Cortisol Stimulates Cell Cycle Activity in the Cardiomyocyte of the Sheep Fetus

The role of cortisol in regulating cardiac myocyte growth in the near-term fetal sheep is unknown. We hypothesized that cortisol would suppress cardiomyocyte proliferation and stimulate cardiomyocyte binucleation and enlargement, signs of terminal differentiation. Cardiomyocyte dimensions and percent binucleation were determined in isolated cardiac myocytes from seven cortisol-treated and seven control fetuses; percentage of myocytes positive for Ki-67 was determined in an additional four cortisol-treated and four control hearts. Cortisol was infused into the circumflex coronary artery at subpressor rates (0.5 microg/kg.min, 7 d). Cortisol infusion had no hemodynamic effects, compared with controls or pretreatment conditions. Cortisol treatment increased heart weight (44.0 +/- 8.7 g vs. control, 34.9 +/- 9.1 g, P < 0.05). Heart to body weight ratio was greater in treated hearts, compared with controls (10.3 +/- 1.9 vs. 7.7 +/- 0.9 g/kg, P < 0.01). Ventricular myocyte length, width, and percent binucleation were not different between groups. The proportion of treated myocytes in the cell cycle staining for Ki-67 was higher in the left ventricle (5.5 +/- 0.1 vs. 2.7 +/- 0.4%, P < 0.005) and right ventricle (4.4 +/- 0.4 vs. 3.7 +/- 0.7%, P < 0.05), compared with controls. Wet weight to dry weight ratios from cortisol-treated and control hearts were not different. In conclusion, whereas cortisol infused into the fetal sheep heart has no effect on cardiomyocyte size or maturational state, it stimulates entry of cardiomyocytes in the cell cycle. Thus, increases in fetal heart mass associated with subpressor doses of cortisol are due to cardiomyocyte proliferation and not hypertrophic growth.