Exclusion of alternative exon 33 of CaV1.2 calcium channels in heart is proarrhythmogenic

Alternative splicing changes the CaV1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure–function studies of heterologously expressed CaV1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the CaV1.2 calcium channel in heart function. Exclusion of exon 33 in CaV1.2 channels has been reported to shift the activation potential −10.4 mV to the hyperpolarized direction, and increased expression of CaV1.2Δ33 channels was observed in rat myocardial infarcted hearts. However, how a change in CaV1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33−/−-null mice. These mice contained CaV1.2Δ33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33−/− mice from β-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing CaV1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in CaV1.2 channels may play in the pathogenesis of human heart failure remains unclear.

Abstract 11670: Presence of Dissociated Pulmonary Vein Activity After Isolation Depends on Fibrillatory Excitation in Pulmonary Vein

Background: Circumferential pulmonary vein (PV) isolation has been widely accepted as catheter ablation for atrial fibrillation (AF). Dissociated PV activity (DPVA) may appear after PV isolation, however, the electrophysiological property and clinical implication of DPVA have not been revealed. Methods and Results: The study subjects were consecutive 37 patients (62±8 years, 28 men) with drug-refractory AF who underwent successful PV isolation. Electrophysiological property of left atrium (LA) and PV during and after PV isolation were investigated. Excluded 21 PVs without LA-PV connection before procedure, all of 112 PVs with successful isolation were analyzed. DPVA appeared in 14 PVs (13%) after PV isolation, from left superior PV in 7 (50%), right superior PV in 5 (36%) and left inferior PV in 2 (14%). Mean cycle length (CL) of DPVA was 5180±3080 ms. DPVA appeared in 9 of 37 PVs (24%) without existence of AF, but in 5 of 75 PVs (7%) with existence of AF during procedure (P=0.008). There was the tendency that the CL of DPVA was shorter with existence of AF compared to that without existence of AF (3792±1815 vs. 6682±3041 ms, P=0.08), and the suppression of DPVA was observed by over drive pacing inside of PV with PV capture in several cases. There was not significant relationship between the presence of DPVA and AF recurrence with 2-month blanking period after PV isolation. Conclusions: The presence of DPVA after PV isolation depended on the existence of AF during procedure, but was not significantly related to the AF recurrence after PV isolation. The long CL and suppressive maneuver with PV over drive pacing suggested the vulnerability of DPVA. Thus, these findings suggest that passive and/or spontaneous fibrillatory excitation in PV might suppress the automatic activity of myocardial sleeves in PV.