Maladaptive cardiomyocyte calcium handling in adult offspring of hypoxic pregnancy: protection by antenatal maternal melatonin

Chronic fetal hypoxia is one of the most common complications of pregnancy and can programme cardiac abnormalities in adult offspring including ventricular remodelling, diastolic dysfunction and sympathetic dominance. However, the underlying mechanisms at the level of the cardiomyocyte are unknown, preventing the identification of targets for therapeutic intervention. Therefore, we aimed to link echocardiographic data with cardiomyocyte function to reveal cellular mechanism for cardiac dysfunction in rat offspring from hypoxic pregnancy. Further, we investigated the potential of maternal treatment with melatonin as antenatal antioxidant therapy. Wistar rats were randomly allocated into normoxic (21% O₂) or hypoxic (13% O₂) pregnancy with or without melatonin treatment (5 µg/ml; normoxic melatonin in the maternal drinking water from gestational day 6 to 20 (term = 22 days). After delivery, male and female offspring were maintained to adulthood (16 weeks). Cardiomyocytes were isolated from the left and right ventricles, and calcium (Ca²⁺) handling was investigated in field-stimulated myocytes. Systolic and diastolic function was negatively impacted in male and female offspring of hypoxic pregnancy demonstrating biventricular systolic and diastolic dysfunction and compensatory increases in cardiac output. Ca²⁺ transients from isolated cardiomyocytes in offspring of both sexes in hypoxic pregnancy displayed diastolic dysfunction with a reduced rate of [Ca²⁺]_i recovery. Cardiac and cardiomyocyte dysfunction in male and female adult offspring was ameliorated by maternal antenatal treatment with melatonin in hypoxic pregnancy. Therefore, cardiomyocyte Ca²⁺ mishandling provides a cellular mechanism explaining functional deficits in hearts of male and female offspring in pregnancies complicated by chronic fetal hypoxia. KEY POINTS: This study identified significant changes in Ca²⁺ handling within cardiomyocytes isolated from offspring of hypoxic pregnancy including reduced systolic Ca²⁺ transients, impaired diastolic recovery of [Ca²⁺]_i and a greater increase in systolic [Ca²⁺]_i amplitude to β-adrenergic stimulation. These changes in cardiomyocyte Ca²⁺ handling help to explain dysregulation of biventricular systolic and diastolic dysfunction determined by echocardiography. The data show protection against maladaptive cardiomyocyte calcium handling and thereby improvement in cardiac function in adult offspring of hypoxic pregnancy treated with melatonin with doses lower than those recommended for overcoming jet lag in humans. Melatonin treatment alone in healthy pregnancy did cause some alterations in cardiac structure. Therefore, maternal treatment with melatonin should only be given to pregnancies affected by chronic fetal hypoxia.