Abstract 1348: Reduction of L-type Ca2+ Current Results in Electrocardiographic Abnormalities in α1D L-Type Ca2+ Channel Knock Out Mice
Background - The novelα1D Ca2+ channel together with the α1C Ca2+ channel contributes to the L-type Ca2+ current (ICa-L) in the mouse supraventricular tissue. In this study, we characterized the electrophysiological features ofα1D Ca2+ channel in the atria using α1D gene knockout (KO) mice.
Methods and Results - Surface ECG demonstrated significant sinus bradycardia, atrio-ventricular block (AV-block) and atrial arrhythmias in the α1D KO mice. The heart rate was 551.2 ± 58.6 beat/min in the wild type (WT) mice vs. 303.5 ± 72.4 beat/min in α1D KO mice (P<<med>0.05). The alpha1D KO mice had prolonged P-R interval (45.07 ± 1.96 ms in α1D KO vs. 33.5 ± 2.02 ms in WT mice, P < 0.05), and exhibited first and second degree AV-block. Sinus node recovery time (SNRT) was also prolonged in the alpha1D KO mice (660 ± 33 in α1D KO mice vs. to 407 ± 91 in WT mice). Three out of 15 α1D KO mice exhibited spontaneous atrial fibrillation (AF) and all KO mice were readily inducible for AF. None of the WT mice showed either spontaneous or inducible AF. Single isolated atrial cells showed reduced ICa-L density from 4.65 ± 0.3 pA/pF in WT to 3.51 ± 0.2 pA/pF in α1D KO mice (P<0.05), without any significant changes in the current density of INa, If, IK, Ito and ICa-T. Intracellular Ca2+ transient [CaiT] assessed during field stimulation (0.5 Hz, 35.5°C) was significantly reduced in KO mice (n=22, P<0.05) indicating that excitation-contraction coupling is compromised at the single cell level.
Conclusions: Genetic deletion of α1D Ca2+ channel leads to sino-atrial electrocardiographic abnormalities and AF in the KO mice. These electrical abnormalities are associated with a decrease in L-type Ca2+ current density and [CaiT] without alterations of other major atrial current densities. Together, abnormal transarcolemmal Ca2+ fluxes and altered intracellular Ca2+ homeostasis may contribute to atrial arrhythmias in the KO mice.