Preclinical model to investigate heart failure development following ischemia-reperfusion injury

Abstract

Heart failure is major public health problem with ischemic cardiomyopathy as the main etiology. Despite therapeutic advances, the high mortality of patients highlights that development of new therapeutic strategies is urgently needed. In this context, the establishment of a pre-clinical model mimicking the clinical pathology would be an asset to characterize the functional mechanisms responsible for the development of heart failure following ischemia-reperfusion injury. In this study, male and female C57Bl/6J mice (8–12 weeks old) underwent left anterior coronary artery ligation for 90 minutes followed by 12 weeks reperfusion (n = 18) or no surgical intervention (CTRL; n = 8). Ejection fraction (EF), left ventricle internal diameter (LVID), E-wave deceleration time (EDT) and the isovolumic relaxation time (IVRT) were assessed by echocardiography during the 12 weeks of post-ischemic reperfusion and cellular Ca2 + (dys)regulation mechanisms in failing isolated cardiomyocytes were investigated at 8 weeks with the imaging Ionoptix system. Our results showed that, despite a significant alteration of EF at day 2 post-infarction (due to ischemic stress by itself), ischemic mice developed a chronical heart dysfunction characterized, on one hand, by a systolic dysfunction with a significant decrease of EF averaging 26% and a LV dilatation around 36% from the day 2 to the week 8 of reperfusion (P < 0.05), and on the other hand, associated with a significant diastolic dysfunction at 12 weeks of reperfusion. Mechanistically, Ca2+ phenotyping showed a significant alteration in excitation/contraction coupling and a contractility defect in failing cardiomyocytes isolated at 8 weeks reperfusion (P < 0.05 vs. CTRL). Our experimental conditions show that 90 minutes ischemia followed by 8 weeks reperfusion seems to be a good algorithm to mimic development of heart failure after an ischemia-reperfusion stress, which is characterized by both systolic and diastolic cardiac dysfunctions.