Podcasts about pcsk9

Send us a textDr. Michael Koren shares insights from his presentation at the American College of Cardiology meeting in Chicago about a groundbreaking oral PCSK9 inhibitor that could lower cholesterol by 80% when combined with a statin. The development represents a significant advancement in treatment options for the 20% of patients who don't respond adequately to statins alone or experience statin intolerance. They also chat about Chicago and the importance of things in moderation.Be a part of advancing science by participating in clinical research.Have a question for Dr. Koren? Email him at askDrKoren@MedEvidence.comListen on SpotifyListen on Apple PodcastsWatch on YouTubeShare with a friend. Rate, Review, and Subscribe to the MedEvidence! podcast to be notified when new episodes are released.Follow us on Social Media:FacebookInstagramX (Formerly Twitter)LinkedInWant to learn more? Checkout our entire library of podcasts, videos, articles and presentations at www.MedEvidence.comMusic: Storyblocks - Corporate InspiredThank you for listening!

Audio roundup of selected biopharma industry content from Scrip over the business week ended 4 April 2025. In this episode: pharma dodges tariffs for now; Marks's departure from FDA rattles industry; Phase 2b win for AstraZeneca's oral PCSK9; Hengrui renews global Phase 3 push; and Novo's new cardio results for semaglutide. https://insights.citeline.com/scrip/podcasts/scrips-five-must-know-things/quick-listen-scrips-five-must-know-things-MPJF4YP4NFAQ5JEDFBEIW62LBE/ This episode was produced with the help of AI text-to-voice and voice emulation tools. Playlist: soundcloud.com/citelinesounds/sets/scrips-five-must-know-things

JACC Associate Editor Khurram Nasir, MBBS, FACC, speaks with author Michael J. Koren, MD, FACC, on his Featured Clinical Research study published in JACC and presented at ACC.25. This randomized, multicenter, double-blind, placebo-controlled, dose-ranging phase 2 study assessed efficacy, safety, and tolerability of AZD0780, a small molecule PCSK9 inhibitor. The study randomized 428 patients (426 started treatment) with hypercholesterolemia on standard-of-care statin therapy to daily oral administrations of AZD0780 1, 3, 10 or 30 mg, or matching placebo for 12 weeks. AZD0780 significantly reduced LDL-C levels versus placebo at all doses (from 35.3% to 50.7%) and demonstrated a safety and tolerability profile similar to placebo. These findings support further development of AZD0780 as part of a simple, oral regimen for lowering LDL-C beyond that achieved with statin therapy.

Μαζί με τον κ. Κοσκινά εστιάζουμε στις σύγχρονες θεραπευτικές στρατηγικές για τη δυσλιπιδαιμία, ξεκινώντας με τη συζήτηση γύρω από τις στατίνες και την εζετιμίμπη: ποια είναι η προτιμότερη προσέγγιση — συνδυασμός μέτριας έντασης στατίνης με εζετιμίμπη ή υψηλής έντασης στατίνη;Αναλύεται επίσης η θέση του μπεμπεδοϊκού οξέος, καθώς και η ραγδαία εξέλιξη των PCSK9 αναστολέων, από τα μονοκλωνικά αντισώματα στους RNA-based παράγοντες όπως το Inclisiran, έως τις νέες θεραπείες τρίτης γενιάς (π.χ. Lerodalcibep) και τις πρώτες προσπάθειες γονιδιακής θεραπείας με CRISPR.Η συζήτηση επεκτείνεται σε νεότερες κατηγορίες, όπως οι αναστολείς ANGPTL3 (π.χ. Evinacumab) και αναστολείς CETP (Obicetrapib), εξετάζοντας τη μελλοντική τους θέση στην καρδιαγγειακή πρόληψη.Τέλος, εξετάζονται οι εξελίξεις στην αντιμετώπιση της λιποπρωτεΐνης (a), με ελπιδοφόρα φάρμακα όπως τα Pelacarsen, Olpasiran, Lepodisiran, και το ανερχόμενο Muvalaplin, και γίνεται αναφορά στις αναμενόμενες νέες κατευθυντήριες οδηγίες και τις πιθανές αλλαγές που αυτές θα φέρουν.

An overview of current and emerging PCSK9-directed therapies; their efficacy, safety, and role in clinical practice. Full text of the manuscript is available at: https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.4635.

In this podcast, expert clinicians will review the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in reducing low-density lipoprotein cholesterol (LDL-C) and reducing cardiovascular risk. https://healio.com/cme/mededtalks/cardiology/20250102/4-lipid-legends-with-your-host-dr-ronald-codario-featuring-dr-peter-toth-pcsk9-inhibition

În cadrul ediției de pe 3 decembrie 2024 a emisiunii Știința360 de pe Radio România Cultural, Dr. Marius Geantă, Președintele Centrului pentru Inovație în Medicină, a comentat ultimele noutăți din domeniul sănătății. Concluzia unui studiu realizat recent în cadrul Universitatii din Londra, a scos la iveală o realitate alarmantă: 81% dintre videoclipurile de pe TikTok care promovează „vindecări miraculoase” pentru cancer conțin informații false. Studiul subliniază pericolul uriaș pe care această platformă îl reprezintă, mai ales pentru tineri, deoarece ei nu folosesc TikTok doar ca mijloc de divertisment, ci și ca sursă de informații despre sănătate. Un aspect îngrijorător al studiului a fost rolul algoritmului TikTok, care nu doar că favorizează răspândirea dezinformării, dar și încurajează utilizatorii să accepte idei conspiraționiste sau să achiziționeze produse potențial periculoase. Printre lucrurile promovate în videoclipurile analizate s-au numărat uleiul de oregano, sâmburii de caise și produse folosite in deparazitarea câinilor, toate fiind prezentate drept remedii pentru cancer. Aceste produse nu doar că nu sunt eficiente, dar pot afecta semnificativ starea de sănătate. Studiul a fost realizat prin crearea unui cont de TikTok, cu căutarea termenului „leac pentru cancer”. Algoritmul de căutare al platformei a fost setat să recomande videoclipuri suplimentare. Pe parcursul lunilor aprilie și mai 2024, au fost colectate și analizate cele mai vizionate 50 de videoclipuri afișate săptămânal pe pagina de recomandări. Mai multe detalii despre subiectele discutate - ▶ Răspândirea dezinformării despre tratamentele pentru cancer prin intermediul aplicatiei TikTok poate reprezenta un pericol ascuns pentru tineri ▶ Pacienții cu boală coronariană care răspund la tratamentul cu inhibitori PCSK9 ar putea fi identificați prin evaluarea biomarkerilor transcriptomici ▶ Accelerarea transformării digitale a sănătății în Europa: cum au progresat Statele Membre în ultimii 2 ani?

A discussion on statins vs. PCSK9 inhibitors; My doctor said I should take a multivitamin instead of the long list of supplements I currently take. What do you think?

This is a replay of one of the most-downloaded episodes of AGE BETTER in 2024.     Take a deep dive into the heart of midlife cardiovascular wellness with this important episode of "Age Better," where host Barbara Hannah Grufferman talks with Dr. Melissa Tracy, a top-tier cardiologist from the RUSH University Medical Center. Dr. Tracy is also the Medical Director of the Cardiac Rehabilitation Program at RUSH.     Dr. Tracy gives a masterclass on statins - those powerhouse medications at the forefront of cholesterol management and heart disease prevention. But the question that lies at the core of this discussion is one that resonates with millions: Who really needs to be on statins? By tuning in, you'll get the knowledge and tools you need to make the decision that is right for you.     KEY TAKEAWAYS:  Understanding Statins: Learn how these powerful medications aid in reducing cholesterol and preventing cardiovascular disease.    Postmenopause and Heart Health: Discover the unique impact of statins for women in midlife.    Shared Decision-Making: The importance of patient-doctor collaboration in deciding if statins are right for you.    Coronary Calcium Score: Uncover how this test is crucial in assessing cardiovascular risks.    Side Effects & Alternatives: Insights into common side effects of statins and who should avoid them, plus a look at natural supplements and other cholesterol management strategies.    Personalized Healthcare: Dr. Tracy emphasizes individualized treatment plans and the role of lifestyle changes alongside statins.    Future-Focused Discussion: A sneak peek into ongoing assessments and evolving conversations in heart health management.    KEY LINKS:  Learn More About Dr. Melissa Tracy: https://doctors.rush.edu/details/1183  What is Cardiac Rehabilitation? https://www.kevinmd.com/2024/02/a-people-first-approach-to-cardiac-rehabilitation.html  USNews+WorldReport Article: https://www.usnews.com/news/health-news/articles/2024-03-05/statin-meds-cholesterol-what-you-need-to-know  Alternatives to Statins Referenced During the Episode:   Ezetimibe: https://www.mayoclinic.org/drugs-supplements/ezetimibe-oral-route/description/drg-20067172  Bempedoic Acid: https://www.mayoclinic.org/drugs-supplements/bempedoic-acid-oral-route/side-effects/drg-20484223?p=1  PCSK9 inhibitors: https://www.medicalnewstoday.com/articles/pcsk9-inhibitor#definition    Whether you're on a statin already, or giving it serious consideration … this episode will help you make the decision that is right for you.    Listen and Subscribe   Remember to subscribe or follow the "Age Better with Barbara Hannah Grufferman" podcast on platforms like Apple Podcasts, Spotify, and YouTube. Yep, you can watch it or just listen!     Share Your Ideas and Questions   Your questions have spurred many episodes, so please keep them coming! Share your ideas for topics and guest suggestions at agebetterpodcast@gmail.com  Learn more about your ad choices. Visit megaphone.fm/adchoices

“It's about symptoms and how you're doing and how you're feeling. It's not necessarily the number on the lab tests,” says Amy Killen, M.D. Amy Killen, M.D., a leading anti-aging and regenerative physician, joins us today to discuss science-backed methods to improve longevity, including stem cell therapies, hormone replacement, and more:  - Women's longevity stack (~2:00) - Hormone health (~4:40) - Hormone replacement therapy (HRT) (~6:05) - Different types of HRT (~7:37) - Killen's story (~9:07) - Stem cell therapy (~11:01) - Sexual health and stem cells (~17:00) - Nitric oxide (~18:10) - How to measure nitric oxide levels (~20:25) - Collagen and hyaluronic acid (~22:30) - Red light and PEMF (~23:36) - Killen's daily routine (~25:15) - Overrated practices in wellness culture (~26:29) - Modern medicine for longevity benefits (~29:45) - Testosterone replacement therapy (TRT) for men (~33:20) - Popular therapies and treatments (~36:40) - The future of longevity and women's health (~42:32) Referenced in the episode:  - Keep up with her @Dr.AmyBKillen (IG, FB, TikTok) - Follow her online (www.dramykillen.com)  - Check out her company (https://hopbox.life/)  - Learn more about her clinic (www.humanauthealth.com)   - Listen to Stacy Sims, Ph.D. on the mbg podcast episode #514  - Research on SGLT2 inhibitors (https://doi.org/10.1016/j.pcad.2023.10.003)  - Research on PCSK9 inhibitors (https://doi.org/10.1016/j.ajpc.2024.100701)  immy is a natural, effective solution to retune your immune system, while addressing inflammatory status and improving mental health and overall resilience.* Learn more about immy today at immy.co. *These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. ​We hope you enjoy this episode, and feel free to watch the full video on YouTube! Whether it's an article or podcast, we want to know what we can do to help here at mindbodygreen. Let us know at: podcast@mindbodygreen.com. Learn more about your ad choices. Visit megaphone.fm/adchoices

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA information, and to apply for credit, please visit us at PeerView.com/CXZ865. CME/AAPA credit will be available until September 17, 2025.Emerging Options for Targeting PCSK9 in Hypercholesterolemia Management: Visualizing New Routes to Individualized Care In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA information, and to apply for credit, please visit us at PeerView.com/CXZ865. CME/AAPA credit will be available until September 17, 2025.Emerging Options for Targeting PCSK9 in Hypercholesterolemia Management: Visualizing New Routes to Individualized Care In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA information, and to apply for credit, please visit us at PeerView.com/CXZ865. CME/AAPA credit will be available until September 17, 2025.Emerging Options for Targeting PCSK9 in Hypercholesterolemia Management: Visualizing New Routes to Individualized Care In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA information, and to apply for credit, please visit us at PeerView.com/CXZ865. CME/AAPA credit will be available until September 17, 2025.Emerging Options for Targeting PCSK9 in Hypercholesterolemia Management: Visualizing New Routes to Individualized Care In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA information, and to apply for credit, please visit us at PeerView.com/CXZ865. CME/AAPA credit will be available until September 17, 2025.Emerging Options for Targeting PCSK9 in Hypercholesterolemia Management: Visualizing New Routes to Individualized Care In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA information, and to apply for credit, please visit us at PeerView.com/CXZ865. CME/AAPA credit will be available until September 17, 2025.Emerging Options for Targeting PCSK9 in Hypercholesterolemia Management: Visualizing New Routes to Individualized Care In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA information, and to apply for credit, please visit us at PeerView.com/CXZ865. CME/AAPA credit will be available until September 17, 2025.Emerging Options for Targeting PCSK9 in Hypercholesterolemia Management: Visualizing New Routes to Individualized Care In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/AAPA information, and to apply for credit, please visit us at PeerView.com/CXZ865. CME/AAPA credit will be available until September 17, 2025.Emerging Options for Targeting PCSK9 in Hypercholesterolemia Management: Visualizing New Routes to Individualized Care In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Merck & Co., Inc.Disclosure information is available at the beginning of the video presentation.

