The term congenital long QT syndrome (LQTS) includes a group of inherited diseases caused by cardiac ion channel mutations, which produce prolonged ventricular repolarization and a predisposition to polymorphic ventricular tachycardia (torsade de pointes) (17,48). LQTS may manifest as syncope and/or sudden cardiac death (SCD) in young individuals and is often associated with exercise (11,48).
The exact prevalence of LQTS is not known, due to the absence of large-scale population studies, but it is recognized with increasing frequency (29). Moreover, given the propensity to life-threatening arrhythmias during physical or emotional stress in young individuals without structural heart disease, the presence or suspicion of LQTS creates practical dilemmas relevant to the management of young athletes and physically active persons in general. Risk stratification algorithms are evolving as more data regarding the natural history of LQTS emerge (23). Genetic testing is now commercially available (www.familion.com), but the high cost, along with the low penetrance of LQTS (24), complicates clinical applicability and decision-making.
Several high-visibility athletes and situations have recently highlighted the issue of LQTS and athletic participation. Dana Vollmer was a 16-yr-old swimmer with LQTS when she participated in the 2004 Athens Olympic Games while her mother sat poolside with a portable defibrillator. Kayla Burt was a 20-yr-old University of Washington basketball player when she survived a cardiac arrest. She was initially diagnosed with LQTS and received an implantable defibrillator, but ultimately was permitted to return to basketball when further testing for LQTS was negative. Moreover, the deaths of 26-yr-old Anna Loyley during the 1998 Bath Half Marathon and of 13-yr-old Laura Moss during a 1997 swimming gala were both attributed to LQTS and raised the question as to whether young athletes should be screened for LQTS.
The purpose of this article is to review the genetic basis, pathophysiology, and clinical characteristics of the congenital LQTS and to make recommendations for its management in the physically active and athletic population.
GENETIC AND MOLECULAR BASIS OF LQTS
Congenital LQTS presents with two distinct clinical phenotypes based on the type of inheritance and the presence of deafness. Romano-Ward syndrome is the most common type and is transmitted as an autosomal-dominant disorder causing QT prolongation without deafness (48). Jervell and Lange-Nielsen syndrome is the less common but more severe phenotype of LQTS and is transmitted as an autosomal-recessive trait associated with congenital sensorineural deafness (48).
Congenital LQTS is caused by more than 150 different mutations in seven currently defined genes (LQT1-LQT7) (22,36). The heterozygous state in one of the LQT1-LQT7 genes results in the Romano-Ward phenotype. The Jervell and Lange-Nielsen phenotype arises in patients who have inherited two abnormal LQT1 or LQT5 genes from their parents. LQTS mutations, through differing mechanisms, prolong ventricular repolarization, which manifests as long QT interval on the surface ECG.
LQT1 accounts for 42-55% of patients with congenital LQTS (30,36). The mutant gene KVLQT1 encodes for the α-subunit of the potassium (K+) channel responsible for the slow outward (delayed) rectifier current IKs (36). The functional role of IKs, which opens late during the plateau phase of the action potential, is to initiate repolarization. Therefore, defects of the IKs result in prolonged repolarization, which predisposes to early after depolarizations (EAD). EAD of sufficient amplitude cause triggered activity and may initiate polymorphic ventricular tachycardia or torsade de pointes.
LQT2 accounts for 35-45% of cases with congenital LQTS (30,36). The mutant gene HERG (or KCNH2) encodes for the α-subunit of the K+ channel responsible for the rapid component of the outward (delayed) rectifier current IKr, which opens early during the plateau phase of the action potential and initiates repolarization (36). Mutations in the HERG gene also produce prolonged repolarization through a loss-of-function mechanism, EAD, and triggered electrical activity.
LQT3 accounts for 8-10% of patients with congenital LQTS and is caused by mutations in the SCN5A gene (30,36). SCN5A encodes for the cardiac sodium (Na+) channel, which normally opens during the initial phase of the action potential, causing an influx of Na+ and, thus, depolarization of the cell. Immediately after depolarization, the channel enters an inactivated state and stays closed for the remainder of the action potential. In LQT3, the mutant Na+ channel has impaired inactivation and opens repetitively during the plateau phase of the action potential, producing a persistent inward (depolarizing) current. This "gain of function" abnormality of the Na+ channel results in prolonged duration of the action potential and delayed repolarization. Administration of Na+ channel blockers, such as mexiletine (31) or flecainide (1), shorten the QT interval in patients with LQT3.
LQT4 is caused by a loss-of-function mutation in the ankyrin-B gene, which results in marked sinus node dysfunction and prolonged repolarization, possibly by increasing the late inward Na+ current (16).
