlier endothelial recovery enhancing vascular response. Non-inferiority of the rapid release was demonstrated, but rather than hints of superiority, there were signs of inferiority. Hereto, target lesion revascularization was problematic and was two and a half fold higher. Dr. Greg Hundley: And so, Carolyn, there's a wonderful editorial from Professor Elazer Edelman from the Massachusetts Institute of Technology entitled, “Karnovsky's Dictum that Endothelium is Good Looking and Smart,” where Dr. Edelman emphasizes that while some endothelial cells may have been present after deployment of these devices, perhaps a fully constituted functioning endothelium may not have been achieved. Dr. Greg Hundley: And as we know, it is a fully functioning endothelium with nitric oxide release, buried platelet adhesion that is most protective. It is a really provocative read that reflects on previous thoughts from Morris Karnovsky, who suggests preservation of endothelial function is optimized by minimizing injury to it. And so, Carolyn, these combined articles really highlight the current state of new developments within interventional cardiology to thwart re-stenosis and highly recommend them to our readers. Dr. Carolyn Lam: Wow, thank you, Greg. That was amazing. But you know what, so's this next paper, because it really provides novel insights into that enigma of the role that the epicardium plays in the pathogenesis of arrhythmogenic cardiomyopathy. Dr. Carolyn Lam: Now, to delineate the contributions of the epicardium to the pathogenesis of arrhythmogenic cardiomyopathy, doctors Marian from University of Texas Health Science Center at Houston, Texas and colleagues performed a series of elegant mouse experiments using conditional deletion of the gene encoding desmoplakin in the epicardial cells of mice. Mutations in genes and coding desmosome proteins, including desmoplakin are known to be major causes of arrhythmogenic cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn, very interesting. So what did they find here? Dr. Carolyn Lam: Epicardial derived cardiac fibroblasts and epithelial cells expressed paracrine factors, including TGF-β1 and fibroblasts growth factors, which mediated epithelial mesenchymal transition and contributed to the pathogenesis of myocardial fibrosis, apoptosis, arrhythmias, and cardiac dysfunction in a mouse model of arrhythmogenic cardiomyopathy. These findings really uncover contributions of the epicardial derived cells to the pathogenesis of arrhythmogenic cardiomyopathy. Dr. Carolyn Lam: Greg, there's a whole lot of other interesting stuff in today's series, as well. There's an exchange of letters among doctors Mehmood, doctors Moayedi and Dr. Birks regarding the article “Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Device.” There's an ECG challenge by Dr. Ezekowitz on a silent arrhythmia. How would you treat this patient? Go quiz yourself. Dr. Carolyn Lam: There is an AHA Update by Dr. Churchwell on how federal policy changes can advance the AHAs mission to achieve health equity. And finally, a Perspective by Dr. Talbert on rheumatic fever and the American Heart Association, The Nearly 100 hundred-Year War. Well, that wraps it up for the summaries. Let's go to the double feature, shall we? Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Wow, today's feature discussion is really all about SGLT2 inhibitors, and that question that we're still asking, how do they work? And today, we are discussing two papers, very interestingly, looking at it from different aspects, one from a preclinical lens, finding a very novel target for SGLT2 inhibitors, and the other from a clinical lens, and really looking at the metabolic effects of the SGLT2 inhibitors in a way you've not seen before. Dr. Carolyn Lam: I'm very pleased to have with us the authors of these very exciting papers. We have Dr. Jesper Jensen from Herlev and Gentofte University Hospital in Denmark. We have Dr. Peter Light from University of Alberta, in Canada, and we have our associate editors, Dr. Thomas Eschenhagen from University Medical Center, Hamburg, and Dr. Justin Ezekowitz from University Alberta. Dr. Carolyn Lam: So, welcome gentlemen, thank you so much for joining us today. I suggest, let's start from the mice before we go to the men, and Peter, if you don't mind by starting us in, please tell us about this novel target you found, why you looked at it, how you found it, what it means. Dr. Peter Light: Hi, Carolyn, yeah, happy to discuss that. So, we all know that through numerous clinical trials, there's a very unexpected and exciting cardioprotective effect against heart failure with the SGLT2 inhibitors. And we decided to investigate some of the molecular mechanisms, which may underlie that protection. And in looking at the literature previously, and from my own lab's work, we're very interested in control of electrical excitability and ionic homeostasis in cells. Dr. Peter Light: So we investigated a known target or a known iron channel, which is involved in the etiology of heart failure as well as cardiac arrhythmias. And that would be the cardiac sodium channel. So, we investigated the effects specifically on a component of the cardiac sodium channel called the late sodium current, which is only induced in disease states, and they could be that during heart failure or ischemia, or can actually be in congenital conditions such as Long QT Syndrome Three, which involves certain mutations in this sodium channel. Dr. Peter Light: So we basically investigate the effects of empagliflozin, dapagliflozin and canagliflozin, in several different models of a sodium channel dysfunction, including mice with heart failure. And really what we've found is that this class of drug, and this is a class effect, it's not specific to just one of these SGLT2 inhibitors, what we found, they are very good inhibitors of this late current of the sodium channel. And in fact, they don't even affect the peak current at all. Dr. Peter Light: And when we did this and we analyzed the data, we found the IC 50s were in the low micromolar or even sub micromolar range for these drugs, which is exciting. And we extended those studies into cardiac myocytes and looked at calcium handling in those cardiac myocytes and saw that we get a very nice reduction in abnormal calcium handling in cardiac myocytes. Dr. Peter Light: We also used in silico molecular docking of these drugs to the cryo-EM structure of the NaV1.5, which is the cardiac sodium channel and identified that these drugs bind to a known region of that channel, which also binds the local anesthetics or anti-arrhythmic drug, Lidocaine, as well as the anti-anginal drug, Ranolazine. Dr. Peter Light: And finally, we showed that these drugs also reduce inflammation through the NLRP3 inflammasome in an isolated beating heart model. So collectively, we provide evidence that the late component of the sodium channel is a really important, or maybe a really important target for the molecular actions of this drug, and may underlie those observations received from the clinical trials relating both to heart failure, as well as sudden cardiac death. Dr. Carolyn Lam: Thomas, could you put this in context for us? Dr. Thomas Eschenhagen: Thanks, Carolyn. I mean, we immediately liked the story because as you said, and Peter as well, these drugs have amazing effects and every clinical paper and indeed some new ones, but it's really unclear how they do that. And what is, besides the established target, the SGL2 in the kidney, what could be the reason for all of this or some of this?   Dr. Thomas Eschenhagen: And then, of course, other examples proposed, like the sodium hydrogen exchanger, but this story didn't go so far. So we saw now this data from Peter showing that, and this is, of course, for a pharmacologist, just like me, very important, it's very potent binding. It's not a binding which happens in a millimolar or high micromolar, but as Peter said in low micromolar range. So that makes it a very realistic effect, for example, much more potent than ranolazine. Dr. Thomas Eschenhagen: And, of course, now the question is, to which extent could this, now I would say, establish the effect on the late sodium current, explain some of the findings which came out of the clinical studies, and actually, a question I would have to Peter, now that I think most of you know, the late sodium current is a reason for the increased sodium for LQT3 syndrome, very rare. Dr. Thomas Eschenhagen: But, of course it would be tempting to say, okay, maybe that would be a very good drug, particularly for people with LQT3. Did you think about that, Peter? Is it something on your list, mexiletine has been tried. Dr. Peter Light: Yeah, so I think that it's a certainly intriguing possibility. In fact, in our study, we did test out several different Long QT3 mutations and saw a reduction in the late component as also sodium channel. It's tempting to speculate that, indeed, these could actually be a rather effective anti-arrhythmic drug in patients with these LQT3 mutations or specific ones. I would love to be able to test that in at least some of the genetic mouse models of Long QT3 and to see whether this concept holds water or not. Dr. Carolyn Lam: Wow, this is incredible. SGLT2 inhibitors from anti-diabetic to now anti failure, and now anti-arrhythmic drugs? That's just amazing. Thank you, Peter. We should move on to this next paper, and this one all the way on the other spectrum, a clinical paper called Empire Heart Failure, Empire Heart Failure Metabolic, actually. Jesper, could you tell us about your trial and what you found? Dr. Jesper Jensen: Sure, thanks for the invitation to take part in the podcast, first of all. I'll tell you a little bit, we designed this study to try to get behind mechanisms, so the clinical benefits of the SGLT2 inhibitors in order to try to make a clinical outcome trial. But as you know, the DAPA-HF and the EMPEROR-Reduced were competed very fast, demonstrating the clinical benefits in HFrEF patients. Dr. Jesper Jensen: So, the data of our study provides some detailed mechanistic insights to these findings. And from the literature, we know that SGLT2 inhibitors improve glucose metabolism in patients with diabetes, and these changes might not be surprising in the diabetes population, but moreover, alterations in glucose metabolism may not be the main mechanism for the early occurring clinical benefits. Dr. Jesper Jensen: However, we know that many of our heart failure patients without diabetes are insulin resistant as a metabolic feature of the heart failure, and the insulin resistance is associated with an increased risk of developing future diabetes, which in turn reduces the long-term survival and quality of life. So, the targeting insulin resistance in HFrEF patients is, therefore, of clinical relevance to our patients. Dr. Jesper Jensen: So, the population of the Empire HF Metabolic consisted of patients with chronic HFrEF, with or without type two diabetes, who are on a stable guideline directed heart failure therapy, and have also indicated on anti-diabetic therapy. And we randomized patients to receive empagliflozin 10 milligrams once daily, or matching placebo as an-add on for 12 weeks. Dr. Jesper Jensen: And this was a modest sized randomized control trial, including 120 patients. A very large proportion of patients received guideline directed heart failure therapy, and they generally consisted of the best one third of atypical HFrEF population, and only 10% had concomitant history of type two diabetes. Dr. Jesper Jensen: We then, at baseline and after 12 weeks, we formed an oral glucose tolerance test to assess the hepatic and a peripheral insulin sensitivity and performed a whole body DXA scan to investigate alterations in body composition. We know that patients lose weight when they get an SGLT2 inhibitor with and without diabetes, but we don't know what it consists of in a HFrEF population. Dr. Carolyn Lam: Tell us what you found after 12 weeks. Dr. Jesper Jensen: Yeah, so a large proportion, actually half of the patients without a history of diabetes, had a new onset diabetes, or impact glucose tolerance at baseline. So even though few have no diabetes, this population were at very high risk of developing future diabetes. And the main finding was that empagliflozin improved insulin sensitivity. So the hepatic insulin sensitivity was improved by 13% and the peripheral insulin resistance was improved by 20% compared to placebo. Dr. Jesper Jensen: And moreover, both fasting and postprandial glucose were significantly reduced. And regarding the body composition, patients in a mean lost at 1.2 kilos, or 2.6 pounds, which mainly consisted of a loss in lean mass and no significant changes were observed in fatness, and this is from the DXA scan. Dr. Carolyn Lam: Hmm. Justin, could you shed some light on what the editors thought about this, and there's lots of questions still, huh? Dr. Justin Ezekowitz: Yeah, absolutely, Carolyn, and thanks Jesper for sharing this paper with Circulation. Thanks for summarizing it so well. I think the questions that come up and the reason why we liked it so much was we're all trying to understand mechanism of how these medications work so profoundly for our patients. Dr. Justin Ezekowitz: Now, in this predominantly non-diabetic population, the fact that the liver and the peripheral insulin sensitivity improves, how does that bear out for the fact that there is no fat loss in the early stages, yet that's all been linked to later improved exercise capacity and increased fat loss later on in life. Dr. Justin Ezekowitz: So, do you think those two are going to be linked if you went to say from 12 weeks beyond the 52 or two years down the road? Dr. Jesper Jensen: Yes, that is what we've seen from diabetes populations, at least. So you could imagine that the same would be the case also in the HFrEF primarily non-diabetic population, but again, we don't know. But early loss is the mass loss. Dr. Justin Ezekowitz: So Jesper, when you think about the peripheral insulin sensitivity improvement, is that largely indicating mostly muscle based insulin sensitivity improvement, and that would indicate that the muscles, perhaps, are functioning better in the short term with just a simple change in therapy. Dr. Jesper Jensen: Yeah, that could be a way to put it. I would agree upon that. Dr. Justin Ezekowitz: So thanks, Jesper, I think that may indicate the quality of life improvement that we may be seeing in the functional status there, Carolyn. Dr. Carolyn Lam: Yeah, but as you said, Justin, there just seems so many other questions. To Jesper, I want to know, what further might you want to do to find out what's happening with this? The loss of lean mass surprised me, frankly. I thought it would have been fat mass. So, what are you doing to look at that? And then to Peter, I want to go the other direction. What are you planning next that might bring this closer to humans and a clinical study? So maybe I'll ask Jesper to go first. Dr. Jesper Jensen: So, I definitely agree with you, Carolyn. We would also have to put our money on the fat from the beginning, before the study. So with respect to the weight loss, then a loss in lean mass is not preferable if it represents muscle. So however, the weight loss works to mediate the observed change in insulin resistance. And additionally, a significant loss in muscle would result in reduced insulin sensitivity. And we observed the opposite. Therefore, the observed loss in lean mass may be speculated to represent water and pointing towards the early diuretic effect SGLT2 inhibitors. So, the DXA scan is good at looking at body composition, but it has difficulties in separating lean mass from whether it's muscle or water, but combined with the findings on the insulin resistance, we speculate that the lean mass loss is more. Dr. Carolyn Lam: Thank you. And Peter, could you very quickly tell us what are next steps, in your view? Dr. Peter Light: Yeah, obviously we were studying mouse model of heart failure. We'd like to make a more of a translational step in the next experiments we do by studying human tissues. So getting access to ventricular tissue from ex-planted hearts, human hearts, too, and then measure electrical activity as well as some calcium imaging. Dr. Peter Light: Looking at some of these Long QT3 animal models would be another thing that we're going to do. And also start looking at to see whether we can get access to any electrophysiological data from electronic medical records to start looking for DCGs and measuring QT interval, for example, would be another nice step to that. Dr. Peter Light: And then, more of a drug development side of things, we are actively synthesizing new derivatives of these drugs and seeing whether we can enhance the cardio-protective effects on the late sodium current, but actually remove the ability to inhibit SGLT2. So we would no longer have a glucose-lowering drug, but we'd have a cardioprotective drug. So, it's all very exciting work going on right now. Dr. Carolyn Lam: You've been listening to Circulation on the Run. From Greg and I, don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

