The Electrophysiological Mechanism of Ventricular Arrhythmias in the Long QT Syndrome

El‐Sherif, Nabil; Caref, Edward B.; Yin, Hong; Restivo, Mark

doi:10.1161/01.res.79.3.474

Cited by 378 publications

(217 citation statements)

References 48 publications

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“…UE measurements on the endocardial surface by contact catheters have been validated as an accurate representation of local refractory periods and transmembrane action potential durations in the dog, 13,15 swine, 9 and human 12,17 heart. Some investigators used intramural plunge needles for measurements in experimental heart preparations, 3 whereas others used sock arrays of 50 to 80 button electrodes to record on the epicardium of the beating heart. 12 We have adopted these validated principles from contact UE measurements to the NCM reconstructed electrograms and their first derivatives to compare local repolarization timings with MAP recordings.…”

Section: Discussionmentioning

confidence: 99%

“…Substantial experimental evidence supports its role in the initiation and maintenance of reentrant ventricular arrhythmias. [1][2][3] Monophasic action potential (MAP) catheters may be used to directly measure endocardial repolarization in a variety of disease states. 4 -7 Although it is possible to determine global endocardial repolarization patterns with electroanatomic mapping, 8,9 contact measurement is still limited by the small area of coverage, need for sequential measurements, and technical requirement for good myocardial contact.…”

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confidence: 99%

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Determination of Human Ventricular Repolarization by Noncontact Mapping

et al. 2004

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Background-Noncontact mapping (NCM) has not been validated as a clinical technique to measure ventricular repolarization. We used NCM to determine repolarization characteristics by analysis of reconstructed unipolar electrograms (UEs) at the same sites as monophasic action potential (MAP) recordings in the human ventricle. Methods and Results-MAPs were recorded from a total of 355 beats at 46 sites in the left or right ventricle of 9 patients undergoing ablation of ventricular tachycardia guided by NCM (EnSite system). Measurements were made during sinus rhythm, constant right ventricular pacing, and ventricular extrastimuli during restitution-curve construction. The EnGuide locator signal was used to document MAP catheter locations on the endocardial geometry. UE-determined activation-recovery interval (ARI) measured at the maximum derivative of the T wave (Wyatt method) and the minimum derivative of the positive T wave (alternative method) was correlated with MAP measured at 90% repolarization (MAP90%) at the same sites. ARI correlated with MAP90% during steady state by the Wyatt method (rϭ0.83, PϽ0.001) and the alternative method (rϭ0.94, PϽ0.001). Restitution curves constructed from MAP and UE data exhibited the same characteristics, with a mean correlation coefficient of 0.95 (range, 0.90 to 0.99, PϽ0.001). The error between ARI and MAP90% was greater over a shorter diastolic coupling interval but was not influenced by distance of the sampling site from the multielectrode array. Conclusions-NCM accurately determines steady-state and dynamic endocardial repolarization in humans. Global, high-density, NCM data could be used to characterize abnormalities of human ventricular repolarization. (Circulation.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Determination of Human Ventricular Repolarization by Noncontact Mapping

et al. 2004

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“…Nevertheless, our numerical work, replicating the experiments in wedges, 11 demonstrates that the creation of an intramural reentry event is plausible under certain conditions. In 3D, an ensuing intramural filament can either close on itself, leading to a scroll ring that remains intramural and is on the scale of the ventricles, 43,44 or can reorient and attach itself to the endo-and epicardium. Possible subsequent instabilities could destabilize this filament, resulting in multiple filaments and fibrillation.…”

Section: Discussionmentioning

confidence: 99%

The role of M cells and the long QT syndrome in cardiac arrhythmias: Simulation studies of reentrant excitations using a detailed electrophysiological model

Henry

Rappel

2004

Chaos: An Interdisciplinary Journal of Nonlinear Science

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In this numerical study, we investigate the role of intrinsic heterogeneities of cardiac tissue due to M cells in the generation and maintenance of reentrant excitations using the detailed Luo-Rudy dynamic model. This model has been extended to include a description of the long QT 3 syndrome, and is studied in both one dimension, corresponding to a cable traversing the ventricular wall, and two dimensions, representing a transmural slice. We focus on two possible mechanisms for the generation of reentrant events. We first investigate if early-after-depolarizations occurring in M cells can initiate reentry. We find that, even for large values of the long QT strength, the electrotonic coupling between neighboring cells prevents earlyafter-depolarizations from creating a reentry. We then study whether M cell domains, with their slow repolarization, can function as wave blocks for premature stimuli. We find that the inclusion of an M cell domain can result in some cases in reentrant excitations and we determine the lifetime of the reentry as a function of the size and geometry of the domain and of the strength of the long QT syndrome. 1Spatial heterogeneity of cardiac tissue causes cells to repolarize at different rates, leading to a dispersion of repolarization time. Dispersion of repolarization has been postulated to function as a substrate for reentry phenomena which occur when the propagation of the electric wave is blocked in one direction causing the wave front to curl and reenter the previously excited tissue. The ensuing incoherent electrical activity of the heart is thought to subsequently lead to ventricular fibrillation, the leading cause of sudden death in the industrialized world. In this numerical study, we investigate the role of intrinsic heterogeneities due to M cells in the generation and maintenance of reentrant excitations. These cells, located in the midmyocardium, exhibit a prolonged action potential duration and the resulting dispersion of repolarization is exacerbated in patients with the long QT syndrome. Using a detailed electrophysiological model, two previously postulated mechanisms are investigated: one in which the M cells create premature stimuli that lead to reentrant events and one in which the M cell domains function as wave blocks for electrically propagating waves originating, as usually, from the endocardium. We find that the first mechanism is unlikely to happen under the conditions we study, due to the strong electrotonic coupling that is normally present between neighboring cells. The second mechanism, on the other hand, can result in reentrant excitations. We determine the lifetime of the reentry as a function of the size and geometry of the domain, and of the strength of the long QT syndrome.

