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Acta Physiol (Oxf). 2008 Apr;192(4):505-17. Epub 2007 Oct 31.

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

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Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Cambridge, UK.



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.

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