Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome

Fadi G. Akar, Gan Xin Yan, Charles Antzelevitch, David S. Rosenbaum

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1247-1253
Number of pages7
JournalCirculation
Volume105
Issue number10
DOIs
StatePublished - Mar 12 2002
Externally publishedYes

Fingerprint

Torsades de Pointes
Long QT Syndrome
Optical Imaging
Ion Channels
Islands
Action Potentials
Heart Ventricles
Canidae
Cardiac Arrhythmias
Myocardium
Mutation

Keywords

  • Action potentials
  • Arrhythmia
  • Ion channels
  • Mapping
  • Torsades de pointes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome. / Akar, Fadi G.; Yan, Gan Xin; Antzelevitch, Charles; Rosenbaum, David S.

In: Circulation, Vol. 105, No. 10, 12.03.2002, p. 1247-1253.

Research output: Contribution to journalArticle

Akar, Fadi G. ; Yan, Gan Xin ; Antzelevitch, Charles ; Rosenbaum, David S. / Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome. In: Circulation. 2002 ; Vol. 105, No. 10. pp. 1247-1253.
@article{c583d950bf294fe9973768f16fed9064,
title = "Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome",
abstract = "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.",
keywords = "Action potentials, Arrhythmia, Ion channels, Mapping, Torsades de pointes",
author = "Akar, {Fadi G.} and Yan, {Gan Xin} and Charles Antzelevitch and Rosenbaum, {David S.}",
year = "2002",
month = "3",
day = "12",
doi = "10.1161/hc1002.105231",
language = "English (US)",
volume = "105",
pages = "1247--1253",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome

AU - Akar, Fadi G.

AU - Yan, Gan Xin

AU - Antzelevitch, Charles

AU - Rosenbaum, David S.

PY - 2002/3/12

Y1 - 2002/3/12

N2 - 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.

AB - 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.

KW - Action potentials

KW - Arrhythmia

KW - Ion channels

KW - Mapping

KW - Torsades de pointes

UR - http://www.scopus.com/inward/record.url?scp=0037066015&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037066015&partnerID=8YFLogxK

U2 - 10.1161/hc1002.105231

DO - 10.1161/hc1002.105231

M3 - Article

C2 - 11889021

AN - SCOPUS:0037066015

VL - 105

SP - 1247

EP - 1253

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 10

ER -