Lipoprotein(a) and Incident Aortic Stenosis Over 30 Years: The ARIC Study

Elevated lipoprotein(a) [Lp(a)] is a genetically determined, causal risk factor for calcific aortic valve disease and is believed to promote calcification through an oxidized phospholipid-mediated pathway. 1 Mendelian randomization and prospective studies, predominantly in White European populations, have definitively established that Lp(a) concentrations above 50mg/dL are associated with aortic stenosis (AS). 2 Long-term data from racially diverse cohorts, however, are lacking, and the competing risk of death has not been fully addressed.Using 30-years of follow-up in the Atherosclerosis Risk in Communities (ARIC) cohort, we examined the association of midlife Lp(a) levels with incident clinical AS, accounting for the competing risk of death.We also assessed whether Lp(a) associations differ by race and sex.ARIC enrolled 15,792 self-reported Black and White adults at visit 1 (1987-1989; age:45-64 years) from 4-US communities.De-identified data from 14,423 participants with a baseline Lp(a) measurement and complete covariates were downloaded from BioLINCC.Lp(a) levels at visit 1 were measured with an immunoassay (kringle-IV type-2 repeatsensitive) that quantified apolipoprotein(a) protein mass and expressed as total particle mass.Lp(a) was modeled continuously (per-SD of the log-transformed and with restricted cubic splines using 4-knots at Harrell percentiles) or at prespecified thresholds.Incident AS was defined as an AS or aortic valve replacement ascertained through active surveillance for hospitalizations with abstraction of all hospitalization ICD discharge codes through 2019.Fine-Gray regression was used to assess associations of Lp(a) with incident AS accounting for the competing risk of death.Cox-regression was used for mortality.Covariates included age, sex, race, systolic blood pressure, diabetes, antihypertensive medication, body mass index, HDL-cholesterol, log-triglycerides, LDL-cholesterol, statin treatment, and cigarette smoking.Population attributable fraction(PAF) estimated by model-based standardization (g-formula) on the absolute-risk scale at 25-years.The analysis was performed using R software (version 4.4.3)using cmprsk (functions crr, cuminc), survival (function coxph) and rms packages (function rcs).