Histopathological correlates of coronary microvascular dysfunction in non-ischaemic heart failure with reduced or mildly reduced ejection fraction

Background Coronary microvascular dysfunction (CMD) is linked to poor outcomes in heart failure. While high index of microcirculatory resistance (IMR) and low coronary flow reserve (CFR) are well described in HFpEF, the myocardial histopathological substrates of CMD in non-ischaemic heart failure with reduced or mildly reduced ejection fraction remain insufficiently characterised. Purpose To examine associations between myocardial histopathology and invasive CMD indices in non-ischaemic heart failure with reduced or mildly reduced ejection fraction (LVEF <50%). Methods In this single-centre retrospective cohort study, we enrolled consecutive patients with non-ischaemic cardiomyopathy and LVEF <50% who underwent endomyocardial biopsy and catheter-based coronary physiological testing at the same session (May 2022–February 2026). CMD indices (CFR, IMR, baseline IMR [b-IMR]) were measured using a pressure-wire system with Coroventis (Abbott). Histopathology was quantified with QuPath software, including CD3+ lymphocyte density, CD68+ macrophage density, and fibrosis area (%) on Masson’s trichrome staining. Correlations were assessed using Spearman’s coefficients. Results We included 28 patients (median age 58 years [IQR 52–69], 86% male). Median LVEF by echocardiography was 33.0% (IQR 27–39) and NT-proBNP 427 pg/mL (IQR 231–1129). IMR and CFR were available in all patients; b-IMR in 24. CFR correlated positively with CD68+ macrophage infiltration (r=0.45, p=0.016). b-IMR correlated inversely with CD3+ lymphocyte infiltration (r=−0.41, p=0.048) and showed a borderline positive association with CD68+ macrophages (r=0.40, p=0.051). IMR did not correlate with immune-cell infiltration or fibrosis. Fibrosis area was not associated with CFR, IMR, or b-IMR. Conclusion In non-ischaemic heart failure with reduced or mildly reduced ejection fraction, myocardial immune-cell profiles, rather than fibrosis burden, were associated with specific components of coronary microvascular physiology. Macrophage infiltration was linked to higher CFR, whereas lymphocyte infiltration was associated with lower baseline microvascular resistance, suggesting distinct inflammatory mechanisms influencing resting and vasodilator microvascular function.