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

Abstract

KCNE1 encodes the β-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 µM) 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 reentrant mechanisms in the arrhythmogenesis observed in KCNE1 −/− hearts.

Ventricular arrhythmogenesis following slowed conduction in heptanol-treated, Langendorff-perfused mouse hearts

“…Nevertheless this empirical observation enabled the demonstration that ventricular arrhythmias could result from acute reductions in conduction velocity without alterations in action potential recovery time course, even with increased refractory periods. Finally, these results contrast with those of the previous studies using hypokalaemic [2], KCNE1 -/- [3], and Scn5a ?/D [4] and Scn5a ?/- [9] hearts, for which alterations in the transmural gradients of repolarization were observed.…”

“…These critical intervals reflect the time periods permitting re-excitation during the course of action potential repolarization [5]. The heptanol-treated hearts therefore contrast with hypokalaemic [5], KCNE1 -/- [3], and Scn5a ?/D [6] hearts, because increased critical intervals in these models were associated with arrhythmogenesis.…”

“…Briefly, mice were killed by cervical dislocation in accordance with Sections 1(c) and 2 of Schedule 1 of the UK Animals (Scientific Procedures) Act 1986. The hearts were rapidly excised and submerged in ice-cold bicarbonate-buffered, Krebs-Henseleit solution (mM: NaCl 119, NaHCO 3 [21]. A small section of aorta (3-4 mm) was identified and cannulated with a tailor-made 21-gauge cannula that had been prefilled with ice-cold buffer.…”

“…First, repolarization abnormalities alone are sufficient to induce arrhythmogenesis in hypokalaemic hearts, Scn5a ?/D hearts containing a gain-of-function mutation in the a-subunit of the sodium channel, and KCNE1 -/-hearts with deletion of the coding sequence for the b-subunit of the slow delayed rectifier potassium (I Ks ) channel. In these hearts action potential duration (commonly measured at 90% repolarization, APD 90 ) is prolonged [2][3][4], transmural repolarization gradients are altered [2][3][4], and critical intervals for re-excitation given by APD 90 -ventricular effective refractory periods (VERP) are increased [3,5,6], predisposing the hearts to triggered and re-entrant arrhythmias.…”

Murine Electrophysiological Models of Cardiac Arrhythmogenesis

“…Regular pacing demonstrated increased bipolar electrogram durations. Premature stimuli during programmed electrical stimulation frequently provoked monomorphic VT episodes (64,447). Prolonged epicardial and endocardial APDs resulted in reduced critical intervals as given by APD 90 -VERP differences.…”