Referenced in: none

Automatically associated channels: Kv7.1 , Nav1.5

Title: Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome.

Authors: G Thomas, M J Killeen, A A Grace, C L-H Huang

Journal, date & volume: Acta Physiol (Oxf), 2008 Apr , 192, 505-17

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/17973950

Abstract
To perform an empirical, pharmacological, separation of early afterdepolarizations (EADs) and transmural gradients of repolarization in arrhythmogenesis in a genetically modified mouse heart modelling human long QT syndrome (LQT) 3.Left ventricular endocardial and epicardial monophasic action potentials and arrhythmogenic tendency were compared in isolated wild type (WT) and Scn5a+/Delta hearts perfused with 0.1 and 1 microm propranolol and paced from the right ventricular epicardium.All spontaneously beating bradycardic Scn5a+/Delta hearts displayed EADs, triggered beats and ventricular tachycardia (VT; n = 7), events never seen in WT hearts (n = 5). Perfusion with 0.1 and 1 microm propranolol suppressed all EADs, triggered beats and episodes of VT. In contrast, triggering of VT persisted following programmed electrical stimulation in 6 of 12 (50%), one of eight (12.5%), but six of eight (75%) Scn5a+/Delta hearts perfused with 0, 0.1 and 1 microm propranolol respectively in parallel with corresponding alterations in repolarization gradients, reflected in action potential duration (DeltaAPD(90)) values. Thus 0.1 microm propranolol reduced epicardial but not endocardial APD(90) from 54.7 +/- 1.6 to 44.0 +/- 2.0 ms, restoring DeltaAPD(90) from -3.8 +/- 1.6 to 3.5 +/- 2.5 ms (all n = 5), close to WT values. However, 1 microm propranolol increased epicardial APD(90) to 72.5 +/- 1.2 ms and decreased endocardial APD(90) from 50.9 +/- 1.0 to 24.5 +/- 0.3 ms, increasing DeltaAPD(90) to -48.0 +/- 1.2 ms.These findings empirically implicate EADs in potentially initiating spontaneous arrhythmogenic phenomena and transmural repolarization gradients in the re-entrant substrate that would sustain such activity when provoked by extrasystolic activity in murine hearts modelling human LQT3 syndrome.