The right ventricle (RV) is the major determinant of functional state and prognosis in
pulmonary arterial hypertension. RV
hypertrophy (RVH) triggered by pressure overload is initially compensatory but often leads to RV failure. Despite similar RV afterload and mass some patients develop adaptive RVH (concentric with retained RV function), while others develop maladaptive RVH, characterized by dilatation,
fibrosis, and RV failure. The differentiation of adaptive versus maladaptive RVH is imprecise, but adaptive RVH is associated with better functional capacity and survival. At the molecular level, maladaptive RVH displays greater impairment of angiogenesis,
adrenergic signaling, and metabolism than adaptive RVH, and these derangements often involve the left ventricle. Clinically, maladaptive RVH is characterized by increased N-terminal pro-
brain natriuretic peptide levels,
troponin release, elevated
catecholamine levels, RV dilatation, and late
gadolinium enhancement on MRI, increased (18)fluorodeoxyglucose uptake on positron emission tomography, and QTc prolongation on the ECG. In maladaptive RVH there is reduced inotrope responsiveness because of
G-protein receptor
kinase-mediated downregulation, desensitization, and uncoupling of β-adrenoreceptors. RV
ischemia may result from
capillary rarefaction or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with
cancer including aerobic glycolysis (resulting from a
forkhead box protein O1-mediated transcriptional upregulation of
pyruvate dehydrogenase kinase), and glutaminolysis (reflecting
ischemia-induced cMyc activation). Augmentation of
glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of
pyruvate dehydrogenase kinase,
fatty acid oxidation, or glutaminolysis. Therapeutic targets in RV failure include chamber-specific abnormalities of metabolism, angiogenesis,
adrenergic signaling, and
phosphodiesterase-5 expression. The ability to restore RV function in experimental models challenges the dogma that RV failure is irreversible without regression of pulmonary
vascular disease.