BACKGROUND: The Long QT Syndrome (LQTS) is an infrequently occurring familial disorder in which affected individuals have electrocardiographic QT interval prolongation and a propensity to ventricular tachyarrhythmic syncope and sudden death. We prospectively investigated the clinical characteristics and the long-term course of 3,343 individuals from 328 families in which one or more members were identified as affected with LQTS (QTc greater than 0.44 sec1/2). METHODS AND RESULTS: The first member of a family to be identified with LQTS, the proband, was usually brought to medical attention because of a syncopal episode during childhood or teenage years. Probands (n = 328) were younger at first contact (age 21 +/- 15 years), more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate less than 60 beats/min (31%), QTc greater than or equal to 0.50 sec1/2 (52%), and a history of ventricular tachyarrhythmia (47%) than other affected (n = 688) and unaffected (n = 1,004) family members. Arrhythmogenic syncope often occurred in association with acute physical, emotional, or auditory arousal. The syncopal episodes were frequently misinterpreted as a seizure disorder. By age 12 years, 50% of the probands had experienced at least one syncopal episode or death. The rates of postenrollment syncope (one or more episodes) and probable LQTS-related death (before age 50 years) for probands (n = 235; average follow-up 54 months per patient) were 5.0% per year and 0.9% per year, respectively; these event rates were considerably higher than those observed among affected and unaffected family members. CONCLUSIONS: Among 232 probands and 1,264 family members with prospective follow-up, three factors made significant independent contributions to the risk of subsequent syncope or probable LQTS-related death before age 50 years, whichever occurred first (Cox hazard ratio; 95% confidence limits): 1) QTc (1.052; 1.017, 1.088), 2) history of cardiac event (3.1; 1.3, 7.2), and 3) heart rate (1.017; 1.004, 1.031). The findings from this prospective longitudinal study highlight the clinical features, risk factors, and course of LQTS.

Background —β-blockers are routinely prescribed in congenital long-QT syndrome (LQTS), but the effectiveness and limitations of β-blockers in this disorder have not been evaluated. Methods and Results —The study population comprised 869 LQTS patients treated with β-blockers. Effectiveness of β-blockers was analyzed during matched periods before and after starting β-blocker therapy, and by survivorship methods to determine factors associated with cardiac events while on prescribed β-blockers. After initiation of β-blockers, there was a significant ( P <0.001) reduction in the rate of cardiac events in probands (0.97±1.42 to 0.31±0.86 events per year) and in affected family members (0.26±0.84 to 0.15±0.69 events per year) during 5-year matched periods. On-therapy survivorship analyses revealed that patients with cardiac symptoms before β-blockers (n=598) had a hazard ratio of 5.8 (95% CI, 3.7 to 9.1) for recurrent cardiac events (syncope, aborted cardiac arrest, or death) during β-blocker therapy compared with asymptomatic patients; 32% of these symptomatic patients will have another cardiac event within 5 years while on prescribed β-blockers. Patients with a history of aborted cardiac arrest before starting β-blockers (n=113) had a hazard ratio of 12.9 (95% CI, 4.7 to 35.5) for aborted cardiac arrest or death while on prescribed β-blockers compared with asymptomatic patients; 14% of these patients will have another arrest (aborted or fatal) within 5 years on β-blockers. Conclusions —β-blockers are associated with a significant reduction in cardiac events in LQTS patients. However, syncope, aborted cardiac arrest, and LQTS-related death continue to occur while patients are on prescribed β-blockers, particularly in those who were symptomatic before starting this therapy.

Background The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A , the cardiac Na ⁺ channel gene, and as HERG , a K ⁺ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate. Methods and Results Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QT _c were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QT _c from 535±32 to 445±31 ms, P <.005) but not among LQT2 patients (QT _c from 530±79 to 503±60 ms, P =NS). LQT3 patients (n=7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n=4) and also more than 18 healthy control subjects (9.45±3.3 versus 3.95±1.97 and 2.83±1.33, P <.05; data expressed as percent reduction in QT per 100-ms shortening in RR). Among these patients, there is also a trend for LQT2 patients to have syncope or cardiac arrest under emotional or physical stress and for LQT3 patients to have cardiac events either at rest or during sleep. Conclusions This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. These findings also suggest that LQT3 patients may be more likely to benefit from Na ⁺ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates. Conversely, LQT2 patients may be at higher risk to develop syncope under stressful conditions because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval when heart rate increases.

The congenital long-QT syndrome, caused by mutations in cardiac potassium-channel genes (KVLQT1 at the LQT1 locus and HERG at the LQT2 locus) and the sodium-channel gene (SCN5A at the LQT3 locus), has distinct repolarization patterns on electrocardiography, but it is not known whether the genotype influences the clinical course of the disease.

Background The long QT syndrome is an inherited disorder with prolonged ventricular repolarization and a propensity to ventricular tachyarrhythmias and sudden arrhythmic death. Recent linkage studies have demonstrated three separate loci for this disorder on chromosomes 3, 7, and 11, and specific mutated genes for long QT syndrome have been identified on two of these chromosomes. We investigated ECG T-wave patterns (phenotypes) in members of families linked to three genetically distinct forms of the long QT syndrome. Methods and Results Five quantitative ECG repolarization parameters, ie, four Bazett-corrected time intervals (QT _onset-c , QT _peak-c , QT _c , and T _duration-c , in milliseconds) and the absolute height of the T wave (T _amplitude , in millivolts), were measured in 153 members of six families with long QT syndrome linked to markers on chromosomes 3 (n=47), 7 (n=30), and 11 (n=76). Genotypic data were used to define each family member as being affected or unaffected with long QT syndrome. Affected members of all six families had longer QT intervals (QT _onset-c , QT _peak-c , or QT _c ) than unaffected family members ( P <.01). Each of the three long QT syndrome genotypes was associated with somewhat distinctive ECG repolarization features. Among affected individuals, the QT _onset-c was unusually prolonged in those individuals with mutations involving the cardiac sodium channel gene SCN5A on chromosome 3 (lead II QT _onset-c [mean±SD]: chromosome 3, 341±42 ms; chromosome 7, 290±56 ms; chromosome 11, 243±73 ms; P <.001); T _amplitude was generally quite small in the chromosome 7 genotype (lead II T _amplitude , mV: chromosome 3, 0.36±0.14; chromosome 7, 0.13±0.07; chromosome 11, 0.37±0.17; P <.001); and T _duration was particularly long in the chromosome 11 genotype (lead II T _duration-c : chromosome 3, 187±33 ms; chromosome 7, 191±51 ms; chromosome 11, 262±65 ms; P <.001). Similar ECG findings were observed in leads aVF and V ₅ . A considerable variability exists in the quantitative repolarization parameters associated with each genotype, with overlap in the T-wave patterns among the three genotypes. Conclusions Three separate genetic loci for the long QT syndrome including mutations in two cardiac ionic channel genes were associated with different phenotypic T-wave patterns on the ECG. This study provides insight into the influence of genetic factors on ECG manifestations of ventricular repolarization.

Background —Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. Methods and Results —Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QT _c >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers ( KVLQT1 on 11p15.5), 62 LQT2 carriers ( HERG on 7q35-36), and 31 LQT3 carriers ( SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8±7 versus 14±10 years, P <0.0001) and had higher event rates by age 15 years than females (74% versus 51%, P <0.0001). Affected family members had similar findings. By Cox analysis adjusting for QT _c duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 ( P <0.001), and it was 1.87 ( P =0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 ( P <0.001) by age 15 years, and it was 3.25 ( P <0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%, P =0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. Conclusions —Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.