0:00- Intro               0:30- PhD process               8:00- Repetitiveness in expertise               14:40- Saturated fat, LDL, and ApoB               41:00- Statins, PCSK9 inhibitors               47:00- Human equivalent doses 

CardioNerds Dan Ambinder and Dr. Devesh Rai join cardiology fellows and National Lipid Association lipid scholars Dr. Jelani Grant from Johns Hopkins University and Dr. Alexander Razavi from Emory University. They discuss a case involving a patient with familial hypercholesterolemia. Dr. Archna Bajaj from University of Pennsylvania provides expert commentary. Drs. Jelani Grant and Alexander Razavi drafted notes. CardioNerds Intern Pacey Wetstein engineered episode audio. This episode is part of a case reports series developed in collaboration with the National Lipid Association and their Lipid Scholarship Program, with mentorship from Dr. Daniel Soffer and Dr. Eugenia Gianos. A classic finding in patients with familial hypercholesterolemia is the presence of markedly elevated levels of total and low-density lipoprotein cholesterol (LDL-C) with an LDL-C concentration of 190 mg/dL or greater. However, severe hypercholesterolemia is not inevitably present, and many patients who carry this diagnosis may have lower LDL-C levels. This case history describes a young woman whose mother and brother met clinical and genetic criteria for heterozygous familial hypercholesterolemia but who had only a mild elevation in LDL-C, falling to 130 mg/dL after dietary intervention. Despite this finding, genetic testing revealed the presence of the same genetic variants as were noted in her mother and brother. In addition, a second genetic variant predisposing them to cholesterol gallstone formation was identified in all three family members. If genetic testing had not been performed, the diagnosis may have been missed or delayed, resulting in an increased risk for vascular complications associated with familial hypercholesterolemia. This case supports the value of genetic testing of family members of those with familial hypercholesterolemia, even when LDL-C levels are not severely elevated. US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - Exposing an Unusual Presentation of Familial Hypercholesterolemia – National Lipid Association Familial hypercholesterolemia (FH) is among the most common autosomal co-dominant genetic conditions (approximately 1:200 to 1:300 for HeFH, 1:160,000 to 1:300,000 for HoFH). Genetic testing has a role for all first-degree relatives when a family history of FH is strongly suggestive, regardless of LDL-C level. Heterogeneity in ASCVD risk among individuals with FH is derived from background polygenic risk, clinical risk factors (e.g., timing of lipid-lowering initiation and adjacent risk factors), as well as subclinical atherosclerosis burden. In clinical or genetically confirmed FH, an LDL-C goal of 55 mg/dL is recommended. Beyond statins, FDA-approved non-statin therapies for FH include ezetimibe, PCSK9 mAb, bempedoic acid, inclisiran, evolocumab (only HoFH), lomitapide (only HoFH), and LDL apheresis. Notes - Exposing an Unusual Presentation of Familial Hypercholesterolemia – National Lipid Association What are the diagnostic criteria for FH? Dutch Lipid Clinic Network1 Variables: family history, clinical history, physical exam, LDL-C level, DNA (LDLR, APOB, PCSK9) Simon-Broome1 Variables: total or LDL-C, physical exam, DNA (LDLR, APOB, PCSK9), family history Emphasis on clinical history and physical exam reduces sensitivity U.S. Make Early Diagnosis Prevent Early Death (MEDPED) 1 Only one of the three where no genetic testing is required, may work well in cascade screening Variables: age, total cholesterol, family relative (and degree) with FH Definite, probable, possible, unlikely Emphasis on clinical history and physical exam reduces sensitivity

Doctor Shawn Baker Key points for quick navigation: 00:01 Dr. Shawn Baker began his carnivore diet journey in late 2016 out of curiosity and health concerns, starting with a single meal and gradually transitioning. 04:23 Vitamin C deficiency (scurvy) is not observed in carnivore diets due to efficient utilization and presence in meat, contrary to common misconceptions. 07:39 Fiber is non-essential and its health benefits are likely associated with dietary quality rather than fiber itself, often improving on carnivore diets. 13:23 Meat contains a wide array of phytonutrients, challenging the notion that only fruits and vegetables provide essential nutrients. 16:11 Normative ranges for thyroid function tests (like TSH) may not reflect individual health outcomes effectively, emphasizing clinical function over lab numbers. 19:26 Dr. Shawn Baker emphasizes that he focuses on how he feels rather than just lab numbers, highlighting individual health over standardized ranges. 19:53 ️‍️ Despite having low normal testosterone levels, Shawn Baker attributes his strength and health to lifestyle factors like exercise and diet, suggesting sensitivity to androgen receptors. 20:37 Shawn Baker discusses the limitations of standard reference ranges in health metrics, advocating for more personalized approaches especially in populations like carnivores. 27:30 ️ Dr. Baker critiques the conventional focus on LDL cholesterol levels, pointing out historical biases and financial interests in promoting certain health narratives. 29:06 Discussing medication, Dr. Shawn Baker predicts potential class action lawsuits against drugs like PCSK9 inhibitors due to adverse effects like muscle loss, highlighting ethical concerns in pharmaceutical practices. 38:12 Using GLP-1 receptor agonists like semaglutide (OIC) can lead to GI side effects and potential long-term digestive issues. 39:23 Beef isolate effectively stimulates GLP-1, slowing down digestion in a natural way, contrasting with drugs like semaglutide. 41:02 GLP-1 receptor agonists may lead to fat cell hyperplasia, increasing the number of small fat cells, potentially causing weight regain after treatment cessation. 47:30 High-protein diets, contrary to common belief, do not adversely affect kidney health and may even improve kidney function in certain cases. 54:10 Eating plant-based is not necessarily environmentally superior to consuming animal products; the sustainability of agricultural practices matters more than the type of diet. 56:39 Dr. Baker emphasizes the importance of measuring nutrition and human thriving rather than just calories or environmental impact when evaluating food choices. 57:46 ️‍️ He advocates for a healthier population, criticizing societal health disparities despite abundant resources, urging for national campaigns promoting nutrition and fitness. 58:56 ️ Dr. Baker discusses how consumer choices impact public health and healthcare systems, encouraging mindful purchasing to support healthier lifestyles. 01:00:35 He reflects on the values and lifestyles of societal leaders, contrasting personal health standards with those of the general population. 01:03:34 Dr. Baker underscores the need for healthcare paradigm shifts driven by grassroots movements, highlighting the importance of patient support in effecting systemic change. https://www.revero.com/

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME information, and to apply for credit, please visit us at PeerView.com/QMF865. CME credit will be available until August 15, 2025.Lipid Management Beyond Statins: Early Screening, Prompt Intervention, and Timely Intensification With PCSK9-Targeted Therapies In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.Disclosure information is available at the beginning of the video presentation.

Link to Buck's Results: https://drive.google.com/file/d/19BJaZNYwBxlPx4nR9695Q2NC3nNpgW6y/view?usp=sharing  https://drive.google.com/file/d/1br1ikAJKmgKev9X3jkS7nUPdXpAqMzYd/view?usp=sharing Section 1: Overview of Cholesterol Metabolism Cholesterol in the Body: Cholesterol is essential for cell membrane integrity, hormone synthesis, and bile acid production. It is produced endogenously in the liver and absorbed exogenously from dietary sources. Endogenous Production: Cholesterol is synthesized in the liver through the mevalonate pathway. Key intermediates: Lathosterol and Desmosterol, indicators of cholesterol production rate. Exogenous Absorption: Dietary cholesterol is absorbed in the intestines along with plant sterols like Beta-sitosterol and Campesterol. These sterols compete with cholesterol for absorption, reflecting dietary cholesterol absorption levels. Section 2: Detailed Analysis of the Test Components Production Markers: Lathosterol: Precursor in the cholesterol biosynthesis pathway. Elevated levels indicate increased hepatic cholesterol synthesis (overproduction). Example: Lathosterol level of 329 µmol x 100/mmol in my study indicates hyperactive cholesterol production. Desmosterol: Another precursor in the synthesis pathway, contributing to total cholesterol production. High levels reinforce the diagnosis of increased cholesterol production. Example: Desmosterol level of 74 µmol x 100/mmol in my study supports elevated production. Absorption Markers: Beta-sitosterol: Plant sterol absorbed in the intestines, competes with cholesterol. High levels suggest increased absorption of dietary cholesterol. Example: Beta-sitosterol level of 120 µmol x 100/mmol indicates borderline absorption. Campesterol: Similar to Beta-sitosterol, reflects cholesterol absorption efficiency. Elevated levels indicate increased absorption. Example: Campesterol level of 113 µmol x 100/mmol within normal limits but suggests absorption could be a factor. Cholesterol Balance Score: Ratio of production to absorption markers. A higher score indicates predominant cholesterol production; a lower score indicates absorption as the main issue. Example: Score of 2.4 suggests overproduction is the dominant issue. Section 3: Clinical Implications and Treatment Strategies (10 minutes) Frequency of Overproduction vs. Overabsorption: Common to see patients with either overproduction or overabsorption, but less commonly both. Overproducers: Significant portion of hypercholesterolemia patients, especially those with genetic conditions like Familial Hypercholesterolemia. Overabsorbers: Often have high-cholesterol diets or genetic predispositions. Treatment Implications: Overproducers: Statins are first-line treatment; they inhibit HMG-CoA reductase in cholesterol synthesis. Overabsorbers: Ezetimibe, which inhibits intestinal cholesterol absorption, can be effective. Combination Therapy: Considered for mixed dyslipidemia cases. Case Examples: Example of a patient with high production markers but borderline absorption: Statin therapy may be appropriate, with potential addition of Ezetimibe. Example of a patient who is a high absorber but not a high producer: Dietary changes and Ezetimibe might suffice without statins. Section 4: Physiological Mechanisms and Genetic Considerations Pathophysiology of Cholesterol Production: Overproduction may result from genetic mutations (LDL receptor or PCSK9) or conditions like insulin resistance. Pathophysiology of Cholesterol Absorption: Increased absorption could be due to genetic polymorphisms (NPC1L1 gene), leading to higher dietary cholesterol absorption. Section 5: Practical Application in Clinical Practice Incorporating the Test into Clinical Workflow: Integrate the Boston Heart Cholesterol Balance Test for patients with unexplained hypercholesterolemia or non-responders to standard therapy. Tailor treatment based on whether a patient is an overproducer, an overabsorber, or both. Patient Communication: Explain test results in an understandable way, emphasizing personalized treatment plans.

