| Title: | Body Mass Index, Clinical Outcomes, and Mortality in Heart Failure A Mendelian Randomization Study |
| Journal: | Journal of the American College of Cardiology |
| Published: | 13 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42017882/ |
| DOI: | https://doi.org/10.1016/j.jacc.2026.02.5093 |
Publication 18012
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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.</p>
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.</p>
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.</p>
RESULTS: The mean BMI 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 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.</p>
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.</p>
58 Authors
- Nicholas Sunderland
- Geraldine Asselin
- Albert Henry
- Christopher P Nelson
- Louis-Philippe Lemieux Perreault
- Folkert W Asselbergs
- Eric Boersma
- Thomas P Cappola
- Olympe Chazara
- William Chutkow
- Marie-Christyne Cyr
- Apostolos Gkatzionis
- Hongsheng Gui
- Carolina Haefliger
- Åsa K Hedman
- Hans Hillege
- Craig L Hyde
- Frederick K Kamanu
- Isabella Kardys
- Andrea L Koekemoer
- William E Kraus
- Chim C Lang
- Anders Malarstig
- Kenneth B Margulies
- Nicholas A Marston
- Giorgio E M Melloni
- Michael P Morley
- Michelle L O'Donoghue
- Anjali T Owens
- Dirk S Paul
- Kate Tilling
- Pim van der Harst
- Jessica van Setten
- Marion van Vugt
- Niek Verweij
- Abirami Veluchamy
- Lars Wallentin
- Xiaosong Wang
- Heming Xing
- Yifan Yang
- Harvey D White
- Faiez Zannad
- J Gustav Smith
- Hans-Peter Brunner-La Rocca
- David E Lanfear
- Douglas L Mann
- Simon de Denus
- Jean-Claude Tardif
- Adriaan A Voors
- Nilesh J Samani
- Patrick T Ellinor
- Christian T Ruff
- Marc S Sabatine
- Naveed Sattar
- John J V McMurray
- Lavinia Paternoster
- Marie-Pierre Dubé
- R Thomas Lumbers
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