Sanford P. Bishop

The cardiomyocyte undergoes dramatic changes in structure, metabolism, and function from the early fetal stage of hyperplastic cell growth, through birth and the conversion to hypertrophic cell growth, continuing to the adult stage and responding to various forms of stress on the myocardium, often leading to myocardial failure. The fetal cell with incompletely formed sarcomeres and other cellular and extracellular components is actively undergoing mitosis, organelle dispersion, and formation of daughter cells. In the first few days of neonatal life, the heart is able to repair fully from injury, but not after conversion to hypertrophic growth. Structural and metabolic changes occur following conversion to hypertrophic growth which forms a barrier to further cardiomyocyte division, though interstitial components continue dividing to keep pace with cardiac growth. Both intra- and extracellular structural changes occur in the stressed myocardium which together with hemodynamic alterations lead to metabolic and functional alterations of myocardial failure. This review probes some of the questions regarding conditions that regulate normal and pathologic growth of the heart.

The failure of adult cardiomyocytes to reproduce themselves to repair an injury results in the development of severe cardiac disability leading to death in many cases. The quest for an understanding of the inability of cardiac myocytes to repair an injury has been ongoing for decades with the identification of various factors which have a temporary effect on cell‐cycle activity. Fetal cardiac myocytes are continuously replicating until the time that the developing fetus reaches a stage of maturity sufficient for postnatal life around the time of birth. Recent reports of the ability for early neonatal mice and pigs to completely repair after the severe injury has stimulated further study of the regulators of the cardiomyocyte cell cycle to promote replication for the remuscularization of injured heart. In all mammals just before or after birth, single‐nucleated hyperplastically growing cardiomyocytes, 1X2N, undergo ≥1 additional DNA replications not followed by cytokinesis, resulting in cells with ≥2 nuclei or as in primates, multiple DNA replications (polyploidy) of 1 nucleus, 2X2(+)N or 1X4(+)N. All further growth of the heart is attributable to hypertrophy of cardiomyocytes. Animal studies ranging from zebrafish with 100% 1X2N cells in the adult to some strains of mice with up to 98% 2X2N cells in the adult and other species with variable ratios of 1X2N and 2X2N cells are reviewed relative to the time of conversion. Various structural, physiologic, metabolic, genetic, hormonal, oxygenation, and other factors that play a key role in the inability of post‐neonatal and adult myocytes to undergo additional cytokinesis are also reviewed.

Inotropic reserve, demonstrated with administration of sympathomimetic amines, is characteristic of hibernating myocardium. The goal of this study was to determine whether inotropic reserve was present following chronic coronary artery constriction in the pig, which is one potential model of hibernating myocardium. The effects of isoproterenol were examined in five conscious pigs 21±2.1 days after ameroid implantation on the left circumflex coronary artery on measurements of left ventricular (LV) pressure, LV dP/dt, and regional wall thickening in the ameroid-dependent zone (posterior wall) and contralateral non-ischemic zone (anterior wall). Isoproterenol, 0.1 μg/kg/min, increased LV dP/dt by 96±11%, heart rate by 43±13 beats/min, and normalized systolic wall thickening, slightly, but not significantly more in the ameroid-dependent zone (+1.57±0.31 mm) than in the contralateral non-ischemic zone (+1.04±031 mm), although the baseline wall thickening was reduced significantly in the ameroid-dependent zone. This occurred at a time when baseline myocardial blood flow was preserved and myocardial perfusion in the ameroid-dependent zone was derived in part from the native coronary circulation and also through collateral channels. Two weeks later histological evidence of lesions characteristics of hibernating myocardium, i.e., myofibrolysis and increased glycogen deposition, were observed. Thus, these histological changes and the confluence of chronically depressed regional function and residual inotropic reserve in the conscious pig with chronic ameroid-induced coronary constriction support this model for further study of hibernating myocardium.