Beta-blockers in pulmonary arterial hypertension: Time for a second thought? [Beta-blockers in pulmonary arterial hypertension: Time for a second thought?]

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 beta 1- receptors and alpha-myosin heavy chain downregulation, downregulation of the sarcoplasmic reticulum Ca(2+)ATPase, and beta-myosin heavy chain upregulation.& nbsp;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.& nbsp;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 beta-blockers according to their different pharmacokinetic and pharmacodynamic profiles.& nbsp;Since the first observation in the clinical setting, showing improvement associated with beta-blocker withdraw in PAH patients, recent studies suggest that the effects of beta-blockers in PAH might be related to the beta 1-adrenergic receptors selectivity and alpha 1- and beta 3-related ancillary properties.& nbsp;While in the advanced stages of PAH beta-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 beta 1-selective blockers and those associated with alpha-or beta 3-activities.& nbsp;At present, all the above are physiologically sound but clinically unproven suggestions, and need to be tested in future randomized controlled trials.