BACKGROUND: Patients with long QT syndrome (LQTS) are at increased risk not only for ventricular arrhythmias but also for atrial pathology including atrial fibrillation (AF). Some patients with "lone" AF carry Na(+)-channel mutations. OBJECTIVE: The purpose of this study was to determine the mechanisms underlying atrial pathology in LQTS. METHODS: In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na(+) channel (ΔKPQ-SCN5A) and wild-type (WT) littermates, atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed. RESULTS: Atrial action potential duration, effective refractory period, cycle length, and PQ interval were prolonged in ΔKPQ-SCN5A hearts (all P < .05). Flecainide (1 μM) reversed atrial action potential duration prolongation and induced postrepolarization refractoriness (P < .05). Arrhythmias were infrequent during regular rapid atrial rate in both WT and ΔKPQ-SCN5A but were inducible in 15 (38%) of 40 ΔKPQ-SCN5A and 8 (29%) of 28 WT mice upon extrastimulation. Pacing protocols generating rapid alterations in rate provoked atrial extrasystoles and arrhythmias in 6 (66%) of 9 ΔKPQ-SCN5A but in 0 (0%) of 6 WT mice (P < .05). Atrial diameter was increased by nearly 10% in ΔKPQ-SCN5A mice > 5 months old without increase in fibrotic tissue. CONCLUSION: Murine hearts bearing an LQT3 mutation show abnormalities in atrial electrophysiology and subtle changes in atrial dimension, including an atrial arrhythmogenic phenotype on provocation. These results support clinical data suggesting that LQTS mutations can cause atrial pathology and arrhythmogenesis and indicate that murine sodium channel LQTS models may be useful for exploring underlying mechanisms.
BACKGROUND:Patients with long QT syndrome (LQTS) are at increased risk not only for ventricular arrhythmias but also for atrial pathology including atrial fibrillation (AF). Some patients with "lone" AF carry Na(+)-channel mutations. OBJECTIVE: The purpose of this study was to determine the mechanisms underlying atrial pathology in LQTS. METHODS: In mice with a heterozygous knock-in long QT syndrome type 3 (LQT3) mutant of the cardiac Na(+) channel (ΔKPQ-SCN5A) and wild-type (WT) littermates, atrial size, function, and electrophysiologic parameters were measured in intact Langendorff-perfused hearts, and histologic analysis was performed. RESULTS: Atrial action potential duration, effective refractory period, cycle length, and PQ interval were prolonged in ΔKPQ-SCN5A hearts (all P < .05). Flecainide (1 μM) reversed atrial action potential duration prolongation and induced postrepolarization refractoriness (P < .05). Arrhythmias were infrequent during regular rapid atrial rate in both WT and ΔKPQ-SCN5A but were inducible in 15 (38%) of 40 ΔKPQ-SCN5A and 8 (29%) of 28 WT mice upon extrastimulation. Pacing protocols generating rapid alterations in rate provoked atrial extrasystoles and arrhythmias in 6 (66%) of 9 ΔKPQ-SCN5A but in 0 (0%) of 6 WT mice (P < .05). Atrial diameter was increased by nearly 10% in ΔKPQ-SCN5Amice > 5 months old without increase in fibrotic tissue. CONCLUSION:Murine hearts bearing an LQT3 mutation show abnormalities in atrial electrophysiology and subtle changes in atrial dimension, including an atrial arrhythmogenic phenotype on provocation. These results support clinical data suggesting that LQTS mutations can cause atrial pathology and arrhythmogenesis and indicate that murinesodium channel LQTS models may be useful for exploring underlying mechanisms.
Authors: Paulus Kirchhof; Gregory Y H Lip; Isabelle C Van Gelder; Jeroen Bax; Elaine Hylek; Stefan Kaab; Ulrich Schotten; Karl Wegscheider; Giuseppe Boriani; Axel Brandes; Michael Ezekowitz; Hans Diener; Laurent Haegeli; Hein Heidbuchel; Deirdre Lane; Luis Mont; Stephan Willems; Paul Dorian; Maria Aunes-Jansson; Carina Blomstrom-Lundqvist; Maria Borentain; Stefanie Breitenstein; Martina Brueckmann; Nilo Cater; Andreas Clemens; Dobromir Dobrev; Sergio Dubner; Nils G Edvardsson; Leif Friberg; Andreas Goette; Michele Gulizia; Robert Hatala; Jenny Horwood; Lukas Szumowski; Lukas Kappenberger; Josef Kautzner; Angelika Leute; Trudie Lobban; Ralf Meyer; Jay Millerhagen; John Morgan; Felix Muenzel; Michael Nabauer; Christoph Baertels; Michael Oeff; Dieter Paar; Juergen Polifka; Ursula Ravens; Ludger Rosin; W Stegink; Gerhard Steinbeck; Panos Vardas; Alphons Vincent; Maureen Walter; Günter Breithardt; A John Camm Journal: Europace Date: 2011-07-26 Impact factor: 5.214
Authors: Elaine Wan; Jeffrey Abrams; Richard L Weinberg; Alexander N Katchman; Joseph Bayne; Sergey I Zakharov; Lin Yang; John P Morrow; Hasan Garan; Steven O Marx Journal: J Clin Invest Date: 2015-11-23 Impact factor: 14.808
Authors: Nicola Detta; Giulia Frisso; Alberto Zullo; Berardo Sarubbi; Carla Cozzolino; Emanuele Romeo; Dao W Wang; Raffaele Calabrò; Francesco Salvatore; Alfred L George Journal: Int J Cardiol Date: 2012-09-12 Impact factor: 4.164
Authors: Julius Obergassel; Molly O'Reilly; Laura C Sommerfeld; S Nashitha Kabir; Christopher O'Shea; Fahima Syeda; Lars Eckardt; Paulus Kirchhof; Larissa Fabritz Journal: Europace Date: 2021-06-07 Impact factor: 5.214
Authors: S Laakmann; L Fortmüller; I Piccini; S Grote-Wessels; W Schmitz; G Breves; P Kirchhof; L Fabritz Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2012-12-19 Impact factor: 3.000