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Paced electrogram fractionation analysis of arrhythmogenic tendency in DeltaKPQ Scn5a mice
Catherine E Head1, Richard Balasubramaniam, Glyn Thomas
1Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, UK.
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.
Insights
Gain-of-function mutations in Scn5a cause Long QT 3 syndrome (LQT3). Mexiletine, unlike beta-blockers, effectively treats ventricular tachycardia in LQT3 mice by targeting triggered arrhythmias, not reentry.
Area of Science:
- Cardiovascular Electrophysiology
- Molecular Cardiology
- Genetics of Arrhythmias
Background:
- Gain-of-function mutations in Scn5a, such as the DeltaKPQ deletion, are linked to Long QT 3 syndrome (LQT3).
- These mutations disrupt myocardial repolarization, leading to ventricular arrhythmias and sudden cardiac death.
Purpose of the Study:
- To investigate the electrophysiological properties of Scn5a+/Delta mutant myocytes.
- To evaluate the antiarrhythmic effects of beta-adrenergic blockade and mexiletine on LQT3-associated ventricular tachycardia (VT).
Main Methods:
- Patch clamp studies on isolated Scn5a+/Delta ventricular myocytes.
- Programmed electrical stimulation (PES) and paced electrogram fractionation analysis (PEFA) in Langendorff-perfused hearts.
- In vivo drug administration of isoproterenol, propranolol, and mexiletine.
Main Results:
- Scn5a+/Delta myocytes exhibited altered electrophysiological properties.
- Ventricular tachycardia (VT) was induced in 8/9 Scn5a+/Delta hearts but not in wild-type controls.
- Beta-blockade (propranolol) failed to prevent VT and increased arrhythmogenic substrate, while mexiletine suppressed VT without altering conduction.
Conclusions:
- Beta-adrenergic blockade is ineffective and potentially arrhythmogenic in LQT3.
- Mexiletine demonstrates antiarrhythmic efficacy in LQT3 by suppressing VT without affecting conduction.
- VT in LQT3 likely involves triggered activity initiation and reentrant propagation.