This is Episode 56 of The Changed Physician Podcast where hosts interview Dr. Caldwell Esselstyn about his journey from pursuing medical school, becoming a surgeon, recognizing the need to do research, and embracing the plant-based diet for his family and for those with severe heart disease. Timeline: 00:15 Why he went into medicine and his path to surgery 04:00 Realized doing surgery that he was not helping PREVENT cancer 05:40 Realizing he needed to do his own research 06:30 Starting research in 1985 with 24 severe heart disease patients 08:45 Saw his 18 patients for 12 years and saw exciting results 11:20 Starting a conference on the prevention & reversal of heart disease 13:20 4-year study to repeat results with 200 patients 15:00 Need to get the medical profession on board; data x 100 years 17:00 How to convince others that diet can change symptoms/disease 19:00 Food and food alone can change heart disease 20:00 Endothelial 21:30 The vocabulary to use to teach others about heart disease (ENDOTHELIUM and NITRIC OXIDE) 23:00 Nitric oxide provides protection from heart disease 26:00 Endothelial cells suffer with age 27:00 Antioxidants from food with high ORAC value 31:00 Which greens are best? 32:30 Joining Nutrition committee of American College of Cardiology 35:00 How he kept his sanity when his findings were not quickly received 36:30 The challenges in life create excitement 37:00 When you are making a lifestyle change 38:40 The two key words to learn and understand 40:00 Visual proof, practical applications, & stories are powerful You can learn more about Dr. Caldwell Esselstyn, his research, and more at www.dresselstyn.com Learn More About the Community at:

