{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:42:12Z","timestamp":1789605732213,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2005,12,8]],"date-time":"2005-12-08T00:00:00Z","timestamp":1134000000000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiovasc electrophysiol"],"published-print":{"date-parts":[[2005,12]]},"abstract":"<jats:p> <jats:italic>Introduction:<\/jats:italic> Gain\u2010of\u2010function mutations within <jats:italic>Scn5a<\/jats:italic>, including the \u0394KPQ 1505\u20101507 deletion in the inactivation domain compromising myocardial repolarization, are implicated in human long QT 3 syndrome (LQT3), associated with ventricular arrhythmogenesis and sudden death.<\/jats:p><jats:p> <jats:italic>Methods and Results:<\/jats:italic> Patch clamp studies on isolated ventricular <jats:italic>Scn5a<\/jats:italic>+\/\u0394 myocytes from \u0394KPQ 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\u2010perfused whole heart preparations demonstrated ventricular tachycardia (VT) in 8 of 9 <jats:italic>Scn5a<\/jats:italic>+\/\u0394 mutant (but no <jats:italic>Scn5a<\/jats:italic>+\/+ (wild\u2010type (WT)) controls; n = 17), with increased electrogram durations (EGD) and more dispersed conduction curves. Isoproterenol (100 nM) was without effect on tachycardic <jats:italic>Scn5a<\/jats:italic>+\/\u0394 hearts (n = 9) yet propranolol (1 \u03bcM) prevented VT in all isoproterenol\u2010infused WT control (n = 4) but no <jats:italic>Scn5a<\/jats:italic>+\/\u0394 hearts (n = 4). Furthermore propranolol itself increased EGD and dispersion in <jats:italic>Scn5a<\/jats:italic>+\/\u0394 hearts. In contrast, mexiletine (10 \u03bcM) suppressed VTs in 4 of 5 <jats:italic>Scn5a<\/jats:italic>+\/\u0394 hearts without altering EGD or dispersion.<\/jats:p><jats:p> <jats:italic>Conclusion:<\/jats:italic>\u03b2\u2010adrenoreceptor blockade does not confer an antiarrhythmic effect and may even enhance arrhythmogenesis by increasing reentrant substrate in <jats:italic>Scn5a<\/jats:italic>+\/\u0394 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.<\/jats:p>","DOI":"10.1111\/j.1540-8167.2005.00200.x","type":"journal-article","created":{"date-parts":[[2010,8,16]],"date-time":"2010-08-16T09:20:17Z","timestamp":1281950417000},"page":"1329-1340","source":"Crossref","is-referenced-by-count":53,"title":["Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in \u0394KPQ <i>Scn5a<\/i> Mice"],"prefix":"10.1111","volume":"16","author":[{"given":"CATHERINE E.","family":"HEAD","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"RICHARD","family":"BALASUBRAMANIAM","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"GLYN","family":"THOMAS","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CATHARINE 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