Aims Type 3 long QT syndrome (LQT3) is caused by gain-of-function mutations in the cardiac sodium channel gene (SCN5A). Previous reports on the long-term use of sodium channel blockers in LQT3 are sparse. The objective of the current study was to evaluate the long-term safety and efficacy of flecainide therapy in patients with LQT3 who carry the D1790G SCN5A mutation. Methods and results The study population comprised 30 D1790G carriers who were treated with flecainide and followed for 1-215 months (mean 145 ± 54 months, median 140 months). The mean baseline (off-drug) QTc was 522 ± 45 ms, and shortened to 469 ± 36 ms with flecainide therapy, a mean decrease of 53 ms [10.1%] (P < 0.01). A QTc longer than 500 ms was evident in 53% of carriers at baseline, and only in 13% on flecainide. All carriers while being compliant with flecainide therapy had no cardiac events during an average follow up of 83 ± 73 months. Twenty carriers stopped flecainide after an average follow up of 40 ± 42 months without symptoms. Six of them (30%) had cardiac events 1-11 months after stopping flecainide. Flecainide induced the appearance of Brugada pattern in six carriers (20%, 5 males), was stopped in three and was not associated with arrhythmia. Sinus-node dysfunction was evident in six carriers (20%) and was fully corrected by flecainide in three. Conclusions These data suggest that long-term flecainide therapy is relatively safe and effective among LQT3 patients who carry the D1790G SCN5A mutation.

BACKGROUND: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β -blocker therapy has not been studied previously in a large LQT3 population. METHODS: The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. RESULTS: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome–related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β -blocker therapy was associated with an 83% reduction in CEs in females ( P =0.015) but not in males (who had many fewer events), with a significant sex × β -blocker interaction ( P =0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events ( P <0.02). CONCLUSIONS: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, β -blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events. Denmark LQTS Registry (n=10). In all centers, institutional review board approval was obtained for this type of study. Not included in the study population were 14 patients with evidence of mutations involving ≥ 2 LQTS genes, and 2 patients with multiple SCN5A mutations. In addition, patients/ families with clear evidence of an SCN5A -mediated hybrid/ overlapping phenotype (ie, conduction disease or right precordial ST elevation, the so-called overlap syndromes as, for example, the large Dutch SCN5A -1795insD family 16 ) were not included in this study. All patients or their guardians provided informed consent for the genetic and clinical studies.

Background— The basic defect in long-QT syndrome type III (LQT3) is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the SCN5A gene. Most sodium channel blockers reduce the early (peak) and late components of the sodium current ( I Na and I NaL ), but ranolazine preferentially reduces I NaL . We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A . Methods and Results— We performed an experimental study of ranolazine in TSA201 cells expressing the D1790G mutation. We then performed a long-term clinical evaluation of ranolazine in LQT3 patients carrying the D1790G mutation. In the experimental study, I NaL was significantly higher in D1790G than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of I NaL of the SCN5A-D1790G channel without reducing peak I Na significantly. In the clinical study, among 8 patients with LQT3 and confirmed D1790G mutation, ranolazine had no effects on the sinus rate or QRS width but shortened the QTc from 509±41 to 451±26 ms, a mean decrease of 56±52 ms (10.6%; P =0.012). The QT-shortening effect of ranolazine remained effective throughout the entire study period of 22.8±12.8 months. Ranolazine reduced the QTc at all heart rates but less so during extreme nocturnal bradycardia. A type I Brugada ECG was never noticed. Conclusions— Ranolazine blocks I NaL in experimental models of LQT3 harboring the SCN5A-D1790G mutation and shortened the QT interval of LQT3 patients. Clinical Trial Registration— URL: https://clinicaltrials.gov ; Unique identifier: NCT01728025.

Objectives . The aim of this study was to examine the dependence of the ischemic threshold during exercise testing on the exercise protocol employed and to determine the relation between the ischenmic thresholds observed during exercise and during daily activity . Background. The ischenmic threshold (heart rate at Wont ST segment depression) daring daily activity has been reported go he lower than that observed during exercise testing . Recent reports have hypothesized that this difference is probably dependent on the exercise protocol employed . Methods . Twenty-two patients with known coronary artery disease, not receiving antianginal medications, were evaluated by repeated exercise testing according to the Bruce and the modified Davidson protocols and by 41h ambulatory electrocardiographic monitoring . Results . Although the heart rate at 1-mm ST segment depres-

LQT3 syndrome is caused by SCN5A mutations that prolong cardiac repolarization. SCN5A dysfunction can be due to increased sustained currents, but other mechanisms are also observed. We evaluated a possible association between ion-channel dysfunction, arrhythmic risk and response to treatment. We

Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care. After presenting the historical background and describing the guideline structure, we make several recommendations to make clinical practice guidelines more user-friendly for clinical cardiologists. Our most important recommendations are that the clinical cardiology guidelines should focus exclusively on (1) class I recommendations with established benefits that are supported by randomized clinical trials and (2) class III recommendations for diagnostic or therapeutic approaches in which quality studies show no benefit or possible harm. Class II recommendations are not evidence based but reflect expert opinions related to published clinical studies, with potential for personal bias by members of the guideline committee. Class II recommendations should be published separately as "Expert Consensus Statements" or "Task Force Committee Opinions," so that both majority and minority expert opinions can be presented in a less dogmatic form than the way these recommendations currently appear in clinical practice guidelines.