Pradeep is a brilliant geneticist and Director of Preventive Cardiology, holds the Paul & Phyllis Fireman Endowed Chair in Vascular Medicine at Mass General Hospital and on faculty at Harvard Medical School and the Broad Institute. His prolific research has been illuminating for the field of improving our approach to reduce the risk of heart disease. That's especially important because heart disease is the global (and US) #1 killer and is on the increase. We didn't get into lifestyle factors here since there was so much ground to cover on new tests. drugs, and strategies.A video snippet of our conversation on ApoB. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to key publications and audioEric Topol (00:06):Well, welcome to Ground Truths. I'm Eric Topol and with me is Pradeep Natarajan from Harvard. He's Director of Preventative Cardiology at the Mass General Brigham Health System and he has been lighting it up on the field of cardiovascular. We're going to get to lots of different parts of that story and so, Pradeep welcome.Pradeep Natarajan (00:31):Thanks Eric, really delighted and honored to be with you and have this discussion.Eric Topol (00:36):Well, for years I've been admiring your work and it's just accelerating and so there's so many things to get to. I thought maybe what we'd start off with is you recently wrote a New England Journal piece about two trials, two different drugs that could change the landscape of cardiovascular prevention in the future. I mean, that's one of the themes we're going to get to today is all these different markers and drugs that will change cardiology as we know it now. So maybe you could just give us a skinny on that New England Journal piece.Two New Lipid Targets With RNA DrugsPradeep Natarajan (01:16):Yeah, yeah, so these two agents, the trials were published at the same time. These phase two clinical trials for plozasiran, which is an siRNA against APOC3 and zodasiran, which is an siRNA against ANGPTL3. The reason why we have medicines against those targets are based on human genetics observations, that individuals with loss of function mutations and either of those genes have reduced lipids. For APOC3, it's reduced triglycerides for ANGPTL3 reduced LDL cholesterol and reduced triglycerides and also individuals that have those loss of function mutations also have lower risk for coronary artery disease. Now that's a very similar parallel to PCSK9. We have successful medicines that treat that target because people have found that carriers of loss of function mutations in PCSK9 lead to lower LDL cholesterol and lower coronary artery disease.(02:11):Now that suggests that therapeutic manipulation without significant side effects from the agents themselves for APOC3 and ANGPTL3 would be anticipated to also lower coronary artery disease risk potentially in complementary pathways to PCSK9. The interesting thing with those observations is that they all came from rare loss of function mutations that are enriched in populations of individuals. However, at least for PCSK9, has been demonstrated to have efficacy in large groups of individuals across different communities. So the theme of that piece was really just the need to study diverse populations because those insights are not always predictable about which communities are going to have those loss of function mutations and when you find them, they often have profound insights across much larger groups of individuals.Eric Topol (03:02):Well, there's a lot there that we can unpack a bit of it. One of them is the use of small interfering RNAs (siRNA) as drugs. We saw in the field of PCSK9, as you mentioned. First there were monoclonal antibodies directed against this target and then more recently, there's inclisiran which isn't an RNA play if you will, where you only have to take it twice a year and supposedly it's less expensive and I'm still having trouble in my practice getting patients covered on their insurance even though it's cheaper and much more convenient. But nonetheless, now we're seeing these RNA drugs and maybe you could comment about that part and then also the surprise that perhaps is unexplained is the glucose elevation.Pradeep Natarajan (03:53):Yeah, so for medicines and targets that have been discovered through human genetics, those I think are attractive for genetic-based therapies and longer interval dosing for the therapies, which is what siRNAs allow you to do because the individuals that have these perturbations, basically the naturally occurring loss of function mutations, they have these lifelong, so basically have had a one-time therapy and have lived, and so far, at least for these targets, have not had untoward side effects or untoward phenotypic consequences and only reduce lipids and reduce coronary artery disease. And so, instead of taking a pill daily, if we have conviction that that long amount of suppression may be beneficial, then longer interval dosing and not worrying about the pill burden is very attractive specifically for those specific therapeutics. And as you know, people continue to innovate on further prolonging as it relates to PCSK9.(04:57):Separately, some folks are also developing pills because many people do feel that there's still a market and comfort for daily pills. Now interestingly for the siRNA for zodasiran at the highest dose, actually for both of them at the highest doses, but particularly for zodasiran, there was an increase in insulin resistance parameters actually as it relates to hyperglycemia and less so as it relates to insulin resistance, that is not predicted based on the human genetics. Individuals with loss of function mutations do not have increased risks in hyperglycemia or type 2 diabetes, so that isolates it related to that specific platform or that specific technology. Now inclisiran, as you'd mentioned, Eric is out there. That's an siRNA against PCSK9 that's made by a different manufacturer. So far, the clinical trials have not shown hyperglycemia or type 2 diabetes as it relates inclisiran, so it may be related to the specific siRNAs that are used for those targets. That does merit further consideration. Now, the doses that the manufacturers do plan to use in the phase three clinical trials are at lower doses where there was not an increase in hyperglycemia, but that does merit further investigation to really understand why that's the case. Is that an expected generalized effect for siRNAs? Is it related to siRNAs for this specific target or is it just related to the platform used for these two agents which are made by the same manufacturer?Eric Topol (06:27):Right, and I think the fact that it's a mystery is intriguing at the least, and it may not come up at the doses that are used in the trials, but the fact that it did crop up at high doses is unexpected. Now that is part of a much bigger story is that up until now our armamentarium has been statins and ezetimibe to treat lipids, but it's rapidly expanding Lp(a), which for decades as a cardiologist we had nothing to offer. There may even be drugs to be able to lower people who are at high risk with high Lp(a). Maybe you could discuss that.What About Lp(a)?Pradeep Natarajan (07:13):Yeah, I mean, Eric, as you know, Lp(a) has been described as a cardiovascular disease risk factors for quite so many years and there are assays to detect lipoprotein(a) elevation and have been in widespread clinical practice increasing widespread clinical practice, but we don't yet have approved therapies. However, there is an abundance of literature preclinical data that suggests that it likely is a causal factor, meaning that if you lower lipoprotein(a) when elevated, you would reduce the risk related to lipoprotein(a). And a lot of this comes from similar human genetic studies. The major challenge of just relating a biomarker to an outcome is there are many different reasons why a biomarker might be elevated, and so if you detect a signal that correlates a biomarker, a concentration to a clinical outcome, it could be related to that biomarker, but it could be to the other reasons that the biomarker is elevated and sometimes it relates to the outcome itself.(08:10):Now human genetics is very attractive because if you find alleles that strongly relate to that exposure, you can test those alleles themselves with the clinical outcome. Now the allele assignment is established at birth. No other factor is going to change that assignment after conception, and so that provides a robust, strong causal test for that potential exposure in clinical outcome. Now, lipoprotein(a) is unique in that it is highly heritable and so there are lots of different alleles that relate to lipoprotein(a) and so in a well powered analysis can actually test the lipoprotein(a) SNPs with the clinical outcomes and similar to how there is a biomarker association with incident myocardial infarction and incident stroke, the SNPs related to lipoprotein(a) show the same. That is among the evidence that strongly supports that this might be causal. Now, fast forward to many years later, we have at least three phase three randomized clinical trials testing agents that have been shown to be very potent at lowering lipoprotein(a) that in the coming years we will know if that hypothesis is true. Importantly, we will have to understand what are the potential side effects of these medicines. There are antisense oligonucleotides and siRNAs that are primarily in investigation. Again, this is an example where there's a strong genetic observation, and so these genetic based longer interval dosing therapies may be attractive, but side effects will be a key thing as well too. Those things hard to anticipate really can anticipate based on the human genetics for off target effects, for example.(09:52):It's clearly a risk signal and hopefully in the near future we're going to have specific therapies.Eric Topol (09:57):Yeah, you did a great job of explaining Mendelian randomization and the fact the power of genetics, which we're going to get into deeper shortly, but the other point is that do you expect now that there's these multiple drugs that lower Lp(a) efficiently, would that be enough to get approval or will it have to be trials to demonstrate improved cardiovascular outcomes?Pradeep Natarajan (10:24):There is a great regulatory path at FDA for approval just for LDL cholesterol lowering and inclisiran is on the market and the phase three outcomes data has not yet been reported because there is a wide appreciation that LDL cholesterol lowering is a pretty good surrogate for cardiovascular disease risk lowering. The label will be restricted to LDL cholesterol lowering and then if demonstrated to have clinical outcomes, the label could be expanded. For other biomarkers including lipoprotein(a), even though we have strong conviction that it is likely a causal factor there hasn't met the bar yet to get approval just based on lipoprotein(a) lowering, and so we would need to see the outcomes effects and then we would also need to understand side effects. There is a body of literature of side effects for other therapies that have targeted using antisense oligonucleotides. We talked about potential side effects from some siRNA platforms and sometimes those effects could overtake potential benefits, so that really needs to be assessed and there is a literature and other examples.(11:31):The other thing I do want to note related to lipoprotein(a) is that the human genetics are modeled based on lifelong perturbations, really hard to understand what the effects are, how great of an effect there might be in different contexts, particularly when introduced in middle age. There's a lot of discussion about how high lipoprotein(a) should be to deliver these therapies because the conventional teaching is that one in five individuals has high lipoprotein(a), and that's basically greater than 75 nanomoles per liter. However, some studies some human genetic studies to say if you want to get an effect that is similar to the LDL cholesterol lowering medicines on the market, you need to start with actually higher lipoprotein(a) because you need larger amounts of lipoprotein(a) lowering. Those are studies and approaches that haven't been well validated. We don't know if that's a valid approach because that's modeling based on this sort of lifelong effect. So I'm very curious to see what the overall effect will be because to get approval, I think you need to demonstrate safety and efficacy, but most importantly, these manufacturers and we as clinicians are trying to find viable therapies in the market that it won't be hard for us to get approval because hopefully the clinical trial will have said this is the context where it works. It works really well and it works really well on top of the existing therapies, so there are multiple hurdles to actually getting it directly to our patients.How Low Do You Go with LDL Cholesterol?Eric Topol (13:02):Yeah, no question about that. I'm glad you've emphasized that. Just as you've emphasized the incredible lessons from the genetics of people that have helped guide this renaissance to better drugs to prevent cardiovascular disease. LDL, which is perhaps the most impressive surrogate in medicine, a lab test that you already touched on, one of the biggest questions is how low do you go? That is Eugene Braunwald, who we all know and love. They're in Boston. The last time I got together with him, he was getting his LDL down to close to zero with various tactics that might be extreme. But before we leave these markers, you're running preventive cardiology at man's greatest hospital. Could you tell us what is your recipe for how aggressive do you go with LDL?Pradeep Natarajan (14:04):Yeah, so when I talk to patients where we're newly getting lipid lowering therapies on, especially because many people don't have a readout of abnormal LDL cholesterol when we're prescribing these medicines, it's just giving them a sense of what we think an optimal LDL cholesterol might be. And a lot of this is based on just empirical observations. So one, the average LDL cholesterol in the modern human is about 100 to 110 mg/dL. However, if you look at contemporary hunter gatherers and non-human primates, their average LDL is about 40 to 50 and newborn babies have an LDL cholesterol of about 30. And the reason why people keep making LDL cholesterol lowering medicines because as you stack on therapies, cardiovascular disease events continue to reduce including down to these very low LDL cholesterol values. So the population mean for LDL cholesterol is high and everybody likely has hypercholesterolemia, and that's because over the last 10,000 years how we live our lives is so dramatically different and there has not been substantial evolution over that time to change many of these features related to metabolism.(15:16):And so, to achieve those really low LDL cholesterol values in today's society is almost impossible without pharmacotherapies. You could say, okay, maybe everybody should be on pharmacotherapies, and I think if you did that, you probably would reduce a lot of events. You'll also be treating a lot of individuals who likely would not get events. Cardiovascular disease is the leading killer, but there are many things that people suffer from and most of the times it still is not cardiovascular disease. So our practice is still rooted in better identifying the individuals who are at risk for cardiovascular disease. And so, far we target our therapies primarily in those who have already developed cardiovascular disease. Maybe we'll talk about better identifying those at risk, but for those individuals it makes lots of sense to get it as low as possible. And the field has continued to move to lower targets.(16:07):One, because we've all recognized, at least based on these empirical observations that lower is better. But now increasingly we have a lot of therapies to actually get there, and my hope is that with more and more options and the market forces that influence that the cost perspective will make sense as we continue to develop more. As an aside, related aside is if you look at the last cholesterol guidelines, this is 2018 in the US this is the first time PCSK9 inhibitors were introduced in the guidelines and all throughout that there was discussions of cost. There are a lot of concerns from the field that PCSK9 inhibitors would bankrupt the system because so many people were on statins. And you look at the prior one that was in 2013 and cost was mentioned once it's just the cost effectiveness of statins. So I think the field has that overall concern.(17:01):However, over time we've gotten comfortable with lower targets, there are more medicines and I think some of this competition hopefully will drive down some of the costs, but also the overall appreciation of the science related to LDL. So long-winded way of saying this is kind of the things that we discussed just to give reassurance that we can go to low LDL cholesterol values and that it's safe and then we think also very effective. Nobody knows what the lower limit is, whether zero is appropriate or not. We know that glucose can get too low. We know that blood pressure can be too low. We don't know yet that limit for LDL cholesterol. I mean increasingly with these trials we'll see it going down really low and then we'll better appreciate and understand, so we'll see 40 is probably the right range.Eric Topol (17:49):40, you said? Yeah, okay, I'll buy that. Of course, the other thing that we do know is that if you push to the highest dose statins to get there, you might in some people start to see the hyperglycemia issue, which is still not fully understood and whether that is, I mean it's not desirable, but whether or not it is an issue, I guess it's still out there dangling. Now the other thing that since we're on LDL, we covered Lp(a), PCSK9, the siRNA, is ApoB. Do you measure ApoB in all your patients? Should that be the norm?Measuring ApoBPradeep Natarajan (18:32):Yeah, so ApoB is another blood test. In the standard lipid panel, you get four things. What's measured is cholesterol and triglycerides, they're the lipids insoluble in blood to get to the different tissues that get packaged in lipoprotein molecules which will have the cholesterol, triglycerides and some other lipids and proteins. And so, they all have different names as you know, right? Low density lipoprotein, high density lipoprotein and some others. But also in the lipid panel you get the HDL cholesterol, the amount of cholesterol in an HDL particle, and then most labs will calculate LDL cholesterol and LDL cholesterol has a nice relationship with cardiovascular disease. You lower it with statins and others. Lower risk for cardiovascular disease, turns out a unifying feature of all of these atherogenic lipoproteins, all these lipoproteins that are measured and unmeasured that relate to cardiovascular disease, including lipoprotein(a), they all have an additional protein called ApoB. And ApoB, at least as it relates to LDL is a pretty good surrogate of the number of LDL particles.(19:37):Turns out that that is a bit better at the population level at predicting cardiovascular disease beyond LDL cholesterol itself. And where it can be particularly helpful is that there are some patients out there that have an unexpected ratio between ApoB and LDL. In general, the ratio between LDL cholesterol and ApoB is about 1.1 and most people will have that rough ratio. I verify that that is the expected, and then if that is the expected, then really there is no role to follow ApoB. However, primarily the patients that have features related to insulin resistance have obesity. They may often have adequate looking LDL cholesterols, but their ApoB is higher. They have more circulating LDL particles relative to the total amount of LDL cholesterol, so smaller particles themselves. However, the total number of particles may actually be too high for them.(20:34):And so, even if the LDL cholesterol is at target, if the ApoB is higher, then you need to reduce. So usually the times that I just kind of verify that I'm at appropriate target is I check the LDL cholesterol, if that looks good, verify with the ApoB because of this ratio, the ApoB target should be about 10% lower. So if we're aiming for about 40, that's like 36, so relatively similar, and if it's there, I'm good. If it's not and it's higher, then obviously increase the LDL cholesterol lowering medicines because lower the ApoB and then follow the ApoB with the lipids going forward. The European Society of Cardiology has more emphasis on measuring ApoB, that is not as strong in the US guidelines, but there are many folks in the field, preventive cardiologists and others that are advocating for the increasing use of ApoB because I think there are many folks that are not getting to the appropriate targets because we are not measuring ApoB.Why Aren't We Measuring and Treating Inflammation?Eric Topol (21:37):Yeah, I think you reviewed it so well. The problem here is it could be part of the standard lipid panel, it would make this easy, but what you've done is a prudent way of selecting out people who it becomes more important to measure and moderate subsequently. Now this gets us to the fact that we're lipid centric and we don't pay homage to inflammation. So I wrote a recent Substack on the big miss on inflammation, and here you get into things like the monoclonal antibody to interleukin-6, the trial that CANTOS that showed significant reduction in cardiovascular events and fatal cancers by the way. And then you get into these colchicine trials two pretty good size randomized trials, and here the entry was coronary disease with a high C-reactive protein. Now somehow or other we abandon measuring CRP or other inflammatory markers, and both of us have had patients who have low LDLs but have heart attacks or significant coronary disease. So why don't we embrace inflammation? Why don't we measure it? Why don't we have better markers? Why is this just sitting there where we could do so much better? Even agents that are basically cost pennies like colchicine at low doses, not having to use a proprietary version could be helpful. What are your thoughts about us upgrading our prevention with inflammation markers?Pradeep Natarajan (23:22):Yeah, I mean, Eric, there is an urgent need to address these other pathways. I say urgent need because heart disease has the dubious distinction of being the leading killer in the US and then over the last 20 years, the leading killer in the world as it takes over non-communicable diseases. And really since the early 1900s, there has been a focus on developing pharmacotherapies and approaches to address the traditional modifiable cardiovascular disease risk factors. That has done tremendous good, but still the curves are largely flattening out. But in the US and in many parts of the world, the deaths attributable to cardiovascular disease are starting to tick up, and that means there are many additional pathways, many of them that we have well recognized including inflammation. More recently, Lp(a) that are likely important for cardiovascular disease, for inflammation, as you have highlighted, has been validated in randomized controlled trials.(24:18):Really the key trial that has been more most specific is one on Canakinumab in the CANTOS trial IL-1β monoclonal antibody secondary prevention, so cardiovascular disease plus high C-reactive protein, about a 15% reduction in cardiovascular disease and also improvement in cancer related outcomes. Major issues, a couple of issues. One was increased risk for severe infections, and the other one is almost pragmatic or practical is that that medicine was on the market at a very high price point for rare autoinflammatory conditions. It still is. And so, to have for a broader indication like cardiovascular disease prevention would not make sense at that price point. And the manufacturer tried to go to the FDA and focus on the group that only had C-reactive protein lowering, but that's obviously like a backwards endpoint. How would you know that before you release the medicine? So that never made it to a broader indication.(25:14):However, that stuck a flag in the broader validation of that specific pathway in cardiovascular disease. That pathway has direct relevance to C-reactive protein. C-reactive protein is kind of a readout of that pathway that starts from the NLRP3 inflammasome, which then activates IL-1β and IL-6. C-reactive protein we think is just a non causal readout, but is a reliable test of many of these features and that's debatable. There may be other things like measuring IL-6, for example. So given that there is actually substantial ongoing drug development in that pathway, there are a handful of companies with NLRP3 inflammasome inhibitors, but small molecules that you can take as pills. There is a monoclonal antibody against IL-6 that's in development ziltivekimab that's directed at patients with chronic kidney disease who have lots of cardiovascular disease events despite addressing modifiable risk factors where inflammatory markers are through the roof.(26:16):But then you would also highlighted one anti-inflammatory that's out there that's pennies on the dollar, that's colchicine. Colchicine is believed to influence cardiovascular disease by inhibiting NLRP3, I say believed to. It does a lot of things. It is an old medicine, but empirically has been shown in at least two randomized controlled trials patients with coronary artery disease, actually they didn't measure C-reactive protein in the inclusion for these, but in those populations we did reduce major adverse cardiovascular disease events. The one thing that does give me pause with colchicine is that there is this odd signal for increased non-cardiovascular death. Nobody understands if that's real, if that's a fluke. The FDA just approved last year low dose colchicine, colchicine at 0.5 milligrams for secondary prevention given the overwhelming efficacy. Hasn't yet made it into prevention guidelines, but I think that's one part that does give me a little bit pause. I do really think about it particularly for patients who have had recurrent events. The people who market the medicine and do research do remind us that C-reactive protein was not required in the inclusion, but nobody has done that secondary assessment to see if measuring C-reactive protein would be helpful in identifying the beneficial patients. But I think there still could be more work done on better identifying who would benefit from colchicine because it's an available and cheap medicine. But I'm excited that there is a lot of development in this inflammation area.Eric Topol (27:48):Yeah, well, the development sounds great. It's probably some years away. Do you use colchicine in your practice?Pradeep Natarajan (27:56):I do. Again, for those folks who have had recurrent events, even though C-reactive protein isn't there, it does make me feel like I'm treating inflammation. If C-reactive protein is elevated and then I use it for those patients, if it's not elevated, it's a much harder sell from my standpoint, from the patient standpoint. At the lower dose for colchicine, people generally are okay as far as side effects. The manufacturer has it at 0.5 milligrams, which is technically not pennies on the dollar. That's not generic. The 0.6 milligrams is generic and they claim that there is less side effects at the 0.5 milligrams. So technically 0.6 milligrams is off label. So it is what it is.CHIP and Defining High Risk People for CV DiseaseEric Topol (28:40):It's a lot more practical, that's for sure. Now, before I leave that, I just want to mention when I reviewed the IL-1β trial, you mentioned the CANTOS trial and also the colchicine data. The numbers of absolute increases for infection with the antibody or the cancers with the colchicine are really small. So I mean the benefit was overriding, but I certainly agree with your concern that there's some things we don't understand there that need to be probed more. Now, one of the other themes, well before one other marker that before we get to polygenic risk scores, which is center stage here, defining high risk people. We've talked a lot about the conventional things and some of the newer ways, but you've been one of the leaders of study of clonal hematopoiesis of indeterminate potential known as CHIP. CHIP, not the chips set in your computer, but CHIP. And basically this is stem cell mutations that increase in people as we age and become exceptionally common with different mutations that account in these clones. So maybe you can tell us about CHIP and what I don't understand is that it has tremendous correlation association with cardiovascular outcomes adverse as well as other system outcomes, and we don't measure it and we could measure it. So please take us through what the hell is wrong there.Pradeep Natarajan (30:14):Yeah, I mean this is really exciting. I mean I'm a little bit biased, but this is observations that have been made only really over the last decade, but accelerating research. And this has been enabled by advances in genomic technologies. So about 10 years or plus ago, really getting into the early days of population-based next generation sequencing, primarily whole exome sequencing. And most of the DNA that we collect to do these population-based analyses come from the blood, red blood cells are anucleate, so they're coming from white blood cells. And so, at that time, primarily interrogating what is the germline genetic basis for coronary artery disease and early onset myocardial infarction. At the same time, colleagues at the Broad Institute were noticing that there are many additional features that you can get from the blood-based DNA that was being processed by the whole exome data. And there were actually three different groups that converged on that all in Boston that converged on the same observation that many well-established cancer causing mutations.(31:19):So mutations that are observed in cancers that have been described to drive the cancers themselves were being observed in these large population-based data sets that we were all generating to understand the relationship between loss of function mutations in cardiovascular disease. That's basically the intention of those data sets for being generated for other things. Strong correlation with age, but it was very common among individuals greater than 70; 10% of them would have these mutations and is very common because blood cancer is extremely, it's still pretty rare in the population. So to say 10% of people had cancer causing driver mutations but didn't have cancer, was much higher than anyone would've otherwise expected. In 2014, there were basically three main papers that described that, and they also observed that there is a greater risk of death. You'd say, okay, this is a precancerous lesion, so they're probably dying of cancer.(32:17):But as I said, the absolute incidence rate for blood cancer is really low and there's a relative increase for about tenfold, but pretty small as it relates to what could be related to death. And in one of the studies we did some exploratory analysis that suggested maybe it's actually the most common cause of death and that was cardiovascular disease. And so, a few years later we published a study that really in depth really looked at a bunch of different data sets that were ascertained to really understand the relationship between these mutations, these cancer causing mutations in cardiovascular disease, so observed it in enrichment and older individuals that had these mutations, CHIP mutations, younger individuals who had early onset MI as well too, and then also look prospectively and showed that it related to incident coronary artery disease. Now the major challenge for this kind of analysis as it relates to the germline genetic analysis is prevalence changes over time.(33:15):There are many things that could influence the presence of clonal hematopoiesis. Age is a key enriching factor and age is the best predictor for cardiovascular disease. So really important. So then we modeled it in mice. It was actually a parallel effort at Boston University (BU) that was doing the same thing really based on the 2014 studies. And so, at the same time we also observed when you modeled this in mice, you basically perturb introduce loss of function mutations in the bone marrow for these mice to recapitulate these driver mutations and those mice also have a greater burden of atherosclerosis. And Eric, you highlighted inflammation because basically the phenotype of these cells are hyper inflamed cells. Interestingly, C-reactive protein is only modestly elevated. So C-reactive protein is not fully capturing this, but many of the cytokines IL-1β, IL-6, they're all upregulated in mice and in humans when measured as well.(34:11):Now there've been a few key studies that have been really exciting about using anti-inflammatories in this pathway to address CHIP associated cardiovascular disease. So one that effort that I said in BU because they saw these cytokines increased, we already know that these cytokines have relationship with atherosclerosis. So they gave an NLRP3 inflammasome inhibitor to the mice and they showed that the mice with or without CHIP had a reduction in atherosclerosis, but there was a substantial delta among the mice that are modeled as having CHIP. Now, the investigators in CANTOS, the manufacturers, they actually went back and they survey where they had DNA in the CANTOS trial. They measured CHIP and particularly TET2 CHIP, which is the one that has the strongest signal for atherosclerosis. As I said, overall about 15% reduction in the primary outcome in CANTOS. Among the individuals who had TET2 CHIP, it was a 64% reduction in event.(35:08):I mean you don't see those in atherosclerosis related trials. Now this has the caveat of it being secondary post hoc exploratory, the two levels of evidence. And so, then we took a Mendelian randomization approach. Serendipitously, just so happens there is a coding mutation in the IL-6 receptor, a missense mutation that in 2012 was described that if you had this mutation, about 40% of people have it, you have a 5%, but statistically significant reduction in coronary artery disease. So we very simply said, if the pathway of this NLRP3 inflammasome, which includes IL-6, if you have decreased signaling in that pathway, might you have an even greater benefit from having that mutation if you had CHIP versus those who didn't have CHIP. So we looked in the UK Biobank, those who didn't have CHIP 5% reduction, who had that IL-6 receptor mutation, and then those who did have CHIP, if they had that mutation, it was about a 60% reduction in cardiovascular disease.(36:12):Again, three different lines of evidence that really show that this pathway has relevance in the general population, but the people who actually might benefit the most are those with CHIP. And I think as we get more and more data sets, we find that not all of the CHIP mutations are the same as it relates to cardiovascular disease risk. It does hone in on these key subsets like TET2 and JAK2, but this is pretty cool as a preventive cardiologist, new potential modifiable risk factor, but now it's almost like an oncologic paradigm that is being applied to coronary artery disease where we have specific driver mutations and then we're tailoring our therapies to those specific biological drivers for coronary artery disease. Hopefully, I did that justice. There's a lot there.Why Don't We Measure CHIP?Eric Topol (36:57):Well, actually, it's phenomenal how you've explained that, but I do want to review for our listeners or readers that prior to this point in our conversation, we were talking about germline mutations, the ones you're born with. With CHIP, we're talking about acquired somatic mutations, and these are our blood stem cells. And what is befuddling to me is that with all the data that you and others, you especially have been publishing and how easy it would be to measure this. I mean, we've seen that you can get it from sequencing no less other means. Why we don't measure this? I mean, why are we turning a blind eye to CHIP? I just don't get it. And we keep calling it of indeterminate potential, not indeterminate. It's definite potential.Pradeep Natarajan (37:51):Yeah, no, I think these are just overly cautious terms from the scientists. Lots of people have CHIP, a lot of people don't have clinical outcomes. And so, I think from the lens of a practicing hematologists that provide some reassurance on the spectrum for acquired mutation all the way over to leukemia, that is where it comes from. I don't love the acronym as well because every subfield in biomedicine has its own CHIP, so there's obviously lots of confusion there. CH or clinical hematopoiesis is often what I go, but I think continuing to be specific on these mutations. Now the question is why measure? Why aren't we measuring it? So there are some clinical assays out there. Now when patients get evaluated for cytopenias [low cell counts], there are next generation sequencing tests that look for these mutations in the process for evaluation. Now, technically by definition, CHIP means the presence of these driver mutations that have expanded because it's detectable by these assays, not a one-off cell because it can only be detected if it's in a number of cells.(38:55):So there has been some expansion, but there are no CBC abnormalities. Now, if there's a CBC abnormality and you see a CHIP mutation that's technically considered CCUS or clonal cytopenia of unknown significance, sometimes what is detected is myelodysplastic syndrome. In those scenarios still there is a cardiovascular disease signal, and so many of our patients who are seen in the cancer center who are being evaluated for these CBC abnormalities will be detected to have these mutations. They will have undergone some risk stratification to see what the malignancy potential is. Still pretty low for many of those individuals. And so, the major driver of health outcomes for this finding may be cardiovascular. So those patients then get referred to our program. Dana-Farber also has a similar program, and then my colleague Peter Libby at the Brigham often sees those patients as well. Now for prospective screening, so far, an insurance basically is who's going to pay for it.(39:51):So an insurance provider is not deemed that appropriate yet. You do need the prospective clinical trials because the medicines that we're talking about may have side effects as well too. And what is the yield? What is the diagnostic yield? Will there actually be a large effect estimate? But there has been more and more innovation, at least on the assay and the cost part of the assay because these initial studies, we've been using whole exome sequencing, which is continuing to come down, but is not a widely routine clinical test yet. And also because as you highlighted, these are acquired mutations. A single test is not necessarily one and done. This may be something that does require surveillance for particular high risk individuals. And we've described some risk factors for the prevalence of CHIP. So surveillance may be required, but because there are about 10 genes that are primarily implicated in CHIP, that can substantially decrease the cost of it. The cost for DNA extraction is going down, and so there are research tests that are kind of in the $10 to $20 range right now for CHIP. And if flipped over to the clinical side will also be reasonably low cost. And so, for the paradigm for clinical implementation, that cost part is necessary.Eric Topol (41:10):I don't know the $10 or $20 ones. Are there any I could order on patients that I'm worried about?Pradeep Natarajan (41:17):Not yet clinical. However, there is a company that makes the reagents for at least the cores that are developing this. They are commercializing that test so that many other cores, research cores can develop it. I think it's in short order that clinical labs will adopt it as well too.Eric Topol (41:36):That's great.Pradeep Natarajan (41:37):I will keep you apprised.What About Polygenic Risk Scores?Eric Topol (41:39):I think that's really good news because like I said, we're so darn lipid centric and we have to start to respect the body of data, the knowledge that you and others have built about CHIP. Now speaking of another one that drives me nuts is polygenic risk score (PRS) for about a decade, I've been saying we have coronary disease for most people is a polygenic trait. It's not just a familial hypercholesterolemia. And we progressively have gotten better and better of the hundreds of single variants that collectively without a parental history will be and independently predict who is at double, triple or whatever risk of getting heart disease, whereby you could then guide your statins at higher aggressive or pick a statin, use one or even go beyond that as we've been talking about. But we don't use that in practice, which is just incredible because it's can be done cheap.(42:45):You can get it through whether it's 23andMe or now many other entities. We have an app, MyGeneRank where we can process that Scripss does for free. And only recently, Mass General was the first to implement that in your patient population, and I'm sure you were a driver of that. What is the reluctance about using this as an orthogonal, if you will, separate way to assess a person's risk for heart disease? And we know validated very solidly about being aggressive about lipid lowering when you know this person's in the highest 5% polygenic risk score. Are we just deadheads in this field or what?Pradeep Natarajan (43:30):Yeah, I mean Eric, as you know, lots of inertia in medicine, but this one I think has a potential to make a large impact. Like CHIP mutations, I said news is about 10% in individuals greater than 70. The prospect here is to identify the risk much earlier in life because I think there is a very good argument that we're undertreating high risk individuals early on because we don't know how to identify them. As you highlighted, Dr. Braunwald about LDL cholesterol. The other part of that paradigm is LDL cholesterol lowering and the duration. And as we said, everybody would benefit from really low LDL cholesterol, but again, you might overtreat that if you just give that to everybody. But if you can better identify the folks very early in life, there is a low cost, low risk therapy, at least related to statins that you could have a profound benefit from the ones who have a greater conviction will have future risk for cardiovascular disease.(44:21):You highlighted the family history, and the family history has given the field of clues that genetics play a role. But as the genome-wide association studies have gotten larger, the polygenic risk scores have gotten better. We know that family history is imperfect. There are many reasons why a family member who is at risk may or may not have developed cardiovascular disease. A polygenic risk score will give a single number that will estimate the contribution of genetics to cardiovascular disease. And the thing that is really fascinating to me, which is I think some of a clinical implementation challenge is that the alleles for an individual are fixed. The genotyping is very cheap. That continues to be extremely cheap to do this test. But the weights and the interpretation of what the effects should be for each of the SNPs are continually being refined over time.(45:18):And so, given the exact same SNPs in the population, the ability to better predict cardiovascular diseases getting better. And so, you have things that get reported in the literature, but literally three years later that gets outdated and those hypotheses need to be reassessed. Today, I'll say we have a great relative to other things, but we have a great polygenic risk score was just reported last year that if you compare it to familial hypercholesterolemia, which has a diagnostic yield of about 1 in 300 individuals, but readily detectable by severe hypercholesterolemia that has about threefold risk for cardiovascular disease. By polygenic risk score, you can find 1 in 5 individuals with that same risk. Obviously you go higher than that, it'll be even higher risk related to that. And that is noble information very early in life. And most people develop risk factors later in life. It is happening earlier, but generally not in the 30s, 40s where there's an opportunity to make a substantial impact on the curve related to cardiovascular disease.(46:25):But there is a lot of momentum there. Lots of interest from NIH and others. The major challenge is though the US healthcare system is really not well set up to prevention, as you know, we practice healthcare after patient's developed disease and prevent the complications related to progression. The stakeholder incentives beyond the patient themselves are less well aligned. We've talked a lot here today about payers, but we don't have a single payer healthcare system. And patients at different times of their lives will have different insurers. They'll start early in life with their parents, their first employer, they'll move on to the next job and then ultimately Medicare. There's no entity beyond yourself that really cares about your longevity basically from the beginning and your overall wellness. That tension has been a major challenge in just driving the incentives and the push towards polygenic risk scores. But there are some innovative approaches like MassMutual Life Insurance actually did a pilot on polygenic risk scoring.(47:33):They're in the business of better understanding longevity. They get that this is important data. Major challenges, there are federal protections against non-discrimination in the workplace, health insurance, not necessarily life insurance. So I think that there are lots of things that have to be worked out. Everybody recognizes that this is important, but we really have to have all the incentives aligned for this to happen at a system-wide level in the US. So there's actually lots of investment in countries that have more nationalized healthcare systems, lots of development in clinical trials in the UK, for example. So it's possible that we in the US will not be the lead in that kind of evidence generation, but maybe we'll get there.The GLP-1 DrugsEric Topol (48:16):Yeah, it's frustrating though, Pradeep, because this has been incubating for some time and now we have multi ancestry, polygenic risk scores, particularly for heart disease and we're not using it, and it's not in my view, in the patient's best interest just because of these obstacles that you're mentioning, particularly here in the US. Well, the other thing I want to just get at with you today is the drugs that we were using for diabetes now blossoming for lots of other indications, particularly the glucagon-like peptide 1 (GLP-1) drugs. This has come onto the scene in recent years, not just obviously for obesity, but it's anti-inflammatory effects as we're learning, mediated not just through the brain but also T cells and having extraordinary impact in heart disease for people with obesity and also with those who have heart failure, about half of heart failure for preserved ejection fraction. So recently you and your colleagues recently published a paper with this signal of optic neuropathy. It was almost seven eightfold increase in a population. First, I wanted to get your sense about GLP-1. We're also going to get into the SGLT2 for a moment as well, but how do you use GLP-1? What's your prognosis for this drug class going forward?Pradeep Natarajan (49:55):As it relates to the paper, I can't claim credit as one of my former students who is now Mass Eye and Ear resident who participated, but we can talk about that. There's obviously some challenges for mining real world data, but this was related to anecdotes that they were observing at Mass Eye and Ear and then studied and observed an enrichment. In general though, I feel like every week I'm reading a new clinical trial about a new clinical outcome benefit as it relates to GLP-1 receptor agonists. This is kind of one thing that stands out that could be interrogated in these other clinical trials. So I would have that caveat before being cautious about ocular complications. But the data has been overwhelmingly beneficial, I think, because at minimum, obesity and inflammation are relayed to myriad of consequences, and I'm really excited that we have therapies that can address obesity that are safe.(50:52):There's a legacy of unsafe medicines for obesity, especially related to cardiovascular disease. So the fact that we have medicines that are safe and effective for lowering weight that also have real strong effects on clinical outcomes is tremendous. We in cardiology are increasingly using a range of diabetes medicines, including GLP-1 receptor agonists and SGLT2 inhibitors. I think that is also the secular changes of what influences cardiovascular disease over time. I talked about over the last 10 years or so with this increase in deaths attributable to cardiovascular disease. If you look at the influences of traditional clinical risk factors today, many of them have decreased in importance because when abnormal, we recognize them, in general we modify them when recognized. And so, many of the things that are unaddressed, especially the features related to insulin resistance, obesity, they start rising in importance. And so, there is a dramatic potential for these kinds of therapies in reducing the residual risks that we see related to cardiovascular disease. So I'm enthusiastic and excited. I think a lot more biology that needs to be understood of how much of this is being influenced specifically through this pathway versus a very effective weight loss medicine. But also interesting to see the insights on how the effect centrally on appetite suppression has profound influences on weight loss as well too. And hopefully that will lead to more innovations in weight management.The SGLT-2 DrugsEric Topol (52:25):And likewise, perhaps not getting near as much play, but when it came on the cardiovascular scene that an anti-diabetic drug SGLT2 was improving survival, that was big, and we still don't know why. I mean, there's some ideas that it might be a senolytic drug unknowingly, but this has become a big part of practice of cardiology in patients with diabetes or with preserved ejection fraction heart failure. Is that a fair summary for that drug?Pradeep Natarajan (53:00):Yeah, I totally agree. I mean, as there has been increased recognition for heart failure preserved ejection fraction, it has been almost disheartening over the last several years that we have not had very specific effective therapies to treat that condition. Now, it is a tremendous boon that we do have medicines interestingly focused on metabolism that are very helpful in that condition for heart failure with preserved ejection fraction. But there is still much more to be understood as far as that condition. I mean, the major challenge with heart failure, as you know, especially with heart failure preserved ejection fraction, it likely is a mix of a wide variety of different etiologies. So in parallel with developing effective therapies that get at some aspect is really understanding what are the individual drivers and then targeting those specific individual drivers. That requires a lot of unbiased discovery work and further profiling to be done. So lot more innovation, but relative to heart failure itself, it is not had widespread recognition as heart failure reduced ejection fraction. So much more to innovate on, for sure.Eric Topol (54:07):Right, right. Yeah, I am stunned by the recent progress in cardiovascular medicine. You have been center stage with a lot of it, and we've had a chance to review so much. And speaking of genetics, I wanted to just get a little insight because I recently came across the fact that your mother here at the City of Hope in Southern California is another famous researcher. And is that, I don't know what chromosome that is on regarding parental transmission of leading research. Maybe you can tell me about that.Pradeep Natarajan (54:41):Yeah, I mean, I guess it is a heritable trait when a parent has one profession that there is a higher likelihood that the offspring will have something similar. So both of my parents are PhDs, nonphysicians. There is a diabetes department at the City of Hope, so she's the chair of that department. So very active. We do overlap in some circles because she does investigate both vascular complications and renal complications. And then sometimes will ask my advice on some visualization. But she herself has just had a science translational medicine paper, for example, just a couple of months ago. So it's fun to talk about these things. To be honest, because my parents are researchers, I was not totally sure that I would be a researcher and kind of wanted to do something different in medicine. But many of my early observations and just how common cardiovascular disease is around me and in my community and wanting to do something useful is what got me specifically into cardiology.(55:45):But obviously there are numerous outstanding, important questions. And as I went through my career, really focused on more basic investigations of atherosclerosis and lipids. What got me excited sort of after my clinical training was the ability to ask many of these questions now in human populations with many new biological data sets, at least first centered on genetics. And the capabilities continue to expand, so now I teach first year Harvard medical students in their genetics curriculum. And when I talk to them just about my career arc, I do remind them they're all doing millions of things and they're exploring lots of things, but when they get to my shoes, the capabilities will be tremendously different. And so, I really advise them to take the different experiences, mainly in an exercise for asking questions, thoughtfully addressing questions, connecting it back to important clinical problems. And then once they start to understand that with a few different approaches, then they'll totally take off with what the opportunities are down the road.Eric Topol (56:51):No, it's great. I mean, how lucky somebody could be in the first year of med school with you as their teacher and model. Wow. Pradeep, we've really gone deep on this and it's been fun. I mean, if there's one person I'm going to talk to you about cardiovascular risk factors and the things that we've been into today, you would be the one. So thank you for taking the time and running through a lot of material here today, and all your work with great interest.Pradeep Natarajan (57:24):Thanks, Eric. I really appreciate it. It's tremendous honor. I'm a big fan, so I would be glad to talk about any of these things and more anytime.***************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. 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Please Subscribe and Review: Apple Podcasts | RSS Submit your questions for the podcast here News Topic: "History Comes In Patterns" Neil Howe: Civil War, Market Crashes, and The Fourth Turning | PBD #441 Show Notes: The Fourth Turning Is Here: What the Seasons of History Tell Us about How and When This Crisis Will End Elevated levels of serum per- and poly-fluoroalkyl substances (PFAS) in contact lens users of U.S. young adults Questions:    PFOAS in Contacts Chrissy writes: Good day, I know pfoas are everywhere but contacts too! I hate wearing glasses. Additionally most are UV blocking, which is something I want in my eyes. Should contacts be ditched! What do you or your family do?   Choosing a Functional Doc Chris writes:  Hello, Long time fan boy... Any advice on picking a good functional medicine doctor in my local area? Google search? Anything to look for, or look out for? I found a local MD with a long time in family medicine, who transitioned to integrative holistic medicine about 10 years ago, and then got an ABoIM about 5 years ago. I can only assume that ABoIM is a board certificate of some kind? Sounds like integrative medicine is similar to functional medicine? I ask because I have become a moody AF little bitch after a year on a statin. My original family doc and my precision health report says the cholesterol is on the risky to highly risky side of things. I have always wanted to get off of the statin, and try the PCSK9 inhibitor you discussed some months back. Finally aiming to start that transition. Any help or advice on doc selection is appreciated! Cheers, Chris R   Sponsor: The Healthy Rebellion Radio is sponsored by our electrolyte company, LMNT. Proper hydration is more than just drinking water. You need electrolytes too! Check out The Healthy Rebellion Radio sponsor LMNT for grab-and-go electrolyte drink mix packets and the new LMNT Sparkling electrolyte performance beverage! Click here to get your LMNT electrolytes Transcript: Coming soon!  

