Impaired Ca2+ homeostasis is associated with atrial fibrillation in the α1D L-type Ca2+ channel KO mouse

Mancarella S, Yue Y, Karnabi E, Qu Y, El-Sherif N, Boutjdir M. Impaired Ca2+ homeostasis is associated with atrial fibrillation in the alpha(1D) L-type Ca2+ channel KO mouse. Am J Physiol Heart Circ Physiol 295: H2017-H2024, 2008. First published September 12, 2008; doi:10.1152/ajpheart.00537.2008. - The novel alpha(1D) Ca2+ channel together with alpha(1C) Ca2+ channel contribute to the L-type Ca2+ current (ICa-L) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the alpha(1D) gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the alpha(1D) Ca2+ channel to the global ICa-L, the intracellular Ca2+ transient, the Ca2+ handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from alpha(1D) KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated alpha(1D) KO atrial myocytes revealed a significant reduction of ICa-L (24.5%; P < 0.05). However, there were no changes in other currents such as I-Na, ICa-T, I-K, I-f, and I-to and no changes in alpha(1C) mRNA levels of alpha(1D) KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca2+ transient (similar to 40%; P < 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca2+ content (P < 0.05) and a 28% reduction (P < 0.05) of fractional SR Ca2+ release in alpha(1D) KO atria. In conclusion, genetic deletion of alpha(1D) Ca2+ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the alpha(1D) KO mice were associated with a decrease in the total ICa-L density, a reduction in intracellular Ca2+ transient, and impaired intracellular Ca2+ handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the alpha(1D) KO mice.