TY - JOUR
T1 - Right ventricular adaptation and failure in pulmonary arterial hypertension
AU - Ryan, John J.
AU - Huston, Jessica
AU - Kutty, Shelby
AU - Hatton, Nathan D.
AU - Bowman, Lindsay
AU - Tian, Lian
AU - Herr, Julia E.
AU - Johri, Amer M.
AU - Archer, Stephen L.
N1 - Funding Information:
This article was supported by NIH 1R01HL113003-01A1 (S.L.A.), NIH 2R01HL071115-08 (S.L.A.), Canada Foundation for Innovation (S.L.A.), Tier 1 Canada Research Chair in Mitochondrial Dynamics and Translational Medicine (S.L.A.), the American Heart Association (A.H.A.) (S.L.A., S.K.), the William J. Henderson Foundation (S.L.A.), Heart and Stroke Foundation of Canada (A.J.), Canadian Vascular Network Scholar Award (L.T.).
Publisher Copyright:
© 2015 Canadian Cardiovascular Society.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.
AB - Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.
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U2 - 10.1016/j.cjca.2015.01.023
DO - 10.1016/j.cjca.2015.01.023
M3 - Review article
C2 - 25840092
AN - SCOPUS:84961288123
SN - 0828-282X
VL - 31
SP - 391
EP - 406
JO - Canadian Journal of Cardiology
JF - Canadian Journal of Cardiology
IS - 4
ER -