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

Abstract

Arrhythmogenic effects of slowed action potential conduction produced by the gap junction and sodium-channel inhibitor heptanol (0.1-2 mM) were explored in Langendorff-perfused mouse hearts. Monophasic action potential recordings showed that 2 mM heptanol induced ventricular tachycardia in the absence of triggered activity arising from early or after-depolarizations during regular 8 Hz pacing and programmed electrical stimulation (PES). It also increased activation latencies and ventricular effective refractory periods (VERPs), but did not alter action potential duration (APD), thereby reducing local critical intervals for re-excitation given by APD(90) - VERP. Bipolar electrogram recordings showed that 2 mM heptanol increased electrogram duration (EGD) and ratios of EGDs obtained at the longest to those obtained at the shortest S1S2 intervals studied during PES, suggesting increased dispersion of conduction velocities. These findings show, for the first time in the mouse heart, that slowed conduction induces reversible arrhythmogenic effects despite repolarization abnormalities expected to reduce arrhythmogenicity.

Gap junction inhibition by heptanol increases ventricular arrhythmogenicity by reducing conduction velocity without affecting repolarization properties or myocardial refractoriness in Langendorff-perfused mouse hearts

“…Previous studies in mouse models have associated increased arrhythmogenicity with reduced CVs, prolonged or shortened APDs and reduce ERPs (2,3,5,7,12). These values were therefore obtained from the experimental recordings described above.…”

“…The right ventricular epicardium was electrically stimulated using either regular 8 Hz or S1S2 pacing (2,3,5,7,12). MAP recordings were obtained from the left ventricular epicardium.…”

“…Heterozygous Cx43 +/− mice were demonstrated to exhibit at 45–50% reduction in Cx43 expression, however, the degree of conduction velocity (CV) slowing was variable: CV was either unchanged (25–30) or reduced by 23–44% (31–33). Additional experiments used a pharmacological approach, demonstrating ventricular arrhythmogenesis associated with reduced CV using 2 mM heptanol (7). This agent inhibits gap junctions specifically at concentrations up to 1–2 mM (34,35) however at ≥2 mM additionally inhibits sodium channels (34,36).…”

Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

“…Reduced CVs have been shown to be an important factor in producing ventricular arrhythmogenesis following heptanol treatment (31). Therefore, in the studythe activation latencies, which provide an indication of the CVs, were quantified to determine whether changes in these values contribute to the arrhythmogenic substrate.…”

“…Reduced ventricular effective refractory periods (VERPs) leading to increased critical intervals given by APD 90 -VERP (29). By contrast, reduced CVs were shown to induce ventricular arrhythmias following treatment with the gap junction and sodium channel inhibitor heptanol through a reduction in excitation wavelengths despite unaltered APDs and even with increased VERPs (31,32). However, to the best of our knowledge, there have been no investigations of the arrhythmogenic effects of hyperkalemia in the mouse system.…”