Phenotypic patterns in feline heart failure: A natural model for understanding variable disease severity in humans

Cats frequently develop myocardial remodeling, for example, hypertrophic cardiomyopathy, affecting 14.7% of domestic cats compared to 0.2% of humans, with shared genetic features making them relevant to human disease. Yet features distinguishing clinical outcomes such as heart failure and arterial thromboembolism remain poorly characterized. Using artificial-intelligence-based digital pathology and Oxford Nanopore sequencing, we analyzed myocardial tissue from 37 cats grouped by outcome: arterial thromboembolism, congestive heart failure, or no documented cardiac disease. Myocardial fibrosis was significantly higher in cats with arterial thromboembolism, indicating a distinct fibrotic phenotype. Cats with heart failure showed nuclear hypertrophy, while cats with arterial thromboembolism had increased numbers of small, hematoxylin-dense non-myocyte nuclei. Higher fibrosis was associated with downregulation of mitochondrial and cardiac conduction genes, and nuclear size correlated with proteostasis and stress-response pathways. This multimodal framework reveals distinct histological and molecular profiles by outcome, with relevance for translational hypertrophic cardiomyopathy research.