An increasing number of academic senior physicians are approaching their potential retirement in good health with accumulated clinical and research experience that can be a valuable asset to an academic institution. Considering the need to let the next generation ascend to leadership roles, when and how should a medical career be brought to a close? We explore the roles for academic medical faculty as they move into their senior years and approach various retirement options. The individual and institutional considerations require a frank dialogue among the interested parties to optimize the benefits while minimizing the risks for both. In the United States there is no fixed age for retirement as there is in Europe, but European physicians are initiating changes. What is certain is that careful planning, innovative thinking, and the incorporation of new patterns of medical practice are all part of this complex transition and timing of senior academic physicians into retirement.

BACKGROUND Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LOTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood.OBJECTIVES To hypothesize that the assessment of QTc variance in patients with congenital LOTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc.METHODS The study population comprised 1206 patients with LOTS with 95 different mutations and >= 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype.RESULTS Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P=.002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P<.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P=.95; P value for QTcSD-by-genotype interaction=.002).CONCLUSIONS Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype.

BACKGROUND Patients with long QT syndrome (LQTS) have inadequate shortening of the QT interval in response to the sudden heart rate accelerations provoked by standing-a phenomenon of diagnostic value. We now validate our original observations in a cohort twice as large. We also describe that this abnormal QT-interval response persists as the heart rate acceleration returns to baseline.OBJECTIVES To describe a novel observation, termed "QT stunning" and to validate previous observations regarding the "QT-stretching" phenomenon in patients with LQTS by using our recently described "standing test."METHODS The electrocardiograms of 108 patients with LQTS and 112 healthy subjects were recorded in the supine position. Subjects were then instructed to stand up quickly and remain standing for 5 minutes during continuous electrocardiographic recording. The corrected QT interval was measured at baseline (QTc(base)), when heart rate acceleration without appropriate QT-interval shortening leads to maximal QT stretching (QTc(stretch)) and upon return of heart rate to baseline (QTc(return)).RESULTS QTc(stretch) lengthened significantly more in patients with LQTS (103 +/- 80 ms vs 66 +/- 40 ms in controls; P < .001) and so did QTc(return) (28 +/- 48 ms for patients with LQTS vs - 3 +/- 32 ms for controls; P < .001). Using a sensitivity cutoff of 90%, the specificity for diagnosing LQTS was 74% for QTc(base), 84% for QTc(return), and 87% for QTc(stretch).CONCLUSIONS The present study extends our previous findings on the abnormal response of the QT interval in response to standing in patients with LQTS. Our study also shows that this abnormal response persists even after the heart rate slows back to baseline.

BACKGROUND Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events.OBJECTIVE We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene.METHODS The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2-S3 and S4-S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations).RESULTS Multivariate analysis showed that during childhood (age group: 0-13 years) men had >2-fold (P < .003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P = .64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P < .001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P = .26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P < .001] and 2.43 [P = .02], respectively), whereas a prolonged corrected QT interval (>= 500 ms) was associated with a higher risk among women than among men.CONCLUSION: Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.

BACKGROUND:Men and women with type 2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2. OBJECTIVE:This study sought to risk-stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information. METHODS:The risk for life-threatening cardiac events from birth through age 40 years (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) was assessed among 1,166 LQT2 male (n = 490) and female (n = 676) patients by the location of the LQTS-causing mutation in the KCNH2 channel (prespecified in the primary analysis as pore-loop vs. non-pore-loop). RESULTS:During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; P <.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (hazard ratio 1.20; P =.33). In contrast, men with pore-loop mutations displayed a significant >2-fold higher risk of a first ACA or SCD as compared with those with non-pore-loop mutations (hazard ratio 2.18; P = .01). Consistently, women experienced a high rate of life-threatening events regardless of mutation location (pore-loop: 35%, non-pore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with non-pore-loop mutations (8%). CONCLUSION:Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2.

