Long-QT syndrome after age 40.

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] > or = 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.

Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome.

BACKGROUND: The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified. METHODS AND RESULTS: Cox proportional-hazards regression modeling was used to identify risk factors for aborted cardiac arrest or sudden cardiac death in 3015 LQTS children from the International LQTS Registry who were followed up from 1 through 12 years of age. The cumulative probability of the combined end point was significantly higher in boys (5%) than in girls (1%; P<0.001). Risk factors for cardiac arrest or sudden cardiac death during childhood included corrected QT interval [QTc] duration > 500 ms (hazard ratio [HR]; 2.72; 95% confidence interval [CI], 1.50 to 4.92; P=0.001) and prior syncope (recent syncope [< 2 years]: HR, 6.16; 95% CI 3.41 to 11.15; P<0.001; remote syncope [> or = 2 years]: HR, 2.67; 95% CI, 1.22 to 5.85; P=0.01) in boys, whereas prior syncope was the only significant risk factor among girls (recent syncope: HR, 27.82; 95% CI, 9.72 to 79.60; P<0.001; remote syncope: HR, 12.04; 95% CI, 3.79 to 38.26; P<0.001). Beta-blocker therapy was associated with a significant 53% reduction in the risk of cardiac arrest or sudden cardiac death (P=0.01). CONCLUSIONS: LQTS boys experience a significantly higher rate of fatal or near-fatal cardiac events than girls during childhood. A QTc duration > 500 ms and a history of prior syncope identify risk in boys, whereas prior syncope is the only significant risk factor among girls. Beta-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.

Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome.

CONTEXT: Analysis of predictors of cardiac events in hereditary long-QT syndrome (LQTS) has primarily considered syncope as the predominant end point. Risk factors specific for aborted cardiac arrest and sudden cardiac death have not been investigated. OBJECTIVE: To identify risk factors associated with aborted cardiac arrest and sudden cardiac death during adolescence in patients with clinically suspected LQTS. DESIGN, SETTING, AND PARTICIPANTS: The study involved 2772 participants from the International Long QT Syndrome Registry who were alive at age 10 years and were followed up during adolescence until age 20 years. The registry enrollment began in 1979 at 5 cardiology centers in the United States and Europe. MAIN OUTCOME MEASURES: Aborted cardiac arrest or LQTS-related sudden cardiac death; follow-up ended on February 15, 2005. RESULTS: There were 81 patients who experienced aborted cardiac arrest and 45 who had sudden cardiac death; 9 of the 81 patients who had an aborted cardiac arrest event experienced subsequent sudden cardiac death. Significant independent predictors of aborted cardiac arrest or sudden cardiac death during adolescence included recent syncope, QTc interval, and sex. Compared with those with no syncopal events in the last 10 years, patients with 1 or 2 or more episodes of syncope 2 to 10 years ago (but none in the last 2 years) had an adjusted hazard ratio (HR) of 2.7; (95% confidence interval [CI], 1.3-5.7; P<.01) and an adjusted HR of 5.8 (95% CI, 3.6-9.4; P<.001), respectively, for life-threatening events; those with 1 syncopal episodes in the last 2 years had an adjusted HR of 11.7 (95% CI, 7.0-19.5; P<.001) and those with 2 or more syncopal episodes in the last 2 years had an adjusted HR of 18.1 (95% CI, 10.4-31.2; P<.001). Irrespective of events occurring more than 2 years ago, QTc of 530 ms or longer was associated with increased risk (adjusted HR, 2.3; 95% CI, 1.6-3.3; P<.001) compared with those having a shorter QTc. Males between the ages of 10 and 12 years had higher risk than females (HR, 4.0; 95% CI, 1.8-9.2; P = .001), but there was no significant risk difference between males and females between the ages of 13 and 20 years. Among individuals with syncope in the past 2 years, beta-blocker therapy was associated with a 64% reduced risk (HR, 0.36; 95% CI, 0.18-0.72; P<.01). CONCLUSIONS: In LQTS, the timing and frequency of syncope, QTc prolongation, and sex were predictive of risk for aborted cardiac arrest and sudden cardiac death during adolescence. Among patients with recent syncope, beta-blocker treatment was associated with reduced risk.

Modulating effects of age and gender on the clinical course of long QT syndrome by genotype.

