BACKGROUND: Patients carrying the cardiac sodium channel (SCN5A) mutation 1795insD show sudden nocturnal death and signs of multiple arrhythmia syndromes including bradycardia, conduction delay, QT prolongation, and right precordial ST-elevation. We investigated the electrophysiological characteristics of a transgenic model of the murine equivalent mutation 1798insD. METHODS AND RESULTS: On 24-hour continuous telemetry and surface ECG recordings, Scn5a(1798insD/+) heterozygous mice showed significantly lower heart rates, more bradycardic episodes (pauses > or = 500 ms), and increased PQ interval, QRS duration, and QTc interval compared with wild-type mice. The sodium channel blocker flecainide induced marked sinus bradycardia and/or sinus arrest in the majority of Scn5a(1798insD/+) mice, but not in wild-type mice. Epicardial mapping using a multielectrode grid on excised, Langendorff-perfused hearts showed preferential conduction slowing in the right ventricle of Scn5a(1798insD/+) hearts. On whole-cell patch-clamp analysis, ventricular myocytes isolated from Scn5a(1798insD/+) hearts displayed action potential prolongation, a 39% reduction in peak sodium current density and a similar reduction in action potential upstroke velocity. Scn5a(1798insD/+) myocytes displayed a slower time course of sodium current decay without significant differences in voltage-dependence of activation and steady-state inactivation, slow inactivation, or recovery from inactivation. Furthermore, Scn5a(1798insD/+) myocytes showed a larger tetrodotoxin-sensitive persistent inward current compared with wild-type myocytes. CONCLUSIONS: Mice carrying the murine equivalent of the SCN5A-1795insD mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similar to the human phenotype. These results demonstrate that the presence of a single SCN5A mutation is indeed sufficient to cause an overlap syndrome of cardiac sodium channel disease.
BACKGROUND:Patients carrying the cardiac sodium channel (SCN5A) mutation 1795insD show sudden nocturnal death and signs of multiple arrhythmia syndromes including bradycardia, conduction delay, QT prolongation, and right precordial ST-elevation. We investigated the electrophysiological characteristics of a transgenic model of the murine equivalent mutation 1798insD. METHODS AND RESULTS: On 24-hour continuous telemetry and surface ECG recordings, Scn5a(1798insD/+) heterozygous mice showed significantly lower heart rates, more bradycardic episodes (pauses > or = 500 ms), and increased PQ interval, QRS duration, and QTc interval compared with wild-type mice. The sodium channel blocker flecainide induced marked sinus bradycardia and/or sinus arrest in the majority of Scn5a(1798insD/+) mice, but not in wild-type mice. Epicardial mapping using a multielectrode grid on excised, Langendorff-perfused hearts showed preferential conduction slowing in the right ventricle of Scn5a(1798insD/+) hearts. On whole-cell patch-clamp analysis, ventricular myocytes isolated from Scn5a(1798insD/+) hearts displayed action potential prolongation, a 39% reduction in peak sodium current density and a similar reduction in action potential upstroke velocity. Scn5a(1798insD/+) myocytes displayed a slower time course of sodium current decay without significant differences in voltage-dependence of activation and steady-state inactivation, slow inactivation, or recovery from inactivation. Furthermore, Scn5a(1798insD/+) myocytes showed a larger tetrodotoxin-sensitive persistent inward current compared with wild-type myocytes. CONCLUSIONS:Mice carrying the murine equivalent of the SCN5A-1795insD mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similar to the human phenotype. These results demonstrate that the presence of a single SCN5A mutation is indeed sufficient to cause an overlap syndrome of cardiac sodium channel disease.
Authors: Hiroshi Watanabe; Tao Yang; Dina Myers Stroud; John S Lowe; Louise Harris; Thomas C Atack; Dao W Wang; Susan B Hipkens; Brenda Leake; Lynn Hall; Sabina Kupershmidt; Nagesh Chopra; Mark A Magnuson; Naohito Tanabe; Björn C Knollmann; Alfred L George; Dan M Roden Journal: Circulation Date: 2011-08-08 Impact factor: 29.690
Authors: Larissa Fabritz; Dierk Damke; Markus Emmerich; Susann G Kaufmann; Kathrin Theis; Andreas Blana; Lisa Fortmüller; Sandra Laakmann; Sven Hermann; Elena Aleynichenko; Johannes Steinfurt; Daniela Volkery; Burkhard Riemann; Uwe Kirchhefer; Michael R Franz; Günter Breithardt; Edward Carmeliet; Michael Schäfers; Sebastian K G Maier; Peter Carmeliet; Paulus Kirchhof Journal: Cardiovasc Res Date: 2010-01-28 Impact factor: 10.787
Authors: Y Zhang; T Wang; A Ma; X Zhou; J Gui; H Wan; R Shi; C Huang; A A Grace; C L-H Huang; D Trump; H Zhang; T Zimmer; M Lei Journal: Acta Physiol (Oxf) Date: 2008-07-24 Impact factor: 6.311
Authors: Kalliopi Pilichou; Carol Ann Remme; Cristina Basso; Maria E Campian; Stefania Rizzo; Phil Barnett; Brendon P Scicluna; Barbara Bauce; Maurice J B van den Hoff; Jacques M T de Bakker; Hanno L Tan; Marialuisa Valente; Andrea Nava; Arthur A M Wilde; Antoon F M Moorman; Gaetano Thiene; Connie R Bezzina Journal: J Exp Med Date: 2009-07-27 Impact factor: 14.307
Authors: C A Remme; A O Verkerk; W M H Hoogaars; W T J Aanhaanen; B P Scicluna; C Annink; M J B van den Hoff; A A M Wilde; T A B van Veen; M W Veldkamp; J M T de Bakker; V M Christoffels; C R Bezzina Journal: Basic Res Cardiol Date: 2009-03-03 Impact factor: 17.165