Pulmonary arterial hypertension (PAH) is a heart failure syndrome characterized by right ventricular (RV) to pulmonary circulation uncoupling, counteracted by the sympathetic nervous system activation leading to β1-receptors and α-myosin heavy chain downregulation, downregulation of the sarcoplasmic reticulum Ca2+ATPase, and β-myosin heavy chain upregulation. Increased ventilation (VE) associated with VE inefficiency further characterizes PAH, as shown by an elevated VE versus carbon dioxide relationship slope during exercise, reflecting a specific behavior with progressive increase of dead space (VD) VE. The sympathetic system interacts with chemoreceptor-mediated VE control with increased VD leading to VE/perfusion mismatch. Growing evidence in the experimental models shows beneficial effects of different adrenoreceptor blockers on both right heart and pulmonary artery morphology and function. These effects can significantly change among β-blockers according to their different pharmacokinetic and pharmacodynamic profiles. Since the first observation in the clinical setting, showing improvement associated with β-blocker withdraw in PAH patients, recent studies suggest that the effects of β-blockers in PAH might be related to the β1-adrenergic receptors selectivity and α1- and β3-related ancillary properties. While in the advanced stages of PAH β-blockers may result deleterious as counteract the compensatory adrenergic-mediated effects of low cardiac output, in the early stages the modulation of the adrenergic system could ultimately improve VE efficiency and promote beneficial effects on heart failure gene expression and RV remodeling, particularly β1-selective blockers and those associated with α- or β3-activities. At present, all the above are physiologically sound but clinically unproven suggestions, and need to be tested in future randomized controlled trials.
Reference: Beta-blockers in pulmonary arterial hypertension: Time for a second thought? Badagliacca R, Mercurio V, Romeo E, Correale M, Masarone D, Papa S, Tocchetti CG, Agostoni P; Members of the Study Group on Right and Left Heart Failure of the Italian Society of Cardiology. Vascul Pharmacol. 2022 Mar 3:106974