Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients

Abstract

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [ 11 C]-hydroxyephedrine positron emission tomography ([ 11 C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity.[ 11 C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [ 11 C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [ 11 C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [ 11 C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [ 11 C]HED retention index was lower compared to LV tracer uptake (p<0.01) and was related to systolic wall tension (R 2 ¼ 0.4731, p<0.01) and RV function (R 2 ¼ 0.44, p ¼ 0.01). In RV failure, the tolerated dosage of bisoprolol did not result in an improvement of RV function nor in a reduction in RV sympathetic activity.

Diagnosis and Treatment of Right Heart Failure in Pulmonary Vascular Diseases: A National Heart, Lung, and Blood Institute Workshop

“…62 Recommendations for Future Research • Define the normal molecular (genomic, metabolomic, and proteomic) and cellular RV profile as well as the effect of perturbations of these factors. 49,[63][64][65][66] The development of an effective therapy for RV remodeling and dysfunction will face distinct challenges, including (1) inability to use short-term exercise capacity as a primary end point in trials of beta-blockers and possibly other drug classes 67 ; (2) lack of end points focused on remodeling in left-sided heart disease (including improved ventricular function) that are accepted by the Food and Drug Administration and other regulatory agencies; (3) potential proarrhythmic properties of therapies that either (a) initially depress ventricular function before improving it or (b) are inotropes; and (4) the requirement that investigators have equipoise.…”

Neurohormonal modulation in pulmonary arterial hypertension

“…Important triggers for SNS activation are atrial and ventricular stretch: β-AR expression is downregulated specifically in the right ventricle but not in the left ventricle in PAH patients [43], and was related to ventricular wall stress [44]. The role of atrial stretch on SNS activation was shown in studies investigating balloon atrial septostomy.…”

Emerging therapies for right ventricular dysfunction and failure

“…Currently, β-blocker application is not recommended for PAH due to their negative inotropic and chronotropic effects. Clinical studies on the use of β-blockers in PAH had inconsistent results dependent on whether the β1-selective bisoprolol (20,21), or β1-and α1-blockade (carvedilol) was employed. Carvedilol was safe in PAH patients and even normalized pathologically increased RV glucose uptake in PAH (18).…”