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Long QT syndrome type 3

The long QT syndrome (LQTS) is a heart disease in which there is an abnormally long delay between the electrical excitation (or depolarization) and relaxation (repolarization) of the ventricles of the heart. It is associated with syncope (loss of consciousness) and with sudden death due to ventricular arrhythmias. Arrhythmias in individuals with LQTS are often associated with exercise or excitement. The cause of sudden cardiac death in individuals with LQTS is ventricular fibrillation. more...

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Individuals with LQTS have a prolongation of the QT interval on the ECG. The Q point on the ECG corresponds to the beginning of ventricular depolarization while the T point corresponds to the beginning of ventricular repolarization. The QT interval is measured from the Q point to the end of the T wave. While many individuals with LQTS have persistent prolongation of the QT interval, some individuals do not always show the QT prolongation; in these individuals, the QT interval may prolong with the administration of certain medications.


The two most common types of LQTS are genetic and drug-induced. Genetic LQTS can arise from mutation to one of several genes. These mutations tend to prolong the duration of the ventricular action potential (APD), thus lengthening the QT interval. LQTS can be inherited in an autosomal dominant or an autosomal recessive fashion. The autosomal recessive forms of LQTS tend to have a more severe phenotype, with some variants having associated syndactyly or congenital neural deafness. A number of specific genes loci have been identified that are associated with LQTS. Following is a list of the most common mutations:

  • LQT1 - mutations to the alpha subunit of the slow delayed rectifier potassium channel (KvLQT1 or KCNQ1). The current through the heteromeric channel (KvLQT1+minK) is known as IKs. This mutation is thought to cause LQT by reducing the amount of repolarizing action potential current that prolongs action potential duration (APD). These mutations tend to be the most common yet least severe.
  • LQT2 - mutations to the alpha subunit of the fast delayed rectifier potassium channel (HERG + miRP). Current through this channel is known as IKr. This phenotype is also probably caused by a reduction in repolarizing current.
  • LQT3 - mutations to the alpha subunit of the sodium channel (SCN5A). Current through is channel is commonly referred to as INa. Depolarizing current through the channel late in the action potential is thought to prolong APD. The late current is due to failure of the channel to remain inactivated and hence enter a bursting mode in which significant current can enter when it should not. These mutations are more lethal but less common.
  • LQT4 - mutations in an anchor protein Ankyrin B which anchors the ion channels in the cell. Very rare.
  • LQT5 - mutations in the beta subunit MinK which coassembles with KvLQT1.
  • LQT6 - mutations in the beta subunit MiRP1 which coassembles with HERG.
  • LQT7 - mutations in the potassium channel KCNJ2 which leads to Andersen-Tawil syndrome.
  • LQT8 - mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c leading to Timothy's syndrome

Other mutations affect the beta subunits ion channels. For example LQT6 affects minK (aka KCNE1) which is the beta subunit that coassembles with KCNQ1 to form IKs channels.


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Torsades de pointes and long QT syndromes
From American Family Physician, 10/1/95 by Louis F. Janeira

Although long QT intervals had previously been associated with syncope and sudden death, it was not until 1966 that the actual arrhythmia associated with this syndrome was identified as a polymorphic form of ventricular tachycardia. Its electrocardiographic appearance was described as a "twisting of the points" or, in French, "torsades de pointes."[1]

Both polymorphic and monomorphic ventricular tachycardia may occur in association with a normal QT interval. Polymorphic ventricular tachycardia may occur, for instance, during myocardial ischemia or infarction, and it may be confused with ventricular fibrillation. The designation "torsades de pointes" should be employed only when polymorphic ventricular tachycardia is associated with long QT intervals.[1]

Prevalence and Risk Factors

The exact incidence of torsades de pointes remains speculative, but the condition is thought to be more unrecognized than rare.[2] The arrhythmia has been reported in all age groups, from newborns3 to the very old.4 Evidence of coexisting structural heart disease is often absent,[5,6] especially in the congenital form of the arrhythmia. Approximately 0.25 percent of deaf-mute children are born with a long QT interval. These individuals have been reported to represent about 30 percent of all patients with torsades de pointes and long QT intervals.[2]

The overall mortality rate for patients with prolonged QT syndromes has been estimated to be 1 to 2 percent per year.[7] Some patients appear to have a benign course and have only one or two episodes in their entire life. Others tend to have recurrent symptomatic episodes.[2]

Independent risk factors for death due to torsades de pointes include female gender, congenital deafness, a history of syncope or resuscitated arrest, and a family history of sudden death. Few, if any, episodes have been reported during pregnancy or in the postpartum period.7 The reason for the lack of occurrence in association with pregnancy remains a mystery but may perhaps be explained, at least in part, by the usual avoidance of drugs during pregnancy. Agents known to prolong the QT interval can predispose individuals to torsades de pointes.


