Potentials of ivabradine to improve cardiac function in dogs with naturally occurring, asymptomatic degenerative mitral valve disease

Abstract

The main hypothesis of the present study is that ivabradine (1.0 mg/kg, orally, twice daily) can reduce heart rate (HR), myocardial oxygen consumption (MVO2) and improve cardiac function in dogs with degenerative mitral valve disease (DMVD) partly due to a reduction of cardiomyocyte apoptosis. In order to test the hypothesis, this study was divided into three parts. The first part aimed to determine the appropriate single oral dose of ivabradine for reduction of HR and MVO2 as assessed by rate-pressure product (RPP= HR x systolic blood pressure). Once the appropriate dose was achieved, the second part was conducted to investigate the long-term effects of repeated oral dose of ivabradine on MVO2, blood pressure (BP), ventricular function, electrocardiographic (ECG) parameters and HR variability (HRV). Simultaneously with study part 2, the study part 3 aimed to evaluate cardiomyocyte apoptosis by investigated the ratio of Bax (pro-apoptotic protein) to Bcl-2 (anti-apoptotic protein) from the endomyocardial tissues compared between before and 3 months after treatment with ivabradine. In the study part 1, seven beagles with naturally occurring DMVD stage B2 were instrumented with the Holter recorder and an oscillometric device to measure ECG and BP for 24 and 12 h, respectively, after drug administration. Each dog was randomly subjected to receive either placebo or ivabradine (0.5, 1.0 and 2.0 mg/kg). The results revealed that oral administration of ivabradine significantly decreased the HR and RPP in a dose-dependent manner without any significant adverse effects. The highest dose of 2.0 mg/kg significantly reduced systolic and mean BP. Therefore, the findings imply that a single oral administration of ivabradine at a dose of 1.0 mg/kg is suitable for dogs with asymptomatic DMVD to reduce the HR and MVO2 without remarkable effects on BP. For the study part 2, four beagles with naturally occurring DMVD stage B2 were instrumented with a 24-h Holter recorder to measure HR and HRV, a device to acquire HR and BP to calculate RPP, ECG to measure cardiac electrical activity and an echocardiography to measure cardiac function. Dogs were given ivabradine (1.0 mg/kg twice daily, orally) for 3 months. Data were obtained at baseline and monthly after oral administration of ivabradine for 3 months (M1 = 1 month, M2 = 2 months, and M3 = 3 months). The results revealed that chronic administration of IVA significantly decreased the HR, BP, and RPP without adverse effects (P < 0.05). All indices of time- and frequency- domains of HRV at M3 were increased significantly when compared with baseline values (P < 0.05). Indices of speckle-tracking echocardiography including global radial strain, global circumferential strain, and fractional area change measured at M2 and M3 were significantly increased when compared with baseline (P < 0.05). In the study part 3, hemodynamic and cardiac function were assessed by invasive technique at baseline and M3. The results revealed that chronic ivabradine treatment did not affect hemodynamic and cardiac function except for the contractility index in which it was increased. The tissue biopsy from endomyocardium of dogs at before and after treatment revealed that ivabradine decreased cardiac fibrosis and tended to reduce BAX to Bcl-2 ratio which is relating to the reduction in cardiomyocyte apoptosis. All of these results suggested that ivabradine (1.0 mg/kg, orally, twice daily) reduces HR, MVO2 and improve cardiac function in dogs with DMVD partly due to a reduction of cardiomyocyte apoptosis.