Lipoprotein(a) and the Risk of Heart Failure: A Dose‐Response Meta‐Analysis

BACKGROUND: Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein implicated in cardiovascular disease, but its role in heart failure (HF) remains uncertain. Observational studies indicate a link between elevated Lp(a) and HF risk, but the dose-response relationship remains unexplored. This meta-analysis aimed to quantify the association between circulating Lp(a) levels and HF incidence. METHODS: A systematic search of PubMed, Embase, and Web of Science identified prospective cohort studies reporting hazard ratios (HRs) for HF incidence across different Lp(a) levels. A random-effects model was applied to pool effect estimates while accounting for heterogeneity, and restricted cubic splines assessed dose-response relationships. RESULTS: Five prospective cohort studies with 400 631 participants were included. During a mean follow-up duration of 11.0 years, 10 598 (2.6%) patients developed HF. A high Lp(a) level was associated with an increased HF risk (HR: 1.34, 95% CI: 1.14-1.59, p < 0.001), with moderate heterogeneity (I² = 69%). Subgroup analysis showed a stronger association in studies using an Lp(a) cutoff of ≥ 50 mg/dL (HR: 1.68) compared to those with a cutoff of < 50 mg/dL (HR: 1.16, p for subgroup difference < 0.01), which completely explained the heterogeneity. The dose-response analysis revealed a nonlinear association (p for non-linearity = 0.001). HF risk increased nearly linearly below 55 mg/dL, then slowed, and plateaued at 160 mg/dL. CONCLUSIONS: Elevated Lp(a) is associated with an increased HF risk in a nonlinear pattern, with risk escalation slowing at higher concentrations.