Thyroid hormone is required for growth adaptation to pressure load in the ovine fetal heart

New Findings center dot What is the central question of this study? The importance of endogenous thyroid hormone in contributing to pathophysiological adaptive growth of the fetal heart is not known. center dot What is the main finding and its importance? The study identifies that thyroid hormone is required for adaptive fetal cardiac growth in response to pressure overload. Understanding the pathophysiological cardiac growth process may allow for improved clinical care and new therapeutic strategies for fetuses and infants with congenital heart disease. Thyroid hormone exerts broad effects on the adult heart, but little is known regarding the role of thyroid hormone in the regulation of cardiac growth early in development and in response to pathophysiological conditions. To address this issue, we determined the effects of fetal thyroidectomy on cardiac growth and growth-related gene expression in control and pulmonary-artery-banded fetal sheep. Fetal thyroidectomy (THX) and/or placement of a restrictive pulmonary artery band (PAB) were performed at 126 +/- 1 days of gestation (term, 145 days). Four groups of animals [n= 56 in each group; (i) control; (ii) fetal THX; (iii) fetal PAB; and (iv) fetal PAB + THX] were monitored for 1 week prior to being killed. Fetal heart rate was significantly lower in the two THX groups compared with the non-THX groups, while mean arterial blood pressure was similar among groups. Combined left and right ventricle free wall + septum weight, expressed per kilogram of fetal weight, was significantly increased in PAB (6.27 +/- 0.85 g kg1) compared with control animals (4.72 +/- 0.12 g kg1). Thyroidectomy significantly attenuated the increase in cardiac mass associated with PAB (4.94 +/- 0.13 g kg1), while THX alone had no detectable effect on heart mass (4.95 +/- 0.27 g kg1). The percentage of binucleated cardiomyocytes was significantly decreased in THX and PAB +THX groups (approximate to 16%) compared with the non-THX groups (approximate to 27%). No differences in levels of activated Akt, extracellular signal-regulated kinase or c-Jun N-terminal kinase were detected among the groups. Markers of cellular proliferation but not apoptosis or expression of growth-related genes were lower in the THX and THX+ PAB groups relative to thyroid-intact animals. These findings suggest that in the late-gestation fetal heart, thyroid hormone has important cellular growth functions in both physiological and pathophysiological states. Specifically, thyroid hormone is required for adaptive fetal cardiac growth in response to pressure overload.