Basic Concepts in Heart Failure 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 too high (potentially leading to chronic heart failure, compromised systemic blood flow, and abnormal pulmonary vascular remodeling). Because subsequent stages of surgical palliation (bidirectional or partial cavopulmonary connection, followed by Fontan-type surgery or total cavopulmonary connection) result in passive pulmonary blood flow in the absence of a pumping ventricle, a normal low pulmonary vascular resistance is critical for maintenance of low central venous pressure, overall health, and long-term survival.5 The underlying mechanisms by which some patients with singleventricle physiology experience increased pulmonary vascular resistance that results in failed surgical palliation whereas others do not remain unclear. We speculate that these differences in outcome are related to early, clinically undetectable pulmonary vascular abnormalities. For example, age at surgery correlates with increased transpulmonary gradient postoperatively in infants with a functional single ventricle undergoing and surviving partial cavopulmonary connection (Figure 1). This may be because of the longer duration over which the pulmonary vasculature was exposed to increased flow. Figure 1 suggests that a relatively large surgical shunt with relatively high pulmonary blood flow (thereby allowing for an older age at partial cavopulmonary connection) may lead to a subtly higher transpulmonary gradient (which suggests higher pulmonary vascular resistance) that may be detrimental in the long-term. This suggestion remains speculative because it is unknown whether subtly increased resistance leads to demonstrably worse outcome. However, it is likely that there are subtle differences in signaling pathways or gene-expression variations between patients. These signaling pathways, acted on by the increases in pulmonary blood flow, can then lead to subtle differences in pulmonary vascular resistance that dramatically affect the surgical outcome. The underlying pathways in these newborns with single-ventricle heart disease are only just beginning to be resolved. In this review, we will focus on the work over the last decade that has begun to elucidate the molecular pathways that appear to be important in the initial pulmonary