Obesity-Related Heart Failure Mechanisms and Treatments

Obesity drives heart failure through a constellation of metabolic, haemodynamic and inflammatory processes. Excess adipose tissue, particularly visceral and epicardial fat, secretes pro-inflammatory cytokines and promotes endothelial dysfunction, while expanded blood volume and heightened activity of the renin–angiotensin–aldosterone system exacerbate cardiac preload and afterload. These alterations lead to myocardial remodelling, impaired relaxation and diastolic dysfunction, defining an obesity-related heart failure phenotype often manifesting as heart failure with preserved ejection fraction. Therapeutic strategies centre on weight reduction and modulation of adverse signalling pathways. Lifestyle interventions combining caloric restriction and exercise improve functional capacity and cardiovascular risk factors. Pharmacotherapies that induce weight loss and favourable cardiometabolic effects—most notably glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/GLP-1 agonists—have demonstrated reductions in symptoms, biomarkers of inflammation and hospitalisations. Sodium-glucose cotransporter-2 inhibitors confer protective renal and cardiac benefits across the body mass index spectrum. Diuretic strategies and emerging molecular approaches targeting cellular stress and immune activation offer additional avenues. A comprehensive approach tailored to obesity severity and heart failure subtype promises to mitigate the global burden of obesity-related heart failure.

Research from Nature Portfolio

In a prespecified analysis of a randomised trial in patients with obesity-related heart failure with preserved ejection fraction, once-weekly semaglutide consistently improved quality of life, exercise capacity and inflammatory markers across obesity classes. The magnitude of symptom relief and functional gain correlated directly with percentage body weight reduction. A mechanistic secondary analysis of a tirzepatide trial revealed that dual GIP/GLP-1 receptor agonism reduced systemic blood volume, arterial pressure and C-reactive protein while enhancing renal filtration and lowering cardiac injury biomarkers; changes in volume status and inflammation were closely linked to improvements in walk distance and patient-reported outcomes. In a preclinical model of pressure overload, semaglutide restored mitophagy, suppressed NLRP3 inflammasome activation and attenuated left ventricular hypertrophy, supporting a direct myocardial benefit beyond weight loss.

Obesity-Related Heart Failure Mechanisms and Treatments publication trend

The graph below shows the total number of articles in obesity-related heart failure mechanisms and treatments across all publications each year (not limited to Nature Index journals).

Technical terms

Heart failure with preserved ejection fraction (HFpEF): A syndrome of impaired diastolic filling despite a normal ejection fraction, commonly linked to obesity and hypertension.

Glucagon-like peptide-1 (GLP-1) receptor agonist: A class of medications that enhance insulin secretion, promote weight loss and exert cardioprotective effects.

Glucose-dependent insulinotropic polypeptide (GIP): An incretin hormone that, when co-activated with GLP-1, augments metabolic and cardiovascular benefits.

NLRP3 inflammasome: A multiprotein complex that drives pro-inflammatory cytokine release in response to cellular stress.

Major adverse cardiovascular events (MACE): A composite endpoint including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

Ejection fraction: The proportion of blood ejected from the left ventricle with each contraction, used to classify heart failure subtypes.

References

1. Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nature Medicine (2023).
2. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. The Lancet (2024).
3. The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF. JACC Basic to Translational Science (2023).
4. Body mass index and cardiorenal outcomes in the EMPEROR‐Preserved trial: Principal findings and meta‐analysis with the DELIVER trial. European Journal of Heart Failure (2024).
5. Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nature Medicine (2024).
6. Semaglutide ameliorates pressure overload-induced cardiac hypertrophy by improving cardiac mitophagy to suppress the activation of NLRP3 inflammasome. Scientific Reports (2024).
7. The Effect of Weight Loss Through Lifestyle Interventions in Patients With Heart Failure With Preserved Ejection Fraction—A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Heart Lung and Circulation (2024).