The Right Ventricle in Pulmonary Arterial Hypertension

Abstract

The right ventricle (RV) is the major determinant of functional state and prognosis in pulmonary arterial hypertension (PAH). 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), whilst 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 NT-proBNP levels, troponin release, elevated catecholamine levels, RV dilatation and late gadolinium-enhancement on magnetic resonance imaging, increased 18fluorodeoxyglucose uptake on positron emission tomography and QTc prolongation on the electrocardiogram. In maladaptive RVH there is reduced inotrope responsiveness due to G-protein receptor kinase (GRK2)-mediated downregulation, desensitization and uncoupling of β-adrenoreceptors. RV ischemia may result from capillary rarefaction and/or decreased right coronary artery perfusion pressure. Maladaptive RVH shares metabolic abnormalities with cancer including aerobic glycolysis (resulting from a FOXO1-mediated transcriptional upregulation of pyruvate dehydrogenase kinase, PDK), and glutaminolysis (reflecting ischemia-induced cMyc activation). Augmentation of glucose oxidation is beneficial in experimental RVH and can be achieved by inhibition of PDK, 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.

Bone marrow transplantation prevents right ventricle disease in the caveolin-1–deficient mouse model of pulmonary hypertension

“…The RV eventually fails when this adaptive RV hypertrophy becomes maladaptive. 37 RV fibrosis, a critical indicator of RV maladaptation, was not observed in our hypoxia studies but was clearly present in the spontaneous development of PH in CAV-1 KO mice. One potential explanation for this is that animals in the hypoxia studies were not kept long enough to observe the transition from adaptive to maladaptive RV hypertrophy.…”

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

“…In PAH, obstructive remodeling of the pulmonary vasculature and reduced PA compliance increase pulmonary arterial pressures and right ventricular (RV) workload 4, 5. As PAH progresses, RV function declines, and many patients succumb from RV failure 6, 7. Although RV dysfunction is repeatedly identified as the major risk factor for mortality in PAH,8, 9, 10 the 4 classes of approved pulmonary hypertension medications primarily target the pulmonary vasculature, with little evidence of direct benefit to the RV.…”

Hypoxia-Induced Molecular and Cellular Changes in the Congenitally Diseased Heart: Mechanisms and Strategies of Intervention

“…The insufficient energy production also arises from the switch from an aerobic metabolism to a high glycolytic metabolic profile. Protein kinase D (PDK), which inhibits pyruvate dehydrogenase during glucose oxidation, is a key factor in the deficient energy supply [25,26]. Another aspect of redox imbalance is the extracellular matrix (ECM) modification deriving from the matrix metalloproteinases (MMP) activation, which leads to heart remodelling and fibrosis [27].…”