Circulation. 2002;105:1247-1253
Published online before print February 18, 2002, doi: 10.1161/hc1002.105231
Published online before print February 18, 2002, doi: 10.1161/hc1002.105231
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(Circulation. 2002;105:1247.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Unique Topographical Distribution of M Cells Underlies Reentrant Mechanism of Torsade de Pointes in the Long-QT Syndrome
From the Heart and Vascular Research Center and Departments of Medicine and Biomedical Engineering (F.G.A., D.S.R.), MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, and Masonic Medical Research Laboratory (G.-X.Y., C.A.), Utica, NY.
Correspondence to David S. Rosenbaum, MD, Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Hamann 322, Cleveland, OH 44109-1998. E-mail drosenbaum{at}metrohealth.org
Background— Specific ion channel mutations underlie the congenital long-QT syndrome (LQTS). However, the mechanisms by which dysfunction at the molecular level translates into functional electrical instability leading to torsade de pointes (TdP) in LQTS are poorly understood.
Methods and Results— The cellular basis of TdP was investigated using a novel approach of transmural optical imaging in the canine wedge preparation (n=14). The spatial organization of repolarization and arrhythmogenesis were determined in a surrogate model of LQT2. Action potentials were recorded simultaneously from 128 sites spanning the transmural wall of the left ventricle. In LQT2, QT interval prolongation was paralleled by an abrupt rise in transmural dispersion of repolarization (DOR) from 2.7±0.9 ms/mm (controls) to 12.2±2.1 ms/mm (LQT2). Islands of midmyocardial (M) cells formed zones of increased refractoriness in LQT2, producing steep spatial gradients of repolarization that were directly responsible for conduction block and self-sustained intramural reentrant circuits underlying TdP.
Conclusions— These data provide direct evidence supporting the functional expression of M cells in intact myocardium and a central role for M cells in the development of reentrant TdP arrhythmias in LQTS.
Key Words: torsades de pointes • action potentials • arrhythmia • ion channels • mapping
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
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