Send us a Text Message.What if understanding cholesterol and triglycerides could dramatically improve your health? This episode is a thorough and in-depth discussion where Dr. Michael Koren sheds light on the intricate relationship between genetics, diet, and lipid levels across different ethnic groups. We'll explore why non-Hispanic whites and Mexican Americans are more prone to high triglycerides than non-Hispanic blacks and dive into the liver's pivotal role in lipid metabolism. Learn the significance of managing LDL cholesterol for high-risk patients and get insights into the ongoing challenges of raising HDL levels and the latest advancements in medications.From practical strategies to lower cholesterol and triglycerides to understanding the impact of fasting for accurate measurements, this episode covers it all. Discover how lifestyle choices, diet, and even the timing of your blood tests can affect your lipid profile. We also delve into the benefits of fish oil and new pharmacological treatments like statins and PCSK9 inhibitors. Equip yourself with the knowledge to make informed health decisions and improve your cardiovascular well-being.Talking Topics:Understanding Cholesterol and TriglyceridesLipids, Genetics, and Health InsightsLowering Cholesterol and Triglycerides AccessiblyUnderstanding Triglycerides and Diet ImpactTriglycerides, HDL, and Heart HealthOmega-3s Impact on TriglyceridesThis episode is a rebroadcast of a live event hosted at ENCORE Research Group on July 15, 2024.Be a part of advancing science by participating in clinical research.Share with a friend. Rate, Review, and Subscribe to the MedEvidence! podcast to be notified when new episodes are released.Follow us on Social Media:FacebookInstagramTwitterLinkedInWant to learn more checkout our entire library of podcasts, videos, articles and presentations at www.MedEvidence.comMusic: Storyblocks - Corporate InspiredThank you for listening!

