Mechanisms of arrhythmias in molecularly engineered mice with long QT

Cardiac arrhythmias remain a major cause of morbidity and mortality. Due to malignant ventricular arrhythmias, patients with congenital long QT syndrome are at an increased risk of sudden cardiac death. Mutations of specific K+ currents (responsible for repolarization of the action potentials) in the heart have been found in long QT syndrome. The precise mechanism of their involvement in arrhythmogenesis is unknown. The aim of this project was to investigate the role of dispersion of repolarization (DR) in the initiation and maintenance of arrhythmias resulting from a particular K+ channel modification. Only the mouse provides the ability to molecularly modify an ionic channel, thus making it possible to identify changes in cardiac phenotype that are a consequence of a particular genotype. The following mouse lines of molecularly engineered mice with K+ channel mutations were used: (a) Dominant negative transgenic mice express an N-terminal fragment of Kv1.1 that results in reduced I_slow current. (b) Mice expressing a dominant negative Kv4.2 α subunit (Kv4.2W362F) resulting in the complete elimination of the I_to,fast current. (c) Kv4.2W362FxKv1.4−/− mice, these mice lack both I_to,fast and I_to,slow current. (d) ‘Knockout’ mice lacking IsK (minK). (e) Mice with a targeted mutation of Merg1 (the mouse homolog of human BERG) reduces the I_Kr current in the heterozygous mouse.; Measurements of the propensity to arrhythmias were performed in isolated Langendorff perfused beating hearts. Hearts were stained with a voltage-sensitive dye and optical action potentials (APs) were measured simultaneously from 124 sites on the epicardium. The following parameters were analyzed: local AP duration (APD), refractory periods, dispersion of repolarizations, action potential amplitude restitution kinetics, longitudinal and transverse conduction velocity, and the depolarization and repolarization sequences.; The results show that the dispersion of repolarization across the epicardial surface of the heart is normally produced by a spatial distribution of K + channel expression. Mutations that enhance DR are pro-arrhythmic and those that decrease DR are anti-arrhythmic. The findings may have a major impact in a conceptual understanding of the molecular basis of cardiac repolarization and the incidence of spontaneous or induced arrhythmias in the mammalian heart.