Exploration of Mediators Associated with Myocardial Remodelling in Feline Hypertrophic Cardiomyopathy

SIMPLE SUMMARY: The hallmark changes in hypertrophic cardiomyopathy (HCM), a naturally occurring heart disease in both humans and cats, are left ventricular hypertrophy (LVH) and myocardial fibrosis. Key myocardial proteins, lumican, lysyl oxidase (LOX) isoenzymes and TGF-β isoforms are critical for the development of fibrosis and cardiomyocyte hypertrophy in various cardiac diseases. The objectives of this study were to measure the expression of these proteins in the left ventricular myocardium and to investigate the association between their expression and alterations of the different collagenous (primarily extracellular matrix) and non-collagenous (primarily cellular) myocardial components in feline HCM. Lumican facilitates the cross-linking of collagen, and its myocardial expression was increased in feline HCM and was localised to cardiomyocytes and the extracellular matrix, particularly in areas with mononuclear cell infiltration. Increased LOX expression was detected in both cardiomyocytes and interstitial mononuclear cells. Additionally, TGF-β2 expression was increased in cardiomyocytes in HCM-affected cats. Based on the knowledge from publications on other species, these results suggest potential crosstalk between different myocardial cell types, resulting in myocardial remodelling, including expansion of the collagen and non-collagen myocardial component and alteration to collagen structure in cats with HCM. Such remodelling may result in diastolic dysfunction and clinical signs. ABSTRACT: Hypertrophic cardiomyopathy (HCM) affects both humans and cats and exhibits considerable interspecies similarities that are exemplified by underlying pathological processes and clinical presentation to the extent that developments in the human field may have direct relevance to the feline disease. Characteristic changes on histological examination include cardiomyocyte hypertrophy and interstitial and replacement fibrosis. Clinically, HCM is characterised by significant diastolic dysfunction due to a reduction in ventricular compliance and relaxation associated with extracellular matrix (ECM) remodelling and the development of ventricular hypertrophy. Studies in rodent models and human HCM patients have identified key protein mediators implicated in these pathological changes, including lumican, lysyl oxidase and TGF-β isoforms. We therefore sought to quantify and describe the cellular location of these mediators in the left ventricular myocardium of cats with HCM and investigate their relationship with the quantity and structural composition of the ECM. We identified increased myocardial content of lumican, LOX and TGF-β2 mainly attributed to their increased expression within cardiomyocytes in HCM cats compared to control cats. Furthermore, we found strong correlations between the expressions of these mediators that is compatible with their role as important components of cellular pathways promoting remodelling of the left ventricular myocardium. Fibrosis and hypertrophy are important pathological changes in feline HCM, and a greater understanding of the mechanisms driving this pathology may facilitate the identification of potential therapies.