#185 - Allan Sniderman, M.D.: Cardiovascular disease and why we should change the way we assess risk
Dr. Allan Sniderman, Professor of Cardiology and Medicine at McGill University, discusses the limitations of current CVD risk assessment models, advocating for ApoB as a superior metric. He highlights the flaws in 10-year risk approaches and the hindrance of scientific advancement by consensus over critical thinking.
Deep Dive Analysis
17 Topic Outline
Critique of Current 10-Year Cardiovascular Risk Assessment
Early Atherosclerosis Development and Prevention Strategy Flaws
Cholesterol, ApoB, and Plasma Lipoproteins Explained
Particle Number vs. Cholesterol Mass in Atherogenic Risk
Historical Context of ApoB and Lipid Measurement
Limitations of Calculated LDL and Triglyceride Interpretation
Understanding Remnant Type 3 Dyslipoproteinemia
Mendelian Randomization Bolsters ApoB's Causal Role
Hypertension's Role in Atherosclerosis and Proximal Aorta Stiffness
Factors Influencing Preventative Intervention Decisions
Coronary Artery Calcium (CAC) Score: Utility and Limitations
Challenges in Motivating Early Interventions for CVD
Medical Advancement Hindered by Consensus and Unanimity
Complex Topics with Differing Interpretations: PCSK9 and FH
Defining Risk and Uncertainty in Medical Guidelines
The Crucial Weakness of Unanimous Consensus in Science
Advantages of a 30-Year Causal Risk Assessment Model
7 Key Concepts
ApoB
ApoB is a protein that provides structural integrity to atherogenic lipoprotein particles like VLDL and LDL. Any cholesterol that enters the arterial wall does so within an ApoB-bearing particle, making the number of these particles a more accurate index of atherogenic risk than cholesterol mass alone.
Non-HDL Cholesterol
Non-HDL cholesterol represents the total mass of cholesterol contained within VLDL and LDL particles. While it is a better metric than LDL cholesterol, it is still considered inferior to ApoB because it measures cholesterol mass rather than the actual number of atherogenic particles.
10-Year Risk Assessment
This is a common method for selecting patients for statin prevention based on their predicted risk of a cardiovascular event within 10 years. However, it is fundamentally flawed for preventing premature disease because it is heavily driven by age and sex, often delaying intervention until disease is well advanced.
Mendelian Randomization
A research method that uses genetic variants (fixed at birth) as proxies for specific risk factors to infer causal relationships between those factors and disease outcomes. This approach helps overcome confounding issues inherent in traditional observational studies, strongly supporting ApoB's causal role in atherosclerosis.
Remnant Type 3 Dyslipoproteinemia
A specific, highly atherogenic condition characterized by high triglycerides, high cholesterol, but paradoxically low ApoB. This occurs because VLDL particles are not properly broken down into LDL, leading to the circulation of large, cholesterol-rich VLDL remnants that are highly dangerous.
Causal Benefit Model
An alternative to the 10-year risk assessment, this model projects cardiovascular risk over 20 or 30 years based on causal factors like ApoB levels. It aims to provide more meaningful risk numbers for individuals and calculate the benefits of early intervention versus delayed treatment.
Coronary Artery Calcium (CAC) Score
A non-invasive imaging technique that detects calcium deposits in the coronary arteries, indicating advanced atherosclerosis. While a positive score is a strong predictor of increased risk, a zero score in younger individuals with high ApoB does not necessarily rule out developing disease.
7 Questions Answered
The 10-year risk assessment is flawed because it heavily relies on age and sex, making risk appear low for younger individuals (under 55-60) even as atherosclerosis develops. This delays prevention until the disease is well advanced, missing nearly half of all infarcts and strokes that occur before age 60.
Cholesterol mass measures the amount of cholesterol in lipoproteins, while ApoB measures the actual number of atherogenic particles. Since cholesterol enters the arterial wall only within ApoB-bearing particles, the number of particles is a more accurate indicator of atherogenic risk.
Mendelian randomization uses genetic variations, which are fixed at birth, to establish causal links between risk factors and disease. Studies using this method have shown that ApoB causally relates to CVD risk and incorporates all the information found in triglycerides, LDL cholesterol, and even HDL cholesterol.
It's a highly atherogenic condition where VLDL particles fail to break down into LDL, leading to high triglycerides and cholesterol but low ApoB. Without measuring ApoB, this specific phenotype cannot be diagnosed, preventing appropriate and effective treatment.
A negative CAC score, especially in younger individuals with high ApoB, does not mean the absence of disease or risk. Calcification is a feature of *advanced* atherosclerosis, and while a zero score might indicate a lower 10-year event risk, the disease can still be developing and progressing.
