Early Determinants of Pulmonary Vascular Remodeling in Animal Models of Complex Congenital Heart Disease

In this article, we review the current state of knowledge about early changes in the pulmonary vasculature that result from persistent systemic-to–pulmonary arterial shunting in newborn lambs. Data generated in this model system may be important in children with various forms of congenital heart disease (CHD), but perhaps most so in those with single-ventricle anomalies. Children born with a functional single ventricle (eg, hypoplastic left heart syndrome, tricuspid atresia, or pulmonary atresia) represent a subgroup of patients with CHD with the poorest outcome, with 5-year mortality rates up to 50%.1 Although functionally single-ventricle heart disease comprises many structural variants, a shared physiological feature is that both systemic and pulmonary circulations are supplied in parallel by a functionally single pumping chamber. Immediately after birth, the pulmonary vasculature of these infants is exposed to abnormal conditions, such as increased flow or pressure.2,–,4 Over time, if these abnormal forces are not modified, they can lead to progressive functional and morphological abnormalities in the pulmonary vasculature that are characterized by altered reactivity, increased resistance, and structural alterations (remodeling).3 Clinically, these abnormalities can have an important impact on surgical options and perioperative outcome. The current approach to neonates with a functional single ventricle is to establish a controlled, low-pressure source of pulmonary blood flow that facilitates systemic oxygen delivery sufficient to permit somatic growth and development without excessive ventricular volume loading, typically by means of a surgical systemic-to–pulmonary artery or ventricle-to–pulmonary artery conduit or by restricting the main or branch pulmonary arteries.2 The pulmonary-to-systemic blood flow balance can be difficult to achieve, and the infant runs the gauntlet between pulmonary blood flow that is too low (resulting in chronic hypoxemia and the potential consequences thereof) or …