Effects of maternal cortisol on perinatal cardiac metabolism and function

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Project Summary Cortisol is a regulator of maturation of fetal organs, including the heart. Maternal hypercortisolemia or stress appears to increase the risk of stillbirth at term and alter growth of the fetal heart. In an animal model with elevated maternal cortisol in late gestation, mimicking mild but chronic stress, we have found a striking increase in stillbirth and changes in gene expression in the fetal heart suggesting changes in glucose metabolism, mitochondrial function, and energy availability. The data support the hypothesis that there is downregulation of TCA cycle activity and mitochondrial number and function. The proposed studies will test the overarching hypothesis that alterations in fetal cortisol alter cardiac metabolism, function and remodeling in late gestation, and ultimately lead to fetal cardiac dysfunction, including both structural and functional changes, that result in adverse events during labor and delivery or in the immediate postnatal period. We will test for progressive changes in pathophysiology in the fetal heart during controlled labor using radiotelemetric monitoring of fetal aortic pressure and ECG, ultrasound analysis of fetal heart dimensions and function, and transcriptomic, metabolomic, histopathologic, and biochemical approaches to investigate changes in cardiac structure and metabolism. We will test the hypothesis that there is disruption of normal pathways for glucose and lactate metabolism and loss of mitochondrial function that will be reflected in changes in mitochondrial respirometry, gene expression and metabolomics. We will test the hypothesis that there will be pathophysiologic changes in cardiac structure and function that will be reflected by changes in ventricular dimensions and function identified by echocardiography, as well as alterations in aortic pressure, and in ECG. We will also test for alterations in glucose utilization by the heart using 13C glucose flux and identification of 13C glucose isoptomers in plasma and in the heart tissue. We will further test the hypothesis that changes in cardiac metabolism and mitochondria underlie changes in cardiac metabolism and ECG changes using administration of dichloroacetate, a small molecule therapeutic that increases activity of the pyruvate dehydrogenase complex, which is required for TCA cycle activity. DCA will be administered acutely during labor, the time at which the abnormalities in ECG become evident in our model. DCA is used in humans with mitochondrial diseases, including children with lactic acidosis, and the data from this study would potentially provide a therapeutic method for acute rescue of neonates.