What is the Causal Benefit Model for cardiovascular risk?

The Causal Benefit Model measures ApoB or non-HDL cholesterol to project long-term risk (20-30 years), especially for younger individuals from age 30 to 60 or 65. This model provides a more meaningful number of risk (e.g., 30% chance of event) and calculates the benefit of early intervention versus the loss from delaying treatment.

What is ApoB and how does it relate to atherosclerosis?

ApoB (Apolipoprotein B) is a protein on the surface of atherogenic lipoprotein particles like LDL and VLDL. It is a critical driver of atherosclerosis because any cholesterol that enters the arterial wall and gets stuck there does so within an ApoB-bearing particle. Counting the number of ApoB particles is shown to be a more accurate index of risk than traditional cholesterol levels.

How does Remnant Type 3 Dyslipoproteinemia manifest and how is it diagnosed?

Remnant Type 3 Dyslipoproteinemia is a highly atherogenic condition where VLDL particles are not properly broken down, leading to high triglycerides and high cholesterol, but often a paradoxically low ApoB count. It is diagnosed using a specific formula based on total cholesterol, triglycerides, and ApoB, a method not widely available or utilized in standard lipid panels.

What is Mendelian Randomization and why is it important for understanding ApoB?

Mendelian Randomization is a genetic epidemiology technique that uses genetic variations as natural experiments to infer causal relationships between risk factors and disease outcomes. It's important for ApoB because studies using this method have strongly supported ApoB as a causal factor for cardiovascular disease, indicating it contains comprehensive information about risk.

Why is HDL cholesterol no longer considered a causal factor in cardiovascular disease?

While epidemiologically linked, Mendelian Randomization studies and clinical trials with CTP inhibitors have demonstrated that manipulating HDL levels does not change cardiovascular outcomes. This suggests that HDL is not causally involved in reducing the risk of atherosclerosis, unlike ApoB.

What is the speaker's alternative view on the pathophysiology of hypertension?

The speaker speculates that hypertension, especially systolic hypertension with normal diastolic pressures, might be more related to the loss of elastance in the proximal aorta as people age, rather than the mainstream view focusing on peripheral arteriolar tone or renal factors. This suggests a repetitive injury to the aorta over time.

How does the Coronary Artery Calcium (CAC) score fit into cardiovascular risk assessment?

A CAC score determines the presence of calcium in coronary arteries, indicating advanced atherosclerosis. While a positive score in younger individuals (under 50) is a major red flag, a positive score in older individuals (over 60) is less informative due to high prevalence. A negative score for a young person with high ApoB doesn't negate risk, as disease development can still be advanced without calcification.

What are the common criticisms of current medical guidelines regarding expert consensus?

Current guidelines are criticized for being overly reliant on unanimous consensus from small groups of experts, lacking diverse viewpoints, and being slow to incorporate new evidence. This process often 'dumbs down' information for clinicians and can lead to clinging to outdated views due to institutional inertia rather than purely scientific reasoning.

Why is early intervention crucial for preventing atherosclerosis, particularly with ApoB?

Early intervention, guided by metrics like ApoB, is crucial because atherosclerosis is a long-term disease. Starting early helps stop disease from developing in the first place, representing 'perfect prevention.' In contrast, waiting until later stages means attempting to modify existing, complex disease, which is 'partial prevention' and less effective due to the already destroyed arterial architecture.

Is ApoB a necessary and sufficient cause of atherosclerosis?

ApoB is considered a necessary but not sufficient driver of atherosclerosis. This means you must have ApoB particles trafficking lipids into the artery wall for atherosclerosis to occur. However, simply having ApoB particles doesn't guarantee disease, as other factors and individual variability play a role. For prevention, targeting a necessary factor like ApoB is more effective than treating a complex, multifactorial disease once it's established.

Key Moments

Cardiovascular disease & why we should change the way we assess risk | The Peter Attia Drive Podcast

Peter Attia MD

People & Blogs5 min read146 min video

Nov 29, 2021|302,394 views|5,080|702

heart disease heart disease prevention cardiovascular disease atherosclerosis ascvd risk ascvd

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Key Moments

TL;DR

Cardiovascular risk assessment needs a shift from 10-year models to ApoB measurements for better prevention. Coronary calcium scans have limitations.

Key Insights

Current 10-year cardiovascular risk calculators are fundamentally flawed, failing to predict premature disease effectively due to age bias and underestimation of risk in younger populations.

ApoB (Apolipoprotein B) particle number is a more accurate and direct measure of atherogenic risk than LDL cholesterol, as it quantifies the number of particles that can enter and damage arterial walls.