Objectives This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) intervals.Background Current data regarding the outcome of patients with concealed LQTS are limited.Methods Clinical and genetic risk factors for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) from birth through age 40 years were examined in 3,386 genotyped subjects from 7 multinational LQTS registries, categorized as LQTS with normal-range QTc (<= 440 ms [n = 469]), LQTS with prolonged QTc interval (>440 ms [ n = 1,392]), and unaffected family members (genotyped negative with <= 440 ms [ n = 1,525]).Results The cumulative probability of ACA or SCD in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (p < 0.001) but higher than in unaffected family members (0.4%) (p < 0.001). Risk factors ACA or SCD in patients with normal-range QTc intervals included mutation characteristics (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1: LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3: LQTS type 2, hazard ratio: 8.04; p = 0.07), whereas clinical factors, including sex and QTc duration, were associated with a significant increase in the risk for ACA or SCD only in patients with prolonged QTc intervals (female age >13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002).Conclusions Genotype-confirmed patients with concealed LQTS make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for ACA or SCD in this overall lower risk LQTS subgroup. (J Am Coll Cardiol 2011;57:51-9) (C) 2011 by the American College of Cardiology Foundation

Background— Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families. Methods and Results— Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402–442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P =0.002), prolonged QTc (HR=1.63 per 100 ms increment, P =0.02), family history of ACA or SCD (HR=1.89, P =0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P =0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold ( P =0.001) increase in the risk of recurrent syncope in genotype-negative subjects. Conclusions— Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.

Objectives We aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS).Background Data regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited.Methods The Prentice-Williams-Peterson conditional gap time model was used to identify risk factors for recurrent syncope from birth through age 20 years among 1,648 patients from the International Long QT Syndrome Registry.Results Multivariate analysis demonstrated that corrected QT interval (QTc) duration (>= 500 ms) was a significant predictor of a first syncope episode (hazard ratio: 2.16), whereas QTc effect was attenuated when the end points of the second, third, and fourth syncope episodes were evaluated (hazard ratios: 1.29, 0.99, 0.90, respectively; p < 0.001 for the null hypothesis that all 4 hazard ratios are identical). A genotype-specific subanalysis showed that during childhood (0 to 12 years), males with LQTS type 1 had the highest rate of a first syncope episode (p = 0.001) but exhibited similar rates of subsequent events as other genotype-sex subsets (p = 0.63). In contrast, in the age range of 13 to 20 years, long QT syndrome type 2 females experienced the highest rate of both first and subsequent syncope events (p < 0.001 and p = 0.01, respectively). Patients who experienced >= 1 episodes of syncope had a 6-to 12-fold (p < 0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc duration. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events.Conclusions Children and adolescents who present after an episode of syncope should be considered to be at a high risk of the development of subsequent syncope episodes and fatal/near-fatal events regardless of QTc duration. (J Am Coll Cardiol 2011;57:941-50) (C) 2011 by the American College of Cardiology Foundation

BACKGROUND:A prolonged QT interval corrected for heart rate (QTc) is a major risk factor in patients with long QT syndrome (LQTS). However, heart rate-related risk in this genetic disorder differs among genotypes. OBJECTIVE:This study hypothesized that risk assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate. METHODS:The independent contribution of 4 repolarization measures (the absolute QT interval, and Bazett's, Fridericia's, and Framingham's correction formulas) to the risk of aborted cardiac arrest or sudden cardiac death during adolescence, before and after further adjustment for the RR interval, was assessed in 727 LQTS type 1 and 582 LQTS type 2 patients. Improved QT/RR correction was calculated using a Cox model, dividing the coefficient on log(RR) by that on log(QT). RESULTS:Multivariate analysis demonstrated that in LQTS type 1 patients 100-ms increments in the absolute QT interval were associated with a 3.3-fold increase in the risk of life-threatening cardiac events (P = .020), and 100-ms decrements in the RR interval were associated with a further 1.9-fold increase in the risk (P = .007), whereas in LQTS type 2 patients, resting heart rate was not a significant risk factor (hazard ratio 1.11; P = .51; P value for heart rate × genotype interaction = .036). Accordingly, analysis of an improved QT correction formula showed that patients with the LQTS type 1 genotype required a greater degree of QT correction for heart rate (improved QTc = QT/RR⁰·⁸) than LQTS type 2 patients (improved QTc = QT/RR⁰·²). CONCLUSION:Our findings suggest that risk stratification for life-threatening cardiac events in LQTS patients can be improved by incorporating genotype-specific QT correction for heart rate.

