Highlight
- Genetically predicted higher BMI is associated with increased all-cause mortality in heart failure patients.
- The risk elevation is consistent across heart failure with reduced and preserved ejection fraction.
- Findings support the role of weight management strategies in improving clinical outcomes for heart failure patients.
- Mendelian randomization provides an unbiased estimate by using genetic variants as proxies for BMI.
Study Background
Heart failure (HF) remains a major cause of morbidity and mortality worldwide, with complex etiologies including metabolic and cardiovascular risk factors. Obesity, commonly assessed by body mass index (BMI), is a well-established risk factor for incident HF. Despite this, the relationship between BMI and outcomes once HF is established remains controversial. Observational studies have paradoxically suggested an “obesity paradox,” where higher BMI may confer a survival advantage in HF, particularly in those with reduced left ventricular ejection fraction (LVEF). However, such associations are prone to confounding and reverse causation. Weight loss therapies have shown benefits primarily in HF with preserved LVEF, but their applicability and impact on HF with reduced LVEF are unclear. This study aims to clarify the causative role of BMI on clinical outcomes in HF across LVEF subgroups using Mendelian randomization (MR), which leverages genetic variants as proxies to minimize confounding biases.
Study Design
This two-sample Mendelian randomization study included 50,636 individuals of European ancestry with established HF, pooled from 22 cohorts comprising clinical trials, observational studies, and population-based cohorts (including UK Biobank). The exposure was genetically predicted BMI, based on genome-wide significant loci identified in large-scale genetic studies. Outcomes assessed included all-cause mortality and a composite endpoint of cardiovascular mortality or HF hospitalization. GWAS summary statistics for clinical outcomes were derived from time-to-event analyses within these HF populations. The study stratified analyses by LVEF subgroups (≤40% vs. >40%) to evaluate effect modification.
Key Findings
The cohort’s mean BMI was 29.2 kg/m2, reflecting an overweight population with a median follow-up of over two years. During follow-up, 23% died, and 22% reached the composite endpoint.
Mendelian randomization analysis showed that each 4.8-unit increment in genetically predicted BMI (1 standard deviation) was associated with a 21% higher hazard of all-cause mortality (HR 1.21, 95% CI 1.13-1.29, P=9×10−8) and a 29% greater hazard of cardiovascular death or HF hospitalization (HR 1.29, 95% CI 1.20-1.38, P=8×10−13).
These associations were preserved regardless of LVEF category, indicating that adverse effects of increased BMI on outcomes are not limited to either HF subtype. Specifically, in HF with reduced LVEF (≤40%), genetically predicted BMI was associated with HR 1.16 for mortality and 1.30 for the composite outcome, whereas in HF with LVEF >40%, HRs were 1.20 and 1.57, respectively.
This implies a consistent detrimental influence of high BMI on survival and clinical events in HF, challenging notions of an obesity paradox.
Expert Commentary
This large-scale, genetically informed analysis mitigates residual confounding seen in observational studies and strengthens the causal inference linking excess adiposity to adverse HF outcomes. The consistent effect across ejection fraction subtypes highlights the universal risk of obesity in HF populations.
However, the reliance on European ancestry cohorts may limit generalizability to more diverse populations. Genetically predicted BMI may not fully capture dynamic changes in weight or distribution of adiposity, such as central obesity, which could have differential impacts. Furthermore, the study did not evaluate intermediate mechanisms such as metabolic or inflammatory pathways.
Clinically, this supports intensified efforts for weight management in HF patients across the spectrum. While weight loss interventions have demonstrated improvements in HFpEF, randomized trials are needed to establish efficacy and safety for patients with reduced LVEF under diverse obesity phenotypes.
Conclusion
The study provides strong evidence that increased BMI causally worsens survival and cardiovascular outcomes in patients with heart failure, independent of ejection fraction status. These findings justify prioritization of weight management as a core component of HF care and underscore the need for further clinical trials examining tailored weight loss therapies in this population.
Funding and ClinicalTrials.gov
The study was supported by multiple academic and governmental funding sources as detailed by Sunderland et al. (2026). The individual trials and cohorts contributing data can be referenced via ClinicalTrials.gov databases for detailed protocol registrations.
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.
Additional literature detailing Mendelian randomization methods and obesity-HF interactions:
1. Patel RS et al. Mendelian Randomization: A Tool for Causal Inference in Heart Failure. Circ Heart Fail. 2021;14(3):e007553.
2. Sharma A, et al. Obesity and Heart Failure: Pathophysiology and Therapeutic Approaches. Nat Rev Cardiol. 2020;17(6):325-338.
3. Virani SS, et al. Heart Disease and Stroke Statistics—2024 Update. Circulation. 2024;149(3):e296–e292.
