Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is defined foremost by a distinct pulmonary vascular pathophenotype that occurs as a result of dysregulated vascular cell proliferation, intimal and medial hypertrophy, inflammation, and fibrosis. This plexogenic arteriopathy with subtotal luminal obliteration increases pulmonary vascular resistance and imposes a hemodynamic stress on the right ventricle (RV). The chronically increased afterload leads to RV hypertrophy and failure that contributes to premature death. Owing to the functional interrelatedness of the pulmonary vasculature and the RV, these 2 compartments are increasingly considered as a collective unit and assessed by examining RV-pulmonary arterial coupling in studies that focus on the pathophysiology of PAH.1 Ideal RV-pulmonary arterial coupling is present when contractility of the RV is sufficient to match the afterload imposed by the pulmonary artery, which is determined by its distensibility or compliance, and is recognized by minimal pressure fluctuation during systole.2 Optimal RV-pulmonary arterial coupling may be defined further based on the ratio of ventricular to arterial elastance, which typically achieves a ratio of 1.5:2.0 and reflects a balance between RV work and oxygen consumption.3 RV-pulmonary arterial uncoupling, therefore, occurs when there is a mismatch between RV contractility and pulmonary arterial compliance. Based on this premise, it is now acknowledged that factors that decrease normal pulmonary vascular compliance to increase resistance adversely affect RV-pulmonary arterial coupling kinetics. This results in a decline in ventricular efficiency and an increased probability of developing right-sided heart failure.4 Similarly, a decrease in RV contractility owing to RV cardiomyocyte dysfunction or impaired RV myocardial performance decreases RV tolerance to increased afterload and lowers the threshold at which pulmonary vascular disease may become clinically evident.5Although PAH is a disease of pulmonary vascular origin with subsequent effects on the RV, the pathobiology and PAH disease severity may be subject …