The polymorphic configuration in torsades de pointes is caused by changes in the QRS axis, as if the QRS complexes were being twisted around the isoelectric line (Figure 1). These polarity oscillations typically occur every three to 20 beats. Characteristically, torsade de pointes occurs in clusters, and it tends to be rapid and self-terminating. The ventricular rhythm is usually irregular, and rates from 160 to over 300 have been described.[4,8]

Since the ventricular rate is typically rapid, sustained torsades de pointes is almost always poorly tolerated. Patients often complain of symptoms that are related to hemodynamic compromise from low cardiac output. These include dizziness, angina, shortness of breath and syncope. Torsades de pointes may degenerate into ventricular fibrillation and sudden death.[3,4,8-10]

The QT Interval

The QT interval is measured from the QRS complex (i.e., the beginning of the Q wave or, if the Q wave is absent, the beginning of the R wave) to the end of the T wave. If a U wave is merged with the T wave, this should be included in the measurement, and the interval in this situation is called the QTU interval.

The measured QT interval ([QT.sub.m]) should be corrected to the heart rate ([QT.sub.c]). The best way to make this calculation is under current dispute. Many formulas have appeared in the literature, but the following is still the one most commonly used: QTc = QTm/RR, where RR (in seconds) indicates the interval between the two R waves preceding the measured QT31

In the absence of intraventricular conduction delays, the normal corrected QT interval ([QT.sub.c]) is 420 to 440 msec. When bundle branch block is present, proper calculation of the [QT.sub.c] is still unsettled.[7] The QT interval should be measured in several leads, and the longest one ([QT.sub.max]) should be used. The anteroseptal leads are often closest to the [QT.sub.max].[12] As a rough guide, if the [QT.sub.m] is greater than half the preceding RR interval, the [QT.sub.c] is likely to be prolonged, though this applies best when the heart rate is less than 100 beats per minute (Figure 2).

Torsades de pointes induction depends not only on QT prolongation but also on the T-wave distortion.[13] Quinidine-induced torsades de pointes (quinidine syncope) has been reported to be accompanied by minimal increases in the QT interval,[13,14] whereas hypocalcemia is an infrequent cause of torsades de pointes despite marked QT prolongation.[15,16] However, quinidine induces T-wave distortions as it prolongs repolarization, whereas hypocalcemia only lengthens the ST segment. T-wave distortions are believed to be essential for torsades de pointes to be initiated, and they indicate a greater vulnerability to the development of the arrhythmia.[5,13,17-19] These distortions may take the form of notched T waves, biphasic T waves or T-wave alternans (i.e., T-wave distortions that vary from beat to beat).

Researchers have tried to correlate the QT interval prolongation with the subsequent risk of torsades de pointes. A measured QT interval of more than 600 msec poses a high risk.[20] Patients with a QTc between 500 and 600 msec are at moderate risk for torsades de pointes.[21,22] If the QTc is less than 500 msec, the risk of torsades de pointes appears to be low.

Regardless of the QTc, other factors that may increase this interval should be avoided in susceptible patients. This includes, for instance, the use of diuretics that may have the potential to cause significant depletion of potassium and/or magnesium. Likewise, patients should be asked to report episodes of prolonged diarrhea or anorexia. The concomitant use of different agents that increase the QT interval should only be used if absolutely necessary. In such cases, frequent ECGs should be obtained to determine the [QT.sub.c].

Etiology of Long QT Intervals

On the basis of the clinical findings and response to therapy, long QT intervals can be separated into two distinct major categories: acquired QT prolongation, and idiopathic and congenital QT prolongation.