LQT5 accounts for 3% of cases of congenital LQTS (36). The mutant gene KCNE1 (or minK) encodes the β-subunit of the IKs potassium channel (36).
LQT6 accounts for 2% of patients with congenital LQTS and is caused by a mutation in the KCNE2 (or MiRP1) gene, which encodes the β-subunit of IKr (36).
LQT7 is a rare autosomal-dominant disorder called Andersen syndrome and is characterized by periodic paralysis, skeletal dysmorphic features, and QT prolongation (40).
Timothy syndrome could be classified as LQT8. It is a recently described disorder, characterized by prolongation of the QT interval, lethal arrhythmias, webbing of fingers and toes, congenital heart disease, hypoglycemia, and behavioral and developmental defects (37).
The majority of the available data on clinical manifestations, risk stratification, and treatment derive from studies examining the most common genotypes LQT1-LQT3 (Table 1). The rarity of LQT4-LQT8 precludes making evidence-based conclusions and genotype specific recommendations for athletes carrying those mutations.
Symptomatic patients with LQTS may present with palpitations, presyncope, syncope, seizures, or cardiac arrest. Syncope as a child or young adult due to self-terminating torsade de pointes is the most frequent symptom of the proband or the first member of a family to be diagnosed with LQTS (17). Cardiac arrest occurs when the polymorphic ventricular tachycardia deteriorates to ventricular fibrillation.
The diagnostic criteria for LQTS include clinical and ECG parameters (Table 2) (32). Asymptomatic mutation carriers are identified by ECG testing for an unrelated reason or during screening because of an affected family member. Similarly, asymptomatic athletes with LQTS may be identified during ECG testing or by genetic analysis performed due to an affected family member. Based on the above, athletes with unexplained syncope, personal history of aborted sudden death, or family history of sudden death at a young age are candidates for diagnostic workup for congenital LQTS.
The QT interval is typically measured in lead II of a 12-lead ECG and corrected for rate by using Bazett's formula (QTc = QT/✓RR). A QTc interval of > 440 ms in men or > 460 ms in women is considered prolonged. However, Bazett's formula has been criticized as inaccurate, especially at HR extremes, and may overestimate the QT interval during slow HR (10), which frequently occurs in athletes due to high vagal tone at rest (7). Although QT interval adjustment nomograms may be more accurate, the majority of the available data for the congenital LQTS are derived from studies using Bazett's formula.
Patients with LQTS often have T-wave morphologic abnormalities that correlate with specific genotypes (47). The LQT1 group may have broad-based, normal or late onset of normal-appearing T waves (Fig. 1).
FIGURE 1-Four typica...Image Tools
The infantile pattern in LQT1 is a short and ill-defined ST segment merged immediately with the T-wave upslope, giving the appearance of a diagonal line to the T-wave upslope; it is primarily seen in children younger than 2 yr old. Bifid T waves are the hallmark of the LQT2 (Fig. 2), whereas late-onset peaked/biphasic or asymmetrical peaked T waves characterize LQT3 (Fig. 3).
Additional repolarization abnormalities in LQTS are T-wave alternans, which is the beat-to-beat alternation in amplitude or polarity of the T wave, and increased QT dispersion, which is the difference between the longest and shortest QT interval among the 12 leads (32,48).
At the same time, athlete's heart may be associated with rhythm and conduction disturbances, morphologic alterations of the QRS, and repolarization abnormalities (7). Changes in ventricular repolarization in athletes are usually benign and not associated with cardiac events. They include ST segment elevation or depression and tall and peaked, notched, low-amplitude, biphasic, and inverted T waves (7). These functional alterations are due to high vagal tone in trained athletes, are resolved during exercise, and should not be confused with the repolarization abnormalities of LQTS.
Exercise testing has been used to enhance the sensitivity and specificity of ECG assessment because shortening of the QT interval is inadequate in patients with LQTS (38). Moreover, repolarization abnormalities in LQTS may become more prominent and recognizable after exercise (39). The variability of the ECG response to exercise is partly dependent on the LQTS genotype. Individuals with LQT1 mutations have impaired chronotropic response and QT shortening during exercise and exaggerated QT prolongation during recovery (38,39). Furthermore, most LQT1 patients demonstrate a broad-based T-wave pattern after exercise (39). Patients with LQT2 demonstrate a normal chronotropic response and QT shortening during exercise, while they have exaggerated QT prolongation as the HR decreases in recovery (38). Most LQT2 patients have bifid T-wave patterns with a prominent notch on the descending T-wave limb after exercise (39). Finally, LQT3 patients have a more pronounced shortening of their QT interval during exercise compared with either the LQT2 or the control group (31). Therefore, during exercise, the QT interval (QTc) corrected for HR prolongs in LQT1, remains unchanged in LQT2, and shortens excessively in LQT3 patients (31,38,39).