Welcome to Supreme Court Opinions. In this episode, you'll hear the Court's opinion in Amgen Inc. v Sanofi. In this case, the court considered this issue: Do Amgen's two patents satisfy the Patent Act's enablement clause—that is, describing the invention with sufficient particularity that would enable a “skilled artisan” to “make and use” the claimed invention? The case was decided on May 18, 2023. The Supreme Court held that Amgen's two patent applications—purporting to cover all antibodies that bind and block the PCSK9 receptor involved in LDL cholesterol metabolism—fail to satisfy the Patent Act's enablement clause. Justice Neil Gorsuch authored the unanimous opinion of the Court affirming the judgment below. It is well established that the enablement requirement means that if a patent claims an entire class of process, machines, manufactures, or compositions of matter, its specification must enable a person skilled in the art to make and use the entire class. While the specification may call for a reasonable amount of experimentation to make and use a claimed invention, it must not be too broad. Amgen's specification fails to enable all that it has claimed, even allowing for a reasonable degree of experimentation. It described 26 antibodies by their amino acid sequences, but it claims to monopolize an entire class of antibodies not described. Thus, its claim is too broad. The opinion is presented here in its entirety, but with citations omitted. If you appreciate this episode, please subscribe. Thank you.  --- Support this podcast: https://podcasters.spotify.com/pod/show/scotus-opinions/support

In episode 529 of Sigma Nutrition Radio, we discuss all things related to cholesterol, atherosclerosis, heart disease, and dietary fat. The discussion extensively covers the impact of LDL cholesterol and ApoB on atherosclerotic plaque progression, cardiovascular events, and the benefits of early LDL lowering interventions, particularly through the use of PCSK9 inhibitors alongside statins. We address misconceptions prevalent in the low-carb and carnivore communities, dissect claims regarding saturated fats, and elucidate why atherosclerosis predominantly affects arteries and not veins. The episode sheds light on the nuanced mechanisms of cholesterol metabolism, the significance of different lipid particles, and the limited dietary impact on LP(a) levels. Comprehensive evidence-based insights and practical recommendations for dietary patterns and cardiovascular health interventions are provided, offering clarity on these complex topics. Note: This discussion is hosted by Simon Hill, and originally appeared as an episode of The Proof podcast. Links: Subscribe to Sigma Nutrition Premium Receive our free weekly email: the Sigma Synopsis Episode with Professor Chris Packard Timestamps: 07:19 Understanding Cholesterol and Lipoproteins 14:35 The Role of ApoB in Cardiovascular Risk 25:10 Atherogenic Lipoproteins and Their Impact 37:42 Causal Pathways and Biomarkers in Heart Disease 47:02 Understanding Residual Risk and Triglycerides 49:46 Paul Saladino's Claims on LDL and Metabolic Health 01:03:01 Addressing Concerns About Lowering Cholesterol 01:16:16 The Importance of Early Intervention in Cholesterol Management 01:23:36 The Future of Cholesterol Management and Gene Editing 01:28:24 Atherosclerosis in Arteries vs. Veins 01:36:08 Dietary Interventions to Lower ApoB Levels 01:47:55 Modifying Keto Diet for Better Health Outcomes 01:56:33 Plant-Based Diets and Fat Consumption 02:05:10 Understanding Lp(a) and Its Impact on Health Subscribe to Sigma Nutrition Premium

