The myocardial microvasculature plays a key role in the pathogenesis of feline hypertrophic cardiomyopathy

Feline hypertrophic cardiomyopathy is the most common cardiac disease in cats and closely resembles its human counterpart, representing a spontaneous animal model. Here, myocardial microvascular alterations were quantified through integrated two- and three-dimensional quantitative histological analysis, complemented by gene pathway enrichment analysis. Left ventricular free wall tissue from cats with hypertrophic cardiomyopathy (n=4) and controls (n=4) was immunolabelled for CD31 across 40 serial sections and analysed using convolutional neural network-based segmentation, morphometry, and 3D reconstruction. Diseased myocardium showed a decrease in capillaries with a significantly increased inter-vessel distance. Remaining vessels were enlarged, with increased diameter and cross-sectional area. Total vascular surface area was increased, and vessels displayed significantly reduced straightness, shorter branches, and increased branching angles, indicating a disorganized architecture. The myocardium exhibited significantly reduced cellular density and nuclear size with interstitial expansion. Gene pathway enrichment analysis identified 19 significantly enriched pathways clustering into cellular energy metabolism, vascular development, endothelial cell biology, and blood circulation and haemostasis. These findings reveal capillary rarefaction with compensatory yet maladaptive angiogenesis and tortuous vascular reorganization, accompanied by transcriptional activation of metabolic stress and vascular developmental pathways, and indicate that microvascular dysfunction is a driver rather than consequence of myocardial alterations in hypertrophic cardiomyopathy.