Body Mass Index, Clinical Outcomes, and Mortality in Heart Failure: A Mendelian Randomization Study
Recommended Citation
Sunderland N, Asselin G, Henry A, Nelson CP, Lemieux Perreault LP, Asselbergs FW, Boersma E, Cappola TP, Chazara O, Chutkow W, Cyr MC, Gkatzionis A, Gui H, Haefliger C, Hedman Å K, Hillege H, Hyde CL, Kamanu FK, Kardys I, Koekemoer AL, Kraus WE, Lang CC, Malarstig A, Margulies KB, Marston NA, Melloni GEM, Morley MP, O'Donoghue ML, Owens AT, Paul DS, Tilling K, van der Harst P, van Setten J, van Vugt M, Verweij N, Veluchamy A, Wallentin L, Wang X, Xing H, Yang Y, White HD, Zannad F, Smith JG, Brunner-La Rocca HP, Lanfear DE, Mann DL, de Denus S, Tardif JC, Voors AA, Samani NJ, Ellinor PT, Ruff CT, Sabatine MS, Sattar N, McMurray JJV, Paternoster L, Dubé MP, Lumbers RT. Body Mass Index, Clinical Outcomes, and Mortality in Heart Failure: A Mendelian Randomization Study. J Am Coll Cardiol. 2026;87(21):2981-2992.
Document Type
Article
Publication Date
6-2-2026
Publication Title
Journal of the American College of Cardiology
Keywords
Humans, Heart Failure, Mendelian Randomization Analysis, Body Mass Index, Genome-Wide Association Study, Female, Obesity, Male, Middle Aged, Stroke Volume, Aged
Abstract
BACKGROUND: Excess adiposity, most commonly indexed through body mass index (BMI), is strongly associated with the development of heart failure (HF). Weight loss therapies improve outcomes in patients with obesity and HF with preserved left ventricular ejection fraction (LVEF), but their effects in HF with reduced LVEF remain unclear. OBJECTIVES: The aim of this work is to determine whether higher BMI is associated with adverse clinical outcomes in patients with HF and whether there is effect modification by LVEF subgroup. METHODS: Two-sample Mendelian randomization (MR) was used, with genome-wide significant loci associated with BMI as instrumental variables and outcome data from a genome-wide association study (GWAS) of time-to-event clinical outcomes in patients with HF. A total of 50,636 individuals of European ancestry with established HF from 22 cohorts were included in the genetic analysis: 12 HF trials, 1 prospective case-cohort study, 9 cohorts nested within non-HF cardiovascular trials, and 1 population-based cohort derived from the UK Biobank. The exposure was genetically predicted BMI and the outcome measures were all-cause mortality and a composite of cardiovascular mortality or HF hospitalization. Genetic associations for the outcomes were derived from our GWAS and MR was used to estimate the unbiased association of genetically predicted BMI with these clinical outcomes. RESULTS: The mean BMI was 29.2 ± 5.8 kg/m(2). 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 both all-cause mortality (HR per SD [4.8 BMI units] 1.21; 95% 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 consistent across LVEF ≤40% and >40%: for all-cause mortality, HR: 1.16 (95% CI: 0.99-1.37) and 1.20 (95% CI: 0.94-1.53); and for the composite outcome, HR: 1.30 (95% CI: 1.15-1.48) and 1.57 (95% CI: 1.29-1.91), respectively. CONCLUSIONS: Among patients with HF, higher BMI was associated with increased all-cause mortality and cardiovascular death or HF hospitalization, supporting the potential role of weight-management strategies across the ejection fraction spectrum.
Medical Subject Headings
Humans; Heart Failure; Mendelian Randomization Analysis; Body Mass Index; Genome-Wide Association Study; Female; Obesity; Male; Middle Aged; Stroke Volume; Aged
PubMed ID
42017882
ePublication
ePub ahead of print
Volume
87
Issue
21
First Page
2981
Last Page
2992