Acquired QT prolongation is most frequently induced by drugs or electrolyte disturbances. The most common culprits are class IA antiarrhythmic agents, especially quinidine. Torsades de pointes in these patients is often not dose-dependent. In fact, 50 percent of patients who develop torsades de pointes due to quinidine therapy do so before therapeutic levels are achieved.[13,14,20]

Established causes of acquired long QT intervals are listed in Table 1. Torsades de pointes in this group is characterized by its association with bradyarrhythmias or pauses in the rhythm that create long-short RR cycles, especially if T-wave distortions are induced (Figures 3a and 3b).[23]


Therapy for torsades de pointes depends on the etiology of the QT prolongation.


In the acquired type, the most important step is to withdraw the offending drug or correct other potential etiologic factors. If the patient presents with hemodynamically compromising torsades de pointes, defibrillation is required. However, until the underlying cause is corrected, torsades de pointes may very likely recur. Therefore, electrical cardioversion must be accompanied by other interventions that protect the heart against the arrhythmia and/or shorten the long QT interval.[15,24]

For most patients, magnesium sulfate is recommended as first-line therapy for torsades de pointes with QT interval prolongation.[25,26] The dose is 2 g of magnesium sulfate, given intravenously over one to five minutes, with a second bolus given, if necessary, five to 15 minutes later. If needed, patients can receive a continuous intravenous infusion of magnesium sulfate (3 to 20 mg per minute) for up to 48 hours or until the QT interval has been normalized by the correction of any obvious underlying factors.[25] The efficacy of magnesium sulfate in treating the arrhythmia is independent of the patient's pretreatment magnesium level. Furthermore, magnesium sulfate therapy does not, in itself, shorten the QT interval.

When bradyarrhythmias and pauses are observed, they also must be treated. Prompt results can usually be achieved with atropine or isoproterenol (Isuprel) while temporary pacing measures are being readied.[20,24,26] Temporary pacing works by increasing the heart rate, which shortens the QT interval. External pacing, while avoiding the risk of transvenous pacemaker insertion, frequently is not a good option, since most conscious patients find this method uncomfortable. Both atrial and ventricular pacing have been used. If atrioventricular conduction is preserved, atrial pacing is preferred, since it is more physiologic.

Overdrive pacing should be implemented by pacing at a rate 20 to 30 beats per minute faster than the intrinsic rate (up to 90 to 120 beats per minute).[16,20] When control of torsades de pointes is gained, the pacing rate is slowly decreased and is maintained at the lowest effective rate. Temporary pacing should be continued until the QTc returns to normal, once correction of the etiologic factor(s) has been accomplished. The QT interval should be measured in sinus rhythm with the temporary pacemaker in the standby mode, especially if ventricular pacing is being carried out.

Many agents commonly used to treat ventricular arrhythmias increase the QT interval. If the ventricular tachycardia is not recognized as torsades de pointes, the usual first-line antiarrhythmic agents may sometimes worsen rather than help the situation and may delay the initiation of appropriate steps to terminate the events.[20] Lidocaine (Xylocaine) and other class IB antiarrhythmic agents theoretically have few adverse effects on the QT interval. Even though some studies have shown lidocaine to successfully terminate torsades de pointes,[27] other trials and reports have implicated class IB drugs as etiologic factors.[19,20,23] Therefore, class I and class III antiarrhythmic agents, including lidocaine, continue to be considered inappropriate choices in the management of torsades de pointes.

Calcium antagonists suppress afterdepolarizations, which occur at the end of the action potential. Afterdepolarizations have been implicated as a cause of torsades de pointes.[6,29-31] Theoretically, at least, calcium antagonists should be considered in the management of torsades de pointes. However, little current information is available to support the use or the avoidance of these agents in patients with torsades de pointes. Bepridil (Vascor), a calcium antagonist with sodium channel blocking properties, is a notable exception. This agent has been implicated as a cause of QT interval prolongation and torsades de pointes.[32]


Since torsades de pointes associated with the congenital form of prolonged QT syndromes occurs in the setting of excess sympathetic tone, beta blockers are the mainstay of management to prevent the arrhythmia. These agents have been shown to reduce the incidence of torsades de pointes in patients with congenital long QT syndrome.[33]

Beta blockers have a stabilizing effect on the myocardium in that they raise the fibrillatory threshold and suppress early afterdepolarizations. The mortality r ate has been reduced from 73 percent in untreated patients with torsades de pointes to 6 percent in those who are treated with beta blockers.2 However, before beta-blocker therapy is initiated, the acquired forms of prolonged QT should be excluded, since beta blockers may worsen that condition by promoting bradyarrhythmias.

