Apical Resection Prolongs the Cell Cycle Activity and Promotes Myocardial Regeneration After Left Ventricular Injury in Neonatal Pig
Authors: Meng Zhao, Eric Zhang, Yuhua Wei, Yang Zhou, Gregory P. Walcott, Jianyi Zhang
Journal: Circulation (2020)

stem cells ◼ swine A dult mammals are unable to regenerate the cardiac muscle lost to myocardial injury. 1 However, we have previously shown that hearts of neonatal pigs can recover from acute myocardial infarction (MI) occurring on postnatal day (P) 1, with little evidence of scar formation or wall thinning 30 days later, 1,2 and cardiac tissue removed during apical resection in P1 mice was shown to have fully regenerated 3 weeks later. 1 Because the primary mechanism of regeneration in both early postnatal animal species appeared to involve the proliferation of preexisting cardiomyocytes located near the injury site, we were curious whether the proliferative cardiomyocytes could be induced to undergo further proliferation after a second cardiac injury.We hypothesized that because of the state of activated cellular proliferation machinery in the proliferative cardiomyocytes and potential extension of the developmentally regulated cardiomyocyte proliferative window resulting from activation of injury repair mechanisms, a second injury induced by left anterior descending coronary artery (LAD) ligation distal to the second diagonal 4 weeks after initial apex resection (AR) at P1 (AR+MI) would result in significantly less myocardial structural and functional damage when evaluated 4 weeks later.All experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Alabama at Birmingham and performed in accordance with the National Institutes of Health "Guide for the Care and Use of Laboratory Animals" (Publication No. 85-23).The study consisted of 44 neonatal piglets.Of the 25 P1 AR+MI piglets, 9 died of lethal arrhythmia within 14 days after AR.The ventricular apex (≈0.2 g) was resected at P1 (n=9), with a recovery period consisting of 27 days until P28, when MI was surgically induced via permanent occlusion of the LAD in a subset of animals (n=6; Figure [A through C]), and the terminal study was performed on P56 (Figure [A through C]).The control group consisted of age-matched intact piglets (n=16).Echography was performed before and after MI at P28 and the terminal study on P56 (Figure [A]).Evaluation of explanted hearts at P56 confirmed that the apex had reformed (Figure [B through E]).At P56, although the LAD occlusion remained visible in coronary angiographic images (Figure [C]), there was no visible left ventricular (LV) infarct in any of the LV anterior wall (Figure [D and E]).Typical cardiac echography before and after LAD ligation on P28 is shown in Figure (Hi).Immediately after LAD ligation, significant myocardial damage was evidenced by LV bulging (Figure [Hi], echo2).Compiled data of pre-MI and post-MI echocardiography on P28 and P56 are shown in Figure (Hii and Hiii), demonstrating that LV anterior wall systolic thickness and fractional shortening did not differ significantly between AR+MI and control animals at P56 (Figure [Hii and Hiii]).Because of critical care requirements immediately after LAD ligation on P28, only 2 of the 3 animals underwent post-MI echography data acquisition.Cardiac magnetic resonance imaging also found no evidence of infarction in the hearts of AR+MI animals (data not shown).