This month on Episode 18 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the October 23 and November 6 issues of Circulation Research. This episode features an in-depth conversation with Drs Eric Boilard from the Université Laval in Quebec, Canada, and Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco regarding their study titled Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19.   Article highlights:   Feng , et al. No Contribution of EMPs to Endothelium   Lin, et al. Step Count and Predicted CVD Risk   González-Hernández, et al; Sox17 in Developmental Coronary Arteriogenesis   Khawaja, et al; HIV Antiretrovirals Alter Endothelial Activation     Dr Cindy St. Hilaire:        Hi, 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'll be highlighting four articles selected from the late October and early November issues of Circ Res. Dr Milka Koupenova, who is a platelet expert at the University of Massachusetts Medical School, will join me to interview Drs. Eric Boilard from the Université Laval in Quebec, Canada, and Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco. They're here to discuss their study, Platelets Can Associate with SARS-CoV-2 RNA and are Hyperactivated in COVID-19. Dr Cindy St. Hilaire:        The first article I want to share is titled No Evidence for Erythro-Myeloid Progenitor-Derived Vascular Endothelial Cells in Multiple Organs. The first authors are Teng Feng and Zibei Gao, and the corresponding author is Hui Zhang from ShanghaiTech University in Shanghai, China. Dr Cindy St. Hilaire:        In the early stages of mammalian embryogenesis, a population of cells called mesoderm-derived angioblasts, gave rise to self-renewing intraembryonic endothelial cells, that go on to populate the entire vasculature of the growing fetus. Recent studies have suggested that there is an additional embryonic source of vascular endothelial cells  that is derived from erythro-myeloid progenitor cells, also called EMPs, that are found in organs such as the liver, the lung, the heart, and the hindbrain. Dr Cindy St. Hilaire:        Evidence of an EMP cell source for vascular endothelial cells stemmed from the use of mirroring cell lineage tracking models. However, the authors of this study argue that these former conclusions were based on flawed genetic tools. To mark erythro-myeloid progenitor cells, the initial study had used a set of supposedly EMP-specific transgenes. However, transgenes are notoriously leaky, meaning, that cells other than EMPs may have been marked. To more accurately mark EMP derived cells, this study used a reporter that they integrated into the endogenous loci of a gene, CSFR1, which is specifically expressed in EMPs. Using this model, they failed to find any evidence of EMP derived vascular endothelial cells in any organ, thus they consider it unlikely that EMPs give rise to vascular endothelial cells. Knowing the true origin of vascular endothelial cells is essential, as it informs the design, development of treatments, and regenerative medicine approaches for vascular diseases. Dr Cindy St. Hilaire:        The second article I want to highlight is titled Association of Habitual Physical Activity with Cardiovascular Disease Risk. First author is Mayank Sardana and the corresponding author is Honghuang Lin, and they're at Boston University School of Medicine. Everybody knows that exercise is very good for overall cardiovascular health and current government guidelines suggest a minimum of 150 minutes of moderate to vigorous exercise per week is necessary to keep hearts healthy. There's an ever-growing interest in the use of smart watches and fitness trackers to assess an individual's activity, and many people believe that 10,000 steps a day is a good health goal. However, it's unknown whether the data obtained from smartwatches actually aligns with cardiovascular health prediction. Dr Cindy St. Hilaire:        To address this gap, this study recruited participants from the Framingham Heart Study to wear Apple smart watches for a month. The participants had also undergone a 10 year atherosclerotic cardiovascular disease risk assessment based on their age, sex, cholesterol levels, blood pressure, diabetes diagnosis, and smoking history. The step count and activity data from 903 participants found that for every 1,000 average daily step increases, there was an associated 0.18% reduction in predicted cardiovascular disease risk. This association was weaker but still significant after adjusting for body mass indices. The authors conclude that like other measures of activity, those recorded by smart watches are correlated with better cardiovascular health. Dr Cindy St. Hilaire:        The third article I want to share is titled, SOX17 Controls Emergence and Remodeling of Nestin-Expressing Coronary Vessels. The first author is Sara González-Hernández and the corresponding author is Joan Isern, and they're from Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain. The exact signals and mechanisms that regulate coronary vascular development are not fully characterized, yet defining these pathways could provide valuable insights into both life threatening congenital coronary abnormalities as well as the neovascularization process that occurs after myocardial injury. To examine coronary vasculature development in more detail, this team created a transgenic reporter system, which used an enhancer region within the Nestin gene to specifically label mouse coronary artery endothelial cells. Dr Cindy St. Hilaire:        Cells were isolated from developing embryos at stages of vessel sprouting and vessel remodeling, embryonic days 13.5 and 17.5 respectively. And transcriptional differences were assessed between coronary and endocardial endothelial cells. They found that the transcription factor SOX17 was more highly expressed in these coronary endothelial cells compared with the endocardial endothelial cells, and that expression of SOX17 increased between these two time points that hearts were collected. Coronary specific deletion of SOX17 in genetically engineered mice lead to severe defects in arterial remodeling, confirming the transcription factor's role in coronary vessel development. The team suggested that perhaps SOX17 could be a future therapeutic target for conditions, where promoting coronary artery regeneration or remodeling might be of clinical benefit. Dr Cindy St. Hilaire:        The last article I want to share with you before we switch to our interview is titled, HIV Antivirals Affect Endothelial Activation and Endothelial-Platelet Crosstalk. The first author is Akif Khawaja, and the corresponding author is Michael Emerson from the Imperial College, London. Infection with HIV is not the death sentence that it once was. With a regime of continuous anti-retroviral medications, the disease can be managed for the long term. Now that people with HIV are living longer, it is clear that they are at a greater risk of developing cardiovascular disease, possibly due to the off-target effects of these drugs. One HIV treatment, Abacavir Sulfate or ABC, was found to cause a 90% increase in the relative risk of myocardial infarction.  ABC has been proposed to cause endothelial dysfunction, however a mechanism by which this may occur has not been established. To see if anti-retrovirals effect endothelial cell function, this group tested three drugs; ABC, as well as tenofovir alafenamide or tenofovir disoproxil fumarate, TAF and TDF respectively, on human endothelial cells in culture. Dr Cindy St. Hilaire:        They found that treatment with ABC, but not TDF or TAF, caused endothelial cells to produce more cell adhesion protein, ICAM-1, and also tissue factor, both of which promote blood clotting. Endothelial-derived microparticles, or EMPs, are a biomarker of vascular dysfunction, and these were produced in the ABC treated cells, not in the TDF or TAF treated cells. These EMPs also promoted the increase of ICAM-1 and tissue factor expression, as well as the activation of platelets which can induce blood clotting. These results suggest that altering HIV treatments to avoid or minimize endothelial damage could help to reduce the cardiovascular disease risk in HIV patients. Dr Cindy St. Hilaire:        Today, I'm excited to have with me Drs. Eric Boilard from Université Laval in Quebec, Canada, Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco, and they are here to discuss their study, Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19. Also, with me today is Dr Milka Koupenova from the University of Massachusetts Medical Center in Worcester Mass, and she's an expert on platelet virus interactions, and she also wrote the editorial that's accompanying this article in our November 6th issue. So thank you, everyone, for joining me today. Dr Eric Boilard:                Thank you for inviting us. I look forward to reading the editorial. Dr Milka Koupenova:     I hope you like it Eric. Dr Cindy St. Hilaire:        Yeah, we're spanning a lot of time zones and we're actually having a little bit of technical difficulties so hopefully Fadila is going to be able to pop in. We can certainly see her on our Zoom call right now. But with that, we're many months into this pandemic now and it is blatantly clear that COVID does not just present with pulmonary symptoms. Many organ systems can be affected, such as the circulatory and neurological systems, but one thing that connects all the parts of the body is the blood system, and before we get into the details of the study, I would love to hear how this collaboration between Quebec and Morocco happened. And then, could you summarize the major findings? Dr Eric Boilard:                We both, in Morocco and in Quebec, we had pretty much the same working hypothesis that platelets may be contributing to the overwhelming inflammation in COVID-19 and why. As you know, in Morocco the pandemic hit before us in Canada, and they had a committee that studied patient samples and studies were going on. Whereas us in Quebec, in fact to be frank, in Quebec City, we didn't really have the first wave even. So we were very excited to evaluate our hypothesis but we had no clues other than the actual virus. We actually were working with the virus and human platelets from healthy individuals, but no samples from patients. Clinicians in Morocco were very willing to contribute and to perform working on patients so that's how Younes Zaid, the first author of the manuscript, and Fadila then contacted us given our past work on platelets and viruses and the collaboration was initiated. Dr Cindy St. Hilaire:        That's wonderful. I love hearing about these multi-institute collaborations. Team science is really the future. I think it really elevates everything. Dr Eric Boilard:                Despite the fact that the distance and I mean, it was through Zoom, but we've been doing weekly meetings with the two labs since March. Dr Cindy St. Hilaire:        So, can you maybe give us a quick summary of the major findings of your study? Then we'll dig into the details of it. Dr Eric Boilard:                Sure. When we actually started the work, what we knew about COVID-19 was that the severity was likely due to the overwhelming inflammation due maybe to a cytokine storm, so we knew that. It was reported that patients with COVID-19 had a lower platelet count and although thrombocytopenia in the patients was very mild or modest, and did not require transfusion, at that time, our hypothesis was that platelets could contribute to inflammation and therefore could release cytokines and other molecules from their granules in COVID-19. So it's only a couple of weeks after that became more of use that thrombosis and cardiovascular manifestations could also contribute to morbidity and mortality. Dr Eric Boilard:                Our design was to look at platelet activation in vitro. So there were studies where we performed aggregation assays with platelets from COVID-19 patients, some were severe and non-severe. There were assays where we actually evaluated a number of molecules and plasma from the patients. We looked at granular components, like PF4 and serotonin, that were greatly increased in COVID-19, both in non-severe and severe patients. We looked at vesicles, or microparticles, released from platelets that were also increased, and cytokines. We look at up to 42 cytokines, if I remember well, in the plasma of the patients and we also look at these cytokines in the platelets from the patients and we found less cytokines in the platelets when there was inflammations, which may suggest that platelets have released their cytokine cargo. I mentioned that platelets were hyperactivated so they bound better on collagen and they aggregated faster with suboptimal concentration of thrombin. Dr Milka Koupenova:     I find this dysregulation of cytokines in the platelets specifically very interesting and the fact perhaps that you see that certain cytokines are decreased in platelets and increased in plasma, basically can suggest that maybe platelets are the ones that are contributing to the overall cytokine storm, as you said. My question for you is, what do you think is the contribution of platelets to the dysregulated immune cell response in immune cell activation during this particular infection? Dr Eric Boilard:                That's a good question. There are studies that show that platelets could interact with leukocytes. The leukocytes migrate to organs through lungs in this case, so one possibility is that molecules derive from platelets and cytokines but also their interaction with leukocytes could further promote their migration to lungs or adhesion to vasculature. There are studies that suggest that NETs form in COVID-19 and could contribute thrombosis and NETs can implicate interaction between platelets and neutrophils. Or molecules derived from platelets that are neutrophils so these might be some of their contributions. Dr Milka Koupenova:     You are reporting changes of IL-7 in platelets which is particularly interesting because they're responsible for T and B cell development and activation. I was wondering if you could comment on that particular fact and how that may be practically responsible for these responses in these patients that come and present with symptoms. Dr Eric Boilard:                Yeah, it's a good question. If we look at the different cytokines that were in platelets, we found that many were reduced. That pointed to their release in COVID-19 and some we had expected, such as some broad factors and there was TGF, CD40 ligands inside the cytokine but we expect that its stored in platelets that was released. That made sense to us. IL7, like you said, it was not really reported in platelets and when we look at the 40... broad area of cytokines using the multiplex, that increased in platelets during COVID-19. So this one was increased. Does it mean that platelets translated but some of it is released but some remain in platelets? We have no explanation for this. Does it impact lymphocytes or B cells? Dr Fadila Guessous:        If we go further and in terms of seeing the front they know what was downstream, IL7 production in general does not look like for psychometry, what happens to B cells and T cells in our complex. So we just look at the panel of the 48 cytokines, but we didn't go really further. Dr Cindy St. Hilaire:        I kind of have a little bit of a more basic question regarding cytokines and where they're coming from. I'm going to guess it's definitely not known for COVID but in maybe any viral infection that can lead to a cytokine storm, is it known what the relative contributions of cytokines are from the platelets, from the leukocytes, and from inflammatory cells? Is there any evidence of which is the bigger player? I mean I know all the different camps have ideas, but has anyone looked at that? Dr Fadila Guessous:        We were talking about this actually with Eric. If I had to rephrase your question, like what's the starting point, right in terms of cytokine storms?   