Pandit A; Biomedical Research Center, Baton Rouge,  USA.
Gupta M; Arabie DA; Milton P; Elbatreek M; Goodchild T; Lefer
DJ; Francis J; Moll D; Allerton TD

Obesity. 34(5):984-996, 2026 May.

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.