Abstract
Studies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation, but less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs to assess regenerative repair in young large mammals at a stage when cardiomyocyte (CM) mitotic activity is still detected. Female and male P30 pigs were subjected to cardiac ischemia (1 h) by occlusion of the left anterior descending artery followed by reperfusion, or to a sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 h post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated CM cell cycling, detectable by phospho-histone H3 staining, at 2 months of age in multinucleated CMs in both sham-operated and IR pigs. Inflammation and regional scar formation in the epicardial region proximal to injury were observed 4 weeks post-IR. Thus, pigs subjected to cardiac IR at P30 show myocardial damage with a prolonged decrease in cardiac function, formation of a regional scar, and increased inflammation, but do not regenerate myocardium even in the presence of CM mitotic activity.
Highlights
The ability of the heart to regenerate has been demonstrated in zebrafish, amphibians and neonatal mammals [1]
Since CM mitotic rates are similar at P0 and P30 in young swine [12], cardiac repair following temporary injury was assessed in P30 pigs
We report cardiac repair related to scar formation following transient ischemia/reperfusion injury in P30 pigs
Summary
The ability of the heart to regenerate has been demonstrated in zebrafish, amphibians and neonatal mammals [1]. It is known that mice can regenerate their hearts with pre-existing CMs being the source of regenerating cardiac muscle following injury in the first week after birth [2,6,7]. This intrinsic capacity for cardiac self-repair is lost by postnatal day (P) coincident with CM binucleation, cell cycle arrest, and the transition to hypertrophic growth [2,8,9,10]. There is incomplete information available as to how the transient regenerative capacity of the neonatal mouse heart relates to CM cell cycle exit, transition to hypertrophic growth, sarcomeric maturation, and fibrotic scar formation in response to injury [2,9,11]
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