It has been postulated that cardiac sympathetic impulses originate predominantly from the left sympathetic cervical chain in patients with congenital long QT syndromes. Left-sided cervicothoracic sympathetic interruption using various agents has been successful in both the urgent and long-term management of prolonged QT intervals associated with torsades de pointes.[34] Surgical resection of the stellate ganglion and the first three or four thoracic segments of the cervical sympathetic chain constitute second-line treatment if medical therapy proves unsatisfactory.[2,17,33,35,36] Postoperative results have been optimistic. In one relatively large trial, three late deaths occurred among 41 patients with congenital QT prolongation syndrome who were followed for periods ranging from three months to 10 years.[17]

If pause-dependent torsades de pointes persists despite other therapeutic measures, permanent atrioventricular sequential pacing should be considered in order to avoid the long-short RR cycling associated with the arrhythmia.

Since the advent of implantable cardioverter defibrillators (ICDs), fewer and fewer patients are receiving medical therapies other than beta blockers or ganglionectomy.[34] Many experts consider ICDs the mainstay of therapy in patients with torsades de pointes who are at high risk for sudden death, such as those with syncope and a family history of sudden death due to this arrhythmia.



[1.] Dessertenne F. Ventricular tachycardia with 2 variable opposing foci. Arch Mal Coeur Vaiss 1966;59: 263-72. [2.] Schwartz PJ, Periti M, Malliani A. The long QT syndrome. Am Heart J 1975;89:378-90. [3.] Finley JP, Radford DJ, Freedom RM. Torsades de pointes ventricular tachycardia in a newborn infant. Br Heart J 1978;40:421 -4. [4.] Rossi L, Matturri L. Histopathological findings in two cases of torsade de pointes with conduction disturbances. Br Heart J 1976;38:1312-8. [5.] Smith WM, Gallgher JJ. "Les torsades de pointe": an unusual ventricular arrhythmia. Ann Intern Med 1980;93:578-84. [6.] Jackman WM, Clark M, Friday KJ, Aliot EM, Anderson J, Lazzara R. Ventricular tachyarrhythmias in the long QT syndrome. Med Clin North Am 1984;68: 1079-109 [7.] Moss AJ. Prolonged QT-interval syndromes. JAMA 1986;256:2985-7 [Published erratum appears in JAMA 1987;257:487]. [8.] Schwartz PJ. The long QT syndrome. In: Kulbertus HE, Wellens HJ, eds. Sudden death. Boston: Martinus Nijhoff, 1980. [9.] Ranquin R, Parizel G. Ventricular fibrillo-flutter ("torsade de pointe"): an established electrocardiographic and clinical entity. Angiology 1977;28:115-8. [10.] Edwards RR, Robbins JA. Polymorphic ventricular tachycardia as the presenting manifestation of a Bjork-Shiley mitral valve prosthesis strut fracture. Am J Cardiol 1988;61 :192. [11.] Bazett HC. An analysis of the time relations of electrocardiograms. Heart 1920;7:353. [12.] Cowan JC, Yusoff K, Moore M, Amos PA, Gold AE, Bourke JP, et al. Importance of lead selection in QT interval measurement. Am J Cardiol 1988;h1:83-7. [13.] Clark M, Lazzara R, Jackman W. Tolsade de pointes: serum drug levels and ECG warning signs [Abstract]. Circulation 1982;66[Suppl 2]:71 [14.] Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL. Torsade de pointes: the long-short initiating sequence and other clinical features: observations in 32 patients. J Am Coll Cardiol 1983;2: 806-17. [15.] Giustiniani S, Robustelli della Cuna F, Sardeo C, Forni MC. "Torsade de pointes" induced by hypocalcemia. G Ital Cardiol 1982;12:889-91. [16.] Kahn MM, Logan KR, McComb JM, Adgey AA. Management of recurrent ventricular tachvarrhythmias associated with Q-T prolongation. Am J Cardiol 1981;47:1301-8. [17.] Moss AJ, Schwartz PJ. Delayed repolarization (QT or QTU prolongation) and malignant ventricular arrhythmias. Mod Concepts Cardiovasc Dis 1982; 51:85-90. [18.] Schechter E, Freeman CC, Lazzara R. Afterdepolarizations as a