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Pathobiology of pulmonary arterial hypertension and right ventricular failure.

ABSTRACT: Pulmonary arterial hypertension (PAH) is no longer an orphan disease. There are three different classes of drugs for the treatment of PAH that are currently being used and an increasing number of patients are being treated with a single drug or combination therapy. During the last 25 yrs, new insights into the pathobiology of PAH have been gained. The classical mechanical concepts of pressure, flow, shear stress, right ventricle wall stress and impedance have been complemented with the new concepts of cell injury and repair and interactions of complex multicellular systems. Integrating these concepts will become critical as we design new medical therapies in order to change the prognosis of patients with these fatal diseases. This review intends to summarise recent pathobiological concepts of PAH and right ventricle failure mainly derived from human studies, which reflect the progress made in the understanding of this complex group of pulmonary vascular diseases.

SUBMITTER: Voelkel NF

PROVIDER: S-EPMC4019748 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Pathobiology of pulmonary arterial hypertension and right ventricular failure.

Voelkel Norbert F NF Gomez-Arroyo Jose J Abbate Antonio A Bogaard Harm J HJ Nicolls Mark R MR

The European respiratory journal 20120627 6

Pulmonary arterial hypertension (PAH) is no longer an orphan disease. There are three different classes of drugs for the treatment of PAH that are currently being used and an increasing number of patients are being treated with a single drug or combination therapy. During the last 25 yrs, new insights into the pathobiology of PAH have been gained. The classical mechanical concepts of pressure, flow, shear stress, right ventricle wall stress and impedance have been complemented with the new conce ...[more]

PMID: 22743666

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Project description: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 ?-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.

Project description:Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. We test the hypothesis that PH promotes spontaneous ventricular fibrillation (VF) during a critical post-PH onset period characterized by a sudden increase in mortality.Rats received either a single subcutaneous dose of monocrotaline (MCT, 60 mg/kg) to induce PH-associated RVF (PH, n=24) or saline (control, n=17). Activation pattern of the RV-epicardial surface was mapped using voltage-sensitive dye in isolated Langendorff-perfused hearts along with single glass-microelectrode and ECG-recordings. MCT-injected rats developed severe PH by day 21 and progressed to RVF by approximately day 30. Rats manifested increased mortality, and ?30% rats died suddenly and precipitously during 23-32 days after MCT. This fatal period was associated with the initiation of spontaneous VF by a focal mechanism in the RV, which was subsequently maintained by both focal and incomplete reentrant wave fronts. Microelectrode recordings from the RV-epicardium at the onset of focal activity showed early afterdepolarization-mediated triggered activity that led to VF. The onset of the RV cellular triggered beats preceded left ventricular depolarizations by 23±8 ms. The RV but not the left ventricular cardiomyocytes isolated during this fatal period manifested significant action potential duration prolongation, dispersion, and an increased susceptibility to depolarization-induced repetitive activity. No spontaneous VF was observed in any of the control hearts. RVF was associated with significantly reduced RV ejection fraction (P<0.001), RV hypertrophy (P<0.001), and RV fibrosis (P<0.01). The hemodynamic function of the LV and its structure were preserved.PH-induced RVF is associated with a distinct phase of increased mortality characterized by spontaneous VF arising from the RV by an early afterdepolarization-mediated triggered activity.

Dataset Information

Pathobiology of pulmonary arterial hypertension and right ventricular failure.

Publications

Pathobiology of pulmonary arterial hypertension and right ventricular failure.

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