title: Heart rate reduction with ivabradine prevents thyroid hormone-induced cardiac remodeling in rat.
abstract: Ivabradine slows the heart rate (HR) by selectively inhibiting the I(f) current in the sinus node without a negative inotropic effect. We aimed to investigate the effects of ivabradine on thyroid hormone-induced left ventricular (LV) remodeling and ion channel activity in rats. Thirty Sprague-Dawley rats were randomly selected into the groups of control, injection of L-thyroxine (T4, 100 μg/kg/day), and injection of L-thyroxine with ivabradine (T4-Iva, T4 + 10 mg/kg/day). Circumferential (S circ), radial (S rad), and longitudinal (S long) strains were assessed by speckle tracking echocardiography (STE). Myocardial width and fibrosis were assessed from histological LV cross sections, and electrophysiological analysis was done by patch clamp method. In comparison with the control group, the T4 group showed significantly increased HR and LV end-systolic diameter (LVESD), reduced S circ (-16.04 ± 3.95 vs. -7.84 ± 2.98 %, p < 0.001), S rad (20.94 ± 3.81 vs. 40.57 ± 6.70 %, p < 0.001), and S long (-15.26 ± 5.15 vs. -23.83 ± 5.19 %, p < 0.001), despite the 59.5 % increase of average I Ca,L density at 0 mV (13.4 ± 1.2 pA/pF) compared to control group (8.4 ± 0.8 pA/pF). Treatment with ivabradine significantly reduced HR and LVESD, improved SRcirc, S long and SRlong in the T4 group, and the average I Ca,L density at 0 mV in T4-Iva groups (9.9 ± 1.6 pA/pF) was restored to the control level. Morphologically, the T4 group showed significantly increased cardiomyocyte width (25.3 ± 1.89 vs. 18.90 ± 1.14 μm in control, p < 0.001) and fibrosis, which were not significantly changed by ivabradine. In conclusion, selective HR reduction by ivabradine attenuates thyroid hormone-induced reduction of myocardial deformation and altered intracellular Ca(2+) handling without modification of the myocyte hypertrophy with fibrosis in rats.
authors.affiliation: Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea.
authors.forename: Bo Hyun
authors.initials: BH
authors.lastname: Kim
authors.forename: Kyoung Im
authors.initials: KI
authors.lastname: Cho
authors.forename: Seong Man
authors.initials: SM
authors.lastname: Kim
authors.forename: Nari
authors.initials: N
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Jee Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: In Ju
authors.initials: IJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D004195:Disease Models, Animal; D005355:Fibrosis; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006980:Hyperthyroidism / Q000139:chemically induced / Q000150:complications*; D000077550:Ivabradine; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume / Q000187:drug effects; D013974:Thyroxine; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D000077550:Ivabradine; D013974:Thyroxine