Multiscale Computational Modeling of the Cardiopulmonary Consequences of Postnatal Hyperoxia with Implications for Preterm Born Children.

Moderate to extreme preterm birth (<32 weeks gestation) affects cardiopulmonary structure and function and is associated with increased risk of heart failure through adulthood. Rodent models capture biventricular changes, including at the cell- and organ-scale, and pulmonary vascular remodeling seen in preterm humans. However, synthesizing these measures across scales and organ systems is challenging. We hypothesized that in-silico modeling of biventricular mitochondrial, myofiber, and organ-scale function plus circulatory function could capture key features of cardiopulmonary abnormalities due to preterm birth. Therefore, we calibrated a multiscale model to subject-specific biventricular pressure-volume data from a hyperoxic rat model of preterm birth alongside normoxic controls to investigate the impact of preterm birth on multiscale cardiopulmonary function. The calibrated model demonstrates excellent agreement with the data and captures the expected increases in pulmonary vascular resistance and right ventricular dilation also seen in preterm born. Simulations also predict an increase in right ventricular myofiber power and rapid septal wall flattening with subsequent rapid return to normal curvature, or "septal bounce." By calibrating a multiscale model to organ-scale data, we identified correlations between septal motion, pulmonary arterial resistance, and right ventricular myofiber power, suggesting that septal bounce may be a non-invasive marker of preterm right ventricular dysfunction severity. Our multiscale modeling approach captures cardiopulmonary abnormalities across spatial scales and provides an innovative approach to explore the consequences of preterm birth beyond experimental data alone. This is a foundational step in understanding the impact of preterm birth on cardiopulmonary disease in childhood as well as adulthood.