Varbo 2016: Remnant Cholesterol, Inflammation, and IHD

Background

Dr. Anette Varbo and colleagues published this follow-up study in Circulation (PMID: 27784698), demonstrating that remnant cholesterol causes both low-grade inflammation and ischemic heart disease through Mendelian randomization.

Study Design

Design: Mendelian randomization study Population: Copenhagen cohorts (>100,000 participants) Genetic instruments: Variants affecting remnant cholesterol Outcomes: CRP levels and ischemic heart disease Analysis: Two-stage Mendelian randomization

Key Findings

Remnant cholesterol → Inflammation:

Genetic Increment	CRP Change
1 mmol/L remnant-C	+37% higher CRP

Remnant cholesterol → IHD:

Genetic Increment	IHD Risk
1 mmol/L remnant-C	HR 1.7 (causal)

Mediation analysis:

• •Part of remnant-C effect on IHD is mediated by inflammation
• •But remnant-C also directly causes atherosclerosis

Key insight: This study established two pathways—remnant cholesterol causes heart disease both through inflammation AND through direct atherogenic effects.

Mechanistic Insights

Remnant particles promote inflammation by:

1. •Activating endothelium
2. •Stimulating cytokine release
3. •Promoting macrophage foam cell formation
4. •Contributing to plaque instability

This explains why CRP is elevated with hypertriglyceridemia.

Clinical Implications

Lowering remnant cholesterol may reduce both inflammation and atherosclerosis. Triglyceride reduction addresses this pathway. CRP improvement may partly reflect remnant reduction.

Metabolic Health Perspective

This study mechanistically explains why TG reduction (through carbohydrate restriction) improves both inflammatory markers and cardiovascular risk—it's mediated partly through remnant cholesterol lowering.