Lipoprotein(a) Elevation and Incident Heart Failure Risk: A Systematic Meta-Analysis

Background: Lipoprotein(a) [Lp(a)] is an established risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease, yet its relationship with incident heart failure (HF) has not been quantitatively synthesised. Methods: We searched MEDLINE and EMBASE through January 2025 for prospective cohort studies enrolling adults free of HF at baseline who had adjudicated incident HF. Four analyses met inclusion criteria: the Copenhagen City Heart and General Population Studies (n=98,097), ARIC (n=14,154), a pooled ARIC-MESA-Framingham Offspring analysis (n=16,771), and UK Biobank (n=299,158). Multivariable-adjusted hazard ratios comparing higher versus lower Lp(a) were pooled using inverse-variance random-effects models. Results: Across 428,180 participants and 14,988 incident HF events, all cohorts demonstrated a positive association between elevated Lp(a) and HF. Pooled HR was 1.26 (95% CI 1.18-1.34; I 2 ≈31%). Among White participants with Lp(a) ≥50 mg/dL, risk was elevated for both HFpEF (HR 1.32; 1.08-1.59) and HFrEF (HR 1.33; 1.05-1.67), but no significant association was observed in Black participants (HR 0.93; 0.78-1.11). Attenuation after MI exclusion in ARIC (HR 1.07; 0.91-1.27) supports mediation through atherosclerotic and valvular pathways. Conclusions: Elevated Lp(a) is a reproducible predictor of incident HF across diverse prospective cohorts. These findings support Lp(a) measurement for HF risk stratification and highlight the need for Lp(a)-lowering trials with HF as a pre-specified endpoint.