While coronary calcium scans can indicate advanced atherosclerosis, a negative scan does not rule out significant risk, especially in individuals with high ApoB levels, making it a limited tool for primary prevention decisions.

The traditional focus on cholesterol content within lipoproteins is less informative than particle number (ApoB), as the particle itself is the driver of arterial plaque formation.

Type 3 dyslipoproteinemia, a dangerous condition with high risk, can be missed if ApoB is not measured, highlighting the inadequacy of standard lipid panels for diagnosing certain atherogenic disorders.

The scientific and medical communities have been resistant to adopting ApoB as a primary risk marker, despite strong evidence, due to inertia, focus on consensus guidelines, and a reluctance to challenge established protocols.

THE FLAWED 10-YEAR RISK MODEL

The current standard for assessing cardiovascular disease (CVD) risk relies heavily on 10-year risk calculators. These algorithms, while a step forward historically, fundamentally underestimate risk, particularly for premature disease. They overly emphasize age and sex, contributing minimally to the actual calculation of risk. This approach often leads to under-treatment because it effectively delays prevention until individuals are in their late 50s or 60s, by which time atherosclerosis is already well-advanced. Half of all heart attacks and strokes occur before age 60, a statistic that highlights the critical deficiency in focusing solely on a 10-year outlook.

APOB: A SUPERIOR MARKER FOR ATHEROSCLEROSIS

Apolipoprotein B (ApoB) is a protein found on all atherogenic lipoprotein particles, including LDL and VLDL. The number of ApoB particles directly correlates with the number of particles that can enter the arterial wall, becoming trapped and initiating atherosclerosis. Unlike LDL cholesterol, which measures the cholesterol content within particles, ApoB quantifies the number of potentially harmful particles. Studies have shown that ApoB is a more precise and robust predictor of CVD events, offering a clearer picture of an individual's true risk than traditional lipid measures.

THE LIMITATIONS OF CORONARY ARTERY CALCIUM (CAC) SCORES

Coronary artery calcium (CAC) scoring, an imaging technique, can detect calcification in the coronary arteries, indicating advanced atherosclerosis. While a positive CAC score signals higher risk, its utility is diminished in older populations where calcification is common. Crucially, a negative CAC score does not eliminate risk, especially in individuals with high ApoB levels, as it only reflects calcified plaque and not the presence of non-calcified plaque or the ongoing process of atherogenesis. Relying solely on a negative CAC score can lead to a false sense of security and missed opportunities for intervention, particularly in younger individuals and those with other risk factors.

UNDERSTANDING LIPIDS AND PARTICLE SIZE

The conversation around lipids often centers on cholesterol levels, but the composition and number of lipoprotein particles are more critical. Total cholesterol measures the sum of cholesterol in various lipoproteins. Non-HDL cholesterol is a better indicator than LDL cholesterol because it includes cholesterol from all atherogenic particles (VLDL, IDL, LDL). However, ApoB remains superior as it directly measures the number of these particles. Differences in LDL particle size can also impact risk; smaller, denser LDL particles, associated with more numerous particles for the same cholesterol mass, confer higher risk because they more easily penetrate the arterial wall.

CHALLENGES IN DIAGNOSIS AND TREATMENT APPROACHES

Certain conditions, like Type 3 dyslipoproteinemia (remnant cholesterol disease), can be missed without ApoB measurement, leading to delayed or incorrect treatment. This highlights the gaps in current diagnostic protocols. Furthermore, the medical community's resistance to incorporating ApoB into guidelines, despite robust evidence, stems from adherence to established practices and a fear of complexity. The argument that ApoB is too costly or complicated is being dismantled, as its price is minimal and its interpretation is more straightforward than complex lipid panels when focusing on the core driver of atherosclerosis.

THE CAUSAL MODEL AND LONG-TERM PREVENTION

Shifting to a causal model of risk assessment, focusing on ApoB and extending the time horizon beyond 10 years (e.g., 30 years), offers a more effective strategy for preventing meaningful cardiovascular events. This approach accurately categorizes individuals into higher or lower risk groups based on fundamental drivers of disease, allowing for more personalized and impactful interventions. By focusing on stopping disease before it starts, rather than managing advanced disease, prevention becomes more successful and utilitarian. This long-term view, combined with accurate markers like ApoB, empowers both clinicians and patients to make informed decisions aligned with lifelong health goals.

THE RESISTANCE TO CHANGE IN MEDICAL GUIDELINES

Despite compelling scientific evidence, the reluctance of major medical organizations to fully embrace ApoB in guidelines is a significant hurdle in improving CVD prevention. This inertia is influenced by the publication process, guideline composition, and a tendency towards consensus that can stifle dissenting views. The emphasis on unanimous recommendations, often driven by a select group, can create dogma rather than fostering a dynamic scientific process. True scientific progress requires the open contention of ideas and the critical evaluation of evidence, which seems to be watered down in current guideline-setting practices, particularly when compared to the historical rigor of scientific debate.