Triggers of cardiac events.
Recently, it has become evident that the triggers of cardiac events in LQTS are genotype specific. Schwartz et al. (30), in a study of 670 symptomatic patients with LQTS and known genotype, demonstrated distinctive event patterns for LQT1, LQT2, and LQT3. In LQT1, 62% of the syncopal or sudden death events were associated with exercise, 26% with emotion, and only 3% with sleep or rest. On the other hand, only 13% of patients with LQT3 experienced cardiac events during exercise and 39% during sleep or rest. An intermediate pattern was observed in LQT2, with 13% of the events occurring with exercise and 43% with emotional stress. Additionally, the lethality of the events was higher in LQT3 and LQT2 compared with LQT1. Most of the lethal events (68%) in LQT1 were associated with exercise, whereas no LQT2 and only 4% of the LQT3 patients experienced cardiac arrest after physical exertion.
The higher incidence of exercise-triggered cardiac events in LQT1 compared with LQT2 and LQT3 may relate to the IKs dysfunction. IKs is activated during exertion and shortens repolarization as a response to the rapid HR and the catecholamine secretion that accompanies exercise. Patients with LQT1 lack the physiologic QT shortening during exercise and the superimposed sympathetic stimulation facilitates EAD and torsade de pointes. In contrast, patients with LQT3 demonstrate a marked reduction in the duration of ventricular depolarization during tachycardia (31) and rapid atrial pacing (25,26). With fast HR, the transmembrane Na+ gradient decreases secondary to intracellular Na+ accumulation. Consequently, the abnormal inward Na+ current during the plateau phase of the action potential is attenuated, and QT interval shortens (26).
Specific triggers of arrhythmic events also differ among the LQTS variants. Swimming is associated with arrhythmic events in LQT1, whereas auditory stimuli are more frequent with LQT2 (30). One third of the events in LQT1 occur during swimming (30). Moreover, in symptomatic patients with LQTS, almost all the swimming-triggered cardiac events, including immediately after diving, occurred in carriers of LQT1 mutations (30). Choi et al. (2) studied the type of the underlying channelopathy in 43 cases of swimming-related cardiac events and found that almost all the LQTS patients had the LQT1 genotype. Auditory stimuli seem to be a trigger specific for LQT2 because 80% of the events associated with auditory stimuli such as a loud noise or ringing phone were observed in LQT2 patients. Conversely, only 26% of the cardiac events in LQT2 patients occurred after auditory stimuli (30). Auditory stimuli as arrhythmia triggers have obvious implications for athletes who may be exposed to abrupt loud noises, such as the starter's pistol in a race.
The exact mechanism of the above genotype-specific arrhythmogenic triggers is unclear, but several possibilities exist (2,43). During swimming, the sympathetic nervous system is activated because of physical effort, which in LQT1 can further prolong the QTc interval (38). At the same time, facial immersion and cold-water exposure lengthen the QT further and may induce T-wave alternans or notched T waves (2). Additionally, voluntary apnea and the diving reflex stimulate vagal tone and may cause bradycardia and premature ventricular contractions. The simultaneous sympathetic and parasympathetic activation may explain why swimming seems to precipitate premature ventricular contractions. Arrhythmias may occur as a result of the exaggerated QT prolongation and increased dispersion of refractoriness in patients with LQT1 during swimming, when premature ventricular contractions are more likely to occur (2). Regarding the auditory stimuli in LQT2, it is possible that the noise causes a sudden release of catecholamines, which produce early afterdepolarizations, premature ventricular contractions at relatively low HR, and eventually torsade de pointes (43).
The natural history and the risk factors for cardiac events in patients with known LQTS have been described based on observational data from the International Registry of Long QT Syndrome (17,23,44). In the most recent and largest cohort, Priori et al. (23) found in 193 consecutive families (647 patients) with known genotype and prior to the initiation of any therapy that the cumulative incidence of cardiac arrest or sudden death over 28 yr was 13% (87/647). The cumulative survival rate varied according to the genotype, with lower survival among patients with LQT2 compared with LQT1 and a trend toward lower survival among patients with LQT3 compared with LQT1. Specifically, the annual incidence of cardiac arrest or sudden death before the age of 40 yr in patients with LQT1, LQT2, and LQT3 was 0.3, 0.6, and 0.56%, respectively (23). Similar patterns were observed in the analysis of total cardiac events (syncope, cardiac arrest, and sudden cardiac death). The mean age at the time of the first cardiac event was 13-18 yr and did not significantly differ among the three genotype subgroups.
