Body Mass Index, Clinical Outcomes, and Mortality in Heart Failure: A Mendelian Randomization Study

Background

Excess body fat, commonly measured by body mass index (BMI), is a known risk factor for developing heart failure (HF). Treatments focused on weight loss improve outcomes in patients who have heart failure with preserved left ventricular ejection fraction (LVEF). However, it remains unclear if similar benefits extend to those with heart failure characterized by reduced ejection fraction.

Objectives

This study aims to clarify whether a higher BMI contributes causally to worse clinical outcomes in heart failure patients and to assess if this relationship differs based on whether patients have reduced or preserved LVEF.

Methods

The researchers employed a two-sample Mendelian randomization approach. This methodology uses genetic variants known to be decisively linked to BMI as instruments to assess causality, reducing confounding and reverse causation biases common in observational studies.

The genetic data came from 50,636 individuals of European ancestry with established heart failure across 22 cohorts. These included 12 HF clinical trials, a prospective case-cohort study, nine cohorts nested within cardiovascular trials unrelated to HF, and one population cohort from the UK Biobank.

The exposure variable was genetically predicted BMI, while clinical outcomes included all-cause mortality and a composite endpoint of cardiovascular death or hospitalization due to heart failure. Outcome genetic associations were derived from a genome-wide association study (GWAS) focused on time-to-event clinical outcomes in HF patients.

Results

The average BMI among participants was 29.2 kg/m2 (±5.8). Over a median follow-up period of 27 months, 23% of patients died from any cause, and 22% reached the composite endpoint.

The study found that genetically increased BMI was significantly associated with higher rates of both all-cause mortality (Hazard Ratio [HR] per standard deviation increase in BMI: 1.21; 95% Confidence Interval [CI]: 1.13–1.29; P=9 × 10-8) and the composite endpoint (HR: 1.29; 95% CI: 1.20–1.38; P=8 × 10-13).

This association held consistent regardless of whether the patient’s LVEF was ≤40% or >40%. Specifically, for all-cause mortality, HR was 1.16 (95% CI: 0.99–1.37) in reduced LVEF and 1.20 (95% CI: 0.94–1.53) in preserved LVEF groups. For the composite outcome, HRs were 1.30 (95% CI: 1.15–1.48) and 1.57 (95% CI: 1.29–1.91), respectively.

Conclusions

The findings affirm that in heart failure patients, a higher genetically determined BMI elevates the risk of all-cause mortality and cardiovascular events, including heart failure hospitalization. This risk is present across the spectrum of ejection fraction categories.

These data support the clinical importance of weight management strategies in heart failure care, regardless of whether patients have preserved or reduced LVEF. Considering that heart failure patients often experience complex challenges in maintaining a healthy weight, integrating personalized weight management interventions could improve survival and reduce hospital admissions.

Clinical Implications

This study highlights the causal role of adiposity in worsening heart failure outcomes. Weight loss interventions, including lifestyle modification, pharmacotherapy for obesity, and where appropriate, bariatric surgery, may confer benefits across different heart failure phenotypes.

Providers should consider incorporating BMI management as a fundamental part of holistic heart failure care. Further randomized controlled trials are necessary to determine the most effective weight loss strategies tailored for HF patients with varying ejection fractions.

Study Strengths and Limitations

The Mendelian randomization design provides robust evidence minimizing confounding factors that typically influence observational studies. Inclusion of a large, diverse cohort strengthens the generalizability of results among European ancestry populations.

Limitations include the study’s restriction to individuals of European descent, which may limit applicability to other ethnic groups. Additionally, the median follow-up of just over two years might not capture long-term effects of BMI on heart failure outcomes.

Future Directions

Expanding research to multi-ethnic cohorts and longer follow-up periods could deepen understanding of BMI’s influence on heart failure globally. Investigations into biological mechanisms linking adiposity to heart failure progression and mortality will help tailor targeted therapies.

References

Sunderland N, Asselin G, Henry A, et al. Body Mass Index, Clinical Outcomes, and Mortality in Heart Failure: A Mendelian Randomization Study. J Am Coll Cardiol. 2026;87(21):2981-2992. PMID: 42017882.