#52 - Ethan Weiss, M.D.: A masterclass in cardiovascular disease and growth hormone - two topics that are surprising interrelated
Dr. Ethan Weiss, a preventative cardiologist at UCSF, discusses cardiovascular disease, including acute coronary syndrome, stent placement, and diagnostic techniques like calcium scores. He also delves into the role of growth hormone and IGF in disease and longevity, touching on his company, Keyto.
Deep Dive Analysis
18 Topic Outline
Ethan Weiss's Background and Path to Cardiology
Understanding Myocardial Infarction: Plaque Rupture and Clotting
Evolution of Heart Attack Nomenclature: Q-wave to STEMI/NSTEMI
Emergency Treatment of ST-Elevation Myocardial Infarction (STEMI)
Coronary Angioplasty and Stent Placement Procedures
Evolution of Stents: Bare Metal to Drug-Eluting Stents
Treatment of Stable Angina: Medical Therapy vs. Stenting
COURAGE Trial: Stents for Stable Angina and Mortality Benefit
ORBITA Trial: Stents for Stable Angina and Symptom Relief
The Art of Prevention and Uncertainty in Cardiology
Coronary Artery Calcium (CAC) Scores: Interpretation and Utility
CT Angiograms (CTA) and HeartFlow for Anatomic Assessment
Sex Differences in Blood Clotting and Liver Gene Expression
Growth Hormone and IGF-1: Regulation and Metabolic Effects
Growth Hormone, Insulin Sensitivity, and Liver Fat Accumulation
Growth Hormone, IGF-1, Longevity, and Cancer Risk
The Importance of Scientific Literacy and Education
Keyto: A Breath Analyzer for Ketone Measurement
10 Key Concepts
Atherosclerotic Plaque Rupture
The primary cause of 99% of heart attacks, where a plaque in an artery ruptures, exposing its contents to the blood and triggering a clotting cascade. This is distinct from a gradual narrowing of the artery.
Tissue Factor
A protein carried by macrophages within atherosclerotic plaques. When a plaque ruptures, tissue factor is exposed to the blood, acting as a trigger for the coagulation cascade, leading to the rapid formation of a blood clot.
ST-Elevation Myocardial Infarction (STEMI)
A severe type of heart attack characterized by specific ST segment elevation on an electrocardiogram (EKG), indicating a complete blockage of a coronary artery. It is considered a medical emergency requiring immediate intervention.
Non-ST-Elevation Acute Coronary Syndrome (NSTE-ACS)
A broader category that includes heart attacks without ST elevation on an EKG, but with chest pain and positive cardiac biomarkers (like troponin). It also encompasses what was previously called unstable angina.
Stable Angina
Chest pain or discomfort that occurs predictably with exertion or stress and is relieved by rest or nitroglycerin. It is caused by a fixed narrowing in a coronary artery that limits blood flow only when myocardial oxygen demand increases.
Drug-Eluting Stents (DES)
Metal scaffolds coated with anti-proliferative drugs (like mTOR inhibitors) that are deployed during angioplasty. These drugs prevent the formation of scar tissue (restenosis) inside the stent, which was a common problem with bare-metal stents.
Coronary Artery Calcium (CAC) Score
A low-dose radiation CT scan that quantifies the amount of calcium in the coronary arteries, which is a marker of atherosclerotic plaque. It helps assess cardiovascular risk, particularly in intermediate-risk asymptomatic individuals.
Growth Hormone (GH) Pulsatile Secretion
The distinct pattern of growth hormone release, which is more pulsatile (spikes with longer intervals) in males and more continuous in females. This dimorphic pattern is a primary regulator of sexually dimorphic gene expression in the mammalian liver.
IGF-1 as GH Biosensor
Insulin-like Growth Factor 1 (IGF-1), primarily produced by the liver, serves as the plasma biosensor for growth hormone. Its levels provide a more stable, long-term indicator of GH activity compared to the rapidly fluctuating GH itself, forming a feedback loop for GH secretion.
Selective GH Resistance in Liver
A phenomenon observed during fasting or in certain genetic conditions (like Laron syndrome) where growth hormone levels may rise, but the liver becomes resistant to its signaling, leading to a significant drop in liver-derived IGF-1 production.
8 Questions Answered
Most heart attacks (99%) are caused by the rupture of an atherosclerotic plaque in a coronary artery, which exposes tissue factor and triggers the formation of a blood clot, completely blocking blood flow.
Stable angina is predictable chest pain with exertion, relieved by rest or medication, due to fixed arterial narrowing. ACS (including STEMI and NSTEMI) involves acute plaque rupture and clot formation, potentially leading to immediate heart muscle damage, with or without EKG changes.
STEMIs are medical emergencies where the patient is rushed to a cardiac catheterization lab (cath lab) to have the blocked artery opened, typically with a balloon and stent, as quickly as possible (within 60 minutes of arrival).
Clinical trials like COURAGE and ORBITA suggest that in patients with stable angina, stents primarily improve symptoms (like chest pain) and quality of life, but do not significantly reduce the risk of future heart attacks or death compared to optimized medical therapy.
A CAC score quantifies calcium in coronary arteries, indicating the presence and extent of atherosclerotic plaque. A zero score in older individuals is highly informative of low risk, while any score in younger individuals is highly informative of increased risk, guiding the aggressiveness of medical therapy.
