Heart failure with a preserved ejection fraction: synergy between cardiac and extracardiac mechanisms and effects of novel therapies

Heart failure with preserved ejection fraction (HFpEF) is a systemic disease in which metabolic comorbidities obesity, type 2 diabetes (T2D), and chronic kidney disease (CKD) converge to drive systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Microvascular dysfunction represents an important link between these comorbidities and abnormalities within and beyond the heart, although its causal contribution to HFpEF remains incompletely established. In addition to promoting myocardial stiffness and diastolic dysfunction, impaired microvascular function across the pulmonary and peripheral circulations may contribute to reduced tissue perfusion, exercise intolerance, and dyspnoea. CKD may further aggravate this process through volume and neurohormonal pathways as well as circulating uraemic and inflammatory factors that impair endothelial function, through a kidney-microvascular axis. Despite its high prevalence and poor prognosis, therapeutic options for HFpEF have historically been limited. Recent advances, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin therapies (GLP-1/GIP RAs), and (non-steroidal) mineralocorticoid receptor antagonists, have reshaped the therapeutic landscape by improving cardiovascular and renal outcomes in patients with HFpEF. These agents exert complementary effects on hemodynamic stress, metabolic dysregulation, inflammation, and fibrosis, and may also improve microvascular function across multiple vascular beds. In this narrative review, we provide an organ-by-organ synthesis of the pathophysiological interactions among the heart, kidney, systemic microvasculature, pulmonary circulation, and skeletal muscle in CKMS-related HFpEF. We further map the clinical and mechanistic effects of aforementioned therapies across these interconnected organ systems and highlight areas in which mechanistic and clinical evidence gaps remain.