Moreover, the same study (23) examined the genotype-specific gender effects on the clinical course of the LQTS. In patients with LQT1 mutations, there were no gender-related differences in the annual incidence of cardiac arrest or sudden death (0.28% in female vs 0.33% in male patients, P = 0.18). However, among patients with LQT2, female gender was associated with a higher annual incidence of cardiac arrest or sudden death (0.82 vs 0.46% in males, P = 0.02). Conversely, in the subgroup with LQT3, male gender carried a higher risk (0.96%) than female (0.3%, P = 0.048).
When QTc was examined, there was a progressive decline in survival with longer QTc intervals (23), which is a consistent finding among the studies of risk stratification in LQTS (17,44). Specifically, a QTc ≥ 500 ms was the most important independent risk factor for cardiac events and was modulated by gender and genotype (23). As a result, the authors proposed an algorithm for risk stratification of patients with LQTS of low, intermediate, and high risk for cardiac events, based on QTc interval, genotype, and gender (Fig. 4).
FIGURE 4-Proposed sc...Image Tools
Given the evidence of the role of the sympathetic nervous system as a trigger of cardiac events, beta-blocker therapy has become the standard first-line prophylactic therapy for patients diagnosed with LQTS (27,30). Recent data from the international LQTS registry (18) demonstrated that beta-blockade reduces the cardiac event rate in both the probands and affected family members with LQTS, but it does not eliminate the risk of SCD. Specifically, the 5-yr cumulative incidence of cardiac arrest or SCD in LQTS patients receiving beta-blockade was < 1% in those without symptoms, 3% in those with a history of syncope, and 14% in those with a history of aborted sudden death prior to treatment initiation (18). Significant predictors of cardiac events on beta-blocker therapy were the first cardiac event in early childhood (at 7 yr and younger), a QTc > 500 ms, and a genetic locus other than LTQ1 (28). These findings indicate that beta-blockade is overall very effective in LQTS, but does not provide acceptable protection from cardiac arrest and SCD in selected subgroups. Because the onset of torsade de pointes in LQTS is associated with sinus bradycardia or pauses, and beta-blockade may worsen bradycardia, permanent pacing has been used mainly in patients with atrioventricular conduction delay or slow HR and LQT3 genotype. This approach appears to be moderately successful, but long-term follow-up of these patients suggests a persistence of life-threatening cardiac events (5).
Left cardiac sympathetic denervation via surgical ablation of the lower half of the left stellate ganglion and the thoracic ganglia T2-4 in highly symptomatic patients with LQTS shortens the QT and reduces cardiac events by 91% (33). However, protection against SCD is not complete, especially in patients with a history of cardiac arrest and/or a QTc > 500 ms 6 months after surgery (33).
Consequently, implantable cardioverter defibrillators (ICD) are increasingly used to prevent sudden death in high-risk LQTS patients. Zareba et al. (45) reported that treatment with ICD prevented sudden death in all but one of 125 high-risk LQTS patients enrolled in the international LQTS registry. The indications for ICD implantation were primarily personal history of aborted sudden death and recurrent syncope on beta-blocker therapy. However, the absolute benefit and the rate of device-associated complications are not well established in this population.
Based on the concept of gene-specific treatment, a variety of novel pharmacotherapies have been attempted, but none has any currently established clinical role. Potassium supplementation in combination with spironolactone shortened the QTc interval in eight patients with LQT2 (6). Sodium channel blockers, such as mexiletine (31) and flecainide (1), shorten repolarization in patients with LQT3, and nicorandil, a specific potassium channel opener, corrected repolarization abnormalities and prevented torsade de pointes in animal models of LQT1 and LQT2, but not in LQT3 (34).
RECOMMENDATIONS RELEVANT TO THE ATHLETIC POPULATION
Competitive sports participation.
Separate recommendations have been published for competitive (49) and recreational (12) sports participation for athletes with LQTS. Guidelines are more restrictive and specific for competitive compared with recreational sports. Athletes who have suffered a cardiac arrest and/or a syncopal episode because of LQTS should be excluded from participation in competitive sports, except those sports with low cardiovascular demand or class IA (49). According to the 36th Bethesda sports classification (15), class IA includes competitive sports with low dynamic and static component (golf, as well as billiards, bowling, cricket, curling, and riflery). Asymptomatic athletes with definite QT prolongation on their surface ECG (≥ 470 ms in males, ≥ 480 ms in females) should also be disqualified from all but class IA competitive sports (49). In asymptomatic athletes with confirmed LQT3, restriction of competitive sports can be more liberal and individualized (49). This statement is based on the observation that even in symptomatic patients with LQT3, only 13% of the total and 4% of the lethal cardiac events were triggered by exercise (30).
