Abstract
Preterm birth increases the risk for pulmonary hypertension and heart failure in adulthood. Oxygen therapy can damage the immature cardiopulmonary system and may be partially responsible for the cardiovascular disease in adults born preterm. We previously showed that exposing newborn mice to hyperoxia causes pulmonary hypertension by 1 year of age that is preceded by a poorly understood loss of pulmonary vein cardiomyocyte proliferation. We now show that hyperoxia also reduces cardiomyocyte proliferation and survival in the left atrium and causes diastolic heart failure by disrupting its filling of the left ventricle. Transcriptomic profiling showed that neonatal hyperoxia permanently suppressed fatty acid synthase (Fasn), stearoyl-CoA desaturase 1 (Scd1), and other fatty acid synthesis genes in the atria of mice, the HL-1 line of mouse atrial cardiomyocytes, and left atrial tissue explanted from human infants. Suppressing Fasn or Scd1 reduced HL-1 cell proliferation and increased cell death, while overexpressing these genes maintained their expansion in hyperoxia, suggesting that oxygen directly inhibits atrial cardiomyocyte proliferation and survival by repressing Fasn and Scd1. Pharmacologic interventions that restore Fasn, Scd1, and other fatty acid synthesis genes in atrial cardiomyocytes may, thus, provide a way of ameliorating the adverse effects of supplemental oxygen on preterm infants.
Highlights
10% of births occur before 37 weeks of gestation and are, considered preterm
We previously showed that hyperoxia causes a loss of the cardiomyocytes wrapping the pulmonary vein by inhibiting their proliferation [29]
Since the pulmonary vein cardiomyocytes are contiguous with the left atria, we investigated whether neonatal hyperoxia altered left atrial morphology
Summary
10% of births occur before 37 weeks of gestation and are, considered preterm. People who were born extremely preterm are 4.6 times more likely to develop pulmonary hypertension and 17 times as likely to suffer heart failure as young adults than people who were born at term [8]. MRI, and CT imaging studies indicate that preterm infants have larger left atria and lower diastolic function than term infants [14,15,16,17]. These changes may be an early and direct response to oxygen exposure because diastolic heart failure has been seen in preterm infants on supplemental oxygen therapies [18]
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