Dr Fadila Guessous:        We don't know. We don't know because when it started in China, everyone was talking about the big cytokine storm. Everyone was talking about monocytes, about neutrophils, so on and so forth but the platelets we were just saying there was thromboembolism in the lungs, right? But no one was talking about cytokine production by the platelets. I think we were the first ones, Eric please correct me if I'm mistaken, we were the first ones to show, when we started, to show that there was the cytokine release by platelets. How big of the extent of the contribution of platelets to the cytokine storm, we don't know, but we have to figure out first what's the key player? The first one to respond, right? Dr Cindy St. Hilaire:        Lots of projects. Dr Fadila Guessous:        Well the big question, actually we have this big contribution in terms of the cytokine release and activation of platelets, but is it the starting point? We don't know. Dr Cindy St. Hilaire:        I guess related to that, you noted that you saw very little ACE2 expression in the platelets which most people appreciate is the entry mechanism of the virus into the platelets. Can you discuss that a little bit more, maybe explain it a little bit more and what that might mean? Your findings versus what other people have seen versus potential other means of entry? Dr Eric Boilard:                Yeah sure. As you mentioned, ACE2 is the putative receptor for the virus so that made sense to us to examine whether the receptor may be expressed by platelets. I don't think we mentioned it but we found that there were some... at least for some patients there were SARS-CoV-2 RNA associated with platelets and that's why in part we look at ACE2 RNA expression by platelets. It seems simple but it wasn't that simple. We were actually using through PCR and different approaches and primers we got different answers using intron-spanning and non-intron-spanning primers from that, the receptor was presented so that in fact we ended up concluding that there was little or no ACE2 RNA in platelets of COVID-19 individuals that we examined but that there was some DNA that could be contaminating, potentially due to extracellular DNA maybe provided by extracellular vesicles[inaudible 00:19:30] or something but either way we're speculating. Dr Eric Boilard:                One intriguing aspect of the study is that the SARS-CoV-2 RNA was not found on platelets from every patient, it was only in 20% of them and we unfortunately were not able to look at the RNA of these positive patients to determine whether these patients were positive for ACE2 RNA and potentially in some donor cells in some patients, there might be some levels of expression and we are not excluding this. Dr Eric Boilard:                So yeah, you ask whether it was consistent with other studies? There was the study by Manny that was published, in Blood where they also could not find the receptor but our studies contrast with the one that was more recently reported by Zhang in Journal Of Hematology & Oncology. In this study they found in fact that a robust expression of ACE2, both protein and RNA, and it was both in humans and mouse so clearly there's still work to do to determine whether ACE2 is present or not, but there could be other means of interaction between the SARS-CoV-2 and platelets if there is indeed an interaction. We speculated that maybe in some patients there could be antibodies against other coronaviruses, you know the cold, the viruses that give the minor cold symptoms and that in some of the patients these cross-reacting antibodies could promote the interaction with platelets through their receptor for IgG , that could be a means. Dr Eric Boilard:                There are other receptors that are expressed by platelets, there's probably several. I'm sure we have a list, but one could be the CD147. It's a receptor that is known to be expressed by platelets and that was suggested to interact with SARS-CoV-2, at least it does interact with SARS-CoV, the first one, CoV-1. So these are potential candidates. So there's work to do. Dr Fadila Guessous:        What we found was that in Eric's lab, that you have this 20% of aged people that have this SARS-CoV RNA in place, in 20% of aged people. So should we look only at aged people for this ACE2? If they have the receptor for ACE2, maybe? It's like 20%, only aged. And this 20% of people we investigated, they were only aged. Not other people. So do we... probably, we have to go further and investigate more of this age group for ACE2. . Dr Milka Koupenova:     So if I can make a comment, despite the fact if ACE2 was expressed or not, right? Could it explain the profound thrombotic response that you see? What's your take on it? Dr Eric Boilard:                Personally, I doubt it. I think the disease starts in the lungs and this is where the damages are made, and that it may expand to blood vessels and then multiple players can then from a place of activation damages themself, the lack of O2 in some patients that are in ICU. And then of course the activation of the other cells, the cytokines themselves. So there are numerous ways I will say that can be to play for activation. In fact, the study by us, the one in Blood, they use plasma from the COVID-19 patient and I would assume there was no actual virus particle in this plasma. And they incubated it with platelets, and platelets were then activated. So there are molecules in COVID-19 that circulate in blood that can activate platelets, and that adds to the vasculature damage trauma. I would think that that could come from principle factors. Dr Milka Koupenova:     Which would explain why is it so dysregulated, which brings it to the next question now with a favorite question in the literature. Should we be using antiplatelet drugs? Your opinion, Eric and Fadila? Dr Fadila Guessous:        Well with my collaborator, Younes Zaid you know, and first author on this paper, actually they are going for that. They are having small trial giving antiplatelets treatment to a few patients in our lab. You will hear the story. I don't know if Eric will allow me to disclose this? I don't know because Younes is not here, but they are using heparin for now and for the treatment, but now they are trying antiplatelet treatment as a small trial. Dr Milka Koupenova:     So when do they give antiplatelet drugs? At what stage of the disease? Dr Cindy St. Hilaire:        I think maybe the way to ask the question is: If you were going to use antiplatelet therapy for changing the course of the disease, where do you think is the best time point within the disease, from the day you get infected to symptom presentation and well after that, what time point do you think it's most critical, the platelet function? Dr Fadila Guessous:        It's a good question. It's a good question because the trial is done in in our lab and I didn't have insight. What time is the time point. Honestly, I don't have an answer for that in time point. Because I have a... they started the trial- Dr Cindy St. Hilaire:        No, but I guess, based on what we know and what you've found in your study, where would you think it's more critical, if we even can speculate on that? Dr Fadila Guessous:        Yeah, the symptoms. I would give them from the beginning of the symptoms for me. Because otherwise, when you are in the cytokine storm and you have all this [thromboembolism in the lungs and everything, it's too late. Dr Eric Boilard:                And if I can add something. When we think of immune cells or B cells, D cells, we don't say anti-lymphocytes or anti-neutrophil therapy. But when we come to platelets, we think that the molecules that are known to impact some of the platelet activities, we think of aspirin, clopidogrel, coagulation, and we call it anti-platelets but. But platelets, I mean, they can do a lot independently of from vaccine, independently of EDP, and sometimes we forget that they are more than just these poor thrombotic cells and that there are different studies that has been published by different groups and us that found that you can use, for example, COX-1-deficient platelets. So they won't make thromboxane yet, they can make lot of IL1 and be pro inflammatory, although they will not make thromboxane. So we actually use mice where were we use a variety of anti-platelet therapies but yet their platelets were able to come out inflammation so there's no one drug that can get all the platelet functions at once, so it's important to remember that. Dr Cindy St. Hilaire:        It sounds like maybe some of them could possibly make things like a cytokine storm almost worse, if we're targeting the wrong anti-activity? Dr Eric Boilard:                All depends on how platelets are activated. Whether we are activating a GP pathway, or a nighttime pathway or both at the same time, and the environment where platelets are localized and activated so that they all back the response to this. Dr Cindy St. Hilaire:        So you're saying it's complicated. Dr Eric Boilard:                Yeah, I think it's not simple. Dr Milka Koupenova:     Anything complicated, it's platelets. So in a way I think that perhaps what we need to acknowledge is targeting platelets for whatever response. I completely agree that platelets should be targeted at one point but what drugs should be used, is the question? What specific receptor or what specific response? And if we manage to figure some form of controlling the inflammatory response, that specific, what you see, that huge amount of cytokine dysregulation that will be great. But if you're targeting platelet-specific function when it comes to thrombosis, I'm a bit concerned that there has to be an exact time in which that's important. And the reason why is because if you have this damage in the endothelium, as you see reproducing the virus in the endothelial cells, and if platelets are not doing their own function then perhaps a lot more virus is leaking into the circulation. And that could be why you see some patients that have it, some patients that don't have it, which is a question that I want to ask. Dr Milka Koupenova:     Why do you think some patients have it and some patients don't have it? And do you think that perhaps as the virus gets processed into a platelet and digested, we are missing a time point? Because we're not taking platelets from patients at the same time after infection. We have no way of doing that. So what is your take on the fact that you have virus in some platelets? And from your study, perhaps, if we rely on the numbers, the people who have more severe symptoms seem to have a little bit more. Correct me if I'm wrong. Dr Eric Boilard:                Actually, the older people have more chance of having it but it was not in the more severe people. In fact, even among the non-severe patients, there was 20% of them that had platelets with positive RNA. So that didn't correlate with severity or any outcomes. The only correlation we could identify was age. Dr Milka Koupenova:     So do you think that perhaps in older individuals there are problems would be degradation of the virus, and hence they are not initiating the proper response? Dr Eric Boilard:                Yeah, potentially. Maybe there's somehow an indication of the virus from the organs and it's a destination or it's not captured fast enough on the first varrier of the immune cells in the lungs. Right now we don't have the evidence that it's actually the virus that is in platelets, right? The RNA and there's still work to determine if the virus is there. Dr Milka Koupenova:      So practically, in summary, we don't know what it is. Although, I mean, with a bias, me probably like you, and you're very nice, you're cautious, but I also believe that the virus... and it's a belief. That the virus gets inside of platelets. Dr Fadila Guessous:        How, Milka? How? Dr Milka Koupenova:     There could be some issue that we don't see, and as Eric says, it's some form of an age factor. There could be other receptors. Platelets are tricky, they don't act like every regular cell so they may have evolved to have other receptors that maybe they are not as functional in the ither cells but they're platelet specific. There is the process that from all these cytokines perhaps, platelets are just sucking in things by micropinocytosis, which has happened. The thing that's important to think and mention is that if a virus is not going into a platelet by receptor-specific mechanism, perhaps it's locating to the wrong compartment, and then not introducing the proper immune response. Perhaps that's the reason of why you're catching it only in 20%. This is all very, very speculative. Dr Eric Boilard:                Yeah. And are you putting in a contribution of megakaryocytes] in the lungs where they will burst … Dr Milka Koupenova:     Yes. That it. Absolutely, it's quite possible. That's a collaboration then you should perhaps consider with Dr Craig Morrell. Which is very interesting, right? We don't know. We were never able to figure, even with our full studies, we also saw, what is it, four out of 18? So it's like 25% of the platelets had RNA for a flu but when you look what the antibody of the virus you find that a lot more platelets have it. So is it that we're missing some form of a process that the virus quickly gets digested and it initiates a response? I don't know until we get the right tools. But currently we are struggling with tools, practically, to assess that question. Dr Eric Boilard:                Yet it's impressive what's been done since March with the Covid. Dr Milka Koupenova:     Oh, some of them is good. Some of them is really important science and some of them is questionable that raises more questions. Dr Eric Boilard:                Absolutely, yeah. Dr Milka Koupenova       I personally think it's very important what your study is showing because it gives a base of truly thinking about how platelets maybe truly acting as an immune cell at the beginning. I know that Eric and I might be a little bit biased when it comes to that, but when does the thrombotic response stop? And when does the immune response stop of a platelet? And is it necessary to stop and to be all together? How do we push one and doesn't stop the other? These are the questions that we in the field truly need to assess and that's what I really like about your study, is that it raises these important questions. Dr Fadila Guessous:        Before the call, I was looking at the paper from University of Verona. I mean, I was hoping they will find more answers to the same question that is a favorite from University of Verona, and actually they are also more speculative. They didn't answer the question, the same questions we are asking. Dr Milka Koupenova:     Well, until we have the virus on hand, the actual virus, it's a little hard for us. And then the other point is even if you have the virus on hands, you're doing all of these in vitro studies, how do you assess the entire immune response? Can we think of platelets just as platelets without being in cells, right? What is your take on that, Eric or Fadila? Can you think of platelets just as platelets when it comes to mediating a response to a viral infection? Because we think okay we do this particular thing with platelets and then they mediate this and they mediate that, but perhaps the interaction between platelets and all the immune cells at the beginning of the response is super important. And I do struggle sometimes with the assessment of what amount is just platelets and what is the communication between each immune cell and platelet. It's very hypothetical. Dr Eric Boilard:                I agree that I see platelets as communicators to other cells. I mean, they're so numerous and there are bags with cytokines and other molecules and RNA and micro RNAs and it can impact for different organs, tissues, cells. The fact that they were activated, even in the non-severe patients, all the non-severe patients we analyzed, platelets were there, they were activated. So there was something going on, although thrombosis was not of use in these patients, so they made plates front row and the front part of the disease and the pathogen as a cell. Dr Milka Koupenova:     So is there a way of somehow, as you perceive in your future studies, to get platelets from people who get the virus but don't have any symptoms, and compare their cytokine profile of platelets to what you see? Because we focus so much on the people who get infected, logically, right? But truly to assess what is the difference, if we can figure why those patients are not having this profound response, right? Dr Eric Boilard:                Something that we dream of. The fact that collecting platelet from someone who has no symptoms is…Because we, if they have no symptoms, then they don't come to us. They don't stop- Dr Fadila Guessous:        They don't show up at the hospital. Dr Milka Koupenova:     And so you have to recruit them by tests, right? Because we screen, for instance, our institution screens. But it's hard, right? No one wants to take blood from a… Dr Fadila Guessous:        You get this kind of calls, people are asymptomatic, they don't have any symptom, they won't show up at the hospital. We used whatever we had in our recruitment from the hospital. Dr Eric Boilard:                In fact, you can maybe go through the transfusion work, the studies on transfusion where they actually collect blood from people and people sign that they have no symptoms when they do give blood. And there are studies from China and more recent ones in France where they then went back to this bags of... these were plasma, but maybe one could do it with platelet concentrates. And then go back to these bags where people had signed they had no symptoms when they gave blood, and screened platelets for RNA and then... but you have dozens of dozens of samples to test, but they are available. And maybe someone could find that many were positive but they were asymptomatic, using transfusion studies, maybe. But recruiting people from outside, asking we want people with no symptoms for… Dr Cindy St. Hilaire:        I know we're doing sentinal testing of our students, so. Somehow the group doing that needs to couple with platelets studies. But that was wonderful. Thank you Dr Boilard, Geussous, and Koupenova for joining me today. This has been an amazing interview. It's a wonderful study. Good luck on the future research and thank you for moving the field forward on this. Dr Eric Boilard:                 Thank you very much for inviting us. It was great and we are pleased to interact with you. Thank you. Dr Milka Koupenova:     Very nice to meet you Fadila, Eric. Dr Fadila Guessous:        Thank you so much for having us. It's really it's a pleasure to have this interview with you and of course I have to say that really it has been a wonderful collaboration with Eric and Younes in our lab. I am from Casablanca so we had really many people involved in this project and everyone, we worked really, really hard to get this very... I mean, you can see the time, it's from March to now, to get this paper out it was really a big effort. A big effort from the Moroccan side and from Eric's team in Quebec City and so we are really very pleased to have this wonderful collaboration. Thank you so much for having us. Dr Cindy St. Hilaire:        That's it for the highlights from the late October and early November 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, Drs. Eric Boilard and Fadila Guessous, as well as Dr Milka Koupenova for co-hosting the interview with me. Dr Cindy St. Hilaire:        This podcast is produced by Rebecca McTavish and Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the 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.  

