Purkinje Cells as Sources of Arrhythmias in Long QT Syndrome Type 3

Long QT syndrome (LQTS) is characterized by ventricular arrhythmias and sudden cardiac death. Purkinje cells (PC) within the specialized cardiac conduction system have unique electrophysiological properties that we hypothesize may produce the primary sources of arrhythmia in heritable LQTS. LQTS type 3 (LQT3) transgenic mice harboring the Delta KPQ(+/-) mutation were crossed with Contactin2-EGFP BAC transgenic mice, which express a fluorescent reporter gene within the Purkinje fiber network. Isolated ventricular myocytes (VMs) (EGFP(-)) and PCs (EGFP(+)) from wild type and Delta KPQ mutant hearts were compared using the whole-cell patch clamp technique and microfluorimetry of calcium transients. Increased late sodium current was seen in Delta KPQ-PCs and Delta KPQ-VMs, with larger density in Delta KPQ-PCs. Marked prolongation of action potential duration of Delta KPQ-PCs was seen compared to Delta KPQ-VMs. Delta KPQ-PCs, but not Delta KPQ-VMs, exhibited frequent early afterdepolarizations, which corresponded to repetitive oscillations of intracellular calcium. Abnormalities in cell repolarization were reversed with exposure to mexiletine. We present the first direct experimental evidence that PCs are uniquely sensitive to LQT3 mutations, displaying electrophysiological behavior that is highly pro-arrhythmic.