Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension

• Published in: Circulation. Heart failure Vol. 5; no. 1; pp. 97 - 105
• Main Authors: de Man, Frances S, Handoko, M Louis, van Ballegoij, Joris J M, Schalij, Ingrid, Bogaards, Sylvia J P, Postmus, Pieter E, van der Velden, Jolanda, Westerhof, Nico, Paulus, Walter J, Vonk-Noordegraaf, Anton
• Format: Journal Article
• Language: English
• Published: United States 01.01.2012
• Subjects: Adrenergic beta-1 Receptor Antagonists - pharmacology; Adrenergic beta-1 Receptor Antagonists - therapeutic use; Animals; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Bisoprolol - pharmacology; Bisoprolol - therapeutic use; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Echocardiography; Fibrosis; Heart Failure - diagnostic imaging; Heart Failure - etiology; Heart Failure - prevention & control; Heart Ventricles - diagnostic imaging; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - complications; Hypertension, Pulmonary - drug therapy; Male; Monocrotaline - adverse effects; Rats; Rats, Wistar; Signal Transduction - drug effects; Signal Transduction - physiology; Vascular Resistance - drug effects; Vascular Resistance - physiology
• ISSN: 1941-3289; 1941-3297
• DOI: 10.1161/circheartfailure.111.964494

In pulmonary arterial hypertension (PH), sympathetic adrenergic activity is highly elevated. Sympathetic overactivity is a compensatory mechanism at first, but might be detrimental for cardiac function in the long run. We therefore investigated whether chronic low-dose treatment with bisoprolol (a cardioselective β-blocker) has beneficial effects on cardiac function in experimental PH. PH was induced in rats 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) or vehicle (n=7/group). At end of study (body mass loss >5%), echocardiography was repeated, with additional pressure-volume measurements and histomolecular analyses. Compared with control, right ventricular (RV) systolic pressure and arterial elastance (measure of vascular resistance) more than tripled in PH. Bisoprolol delayed time to right heart failure (P<0.05). RV afterload was unaffected, however, bisoprolol treatment increased RV contractility and filling (both P<0.01), and partially restored right ventriculo-arterial coupling and cardiac output (both P<0.05). Bisoprolol restored RV β-adrenergic receptor signaling. Histology revealed significantly less RV fibrosis and myocardial inflammation in bisoprolol treated PH rats. In experimental PH, treatment with bisoprolol delays progression toward right heart failure, and partially preserves RV systolic and diastolic function. These promising results suggest a therapeutic role for β-blockers in PH that warrants further clinical investigation.