The Robyn Barst Memorial Lecture: Differences between the Fetal, Newborn, and Adult Pulmonary Circulations: Relevance for Age‐Specific Therapies (2013 Grover Conference Series)

Abstract

Pulmonary arterial hypertension (PAH) contributes to poor outcomes in diverse diseases in newborns, infants, and children. Many aspects of pediatric PAH parallel the pathophysiology and disease courses observed in adult patients; however, critical maturational differences exist that contribute to distinct outcomes and therapeutic responses in children. In comparison with adult PAH, disruption of lung vascular growth and development, or angiogenesis, plays an especially prominent role in the pathobiology of pediatric PAH. In children, abnormalities of lung vascular development have consequences well beyond the adverse hemodynamic effects of PAH alone. The developing endothelium also plays critical roles in development of the distal airspace, establishing lung surface area for gas exchange and maintenance of lung structure throughout postnatal life through angiocrine signaling. Impaired functional and structural adaptations of the pulmonary circulation during the transition from fetal to postnatal life contribute significantly to poor outcomes in such disorders as persistent pulmonary hypertension of the newborn, congenital diaphragmatic hernia, bronchopulmonary dysplasia, Down syndrome, and forms of congenital heart disease. In addition, several studies support the hypothesis that early perinatal events that alter lung vascular growth or function may set the stage for increased susceptibility to PAH in adult patients ("fetal programming"). Thus, insights into basic mechanisms underlying unique features of the developing pulmonary circulation, especially as related to preservation of endothelial survival and function, may provide unique therapeutic windows and distinct strategies to improve short-and long-term outcomes of children with PAH.Keywords: pulmonary vascular development, angiogenesis, alveolarization, persistent pulmonary hypertension of the newborn, congenital diaphragmatic hernia, bronchopulmonary dysplasia, Down syndrome, pediatric pulmonary hypertension. Pulmonary arterial hypertension (PAH) is a devastating and progressive disease that is characterized by abnormalities of vascular tone and reactivity, vessel wall structure, growth, and thrombosis. 1 Mechanisms contributing to PAH and its progression are complex and remain incompletely understood. Insights into vascular biology over the past few decades have led to remarkable improvements in the clinical course, outcomes, and survival in adults with PAH, yet relatively few studies have been performed in children. As in adults, PAH contributes to poor outcomes in diverse cardiac, pulmonary, and systemic diseases in newborns, infants, and children (Table 1). 2 There is a clear need to define the natural history of pediatric PAH in diverse settings; to develop new strategies to identify at-risk patients early in their course; and to establish novel approaches to better diagnose, evaluate, and treat children with PAH. 3,4 Despite many similarities between pediatric and adult PAH, critical differences exist that currently limit our clinical appr...

Executive Summary of the American Heart Association and American Thoracic Society Joint Guidelines for Pediatric Pulmonary Hypertension

“…Vascular injury during susceptible periods of lung growth and adaptation can have longstanding effects throughout childhood and may impact distal lung airspace structure as well (6). The most striking examples include the important impact of PVD after premature birth, the contribution of PVD to poor outcomes in many developmental lung diseases, the association of PVD with genetic syndromes (especially Down syndrome), and other factors that reflect both prenatal and postnatal influences that may act through epigenetic mechanisms (7,8). Along with hemodynamic changes during the transition at birth, normal maturation of the lung circulation also plays a critical role during lung organogenesis and formation of the distal airspace through angiocrine signaling, and disruption of endothelial function can impair lung structure in diverse neonatal diseases (9,10).…”

Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice

“…Likely due to the dysregulation of IGF-1 in the neonatal period, a conditional knockout of IGF-1 in SMCs is protective only in neonatal mice exposed to chronic hypoxia, and not in adult mice. This highlights the complexity of the interactions between normal physiological processes and pathophysiologic stimuli, with particular focus on age (43). In addition to implicating IGF-1 in the development of neonatal PH, we have shown that targeting the IGF-1/IGF-1R pathway using a smallmolecule inhibitor can be a possible therapeutic strategy.…”

Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension

“…Broncho‐pulmonary anastomoses, as seen on autopsy of Patient 1 (Figure 1e), are known to be present in early life, during which they may increase in number, but eventually obliterate (McMullan, Hanley, Cohen, Portman, & Riemer, ; Robertson, ). However, it is thought that such connections persist in developmental lung disorders as compared to controls of the same age (Abman et al, ). Broncho‐pulmonary anastomoses have been found in the autopsy specimens of children with the previously mentioned pathologies and in adults with severe idiopathic pHTN (Abman et al, ; Acker et al, ; Bush et al, ; Galambos, Sims‐Lucas, & Abman, ; Galambos, Sims‐Lucas, Abman, & Cool, ).…”