1 Abstract—Contrasting with the major attention that left heart failure has received, right heart failure remains understudied both at the preclinical and clinical levels. However, right ventricle failure is a major predictor of outcomes in patients with precapillary pulmonary hypertension because of pulmonary arterial hypertension, and in patients with postcapillary pulmonary hypertension because of left heart disease. In pulmonary hypertension, the status of the right ventricle is one of the most important predictors of both morbidity and mortality. Paradoxically, there are currently no approved therapies targeting the right ventricle in pulmonary hypertension. By analogy with the key role of β-blockers in the management of left heart failure, some authors have proposed to use these agents to support the right ventricle function in pulmonary hypertension. In this review, we summarize the current knowledge on the use of β-blockers in pulmonary hypertension. (Circ Heart Fail. 2017;10:e003703. DOI: 10.1161/CIRCHEARTFAILURE.116.003703.) Key Words: β-blocker ■ heart failure ■ heart ventricles ■ hypertension, pulmonary ■ receptors, adrenergic ■ sympathetic nervous system © 2017 American Heart Association, Inc. Circ Heart Fail is available at http://circheartfailure.ahajournals.org DOI: 10.1161/CIRCHEARTFAILURE.116.003703 Received November 3, 2016; accepted February 24, 2017. From the University Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France (F.P., F.A., G.S., M.H.); AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France (F.P., F.A., G.S., M.H.); Inserm UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France (F.P., F.A., G.S., M.H.); Department of Pulmonology, VU University Medical Centre, Amsterdam, The Netherlands (F.S.d.M., H.J.B.); Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Ville de Québec, Canada (S.B., S.P.); Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Italy (N.G.). *Drs Galiè and Humbert contributed equally to this work. Correspondence to Frédéric Perros, PhD, INSERM U999, Centre Chirurgical Marie Lannelongue, 133, Ave de la Résistance, F-92350 Le Plessis Robinson, France. E-mail frederic.perros@inserm.fr Use of β-Blockers in Pulmonary Hypertension Frédéric Perros, PhD; Frances S. de Man, PhD; Harm J. Bogaard, MD; Fabrice Antigny, PhD; Gérald Simonneau, MD; Sébastien Bonnet, PhD; Steeve Provencher, MD; Nazzareno Galiè, MD*; Marc Humbert, MD, PhD* Advances in Heart Failure P ulmonary hypertension (PH) is defined by an increase in mean pulmonary arterial pressure ≥25 mm Hg at rest as assessed by right heart catheterization. PH has been classi- fied into 5 clinical subgroups. 1 PH results from an increase in pulmonary vascular resistance, which is because of either an active remodeling of distal pulmonary arteries (pulmonary arterial hypertension [PAH]: group 1 of the PH classification), a consequence of passive back stream elevation in left heart pressures with elevated pulmonary artery wedge pressure (PH complicating left heart disease [LHD-PH]: group 2) or lung parenchymal changes and consequent capillary bed reduction resulting in chronic alveolar hypoxia, pulmonary vasoconstric- tion, and remodeling of distal pulmonary arteries (PH caused by lung diseases: group 3). Other PHs include PH caused by chronic thromboembolic pulmonary disease (group 4) and miscellaneous/complex disorders (group 5). In this review, we focus on the use of β-blockers in groups 1 and 2, which is the best documented and relevant use of these molecules in PH. PAH therapies targeting endothelial dysfunction have been successfully developed in recent years in PAH, 2 whereas LHD-PH and PH caused by lung diseases should be managed by treating the cardiopulmonary causal condition. 1 Because right heart failure (RHF) is the leading cause of death in PH, some authors have hypothesized to support right ventricular (RV) function with β-blockers, by analogy with the key role of β-blockers in the management of left heart failure (LHF). 3,4 However, this is certainly an oversimplification. Indeed, the left ventricle (LV) and the RV have a distinct embryological origin, critical differences in their metabolism, vascularity or response to pressure overload. 5,6 Overall the RV seems to be less able to adapt to pressure overload than the LV. Thus, it is not possible to extrapolate knowledge-derived from the stud- ies on LV to the studies on RV. 5,6 Evidence for β-blocker use in PH is currently lacking. β-blocker use remains contraindicated in PAH unless required by comorbidity. 1 Moreover, the proportion of PH cases in the randomized controlled trials with β-blockers in patients with LHD has not been reported and limited data exist about the efficacy of β-blockers in PH caused by lung diseases. In this review, we report and discuss the data on the use of β-blockers in human PH (groups 1 and 2) and experimental animal models of PH. We propose a comprehensive overview on this contem- porary, controversial, and translational topic, to guide further experimental and clinical research according to PH groups. Preclinical Data Preclinical studies have shown benefit of β-blocker therapy in experimental PH and associated RHF. The first studies were Downloaded from http://ahajournals.org by on June 8, 2020