In contrast to the 36th Bethesda conference, the European Society of Cardiology (ESC) incorporated a much more conservative approach, excluding any individual with LQTS from all competitive sports participation (21). In the era of genetic testing, such a generalized recommendation does not address questions about the risk of exercise in specific genetic subgroups and may imply unnecessary restrictions in "silent carriers" of LQTS mutations. For example, genotype positive-phenotype negative individuals may not need to be restricted from competitive sports, with the exception of LQT1 mutation carriers, who should not participate in competitive swimming (49).
Individuals treated with ICD or pacemakers for LQTS should also be restricted to class IA competitive sports, and ICD should not be implanted to allow competitive sports participation (49). Activities with risk of bodily collision and device damage should also be avoided (49). The ESC made similar recommendations for patients with ICD and added that no sports participation should be allowed for at least 6 months after implantation, or after the most recent arrhythmic episode requiring intervention from the device (21). Moreover, exercise testing is indicated to guide the programming of the lower detection rate of the ICD to avoid inappropriate shocks for sinus tachycardia (21).
Automated external defibrillators (AED) should be readily available at facilities with competitive athletic programs in an effort to reduce time to defibrillation in out-of-hospital cardiac arrest (20). However, their availability does not guarantee successful resuscitation and does not affect recommendations for disqualification from competitive sports in athletes with LQTS or other underlying cardiac conditions (20).
Recreational sports participation.
Acceptability of noncompetitive (recreational) sports in patients with the clinical diagnosis of LQTS is graded on a relative scale, where most of the high-intensity sports are "not advised or strongly discouraged" and the majority of low-intensity activities are "probably permitted" (Table 3). However, these guidelines cannot define the level of emotional stress imposed on the patient either during sports participation or because of the activity restriction. Indeed, emotional stress increases sympathetic drive and is an established trigger of cardiac events in patients with LQTS, especially those with LQT2 (30).
Moreover, there are no genotype-specific recommendations for recreational sports participation in LQTS, despite the diversity of genotype-specific triggers. Individuals with LQT1 are at particular risk during exercise, and it is reasonable to avoid physical and emotional stress whenever possible (27,30). They should also be restricted from diving and swimming because both are established triggers of cardiac events in LQT1 (2,30,43). On the other hand, patients with LQT2 are at relatively low risk during exercise, and limits on recreational physical activity can be more flexible compared with LQT1 (27,30). Because auditory stimuli trigger cardiac events in LQT2 patients (30,43), they should avoid sudden loud noises, such as the starter's pistol in track and field events and the referee's whistle in a variety of sports. Emotional stress should also be considered because it is also a specific trigger for LQT2 (30). On the other hand, recreational activity does not have to be restricted in patients with LQT3, except for those who have already suffered cardiac events during exercise (30).
Based on the above, the decision for recreational sports participation in patients with LQTS can be highly individualized after evaluating the absolute risk of exercise, gene-specific triggers, personal preferences, and the emotional impact of not only the activity but also of the imposed restriction. While making decisions about competitive and recreational sports participation, specific treatment for LQTS should be initiated based on the presence of symptoms and knowledge of the underlying genotype. All patients with the diagnosis of LQTS, even asymptomatic mutation carriers, should avoid medications that prolong the QT interval and conditions associated with hypokalemia, hypocalcemia, and hypomagnesemia.
Treatment of symptomatic patients and unknown genotype.
All symptomatic patients with LQTS should be offered lifelong beta-blocker therapy in the absence of contraindications (18,27,28). Those who present with only syncope and who become asymptomatic on beta-blocker therapy probably require no additional therapy (18,28). Those who suffer syncope on beta-blocker therapy require additional therapy with left cardiac sympathetic denervation or, preferably, implantation of an ICD (8,27,33). In patients who elect left cardiac sympathetic denervation, persistence of a QTc > 500 ms 6 months after the surgery indicates a high risk of SCD and ICD implantation should be considered (45). A history of aborted cardiac arrest before or after initiation of beta-blockade warrants treatment with an ICD for secondary prevention of SCD (8,27,45). Both beta-blocker therapy and left cardiac sympathetic denervation may be required to improve quality of life in patients with multiple ICD discharges (33).
