Bisoprolol Delays Progression Towards Right Heart Failure in Experimental Pulmonary Hypertension

Abstract

Background-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 ␤-blocker) has beneficial effects on cardiac function in experimental PH. Methods and Results-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 (nϭ7/group). At end of study (body mass loss Ͼ5%), 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 (PϽ0.05). RV afterload was unaffected, however, bisoprolol treatment increased RV contractility and filling (both PϽ0.01), and partially restored right ventriculo-arterial coupling and cardiac output (both PϽ0.05). Bisoprolol restored RV ␤-adrenergic receptor signaling. Histology revealed significantly less RV fibrosis and myocardial inflammation in bisoprolol treated PH rats. Conclusions-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 ␤-blockers in PH that warrants further clinical investigation. (Circ Heart Fail. 2012;5:97-105.)Key Words: pulmonary hypertension Ⅲ right ventricular dysfunction Ⅲ ␤-adrenergic receptor blocker Ⅲ pressure-volume relationship Ⅲ Wistar rats P ulmonary arterial hypertension (PH) is a fatal disease, characterized by progressive vascular remodeling and increased right ventricular (RV) afterload, which eventually leads to manifest right heart failure (RHF) and premature death. Current available medical treatments aim to reduce RV afterload, thereby secondarily improving RV function. 1 No treatment is currently available that improves RV function directly, partially because it was not considered a therapeutic target in PH. 2 Clinical Perspective on p 105Recently, several reports have shown that sympathetic activity is increased in patients with PH. [3][4][5][6][7] Similar to left heart failure (LHF), "ventricle-specific" down regulation of ␤ 1 -adrenergic receptors was observed in RV samples of PH patients. 8 In addition, we recently demonstrated that exercise training was detrimental in experimental and progressive PH. 9 The deleterious effects could be related to bouts of exercise-induced sympathetic stimulation.Although increased adrenergic activity is a compensatory mechanism to maintain cardiac function by increasi...

The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

“…As mentioned before, it has been proposed that maladaptive RVH is characterized by capillary rarefaction, 16 myocardial ischemia, 19 fibrosis, 2,20 and cardiomyocyte apoptosis, 2 and more recently it has been reported that the dysfunctional RV is characterized by significant metabolic remodeling and mitochondrial dysfunction. 21 These molecular and cellular changes are associated with a decrease in cardiac output, marked RV dilatation, and decreased exercise capacity.…”

“…Bogaard et al 18 demonstrated that treatment with the nonselective adrenergic blocker carvedilol improved maladaptive RVH functionally and histologically without affecting the lung circulation, and similar effects have been demonstrated utilizing other adrenergic receptor blockers. 19 More recently, Piao et al 12 evaluated the role of adrenergic desensitization in RVF and demonstrated that G protein-coupled receptor kinase 2 mediated an uncoupling of β-adrenergic receptor signaling, therefore impairing inotropic reserve. A particularly interesting finding from this study is that, at least in rats, downregulation of the β1, α1, and dopamine 1 receptors was partially independent of pressure overload.…”

The Adrenergic System in Pulmonary Arterial Hypertension: Bench to Bedside (2013 Grover Conference Series)

“…11 In addition, in PAH animal models β-blockers clearly have beneficial effects. [42][43][44] Why, then, has there not been an attempt to develop an antiadrenergic therapeutic strategy in PAH, where the status of the RV function is a major Figure 6. Chamber-specific norepinephrine (NE) and neuropeptide Y (NPY) depletion in failing right ventricles (RVs) from patients with pulmonary arterial hypertension (PAH).…”

Outcomes of β-blocker use in pulmonary arterial hypertension: a propensity-matched analysis

“…β blockade using carvedilol has been shown to reverse RV remodelling and maladaptive RV hypertrophy and improve RV function in experimental rats, similar to its effect on the left ventricle [9,10]. In addition, bisoprolol has been found to delay RV failure and preserve RV function in experimental pulmonary hypertension [11]. Patients with PAH are also known to have a high prevalence of left ventricular diastolic dysfunction [12], where β blockade may produce a salutary effect.…”