Background: Lipoprotein(a) Lp(a) has been implicated in the pathogenesis of calcific aortic valve disease through pro-inflammatory and pro-calcific mechanisms. However, large-scale population data assessing its impact on incident aortic stenosis (AS), particularly independent of low-density lipoprotein cholesterol (LDL-C), remains limited. Clarifying this relationship is increasingly relevant as Lp(a)-lowering therapies emerge. Methods: We used the TriNetX U.S. Collaborative Network (2015–2025; 71 health systems) to identify adults aged 18–75 with measured Lp(a). Patients were divided into two cohorts based on Lp(a) level: elevated (≥50 mg/dL or ≥125 nmol/L) and non-elevated (≤49 mg/dL or ≤124 nmol/L). Individuals with prior aortic valve disease or procedures (aortic stenosis, bicuspid or congenital valve, rheumatic disease, endocarditis, prosthetic valve, or prior AVR/TAVR) were excluded. We used 1:1 greedy nearest-neighbor propensity-score matching to balance baseline characteristics by age, sex, race, and ethnicity. Matched analyses evaluated the risk of incident non-rheumatic aortic stenosis (ICD-10 I35.0). Aortic stenosis with insufficiency (I35.2) served as a secondary outcome. A sensitivity analysis restricted to individuals with LDL-C ≤70 mg/dL examined residual risk beyond LDL-C. Results: Among 84,138 matched patients (42,069 per group), incident AS occurred in 0.9% of those with elevated Lp(a) versus 0.7% with non-elevated Lp(a) (risk ratio RR 1.33, 95% CI 1.14–1.55; p < 0.001). Aortic stenosis with insufficiency showed a similar but non-significant association (RR 1.35, 95% CI 0.97–1.87; p = 0.07). In the LDL-restricted cohort (n = 30,098; 15,049 per group), the association with incident AS remained statistically significant (1.5% vs 1.2%; RR 1.28, 95% CI 1.05–1.55; p = 0.014), indicating residual risk independent of LDL-C. Conclusions: Elevated Lp(a) was independently associated with a higher risk of incident AS, and this relationship persisted even among individuals with optimal LDL-C levels. These findings support Lp(a) as an independent risk pathway in calcific aortic valve disease and emphasize the potential clinical impact of emerging Lp(a)-lowering therapies.
Maymi-Quintana et al. (Tue,) studied this question.
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