If you fear COVID, the most important thing to do is to clean up your diet and nutrition. By doing so, you optimize your immune system, specifically the anti-viral capacity. Despite the mainstream media's chronic refusal to admit that nutrition and many vitamins are key to immune health, the research cannot be denied. If you strip away all financial interests, the best defense is a healthy lifestyle, which includes healthy nutrition. Watch the video to see the research graphics referenced here: https://youtu.be/uYe2HxUXvHM

This month on Episode 16 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the August 28 and September 11 issues of Circulation Research. This episode features an in-depth conversation with Drs Andrew Murphy and Michelle Flynn from The Baker Heart and Diabetes Institute at Monash University in Melbourne, Australia regarding their study Transient Intermittent Hyperglycemia Accelerates Atherosclerosis By Promoting Myelopoiesis.   Article highlights:   Fish, et al. KRAS Mutations Cause Arteriovenous Malformations   Ehling, et al. B55a in Vascular Biology   Barrett, et al.  Platelet Activity and Vascular Health in COVID-19   Furmanik, et al. Nox5 in VSMC Phenotype and Calcification     Cindy St. Hilaire:  Hi. Welcome to Discover CircRes, the podcast to 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 share with you four articles selected from our late August and early September issues of Circulation Research. I'm also going to speak with Drs Andrew Murphy and Michelle Flynn from The Baker Heart and Diabetes Institute at Monash University in Melbourne, Australia regarding their study Transient Intermittent Hyperglycemia Accelerates Atherosclerosis By Promoting Myelopoiesis. So first, the highlights. The first article I'm sharing with you is titled Somatic Gain of KRAS Function in the Endothelium is Sufficient to Cause Vascular Malformations that Require MEK but not PI 3-Kinase Signaling. First authors are Jason Fish, Carlos Perfecto Flores-Suarez, and Emily Boudreau. And the corresponding authors are Jason Fish and Joshua Wythe, and they're from University of Toronto and Baylor College of Medicine. Arterial venous malformations, or AVMs, are tangles of blood vessels in which the arteries are directly connected to the veins without going through the capillary bed. These are thought to be present from birth and when they occur in the brain, they can cause an array of symptoms such as headaches or seizures, but they are also the leading cause of hemorrhagic stroke in children and young adults. This is because the venous system is not muscularized to respond to the pressure forces that are exerted on arteries. These pressure forces cause distension and eventual leakage at the site of AVMs. Vessel tissue recovered from patients undergoing AVM repair has been shown to contain sematic gain of function mutations in the protein RAS GTPase, which is encoded by the gene, KRAS. However, whether these gain of function mutations directly cause AVMs has not been established. This study now shows that endothelial cells with constitutive expression of gain of function KRAS mutants in mice and zebra fish causes vascular malformations and cranial hemorrhages. Inhibiting a MEK kinase, which is a downstream mediator of RAS signaling, prevented hemorrhages in the mutant KRAS carrying fish. In vitro studies also showed that overactive RAS GTPase protein caused excessive angiogenic behavior of endothelial cells. Together, this work confirms the link between gain of function KRAS mutations and brain AVMs, and suggests that MEK inhibition could be a potential strategy for nonsurgical treatment. The second article I want to share with you is titled B55a/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complimentary Approach To Kill Pathological Vessels. The first author is Manuel Ehling and the corresponding author is Massimiliano Mazzone. And the work was completed at Leuven Center for Cancer Biology in Belgium. Building a mammalian vascular system is a dynamic process that is dependent on both growth of new vessels, as well as the pruning of unwanted ones. But while much is known about molecular mechanisms underlying angiogenesis, comparatively little is understood about the mechanisms regulating vascular pruning. This study discovered that suppression of the protein phosphatase 2 subunit, B55A, is a key protein regulating the pruning process. They found that in mouse vascular development, B55a is widely expressed. However, in adult mice expression is restricted only to sites of active angiogenesis. Deletion of B55a in mice caused death in mid to late stages of embryogenesis as a result of vascular problems that appeared to be due to excessive vessel pruning. Switching off B55a in adult mice when the vascular development is for the most part complete did not cause any apparent problems. They did find though, that inhibition of B55a significantly delayed growth of tumors that form from the injection of cancerous cells. Inhibition of B55a produced tumors with less dense vasculature and reduced metastatic potential. Thus, the author suggests that ramping up blood vessel pruning, be it inhibition of B55a, could be a novel strategy for limiting tumor growth. The next article I want to share is titled Platelet and Vascular Biomarkers Associated With Thrombosis and Death in COVID-19. The first author is Tessa Barrett and the corresponding author is Jeffrey Berger, and they're from New York University. Our knowledge of the complications of COVID-19 is evolving every day. Laboratory testing done to date suggests that approximately 30% of hospitalized COVID-19 patients go on to develop thrombotic events. Platelets are central characters in both arterial and venous thrombosis, and it is known that virus platelet interactions can stimulate a pro-coagulant and inflammatory state during a viral infection. Further, recent studies have reported COVID-19 patients have hyperactive platelets and autopsies of COVID-19 patients exhibit micro and macro thrombi across vascular beds, even in patients without clinical thrombosis. This group then hypothesized that biomarkers of platelet activation are associated with incident thrombosis or death in COVID-19 patients. To test this, they randomly selected 100 COVID-19 positive patients and analyzed banked samples collected on the day of the COVID-19 diagnosis to investigate in vivo platelet activity, as well as vascular health biomarkers. They show for the first time that biomarkers of platelet activation at the time of diagnosis are associated with thrombosis or death in patients hospitalized with COVID-19. Their findings suggest platelet activation mechanisms may contribute to adverse events and highlight the potential role of antiplatelet therapy in this disease. The last article I want to share with you before we switch to our interview is titled Reactive Oxygen-Forming Nox5 Links Vascular Smooth Muscle Cell Phenotypic Switching and Extracellular Vesicle-Mediated Vascular Calcification. The first authors are Malgorzata Furmanik and Martijn Chatrou. And the corresponding author is Leon Schurgers from Maastricht University in The Netherlands. Vascular calcification is an active process regulated by several mechanisms, including vascular smooth muscle cell apoptosis, osteochondral genic transdifferentiation, extracellular vesicle release, and cellular senescence. In healthy adult arteries, smooth muscle cells maintain a contractile phenotype. However, various insults such as oxidative or mechanical stress, can induce smooth muscle cells to lose their contractility and this process of de-differentiation is termed phenotypic switching. And phenotypic switching is thought to precede the development of vascular disease. Patients with conditions such as chronic kidney disease have mineral imbalances in their circulation and also exhibit higher levels of vascular calcification. However, the mechanisms behind these observations are not well defined. This group found that extracellular calcium can enter the smooth muscle cells via extracellular vesicles and this increased cytosolic calcium concentration. Increased calcium induces expression and activity of Nox5 in NADPH oxidase. Activation of Nox5 increased production of reactive oxygen species, which in turn decreased contractile marker expression, and also promoted calcification in vitro. Intracellular calcium signaling also further enhanced extracellular vesicle secretion, and decreased extracellular vesicle uptake. This then promoted the accumulation of extracellular vesicles in the extracellular matrix, which is a mechanism that promotes calcification. Together, these data suggest that mineral imbalances, such as those seen in chronic kidney disease patients, contribute to loss of smooth muscle cell contractility, which promotes osteochondral genic transdifferentiation. For the interview portion today, I have with me Drs Andrew Murphy and Michelle Flynn from the Baker Heart and Diabetes Institute and Monash University in Melbourne Australia. And we're going to be discussing their manuscript titled Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis. But really I like the running title, which is Hyperglycemic Spikes Accelerate Atherosclerosis. So thank you both very much for joining me today. Michelle Flynn: Thanks for having us. Cindy St. Hilaire: So before we start to ‘stalk a bit about what the details of this study is, could you maybe give us a little primer on what you've done that led up to this study? Andrew Murphy: Yeah, so this really was a continuation of a study that began actually when I was in my postdoc in Allan Tall lab and working with Ira Goldberg’s lab with the postdoc  Prabhakara R Nagareddy there. We've shown along with Ed Fisher’s group at NYU, that mice that had established atherosclerotic lesions that were then made diabetic, failed to have lesion regression compared to those that were non-diabetic with normalized plasma cholesterol levels. We showed that if we gave an SGLT-2 inhibitor to normalize glucose that regression then started to occur. And then we found that this was primarily driven by myelopoiesis, suddenly increased production of monocytes, which through that entered the plaque. And so from that, that was in the hyperglycemic model which is sort of a very rare patient group these days, because most people are on well-controlled glucosteroid drugs. And really the SGLT-2 inhibitors have been a game changer in that scenario. And what we were trying to do with this study was bring it into a more clinically relevant setting that might show the potential importance of glucose on a much larger population. Cindy St. Hilaire: Excellent. Maybe you could give us an introduction to the link between what's known about diabetes and cardiovascular disease and the interplay? Michelle Flynn: So diabetic and pre-diabetic patients actually account for 65% of all cardiovascular deaths, which really indicates that diabetes itself plays a major factor alongside other things like obesity and hypercholesterolemia. And so we've previously shown that hyperglycemia was actually driving atherosclerosis in a chronic hyperglycemic setting. So given that kind of vascular disease actually affects both diabetic and pre-diabetic patients, we suspected that it may not just be chronic hyperglycemia or really intense hyperglycemia that could be driving this issue. And so what we were actually looking at in this paper was how more transient levels of hyperglycemia, which actually occur quite often in both diabetic patients and pre-diabetic patients, how much this can contribute to cardiovascular disease. Andrew Murphy: I guess this link between poor glucose control and cardiovascular disease is obviously very well established. The interesting part is that HbA1c only predicts part of the risk. If you look at fasting blood glucose, again, that's only partially responsible, but if you look at postprandial or two hour glucose loads, you'll see that that is more predictive of cardiovascular events than the other two measures. And it seems to be a continuum. So even if you are a healthy or non-diabetic individual, you obviously still have those postprandial events and depending how high that goes up is thought to be a predictive of future cardiovascular outcomes. And so obviously that's worse than people with pre-diabetes and then again worse with people that have actual, full blown diabetes. Cindy St. Hilaire: And what is a transient hyperglycemic event? What would do that in maybe you and me who don't have diabetes versus someone who has diabetes or is pre-diabetic? Michelle Flynn: So essentially what we're modeling with this transient hyperglycemia is that postprandial increase in glucose after you have a meal, which in people who have impaired glucose tolerance is going to be more pronounced than in someone who has a normal glucose tolerance. Cindy St. Hilaire: Got it. And so how did you test this in the mice? Michelle Flynn: We did this by developing a novel model of transient hyperglycemia. So we used ordinary wild type mice that weren't diabetic, and we injected them with glucose intraperitoneally, which then increased blood glucose levels in the plasma after about 15 minutes up to about 15 to 20 millimolar. And then after about two hours, this decreased back down to baseline levels. So this was very similar to what you actually see in a postprandial event. And by doing this four times throughout the day, we were able to mimic what you might see in a patient who has had several meals across the day who has impaired glucose tolerance. Andrew Murphy: One other advantage with the model that we used was that we were trying to really isolate the effects of glucose. And so by injecting glucose intraperitoneally in otherwise healthy mice, it bypasses the incretin response, which we know loses efficacy, I guess, in people that are diabetic. And so we were just really mimicking acute glucose rises that would occur after a meal. And then obviously in this wild type mouse the insulin response would then kick in to clear the glucose so it really tests that glucose hypothesis. Cindy St. Hilaire: So it's really digging in deeply on the actual sugar component, not just eating in general or other aspects. So in some of your experiments, or I guess in actually most of them, you show that the injection of glucose, it increased the plaque size in these mice, but it didn't alter the cholesterol levels. So can you explain a bit what's going on there? A little bit about the mechanism you discovered and kind of specifically introducing RAGE and the S100A8 and A9 axis? Michelle Flynn: Yeah, so what we showed was that regardless of cholesterol levels, we were seeing an increase in clot plaque size, and this was actually driven by the monocytes and neutrophils which were increased in the circulation of these mice. And then these are able to infiltrate into the plaque where they promote plaque progression. And what we found was that the increase in monocytes and neutrophils was due to an increase in their production within the bone marrow. And this was in turn due to the signaling by a protein heterodimer of S100A8 and A9, which signals via the receptor RAGE in the bone marrow on the progenitors of these cells, which induces their proliferation and differentiation. And then that produces an increase in the production of those immune cells, which promote plaque progression. Cindy St. Hilaire: Interesting. So it's really independent of kind of the basic thing that everyone thinks about, or I guess as non-scientists think about, is cholesterol. The public really focus on cholesterol, but what your study's showing is there's this whole other glucose mediated immune arm to it. What else does this S100A8-A9 regulate? Andrew Murphy: So S100A8 and A9 has some intracellular roles, which may direct the development of the model itself, but really a lot of its extracellular roles and so on is promoting sterile inflammation, chemotaxis, so activation of local immune cells. And in the context of diabetes and obesity, many of other diseases, it can signal via RAGE, as Michelle said, but it can also signal by TLR4. And so it seems as though in those diseases driven mainly by glucose, such as the modeling of postprandial hyperglycemia or all kinase in general, it will signal via RAGE, but we've also shown in the setting of obesity that it will signal via TLR4 to stimulate things like interleukin 1 beta. We've also had a paper just recently in Circulation  with Prabhakara Nagareddy’s group where we've shown post myocardial infarction that prime neutrophils in the heart to eventually release IL1-beta and cause myelopoiesis in that way. Cindy St. Hilaire: Wow, so this is really kind of an early activator of a much bigger immune response, whether it's in atherosclerosis or MI or probably, I don't know, a handful other things, I guess, right? Andrew Murphy: It seems to be really important when neutrophils are involved. So in a setting of an MI, we know that they come into the heart very early and become activated and it really makes them about 40% of the cytosol proteins of the cells. So when it degranulates or lyses, they are kind of neutral, at least in the predominant protein. Cindy St. Hilaire: Okay. So this is released in NETs in NETosis then? Andrew Murphy: That's what we're sort of discovering so far. So I guess all I can say is, stay tuned, this is a story for another day. Cindy St. Hilaire: Okay. That's really interesting though. Andrew Murphy: We haven’t looked in gglucose driven events yet. Cindy St. Hilaire: Yeah and actually one of the interesting things I've learned from your study, I had known about GLUT1 and that GLUT1 was I guess the constituently active of the glucose transporters, but I didn't realize it was so high on neutrophils and that neutrophils were so dependent metabolically on glucose. Can you maybe tell a little bit more about that story? Michelle Flynn: Yes. So the neutrophil itself is actually very highly dependent on glycolysis because it doesn't actually have many mitochondria. So compared to most cells, they have very few mitochondria so they can't really rely upon the oxidative phosphorylation for their general metabolism. And so they predominantly rely on glucose coming into the cell and then being shuttled through glycolysis to generate their energy. And yeah this does seem to be predominantly due to uptake of glucose through GLUT1. Cindy St. Hilaire: And then that excess glucose, the byproduct, is reactive oxygen species and upregulation and this cascade of- Michelle Flynn: Yes, yes that's correct. Cindy St. Hilaire: Okay, great. So currently we use HbA1c as a biomarker for overall kind of glucose regulation in diabetic patients. And based on your studies and perhaps the studies of others, would neutrophil numbers or even S100A8 or A9 be a better metric to figure out where a pre-diabetic or even a healthy patient is in terms of their glucose tolerability? Michelle Flynn: Yeah. That could actually be an interesting marker to look at. Given that neutrophils and S100 are also associated with obesity and diabetes in general, and as well as the risk for cardiovascular disease. So with the progression of diabetes, you could expect that the levels of these would increase as well. Andrew Murphy: We've shown previously when we first discovered that the S100 was important in diabetes, that in the Pittsburgh study with Trevor Orchard's group, he had followed people with type one diabetes for 20 years, that those that did develop a cardiovascular event had a higher S100A8 and A9 levels and that correlated with neutrophils. And so it certainly seems to be a marker of predictive outcomes. And so those that do have poorer glycemic control will have higher neutrophils. That's well known. And so perhaps you're right that probably in combination with HbA1c or things like two hour post glucose challenges, S100A8 and A9 and perhaps neutrophil counts would also be a nice predictive measure of potential cardiovascular outcomes of that person. Cindy St. Hilaire: Wow. That'd be really great because you could then maybe kind of more fine tune and predict which patients might be more or less susceptible to cardiovascular events. Andrew Murphy: That's right. Yeah. I think one other important aspect would be if HbA1c is deemed to be relatively well under control, yet you still have a high level of S100A8 and A9, that perhaps those transient spikes are contributing. You're not picking that up in the HbA1c, which looks like the average over approximately a month. And so that could be a nice way to add value onto that score. Cindy St. Hilaire: Interesting. I didn't realize it was that stable about over a month. All right. So I'm relatively healthy. I'm not pre-diabetic, but if I eat a whole bunch of cake or a whole bunch of ice cream or drink a lot of beer, does that create un me a transient hyperglycemic event that is of the same range we're talking about and what do your findings suggest for people who are relatively healthy and things we should be aware about regarding eating habits and things like that? Andrew Murphy: Yeah. I think it's a really good question. And it's sort of hard to give you an exact answer to that right now. We need to look at that in people, model these sort of same spikes in people, but what we I guess don't know yet, even in the preclinical models is how high and how long does that glucose have to be? And I think that's one of the most important questions first. So is there a danger zone where these neutrophils start be the innate senses of hyperglycemia that start to then release S100A8 and A9 to cause these downstream events? But what our data does show is that if you're doing this, having a binge night or a binge day once a week for your life, then that's probably not going to be a great thing. Cindy St. Hilaire: Yeah. All right. So you need to figure out is one scoop of ice cream okay, but two not so great. Andrew Murphy: Maybe if it's two different flavors it'll be okay. Cindy St. Hilaire: Maybe, right? That's great. So, I mean, is there a way we could potentially therapeutically target this signaling axis or is it too ubiquitous in terms of what it regulates? Is there a way to harness what you've found potentially in the clinic? Michelle Flynn: Yeah, so there's an inhibitor of S100A8 and A9 that prevents its binding to RAGE. It's currently approved as an Orphan Drug for systemic sclerosis in both the US and the UK. And that drug itself, we tested in our preclinical mouse model, and we found that it was in fact able to prevent their production of these immune cells, as well as prevent the accelerated atherosclerosis in response to these transient hypoglycemic spikes. Andrew Murphy: So another sort of line of thinking that we're exploring is that we could actually target neutrophil metabolism itself. And so now we're sort of understanding, are there certain proteins that are more abundantly expressed in neutrophils and not other cells in the body that would regulate glycolysis? I know that might sound a bit of a pie in the sky sort of idea, because glycolytic pathway's quite regulated, but there we have found some proteins that are rich in neutrophils and not other cells that may be responsible for the early steps of glycolysis. And so whether that can be harnessed or not, we'll have to see in the future, but it might be a way of more directly targeting neutrophils rather than approaching that's important in sterile inflammation. Cindy St. Hilaire: That makes sense. That is such a cool idea and this is really such a beautiful story. It's one of those papers that you just read it and it's just such a logical progression, but it's also really interesting and I really appreciated all those bone marrow transplants. I did those in grad school, so well done. It's a beautiful story. And then I'm just really happy that you published it with us. So thank you so much for joining me today. Andrew Murphy: Yeah thanks for having us. Michelle Flynn: Thank you. Cindy St. Hilaire: That's it for highlights from the late August and early September issues of Circulation Research. Thank you so much for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Drs Andrew Murphy and Michelle Flynn. This podcast is produced by Rebecca McTavish and Ashara Ratnayaka, edited by Melissa Stoner, and supported by the Editorial Team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research.  

