A One Health Approach to Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease in humans and results in significant morbidity and mortality. Research over the past 25 years has contributed enormous insight into this inherited disease particularly in the areas of genetics, molecular mechanisms, and pathophysiology. Our understanding continues to be limited by the heterogeneity of clinical presentations with various genetic mutations associated with HCM. Transgenic mouse models have been utilized especially studying the genotypic and phenotypic interactions. However, mice possess intrinsic cardiac and hemodynamic differences compared to humans and have limitations preventing their direct translation. Other animal models of HCM have been studied or generated in part to overcome these limitations. HCM in cats shows strikingly similar molecular, histopathological, and genetic similarities to human HCM, and offers an important translational opportunity for the study of this disease. Recently, inherited left ventricular hypertrophy in rhesus macaques was identified and collaborative investigations have been conducted to begin to develop a non-human primate HCM model. These naturally-occurring large-animal models may aid in advancing our understanding of HCM and developing novel therapeutic approaches to this disease. This review will highlight the features of HCM in humans and the relevant available and developing animal models of this condition.

Keywords: animal models; cardiomyopathy; familial hypertrophic cardiomyopathy; genetics; left ventricular hypertrophy.

Figure 1

Gross necropsy images of (A) cat and (B) rhesus macaque with severe left ventricular hypertrophy. Hearts were transversely transected midway between the apex and base of the hearts (Gross necropsy image of rhesus macaque courtesy of R. Reader).

Figure 2

2-Dimensional right parasternal left ventricular outflow tract view in systole with color-Doppler showing left ventricular outflow tract obstruction secondary to systolic anterior motion of the mitral valve in a cat with HCM. Mitral valve regurgitation is also evident.

Figure 3

Right parasternal short axis imaging at the level of the papillary muscle in a normal rhesus macaque (A and B) and a rhesus macaque with severe left ventricular hypertrophy consistent with HCM (C and D). The images are presented as systole (B and D) and diastole (A and C).