Disrupting growth hormone signaling specifically in liver cells (e.g., by knocking out JAK2) leads to a profound increase in liver fat (NAFLD) and can paradoxically increase whole-body insulin sensitivity, primarily by turning off endogenous glucose production from the liver.
Excessive growth hormone signaling is linked to shortened lifespan and increased risk of diseases like cardiovascular disease and cancer. While GH can increase lean muscle mass and reduce fat, there is no evidence it promotes longevity, and it may even decrease it.
During fasting, growth hormone levels typically rise, but IGF-1 levels plummet due to selective growth hormone resistance in the liver. This suggests a complex interplay where GH may be directed to mobilize fat from peripheral tissues rather than promoting liver-derived growth factors.
15 Actionable Insights
1. Act Quickly for STEMI
If a patient presents with ST elevation on an EKG and symptoms of a heart attack (STEMI), activate the cath lab immediately, as the standard of care is to open the artery within an hour to save heart muscle and lives.
2. Prioritize Plavix for Stents
If you have a stent, ensure you take your prescribed blood-thinning medication like Plavix daily, especially in the initial months, as it is critical to prevent life-threatening stent thrombosis.
3. Manage Stable Angina Medically First
For stable angina, prioritize optimized medical therapy to manage symptoms before considering a stent. Stents are useful if medicines are ineffective or cause intolerable side effects, but they don’t typically extend life in stable angina.
4. Understand Growth Hormone Trade-offs
If considering growth hormone, understand that while it may improve lean muscle mass and fat mass for aesthetic or performance goals, there is no evidence it promotes longevity and may even decrease it.
5. Use Ketone Monitoring for Adherence
If following a ketogenic diet or fasting, utilize a ketone biomarker measurement (e.g., with a device like Keyto) as a real-time guide to reinforce behavioral changes and improve adherence, as scale weight is a lagging indicator.
6. Interpret Calcium Scores Contextually
For asymptomatic individuals, a coronary artery calcium (CAC) score is most informative in two scenarios: if you are young (under 45-50) and have any calcification, or if you are older (over 70) and have a score of zero, as these results can significantly guide the aggressiveness of medical therapy.
7. Consider Patient Anxiety for CTAs
When considering a CT angiogram (CTA) for asymptomatic patients, evaluate their psychological disposition. For anxious patients, seeing plaque on a CTA might cause significant distress and sleeplessness, which could outweigh the clinical benefit of the information.
8. Reconsider HeartFlow Utility
As a clinician, reconsider the routine ordering of HeartFlow analysis with CT angiograms for stable angina patients, as current data from trials like Orbita suggest it may not add significant value to management beyond the anatomical information from the CTA itself.
9. Embrace Evidence-Informed Medicine
Adopt an ’evidence-informed’ approach to medicine, recognizing that clinical trials provide data on averages, but individual patient decisions often require judgment and art, especially in areas like prevention where direct trial data may be lacking.
10. Cultivate Scientific Humility
Maintain scientific humility by acknowledging that ‘all facts have a half-life’ and scientific truth is constantly refined. Be open to being wrong and view unexpected results as opportunities for learning and discovery.
11. Prioritize Scientific Literacy
Recognize that understanding science and critical thinking is essential to avoid being ‘overrun with propaganda and nonsense.’ Actively seek to improve your scientific literacy, regardless of your profession.
12. Improve Science Communication
As scientists and educators, strive to communicate scientific concepts in an interesting and exciting way without oversimplifying, to engage a broader audience and foster scientific literacy.
13. Support Podcast for Exclusive Content
To access exclusive content like full show notes, downloadable transcripts, and participation in Ask Me Anything episodes, consider becoming a member and supporting the podcast directly.
14. Use Journal Club App for Trials
Physicians and those interested in clinical trials should download the ‘Journal Club’ app, which provides comprehensive summaries and details of clinical trials, serving as a valuable resource for staying informed.
15. Curate Science on Twitter
Utilize Twitter as a tool to curate scientific information and research from experts in adjacent fields, helping to stay updated on developments outside one’s immediate specialization.
6 Key Quotes
I only know success by the absence of failure.
Ethan Weiss
All facts have a half life.
Peter Attia
If you know the answer to the experiment before you do them, we don't need to, we don't need to experiment, just stop. We can write it up, right? What are we going to learn?
Ethan Weiss
If you're going to an island and you can only bring one thing with you for the first, you know, whatever it is, few months, all that matters is your Plavix. You've got to take it every day.
Ethan Weiss
The biggest risk factor for having a heart attack is your age. So age supersedes everything else.
Ethan Weiss
If you can't at least have some understanding of science and think critically, you are going to be overrun with propaganda and nonsense. And the consequence of that is enormous.
Peter Attia
1 Protocols
Emergency Treatment for ST-Elevation Myocardial Infarction (STEMI)
Ethan Weiss- Immediate recognition, often in the field by EMS.
- Activate the cardiac catheterization lab (cath lab) team.
- Administer heparin, aspirin, and clopidogrel (or similar antiplatelet drugs).
- Transport patient directly to the cath lab for primary angioplasty (balloon and stent placement) to open the blocked artery.