Ivabradine ameliorates cardiomyopathy progression in a Duchenne muscular dystrophy model rat

Figures

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  Fig. 1.. Baseline telemetry-monitored heart rate in wild type and Duchenne muscular dystrophy rats. In comparison to 1-month-old wild type (WT) rats, 1-month-old DMD rats demonstrated significant tachycardia (*P<0.05) in telemetry-monitored heart rates both in dark and light period (n=3 for each group).

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  Fig. 2.. Time-course effects of single ivabradine administrations on telemetry-monitored heart rate. Ivabradine administrations decreased telemetry-monitored heart rates in 2-month-old Duchenne muscular dystrophy rats (n=3 for each group). The heart rate kept declining until 3 h after the 5.0 mg/kg of ivabradine administration. The administration of ivabradine and ECG recording were performed in the light period. * P<0.05 vs. Vehicle-treated DMD rats. †P<0.05 vs. Ivabradine of 2.5 mg/kg-treated DMD rats.

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  Fig. 3.. Effects of single administrations of ivabradine and carvedilol on tail cuff-monitored heart rate and blood pressure. Blood pressure at systole and heart rate in DMD rats (n=3 for each group) were evaluated by tail-cuff monitoring before and 3 h after the 5.0 mg/kg of ivabradine or 30 mg/kg of carvedilol, a positive control for blood pressure decrease. Although carvedilol administration decreased both in blood pressure and heart rate, ivabradine administration decreased only heart rate (P<0.05). Each line represents the individual values of DMD rat, with the solid lines showing ivabradine administration and the dotted lines showing carvedilol administration.

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  Fig. 4.. Echocardiographic evaluation after 3 months of repeated ivabradine administrations. The echocardiographic evaluation showed no left ventricular (LV) size difference (Panel A), but showed significant LV dysfunction (Panels B and C) and right ventricular (RV) dysfunction (Panel D and F) in vehicle-treated DMD rats after ivabradine administration of 5.0 mg/kg twice a day or vehicle administration for 3 months, as compared with non-treated wild type (WT) rat group. A nonsignificant trend toward LV diastolic dysfunction in vehicle-treated DMD rats was also observed (Panel E). These dysfunctions were significantly ameliorated in ivabradine-treated DMD rats as compared with vehicle-treated DMD rats (Panels B, C, D, E, and F; n=3 for each DMD rat group, and n=4 for WT rat group). * P<0.05 vs. wild type (WT) rats. †P<0.05 vs. vehicle-treated DMD rats.

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  Fig. 5.. Histopathological myocardial evaluation after 3 months of ivabradine administration. Representative histopathological images from vehicle-treated DMD rats demonstrated significant fibrosis (blue-stained area by Masson’s trichrome stain) after ivabradine administration of 5.0 mg/kg twice a day or vehicle administration for 3 months, as compared with the non-treated wild type (WT) rat group. A trend toward ameliorated myocardial fibrosis was observed in ivabradine-treated DMD rats (n=3 for each DMD rat group, and n=4 for the WT rat group). * P<0.05 vs. WT rats.