Treatment of symptomatic patients with known genotype.
The growing evidence of genotype-specific risk stratification and treatment options resulted in the development of a commercially available genetic test that is expected to identify 75% of the LQTS mutations in LQT1, LQT2, LQT3, LQT5, and LQT6 genes (www.familion.com). It is a blood test that can be ordered as a comprehensive cardiac ion channel analysis ($5400 in August 2005) or family-specific analysis to test family members of a proband with a known mutation ($900 in August 2005). When genetic information is available, treatment can be tailored to the specific genotype.
Given the association of cardiac events with increased adrenergic tone in LQT1, these patients are the most likely to respond to antiadrenergic measures (5,18,23,30). Indeed, 81% of 162 symptomatic LQT1 patients treated with beta-blocker therapy had no recurrence and the cumulative incidence of cardiac arrest or SCD before the age of 40 yr was only 4% (30). This is a significant response because a lower risk cohort of 386 symptomatic and asymptomatic LQT1 patients, not similarly treated, experienced a cumulative incidence of cardiac arrest or SCD of 9.6% before the age of 40 (23). Patients with LQT1 and recurrent syncope on beta-blocker therapy should be offered left cardiac sympathetic denervation and/or ICD implantation (8,27,33,45). Aborted cardiac arrest either prior to or after initiation of beta-blockade warrants ICD implantation (8,27). Permanent pacing is not advised in LQT1 patients because they have an increased risk of cardiac events at high HR (30).
Symptomatic patients with LQT2 should avoid emotional stress whenever possible and remove telephones and alarm clocks from their bedrooms because stress and auditory stimuli are specific triggers for SCD in LQT2 (30,43). Treatment includes beta-blockade, although it is less effective than in patients with LQT1 (30). Similar to LQT1, ICD implantation is indicated for a history of aborted cardiac arrest and for recurrent cardiac symptoms on beta-blocker therapy (8,27). Priori et al. (28) suggested that prophylactic ICD implantation may be a reasonable addition to beta-blocker therapy in LQT2 and LQT3 patients because of the considerably higher rate of cardiac events despite beta-blockade in these genotypes compared with LQT1. Such a decision is complex in the absence of randomized data, given the potential complications of the device implantation, impact on quality of life, cost, inappropriate discharges, proarrhythmia, and need for repeat procedures in young individuals.
Symptomatic patients with LQT3 are at higher risk at slow HR and the benefit of beta-blocker therapy is questionable (18,30). Theoretically, they may derive more benefit from avoiding low HR with permanent pacing. However, given the high rate and lethality of cardiac events in LQT3 patients despite beta-blocker therapy (18,28,30), the threshold for ICD implantation with pacing capabilities is lower than in LQT1. It is not known whether beta-blockade needs to be continued after ICD implantation in LQT3 patients. Mexiletine shortens the QTc in LQT3 patients (31), but lacks clinical outcome data on its efficacy in these patients.
Treatment of asymptomatic individuals with unknown genotype.
Individuals with ECG findings but no symptoms of LQTS should be offered prophylactic beta-blocker therapy (27). ICD implantation is generally not recommended in asymptomatic LQTS patients (27). Enrollment in research registries and genotyping is also advisable.
Treatment of asymptomatic individuals with known genotype.
The decision for implementing lifelong prophylactic beta-blocker therapy in asymptomatic genotyped LQTS patients can be based on the risk stratification model proposed by Priori et al. (23) (Fig. 4). Based on this model, prophylactic treatment is warranted in male and female patients with LQT1 and QTc ≥ 500 ms, male patients with LQT2 and QTc ≥ 500 ms, all female patients with LQT2 irrespective of QTc, and all patients with LQT3 (23).
Athletes in LQTS families.
Athletes who have first- or second-degree relatives with LQTS should be evaluated with at least a complete history, physical examination, and 12-lead ECG. However, identification of affected family members without genetic testing is problematic. Initial reports of cardiac events in family members with normal QT interval (17) were followed by the observation that 6-10% of individuals carrying a LQTS mutation had QTc ≤ 440 ms (41). Moreover, Priori et al. (24) demonstrated that the LQTS has as low as 25% penetrance in some families. These data show that there is a substantial number of LQTS mutation carriers without the LQTS phenotype who do not demonstrate any symptoms or QT prolongation on their surface ECG. Syncope and SCD have anecdotally been reported in this population of "silent carriers" (9,41), but the precise risk of cardiac events is not yet defined and there are only limited data on risk stratification. Specifically, the clinical profile of LQTS in a proband is not helpful in predicting the risk of events in the affected family member (9). The location of the mutation does not influence the phenotype in LQT1 (46), whereas mutations in the pore region of the HERG gene carry increased arrhythmia risk compared to nonpore mutations in LQT2 (19). Additionally, compound mutations are associated with a high risk of cardiac events, but usually cause a severe phenotype (42). One study suggests that significant QTc prolongation after epinephrine infusion conveys high risk of cardiac events in silent carriers of LQT1 mutations (35). Therefore, there are no compelling data to justify excluding silent LQTS mutation carriers from competitive or recreational sports, except LQT1 silent mutation carriers, who should not participate in competitive swimming (49).
