Using ischemia-reperfusion model to re-investigate congestive and chronic heart failure development in mice according to sex

Heart failure (HF) is a chronic disease with increasing global incidence, requiring the development of personalized therapeutic strategies. Despite remarkable progress in the treatment of acute myocardial infarction (MI), MI remains the most common cause of HF. Many animal models have been developed to attempt to recreate the chronic HF phenotype after MI. Still, few characterize the consequences of ischemia-reperfusion (I/R) injury on the progression of MI to HF according to sex. To this end, we aimed to develop a preclinical model capable of reproducing post-MI clinical symptoms and to compare, after constitutive infarction, the progression of post-I/R remodeling. Twelve to sixteen weeks-old female and male C57BL/6J mice underwent 90 minutes of ischemia followed by 16 weeks of reperfusion. Mortality, cardiac structural and functional characteristics were assessed on day 2 and at 4, 8, 12, and 16 weeks after reperfusion. Our results showed that 90-minute I/R injury induces comparable acute contractile dysfunction, cardiac remodeling, and interstitial fibrosis during the first 8 weeks of reperfusion in females and males. While fractional area change was significantly decreased at week 8, leading males to congestive and chronic HF from week 12, females exhibited a 4-week delay in developing similar post-I/R HF symptoms. Mechanically, at week 16, failing cardiomyocytes exhibited reduced contractility with a decrease in Ca 2+ transients that was more pronounced in males. In conclusion, our 90-minute I/R mouse model mimicked clinical post-MI HF and could be used to elucidate the sex-dependent pathophysiology of post-I/R HF further to identify novel targets against HFrEF.