The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure

Abstract

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.

Keywords: Forkhead box protein O1 (FOXO1); G protein receptor kinase 2 (GRK2); adrenergic receptors; fluorodeoxyglucose; glutamine; glycolysis; pyruvate dehydrogenase complex.

Figure 1

Increased glycolysis in the right ventricle (RV) in right ventricular hypertrophy (RVH) in PAH patients. (A) The cross sections of RVs from patients with adaptive versus maladaptive RVH. RV chambers are enlarged in both patients however adaptive RVH is concentric with less dilatation and fibrosis. (B) Immunostaining shows up-regulation of Glut1 and PDK4 expression in RV myocytes and is less profound in the PAH patient with adaptive RVH. (C) Imaging modalities showing RV dilatation in MRI, RV fibrosis in MRI and increased FDG uptake in PET scan. The figure is partially adapted from references^{, ,} with permission.

Figure 2

Vicious cycle of right ventricular failure including metabolic changes and RV ischemia.

Figure 3

Decreased capillary density in animal models of maladaptive PAH but not in adaptive PAH.

Figure 4

A: Mechanism of impaired glucose oxidation and enhanced glycolysis in RVH. In RVH, activation of various transcription factors, including FOXO1, cMyc and HIF-1α upregulates expression of many glycolytic gene. A common finding in RVH is increased PDK expression, which inhibits PDH and reduces mitochondrial respiration. PDK activation also occurs in the lung in PAH, although the transcriptional regulation and isoform specificity may differ than that seen in the RV. Dichloroacetate inhibits PDK and thereby promotes glucose oxidation and inhibits glycolysis. ETC = electron transport chain, HK = hexokinase, H₂O₂ = hydrogen peroxide, LDHA = lactate dehydrogrenase A, PFK = phosphofructokinase. Adapted from B: The Randle cycle in RVH The inhibition of β-FAO by trimetazidine and ranolazine increases PDH activity and improves GO. This reciprocal relationship between GO and FAO is referred to as the Randle cycle. Adapted with permission from . C: Proposed mechanism of glutaminolysis in RVH. RV ischemia and capillary rarefaction activate cMyc and Max, which increases glutamine uptake and production of α-ketoglutarate (α-KG). α-KG enters Krebs’ cycle leading to production of malate. Krebs’ cycle-derived malate generates cytosolic pyruvate, which is converted by lactate dehydrogenase A (LDHA) to lactate. In conditions of high glutaminolysis GO is inhibited. Reproduced from (Illustration Credit: Ben Smith).

Figure 5

(A)DCA Reduces Glut-1 expression in RV in monocrotaline-PAH. (B) DCA Reduces FDG uptake on in RV on PET scan in monocrotaline-PAH. (C) DCA Improves RV function in monocrotaline-PAH.(D)Representative traces and mean data showing MAPD20 and MAPD90 are significantly prolonged in the monocrotaline (MCT) group vscontrol (CTR) and that repolarization is improved by DCA. (E) Representative traces and mean data of lead II surface ECG. DCA reduces the QTc prolongation in RVH. Red highlighted arrows indicate QTc intervals. Adapted with permission from ^,

Figure 5

(A)DCA Reduces Glut-1 expression in RV in monocrotaline-PAH. (B) DCA Reduces FDG uptake on in RV on PET scan in monocrotaline-PAH. (C) DCA Improves RV function in monocrotaline-PAH.(D)Representative traces and mean data showing MAPD20 and MAPD90 are significantly prolonged in the monocrotaline (MCT) group vscontrol (CTR) and that repolarization is improved by DCA. (E) Representative traces and mean data of lead II surface ECG. DCA reduces the QTc prolongation in RVH. Red highlighted arrows indicate QTc intervals. Adapted with permission from ^,