Chronic Perinatal Hypoxia Delays Cardiac Maturation in a Mouse Model for Cyanotic Congenital Heart Disease

Romanowicz, J.; Dhari, Z.; Mulvany, C.; Guerrelli, D.; Reilly, M.; Swift, L.; Vasandani, N.; Ramadan, M.; Ishibashi, N.; Posnack, N.

doi:10.1101/2020.05.28.117648

bioRxiv · 10.1101/2020.05.28.117648

Chronic Perinatal Hypoxia Delays Cardiac Maturation in a Mouse Model for Cyanotic Congenital Heart Disease

Romanowicz, J.·Dhari, Z.·Mulvany, C.·Guerrelli, D.·Reilly, M.·Swift, L.·Vasandani, N.·Ramadan, M.·Ishibashi, N.·Posnack, N.

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Abstract

BackgroundCompared to 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. MethodsMouse dams were housed in hypoxia beginning at embryonic day 16. Pups stayed in hypoxia until postnatal day (P)8 when cardiac development is nearly complete. Global gene expression was quantified at P8 and at P30, after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, and ex-vivo electrophysiology study. ResultsHypoxic animals were 48% smaller than controls. Gene expression was grossly altered by hypoxia at P8 (1427 genes affected), but normalized after recovery (P30). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at P8, which resolved after recovery (P30). Notable differences that persisted after recovery (P30) included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, and a 24% reduction in contractile function in animals exposed to hypoxia. ConclusionsWe 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 electrophysiologic substrate and contractile function warrant further investigation, and may contribute to adverse outcomes observed in the cyanotic CHD population.

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Romanowicz, J., Dhari, Z., Mulvany, C., Guerrelli, D., Reilly, M., Swift, L., Vasandani, N., Ramadan, M., Ishibashi, N., Posnack, N.. 2020-05-30. Chronic Perinatal Hypoxia Delays Cardiac Maturation in a Mouse Model for Cyanotic Congenital Heart Disease. https://doi.org/10.1101/2020.05.28.117648

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