mechanism for the long QT syndrome: electrophysiologic studies of a case. J Am Coll Cardiol 1984;3:1556-61. [19.] Stratmann HG, Kennedy HL. Torsades de pointes associated with drugs and toxins: recognition and management. Am Heart J 1987;113:1470-82. [20.] Keren A, Tzivoni D, Gavish D, Levi J, Gottlieb S, Benhorin J, et al. Etiology, warning signs and therapy of torsade de pointes. A study of 10 patients. Circulation 1981;64:1167-74. [21.] Keren A, Tzivoni D. Torsades de pointes: prevention and therapy. Cardiovasc Drugs Ther 1991;5: 509-13. [22.] Rao KA, Adlakha A, Verma-Ansil B, Meloy TD, Stanton MS. Torsades de pointes ventricular tachycardia associated with overdose of astemizole. Mayo Clin Proc 1994;69:589-93. [23.] Jackman WM, Szabo B, Friday KJ, Margolis PD, Moulton K, Wang X, et al. Ventricular tachyarrhythmias related to early afterdepolarizations and triggered firing: relationship to QT interval prolongation and potential therapeutic role for calcium channel blocking agents. J Cardiovasc Electrophysiol 1990;3:170-95. [24.] Miller DS, Blount AW Jr. Quinidine-induced recurrent ventricular fibrillation: (quinidine-syncope) treated with transvenous pacemaker. South Med J 1971;64:597-601 . [25.] Tzivoni D, Banai S, Schuger C, Benhorin J, Keren A, Gottlieb S, et al. Treatment of torsades de pointes with magnesium sulfate. Circulation 1988;77:392-7. [26.] Banai S, Tzivoni D. Drug therapy for torsade de pointes. J Cardiovasc Electrophysiol 1993;4:206-10. [27.] Kaplinsky E, Yahini JH, Barzilai J, Neufeld HN. Quinidine syncope; report of a case successfully treated with lidocaine. Chest 1972;62:764-6. [28.] Anderson JL, Mason JW. Successful treatment by overdrive pacing of recurrent quinidine syncope due to ventricular tachycardia. Am J Med 1978; 64:715-8. [29.] Napolitano C, Priori SG, Schwartz PJ. Torsade de pointes. Mechanisms and management. Drugs 1994;47:51-65. [30.] D'Alnoncourt CN, Zierhut W, Bluderitz B. "Torsade de pointes" tachycardia. Re-entry or focal activity? Br Heart J 1982;48:213-6. [31]. Roden DM. Early after-depolarizations and torsade de pointes: implications for the control of cardiac arrhythmias by prolonging repolarization. Eur Heart J 1993;14(Suppl H):56-61 [32.] Somberg J, Torres V, Flowers D, Miura D, Butler B, Gottlieb S. Prolongation of QT interval and antiarrhythmic action of bepridil. Am Heart J 1985;109: 19-27. [33.] Milne JR, Ward DE, Spurrell RA, Camm AJ. The long QT syndrome: effects of drugs and left stellate ganglion block. Am Heart J 1982;104(2 Pt 1):194-8. [34.] Mirowski M, Reid PR, Mower MM, Watkins L, Gott VL, Schauble JF, et al. Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med 1980;303:322-4. [35.] Yanowitz F, Preston JB, Abildskov JA. Functional distribution of right and left stellate innervation to the ventricles. Circ Res 1966;18:416-28. [36.] Crampton R. Preeminence of the left stellate ganglion in the long QT syndrome. Circulation 1979;59:769-78.

LOUIS F. JANEIRA, M.D. is chief of the cardiac electrophysiology section at St. Mary's Medical Center in Evansville, Ind., where he is also in private practice as a cardiologist-electrophysiologist. Dr. Janeira completed his training in cardiology and electrophysiology at Deborah Heart and Lung Center, Browns Mill, N.J.

Address correspondence to Louis F. Janeira, M.D., Section of Cardiac Electrophysiology, St. Mary's Medical Center, 1400 Professional Blvd., Evansville, IN 47714. Figure 3b from Jackman WM, Szabo B, Friday KJ, Margolis PD, Moulton K, Wang X, et al. Ventricular tachyarrhythmias related to early afterdepolarizations and triggered firing: relationship to QT interval prolongation and potential therapeutic role for calcium channel blocking agents. J Cardiovasc Electrophysiol 1990;3:174. Used with permission.

COPYRIGHT 1995 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group

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