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Impaired Ca²⁺ homeostasis is associated with atrial fibrillation in the _1D L-type Ca²⁺ channel KO mouse

¹Molecular and Cellular Cardiology Program, Veterans Affairs New York Harbor Healthcare System, ²State University of New York Downstate Medical Center, and ³New York University School of Medicine, New York, New York

Submitted 21 May 2008 ; accepted in final form 2 September 2008

The novel _1D Ca²⁺ channel together with _1C Ca²⁺ channel contribute to the L-type Ca²⁺ current (I_Ca-L) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the _1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the _1D Ca²⁺ channel to the global I_Ca-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 _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 _1D KO atrial myocytes revealed a significant reduction of I_Ca-L (24.5%; P < 0.05). However, there were no changes in other currents such as I_Na, I_Ca-T, I_K, I_f, and I_to and no changes in _1C mRNA levels of _1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca²⁺ transient (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 _1D KO atria. In conclusion, genetic deletion of _1D Ca²⁺ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the _1D KO mice were associated with a decrease in the total I_Ca-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 _1D KO mice.

mice; calcium transient; arrhythmia; myocyte

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				K. Nishida, G. Michael, D. Dobrev, and S. Nattel Animal models for atrial fibrillation: clinical insights and scientific opportunities Europace, October 29, 2009; (2009) eup328v1. [Abstract] [Full Text] [PDF]