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

• Published in: Acta Physiologica Vol. 192; no. 4; pp. 505 - 517
• Main Authors: Thomas, G, Killeen, M.J, Grace, A.A, Huang, C.L.-H
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.04.2008; Blackwell Publishing Ltd; Blackwell
• Subjects: arrhythmogenesis; Biological and medical sciences; Cardiovascular; Fundamental and applied biological sciences. Psychology; long QT3 syndrome; propranolol; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Heart; Human; Arrhythmia; long QT3 syndrome; arrhythmogenesis; Prolonged QT interval; Cardiovascular disease; Conduction disorder; β-Adrenergic receptor; Vertebrata; Mammalia; Heart block; Heart disease; Early; Antagonist; Circulatory system; Propranolol; Beta blocking agent
• ISSN: 1748-1708; 1748-1716
• DOI: 10.1111/j.1748-1716.2007.01770.x

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+/Δ hearts perfused with 0.1 and 1 μ m propranolol and paced from the right ventricular epicardium. All spontaneously beating bradycardic Scn5a+/Δ 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 μ m 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+/Δ hearts perfused with 0, 0.1 and 1 μ m propranolol respectively in parallel with corresponding alterations in repolarization gradients, reflected in action potential duration (ΔAPD₉₀) values. Thus 0.1 μ m propranolol reduced epicardial but not endocardial APD₉₀ from 54.7 ± 1.6 to 44.0 ± 2.0 ms, restoring ΔAPD₉₀ from -3.8 ± 1.6 to 3.5 ± 2.5 ms (all n = 5), close to WT values. However, 1 μ m propranolol increased epicardial APD₉₀ to 72.5 ± 1.2 ms and decreased endocardial APD₉₀ from 50.9 ± 1.0 to 24.5 ± 0.3 ms, increasing ΔAPD₉₀ 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.