On the mechanisms of arrhythmias in the myocardium of mXinα-deficient murine left atrial-pulmonary veins

We have previously shown that left atrial-pulmonary vein tissue (LA-PV) can generate reentrant arrhythmias (atrial fibrillation, AF) in wild-type (mXin alpha+/+) but not in mXin alpha-null (mXin alpha-/-) mice. With the present experiments, we investigated the arrhythmogenic activity and the underlying mechanisms in mXin alpha+/+ vs. mXin alpha-/- LA-PV. Electrical activity and conduction velocity (CV) were recorded in LA-PV by means of a MED64 system. CV was significantly faster in mXin alpha+/+ than in mXin alpha-/- LA-PV and it was increased by 1 mu M isoproterenol (ISO). AF could be induced by fast pacing in the mXin alpha+/+ but not in mXin alpha-/- LA-PV where automatic rhythms could occur. ISO increased the incidence of AF in Xin alpha+/+ whereas it increased that of automatic rhythms in mXin alpha-/- LA-PV. In LA-PV with the right atrium attached (RA-LA-PV), automatic rhythms occurred in all preparations. In mXin alpha+/+ RA-LA-PV simultaneously treated with ISO, strophanthidin and atropine, the incidence of the automatic rhythm was about the same, but AF increased significantly. In contrast, in mXin alpha-/- RA-LA-PV under the same condition, the automatic rhythm was markedly enhanced, but still no AF occurred. Conventional microelectrode techniques showed a longer APD(90) and a less negative maximum diastolic potential (MDP) in mXin alpha-/- than mXin alpha+/+ LA-PV tissues. Whole-cell current clamp experiments also showed a less negative MDP in mXin alpha-/- vs. mXin alpha+/+ LA-PV cardiomyocytes. The fact that AF could be induced by fast pacing under several conditions in mXin alpha+/+ but not in mXin alpha-/- LA-PV preparations appears to be due to a slower CV, a prolonged APD(90), a less negative MDP and possibly larger areas of conduction block in mXin alpha-/- myocardial cells. In contrast, the non-impairment of automatic and triggered rhythms in mXin alpha-/- preparations may be due to the fact that the mechanisms underlying these rhythms do not involve cell-to-cell conduction. (C) 2008 Elsevier Inc. All rights reserved.