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“…Mutation of HERG is a common cause of inherited long QT syndrome, a disorder of cardiac repolarization that predisposes affected individuals to torsade de pointes arrhythmia and sudden death (4). Acquired long QT syndrome is far more common than inherited long QT syndrome and is most often caused by block of HERG channels as a side effect of treatment with commonly used medications including antiarrhythmic, antihistamine, antibiotic, and psychoactive agents (5,6). Although rare, treatment with the antimalarial drug chloroquine has also been associated with acquired arrhythmias.…”

Section: Hergmentioning

confidence: 99%

Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block

Sánchez-Chapula¹,

Navarro‐Polanco²,

Culberson³

et al. 2002

Journal of Biological Chemistry

172

139

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The structural determinants for the voltage-dependent block of ion channels are poorly understood. Here we investigate the voltage-dependent block of wild-type and mutant human ether-a-go-go related gene (HERG) K ؉ channels by the antimalarial compound chloroquine. The block of wild-type HERG channels expressed in Xenopus oocytes was enhanced as the membrane potential was progressively depolarized. The IC 50 was 8.4 ؎ 0.9 M when assessed during 4-s voltage clamp pulses to 0 mV. Chloroquine also slowed the apparent rate of HERG deactivation, reflecting the inability of drug-bound channels to close. Mutation to alanine of aromatic residues (Tyr-652 or Phe-656) located in the S6 domain of HERG greatly reduced the potency of channel block by chloroquine (IC 50 > 1 mM at 0 mV). However, mutation of Tyr-652 also altered the voltage dependence of the block. In contrast to wild-type HERG, block of Y652A HERG channels was diminished by progressive membrane depolarization, and complete relief from block was observed at ؉40 mV. HERG channel block was voltage-independent when the hydroxyl group of Tyr-652 was removed by mutating the residue to Phe. Together thesefindingsindicateacriticalroleforTyr-652involtage-dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings of chloroquine to the central cavity of HERG. Our experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by cationand -stacking interactions with Tyr-652 and Phe-656 of multiple subunits. HERG1 (1) encodes the pore-forming subunits of channels that conduct the rapid delayed rectifier K ϩ current, I Kr (2, 3). Mutation of HERG is a common cause of inherited long QT syndrome, a disorder of cardiac repolarization that predisposes affected individuals to torsade de pointes arrhythmia and sudden death (4). Acquired long QT syndrome is far more common than inherited long QT syndrome and is most often caused by block of HERG channels as a side effect of treatment with commonly used medications including antiarrhythmic, antihistamine, antibiotic, and psychoactive agents (5, 6). Although rare, treatment with the antimalarial drug chloroquine has also been associated with acquired arrhythmias. Prolonged therapy with chloroquine can lead to electrocardiographic changes including T-wave depression or inversion and prolonged QRS and QT intervals (7,8). Prolonged QT intervals caused by chloroquine can induce torsade de pointes (9, 10). At the cellular level, chloroquine decreases the maximum upstroke velocity due to block of sodium current and prolongs the duration of action potentials due to block of inward rectifier current (I K1 ) and I Kr (11). Elucidating the molecular mechanisms of HERG channel block by chloroquine and other drugs may enable the rational design of new pharmaceuticals devoid of this unwanted side effect.The structural basis of HERG channel block by several potent drugs was recently investigated using alanine-scanning mutagenesis (12). Mutation of several amino acid res...

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The Electrophysiological Mechanism of Ventricular Arrhythmias in the Long QT Syndrome

Cited by 378 publications

References 48 publications

Determination of Human Ventricular Repolarization by Noncontact Mapping

Determination of Human Ventricular Repolarization by Noncontact Mapping

The role of M cells and the long QT syndrome in cardiac arrhythmias: Simulation studies of reentrant excitations using a detailed electrophysiological model

Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block

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