Melatonin treatment alters cardiopulmonary structure, function, and acute hypoxic response in the newborn lamb

BACKGROUND: Melatonin, an anti-inflammatory-antioxidant neurohormone, is considered for the treatment of neonatal hypoxic-ischemic-encephalopathy. However, its effects on the developing cardiopulmonary system are poorly defined. We investigated how postnatal melatonin administration alters cardiopulmonary structure, function, and responses to acute hypoxia in newborn lambs. METHODS: , n = 9) or vehicle (n = 11) daily from birth to day 5. Echocardiography was performed in 15 lambs (7 melatonin; 8 vehicle; day 5). On day-6, five lambs per group underwent 30-min of hypoxia followed by euthanasia. Cardiovascular physiology, morphology, cardiomyocyte size, gene expression, and lung morphology were analyzed. RESULTS: At normoxia, melatonin-treated lambs showed normal systemic function but altered cardiac hemodynamics and morphology compared to vehicle-treated lambs. During hypoxia, melatonin-treated lambs exhibited a blunted sympatho-circulatory response, with no increase in mean pulmonary arterial pressure and cardiac output. Additionally, heart weight and cardiomyocyte cross-sectional area were reduced, and pulmonary arteriole density increased. Gene expressions showed reduced cardiomyocyte markers in the right ventricle and left atrium but increased protective gene expression in the left ventricle. CONCLUSIONS: Postnatal melatonin triggers notable cardiopulmonary remodeling, reducing physiological flexibility to respond to hypoxic stress, highlighting the need to weigh its therapeutic benefits against potential cardiovascular risks. IMPACT: This study examined the effects of melatonin treatment on the cardiopulmonary system during the early neonatal period in lambs, when endogenous melatonin production is limited. Melatonin induces significant cardiopulmonary remodeling in newborn lambs, characterized by reduced heart weight and ventricular cardiomyocyte size, increased pulmonary arteriole density, and altered cardiac chamber gene expression. While these changes maintain normal cardiovascular function at normoxic-baseline, they compromise the system's ability to respond to acute hypoxia, revealing a diminished physiological flexibility. The study highlights the need to balance melatonin's therapeutic promise with caution regarding its potential developmental consequences on the cardiopulmonary system.