OBJECTIVES: We aimed to determine whether long QT syndrome (LQTS) genotype has a differential effect on clinical course of disease in male and female children and adults after adjustment for QTc duration. BACKGROUND: Genotype influences clinical course of the LQTS; however, data on the effect of age and gender on this association are limited. METHODS: The LQTS genotype, QTc duration, and follow-up were determined in 243 cases of LQTS caused by the KCNQ1 potassium channel gene mutations (LQT1), 209 cases of LQTS caused by the HERG potassium channel gene mutations (LQT2), and 81 cases of LQTS caused by the SCN5A sodium channel gene mutation (LQT3) gene carriers. The probability of cardiac events (syncope, aborted cardiac arrest, or sudden death) was analyzed by genotype, gender, and age (children < or = 15 years and adults 16 to 40 years). In addition, the risk of sudden death and lethality of cardiac events were evaluated in 1,075 LQT1, 976 LQT2, and 324 LQT3 family members from families with known genotype. RESULTS: During childhood, the risk of cardiac events was significantly higher in LQT1 males than in LQT1 females (hazard ratio [HR] = 1.72), whereas there was no significant gender-related difference in the risk of cardiac events among LQT2 and LQT3 carriers. During adulthood, LQT2 females (HR = 3.71) and LQT1 females (HR = 3.35) had a significantly higher risk of cardiac events than respective males. The lethality of cardiac events was highest in LQT3 males and females (19% and 18%), and higher in LQT1 and LQT2 males (5% and 6%) than in LQT1 and LQT2 females (2% for both). CONCLUSIONS; Age and gender have different, genotype-specific modulating effects on the probability of cardiac events and electrocardiographic presentation in LQT1 and LQT2 patients.

Effects of acute myocardial ischemia on QT dispersion by dipyridamole stress echocardiography.

Increased dispersion of the QT interval has been observed during pacing or exercise stress testing in patients with coronary artery disease (CAD). It has not been established whether this phenomenon is a consequence of ischemia. Therefore, we sought to evaluate whether dipyridamole-induced myocardial ischemia, as directly detected by echocardiographic monitoring of regional contractile function, would affect QT dispersion. Twenty-four patients with nonsignificant and 34 patients with significant CAD but no previous myocardial infarction underwent dipyridamole stress echocardiography while not taking medications. QT dispersion was measured on a 12-lead electrocardiogram at baseline and at various times after dipyridamole infusion. Dipyridamole infusion did not influence QT dispersion in patients without CAD. QT dispersion was similarly unaffected in patients with CAD in whom dipyridamole did not induce wall motion abnormalities. In contrast, in patients with positive dipyridamole stress test findings, QT dispersion increased from 60 +/- 17 ms at baseline to 94 +/- 25 ms during peak infusion (p <0.0001), with a time course mirroring that of development of contractile abnormalities. QT dispersion returned to 63 +/- 25 ms upon relief of ischemia by administration of aminophylline. The increase in QT dispersion was significantly related to the extent of contractile dysfunction induced by dipyridamole. Although ST-segment depression occurred in only 40% of patients with positive dipyridamole stress test findings, 88% of such patients had an increase in QT dispersion. Analysis of the receiver-operating characteristic curve showed that a QT dispersion increase of > or =20 ms identified positive findings for dipyridamole stress echocardiography with 68% sensitivity and 91% specificity. Thus, QT dispersion is acutely affected by myocardial ischemia induced by the administration of dipyridamole. Measurement of QT dispersion may improve detection of stress-induced ischemia on surface electrocardiograms.

[Evaluation of the effects of occupational noxae on the cardiovascular system]. / Valutazione degli effetti di noxae lavorative sull'apparato cardiovascolare.

BACKGROUND: Working conditions and the environment may contribute to the multi-factorial aetiology of cardiovascular disease. OBJECTIVES: To provide a critical assessment of epidemiological and clinical methods and tools for evaluating the effects of occupational pathogenic noxae on the cardiovascular system. METHODS: A review was made of epidemiological and clinical studies published in the main scientific journals of occupational medicine and cardiology, in the period 1980-2003. Data sources were electronic medical data bases and conference proceedings. RESULTS AND CONCLUSION: Collecting case histories by means of free or questionnaire-structured interviews, observing specific physical signs, detecting changes in blood chemistry parameters and identifying morphological or functional abnormalities in the heart and vessels are all useful approaches. Some blood chemistry parameters that may be modified by occupational exposure or by particular conditions arising from work organization are cholesterol, triglycerides, apolipoproteins A and B, platelets, fibrinogen, factor VIIc, fibrinolysis products, plasminogen tissue activating factor, complement and glycated hemoglobin. They can all be measured easily and quickly and provide an estimate of the risk of cardiovascular disease. As high blood pressure is closely correlated to heart disease, blood pressure levels can be monitored in a working population using a standard mercury sphygmomanometer. Electronic measurement before and after a work shift and 24 hour Holter monitoring help reduce the "white coat effect" and provide further useful information. Occupational risk factors such as toxins (metals, solvents, pesticides), electromagnetic fields, extreme temperatures, noise, radiation and psychophysical stress can affect the cardiac neuro-autonomic balance of the exposed workers and cause cardiovascular abnormalities. These can be detected by long-term ECG monitoring, and are revealed as reduced heart rate variability and prolonged QT interval. Recently non-invasive systems have been adopted to detect cardiovascular lesions that are usually due to atherosclerosis. In occupational and environmental studies ultrasound measurement of intima-medial carotid thickness and brachial artery reactivity have been used to determine the effects of exposure to carbon disulfide and passive smoking. Occupational Medicine has yet to include the use of the very expensive electron-beam computed tomography for a rapid and non-invasive study of coronary artery disease.

Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome.

BACKGROUND: Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LQTS) 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 LQTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. METHODS: The study population comprised 1206 patients with LQTS 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.

Risk factors for recurrent syncope and subsequent fatal or near-fatal events in children and adolescents with long QT syndrome.

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.

Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals.

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.

Clinical implications for patients with long QT syndrome who experience a cardiac event during infancy.

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) > or =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 > or =500 ms, heart rate < or =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.

Long QT syndrome and pregnancy.

OBJECTIVES: This study was designed to investigate the clinical course of women with long QT syndrome (LQTS) throughout their potential childbearing years. BACKGROUND: Only limited data exist regarding the risks associated with pregnancy in women with LQTS. METHODS: The risk of experiencing an adverse cardiac event, including syncope, aborted cardiac arrest, and sudden death, during and after pregnancy was analyzed for women who had their first birth from 1980 to 2003 (n = 391). Time-dependent Kaplan-Meier and Cox proportional hazard methods were used to evaluate the risk of cardiac events during different peripartum periods. RESULTS: Compared with a time period before a woman's first conception, the pregnancy time was associated with a reduced risk of cardiac events (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.10 to 0.76, p = 0.01), whereas the 9-month postpartum time had an increased risk (HR 2.7, 95% CI 1.8 to 4.3, p < 0.001). After the 9-month postpartum period, the risk was similar to the period before the first conception (HR 0.91, 95% CI 0.55 to 1.5, p = 0.70). Genotype analysis (n = 153) showed that women with the LQT2 genotype were more likely to experience a cardiac event than women with the LQT1 or LQT3 genotype. The cardiac event risk during the high-risk postpartum period was reduced among women using beta-blocker therapy (HR 0.34, 95% CI 0.14 to 0.84, p = 0.02). CONCLUSIONS: Women with LQTS have a reduced risk for cardiac events during pregnancy, but an increased risk during the 9-month postpartum period, especially among women with the LQT2 genotype. Beta-blockers were associated with a reduction in cardiac events during the high-risk postpartum time period.

Long QT syndrome in adults.

OBJECTIVES: The aims of this study were: 1) to evaluate risk factors influencing the clinical course of mutation-confirmed adult patients with long QT syndrome (LQTS), 2) to study life-threatening cardiac events as a specific end point in adults, and 3) to examine the protective effect of beta-blocker therapy on cardiac events in adult LQTS patients with known cardiac channel mutations. BACKGROUND: The clinical course and risk factors for cardiac events in genotype-confirmed adult patients with LQTS have not been previously investigated. METHODS: The clinical characteristics of 812 mutation-confirmed LQTS patients age 18 years or older were studied with both univariate and multivariate analyses to determine the genotype-phenotype factors that influence the clinical course of adult patients with this disorder. RESULTS: Female gender, corrected QT (QTc) interval, LQT2 genotype, and frequency of cardiac events before age 18 years were associated with increased risk of having any cardiac events between the ages of 18 and 40 years. Female gender, QTc interval > or =500 ms, and interim syncopal events during follow-up after age 18 years were associated with significantly increased risk of life-threatening cardiac events in adulthood. Beta-blockers provided a 60% reduction in risk of any cardiac event and life-threatening events, with somewhat greater effect in higher-risk subjects. CONCLUSIONS: The severity of LQTS in adulthood can be risk stratified with information regarding genotype, gender, QTc duration, and history of cardiac events. Beta-blockers effectively reduce but do not eliminate the risk of both syncopal and life-threatening cardiac events in adult patients with mutation-confirmed LQTS.