Abstract 322: Role of T-Type Calcium Current in Cardiac Remodeling Probed with Genetically Engineered Knockout Mice

Abstract

Background: Previous studies suggested that T-type Ca 2+ -current (I CaT ) blockers suppress disease-related cardiac remodeling, but all available I CaT -blockers have non-specific actions on other currents and/or functions. To obtain a clearer sense of the role of I CaT in cardiac remodeling, we studied mice with the principal cardiac I CaT subunit (Cav3.1) knocked out. Methods: Adult male Cav3.1 knockout mice (KO) were compared with wild type (WT). LAD-ligation was performed to create anterior-wall myocardial infarction (MI). Echocardiography was used to evaluate cardiac performance at baseline, 2-w and 4-w post-MI. Intracardiac programmed stimulation was performed 4-w post-MI. Standard pacing protocols were used to determine atrial and ventricular electrophysiological properties and to induce arrhythmias. Results: Surface ECG parameters were examined in 10 KO and 10 WT mice prior to LAD ligation. At baseline, PQ interval was significantly longer in KO mice than in WT animals (44 ± 1 ms vs 40 ± 1 ms, respectively; p < 0.05); no significant differences were observed in RR, QRS or QTc intervals. At 10 minutes post-MI, WT (but not KO) mice showed increased heart rate (p = 0.002). Baseline echocardiography showed smaller LV fractional shortening (FS) and ejection fraction (EF) in KO mice compared with WT (34 ± 1% KO vs 42 ± 3% WT; 69 ± 2% KO vs 77 ± 3% WT; respectively, p < 0.05). At 4-w post-MI, FS and EF of KO mice were still smaller than WT mice (15.5 ± 1.6% vs 21.0 ± 1.5%; 37.4 ± 3.2% vs 48.1 ± 2.8%, respectively; p < 0.05). At baseline and 4-w post-MI, the contractility index (pressure-volume curves) was decreased in KO mice (p < 0.05). Intracardiac electrophysiological recordings revealed no differences in atrial and ventricular ERP or sinus node recovery time for WT vs KO. At 4-w post-MI, extrastimuli induced sustained atrial fibrillation (> 2 s) in 60% (6/10) KO mice, versus 17% (1/6) in WT (p = 0.05) and ventricular tachyarrhythmias in 82% (9/11) of KO mice versus 17% (1/6) of WT (p < 0.01). Conclusion: Contrary to previous studies with (imperfectly selective) pharmacological agents having T-type Ca 2+ channel blocking actions, our findings suggests that reductions in I CaT do not favorably alter post-MI remodeling and may negatively affect cardiac function and arrhythmias.