Obesity, affecting approximately 80% of HFpEF patients, is a central, modifiable driver of exercise intolerance that promotes both cardiac remodeling and peripheral muscle dysfunction.
This review positions obesity as a central, modifiable determinant of HFpEF and exercise intolerance, emphasizing the need for targeted therapies.
Heart failure with preserved ejection fraction (HFpEF) now represents the dominant form of heart failure in the United States. Approximately 80% of HFpEF patients also live with obesity. This review highlights the central role of obesity in driving the pathophysiology and clinical presentation of HFpEF, particularly exercise intolerance, which is the hallmark symptom of heart failure. We summarize evidence that obesity promotes early concentric remodeling, diastolic dysfunction, and atrial enlargement while reducing the diagnostic utility of natriuretic peptides. We also examine how cardiopulmonary exercise testing (CPET), the gold standard for assessing exercise capacity, reveals obesity-related impairments in peak oxygen uptake, chronotropic response, and pulmonary pressures. Beyond cardiac contributions, obesity amplifies peripheral drivers of exercise intolerance, including vascular stiffening, endothelial dysfunction, impaired skeletal muscle oxygen utilization, mitochondrial dysfunction, and myosteatosis. We also discuss new evidence that the chronic inflammatory response can drive central and peripheral dysfunction (systemic fibrosis and skeletal muscle atrophy) to reduce functional capacity in HFpEF. Together, these findings position obesity as a central, modifiable determinant of HFpEF and underscore the need for mechanistic studies targeting skeletal muscle, vascular, and inflammatory pathways.
Pandit et al. (2026) studied this question. Obesity, affecting approximately 80% of HFpEF patients, is a central, modifiable driver of exercise intolerance that promotes both cardiac remodeling and peripheral muscle dysfunction.