Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains a major clinical and therapeutic challenge. Despite having preserved systolic function, patients experience symptoms such as congestion, dyspnoea, and exercise intolerance. The condition is more prevalent in women and is strongly linked to cardiometabolic risk factors (hypertension, diabetes, and obesity), yet its underlying mechanisms remain only partially defined.1-3

Growing evidence implicates coronary microvascular dysfunction (CMD) as a crucial pathophysiologic substrate that links these comorbidities to diastolic dysfunction. Endothelial inflammation, oxidative stress, and capillary rarefaction may induce myocardial ischemia and fibrosis, promoting ventricular stiffness and impaired relaxation, even in the absence of epicardial coronary stenosis.4 Yet, the true prevalence and prognostic impact of CMD in HFpEF, and whether it defines a distinct mechanistic endotype, have not been fully established.

In a recent meta-analysis published in ESC Heart Failure (2024), D'Amario D et al.5 synthesized data from multiple studies. The goal was to connect coronary haemodynamics to multimodality imaging studies. It assessed CMD in HFpEF to determine its prevalence, clinical correlations, and its prognostic significance. Across the included cohorts, CMD was diagnosed through diverse modalities, including PET-derived myocardial blood flow and coronary flow reserve, cardiac magnetic resonance perfusion imaging, and invasive microcirculatory indices such as the index of microvascular resistance. The pooled prevalence of CMD among HFpEF patients was high (up to two-thirds), depending on the diagnostic threshold used.

Importantly, CMD was associated with adverse hemodynamic and structural features, including elevated left atrial volume index (LAVi), higher E/e′ ratios reflecting increased filling pressures, and concentric remodelling patterns. Most significantly, the presence of CMD predicted worse clinical outcomes, with higher rates of death or heart-failure hospitalization compared with HFpEF patients without CMD. These findings support the hypothesis that CMD is not merely a secondary by-product of HFpEF but rather a key determinant of its severity and prognosis. While heterogeneity in diagnostic techniques and population selection remains a limitation, the study provides evidence consolidating CMD as a common and clinically relevant feature of HFpEF.

Compromised coronary microvascular function can limit coronary flow reserve, leading to ischaemia, inflammation, and reactive oxygen species generation. This process may create a self-perpetuating inflammatory cycle that promotes further CMD and myocardial fibrosis.2,3,6 Recent imaging studies have expanded this perspective. Cardiac magnetic resonance studies in HFpEF have reported diffuse interstitial fibrosis, reflected by elevated extracellular volume and increased myocardial stiffness.7 Dynamic SPECT studies demonstrated a close association between microvascular impairment and abnormal cardiac mechanics in HFpEF, while arterial stiffness correlates with CMD severity in CMR-based assessments.8,9 This suggests that large-artery and microvascular dysfunction may act synergistically in driving diastolic failure.

The underlying causality in HFpEF remains a “which came first, the chicken or the egg” dilemma. Whether CMD precedes ischaemia, fibrosis, and diastolic dysfunction, or whether comorbidities drive inflammation that secondarily induces CMD, is still uncertain. A bidirectional mechanism is also plausible. This uncertainty exemplifies the broader challenge of establishing causality in clinical research. Although the study by D'Amario D et al.5  does not prove a causal relationship between HFpEF and CMD, it confirms a significant association. It strengthens the concept of a CMD-driven HFpEF endotype in a subgroup of patients whose symptoms and progression are largely driven by microvascular ischemia and endothelial dysfunction. Identifying this endotype could refine the current “one-size-fits-all” approach to HFpEF and enable personalized therapeutic targeting. Standardization of CMD assessment in HFpEF is urgently needed. Multimodal evaluation should be complemented by efforts to develop non-invasive surrogates such as circulating endothelial biomarkers or perfusion mapping indices.

If CMD is a causal factor in diastolic dysfunction, treatments that improve microvascular function may yield symptomatic and structural benefits. SGLT2 inhibitors, endothelin receptor antagonists, NO–cGMP enhancers, and anti-inflammatory agents represent potential candidates. However, most HFpEF trials to date have not stratified patients based on their microvascular status. Embedding CMD characterization into future interventional trials could help to identify responders and provide mechanistic insights.

By reframing HFpEF through the lens of coronary microvascular health, clinicians and researchers can move towards targeted diagnostics and therapies that address the true root cause of myocardial dysfunction. Recognizing and treating the CMD-HFpEF endotype could be a significant step forward in the long-standing quest to personalize care for patients with diastolic heart failure.