Systemic arterial hypertension but not IGF-1 treatment stimulates cardiomyocyte enlargement in neonatal lambs.

Although cardiomyocyte terminal differentiation is nearly complete at birth in sheep, very limited postnatal expansion of myocyte number may occur. The capacity of newborn cardiomyocytes to respond to growth stimulation by proliferation is poorly understood. Our objective was to test this growth response in newborn lambs using two different stimuli shown to induce strong responses in fetuses and adults: increased systolic load (Load) and insulin-like growth factor I (IGF-1). METHODS Vascular catheters and an inflatable aortic occluder were implanted in lambs. Hearts were collected for analysis at 18 days of age after a 7-day experiment, and compared to Control hearts. RESULTS Load hearts, but not IGF-1 hearts, were heavier (P=0.001) due to increased mass of the LV, septum and left atrium (40-50%, P=0.004). Terminal differentiation and cell cycle activity were not different between groups. Myocyte length was 7% greater in Load lamb hearts (P<0.05), and binucleated myocytes, which comprise ~90% of LV cells, were 25% larger in volume (P=0.03). Myocyte number per gram of myocardium was decreased in all ventricles of Load lambs (P=0.01). Cells from the IGF-1 group were not found to be different by any comparison. CONCLUSIONS These results suggest that the newborn sheep LV responds to systolic stress with cardiomyocyte hypertrophy, not proliferation. Further, IGF-1 is ineffective at stimulating cardiomyocyte proliferation at this age (despite effectiveness prior to birth). Thus to expand cardiomyocyte number in the newborn heart, therapies other than systolic pressure load and IGF-1 treatment need to be developed.