In this podcast, Thomas Czech, Distinguished Professor at the University of Colorado, Boulder, with a lineage of remarkable contributions on RNA, ribozyme, and telomeres, discuss why RNA is so incredibly versatile.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to the audio and external linksEric Topol (00:07):Well, hello, this is Eric Topol from Ground Truths, and it's really a delight for me to welcome Tom Cech who just wrote a book, the Catalyst, and who is a Nobel laureate for his work in RNA. And is at the University of Colorado Boulder as an extraordinary chemist and welcome Tom.Tom Cech (00:32):Eric, I'm really pleased to be here.The RNA GuyEric Topol (00:35):Well, I just thoroughly enjoyed your book, and I wanted to start out, if I could, with a quote, which gets us right off the story here, and let me just get to it here. You say, “the DNA guy would need to become an RNA guy. Though I didn't realize it at the time, jumping ship would turn out to be the most momentous decision in my life.” Can you elaborate a bit on that?Tom Cech (01:09):As a graduate student at Berkeley, I was studying DNA and chromosomes. I thought that DNA was king and really somewhat belittled the people in the lab next door who were working on RNA, I thought it was real sort of second fiddle material. Of course, when RNA is acting just as a message, which is an important function, a critical function in all life on earth, but still, it's a function that's subservient to DNA. It's just copying the message that's already written in the playbook of DNA. But little did I know that the wonders of RNA were going to excite me and really the whole world in unimaginable ways.Eric Topol (02:00):Well, they sure have, and you've lit up the world well before you had your Nobel Prize in 1989 was Sid Altman with ribozyme. And I think one of the things that struck me, which are so compelling in the book as I think people might know, it's divided in two sections. The first is much more on the biology, and the second is much more on the applications and how it's changing the world. We'll get into it particularly in medicine, but the interesting differentiation from DNA, which is the one trick pony, as you said, all it does is store stuff. And then the incredible versatility of RNA as you discovered as a catalyst, that challenging dogma, that proteins are supposed to be the only enzymes. And here you found RNA was one, but also so much more with respect to genome editing and what we're going to get into here. So I thought what we might get into is the fact that you kind of went into the scum of the pond with this organism, which by the way, you make a great case for the importance of basic science towards the end of the book. But can you tell us about how you, and then of course, many others got into the Tetrahymena thermophila, which I don't know that much about that organism.Tom Cech (03:34):Yeah, it's related to Tetrahymena is related to paramecium, which is probably more commonly known because it's an even larger single celled animal. And therefore, in an inexpensive grade school microscope, kids can look through and see these ciliated protozoa swimming around on a glass slide. But I first learned about them when I was a postdoc at MIT and I would drive down to Joe Gall's lab at Yale University where Liz Blackburn was a postdoc at the time, and they were all studying Tetrahymena. It has the remarkable feature that it has 10,000 identical copies of a particular gene and for a higher organism, one that has its DNA in the nucleus and does its protein synthesis in the cytoplasm. Typically, each gene's present in two copies, one from mom, one from dad. And if you're a biochemist, which I am having lots of stuff is a real advantage. So 10,000 copies of a particular gene pumping out RNA copies all the time was a huge experimental advantage. And that's what I started working on when I started my own lab at Boulder.Eric Topol (04:59):Well, and that's where, I guess the title of the book, the Catalyst ultimately, that grew into your discovery, right?Tom Cech (05:08):Well, at one level, yes, but I also think that the catalyst in a more general conversational sense means just facilitating life in this case. So RNA does much more than just serve as a biocatalyst or a message, and we'll get into that with genome editing and with telomerase as well.The Big Bang and 11 Nobel Prizes on RNA since 2000Eric Topol (05:32):Yes, and I should note that as you did early in the book, that there's been an 11 Nobel prize awardees since 2000 for RNA work. And in fact, we just had Venki who I know you know very well as our last podcast. And prior to that, Kati Karikó, Jennifer Doudna who worked in your lab, and the long list of people working RNA in the younger crowd like David Liu and Fyodor Urnov and just so many others, we need to have an RNA series because it's just exploding. And that one makes me take you back for a moment to 2007. And when I was reading the book, it came back to me about the Economist cover. You may recall almost exactly 17 years ago. It was called the Biology's Big Bang – Unravelling the secrets of RNA. And in that, there was a notable quote from that article. Let me just get to that. And it says, “it is probably no exaggeration to say that biology is now undergoing its neutron moment.”(06:52):This is 17 years ago. “For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which is genes encode and which do the donkey work of keeping living organisms living. The past couple of years, 17 years ago, however, has seen the rise and rise of a third type of molecule, called RNA.” Okay, so that was 2007. It's pretty extraordinary. And now of course we're talking about the century of biology. So can you kind of put these last 17 years in perspective and where we're headed?Tom Cech (07:34):Well, Eric, of course, this didn't all happen in one moment. It wasn't just one big bang. And the scientific community has been really entranced with the wonders of RNA since the 1960s when everyone was trying to figure out how messenger RNA stored the genetic code. But the general public has been really kept in the dark about this, I think. And as scientists, were partially to blame for not reaching out and sharing what we have found with them in a way that's more understandable. The DNA, the general public's very comfortable with, it's the stuff of our heredity. We know about genetic diseases, about tracing our ancestry, about solving crimes with DNA evidence. We even say things like it's in my DNA to mean that it's really fundamental to us. But I think that RNA has been sort of kept in the closet, and now with the mRNA vaccines against Covid-19, at least everyone's heard of RNA. And I think that that sort of allowed me to put my foot in the door and say, hey, if you were curious about the mRNA vaccines, I have some more stories for you that you might be really interested in.RNA vs RNAEric Topol (09:02):Yeah, well, we'll get to that. Maybe we should get to that now because it is so striking the RNA versus RNA chapter in your book, and basically the story of how this RNA virus SARS-CoV-2 led to a pandemic and it was fought largely through the first at scale mRNA nanoparticle vaccine package. Now, that takes us back to some seminal work of being able to find, giving an mRNA to a person without inciting massive amount of inflammation and the substitution of pseudouridine or uridine in order to do that. Does that really get rid of all the inflammation? Because obviously, as you know, there's been some negativism about mRNA vaccines for that and also for the potential of not having as much immune cell long term activation. Maybe you could speak to that.Tom Cech (10:03):Sure. So the discovery by Kati Karikó and Drew Weissman of the pseudouridine substitution certainly went a long way towards damping down the immune response, the inflammatory response that one naturally gets with an RNA injection. And the reason for that is that our bodies are tuned to be on the lookout for foreign RNA because so many viruses don't even mess with DNA at all. They just have a genome made of RNA. And so, RNA replicating itself is a danger sign. It means that our immune system should be on the lookout for this. And so, in the case of the vaccination, it's really very useful to dampen this down. A lot of people thought that this might make the mRNA vaccines strange or foreign or sort of a drug rather than a natural substance. But in fact, modified nucleotides, nucleotides being the building blocks of RNA, so these modified building blocks such as pseudoU, are in fact found in natural RNAs more in some than in others. And there are about 200 modified versions of the RNA building blocks found in cells. So it's really not an unusual modification or something that's all that foreign, but it was very useful for the vaccines. Now your other question Eric had to do with the, what was your other question, Eric?Eric Topol (11:51):No, when you use mRNA, which is such an extraordinary way to get the spike protein in a controlled way, exposed without the virus to people, and it saved millions of lives throughout the pandemic. But the other question is compared to other vaccine constructs, there's a question of does it give us long term protective immunity, particularly with T cells, both CD8 cytotoxic, maybe also CD4, as I know immunology is not your main area of interest, but that's been a rub that's been put out there, that it isn't just a weaning of immunity from the virus, but also perhaps that the vaccines themselves are not as good for that purpose. Any thoughts on that?Tom Cech (12:43):Well, so my main thought on that is that this is a property of the virus more than of the vaccine. And respiratory viruses are notoriously hard to get long-term immunity. I mean, look at the flu virus. We have to have annual flu shots. If this were like measles, which is a very different kind of virus, one flu shot would protect you against at least that strain of flu for the rest of your life. So I think the bad rap here is not the vaccine's fault nearly as much as it's the nature of respiratory viruses.RNA And Aging Eric Topol (13:27):No, that's extremely helpful. Now, let me switch to an area that's really fascinating, and you've worked quite a bit on the telomerase story because this is, as you know, being pursued quite a bit, has thought, not just because telomeres might indicate something about biologic aging, but maybe they could help us get to an anti-aging remedy or whatever you want to call it. I'm not sure if you call it a treatment, but tell us about this important enzyme, the role of the RNA building telomeres. And maybe you could also connect that with what a lot of people might not be familiar with, at least from years ago when they learned about it, the Hayflick limit.Tom Cech (14:22):Yes. Well, Liz Blackburn and Carol Greider got the Nobel Prize for the discovery of telomerase along with Jack Szostak who did important initial work on that system. And what it does is, is it uses an RNA as a template to extend the ends of human chromosomes, and this allows the cell to keep dividing without end. It gives the cell immortality. Now, when I say immortality, people get very excited, but I'm talking about immortality at the cellular level, not for the whole organism. And in the absence of a mechanism to build out the ends of our chromosomes, the telomeres being the end of the chromosome are incompletely replicated with each cell division. And so, they shrink over time, and when they get critically short, they signal the cell to stop dividing. This is what is called the Hayflick limit, first discovered by Leonard Hayflick in Philadelphia.(15:43):And he, through his careful observations on cells, growing human cells growing in Petri dishes, saw that they could divide about 50 times and then they wouldn't die. They would just enter a state called senescence. They would change shape, they would change their metabolism, but they would importantly quit dividing. And so, we now see this as a useful feature of human biology that this protects us from getting cancer because one of the hallmarks of cancer is immortality of the tumor cells. And so, if you're wishing for your telomeres to be long and your cells to keep dividing, you have to a little bit be careful what you wish for because this is one foot in the door for cancer formation.Eric Topol (16:45):Yeah, I mean, the point is that it seems like the body and the cell is smart to put these cells into the senescent state so they can't divide anymore. And one of the points you made in the book that I think is worth noting is that 90% of cancers have the telomerase, how do you say it?Tom Cech (17:07):Telomerase.Eric Topol (17:08):Yeah, reactivate.Tom Cech (17:09):Right.Eric Topol (17:10):That's not a good sign.Tom Cech (17:12):Right. And there are efforts to try to target telomerase enzyme for therapeutic purposes, although again, it's tricky because we do have stem cells in our bodies, which are the exception to the Hayflick limit rule. They do still have telomerase, they still have to keep dividing, maybe not as rapidly as a cancer cell, but they still keep dividing. And this is critical for the replenishment of certain worn out tissues in our such as skin cells, such as many of our blood cells, which may live only 30 days before they poop out. That's a scientific term for needing to be replenished, right?Eric Topol (18:07):Yeah. Well, that gets me to the everybody's, now I got the buzz about anti-aging, and whether it's senolytics to get rid of these senescent cells or whether it's to rejuvenate the stem cells that are exhausted or work on telomeres, all of these seem to connect with a potential or higher risk of cancer. I wonder what your thoughts are as we go forward using these various biologic constructs to be able to influence the whole organism, the whole human body aging process.Tom Cech (18:47):Yes. My view, and others may disagree is that aging is not an affliction. It's not a disease. It's not something that we should try to cure, but what we should work on is having a healthy life into our senior years. And perhaps you and I are two examples of people who are at that stage of our life. And what we would really like is to achieve, is to be able to be active and useful to society and to our families for a long period of time. So using the information about telomerase, for example, to help our stem cells stay healthy until we are, until we're ready to cash it in. And for that matter on the other side of the coin, to try to inhibit the telomerase in cancer because cancer, as we all know, is a disease of aging, right? There are young people who get cancer, but if you look at the statistics, it's really heavily weighted towards people who've been around a long time because mutations accumulate and other damage to cells that would normally protect against cancer accumulates. And so, we have to target both the degradation of our stem cells, but also the occurrence of cancer, particularly in the more senior population. And knowing more about RNA is really helpful in that regard.RNA DrugsEric Topol (20:29):Yeah. Well, one of the things that comes across throughout the book is versatility of RNA. In fact, you only I think, mentioned somewhere around 12 or 14 of these different RNAs that have a million different shapes, and there's so many other names of different types of RNAs. It's really quite extraordinary. But one of the big classes of RNAs has really hit it. In fact, this week there are two new interfering RNAs that are having extraordinary effects reported in the New England Journal on all the lipids, abnormal triglycerides and LDL cholesterol, APOC3. And can you talk to us about this interfering the small interfering RNAs and how they become, you've mentioned in the book over 400 RNAs are in the clinic now.Tom Cech (21:21):Yeah, so the 400 of course is beyond just the siRNAs, but these, again, a wonderful story about how fundamental science done just to understand how nature works without any particular expectation of a medical spinoff, often can have the most phenomenal and transformative effects on medicine. And this is one of those examples. It came from a roundworm, which is about the size of an eyelash, which a scientist named Sydney Brenner in England had suggested would be a great experimental organism because the entire animal has only about a thousand cells, and it's transparent so we can look at, see where the cells are, we can watch the worm develop. And what Andy Fire and Craig Mello found in this experimental worm was that double-stranded RNA, you think about DNA is being double-stranded and RNA as being single stranded. But in this case, it was an unusual case where the RNA was forming a double helix, and these little pieces of double helical RNA could turn off the expression of genes in the worm.(22:54):And that seemed remarkable and powerful. But as often happens in biology, at least for those of us who believe in evolution, what goes for the worm goes for the human as well. So a number of scientists quickly found that the same process was going on in the human body as a natural way of regulating the expression of our genes, which means how much of a particular gene product is actually going to be made in a particular cell. But not only was it a natural process, but you could introduce chemically synthesized double helical RNAs. There are only 23 base pairs, 23 units of RNA long, so they're pretty easy to chemically synthesize. And that once these are introduced into a human, the machinery that's already there grabs hold of them and can be used to turn off the expression of a disease causing RNA or the gene makes a messenger RNA, and then this double-stranded RNA can suppress its action. So this has become the main company that is known for doing this is Alnylam in Boston, Cambridge. And they have made quite a few successful products based on this technology.Eric Topol (24:33):Oh, absolutely. Not just for amyloidosis, but as I mentioned these, they even have a drug that's being tested now, as you know that you could take once or twice a year to manage your blood pressure. Wouldn't that be something instead of a pill every day? And then of course, all these others that are not just from Alnylam, but other companies I wasn't even familiar with for managing lipids, which is taking us well beyond statins and these, so-called PCSK9 monoclonal antibodies, so it's really blossoming. Now, the other group of RNA drugs are antisense drugs, and it seemed like they took forever to warm up, and then finally they hit. And can you distinguish the antisense versus the siRNA therapeutics?Tom Cech (25:21):Yes, in a real general sense, there's some similarity as well as some differences, but the antisense, what are called oligonucleotides, whoa, that's a big word, but oligo just means a few, right? And nucleotides is just the building blocks of nucleic acid. So you have a string of a few of these. And again, it's the power of RNA that it is so good at specifically base pairing only with matching sequences. So if you want to match with a G in a target messenger RNA, you put a C in the antisense because G pairs with C, if you want to put an A, if want to match with an A, you put a U in the antisense because A and U form a base pair U is the RNA equivalent of T and DNA, but they have the same coding capacity. So any school kid can write out on a notepad or on their laptop what the sequence would have to be of an antisense RNA to specifically pair with a particular mRNA.(26:43):And this has been, there's a company in your neck of the woods in the San Diego area. It started out with the name Isis that turned out to be the wrong Egyptian God to name your company after, so they're now known as Ionis. Hopefully that name will be around for a while. But they've been very successful in modifying these antisense RNAs or nucleic acids so that they are stable in the body long enough so that they can pair with and thereby inhibit the expression of particular target RNAs. So it has both similarities and differences from the siRNAs, but the common denominator is RNA is great stuff.RNA and Genome EditingEric Topol (27:39):Well, you have taken that to in catalyst, the catalyst, you've proven that without a doubt and you and so many other extraordinary scientists over the years, cumulatively. Now, another way to interfere with genes is editing. And of course, you have a whole chapter devoted to not just well CRISPR, but the whole genome editing field. And by the way, I should note that I forgot because I had read the Codebreaker and we recently spoke Jennifer Doudna and I, that she was in your lab as a postdoc and you made some wonderful comments about her. I don't know if you want to reflect about having Jennifer, did you know that she was going to do some great things in her career?Tom Cech (28:24):Oh, there was no question about it, Eric. She had been a star graduate student at Harvard, had published a series of breathtaking papers in magazines such as Science and Nature already as a graduate student. She won a Markey fellowship to come to Colorado. She chose a very ambitious project trying to determine the molecular structures of folded RNA molecules. We only had one example at the time, and that was the transfer RNA, which is involved in protein synthesis. And here she was trying these catalytic RNAs, which we had discovered, which were much larger than tRNA and was making great progress, which she finished off as an assistant professor at Yale. So what the general public may not know was that in scientific, in the scientific realm, she was already highly appreciated and much awarded before she even heard anything about CRISPR.Eric Topol (29:38):Right. No, it was a great line you have describing her, “she had an uncanny talent for designing just the right experiment to test any hypothesis, and she possessed more energy and drive than any scientist I'd ever met.” That's pretty powerful. Now getting into CRISPR, the one thing, it's amazing in just a decade to see basically the discovery of this natural system to then be approved by FDA for sickle cell disease and beta thalassemia. However, the way it exists today, it's very primitive. It's not actually fixing the gene that's responsible, it's doing a workaround plan. It's got double strand breaks in the DNA. And obviously there's better ways of editing, which are going to obviously involve RNA epigenetic editing, if you will as well. What is your sense about the future of genome editing?Tom Cech (30:36):Yeah, absolutely, Eric. It is primitive right now. These initial therapies are way too expensive as well to make them broadly applicable to the entire, even in a relatively wealthy country like the United States, we need to drive the cost down. We need to get them to work, we need to get the process of introducing them into the CRISPR machinery into the human body to be less tedious and less time consuming. But you've got to start somewhere. And considering that the Charpentier and Doudna Nobel Prize winning discovery was in 2012, which is only a dozen years ago, this is remarkable progress. More typically, it takes 30 years from a basic science discovery to get a medical product with about a 1% chance of it ever happening. And so, this is clearly a robust RNA driven machine. And so, I think the future is bright. We can talk about that some more, but I don't want to leave RNA out of this conversation, Eric. So what's cool about CRISPR is its incredible specificity. Think of the human genome as a million pages of text file on your computer, a million page PDF, and now CRISPR can find one sentence out of that million pages that matches, and that's because it's using RNA, again, the power of RNA to form AU and GC base pairs to locate just one site in our whole DNA, sit down there and direct this Cas9 enzyme to cut the DNA at that site and start the repair process that actually does the gene editing.Eric Topol (32:41):Yeah, it's pretty remarkable. And the fact that it can be so precise and it's going to get even more precise over time in terms of the repair efforts that are needed to get it back to an ideal state. Now, the other thing I wanted to get into with you a bit is on the ribosome, because that applies to antibiotics and as you call it, the mothership. And I love this metaphor that you had about the ribosome, and in the book, “the ribosome is your turntable, the mRNA is the vinyl LP record, and the protein is the music you hear when you lower the needle.” Tell us more about the ribosome and the role of antibiotics.Tom Cech (33:35):So do you think today's young people will understand that metaphor?Eric Topol (33:40):Oh, they probably will. They're making a comeback. These records are making a comeback.Tom Cech (33:44):Okay. Yes, so this is a good analogy in that the ribosome is so versatile it's able to play any music that you feed at the right messenger RNA to make the music being the protein. So you can have in the human body, we have tens of thousands of different messenger RNAs. Each one threads through the same ribosome and spills out the production of whatever protein matches that mRNA. And so that's pretty remarkable. And what Harry Noller at UC Santa Cruz and later the crystallographers Venki Ramakrishnan, Tom Steitz, Ada Yonath proved really through their studies was that this is an RNA machine. It was hard to figure that out because the ribosome has three RNAs and it has dozens of proteins as well. So for a long time people thought it must be one of those proteins that was the heart and soul of the record player, so to speak.RNA and Antibiotics(34:57):And it turned out that it was the RNA. And so, when therefore these scientists, including Venki who you just talked to, looked at where these antibiotics docked on the ribosome, they found that they were blocking the key functional parts of the RNA. So it was really, the antibiotics knew what they were doing long before we knew what they were doing. They were talking to and obstructing the action of the ribosomal RNA. Why is this a good thing for us? Because bacterial ribosomes are just enough different from human ribosomes that there are drugs that will dock to the bacterial ribosomal RNA, throw a monkey wrench into the machine, prevent it from working, but the human ribosomes go on pretty much unfazed.Eric Topol (36:00):Yeah, no, the backbone of our antibiotics relies on this. So I think people need to understand about the two subunits, the large and the small and this mothership, and you illuminate that so really well in the book. That also brings me to phage bacteria phage, and we haven't seen that really enter the clinic in a significant way, but there seems to be a great opportunity. What's your view about that?Tom Cech (36:30):This is an idea that goes way back because since bacteria have their own viruses which do not infect human cells, why not repurpose those into little therapeutic entities that could kill, for example, what would we want to kill? Well, maybe tuberculosis has been very resistant to drugs, right? There are drug resistant strains of TB, yes, of TB, tuberculosis, and especially in immunocompromised individuals, this bug runs rampant. And so, I don't know the status of that. It's been challenging, and this is the way that biomedicine works, is that for every 10 good ideas, and I would say phage therapy for bacterial disease is a good idea. For every 10 such ideas, one of them ends up being practical. And the other nine, maybe somebody else will come along and find a way to make it work, but it hasn't been a big breakthrough yet.RNA, Aptamers and ProteinsEric Topol (37:54):Yeah, no, it's really interesting. And we'll see. It may still be in store. What about aptamers? Tell us a little bit more about those, because they have been getting used a lot in sorting out the important plasma proteins as therapies. What are aptamers and what do you see as the future in that regard?Tom Cech (38:17):Right. Well, in fact, aptamers are a big deal in Boulder because Larry Gold in town was one of the discoverers has a company making aptamers to recognize proteins. Jack Szostak now at University of Chicago has played a big role. And also at your own institution, Jerry Joyce, your president is a big aptamer guy. And you can evolution, normally we think about it as happening out in the environment, but it turns out you can also make it work in the laboratory. You can make it work much faster in the laboratory because you can set up test tube experiments where molecules are being challenged to perform a particular task, like for example, binding to a protein to inactivate it. And if you make a large community of RNA molecules randomly, 99.999% of them aren't going to know how to do this. What are the odds? Very low.(39:30):But just by luck, there will be an occasional molecule of RNA that folds up into a shape that actually fits into the proteins active sighting throws a monkey wrench into the works. Okay, so now that's one in a billion. How are you going to find that guy? Well, this is where the polymerase chain reaction, the same one we use for the COVID-19 tests for infection comes into play. Because if you can now isolate this needle in a haystack and use PCR to amplify it and make a whole handful of it, now you've got a whole handful of molecules which are much better at binding this protein than the starting molecule. And now you can go through this cycle several times to enrich for these, maybe mutagen it a little bit more to give it a little more diversity. We all know diversity is good, so you put a little more diversity into the population and now you find some guy that's really good at recognizing some disease causing protein. So this is the, so-called aptamer story, and they have been used therapeutically with some success, but diagnostically certainly they are extremely useful. And it's another area where we've had success and the future could hold even more success.Eric Topol (41:06):I think what you're bringing up is so important because the ability to screen that tens of thousands of plasma proteins in a person and coming up with as Tony Wyss-Coray did with the organ clocks, and this is using the SomaLogic technology, and so much is going on now to get us not just the polygenic risk scores, but also these proteomic scores to compliment that at our orthogonal, if you will, to understand risk of people for diseases so we can prevent them, which is fulfilling a dream we've never actually achieved so far.Tom Cech (41:44):Eric, just for full disclosure, I'm on the scientific advisory board of SomaLogic in Boulder. I should disclose that.Eric Topol (41:50):Well, that was smart. They needed to have you, so thank you for mentioning that. Now, before I wrap up, well, another area that is a favorite of mine is citizen science. And you mentioned in the book a project because the million shapes of RNA and how it can fold with all hairpin terms turns and double stranded and whatever you name it, that there was this project eteRNA that was using citizen scientists to characterize and understand folding of RNA. Can you tell us about that?RNA Folding and Citizen ScienceTom Cech (42:27):So my friend Rhiju Das, who's a professor at Stanford University, sort of adopted what had been done with protein folding by one of his former mentors, David Baker in Seattle, and had repurposed this for RNA folding. So the idea is to come up with a goal, a target for the community. Can you design an RNA that will fold up to look like a four pointed cross or a five pointed star? And it turned out that, so they made it into a contest and they had tens of thousands of people playing these games and coming up with some remarkable solutions. But then they got a little bit more practical, said, okay, that was fun, but can we have the community design something like a mRNA for the SARS-CoV-2 spike protein to make maybe a more stable vaccine? And quite remarkably, the community of many of whom are just gamers who really don't know much about what RNA does, were able to find some solutions. They weren't enormous breakthroughs, but they got a several fold, several hundred percent increase in stability of the RNA by making it fold more tightly. So I just find it to be a fascinating approach to science. Somebody of my generation would never think of this, but I think for today's generation, it's great when citizens can become involved in research at that level.Eric Topol (44:19):Oh, I think it's extraordinary. And of course, there are other projects folded and others that have exemplified this ability for people with no background in science to contribute in a meaningful way, and they really enjoy, it's like solving a puzzle. The last point is kind of the beginning, the origin of life, and you make a pretty strong case, Tom, that it was RNA. You don't say it definitively, but maybe you can say it here.RNA and the Origin of LifeTom Cech (44:50):Well, Eric, the origin of life happening almost 4 billion years ago on our primitive planet is sort of a historical question. I mean, if you really want to know what happened then, well, we don't have any video surveillance of those moments. So scientists hate to ever say never, but it's hard to sort of believe how we would ever know for sure. So what Leslie Orgel at the Salk Institute next to you taught me when I was a starting assistant professor is even though we'll never know for sure, if we can recapitulate in the laboratory plausible events that could have happened, and if they make sense chemically and biologically, then that's pretty satisfying, even if we can never be absolutely sure. That's what a number of scientists have done in this field is to show that RNA is sort of a, that all the chemistry sort of points to RNA as being something that could have been made under prebiotic conditions and could have folded up into a way that could solve the greatest of all chicken and egg problems, which came first, the informational molecule to pass down to the next generation or the active molecule that could copy that information.(46:32):So now that we know that RNA has both of those abilities, maybe at the beginning there was just this RNA world RNA copying itself, and then proteins came along later, and then DNA probably much more recently as a useful but a little bit boring of genetic information, right?Eric Topol (46:59):Yeah. Well, that goes back to that cover of the Economist 17 years ago, the Big Bang, and you got me convinced that this is a pretty strong story and candidate. Now what a fun chance to discuss all this with you in an extraordinary book, Tom. Did I miss anything that you want to bring up?Tom Cech (47:21):Eric, I just wanted to say that I not only appreciate our conversation, but I also appreciate all you are doing to bring science to the non-scientist public. I think people like me who have taught a lot of freshmen in chemistry, general chemistry, sort of think that that's the level that we need to aim at. But I think that those kids have had science in high school year after year. We need to aim at the parents of those college freshmen who are intelligent, who are intellectually curious, but have not had science courses in a long time. And so, I'm really joining with you in trying to avoid jargon as much as possible. Use simple language, use analogies and metaphors, and try to share the excitement of what we're doing in the laboratory with the populace.Eric Topol (48:25):Well, you sure did that it was palpable. And I thought about it when I read the book about how lucky it would be to be a freshman at the University of Boulder and be having you as the professor. My goodness. Well, thank you so much. This has been so much fun, Tom, and I hope everybody's going to get out there and read the Catalyst to get all the things that we didn't even get a chance to dive into. But this has been great and look forward to future interactions with you.Tom Cech (48:53):Take care, Eric.*********************Thanks for listening or reading this edition of Ground Truths.Please share this podcast with your friends and network. That tells me you found it informative and makes the effort in doing these worthwhile.All Ground Truths newsletters and podcast are free. Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

