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Clinical history

A. Syncope!

With stress 2

Without stress 1

B. Congenital deafness 0.5 Family history ||

A. Family members with definite LQTS# 1

B. Unexplained sudden cardiac death below age 30 among immediate family members 0.5

Clinical history

A. Syncope!

With stress 2

Without stress 1

B. Congenital deafness 0.5 Family history ||

A. Family members with definite LQTS# 1

B. Unexplained sudden cardiac death below age 30 among immediate family members 0.5

* In the absence of medications or disorders known to affect these electrocardiographic features. t Calculated by Bazett's formula. $ Mutually exclusive.

ยง Resting heart rate below second percentile for age. | The same family member cannot be counted in both A and B.

#Definite LQTS is defined by a LQTS score >4. Scoring: <1 point, low probability of LQTS; 2 to 3 points, intermediate probability of LQTS; >4 points, high probability of LQTS. (Reproduced with permission from: Schwartz et al. Diagnostic criteria for long QT syndrome. Circulation 1993;88[2]:783.)

in order to establish a definitive diagnosis and enable screening of the entire kindred to identify asymptomatic gene carriers. After a patient has been definitively diagnosed with LQTS by conventional or molecular criteria, all family members should be screened for LQTS, so that prophylactic beta-blocker treatment can be initiated in affected individuals. It is now established that up to 5% of asymptomatic gene carriers have normal QT intervals (29). Identification of these individuals using molecular diagnostic techniques is required because they may generate affected offspring and remain at risk for serious arrhythmic events, which can be prevented in some instances by prophylactic beta-blocker therapy. Molecular diagnostic techniques have also changed the approach to the so-called "sporadic cases." In these kindreds, the proband is the only individual diagnosed with LQTS on clinical grounds. Priori et al. recently reported that 33% of family members of "sporadic cases" who were previously considered normal were found to be asymptomatic gene carriers (30). These individuals must be identified if they are to receive appropriate genetic counseling, instruction regarding avoidance of QT-prolonging drugs, and consideration of prophylactic therapy.

Mechanism of Torsades de Pointes

Congenital and acquired LQTS are both characterized by an increased proclivity for torsades de pointes, which is the arrhythmia responsible for clinical events in this syndrome. Numerous in vitro experiments and mapping studies in animal models of torsades de pointes have yielded important clues as to the mechanism of this arrhythmia. The beat that initiates torsades de pointes is likely triggered from an early after-depolarization (31). The prolongation of repolarization that is characteristic of both forms of LQTS is a known precipitant of early after-depolarizations. Two competing hypotheses have been proposed to explain the maintenance of torsades de pointes. The first theory posits that several competing foci of triggered activity exist, which originate from different regions of the ventricle. Alternatively, dispersion of ventricular repolar-ization may create the substrate for reentrant scroll waves that wander across the ventricular myocardium. The motion of these reentrant circuits creates a Doppler effect, which causes the polymorphic ECG appearance (32). These new insights into the mechanism of torsades de pointes have stimulated the development of novel strategies to identify individuals who are at the greatest risk for this arrhythmia.

Risk Stratification For Arrhythmic Events

Once an individual has been definitively diagnosed with LQTS, the risk of subsequent cardiac events can be estimated using clinical and electrocardiographic criteria. The proband, defined as the first individual identified in a given kindred, is at greater risk for subsequent cardiac events than affected family members (33). Patients with a prior history of cardiac events are at increased risk compared to individuals with asymptomatic QT prolongation. The length of the QT interval also bears a direct relation to the risk for subsequent events (33). Among family members, relative bradycardia or tachycardia and female gender are associated with increased risk (34). The association of female gender with cardiac events is unexpected in an autosomal dominant disorder, and may relate to the effects of female hormones on potassium-channel expression (35). The specific genotype also appears to provide some prognostic information. Zareba et al. recently reported that the risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus (36). Although cumulative mortality is similar regardless of the genotype, the percentage of lethal cardiac events is significantly higher in families with mutations at the LQT3 locus. Invasive electrophysiologic studies (EPS) do not appear to be useful for risk stratification of patients with LQTS (37).

