Abstract 1877: Potential Adaptive Role of T-Type Calcium Current Upregulation after Myocardial Infarction
Previous studies suggested that T-type Ca2+ current (ICaT) is up-regulated in response to hypertrophic signals in adult feline and rat left ventricular myocytes, whereas L-type Ca2+ current (ICaL) is unaltered or decreased. To assess more precisely the role of ICaT in cardiac remodeling, we studied mice with the principal cardiac ICaT subunit (Cav3.1) intact (wild type, WT) or knocked out (KO). Adult male KO and WT mice were studied at baseline and 4 wks post-myocardial infarction (MI). Whole cell patch-clamp was applied to record ICaL and ICaT in isolated ventricle cardiomyocytes. Intracardiac programmed stimulation was performed to induce tachyarrhythmias. Quantitative PCR was used to investigate mRNA expression. ICaL density was similar for WT and KO mice at baseline, but ICaL activation showed a slight (3.4 mV) negative voltage shift in KO mice. In WT mice, peak ICaT was substantially smaller than ICaL (e.g. 1.3 ± 0.1 pA/pF vs 10.7 ± 0.8 pA/pF*, *P < 0.05), but ICaT was nearly absent in KO mice (peak 0.2 ± 0.1 pA/pF). At 4 wks post-MI, ICaL was significantly decreased in WT and KO mice (peak ICaL density decreased by 37%* and 26%*, respectively). ICaT was upregulated post-MI in WT mice (peak ICaT increased from 1.3 ± 0.1 to 1.9 ± 0.1 pA/pF, p < 0.001), with no significant change from baseline values in KO mice. Echocardiography showed smaller baseline LV fractional shortening (FS) and ejection fraction (EF) in KO mice compared with WT. LVFS and LVEF decreased significantly post-MI in both groups, with KO values (FS 14 ± 1%; EF 33 ± 3%) remaining significantly smaller than WT (20 ± 1%*, 47 ± 2%* respectively). Cav3.1 mRNA expression was ~3-fold greater than Cav3.2 in WT and was undetectable in KO, confirming KO of the major cardiac ICaT subunit. At 4-wk post-MI, ventricular tachyarrhythmia was inducible in 83% (10/12) of KO mice vs. 25%* (3/12) of WT. Our results show for the first time that ICaT upregulation occurs post-MI in mice, and suggest that this change may be an adaptive response of the Ca2+-current system. Contrary to previous studies suggesting anti-remodeling benefit with imperfectly selective pharmacological ICaT inhibitors, our findings suggest that ICaT suppression is not beneficial and may even be detrimental post-MI.