Heart failure with preserved ejection fraction (HFpEF) is characterized in this review as a systemic disorder in which metabolic comorbidities converge to produce multisystem pathophysiology. Rather than a purely cardiac problem, HFpEF arises from interactions among the heart, kidney, systemic microvasculature, pulmonary circulation, and skeletal muscle. The authors frame HFpEF within the context of cardio‑kidney metabolic syndrome (CKMS), emphasizing systemic inflammation, endothelial dysfunction, and myocardial fibrosis as central features.
Obesity, type 2 diabetes (T2D), and chronic kidney disease (CKD) are highlighted as prevalent comorbid drivers of HFpEF. These conditions promote metabolic dysregulation and chronic inflammation, which in turn foster endothelial injury and fibrotic remodeling of the myocardium. The review positions these comorbidities as upstream contributors that shape both cardiac structure and extracardiac organ function in HFpEF.
A key mechanistic link described is microvascular dysfunction, which connects systemic metabolic disturbances to tissue‑level abnormalities. Microvascular impairment is implicated in promoting myocardial stiffness and diastolic dysfunction. The authors note that while microvascular dysfunction is an important link, its definitive causal contribution to HFpEF has not been fully established and remains an active area for further investigation.
CKD is described as a modifier and amplifier of HFpEF pathophysiology. Through volume overload, neurohormonal activation, and circulating uraemic and inflammatory mediators, CKD can worsen endothelial function and thereby contribute to a kidney–microvascular axis. The review emphasizes that CKD’s systemic effects likely intensify microvascular dysfunction across multiple vascular beds and thereby exacerbate HFpEF manifestations.
Beyond the heart, impaired microvascular function in the pulmonary and peripheral circulations is proposed to have clinically meaningful consequences. In the pulmonary circulation, microvascular abnormalities can contribute to elevated pulmonary pressures and hemodynamic burden. In peripheral tissues, microvascular dysfunction may reduce local perfusion, which is linked to exercise intolerance and dyspnoea commonly observed in HFpEF.
Skeletal muscle is presented as a downstream organ affected by systemic and microvascular derangements. Reduced perfusion and impaired oxygen delivery in peripheral muscles are connected to reduced exercise capacity. The review highlights that extracardiac impairments—mediated in part by microvascular dysfunction—are central to symptom generation in HFpEF patients.
Therapeutic options for HFpEF have historically been limited. The review summarizes recent pharmacologic advances that have reshaped the treatment landscape. These include sodium–glucose cotransporter 2 inhibitors (SGLT2i), glucagon‑like peptide‑1 receptor agonists (GLP‑1 RAs) and dual incretin (GLP‑1/GIP) therapies, and (non‑steroidal) mineralocorticoid receptor antagonists. The authors report that these agents have improved cardiovascular and renal outcomes in patients with HFpEF and related comorbidities.
The review maps how the aforementioned therapies exert complementary and potentially synergistic effects across organ systems. Mechanisms discussed include reductions in hemodynamic stress, improvements in metabolic control, attenuation of inflammation, and mitigation of fibrosis. The authors also suggest that these agents may improve microvascular function across multiple vascular beds, potentially addressing both cardiac and extracardiac contributors to HFpEF. The review synthesizes organ‑by‑organ mechanistic evidence to illustrate how therapies may influence the heart, kidney, pulmonary circulation, systemic microvasculature, and skeletal muscle.
Although the review highlights promising therapeutic directions, it also emphasizes remaining gaps. The causal role of microvascular dysfunction in HFpEF is not fully resolved. Mechanistic pathways linking CKD and systemic microvascular impairment require further clarification. The authors identify areas where clinical and translational evidence is limited and where targeted research is needed to better define which patients will derive the greatest benefit from specific therapies.
This narrative review characterizes HFpEF as a multisystem disorder driven by metabolic comorbidities that promote inflammation, endothelial dysfunction, and fibrosis, with microvascular dysfunction serving as a central mechanistic link. Recent pharmacologic advances—SGLT2i, GLP‑1‑based therapies including dual incretin approaches, and mineralocorticoid receptor antagonists—have improved cardiovascular and renal outcomes and may beneficially affect microvascular function. The authors present an organ‑by‑organ synthesis of pathophysiologic interactions and map therapeutic effects across interconnected systems, while noting important mechanistic and clinical evidence gaps that warrant further study.