Long QT Syndrome

The long QT syndrome (LQTS) was first described in 1957 in a family in which several children with congenital bilateral neural deafness and QT prolongation on electrocardiogram (ECG) experienced recurrent syncope and sudden death, with a family pattern that suggested autosomal recessive inheritance (Jervell and Lange-Nielsen syndrome).¹ A similar and much more common familial disorder with QT prolongation but without deafness was described a few years later, with family patterns that suggested autosomal dominant inheritance (Romano-Ward syndrome). These reports highlighted the familial nature of this QT prolongation disorder, and subsequent studies identified malignant ventricular arrhythmias as the cause of syncope and sudden death in patients with LQTS. The molecular-genetic basis of LQTS was discovered in the 1990s and, currently, mutations have been identified in 7 LQTS genes (Table 1).

Ventricular repolarization is determined by cardiac ion-channel proteins that regulate the flux of sodium, potassium, and calcium ions across myocellular membranes. Ion channels are complex proteins encoded by specific genes. The LQTS is caused by mutations in 6 defined genes that encode channels that regulate sodium and potassium currents and by a mutation in a cytoskeletal gene (ankyrin B) that may affect sodium channel kinetics. The LQTS genes are identified by an LQT number that reflects the chronological order in which the LQTS gene locus was discovered and by the name of the mutated gene that has been linked to LQTS (Table 1). Currently, more than 150 different mutations have been identified in 7 LQTS genes, with LQT1 (43%), LQT2 (45%), and LQT3 (7%) accounting for 95% of the identified mutations.² Approximately 2% to 3% of LQTS patients who have undergone genotyping carry 2 mutations in LQT genes. Currently, known mutations in the 7 LQT genes account for an estimated 50% of those affected with LQTS.

The LQTS is considered an ion-channel disorder in which the type and location of the genetic mutation, the genotype, determines to a large extent the expression of the clinical syndrome, the phenotype. However, this disorder, like most other genetic conditions, has variable expression of severity (ie, variable penetrance). An affected individual within a given family with a specific LQTS mutation may be asymptomatic throughout life, whereas another affected family member with the same gene mutation may experience recurrent syncope and sudden cardiac death at a young age. This variability in expression in related individuals with the same mutation suggests the influence of environmental factors and/or the presence of other genetic effects.

The LQTS is an infrequently occurring disorder in the general population. Affected persons may present with sudden death, syncope, or QT prolongation on an incidental ECG. If the presenting event is a syncopal episode, clinical evaluation that includes an ECG will almost always reveal prolongation of the corrected QT interval (QTc), the clinical hallmark of this disorder (Figure 1). When QTc prolongation is identified following a syncopal event, the diagnosis of LQTS is certain, and ECGs should be obtained on all first-degree family members to determine whether others are affected. Unexplained sudden death in a young individual should trigger a similar evaluation to determine if LQTS is present in the family. Rarely, an asymptomatic individual is identified with LQTS by QTc prolongation on an ECG obtained for another reason. Several different drugs can prolong the QTc interval, and it is important to distinguish drug-induced QTc prolongation from the inherited form of LQTS. A careful medication history should be ascertained when evaluating a patient with QTc prolongation.

Diagnostic criteria have been established to increase the probability of correctly diagnosing LQTS (Table 2).³ The summed point score from the diagnostic criteria allows classification of a patient on clinical grounds into low-, intermediate-, or high-risk probability of having LQTS (Table 2). Syncope and sudden death can occur at any age, but these events have an increased frequency in adolescence.

Several different ECG findings in LQTS should alert the physician to the presence of this disorder. The QT interval should be measured from the onset of the Q wave to the end of the T wave in an ECG lead, usually lead II, in which the amplitude of the T wave is large enough to accurately identify the termination of the repolarization T wave. Because the QT interval varies inversely with the heart rate, various formulas have been used to correct the QT interval for the underlying heart rate. When the heart rate is in the range of 50 to 90/min, the standard Bazett correction works well (QTc = QT/√RR with all intervals in seconds). The QTc interval is prolonged (top 1% of the normal QTc distribution) when it is more than 0.45 seconds in men or more than 0.46 seconds in children and women.⁴ In addition to QTc prolongation, LQTS is frequently associated with a notched or bifid T wave in the precordial V₂ through V₄ leads. Distinctive T-wave patterns have been observed in patients with each of the 3 major LQTS genotypes (LQT1, LQT2, LQT3).^{5 - 6} A complex polymorphic ventricular tachycardia, torsades de pointes, can occur in the setting of QTc prolongation. Syncope is often due to a transient, self-limited episode of torsades de pointes. However, this arrhythmia can deteriorate into ventricular fibrillation with resultant sudden cardiac death.

Life-threatening cardiac events (syncope or sudden death) tend to occur under specific circumstances in a gene-specific manner.⁷ In general, LQT1 patients experience a predominance of their events during exercise, LQT2 patients experience events with acute arousal-type emotions, and LQT3 patients experience events without emotional arousal during sleep or at rest. Patients with the LQT1 genotype seem to have a high frequency of cardiac events associated with vigorous physical activities, whereas patients with the LQT2 genotype are at high risk of having arrhythmic events triggered by a sudden loud noise, such as the ringing of an alarm clock.^{8 - 9}

The clinical course of patients with LQTS is variable and is influenced by genotype, sex, environmental factors, and therapy.¹⁰ The risk of cardiac events is significantly higher among patients with LQT1 and LQT2 mutations than those with LQT3 mutations.¹¹ The phenotype of individuals carrying 2 mutations in LQT genes, such as in the Jervell and Lange-Nielsen syndrome, is more severe than in individuals carrying only 1 mutation. The probability of experiencing a cardiac event increases significantly during adolescence in all 3 genotypes. The risk of cardiac events is higher in males before puberty and higher in females during adulthood. In women, pregnancy confers a small additional risk, but there is a significant increase in risk for cardiac events in the 9-month postpartum period. The most significant risk factor for cardiac events is the length of the QTc interval, with the risk an exponential function of the QTc duration.¹² Although a few families have a disproportionately high frequency of sudden cardiac death at a young age, the risk to individual family members is influenced more by the length of the QTc interval than by family membership. Patients who have had one syncopal event are at considerably increased risk of experiencing recurrent events. Individuals who have been resuscitated from cardiac arrest are at high risk of a subsequent fatal event.