Therapeutic Options

Beta-adrenergic blockers should be instituted in all symptomatic patients (syncope and aborted cardiac arrest) and in asymptomatic affected individuals who are members of high-risk families (4). Recent data indicates that the chance of having a recurrent cardiac event within 5 yr after starting beta-blockers is 32% in probands; 14% of patients who had aborted sudden cardiac death prior to taking beta-blockers had recurrent cardiac arrest within 5 yr despite beta-blocker therapy. Among affected family members, beta-blocker therapy reduced the event rate during follow-up, but cardiac events did occur (38). These findings highlight the limitations of beta-blocker therapy, and the importance of identifying those individuals who are likely not to respond to beta-blockers. There is some data to suggest that patients who are likely to respond to beta-

blockers are more likely to manifest a decrease in QT dispersion than nonresponders after therapy is initiated (39); however, the significance and reproducibility of QT dispersion remains controversial. A major focus of future research will be to develop automated electrocardiographic methods that can be employed to identify individuals at particularly high risk, and to assess the response to therapy. The adequacy of the beta-blocker dose should be assessed in all patients by determining the heart rate response to treadmill exercise, aiming for a heart rate of <130 beats per minute (BPM) (4). Concomitant pacemaker therapy may be required in individuals with resting or drug-induced sinus bradycardia. Beta-blockers would be expected to be most effective in LQT1 and LQT2 patients, who appear to have an adrenergic trigger for cardiac events in many instances. The benefit of beta-blockade may be less in LQT3 patients, who are more likely to experience cardiac events at rest or during sleep (9). It is now clear that women with LQTS who become pregnant are at increased risk for cardiac events during the postpartum interval; beta-blockers should therefore be continued during and after pregnancy in all affected individuals (40).

It is often difficult to decide how aggressively to treat LQTS patients at the time of their initial presentation. Implantable cardioverter defibrillator (ICD) implantation should be strongly considered in individuals who present with aborted cardiac arrest; the approach to patients who present with syncope should be individualized based on the severity of the disorder in a given kindred and the presence of other high-risk features. The management of asymptomatic affected members of high-risk families is also difficult. The choice of therapy must be based upon clinical judgment, as no comparative clinical trials have been conducted. Combination therapy with beta-blockers and a permanent pacemaker is highly effective in high-risk individuals (41,42). The mechanism of the benefit of pacing probably relates to the prevention of arrhythmogenic pauses; in addition, beta-blockers can often be titrated to higher doses. The advent of dual-chamber ICDs is likely to change the approach to pacing in LQTS, as these devices provide dual-chamber pacing capabilities as well as definitive sudden death protection. At present, it is reasonable to proceed to ICD implantation in individuals who initially present with aborted cardiac arrest or syncope with high-risk clinical features. Patients who have recurrent syncope on beta-blockers should also undergo ICD implantation. The effectiveness of left cervicothoracic sympathetic denervation remains controversial (43,44); this procedure should be reserved for patients who remain symptomatic despite treatment with beta-blockers and pacing.

The recognition that LQTS is caused by mutations in specific ion channels has stimulated the development of novel pharmacologic therapies designed to improve the function of the mutant ion channels ("gene-specific therapy"). In the case of LQT3, which is caused by persistent inward leakage of sodium current, class IB agents (e.g., lidocaine, mexilitene) appear to produce dramatic shortening of the QT interval. Some LQT2 patients also appear to exhibit shortening of the QT interval with mexilitene (19). It is also well-known that increases in the extracellular potassium-ion concentration result in activation of IKr. Compton et al. recently demonstrated that increases in the extracellular potassium concentration produce normalization of the length and morphology of the repolarization interval in LQT2 patients (45) (Fig. 2). Although these preliminary data are encouraging, none of these novel therapies have yet been demonstrated to decrease the risk for cardiac events.

Baseline Potassium

Fig. 2. Effect of potassium administration on resting QT morphology. (Reproduced with permission from: Compton et al. Genetically defined therapy of inherited long QT syndrome. Correction of abnormal repolarization by potassium. Circulation 1996;94:1021.)

Table 2

List of Drugs That Cause QT Prolongation and Torsades de Pointes

Table 2

List of Drugs That Cause QT Prolongation and Torsades de Pointes

Category of drug

Specific drugs

Antiarrhythmic

Quinidine, procainamide, disopyramide d-sotalol, d,l-sotalol,

Class IA

ibutilide, amiodarone, bretylium, almokalant, sematilide,

Class III

dofetilide

Antimicrobial

Erythromycin, clarithromycin, trimethoprim-sulfamethoxazole

Antihistamine

Astemizole, terfenadine

Antimalarial/protozoal

Chloroquine, halofantrine, mefloquine, pentamidine, quinine

Gastrointestinal prokinetic

Cisapride

Psychoactive

Chloral hydrate, haloperidol, lithium, phenothiazines, pimozide,

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