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Background: High lipoprotein(a) (Lp[a]) associates with elevated coronary heart disease event risk, but it remains uncertain whether this excess risk can be explained by increased coronary plaque burden.

Objectives: This study aims to determine whether Lp(a)-related excess cardiovascular risk in the general population is primarily explained by increased coronary atherosclerosis or by additional plaque vulnerability–related effects.

Methods: This study included 28,529 middle-aged individuals from the SCAPIS (Swedish CArdioPulmonary bioImage Study), a population-based cohort. Coronary atherosclerosis was assessed using coronary computed tomography angiography in 25,916 participants. Incident coronary events, defined as fatal or nonfatal myocardial infarction, were ascertained over a median follow-up of 7.8 years.

Results: High Lp(a) was present in 14% of participants and associated with severe/extensive coronary atherosclerosis (Segment Involvement Score >4; OR: 1.38; 95% CI: 1.21-1.57) and coronary events (HR: 1.54; 95% CI: 1.18-2.0). Stratified, adjusted, and mediation analyses consistently suggested that the association between Lp(a) and coronary event risk is largely explained by greater atherosclerotic burden (P for mediation <0.0001). Individuals with high Lp(a) developed atherosclerosis 2 to 3 years earlier and the population-attributable fraction of Lp(a) was 5% to 10% for severe atherosclerosis and around 7% for coronary events.

Conclusion: The findings suggest that Lp(a) increases coronary event risk primarily by driving a higher burden of atherosclerosis and that high Lp(a) accounts for 5% to 10% of total coronary disease burden in the population. These results support broad Lp(a) measurements and the use of coronary imaging for risk stratification in individuals with high Lp(a).