For years, a coronary artery calcium score of zero has been used as a powerful reassurance tool — effectively a "warranty" against near-term cardiovascular events. That reassurance may need an important asterisk for the roughly 20% of the population carrying elevated lipoprotein(a), a genetically determined cardiovascular risk factor that operates through mechanisms distinct from traditional cholesterol-driven atherosclerosis.
This multicohort analysis pooled data from four prospective U.S. cohort studies, yielding 11,319 participants without prior cardiovascular disease, followed for nearly 15 years with 1,569 incident ASCVD events — encompassing myocardial infarction, stroke, and coronary revascularization. Elevated Lp(a), defined as greater than 50 mg/dL, independently predicted ASCVD risk with a hazard ratio of 1.24, while a CAC score above zero carried a hazard ratio of 2.44. Critically, even among individuals with a CAC of zero — a group typically considered low-risk — those with elevated Lp(a) experienced higher event rates compared to those without it (4.9 versus 3.8 per 1,000 person-years, HR 1.28). Among those with detectable calcium, elevated Lp(a) amplified risk substantially, reaching a hazard ratio of 3.03.
The biological rationale is well-established but clinically underappreciated: Lp(a) preferentially promotes noncalcified, lipid-rich plaque — the kind that CAC imaging simply cannot detect. This finding reinforces a growing body of evidence suggesting that CAC scoring, while valuable, measures only one pathway to atherosclerotic disease. The study's strengths include its large pooled cohort, long follow-up, and sex diversity (54% women). Key limitations include its observational design, single Lp(a) measurement at baseline, and the fact that Lp(a) assay standardization varied across cohorts. With specific Lp(a)-lowering therapies in late-stage development, identifying which high-Lp(a) individuals remain underclassified by standard imaging tools is increasingly consequential. This is a confirmatory but clinically significant finding — one that may reshape how CAC zero results are communicated to patients with known Lp(a) elevation.