Chronic perinatal hypoxia delays cardiac maturation in a mouse model for cyanotic congenital heart disease.

Compared with acyanotic congenital heart disease (CHD), cyanotic CHD has an increased risk of lifelong mortality and morbidity. These adverse outcomes may be attributed to delayed cardiomyocyte maturation, since the transition from a hypoxic fetal milieu to oxygen-rich postnatal environment is disrupted. We established a rodent model to replicate hypoxic myocardial conditions spanning perinatal development, and tested the hypothesis that chronic hypoxia impairs cardiac development. Pregnant mice were housed in hypoxia beginning at . Pups stayed in hypoxia until () when cardiac development is nearly complete. Global gene expression was quantified at and at , after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, and ex vivo electrophysiology study. Hypoxic animals were 47% smaller than controls with preserved heart size. Gene expression was grossly altered by hypoxia at (1,427 genes affected), but normalized after recovery (). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at , with noticeable resolution after recovery (). Notable differences that persisted after recovery () included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, 23% reduction in ejection fraction, and 16% reduction in fractional shortening in animals exposed to hypoxia. We investigated the impact of chronic hypoxia on the developing heart. Perinatal hypoxia was associated with changes in gene expression and cardiac function. Persistent changes to the electrophysiological substrate and contractile function warrant further investigation and may contribute to adverse outcomes observed in the cyanotic CHD population. We utilized a new mouse model of chronic perinatal hypoxia to simulate the hypoxic myocardial conditions present in cyanotic congenital heart disease. Hypoxia caused numerous abnormalities in cardiomyocyte gene expression, the electrophysiologic substrate of the heart, and contractile function. Taken together, alterations observed in the neonatal period suggest delayed cardiac development immediately following hypoxia.