Development of an Ovine Model of Dilated Cardiomyopathy to Facilitate Clinically Translational Research

Abstract

Preclinical studies of heart failure are critical in understanding disease pathophysiology and for development of novel therapies. Existing models that induce ventricular dysfunction suffer from various limitations, including their reversibility, minimal ventricular remodelling, or their highly invasive approach. Therefore, the aim of this research was to develop a percutaneous ovine survival model of cardiomyopathy that can be used for evaluation and optimisation of mechanical cardiac support and stem-cell therapies. Myocardial infarction (MI) was induced percutaneously using agarose gel bead solution to occlude obtuse marginal branches of the left circumflex coronary artery in merino sheep (n = 2). Comparatively, mitral regurgitation (MR) was induced (n = 2) by disrupting the chordae tendinae of the posterior leaflet of the mitral valve. Serial echocardiographic and myocardial strain measurements were performed pre- and post–procedure and weekly for 16 weeks. Electrocardiographic ST-segment elevation post-MI correlated with echocardiographic changes. Mean reduction in left ventricular ejection fraction immediately post–procedure was 18.8% and reduction in circumferential and radial strain was seen secondary to regional wall motion akinesis. Ejection fraction was reduced from 77% to 47% over 16 weeks. End-diastolic volume increased in the MI sheep by 92% and the MR sheep by 84%. We have demonstrated the feasibility of a percutaneous ovine infarct and MR survival model in producing progressive LV dilation and systolic dysfunction. Ultimately, the development of this clinically relevant survival model of heart failure will be critical for the evaluation of novel therapies.