Abstract 15251: Systemic Maternal Inflammation and Neonatal Hyperoxia Induce Remodeling and Left Ventricular Dysfunction in Mice
Aims: Systemic maternal inflammation causes growth retardation, maturation deficits, and preterm birth in the developing fetus. Insults occurring during development can elicit lasting structural or functional effects that lead to adult morbidities. Preterm or small-for-gestational age infants often require life sustaining medical interventions, including oxygen therapy. However, long-term cardiovascular consequences of medical interventions on an immature physiology remain unknown. In the present study, we hypothesized that systemic maternal inflammation and neonatal hyperoxia exposure compromise cardiac structure, resulting in LV dysfunction during adulthood.
Methods and Results: Pregnant C3H/HeN mice were injected on E16 with LPS (80 µg/kg; i.p.) or saline. Offspring were placed in room air (RA) or 85% O2 for 14 days and subsequently maintained in RA. Cardiac echocardiography, cardiomyocyte contractility, and molecular analyses were performed. Echocardiography revealed persistently lower left ventricular fractional shortening with greater left ventricular end systolic diameter from 2 to 8 weeks of life in LPS/O2 than in saline/RA treated mice. Isolated cardiomyocytes from LPS/O2 mice had slower rates of contraction and relaxation, a slower return to baseline length, and reduced contractile reserve in response to a β1-adrenergic agonist than cardiomyocytes isolated from saline/RA controls. SERCA2a protein expression and α-/β-MHC ratio were increased, while Connexin-43 expression was decreased in LPS/O2 mice at 8 weeks. VEGEFA protein expression was decreased at day 3 in LPS/O2 mice, but returned to control levels at day 7. Nox4 protein expression was reduced between days 3 and 14 and capillary density was lower at 8 weeks of life in LPS/O2 mice.
Conclusion: The results of these studies indicate that systemic maternal inflammation combined with neonatal hyperoxia exposure induces alterations in cardiac structure leading to the development of cardiac dysfunction. Furthermore, we conclude that the cardiac deficits involve a shift in MHC isoforms and Nox4-associated decreases in capillary formation. Our data support the hypothesis that perinatal insults can contribute to development of cardiac disease later in life.
- © 2011 by American Heart Association, Inc.