The right kind of rarefaction: Coronary microvascular remodeling in right ventricle failure

Right ventricular failure (RVF) is the primary determinant of outcomes in pulmonary hypertension (PH). Coronary microvascular dysfunction (CMD), defined by capillary rarefaction and endothelial dysfunction, may contribute to RVF but remains poorly characterized. CMD, defined by capillary rarefaction and endothelial dysfunction, may contribute to RVF through impaired myocardial oxygen delivery and fibrotic remodeling.

To characterize right ventricle (RV) CMD and myocardial fibrosis in explanted human hearts and examine associations with echocardiographic and hemodynamic indices of RVF across PH subtypes.

We retrospectively analyzed 57 adult patients who underwent orthotopic heart transplantation at 3 institutions (2023-2024). Explanted hearts were classified by PH subtype: combined pre-/post-capillary PH (CpcPH, n = 24), isolated post-capillary PH (IpcPH, n = 22), and no PH (n = 11). Digital pathology quantified RV and left ventricle (LV) capillary density and interstitial fibrosis across epicardial, mid-wall, and endocardial regions. Associations with echocardiographic measures and hemodynamic parameters were assessed.

A total of 57 hearts (70% male, median age 52 years) were analyzed. Median time from listing to transplantation was 1.6 months (IQR: 0.7-6.1). Mean RV capillary density was 653 ± 204 microvessels/mm² and correlated significantly with TAPSE (ρ_s = 0.49, p < 0.001) and tricuspid annular plane systolic excursion to systolic pulmonary artery pressure (TAPSE/sPAP) ratio (ρ_s = 0.33, p = 0.037). Compared to patients without PH, patterns of reduced mid-wall capillary density in PH subtypes were observed (CpcPH: β = -228 microvessels/mm², p = 0.031; IpcPH: β = -238 microvessels/mm², p = 0.043). Diabetes mellitus was associated with reduced LV sub-endocardial capillary density (β = -207, p = 0.006). Unadjusted analysis showed higher RV fibrosis in patients without PH (p = 0.024); however, after adjusting for clinical confounders, including heart failure etiology, this difference was not significant, highlighting the heterogenous nature of fibrosis in end-stage heart failure.

Capillary rarefaction is a measurable histopathologic feature in explanted RV tissue that correlates with functional indices of RV performance. Our proof-of-concept findings suggest CMD may contribute to RV systolic dysfunction independent of PH subtype.