Paced electrogram fractionation analysis of arrhythmogenic tendency in DeltaKPQ Scn5a mice
| Autor: | Richard Balasubramaniam, Andrew A. Grace, Catherine E. G. Head, Glyn Thomas, Ming Lei, Christopher L.-H. Huang, C. A. Goddard, William H. Colledge |
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| Rok vydání: | 2006 |
| Předmět: |
medicine.medical_specialty
Adrenergic beta-Antagonists Action Potentials Stimulation Mexiletine Mice Transgenic Propranolol Ventricular tachycardia Sudden death Sodium Channels NAV1.5 Voltage-Gated Sodium Channel Mice Physiology (medical) Internal medicine medicine Myocyte Animals cardiovascular diseases Patch clamp Muscle Cells business.industry Cardiac Pacing Artificial medicine.disease Electric Stimulation Electrophysiology Disease Models Animal Long QT Syndrome cardiovascular system Cardiology Tachycardia Ventricular Cardiology and Cardiovascular Medicine business Anti-Arrhythmia Agents Gene Deletion medicine.drug |
| Zdroj: | Journal of cardiovascular electrophysiology. 16(12) |
| ISSN: | 1045-3873 |
| Popis: | INTRODUCTION Gain-of-function mutations within Scn5a, including the DeltaKPQ 1505-1507 deletion in the inactivation domain compromising myocardial repolarization, are implicated in human long QT 3 syndrome (LQT3), associated with ventricular arrhythmogenesis and sudden death. METHODS AND RESULTS Patch clamp studies on isolated ventricular Scn5a+/Delta myocytes from DeltaKPQ mice produced by homologous recombination in embryonic stem (ES) cells confirmed such altered electrophysiological properties of the mutant channel. Programmed electrical stimulation (PES) with decremental pacing from the basal right ventricular epicardial surface and paced electrogram fractionation analysis (PEFA) of electrograms recorded from the basal left ventricular epicardial surface of Langendorff-perfused whole heart preparations demonstrated ventricular tachycardia (VT) in 8 of 9 Scn5a+/Delta mutant (but no Scn5a+/+ (wild-type (WT)) controls; n = 17), with increased electrogram durations (EGD) and more dispersed conduction curves. Isoproterenol (100 nM) was without effect on tachycardic Scn5a+/Delta hearts (n = 9) yet propranolol (1 microM) prevented VT in all isoproterenol-infused WT control (n = 4) but no Scn5a+/Delta hearts (n = 4). Furthermore propranolol itself increased EGD and dispersion in Scn5a+/Delta hearts. In contrast, mexiletine (10 microM) suppressed VTs in 4 of 5 Scn5a+/Delta hearts without altering EGD or dispersion. CONCLUSION Beta-adrenoreceptor blockade does not confer an antiarrhythmic effect and may even enhance arrhythmogenesis by increasing reentrant substrate in Scn5a+/Delta hearts while mexiletine protects against VT without modifying conduction characteristics. Together these findings permit a scheme where VT in LQT3 is initiated by triggered mechanisms but propagated by reentry. |
| Databáze: | OpenAIRE |
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