Empirical correlation of triggered activity and spatial and temporal re-entrant substrates with arrhythmogenicity in a murine model for Jervell and Lange-Nielsen syndrome.

KCNE1 encodes the beta-subunit of the slow component of the delayed rectifier K(+) current. The Jervell and Lange-Nielsen syndrome is characterized by sensorineural deafness, prolonged QT intervals, and ventricular arrhythmogenicity. Loss-of-function mutations in KCNE1 are implicated in the JLN2 subtype. We recorded left ventricular epicardial and endocardial monophasic action potentials (MAPs) in intact, Langendorff-perfused mouse hearts. KCNE1 (-/-) but not wild-type (WT) hearts showed not only triggered activity and spontaneous ventricular tachycardia (VT), but also VT provoked by programmed electrical stimulation. The presence or absence of VT was related to the following set of criteria for re-entrant excitation for the first time in KCNE1 (-/-) hearts: Quantification of APD(90), the MAP duration at 90% repolarization, demonstrated alterations in (1) the difference, APD(90), between endocardial and epicardial APD(90) and (2) critical intervals for local re-excitation, given by differences between APD(90) and ventricular effective refractory period, reflecting spatial re-entrant substrate. Temporal re-entrant substrate was reflected in (3) increased APD(90) alternans, through a range of pacing rates, and (4) steeper epicardial and endocardial APD(90) restitution curves determined with a dynamic pacing protocol. (5) Nicorandil (20 microM) rescued spontaneous and provoked arrhythmogenic phenomena in KCNE1 (-/-) hearts. WTs remained nonarrhythmogenic. Nicorandil correspondingly restored parameters representing re-entrant criteria in KCNE1 (-/-) hearts toward values found in untreated WTs. It shifted such values in WT hearts in similar directions. Together, these findings directly implicate triggered electrical activity and spatial and temporal re-entrant mechanisms in the arrhythmogenesis observed in KCNE1 (-/-) hearts.