Abstract
Newborn mice and piglets exhibit natural heart regeneration after myocardial infarction (MI). Discovering other mammals with this ability would provide evidence that neonatal cardiac regeneration after MI may be a conserved phenotype, which if activated in adults could open new options for treating ischemic cardiomyopathy in humans. Here, we hypothesized that newborn rats undergo natural heart regeneration after MI. Using a neonatal rat MI model, we performed left anterior descending coronary artery ligation or sham surgery in one-day-old rats under hypothermic circulatory arrest (n = 74). Operative survival was 97.3%. At 1 day post-surgery, rats in the MI group exhibited significantly reduced ejection fraction (EF) compared to shams (87.1% vs. 53.0%, p < 0.0001). At 3 weeks post-surgery, rats in the sham and MI groups demonstrated no difference in EF (71.1% vs. 69.2%, respectively, p = 0.2511), left ventricular wall thickness (p = 0.9458), or chamber diameter (p = 0.7801). Masson’s trichome and picrosirius red staining revealed minimal collagen scar after MI. Increased numbers of cardiomyocytes positive for 5-ethynyl-2′-deoxyuridine (p = 0.0072), Ki-67 (p = 0.0340), and aurora B kinase (p = 0.0430) were observed within the peri-infarct region after MI, indicating ischemia-induced cardiomyocyte proliferation. Overall, we present a neonatal rat MI model and demonstrate that newborn rats are capable of endogenous neocardiomyogenesis after MI.
Highlights
Ischemic heart disease represents one of the greatest threats to human health, affecting over 150 million people worldwide and accounting for 10 million deaths globally per year [1]
We demonstrate that neonatal rats at age postnatal day 1 (P1) are capable of natural heart regeneration after myocardial infarction (MI), resulting in minimal left ventricle (LV)
left anterior descending (LAD) ligation in P1 rats occurs during the first few weeks after ischemic injury, we observed a significant increase in EdU+ /troponin+ cardiomyocytes within both the peri-infarct and remote regions of the LV during this timeframe
Summary
Ischemic heart disease represents one of the greatest threats to human health, affecting over 150 million people worldwide and accounting for 10 million deaths globally per year [1]. In the United States, the cost of treating ischemic heart disease may increase by 100% over the two decades [2]. New pharmacologic therapies and coronary revascularization strategies are being developed [3,4], but many patients progress to heart failure and succumb to ischemic cardiomyopathy despite optimal treatment of MI [5]. There exists a significant unmet clinical need for the development of novel therapeutic strategies to prevent and treat ischemic heart failure after MI. Heart regeneration has been the focus of extensive recent research [6]. After MI, insufficient tissue perfusion results in cardiomyocyte cell death, followed by replacement of non-viable cardiac
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