Cardio-Selective Beta-Blocker Therapy Improves Survival and Cardiac Function in Experimental Pulmonary Hypertension

Background – Pulmonary arterial hypertension (PH) eventually leads to right heart failure. The use of β-blockers is strongly discouraged in PH, because of their acute negative inotropic and chronotropic e¡ ects. However, use of β-blockers in chronic (left) heart failure is safe and signi cantly reduces mortality. We investigated whether chronic low-dose treatment with bisoprolol (a cardioselective β1-adrenergic receptor antagonist) has bene cial e¡ ects on mortality and cardiac function in experimental PH. Methods and Results – Progressive PH in rats was induced by a single injection of monocrotaline (60 mg/kg). Pressure-telemetry in PH-rats revealed that 10 mg/kg bisoprolol was the lowest dose that blunted heart rate response during daily activity. Ten days after monocrotaline-injection, echocardiography was performed, and PH-rats were randomized for bisoprolol-treatment (oral gavage; n=7/group). At end-of-study (body mass loss >10%), echocardiography was repeated with additional pressure-volume measurements. After euthanization, heart and lungs were harvested for histomorphological analyses. Echocardiography con rmed PH-status at start-of-treatment. Bisoprolol delayed disease progression and improved survival (p<0.05). Compared to control, RV systolic pressure and arterial elastance (Ea; measure of vascular resistance) more than tripled in PH. RV afterload was una¡ ected, however bisoprolol-treatment increased RV contractility (Ees) and elastance (Eed; both p<0.01), and partially restored RV ventriculo-arterial coupling (Ees/Ea) and cardiac output (both p<0.05). Histology revealed signi cantly less RV brosis and less RV myocardial ina ammation in bisoprolol-treated PH-rats. Conclusions – In experimental PH, treatment with bisoprolol improves survival, RV ventriculoarterial coupling and reduces RV diastolic dysfunction. These promising results suggest a therapeutic role for β-blockers in PH that warrants further clinical investigation. Ch ap te r 5 Bisoprolol in Experimental Pulmonary Hypertension 73