In asymptomatic patients with borderline QTc prolongation in the range of 0.44 to 0.46 seconds, the diagnosis of LQTS may be uncertain. Because the QTc interval can be somewhat variable, frequent follow-up ECGs at monthly intervals may clarify the diagnosis, especially if the QTc becomes unequivocally prolonged on one of the recordings. One or more 24-hour Holter recordings may uncover a transient, asymptomatic torsades de pointes that is diagnostic for LQTS, but such an arrhythmia is an infrequent finding during screening Holter recordings. In suspected LQTS cases, Holter-recorded QTc prolongation is difficult to use for diagnosis since QTc variability in healthy patients during prolonged ECG recordings has not been defined. Exercise testing is frequently used in the evaluation of patients with suspected LQTS, although there are few studies to support the diagnostic value of exercise testing. Failure of the QTc to shorten during exercise is a nonspecific finding and should not be used for diagnosis. Furthermore, quantification of the QT interval during exercise-induced tachycardia is difficult because of the overlap of the end of the T wave with the subsequent P wave. Exercise testing can be useful if the activity precipitates a diagnostic arrhythmia or if the QTc interval becomes unequivocally prolonged during recovery after exercise. Invasive electrophysiologic testing with programmed extra-stimuli has not proved useful for diagnosing LQTS or for prognosticating arrhythmic events in those with LQTS.

In patients with established LQTS, Holter monitoring and exercise testing have limited usefulness in uncovering the presence of ventricular tachyarrhythmias during daily living and with vigorous exercise. Negative test results do not provide reassurance that the affected individual is at low risk.

Genetic testing may be useful but is performed only in research laboratories, and the interval to obtain test results can be long. Detection of an LQTS mutation identifies the individual as an affected carrier of the mutant gene. A negative test result is not helpful unless testing is performed for a mutation that is already known to be present within the family.

β-Blocking drugs are the treatment of choice for asymptomatic and symptomatic patients with LQTS. It is believed that the efficacy of β-blockers involves the attenuation of adrenergic-mediated trigger mechanisms in this disorder.⁷ Clinical observations and retrospective studies that evaluate cardiac event rates before and after initiation of β-blocker therapy indicate that β-blockers reduce the frequency of syncope even though they have little or no effect on QTc duration.¹³ The reduction in the rate of cardiac events was most marked in patients with the highest event rates before β-blocker therapy was initiated. β-Blockers were associated with a significant reduction in cardiac event rates in persons with LQT1 and LQT2 mutations, with no evident reduction in cardiac event rates in those with LQT3 mutations.¹³ In a retrospective analysis of 33 LQTS patients who died after starting β-blocker therapy, 76% were receiving β-blockers at the time of their death. Thus, β-blockers do not provide absolute protection against fatal cardiac events. Given the lack of randomized, prospective trials of β-blocker use in LQTS, a reduction in deaths cannot be proven.

Surgical sympathetic denervation of the heart with left cervicothoracic sympathetic ganglionectomy was introduced for the treatment of LQTS in 1970 before β-blockers became available.¹⁴ Currently, sympathectomy is considered adjunctive therapy and is reserved for high-risk LQTS patients who cannot be effectively treated with drugs and devices. The long-term efficacy of sympathectomy is uncertain at this time. Pacemakers have been used in selected LQTS patients with sinus bradycardia, but long-term follow-up studies indicate an inappropriately high rate of sudden death in this group of patients.¹⁵ Preliminary results from the International LQTS Registry indicate that implanted cardioverter defibrillators save lives in high-risk patients who experience recurrent syncope while taking β-blockers or have had an aborted cardiac arrest episode. Implanted defibrillators in combination with β-blockers are the safest form of therapy available for managing high-risk LQTS patients.¹⁶ Gene-specific LQTS therapy is under investigation. A few small pilot studies have reported use of mexiletine,¹⁷ flecainide,¹⁸ or potassium therapy¹⁹ in specific LQTS genotypes, but the available data are not sufficient to make any therapeutic recommendations regarding the use of these medications in LQTS.

Patients with LQTS should avoid adrenergic-type stimuli that can trigger life-threatening arrhythmias.⁷ Competitive athletics should be prohibited. Alarm clocks should be removed, and the intensity of the sound from doorbells and telephones should be attenuated. Patients and their families should be informed that a fainting episode is a serious event that requires prompt medical attention so that more effective prophylactic therapy can be instituted. Once β-blockers are initiated, complete compliance is essential because life-threatening arrhythmias can occur on discontinuance of use of this medication due to rebound receptor catecholamine hypersensitivity. Unnecessary medications, especially stimulants, weight-reducing drugs, certain antibiotics, and most over-the-counter medications, should be avoided. Further sources of information about LQTS are provided in the Article .

The Cardiac Arrhythmia Research and Education Foundation—http://www.longqt.org

The Sudden Arrhythmic Death Syndrome Foundation—http://www.sads.org

The University of Arizona Center for Education and Research on Therapeutics—http://www.torsades.org, which lists drugs that can prolong the QT interval