Based on the 36th Bethesda conference, the focus of preparticipation cardiovascular screening should be on personal and family history and physical examination findings that would raise a suspicion of diseases associated with SCD in young athletes (13). Routine preparticipation screening with a 12-lead ECG is not recommended (13). However, athletes with a family history of SCD or genetic cardiovascular diseases associated with SCD (including LQTS) and/or personal history of unexplained syncope or resuscitated cardiac death should undergo further evaluation, including an ECG with exact measurement of the QT interval. Genetic testing for LQTS should be reserved for athletes with family members affected by LQTS and for individuals with an inconclusive clinical and ECG evaluation.
On the other hand, the ESC recently recommended the addition of 12-lead ECG during routine preparticipation screening of competitive athletes (3). That recommendation is based on the incremental diagnostic value of ECG during screening of athletes in Italy, especially for hypertrophic cardiomyopathy (4). However, there are many potential obstacles to implementation of this proposal, such as the financial burden of the test itself and the additional evaluation possibly required because of borderline or abnormal results, competing priorities in healthcare systems, the psychological impact on athletes and their families, medicolegal concerns, and overall cost-effectiveness (14). Moreover, the prevalence of cardiac conditions that may cause SCD in the large population of young athletes is ≤ 0.3%, and LQTS is responsible for only 0.8% of the SCDs in young athletes (11). Therefore, routine preparticipation screening of young athletes with 12-lead ECG is impractical and has not been recommended in the United States (13,14).
Expanding knowledge of the genetic basis and natural history of the LQTS has produced genotype-phenotype correlations that affect the clinical management of these patients. The association of life-threatening cardiac events with exercise in LQTS creates concerns relevant to young athletes and to young active individuals in general. However, LQTS-related SCD in young athletes are rare, and routine screening with ECG is impractical and not recommended for the general population in the United States (13). Individuals with a personal or family history suggestive of LQTS should be further evaluated, at least with ECG. Genetic testing is now commercially available and will likely have an increasing role in the diagnosis, risk stratification, and management of patients with LQTS, as well as in screening of asymptomatic family members.
1. Benhorin, J., R. Taub, M. Goldmit, et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation
2. Choi, G., L. J. Kopplin, D. J. Tester, M. L. Will, C. M. Haglund, and M. J. Ackerman. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation
3. Corrado, D., A. Pelliccia, H. H. Bjornstad, et al. Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death: proposal for a common European protocol. Eur. Heart J.
4. Corrado, D., C. Basso, M. Schiavon, and G. Thiene. Screening for hypertrophic cardiomyopathy in young athletes. N. Engl. J. Med.
5. Dorostkar, P. C., M. Eldar, B. Belhassen, and M. M. Scheinman. Long-term follow-up of patients with long-QT syndrome treated with beta-blockers and continuous pacing. Circulation
100:<fpage >2431-2436, 1999.
6. Etheridge, S. P., S. J. Compton, M. Tristani-Firouzi, and J. W. Mason. A new oral therapy for long QT syndrome: long-term oral potassium improves repolarization in patients with HERG mutations. J. Am. Coll. Cardiol.
7. Fagard, R. Athlete's heart. Heart
8. Gregoratos, G., J. Abrams, A. E. Epstein, et al. ACC/AHA/NASPE 2002 Guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article. Circulation
9. Kimbrough, J., A. J. Moss, W. Zareba, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation
10. Malik, M., P. Farbom, V. Batchvarov, K. Hnatkova, and A. J. Camm. Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval. Heart
11. Maron, B. J. Sudden death in young athletes. N. Engl. J. Med.
12. Maron, B. J., B. R. Chaitman, M. J. Ackerman, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation
13. Maron, B. J., P. S. Douglas, T. P. Graham, R. A. Nishimura, and P. D. Thompson. Task Force 1: preparticipation screening and diagnosis of cardiovascular disease in athletes. J. Am. Coll. Cardiol.