The clinical course of patients with 2 relatively common long QT syndrome type 3 mutations has not been well described. In the present study, we investigated the mutational-specific risk in patients with deletional (DeltaKPQ) and missense (D1790G) mutations involving the SCN5A gene. The study population involved 50 patients with the DeltaKPQ mutation and 35 patients with the D1790G mutation. The cumulative probability of a first cardiac event (syncope, aborted cardiac arrest, or long QT syndrome-related sudden death) was evaluated using the Kaplan-Meier method. The Cox proportional hazards survivorship model was used to determine the independent contribution of clinical and genetic factors to the first occurrence of cardiac events from birth through 40 years of age. The Andersen-Gill proportional intensity regression model was used to analyze the factors associated with recurrent syncope. Patients with a DeltaKPQ mutation had a significantly greater probability of a first cardiac event from birth through 40 years of age (34%) than those with the D1790G mutation (20%; p <0.001). Multivariate analysis demonstrated an increased risk of cardiac events among DeltaKPQ carriers compared to D1790G carriers (hazard ratio 2.42, p <0.0001) after adjustment for gender and QTc duration. Patients with DeltaKPQ mutations also had an increased risk of recurrent syncope (hazard ratio 5.20, p <0.001). In conclusion, the clinical course of patients with long QT syndrome type with DeltaKPQ mutations was shown to be more virulent than those with D1790G mutations, and this effect was independent of QTc duration. The findings highlight the importance of knowing the specific mutation in risk stratification of patients with long QT syndrome type 3.

Objectives This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome (LQTS)-related cardiac events that occur in the first year of life (infancy).Background The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously.Methods The study population of 3,323 patients with QT interval corrected for heart rate (QTc) >= 450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life.Results The risk factors for a cardiac event among 212 patients who had an electrocardiogram recorded in the first year of life included QTc >= 500 ms, heart rate <= 100 beats/min, and female sex. An ACA before age 1 year was associated with a hazard ratio of 23.4 ( p < 0.01) for ACA or SCD during ages 1 to 10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD but not for those who survived ACA in infancy.Conclusions Patients with LQTS who experience ACA during the first year of life are at very high risk for subsequent ACA or death during their next 10 years of life, and beta-blockers might not be effective in preventing fatal or near-fatal cardiac events in this small but high-risk subset. (J Am Coll Cardiol 2009; 54: 832-7) (C) 2009 by the American College of Cardiology Foundation

BACKGROUND:Sudden death of a sibling is thought to be associated with greater risk of death in long QT syndrome (LQTS). However, there is no evidence of such an association. OBJECTIVE:This study sought to test the hypothesis that sudden death of a sibling is a risk factor for death or aborted cardiac arrest (ACA) in patients with LQTS. METHODS:We examined all probands and first-degree and second-degree relatives in the International Long QT Registry from birth to age 40 years with QTc >/= 0.45 s. Covariates included sibling death, QTc, gender by age, syncope, and implantable cardioverter-defibrillator (ICD) and beta-blocker treatment. End points were (1) severe events (ACA, LQTS-related death) and (2) any cardiac event (syncope, ACA, or LQTS-related death). RESULTS:Of 1915 subjects, 270 had a sibling who died. There were 213 severe events and 829 total cardiac events. More subjects with history of sibling death received beta-blocker therapy. Sibling death was not significantly associated with risk of ACA or LQTS-related death, but was associated with increased risk of syncope. QTc >/= 0.53 s (hazard ratio 2.5, P <.01), history of syncope (hazard ratio 6.1, P <.01), and gender were strongly associated with risk of ACA or LQTS-related death. CONCLUSION:Sudden death of a sibling prompted more aggressive treatment but did not predict risk of death or ACA, whereas QTc >/= 0.53 s, gender, and syncope predicted this risk. All subjects should receive appropriate beta-blocker therapy. The decision to implant an ICD should be based on an individual's own risk characteristics (QTc, gender, and history of syncope).

Background— Previous studies that assessed the risk of life-threatening cardiac events in patients with congenital long-QT syndrome (LQTS) have focused mainly on the first 4 decades of life, whereas the clinical course of this inherited cardiac disorder in the older population has not been studied. Methods and Results— The risk of aborted cardiac arrest or death from age 41 though 75 years was assessed in 2759 subjects from the International LQTS Registry, categorized into electrocardiographically affected (corrected QT interval [QTc] ≥470 ms), borderline (QTc 440 to 469 ms), and unaffected (QTc <440 ms) subgroups. The affected versus unaffected adjusted hazard ratio for aborted cardiac arrest or death was 2.65 ( P <0.001) in the age range of 41 to 60 years and 1.23 ( P =0.31) in the age range of 61 to 75 years. The clinical course of study subjects displayed gender differences: Affected LQTS women experienced a significantly higher cumulative event rate (26%) than borderline (16%) and unaffected (12%) women ( P =0.001), whereas event rates were similar among the 3 respective subgroups of men (29%, 26%, and 27%; P =0.16). Recent syncope (<2 years in the past) was the predominant risk factor in affected subjects (hazard ratio 9.92, P <0.001), and the LQT3 genotype was identified as the most powerful predictor of outcome in a subset of 871 study subjects who were genetically tested for a known LQTS mutation (hazard ratio 4.76, P =0.02). Conclusions— LQTS subjects maintain a high risk for life-threatening cardiac events after age 40 years. The phenotypic expression of affected subjects is influenced by age-specific factors related to gender, clinical history, and the LQTS genotype.