Sorcha Ní Dhubhghaill talks to Roberto Bellucci about corneal endothelium and phakic IOLs.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.12.199869v1?rss=1 Authors: Leite, D. M., Seifi, M., Swinny, J. D., Battaglia, G. Abstract: A faulty transport of amyloid-{beta} (A{beta}) across the blood-brain barrier (BBB), and its diminished clearance from the brain, contributes to neurodegenerative and vascular pathologies, including Alzheimer disease (AD) and cerebral amyloid angiopathy, respectively. At the BBB, A{beta} efflux transport is associated with the low-density lipoprotein receptor-related protein 1 (LRP1). However, the precise mechanisms governing the A{beta} transport across the BBB, in health and disease, remain to be fully understood. New evidences suggest that LRP1 transcytosis occur through a tubular mechanism mediated by an F-BAR protein, syndapin-2. We show here that syndapin-2 is associated with A{beta} clearance across the BBB. We further demonstrate whether risk factors for AD, A{beta} expression and ageing, impact on native syndapin-2 expression in the brain endothelium, with syndapin-2 mediating A{beta} transcytosis. Both increased A{beta} expression and ageing significantly decreased expression of syndapin-2. These are mirrored by an alteration of the endosome-associated protein Rab5, with an increase of expression with A{beta} accumulation and ageing. Collectively, our data reveal that the syndapin-2-mediated pathway and its balance with endosomal sorting at endothelial level are critical for the clearance of neuronally-derived A{beta}, and thus proposing a new measure to assess AD and ageing, as well as, a potential target for counteracting the build-up of brain A{beta}. Copy rights belong to original authors. Visit the link for more info

Getting ready to pop an antacid or a swig of your favorite mouthwash? Wait! Hold up just a moment. Today, we take a deep dive on the subject of nitric oxide with Dr. Nathan Bryan, the preeminent expert on the subject and author of “The Nitric Oxide Solution.” It may be new to you, but know this...Our body’s ability to produce nitric oxide is KEY to staving off those killers - stroke, heart disease, and other vascular complications like - well, erectile dysfunction. What is nitric oxide and what role does it play in our health? We break it down into interesting and actionable takeaways. You’ll learn: What happens to our body’s ability to create nitric oxide as we age? What is its role in our heart health? And why do so many common over-the-counter products like mouthwash, antacids and antibiotics crush our body’s ability to produce nitric oxide? What foods can we eat to pump up the production of this magic molecule? (spoiler alert: green leafy vegetables and beets, of course) And, what are some smart and simple ways to increase production? As Dr. Bryan says, chronic diseases is caused by two things and two things only: The body missing something that it needs or it’s exposed to something that it doesn’t need. Today, we want to give you what your body needs, so listen in closely and say “YES” to N.O. - nitric oxide! Episode Resources: Support for this week's episode comes from Wild Earth Dog Food. Visit the episode page at plantstrongpodcast.com to claim their offer of up to 50% your purchase. The NutraMilk - Make Alternative Milks and Butters in Minutes Use code: PLANTSTRONG for $50 off Plant-Stock 2020 Details and Registration Theme music for the episode Photo from Prevent & Reverse Heart Disease written by Dr. Caldwell B. Esselstyn, Jr.

In honor of Father’s Day last week, I gathered up your questions and called my Dad, Dr. Caldwell B. Esselstyn, affectionately known as Essy to many. There’s nothing he loves more than helping you understand the importance of what you put on your forks to fight disease and to create and sustain healthy and vibrant endothelial cells. Essy is the ultimate taskmaster and, much to everyone’s disappointment, he doesn’t prescribe a 90% plan. He’s 100% ALL IN and he expects the rest of us to follow suit. While he may not believe in moderation, he does believe in you and your ability to tackle this head-on and bring heart disease to its knees. Nobody said this was going to be easy and that’s ok. All of us need a really good challenge in our lives to push outside of our comfort zones, test our limits, and see exactly what we’re made of. You're stronger than you think. Topics covered? A huge variety, thanks to you, our listeners and fans. Among them: Nitric Oxide and why chewing your greens is your best defense against chronic western disease, including COVID-19. Why fluoride toothpaste is a no-no for your health Dr. Esselstyn's opinions on statins and supplements Your fear of not getting enough protein ...and more Essy speaks the truth and never rounds up to make an argument land in his favor. He simply wants us to live our best and most vibrant lives and, at the young age of 86, I think he's on the right track. Episode Resources: Support for this week's episode comes from Wild Earth Dog Food. Visit the episode page at plantstrongpodcast.com to claim their offer of up to 50% your purchase. The NutraMilk - Make Alternative Milks and Butters in Minutes Use code: PLANTSTRONG for $50 off Plant-Stock 2020 Details and Registration Theme music for the episode

In this episode of Bulletproof Radio, my guest, Dr. William Li, is sharing brand new research that shows COVID-19 causes severe damage to blood vessels. This leads to widespread blood clotting in the lungs.He explains what all this means in real terms you can understand. He’s been deep into new research and is one of the authors of a study that was just published in the New England Journal of Medicine.Dr Li is an experienced internal medicine physician and author of the book, “Eat to Beat Disease.” He’s also a research scientist—specifically a vascular biologist. He’s been actively involved in angiogenesis research and clinical analysis for more than two decades. Angiogenesis is the development of new blood vessels and Dr. Li is one of the world’s leading experts in this field.“Endothelium is just a fancy word to describe the cells that line the lining of our blood vessels,” Dr. Li says. “Endothelium is the connector that brings blood, oxygen, nutrients, everything to every single cell in our body, and if we block those channels, we wind up actually having big problems that happen in the heart, happen in the brain, and then diabetes.”“It's actually very rare that you actually find a virus or bacteria invading an endothelial cell,” explains Dr. Li. But Covid-19 changed that game.“We actually saw for the first time viruses invading endothelial cells and filling them up like a gumball machine. They were literally like zombies getting in infecting and then basically pulverizing the membranes from the inside out. There's something very unusual about this.”Dr. Li and I talk about how Covid-19 acts more like a cold than the flu and other weird things. “The other thing we saw is massive inflammation–your immune system trying to clear out the virus in the infected endothelium,” he says.Listen on as Dr. Li and I go way into the newest research about what else Covid-19 is doing in the human body and what you can do to strengthen your own immunity.Enjoy the show! And get more resources at https://blog.daveasprey.com/category/podcasts/

