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Body Mass Index, Clinical Outcomes, and Mortality in Heart Failure: A Mendelian Randomization Study
Nicholas Sunderland1, Geraldine Asselin2, Albert Henry3
1MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom; NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, United Kingdom.
Insights
Higher body mass index (BMI) is linked to increased mortality and hospitalizations in heart failure (HF) patients. These findings suggest weight management may benefit all HF patients, regardless of ejection fraction.
Area of Science:
- Cardiology
- Genetics
- Obesity Research
Background:
- Excess adiposity, measured by body mass index (BMI), is a known risk factor for heart failure (HF).
- While weight loss improves outcomes in HF with preserved ejection fraction (HFpEF), its impact on HF with reduced ejection fraction (HFrEF) is less understood.
Purpose of the Study:
- To investigate the association between higher BMI and adverse clinical outcomes in patients with HF.
- To determine if left ventricular ejection fraction (LVEF) modifies the relationship between BMI and HF outcomes.
Main Methods:
- Utilized two-sample Mendelian randomization (MR) with genome-wide association study (GWAS) data from 50,636 European ancestry individuals across 22 cohorts.
- Employed genetically predicted BMI as instrumental variables to assess unbiased associations with all-cause mortality and a composite of cardiovascular death or HF hospitalization.
Main Results:
- Genetically predicted higher BMI was significantly associated with increased all-cause mortality (HR 1.21 per SD) and the composite outcome (HR 1.29 per SD).
- These associations remained consistent across subgroups with LVEF ≤40% and >40%, indicating no significant effect modification by LVEF.
Conclusions:
- Elevated BMI is associated with poorer clinical outcomes, including mortality and cardiovascular events, in patients with heart failure.
- Findings support the consideration of weight management interventions for patients with HF across the full spectrum of LVEF.
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/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.
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.
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