Excess adiposity, typically measured using body mass index (BMI), is strongly associated with the development of heart failure (HF), although its impact on outcomes across left ventricular ejection fraction (LVEF) subgroups remains uncertain.

A two-sample Mendelian randomization (MR) analysis published in the Journal of the American College of Cardiology evaluated the association between genetically predicted BMI and clinical outcomes in patients with established HF. The study included 50,636 individuals of European ancestry from 22 cohorts, comprising HF clinical trials, a prospective case-cohort study, cohorts nested within cardiovascular trials, and a population-based cohort from the UK Biobank.

Genome-wide significant loci associated with BMI were used as instrumental variables. Outcomes included all-cause mortality and a composite of cardiovascular (CV) mortality or HF hospitalization, derived from a genome-wide association study (GWAS) of time-to-event outcomes.

The mean BMI in the cohort was 29.2 ± 5.8 kg/m². Over a median follow-up of 27.0 months, all-cause mortality occurred in 11,454 patients (23%), and 11,360 participants (22%) experienced the composite endpoint.

Genetically predicted BMI was associated with an increased rate of all-cause mortality (hazard ratio [HR] per standard deviation [SD, 4.8 BMI units] increase 1.21; 95% confidence interval [CI] 1.13-1.29; p=9×10⁻⁸) and the composite outcome (HR 1.29; 95% CI 1.20-1.38; p=8×10⁻¹³). Associations were directionally similar across LVEF subgroups (≤40% and >40%) for both endpoints.

Higher genetically predicted BMI was associated with adverse clinical outcomes in HF. Associations were directionally similar across LVEF strata.