Abstract 17810: Sustained Natural Heart Regeneration After Myocardial Infarction in One-Week-Old Rats Without Significant Cardiomyocyte Proliferation

Abstract

Introduction: Newborn mammals are capable of natural heart regeneration after cardiac injury during the first week of life, but whether a decline in cardiomyocyte (CM) proliferation directly leads to the loss of regenerative potential is unknown. We hypothesized that, after myocardial infarction (MI) in neonatal rats, the extent of regeneration is directly correlated with the degree of CM proliferation. Methods: Neonatal Wistar rats, including both males and females, underwent left coronary artery ligation to induce MI on postnatal day 1 (P1, n=12), day 7 (P7, n=14), day 8 (P8, n=14), or day 9 (P9, n=15). Sham surgery was performed at each age (n=14, 13, 12, 16, respectively). CM proliferation was assessed using Ki67 staining in a subset of each age group, sacrificed 1 week after MI (n=4, 3, 5, 4) or sham surgery (n=4, 3, 3, 5). At 9 weeks post-MI, echocardiography was performed, and the hearts were explanted for Masson’s trichome staining. Results: At 9 weeks after surgery, left ventricular (LV) end-diastolic diameter (Fig 1A) and ejection fraction (EF, Fig 1B) were similar for P1 MI vs P1 sham (EF 62.5±5.2% vs 62.4±3.3%, p=0.941), as well as for P7 MI vs P7 sham (EF 61.4±3.3% vs 63.3±3.3%, p=0.210), consistent with robust natural regeneration. Progressive LV remodeling, dysfunction, and scar formation were observed after P8 MI (EF 50.1±2.6% vs 63.5±3.6%, p<0.001) and P9 MI (EF 39.4±3.4% vs 63.1±3.9%, p<0.001), but minimal scar was observed after P1 MI and P7 MI (Fig 1C). While the proportion of Ki67-positive CM was increased after P1 MI vs P1 Sham (4.0±2.0% vs 0.5±0.5%, p=0.013), CM proliferation was not significantly increased after P7 MI (1.0±0.4% vs 0.3±0.4%, p=0.105), or after P8 or P9 MI (Fig 1D). Conclusions: In rats, CM proliferation is not significantly stimulated after P7 MI, but the hearts develop with preserved geometry, normal function, and minimal infarct. Further studies are needed to examine non-CM-related mechanisms influencing the extent of natural heart regeneration.