This case report explores the intricacies of familial hypercholesterolemia (FH), delving into its genetic basis, atherosclerotic cascade, and early-onset cardiovascular complications. It examines established diagnostic criteria and emphasizes personalized management, including statins, novel therapies, and lifestyle modifications. CardioNerds cofounders (Drs. Amit Goyal and Danial Ambinder) join Dr. Irfan Shafi, Dr. Preeya Prakash, and Dr. Rebecca Theisen from the Wayne State University/DMC and Central Michigan University at Campus Martius in Downtown Detroit for some holiday ice-skating! They discuss an interesting pediatric case (see case synopsis below). Dr. Luis C Afonso provides the Expert CardioNerd Perspectives & Review segment for this episode. Audio editing by CardioNerds academy intern, Pace Wetstein. US Cardiology Review is now the official journal of CardioNerds! Submit your manuscript here. CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Case Synopsis FH, a 9-year-old female with no previous medical history, recently moved back to the US from Iraq. She presented to establish care and discuss new-onset chest pain and dyspnea. A systolic ejection murmur was noted during her initial visit to the pediatrician, prompting cholesterol testing and a cardiology referral. Testing revealed, alarming cholesterol levels (Total Cholesterol: 802 mg/dL, LDL: 731 mg/dL, Triglycerides: 123 mg/dL) prompted concern for cardiac involvement. Due to persistent symptoms, FH was transferred to Children's Hospital of Michigan. Despite normal findings on EKG and chest x-ray, a 2/6 systolic murmur was noted. She was discharged with a cardiology clinic follow-up. However, two days later, FH experienced severe chest pain at rest, sweating, and difficulty breathing. She was transported to Children's Hospital again, and her troponin level measured 3000, and her total cholesterol was 695 mg/dL. An echocardiogram revealed valvar and supravalvar aortic stenosis, necessitating collaboration between Pediatric and Adult cardiology teams. CTA thorax revealed severe supravalvular stenosis, a hypoplastic right coronary artery, and significant coronary artery obstructions. Diagnostic cardiac catheterization confirmed severe aortic stenosis and coronary artery disease, leading to the decision for surgical intervention. FH underwent the Ross operation, left main coronary artery augmentation, and right coronary artery reimplantation. Intraoperatively, atherosclerotic plaques were observed in multiple cardiac structures. FH's recovery was uneventful, discharged on a regimen including Atorvastatin, Ezetimibe, evolocumab, and antiplatelet therapy. Persistent high LDL levels required regular plasmapheresis. Plans for evaluations in Genetics, Lipid Clinic, Endocrine, and Gastroenterology were made, potentially leading to a liver transplant assessment. Given the severity of her condition, a heart/liver transplant might be considered in the future. Conclusion: This case of FH highlights the complex presentation of severe aortic stenosis and coronary artery disease in a pediatric patient. Urgent diagnosis, interdisciplinary collaboration, and aggressive management were crucial. The case underscores the importance of comprehensive care for pediatric patients with rare cardiac conditions, emphasizing collaboration between specialties for optimal outcomes and long-term well-being. Case Media Pearls - Familial Hypercholesterolemia Mutations in LDLR, ApoB, or PCSK9 genes disrupt LDL-C clearance, leading to a cascade of events culminating in accelerated atherosclerosis and early-onset cardiovascular complications (e.g., CAD, aortic stenosis, PAD, stroke). Diagnosis of familial hypercholesterolemia relies on ...

Edição genética para PCSK9 by Cardiopapers

Inibidores orais da PCSK9 by Cardiopapers

“Menopause is inevitable, but suffering through it is not," says Mary Claire Haver, M.D. Mary Claire, a board-certified OBGYN and certified menopause practitioner, joins us to discuss everything a woman needs to know during this hormonal transition and beyond, including: - Old vs. new menopause (~00:07) - Signs of peri menopause in 30s, 40s & 50s (~02:04) - Sleep deprivation during menopause (~05:09) - Menopause weight gain (~06:36) - How to enhance body composition as you age (~09:25) - Protein needs for women (~14:20) - The link between food & hot flashes (~16:09) - Pros & cons of hormone replacement therapy (~18:43) - How to know if you're a good candidate for HRT (~25:02) - Best questions to ask your doctor (~27:23) - Why we should have annual midlife wellness visits (~28:28) - The future of menopause care (~31:23) - A drug that can prolong estrogen production (~33:02) - How to measure estrogen swings (~35:10) - How to be your own menopause advocate (~39:35) Visit shop.mindbodygreen.com/whey20 to get 20% off whey protein isolate+. Cannot combine with gift cards or other discount codes. Referenced in the episode: - Mary Claire's book, The New Menopause - The Galveston Diet - Follow Mary Claire on Instagram - mbg Podcast episode #529, with Lisa Mosconi, Ph.D. - mbg Podcast episode #480, with Peter Attia, M.D. - Statins Peter mentions: PCSK9 inhibitors, Ezetimibe, and Bempedoic Acid - WHI study on frailty - A study on estrogen therapy & dementia - menopause.org - Mary Claire's Menopause Empowerment Guide - Tests to ask for at the doctor - Oviva Therapeutics We hope you enjoy this episode, and feel free to watch the full video on YouTube! Whether it's an article or podcast, we want to know what we can do to help here at mindbodygreen. Let us know at: podcast@mindbodygreen.com. Learn more about your ad choices. Visit megaphone.fm/adchoices

Welcome to my podcast. I am Doctor Warrick Bishop, and I want to help you to live as well as possible for as long as possible. I'm a practising cardiologist, best-selling author, keynote speaker, and the creator of The Healthy Heart Network. I have over 20 years as a specialist cardiologist and a private practice of over 10,000 patients. Dr. Warrick Bishop discusses lowering LDL cholesterol levels and whether it is safe to lower them very low. He explains that babies are born with very low cholesterol, and people with genetic mutations also have low cholesterol without negative effects. Studies show that lowering LDL to very low levels, even under 0.2 mmol/L, significantly reduces heart disease risk without increasing other health issues. Tests found no cognitive impacts of lowering LDL cholesterol levels using PCSK9 inhibitors. While statins may slightly increase diabetes risk, other cholesterollowering drugs do not appear to have this effect when lowering cholesterol alone.