14. Maron, B. J. How should we screen competitive athletes for cardiovascular disease? Eur. Heart J.
15. Mitchell, J. H., W. Haskell, P. Snell, and S. P. Van Camp. Task Force 8: classification of sports. J. Am. Coll. Cardiol.
16. Mohler, P. J., J. J. Schott, A. O. Gramolini, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature
17. Moss, A. J., P. J. Schwartz, R. S. Crampton, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation
18. Moss, A. J., W. Zareba, W. J. Hall, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation
19. Moss, A. J., W. Zareba, E. S. Kaufman, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation
20. Myerburg, R. J., N. A. Estes 3rd, J. M. Fontaine, M. S. Link, and D. P. Zipes. Task Force 10: automated external defibrillators. J. Am. Coll. Cardiol.
21. Pelliccia, A., R. Fagard, H. H. Bjornstad, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease. Eur. Heart J.
22. Plaster, N. M., R. Tawil, M. Tristani-Firouzi, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell
23. Priori, S. G., P. J. Schwartz, C. Napolitano, et al. Risk stratification in the long-QT syndrome. N. Engl. J. Med.
24. Priori, S. G., C. Napolitano, and P. J. Schwartz. Low penetrance in the long-QT syndrome: clinical impact. Circulation
25. Priori, S. G., J. Barhanin, R. N. Hauer, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management parts I and II. Circulation
26. Priori, S. G., J. Barhanin, R. N. Hauer, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management part III. Circulation
27. Priori, S. G., E. Aliot, C. Blomstrom-Lundqvist, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur. Heart J.
28. Priori, S. G., C. Napolitano, P. J. Schwartz, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA
29. Schwartz, P. J., S. G. Priori, and C. Napolitano. How really rare are rare diseases?: the intriguing case of independent compound mutations in the long QT syndrome. J. Cardiovasc. Electrophysiol.
30. Schwartz, P. J., S. G. Priori, C. Spazzolini, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation
31. Schwartz, P. J., S. G. Priori, E. H. Locati, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation
32. Schwartz, P. J., A. J. Moss, G. M. Vincent, and R. S. Crampton. Diagnostic criteria for the long QT syndrome. An update. Circulation
33. Schwartz, P. J., S. G. Priori, M. Cerrone, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation
34. Shimizu, W., and C. Antzelevitch. Effects of a K(+) channel opener to reduce transmural dispersion of repolarization and prevent torsade de pointes in LQT1, LQT2, and LQT3 models of the long-QT syndrome. Circulation
35. Shimizu, W., T. Noda, H. Takaki, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J. Am. Coll. Cardiol.
36. Splawski, I., J. Shen, K. W. Timothy, et al. Spectrum of mutations in long-QT syndrome genes. KvLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation
37. Splawski, I., K. W. Timothy, L. M. Sharpe, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell
38. Swan, H., M. Viitasalo, K. Piippo, P. Laitinen, K. Kontula, and L. Toivonen. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. J. Am. Coll. Cardiol.
39. Takenaka, K., T. Ai, W. Shimizu, et al. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation
40. Tristani-Firouzi, M., J. L. Jensen, M. R. Donaldson, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J. Clin. Invest.
41. Vincent, G. M., K. W. Timothy, M. Leppert, and M. Keating. The spectrum of symptoms and QT intervals in carriers of the gene for the long QT syndrome. N. Engl. J. Med.
42. Westenskow, P., I. Splawski, K. W. Timothy, M. T. Keating, and M. C. Sanguinetti. Compound mutations: a common cause of severe long-QT syndrome. Circulation
43. Wilde, A. A., R. J. Jongbloed, P. A. Doevendans, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J. Am. Coll. Cardiol.
44. Zareba, W., A. J. Moss, P. J. Schwartz, et al. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N. Engl. J. Med.
45. Zareba, W., A. J. Moss, J. P. Daubert, W. J. Hall, J. L. Robinson, and M. Andrews. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J. Cardiovasc. Electrophysiol.
46. Zareba, W., A. J. Moss, G. Sheu, et al. Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. J. Cardiovasc. Electrophysiol.
47. Zhang, L., K. W. Timothy, G. M. Vincent, et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation
48. Zipes, D. P., and J. Jalife. Cardiac Electrophysiology. From Cell to Bedside
, 3rd ed. Philadelphia, PA: WB Saunders, 2000, pp. 597-614.
49. Zipes, D. P., M. J. Ackerman, N. A. Estes, 3rd, A. O. Grant, R. J. Myerburg, and G. Van Hare. Task Force 7: arrhythmias. J. Am. Coll. Cardiol.