In this episode of Bulletproof Radio, my guest, Dr. William Li, is sharing brand new research that shows COVID-19 causes severe damage to blood vessels. This leads to widespread blood clotting in the lungs.He explains what all this means in real terms you can understand. He’s been deep into new research and is one of the authors of a study that was just published in the New England Journal of Medicine.Dr Li is an experienced internal medicine physician and author of the book, “Eat to Beat Disease.” He’s also a research scientist—specifically a vascular biologist. He’s been actively involved in angiogenesis research and clinical analysis for more than two decades. Angiogenesis is the development of new blood vessels and Dr. Li is one of the world’s leading experts in this field.“Endothelium is just a fancy word to describe the cells that line the lining of our blood vessels,” Dr. Li says. “Endothelium is the connector that brings blood, oxygen, nutrients, everything to every single cell in our body, and if we block those channels, we wind up actually having big problems that happen in the heart, happen in the brain, and then diabetes.”“It's actually very rare that you actually find a virus or bacteria invading an endothelial cell,” explains Dr. Li. But Covid-19 changed that game.“We actually saw for the first time viruses invading endothelial cells and filling them up like a gumball machine. They were literally like zombies getting in infecting and then basically pulverizing the membranes from the inside out. There's something very unusual about this.”Dr. Li and I talk about how Covid-19 acts more like a cold than the flu and other weird things. “The other thing we saw is massive inflammation–your immune system trying to clear out the virus in the infected endothelium,” he says.Listen on as Dr. Li and I go way into the newest research about what else Covid-19 is doing in the human body and what you can do to strengthen your own immunity.Enjoy the show! And get more resources at https://blog.daveasprey.com/category/podcasts/

A brief preview of the upcoming full episode 53, featuring upcoming topics that include tips for amplifying learning in the A&P course, updates regarding the role of exosomes in the spread of cancer and how heart shape relates to human activity. There's more... some word dissections and Kevin's recommendation for The A&P Professor Book Club. If you cannot see or activate the audio player click here. Questions & Feedback: 1-833-LION-DEN (1-833-546-6336) Follow The A&P Professor on Twitter, Facebook, Blogger, Nuzzel, Tumblr, or Instagram!       Topics 1 minute Strategies to amplify learning in the A&P course The role of exosomes in the spread of cancer How heart shape relates to type of activity Word Dissections 8.5 minutes Metastasis Extracellular vesicle (EV) Exosome Oncosome Transcytosis Book Club 3.5 minutes Prime Mover:  A Natural History of Muscle by Steve Vogel amzn.to/30jcKcm Special opportunity Contribute YOUR book recommendation for A&P teachers! First five submitted and used will be in a drawing for a Kindle Fire HD 10 tablet amzn.to/2WwLZvb Any contribution used will receive a $25 gift certificate The best contribution is one that you have recorded in your own voice (or in a voicemail at 1-833-LION-DEN) Check out The A&P Professor Book Club   If the hyperlinks here are not active, go to TAPPradio.org to find the episode page. More details at the episode page. Transcript available at the script page. Listen to any episode on your Alexa device. Need help accessing resources locked behind a paywall? Check out this advice from Episode 32 to get what you need! https://youtu.be/JU_l76JGwVw?t=440   Sponsors   Transcript and captions for this episode are supported by the  American Association for Anatomy. anatomy.org     The Human Anatomy & Physiology Society  also provides marketing support for this podcast.  theAPprofessor.org/haps     Distribution of this episode is supported by  NYCC's online graduate program in  Human Anatomy & Physiology Instruction (HAPI)  nycc.edu/hapi   Clicking on sponsor links  helps let them know you appreciate their support of this podcast!   Referrals also help defray podcasting expenses.  Amazon TextExpander Snagit & Camtasia The A&P Professor Logo Items   Follow The A&P Professor on  Twitter, Facebook, Blogger, Nuzzel, Tumblr, or Instagram!   The A&P Professor® and Lion Den® are registered trademarks of Lion Den Inc. (Kevin Patton)  

In this episode we talk about what happens to our circulation system and blood vessels as we age. We also discuss how mitochondria and Nitric Oxide play a role in our blood circulation. Finally, we will talk about how exercise or antioxidants can impact the health of our blood vessels. Our guest today is Dr. Song-Young Park. He completed his post-doctoral research fellowship in department of cardiology at Boston University School of Medicine, and earned his PhD in integrative physiology from the University of Utah in 2015. Utilizing an integrative approach, Dr. Song-young Park's research examines the impact of age and disease on circulation systems and blood pressure regulation. Heart disease is the #1 cause of death in North America and worldwide. Heart disease can be caused by high blood pressure due to stiffness in the arteries. Arterial stiffness can be caused by physical stress, mental stress or aging. Mitochondria live in every cell of our bodies, they are the power plants of about every living animal and plant. They take the nutrients in our body such as the sugars, fats and proteins and turn them into energy. They also need oxygen to create this energy. We will be talking about mitochondria a lot more in future episodes, but lets move on for now. The vascular or circulation system contains the vessels that carry blood and lymph through the body. The arteries carry blood which is full of oxygen to all the cells of body. The veins take away tissue waste from the body.    Endothelium is the most inner layer of the blood vessel. The mitochondria in the Endothelium produce the energy that helps to release Nitric Oxide, and this Nitric Oxide is then absorbed by the smooth muscles of the blood vessels to expand/dilate them when there is more blood flowing. Dr. Song-young Park information: Email: songyoung.park@gmail.com University of Omaha profile here Visit Anti-Aging hacks at: Website: antiaginghacks.net Instagram: @antiaginghacks Facebook: https://www.facebook.com/Antiaginghacks

The Tremendous Trio solve the case of the Woman With Foul Steatorrhea, and reveal breakdown of the glycocalyx associated with severe and fatal malaria. Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiP. Links for this episode: Glycocalyx and severe malaria (Clin Inf Dis) Hero: Bridget Ogilvie Letters read on TWiP 167 Case Study for TWiP 167 Woman 30 yo, traveled to DR, went to tourist part. On return for yearly physical, asked about her chronic constipation. She said does not have it any more, has normal bowel habits. A few weeks after her return this occurred. Primary care doc was intrigued, sent off some tests. Found Entamoeba hartmanni. What might the doc have done? What were the consequences of infection? Send your case diagnosis, questions and comments to twip@microbe.tv Music by Ronald Jenkees

Guests: Greg Moloney, MD Mosman, Australia Rohit Shetty, MD Vice Chairman Narayana Nethralaya Eye Institute Bangalore, India

Master teachers focus more on promoting a culture of integrity than on specific anti-cheating strategies, but what are some practical ways to do that? Greg Clowther sings a song for A&P and challenges us to do the same. Button junctions in lymphatic capillaries explain how endothelial cells act as valves. Greg Crowther sings A Physiologist's Blessing (3.5 min) Button & zipper junctions in the lymphatic capillaries (7.5 min) Methods to promote academic honesty and reduce cheating (28.5 min) If you cannot see or activate the audio player click here. Questions & Feedback: 1-833-LION-DEN (1-833-546-6336) Follow The A&P Professor on Twitter, Facebook, Blogger, Nuzzel, Tumblr, or Instagram!   You never really understand a person until you consider things from his point of view […] until you climb into his skin and walk around in it. Harper Lee   (0:44) If you keep up with the HAPS Blog from the Human Anatomy & Physiology Society (HAPS), you may have already accept Dr. Greg Crowther's challenge to incorporate songs into your A&P course this semester. With his permission, here's a song from Greg that's great for the first day of class! Starting on a high note: a first-week-of-fall A&P challenge (HAPS Blog post with a fun challenge from Greg Crowther) A Physiologists Blessing (the home page for the song in this episode; inlcudes lyrics, mp3 demo, karaoke file, sheet music, background info; used in this podcast by permission) VOICES (online conference on using songs in STEM education; only $10; features Crowther) https://hapsblog.org/ (HAPS Blog; one of my favorite blogs for A&P teachers) Playful & Serious Is the Perfect Combo for A&P (previous episode explaining the value of playfulness in the A&P course) Dr. Greg Crowther teaches anatomy and physiology at Everett Community College (WA).  His peer-reviewed articles on enhancing learning with content-rich music have collectively been cited over 100 times.     (4:14) Are you familiar with the button junctions that connect overlapping endothelial cells in lymphatic capillaries in a way that forms valves? What about zippers? Where do they fit into the story? (They do.) Here are some links to the details behind a great demo that Kevin shares for understanding lymphatic structure and function. Functionally specialized junctions between endothelial cells of lymphatic vessels (2007 research article outlining button and zipper junctions; great images) Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. (2012 research article shows that zippers predominate in early development, but are then convert to buttons; also has some really cool images showing these junctions) Lacteal junction zippering protects against diet-induced obesity (2018 research article) Tighter lymphatic junctions prevent obesity (perspective and summary of the research article; includes a nice slide you can use in teaching)       (11:55) One way to approach "the cheating issue" in our courses is to promote a culture of academic honesty from the start. But how do we do that? Kevin shares some practical tips you can use for a comprehensive approach to creating and maintaining a culture of professional and academic integrity in your A&P courses (or any courses, really). What the Best College Teachers Do (the Ken Bain book mentioned in this episode) The Syllabus Episode (mentioned several times in this podcast) Academic Integrity (A special topic page at The A&P Professor website; includes additional information and links to resources) Why be honest? (about academic integrity; for students) Kevin's Academic Integrity statement (This is a statement I have used in my course syllabi. You are welcome to adapt it according to your own course and institution's needs. It's an example to get you thinking about actively promoting honesty.) Kevin' Academic Integrity Case Study handout/activity (This document is an example of an in-class activity that I use to promote discussion of academic integrity. It's a handout used for small group discussions. You can adapt it to fit your needs, per the attribution/share-alike license enclosed in the document.) Frank O'Neill @growgraymatter (Turn on your "Frank O'Neill filter.") Using copyrightable materials in teaching (Some good practical advice from the University of Minnesota Libraries. But ask your own librarians for help. And don't forget, I've got an upcoming episode with an expert!) Testing as Teaching (this seminar at The A&P Professor website shows you how I use Respondus test editor, one of many available test editors that can also easily produce multiple versions of a test) Caring for Students Helps Them Succeed (the episode where I focused on "that empathy thing") Cheating in College: Why Students Do It and What Educators Can Do about It (a book you might find to be helpful) Please call in with your ideas and tips for promoting academic integrity: 1-833-LION-DEN or 1-833-546-6336 podcast@theAPprofessor.org   If the hyperlinks here are not active, go to TAPPradio.org to find the episode page. More details at the episode page. Transcript available at the script page. Listen to any episode on your Alexa device. Join The A&P Professor social network: Blog Twitter @theAPprofessor Facebook theAPprofessor Instagram theAPprofessor YouTube Amazon referrals help defray podcasting expenses.