As I've been researching and writing Boundless 2.0, I've found myself reevaluating many of the health and fitness strategies that I previously endorsed.In this episode, prepare to have your perspective challenged as I discuss some of the significant shifts in thinking I've undergone while exploring the latest science and experimenting with biohacking. To kick off the show, I discuss one of the biggest areas where I've updated my thinking — the ketogenic diet. While I was previously gung-ho about strict therapeutic ketosis for all sorts of applications, I now have a more nuanced view that involves limiting carbohydrates during the day for enhanced focus and consuming 200 to 300g in the evening to support better sleep and hormonal balance. Additionally, I've moved away from a saturated fat-heavy keto diet to a Mediterranean-style approach with foods like avocados, olives, oily fish, and olive oil. When it comes to exercise, I used to be that guy who obsessively crushed two-a-day workout sessions. But the more I dig into the research, the more I've come to understand the importance of staying within the "Goldilocks Zone" — enough training to accrue benefits, but not so much that you risk overtraining. Another controversial mind shift I've experienced is around statins, which was prompted by my advanced cardiac screening. My Cleerly test revealed plaque buildup, leading me to start a PCSK9 inhibitor and a daily dose of rosuvastatin and acetamide. While I still don't think these drugs should be blindly taken, in some cases the benefits can outweigh the risks if properly monitored. My view on cold exposure has also slightly changed after digging into research. I used to be all about long ice baths and open-water cold swims, but now I've shifted to shorter, more frequent cold exposures. (You'll hear multiple times throughout this show that optimizing your body is all about finding the right balance and avoiding excessive stress.) This show also covers topics like the hidden benefits of aspirin, ginger, and yes... even "dick pills." Plus, you'll gain insights into sleep hacking, why I'm taking a more discerning stance on cannabis, and the dangers of extreme biohacking. For the full show notes, visit: https://bengreenfieldlife.com/470 Episode Sponsors: Paleovalley: Go to paleovalley.com/ben to get 15% off your first order. C60: Visit shopc60.com/ben-greenfield and use code GREENFIELD15 for 15% OFF your first order. Mito Red Light: Go to mitoredlight.com and use code BGLIFE to save 5%. Ion Layer: Use code GREENFIELD at ionlayer.com/ben for $150 off your kit and start reaping the benefits of NAD+. Jigsaw Health: Visit JigsawAC.com and use "GREENFIELD10" to get 10% off.See omnystudio.com/listener for privacy information.

Take a deep dive into the heart of midlife cardiovascular wellness with this important episode of "Age Better," where host Barbara Hannah Grufferman talks with Dr. Melissa Tracy, a top-tier cardiologist from the RUSH University Medical Center. Dr. Tracy is also the Medical Director of the Cardiac Rehabilitation Program at RUSH.   Dr. Tracy gives a masterclass on statins - those powerhouse medications at the forefront of cholesterol management and heart disease prevention. But the question that lies at the core of this discussion is one that resonates with millions: Who really needs to be on statins? By tuning in, you'll get the knowledge and tools you need to make the decision that is right for you.   KEY TAKEAWAYS:  Understanding Statins: Learn how these powerful medications aid in reducing cholesterol and preventing cardiovascular disease.  Postmenopause and Heart Health: Discover the unique impact of statins for women in midlife.  Shared Decision-Making: The importance of patient-doctor collaboration in deciding if statins are right for you.  Coronary Calcium Score: Uncover how this test is crucial in assessing cardiovascular risks.  Side Effects & Alternatives: Insights into common side effects of statins and who should avoid them, plus a look at natural supplements and other cholesterol management strategies.  Personalized Healthcare: Dr. Tracy emphasizes individualized treatment plans and the role of lifestyle changes alongside statins.  Future-Focused Discussion: A sneak peek into ongoing assessments and evolving conversations in heart health management.    KEY LINKS:  Learn More About Dr. Melissa Tracy: https://doctors.rush.edu/details/1183  What is Cardiac Rehabilitation? https://www.kevinmd.com/2024/02/a-people-first-approach-to-cardiac-rehabilitation.html  USNews+WorldReport Article: https://www.usnews.com/news/health-news/articles/2024-03-05/statin-meds-cholesterol-what-you-need-to-know  Alternatives to Statins Referenced During the Episode:   Ezetimibe: https://www.mayoclinic.org/drugs-supplements/ezetimibe-oral-route/description/drg-20067172  Bempedoic Acid: https://www.mayoclinic.org/drugs-supplements/bempedoic-acid-oral-route/side-effects/drg-20484223?p=1  PCSK9 inhibitors: https://www.medicalnewstoday.com/articles/pcsk9-inhibitor#definition  Whether you're on a statin already, or giving it serious consideration … this episode will help you make the decision that is right for you.  Learn More About ‘Age Better' Podcast:  Age Better podcast delves into a diverse range of topics, including finance, work, health, fitness, style, makeup, hair, nutrition, travel, relationships, sex, and more.   Listen and Subscribe   To join this adventure, remember to subscribe or follow the "Age Better with Barbara Hannah Grufferman" podcast on platforms like Apple Podcasts, Spotify, and YouTube. Yep, you can watch it or just listen!   Share Your Ideas and Questions   Your questions have spurred many episodes, so please keep them coming! Share your ideas for topics and guest suggestions at agebetterpodcast@gmail.com  Learn more about your ad choices. Visit megaphone.fm/adchoices

Heart Health Month provides the backdrop for a timely discussion on the latest breakthroughs in treating cardiovascular disease. This is a rebroadcast of Dr. Michael Koren and Dr. Victoria Helow's examination of the sobering reality of heart disease statistics, the impact of statins, and the promising PCSK9 inhibitors on the horizon. We'll provide you with a snapshot of what you need to know about lowering dangerous LDL levels and the accessibility of cutting-edge treatments. By comparing the effects of lifestyle changes and medical interventions, we give you a well-rounded perspective on how to approach heart disease management.Rounding off our episode, we're on the cusp of a revolution in heart disease prevention with a semi-annual injectable targeting PCSK9. We're excited to discuss the prospects of this game-changing treatment, designed to offer long-term protection against high LDL cholesterol. The anticipation builds as we prepare to bring you the latest findings from the American College of Cardiology meeting in Atlanta. So stay with us, and together let's navigate the future of cardiovascular care, keeping you informed and heart-healthy for years to come.Talking Tips to Share:Understanding Lipid Issues and Cholesterol NumbersUnderstanding Lipoproteins and LDL LevelsBreakthroughs in Heart Disease TreatmentCholesterol, Lipoproteins, and Heart HealthInjectable PCS-K9 Vaccine Study PresentationRecording Date: February 21, 2024Be a part of advancing science by participating in clinical researchShare with a friend. Rate, Review, and Subscribe to the MedEvidence! podcast to be notified when new episodes are released.Follow us on Social Media:FacebookInstagramTwitterLinkedInWant to learn more checkout our entire library of podcasts, videos, articles and presentations at www.MedEvidence.com Powered by ENCORE Research GroupMusic: Storyblocks - Corporate InspiredThank you for listening!

In this week's episode of the Metabolic Classroom, Dr. Ben Bikman welcomes viewers to a discussion on commonly used cardiometabolic and weight loss drugs. The focus of this particular lecture is on drugs targeting heart disease, a leading cause of mortality globally. Dr. Bikman acknowledges the controversy surrounding cardiovascular drugs due to the severity of heart disease and the passionate advocacy for drug therapies.The lecture begins with an overview of two main categories of cardiovascular drugs: those addressing blood pressure and those targeting cholesterol levels. Dr. Bikman explains the significance of blood pressure in cardiovascular health, emphasizing its correlation with heart attacks and hypertension. He delves into the physiological effects of high blood pressure, likening it to over-inflating a balloon and causing stress and damage to the inner lining of blood vessels.Moving on to drugs that control blood pressure, Dr. Bikman highlights the potential impact on insulin resistance and mitochondrial function, crucial factors in heart disease risk. He discusses common classes of antihypertensive drugs such as beta blockers, ACE inhibitors, calcium channel blockers, and diuretics, detailing their mechanisms and side effects.Transitioning to cholesterol-lowering drugs, Dr. Bikman discusses the controversy surrounding the assumption that cholesterol is solely responsible for heart disease. He challenges the oversimplified view of LDL cholesterol's role in plaque formation and suggests alternative paradigms, including the immune response to infections in blood vessels.Dr. Bikman then discusses two classes of anti-cholesterol medications: PCSK9 inhibitors and statins. He explains how PCSK9 inhibitors increase LDL receptor expression to enhance LDL clearance and discusses potential side effects such as worsened insulin resistance and mitochondrial dysfunction. Finally, he explores the mechanism of statins in reducing cholesterol production and addresses controversies surrounding their use, including potential risks of developing type 2 diabetes and Alzheimer's disease.#insulinresistance #metabolicsyndrome #metabolichealth #type2diabetes #type1diabetes #weightloss #intermittentfasting #intermittantfasting #fasting #lowcarb Learn more at: Insulin IQ Hosted on Acast. See acast.com/privacy for more information.

Today you'll learn about a zombie virus recovered from the arctic permafrost and brought back to life, some good news about 26 Australian animal species that have been brought back from the brink, and how a new pill could potentially limit the levels of “bad” cholesterol in the body. Zombie Virus “Scientists have revived a ‘zombie' virus that spent 48,500 years frozen in permafrost.” By Katie Hunt. 2023. “Arctic permafrost is thawing rapidly. It affects us all.” By Katie Hunt. 2022. Back From the Brink “Researchers find 26 Australian species recovered from the brink of extinction.” abc.net. 2023. “Lights at the end of the tunnel: The incidence and characteristics of recovery for Australian threatened animals.” by Woinarski, et al. 2023. “Humpback whales no longer listed as endangered after major recovery.” by Claudia Long. 2022. “Red List: Summary Statistics.” n.a. N.d. Bad Cholesterol “Oral pill cuts bad cholesterol by 60% in phase 2 clinical trial” By Michael Irving “Efficacy and safety of the oral PCSK9 inhibitor MK-0616: a phase 2b randomized controlled trial” by Christie M. Ballantyne et al. “What Is the Difference Between Good and Bad Cholesterol?” by Keck Medicine of USC “Coronary artery disease” by Mayo Clinic “PCSK9 gene” by MedLine Plus Hosted on Acast. See acast.com/privacy for more information.

Welcome to my podcast. I am Doctor Warrick Bishop, and I want to help you to live as well as possible for as long as possible. I'm a practising cardiologist, best-selling author, keynote speaker, and the creator of The Healthy Heart Network. I have over 20 years as a specialist cardiologist and a private practice of over 10,000 patients. This episode discusses presentations from the annual Queensland lipid group meeting. Professor Derek Connelly spoke about overcoming inertia in cholesterol lowering. A new drug called Inclisiran was discussed, which reduces LDL cholesterol through the PCSK9 protein system and only requires dosing every 6 months. Karam Kostner presented on lipoprotein(a), an emerging risk factor for cardiovascular disease. Professor David Cahun emphasized the importance of measuring the omega-3 index through a blood test. Talks addressed inflammation and how diet and certain drugs may help reduce it. Imaging techniques are blurring the line between primary and secondary prevention by finding plaque in asymptomatic patients. Coronary calcium scoring provided insights into risk assessment. The meeting covered various topics around optimizing cardiovascular health and risk reduction.

Have you heard of Lp(a)? Want to know how you can lower this important cardiovascular risk marker? Tune in to hear us discuss lipoprotein a, what it means, ideal ranges, and how you can lower it naturally to decrease your risk.    Lp(a) is an independent risk factor for heart disease and stroke, yet often overlooked or left unchecked. Conventional treatment with statin drugs can actually increase Lp(a) values by 15-20%, increasing your risk. In this episode we will discuss natural ways to lower Lp(a) from PCSK9 inhibitors, to bile drivers, to fiber, and specific nutrients that address this lab value without the side effects of medication.    Also in this episode:  Save $50 on the CardioMetabolic Panel with code CMP50 Episode 284 on how to navigate a cardiometabolic panel + interventions Episode 296 Carnitine + arrhythmia and heart failure Episode 331 Homocysteine and vascular health + blood pressure updates What is Lp(a)? Do statins lower Lp(a)? Effect of an increase in Lp(a) following statin therapy on cardiovascular prognosis in secondary prevention population of coronary artery disease Study Alleges Mortality Miscount in FOURIER Trial; TIMI Group Disagrees Functional Medicine Approach to Elevated Lp(a) Natural Inhibitors of PCSK9Naturally Occurring PCSK9 Inhibitors BerberineBerberine Boost 2 twice daily  Berberine: Ins and outs of a nature-made PCSK9 inhibitor - PMC Hempseed 2 Tbsp daily Polyphenols: Get daily herbs, seasonings, spices, teaGreen Tea QuercetinBio-C Plus 1 twice daily Inflammazyme 2-3 3x/day (6-9/day) Resveratrol Honey Nutrients of Focus for lowering Lp(a)NiacinB Complex Niatain Increase Fiber in the DietPhytoFiber Flax Seeds Chia Seeds Glucomannan Konjac Noodles 2-3 cups leafy greens Drive Bile Flow10 Day Detox Reset, Restore, Renew Detox Packs 1 at rise, 1 at bed Cellular Antiox COQ10 Cardiovascular Health and Lipoprotein(a): How to Address a Genetic Issue and Support Cardiovascular Health Naturally CoQ10 Complex L-carnitineImpact of L-carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials Boost and Burn Fish OilEPA DHA Extra 1 twice daily  Keto for lowering Lp(a)Archive Keto Program   This episode is sponsored by: Noble Origins, an animal-based organs focused company serving up Nose-To-Tail Protein With Organs, Collagen, & Colostrum. Our Noble Organs Complex is a powdered blend of high-quality beef organs from New Zealand-sourced grass-fed Beef liver, heart, kidney, pancreas, and spleen. Bring Nose-to-tail nutrition to the masses that need it most: Americans. We do this through a delicious once-a-day shake that the whole family can love. Check it out here and use code ALIMILLERRD to get a free bag of Noble Organs Complex at checkout.