Mechanisms of Atrial Fibrillation in Mice with Genetic Ablation of the α1D L-type Calcium Channel

Atrial fibrillation (AF) is the most common supraventricular arrhythmia with a multifactorial pathophysiology. Reductions in α1 L-type calcium channel (LTCC) current (ICaL) and action potential duration is commonly observed in human AF patients. As expected, mice lacking the α1D (Cav1.3) LTCC gene are more susceptible to inducible AF, albeit without a reduction in atrial refractoriness. Despite increased fibrosis and delayed conduction velocity in Cav1.3-/- mice, spectral analysis of AF revealed a highly disorganized pattern consistent with electrical remodeling. Conforming to electrical remodeling, Cav1.3-/- atrial myocytes displayed increased sensitivity to calcium alternans, which was alleviated with inotropic agents and absent in α1C LTCC heterozygous atrial myocytes. In addition, we observed increased electrical alternans in Cav1.3-/- atria, which coupled positively to voltage. These electrical alternans were in-turn associated with AF in Cav1.3-/- atria. Our findings support the conclusion that preferential loss of Cav1.3 promotes calcium alternans, resulting in arrhythmogenic electrical alternans.MAS