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Electrophysiologic Mechanisms of the Long QT Interval Syndromes and Torsade de Pointes

Hanno L. Tan, MD, PhD; Charles J. Y. Hou, MD; Michael R. Lauer, MD, PhD; and Ruey J. Sung, MD
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From Stanford University School of Medicine, Stanford, California. Requests for Reprints: Ruey J. Sung, MD, Cardiac Electrophysiology and Arrhythmia Service, Stanford University Hospital, Room H2146, 300 Pasteur Drive, Stanford, CA 94305. Grant Support: Dr. Tan was supported by the Netherlands Heart Foundation (Grant R93314) and the Durrer Fund Netherlands. Dr. Hou was supported by the MacKay Memorial Hospital, Taipei, Taiwan.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1995;122(9):701-714. doi:10.7326/0003-4819-122-9-199505010-00009
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Purpose: To review the current understanding of the mechanisms and treatment of the long QT interval syndromes and torsade de pointes.

Data Sources: Personal databases of the authors and a search of the MEDLINE database from 1966 to 1994.

Study Selection: Experimental and clinical studies and topical reviews on the electrophysiologic mechanisms and treatment of torsade de pointes were analyzed.

Results: The long QT interval syndromes have been classified into acquired and hereditary forms, both of which are associated with a characteristic type of life-threatening polymorphic ventricular tachycardia called torsade de pointes. The acquired form is caused by various agents and conditions that reduce the magnitude of outward repolarizing K+ currents, enhance inward depolarizing Na+ or Ca2+ currents, or both, thereby triggering the development of early afterdepolarizations that initiate the tachyarrhythmia. The hereditary form appears to result from an abnormal response to adrenergic or sympathetic nervous system stimulation. At least some cases of the hereditary long QT interval syndromes may result from a single gene defect that alters the intracellular regulatory proteins responsible for the modulation of K+ channel function. Treatment of the acquired form is primarily directed at identifying and withdrawing the offending agent, although emergent therapy using maneuvers and agents that favorably modulate transmembrane ion currents can be lifesaving. In torsade de pointes associated with the hereditary long QT interval syndromes, early diagnosis leading to treatments designed to both shorten the QT interval and block the β-adrenergic-induced instability of the QT interval is essential.

Conclusions: The long QT interval syndromes and torsade de pointes are potentially life-threatening conditions caused by various agents, conditions, and genetic defects. The mechanisms responsible for these conditions and available treatment options for them are reviewed.


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Figure 1.
Relation between phases of the cardiac action potential and the surface electrocardiogram.

The QT interval roughly corresponds to the plateau phase of the action potential. The broad T wave is inscribed as a result of the rapid repolarization occurring nonsimultaneously throughout the ventricles. The QT interval is prolonged by agents or conditions that delay repolarization in the ventricular cells. ECG = electrocardiographic.

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Figure 2.
Electrocardiogram showing the typical short-long-short RR interval initiation sequence triggering an episode of torsade de pointes.

A sinus beat (A) is followed by a premature ventricular depolarization (B) after a short coupling interval, which is followed, after a long pause after extrasystole, by a sinus beat (C) and another short-coupled premature ventricular depolarization (D), which is the first beat of the tachycardia and which is characterized by an apparent twisting of the electrical axis around the isoelectric line.

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Figure 3.
Schematic drawing illustrating transmembrane action potentials from a Purkinje fiber, a ventricular muscle fiber, and a surface electrocardiogram.dotted linedotted line[32]

It shows the development of early afterdepolarizations and their effect on the surface electrocardiogram, including the QT interval. A. Baseline recordings. B. Phase 2 early afterdepolarization. The action potential is more prolonged in the Purkinje fiber than in the muscle fiber and shows a flattening of the plateau phase. Because of failure of normal repolarization ( ), the Purkinje fiber again depolarizes from its plateau phase potential. The depolarizing potential reaches threshold and is transmitted to the muscle fiber. This beat is seen on the surface electrocardiogram as a premature ventricular depolarization arising from the end of a prolonged QT interval (or in the midst of a pronounced U wave) ( ). The premature ventricular depolarization coincides with the prolonged action potential duration resulting from the early afterdepolarization. C. Phase 3 early afterdepolarization. The sequence is the same except that the early afterdepolarization arises during phase 3 of the Purkinje fiber action potential. (Reproduced with permission from ). PF = Purkinje fiber; MF = ventricular muscle fiber; ECG = surface electrocardiogram.

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Figure 4.
Prolongation of the QT interval resulting from quinidine-induced early afterdepolarizations arising from the plateau phase of the action potential.

Transmembrane action potentials recorded from single isolated epicardial, endocardial, and M cells. Action potential recordings from cells electrically stimulated at various cycle lengths (A = 3.5 s; B = 5.0 s; and C = 20 s). Notice the dramatic prolongation of the action potential duration that occurs (note different time base in panel C with the development of repetitive early afterdepolarizations during the plateau phase of the action potential. [Reproduced with permission from Sicouri and Antzelevitch. J Cardiovasc Electrophys. 1993; 4:48-58.] Epi = epicardial; Endo = endocardial.

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Figure 5.
The acquired long QT interval syndrome resulting from treatment with a class IA agent.

This 12-lead electrocardiogram was obtained from an 80-year-old woman who was treated with quinidine for atrial tachycardia. A few hours after this electrocardiogram was obtained, the patient had a torsade de pointes-related cardiac arrest. The maximum uncorrected QT interval lasted approximately 600 ms. The patient was successfully resuscitated but the tachyarrhythmia was suppressed only after 10 g of magnesium sulfate was administered intravenously.

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Figure 6.
Example of extreme prolongation of the QT interval in a 21-year-old woman with the hereditary long QT interval syndrome (the Romano-Ward syndrome).

This 12-lead electrocardiogram was obtained 48 hours after the patient had a cardiac arrest. The patient had a long history of exertion-related syncope, probably due to recurrent episodes of adrenergic-dependent torsade de pointes. The QT segment was bizarrely inverted in all leads and measured 520 ms even though the RR interval was only 630 ms. Because of the dramatic T-wave changes, the patient was initially misdiagnosed with myocardial ischemia, but a coronary arteriogram and a left ventricular angiogram were normal. She was successfully treated with β-adrenergic blockade and overdrive permanent pacing.

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