Lymphatic exosomes help dendritic cells find their way Under inflammatory conditions, antigen-presenting dendritic cells are attracted to lymphatic vessels by chemokines secreted from the basolateral surface of lymphatic endothelial cells. Brown et al. reveal that lymphatic endothelial cells also release exosomal vesicles that, by inducing the formation of cellular protrusions, improve the ability of dendritic cells to detect guidance cues and navigate their way through complex tissue environments. This biosights episode presents the paper by Brown et al. from the June 4th, 2018, issue of the Journal of Cell Biology and includes an interview with one of the paper's senior authors, Dontscho Kerjaschki (Medical University of Vienna). Produced by Caitlin Sedwick and Ben Short. See the associated paper in JCB for details on the funding provided to support this original research. Subscribe to biosights via iTunes or RSS View biosights archive The Rockefeller University Press biosights@rockefeller.edu

Guest: Dr. Valeria Orlova is the Principal Investigator at the Leiden University Medical Center. Dr. Orlova’s lab uses stem cells to study the blood vessels and vasculature. She joins us to talk about her work…

Dr. Malcolm Kendrick is a medical doctor, author, speaker, and sceptic living in Cheshire, England.  His evidence-based arguments refute the lipid hypothesis and other ideas related to chronic illness that has resulted in a pervasive culture of fear and misinformation.  His popular blog features an ongoing series of posts on the real causes of heart disease, pointing to endothelial damage as a causal factor and nitric oxide as vital for preserving health. Dr. Kendrick is with us to share not only what really causes cardiovascular disease, but the specific environmental and psychosocial factors that cause the most harm, and what we need to do to maintain good health. We also discuss unexpected side effects of common medications and supplements and the healing power of specific micronutrients.  If you enjoy this podcast, you can support Dr. Kendrick’s work by pre-ordering his latest book, A Statin Nation: Damaging Millions in a Brave New Post-Health World, available 7/12/18. Here’s the outline of this interview with Malcolm Kendrick: [00:01:05] Book: The Great Cholesterol Con: The Truth About What Really Causes Heart Disease and How to Avoid it, by Malcolm Kendrick. [00:01:07] Book: Doctoring Data: How to Sort Out Medical Advice from Medical Nonsense, by Malcolm Kendrick. [00:01:14] The International Network of Cholesterol Skeptics (THINCS). [00:01:46] Trail Runner Nation Podcast: Metabolic Flexibility with Christopher Kelly. [00:02:59] Highlights email series. [00:03:01] Podcast: The True Root Causes of Cardiovascular Disease, with Jeffry Gerber. [00:03:07] Blog series: What causes heart disease? [00:05:28] Study: Hayashi, Keiko, et al. "Laughter lowered the increase in postprandial blood glucose." Diabetes care 26.5 (2003): 1651-1652. [00:06:20] Stress hormones, sympathetic nervous system. [00:07:32] Graph: Lithuanian death rate; Study: Kristenson, Margareta, et al. "Increased psychosocial strain in Lithuanian versus Swedish men: the LiVicordia study." Psychosomatic Medicine 60.3 (1998): 277-282. [00:08:25] Paul Rosch, M.D, founder of the American Institute of Stress. [00:10:20] Endothelium, glycocalyx. [00:11:12] Nitric Oxide (NO). [00:11:37] Alfred Nobel, nitroglycerin (glyceryl trinitrate, or GTN), Viagra. [00:13:13] Study: Andersson, Daniel P., et al. "Association between treatment for erectile dysfunction and death or cardiovascular outcomes after myocardial infarction." Heart (2017): heartjnl-2016. [00:13:39] Sunlight as nitric oxide stimulant. [00:14:45] Vasculitis, Systemic lupus erythematosus (SLE), Rheumatoid arthritis, Sickle-cell disease. [00:17:05] Endothelial progenitor cells. [00:17:55] Carl von Rokitansky, Rudolf Virchow. [00:21:19] Endothelial damage required for arterial plaque. [00:21:52] Study: Law, M. R., and S. G. Thompson. "Low serum cholesterol and the risk of cancer: an analysis of the published prospective studies." Cancer causes & control 2.4 (1991): 253-261. [00:23:49] Study: Ravnskov, Uffe, et al. "Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review." BMJ open 6.6 (2016): e010401. [00:25:03] Statins increasing NO, studies: 1, 2, 3. [00:26:52] Study: Lanphear, Bruce P., et al. "Low-level lead exposure and mortality in US adults: a population-based cohort study." The Lancet Public Health (2018). [00:28:17] Corticosteroids. [00:30:25] Familial Hypercholesterolemia. [00:34:56] Study: Winnik, Stephan, et al. "Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis–implications for cardiovascular safety." International journal of cardiology 168.3 (2013): 2453-2461. [00:36:29] QRISK survey for heart disease. [00:41:21] Inflammation as healing. [00:42:40] Study: Willis, G. C. "The reversibility of atherosclerosis." Canadian Medical Association Journal 77.2 (1957): 106. [00:44:36] Corticosteroids reduce inflammation, increase CVD risk, NSAIDs. [00:45:05] Study: Guilhem, Gaël, et al. "Effects of air-pulsed cryotherapy on neuromuscular recovery subsequent to exercise-induced muscle damage." The American journal of sports medicine 41.8 (2013): 1942-1951. [00:49:06] Lipoprotein A. [00:51:27] Vitamin C deficiency as possible cause of CVD. [00:53:01] Study: Lee, A. J., et al. "Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study." Journal of clinical epidemiology 43.9 (1990): 913-919. [00:55:27] Diabetes, triglycerides, sepsis, gingivitis as procoagulants. [00:58:39] Major endothelial offenders. [01:00:03] Study: Escolar, Esteban, et al. "The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT)." Circulation: Cardiovascular Quality and Outcomes (2013): CIRCOUTCOMES-113. [01:01:03] Study: Douaud, Gwenaëlle, et al. "Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment." Proceedings of the National Academy of Sciences 110.23 (2013): 9523-9528. [01:01:44] Study: Marik, Paul E., et al. "Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study." Chest 151.6 (2017): 1229-1238. [01:02:27] Allen Smith, dying of flu, recovered with Vitamin C. [01:03:13] sunlight, viagra, stress management, alcohol. [01:04:23] Blue zones, strong social relationships. [01:05:07] Lifestyle and environmental factors associated with lower life expectancy. [01:13:05] Statins. [01:15:49] Absolute risk vs. relative risk; side effect vs. adverse effect, adverse events. [01:21:07] Problems caused by statins. [01:21:29] CoQ10, ATP. [01:23:47] Placebo effect, nocebo effect. [01:24:40] Study: Gupta, Ajay, et al. "Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase." The Lancet 389.10088 (2017): 2473-2481. [01:25:45] Study: Cohen, Jerome D., et al. "Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users." Journal of clinical lipidology 6.3 (2012): 208-215. [01:26:32] PCSK9 inhibitors. [01:27:54] Study: Sabatine, Marc S., et al. "Evolocumab and clinical outcomes in patients with cardiovascular disease." New England Journal of Medicine 376.18 (2017): 1713-1722. [01:35:16] L-arginine, citrulline. [01:39:34] Study: Tunstall-Pedoe, Hugh. "Does dietary potassium lower blood pressure and protect against coronary heart disease and death? Findings from the Scottish Heart Health Study?." Seminars in nephrology. Vol. 19. No. 5. 1999. [01:40:40] Study: Graudal, Niels. "A radical sodium reduction policy is not supported by randomized controlled trials or observational studies: grading the evidence." American journal of hypertension 29.5 (2016): 543-548. [01:43:55] Groupthink, cognitive bias. [01:44:21] Michael Alderman, M.D. [01:44:48] Evolutionary Psychology. [01:45:58] Peer Review. [01:51:36] Study: Bronstein, Alvin C., et al. "2010 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th Annual Report." Clinical Toxicology 49.10 (2011): 910-941. [01:52:57] Book: A Statin Nation: Damaging Millions in a Brave New Post-Health World, by Malcolm Kendrick.   [01:57:37] drmalcolmkendrick.org.

Dr. Nguyen and Dr. Daaboul Discuss Subscribe on iTunes or Google Play.

By Steve Morgan & Sophie Connolly Welcome back to the Basic Science Clinic podcast on ICN. Post-hiatus we are ready to reinvigorate the examination of oxygen cascade physiology, from the prevailing atmosphere down to the only organelle that boasts its own bespoke genome, the mitochondrion. In the last podcast we decomposed the minutiae of passive respiratory gas diffusion across the alveolar capillary membrane. Prior to expounding the pre-eminence of V/Q ratios in determining gas exchange sufficiency, we need to publically vivisect the pulmonary circulation to bring you the belated Raw Science 11, pulmonary perfusion. This detailed inspection of pulmonary perfusion is the longest podcast yet, no doubt we got slightly carried away and thus we have broken it up into three more comfortably digested sections. Section 1 (start to 18:24) will include the historical bit and both adult and fetal anatomy. Section 2 (18:30 to 40:26) examines pulmonary haemodynamics and the integrated control of pulmonary vascular tone. Section 3 (40:35 to end) details the protean functions of the pulmonary endothelium and endothelial glycocalyx, the determinants of transvascular fluid flux in the lung, all with reference to the pathophysiology of acute lung injury.  The pulmonary circulation participates in gas exchange, blood filtration, metabolic regulation of endogenous vasoactive mediators, drug uptake, metabolism and excretion and the regulation of lung interstitial fluid homeostasis, a dexterous function devastated by the clinical syndrome of ARDS. Understanding the idiosyncracies of the pulmonary circuit is imperative for interpreting heart-lung interactions that influence V/Q distribution & gas exchange efficiency as well as overall cardiovascular performance, particularly during positive pressure ventilation in the context of concomitant shock states.

Guest: Greg Moloney, MD Mosman, Australia

Normally the endothelium plays a key role in maintaining homeostasis. Systemic and pulmonary endothelial dysfunction in the setting of critical illness results in multiple organ dysfunction. In this presentation, the following will be reviewed; 1) Evidence for the role of endothelial dysfunction in the pathogenesis of critical illness. Systemic endothelial dysfunction is implicated in the pathophysiology of sepsis and trauma, pulmonary endothelial dysfunction is involved in the development of ARDS. 2) Methods used to assess endothelial function in critical illness will be reviewed. 3) Mechanisms by which interventions may modify endothelial function will be discussed. The future potential role for treatments to modulate endothelial function in the management of the critically ill will be speculated. In summary the aim of this review will be to highlight an important role for endothelial dysfunction in the critically ill. 9vhphp4z

Giovanna Tosato explains how a cytokine subunit activates inflammatory signaling inside endothelial cells.

Claus Jrgensen describes how his group used phosphoproteomic analysis to identify signaling events required for transendothelial migration of metastatic cancer cells.

Michael Simons describes how signaling through the receptor FGFR1 prevents endothelial-to-mesenchymal transition by inhibiting TGF-β signaling.

Jeremy Cohen examines changing paradigms in fluid resuscitation. Is recent focus on the glycocalyx justified?

Listen to Catherine Brissette and John Watt discuss their latest ASN NEURO paper the multifaceted responses of primary human astrocytes and brain microvascular endothelial cells to the Lyme disease spirochete, Borrelia burgdorferi.

Ariel Feldstein discusses the identification of microparticles released by fat-laden hepatocytes that stimulate angiogenesis and contribute to the progression of fatty liver disease.

Here's a scary statistic: over 40% of the American population dies of some form of heart disease. 40%? That's a really big number! Atherosclerosis, or "hardening of the arteries", is the primary cause of heart disease; however, it can be prevented!!!!! In addition to healthy diet and exercise, take 400 IUs of Vitamin E , which prevents atherosclerosis by entering the LDL (BAD cholesterol, there are good ones too!) molecule and inhibiting hazardous oxidation. Now isn't that interesting! Tune in to Eve's latest show with her guest Dr. Fred Harvey, to hear more heart facts and get your jump start on keeping your heart healthy and happy.

Fri, 12 Mar 2010 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/11382/ https://edoc.ub.uni-muenchen.de/11382/1/Hennig_Theres.pdf Hennig, Theres ddc:540, dd

Thu, 12 Feb 2009 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9843/ https://edoc.ub.uni-muenchen.de/9843/1/Eilken_Hanna.pdf Eilken, Hanna ddc:570, ddc:500, Fakultät

Guest: Amir Lerman, MD Host: Larry Kaskel, MD What is the endothelium and how does it regulate itself in wellness and in illness? What are the consequences of endothelial dysfunction and how we can measure it? Join Host, Dr. Larry Kaskel talking with our guest Dr. Amir Lerman to answer these questions and more.

Enhanced Audio PodcastAired date: 2/27/2008 3:00:00 PM Eastern Time

Enhanced Video PodcastAired date: 2/27/2008 3:00:00 PM Eastern Time

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