Cholesterol-Year Score and Severity of Calcific Atherosclerosis in Homozygous Familial Hypercholesterolemia

This small observational study examined the relationship between cholesterol-year score — a cumulative lifetime LDL-C exposure measure calculated as LDL-C × years — and the severity of calcific coronary atherosclerosis and extravascular tissue lipid deposition in 17 patients with homozygous familial hypercholesterolemia (HoFH).

Cholesterol-year score strongly correlated with both coronary artery calcium burden and Achilles tendon xanthoma size, providing early evidence that cumulative LDL-C exposure — rather than cross-sectional LDL-C level alone — determines the degree of atherosclerotic and ectopic lipid accumulation.

The cholesterol-year concept is important because it aligns with the mechanistic understanding of atherosclerosis as a cumulative process: arterial damage accumulates proportionally to both the concentration of atherogenic particles and the duration of exposure. HoFH patients, with LDL-C often exceeding 500 mg/dL from birth without treatment, represent an extreme natural experiment confirming this relationship.

For clinical practice, the concept supports starting lipid-lowering therapy as early as possible — minimizing the cholesterol-year accumulation that drives plaque formation over decades. Mendelian randomization studies have since confirmed this principle: lifelong exposure to lower LDL-C through genetic variants confers proportionally greater cardiovascular protection than equivalent LDL-C reductions achieved pharmacologically in midlife.

We rate the evidence limited. A small observational study in an extreme phenotype establishing the cholesterol-year concept — foundational for understanding cumulative LDL-C exposure as the mechanistic driver of atherosclerosis severity.