IMPORTANCE OF EXPERIMENTAL EVIDENCE OVER CONSENSUS

The scientific method, driven by experimentation and the rigorous testing of hypotheses, should be the bedrock of medical practice. While consensus guidelines have their place, they should not become impervious to challenge or replace the critical assessment of individual studies. Mendelian randomization studies, for instance, provide strong causal evidence for ApoB's role and question the role of HDL, yet this is not fully reflected in current clinical approaches. Prioritizing the quality and interpretation of experimental data, rather than relying solely on committee-driven consensus, is crucial for advancing medical knowledge and improving patient outcomes.

Mentioned in This Episode

●Software & Apps

●Organizations

●Books

●Studies Cited

●Concepts

●People Referenced

Common Questions

The 10-year risk model is flawed because it primarily relies on age and sex, making risk appear low for younger individuals (under 55-60) even though half of all heart attacks and strokes occur before age 60. By the time the risk is high enough for intervention according to these guidelines, the disease is already well-advanced.

Topics

Risk Assessment Health & Longevity Neuroscience & the Brain Cardiovascular Disease Medicine & Clinical Atherosclerosis Prevention Lipid Management Medical Guidelines Coronary Artery Calcium

Mentioned in this video

People

Tom Dayspring

Mentioned as someone who has referenced Alan before on the show.

Herbert Stary

Author of a pathology textbook on atherosclerosis, which blew Peter's mind and influenced Alan's work.

George Stanislas

A colleague of Alan's at McGill University, who helped develop the causal benefit model.

Carol Panzina

A colleague from Harvard University who contributed to the causal benefit model.

George Davey Smith

Arguably one of the founders of Mendelian randomization, who has shown ApoB incorporates and beats triglycerides and LDL cholesterol for causal information.

Michael Pincina

A colleague from Duke University who collaborated on the causal benefit model.

John Wilkins

Co-author of a paper in JAW (likely Journal of the American Heart Association) discussed for its observations on starting treatment versus waiting for coronary calcium.

Kevin Jon Williams

A researcher from Philadelphia recognized for his work on understanding factors affecting the trapping of ApoB particles within the arterial wall.

Don Lloyd-Jones

Co-author from Northwestern University of a paper in JAW covering observations about early treatment for atherosclerosis.

Organizations

American College of Cardiology

Organization responsible for some of the risk algorithms for cardiovascular disease, which primarily consider 10-year risk.

AHA Multi-Society

Organization involved in cardiovascular disease risk assessment guidelines that focus on 10-year risk.

Books

JAMA Cardiology

A medical journal where a paper critiquing the 10-year risk approach for atherosclerosis was published.

Concepts

Familial hypercholesterolemia

A genetic disorder causing very high LDL-C, mentioned as a more challenging condition to treat compared to Type 3 dyslipoproteinemia, and one where genetic abnormality is believed to convey an even higher risk of heart disease.

atherosclerosis

A disease in the tissue that begins in the artery in the first three decades of life, with lesions developing in the fourth decade. The core cause is the sticking of ApoB particles within the arterial wall.

Remnant Hyperlipidemia

A highly atherogenic condition characterized by high triglycerides and high cholesterol but paradoxically low ApoB, due to impaired breakdown of VLDL particles. It is difficult to diagnose without ApoB measurement.

Software & Apps

ApoB App

An algorithm and app devised to diagnose atherogenic dyslipidemias based on total cholesterol, triglyceride, and ApoB levels.

Studies & Research

ODYSSEY trial

A clinical trial similar to the FOURIER trial, which likely showed a greater risk reduction due to patients starting at higher LDL-C levels.

Mendelian randomization

A genetic epidemiological method that uses genetic variants as instrumental variables to assess the causal effect of a modifiable exposure on disease outcome, allowing for closer inference to causality than traditional observational studies.

FOURIER trial

A clinical trial for the PCSK9 inhibitor Repatha, which showed a reduction in cardiac revascularization but no change in mortality over a five-year period in heavily statinized patients with very low LDL-C.

Drugs & Medications

CTP Inhibitors

A class of drugs that proved manipulating HDL cholesterol does not change cardiovascular outcomes, providing evidence that HDL is not causal.

Supplements

Statin

A type of medication used for prevention of cardiovascular disease, which works by lowering ApoB particle number. Its relationship with diabetes is not fully understood.