Consensus-driven guidelines can suppress legitimate dissenting views and critical discussion, which are essential for scientific progress. This can lead to conventional views persisting longer than they should, preventing the adoption of newer, more accurate evidence and potentially leading to suboptimal patient care.
A 30-year model provides a more meaningful time horizon for patients, especially younger ones, allowing for earlier intervention based on causal factors like ApoB. It can present higher, more understandable risk numbers (e.g., 30% chance over 30 years) and quantify the benefits of starting prevention early versus delaying.
14 Actionable Insights
1. Measure ApoB for Atherosclerosis Risk
Measure ApoB levels as it is a superior metric for predicting atherosclerosis risk compared to LDL cholesterol and non-HDL cholesterol, providing a more accurate count of atherogenic particles.
2. Target ApoB in Lipid-Lowering Therapy
Use ApoB as the primary target for lipid-lowering therapy, as its reduction directly correlates with fewer atherogenic particles entering the arterial wall, which is the fundamental cause of atherosclerosis.
3. Assess Long-Term Cardiovascular Risk
Evaluate cardiovascular risk over a 20-30 year horizon, especially for individuals in their 30s and 40s, to make prevention decisions more meaningful and capture premature disease risk that 10-year models miss.
4. Intervene Early for High-Risk Individuals
Identify and consider early intervention for the approximately 20% of the population at evident high risk (e.g., high ApoB levels) to prevent disease development rather than just modifying existing disease later in life.
5. Measure LP(a) for Enhanced Risk Assessment
Measure LP(a) (lipoprotein(a)) once for additional risk assessment, particularly when combined with high ApoB, as it can indicate a ‘double whammy’ of increased atherogenic risk.
6. Diagnose Type 3 Dyslipoproteinemia with ApoB
Measure ApoB along with total cholesterol and triglycerides to diagnose Type 3 dyslipoproteinemia, a highly atherogenic condition that cannot be identified without ApoB measurement.
7. Treat Type 3 Dyslipoproteinemia Effectively
Treat Type 3 dyslipoproteinemia, once diagnosed, with statins and/or fibrates, as patients typically respond very well to these therapies.
8. Utilize the ApoB App for Diagnosis
Use the ApoB app (www.apoBapp) by plugging in total cholesterol, triglycerides, and ApoB values to aid in the diagnosis of atherogenic ApoB dyslipoproteinemias.
9. Consider CAC for Young, Undecided Patients
Consider a Coronary Artery Calcium (CAC) score for younger patients (under 60) who are on the cusp of treatment decisions or need more information, as a positive score can be extremely helpful in motivating intervention.
10. Don’t Delay Treatment on Negative CAC
Do not use a negative Coronary Artery Calcium (CAC) score to delay treatment decisions for individuals with high ApoB or other vascular disease causes, as calcification is a feature of advanced disease and its absence doesn’t rule out developing atherosclerosis.
11. Monitor Therapy with ApoB Levels
Monitor the effectiveness and adherence to lipid-lowering therapy by tracking ApoB levels, as a significant reduction indicates the medication is working to lower atherogenic particles.
12. Understand Atherosclerosis Natural History
Gain a deep understanding of the natural history of atherosclerosis, recognizing that the disease begins in the first three decades of life, to construct effective long-term prevention strategies.
13. Be Aware of Statin Risks
Be aware that while statin therapy is highly effective, it is not without cost, and the full relationship between statins and conditions like diabetes is not yet completely understood.
14. Access In-Depth Health Content
Consider joining a membership program, such as the one offered by The Drive podcast, to access more in-depth and exclusive content to elevate your knowledge in health and wellness.
7 Key Quotes
Atherosclerosis, it's a disease in the tissue. And almost everything that lipid people talk about is in plasma.
Alan Sniderman
When we say people should be treated with a risk above 7.5%, that means 92.5% of the time, nothing will happen. Well, that's not a great incentive, I think, for helping people understand what's truly going to happen.
Alan Sniderman
Any cholesterol in the artery only got there within an ApoV particle. It doesn't just float in. It gets there within an ApoV particle, either VLD or LDL, that gets into the arterial wall and gets stuck there. And that's the cause of atherosclerosis.
Alan Sniderman
You cannot characterize any phenotype without the APOB.
Alan Sniderman
Science is a democratic activity where legitimate, contending legitimate views have equal, differing views that are legitimate have a chance to contend.
Alan Sniderman
Any process that has unanimous recommendations has a weakness.
Alan Sniderman
To quit is wrong. Part of this is for yourself just to see, can you understand what looks like chaos? Is there any pattern to what looks like there's no pattern?
Alan Sniderman