Varbo 2013: Remnant Cholesterol as a Causal Risk Factor for IHD

Background

Dr. Anette Varbo and colleagues from Copenhagen published this landmark Mendelian randomization study in the Journal of the American College of Cardiology (PMID: 23265341), establishing remnant cholesterol as a causal risk factor for ischemic heart disease.

Study Design

Design: Mendelian randomization study Population: 73,513 participants from Copenhagen General Population Study and Copenhagen City Heart Study Genetic instruments: Variants affecting remnant cholesterol levels Outcome: Ischemic heart disease

Key Findings

Observational association:

• •Each 1 mmol/L (39 mg/dL) increase in remnant-C → 2.8x increased IHD risk

Mendelian randomization (causal estimate):

Genetic Increment	IHD Risk
1 mmol/L remnant-C	HR 2.8 (1.9-4.2)

Comparison with LDL-C:

• •Both remnant-C and LDL-C causally associated with IHD
• •Remnant-C effect size similar or larger than LDL-C per mmol/L

Key insight: Mendelian randomization confirms causation—genetic elevation of remnant cholesterol directly causes heart disease, not just associates with it.

Mechanistic Insights

Remnant particles are directly atherogenic:

1. •Small enough to enter arterial wall (unlike large VLDL)
2. •Taken up by macrophages without requiring oxidation
3. •More cholesterol-rich than LDL (more cholesterol per particle)
4. •Pro-inflammatory

Clinical Implications

Remnant cholesterol is an underappreciated cardiovascular risk factor. LDL-C alone may underestimate risk when remnants are elevated (high TG states).

Metabolic Health Perspective

Remnant cholesterol (calculated as TC − LDL-C − HDL-C) provides actionable insight. It falls dramatically with carbohydrate restriction as triglycerides decrease. Target: <30 mg/dL.