Relevant preclinical model of heart failure in rat: Impact of myocardial infarction and hypertension

Abstract

In acute myocardial infarction (MI) setting, successful revascularization of the ischemic myocardium improves prognosis. However, MI remains a leading cause of heart failure (HF) associated with mortality [1] and the risk to develop HF is increased by co-morbidities especially hypertension [2], [3]. Relevant preclinical models of heart failure with comorbidities as in human are needed to improve the selection of new therapeutic strategies. to determine the best HF model by comparing left ventricular (LV) dysfunction and signs of HF in 3 preclinical models of MI in normotensive and hypertensive rats. In total, 60 minutes MI was induced by coronary ligation in male rats (8-week old) followed by reperfusion (I/R) or not (permanent, PMI) in normotensive Wistar rats (Wi) or in hypertensive rats (SHR PMI). Ejection fraction (EF, %) and LV end-diastolic volume (LVEDV, μl) were measured using echocardiography. Signs of heart failure were assessed by LV end-diastolic pressure (LVEDP, mmHg), right ventricle weight (RV, mg) and plasma NT-Pro-BNP (pg/ml). These different parameters were assessed post-MI at 3 months for the groups (Wi Sham, Wi I/R and SHR PMI) and at 6 months for the Wi PMI group. MI led to a clear LV dysfunction and adverse eccentric remodeling. As expected, these alterations were limited by reperfusion of the ischemic myocardium in normotensive rats. Hypertension exacerbated post ischemic cardiac dysfunction. Three months post-MI, signs of HF were observed only in SHR PMI while no sign were detected in Wi rats 6 months after MI. in line with human disease, our results show that hypertensive rats are more prone to develop signs of HF after MI than normotensive rats. SHR PMI should be considered as a relevant preclinical model for the efficacy assessment of new HFrEF therapeutic strategies.