Long-term flecainide therapy in type 3 long QT syndrome.

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.

Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study.

BACKGROUND: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of ß-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 ß-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 × ß-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, ß-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events.

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.

Ranolazine for Congenital Long-QT Syndrome Type III: Experimental and Long-Term Clinical Data.

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 (INa and INaL), but ranolazine preferentially reduces INaL. 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, INaL was significantly higher in D1790G than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of INaL of the SCN5A-D1790G channel without reducing peak INa 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 INaL 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.

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.

BACKGROUND: The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go-related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I(Kr)). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder. METHODS AND RESULTS: A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P<0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 (P<0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc. CONCLUSION: Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.

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.

Prediction of coronary artery disease severity in patients referred for coronary angiography.

BACKGROUND: Diagnostic coronary angiography is often followed by coronary stenting. Therapy with aspirin and clopidogrel is currently the standard treatment for patients undergoing coronary stenting. Clopidogrel loading is usually given prior to the procedure. Some pretreated patients, however, are found to have triple-vessel disease (3VD) or left main disease (LMD) that requires referral for coronary artery bypass graft (CABG) surgery. Surgery in patients pretreated with clopidogrel may be complicated by excessive bleeding or delayed to avoid that risk. HYPOTHESIS: A risk factor-based formula may predict the likelihood that patients referred for coronary angiography will have 3VD or LMD. METHODS: Consecutive patients (n = 2,180) referred for coronary angiography constitute the training subset (n = 1,296) used to build the model, and the validation subset (n = 884) used to test the model. Logistic regression models selected five variables showing strong associations with the presence of 3VD or LMD: age, gender, diabetes, hypercholesterolemia, and prior myocardial infarction (MI). A formula based on these variables and on the training subset was constructed to calculate the probability of 3VD or LMD. RESULTS: Applying this model to the validation subset predicted 3VD or LMD with 79% sensitivity, 53% specificity, 45% positive predictive value, and 83% negative predictive value. CONCLUSIONS: This simple formula based on five clinical variables is helpful in predicting the likelihood that patients, referred for coronary angiography, will have 3VD or LMD. Use of this formula can help decide in which patients clopidogrel loading prior to angiography should be avoided.

The value of electrocardiography-gated multi-slice computed tomography in the evaluation of patients with chest pain.

BACKGROUND: Multi-detector spiral computed tomography with retrospective electrocardiography-gated image reconstruction allows detailed anatomic imaging of the heart, great vessels and coronary arteries in a rapid, available and non-invasive mode. OBJECTIVES: To investigate the spectrum of findings in 32 consecutive patients with chest pain who underwent CT coronary angiogram in order to determine the clinical situations that will benefit most from this new technique. METHODS: Thirty-two patients with chest pain were studied by MDCT using 4 x 1 mm cross-sections, at 500 msec rotation with pitch 1-1.5, intravenous non-ionic contrast agent and a retrospectively ECG-gated reconstruction algorithm. The heart anatomy was evaluated using multi-planar reconstructions in the axial, long and short heart axes planes. Coronary arteries were evaluated using dedicated coronary software and the results were compared to those of conventional coronary angiograms in 12 patients. The patients were divided into four groups according to the indication for the study: group A--patients with high probability for coronary disease; group B--patients after CCA with undetermined diagnosis; group C--patients after cardiac surgery with possible anatomic derangement; and group D--symptomatic patients after coronary artery bypass graft, before considering conventional coronary angiography. RESULTS: Artifacts caused by coronary motion, heavy calcification and a lumen diameter smaller than 2 mm were the most frequent reasons for non-evaluable arteries. Assessment was satisfactory in 83% of all coronary segments. The overall sensitivity of 50% stenosis was 74% (85% for main vessels) with a specificity of 96%. Overall, the CTCA results were critical for management in 18 patients. CONCLUSIONS: Our preliminary experience suggests that CTCA is a reliable and promising technique for the detection of coronary artery stenosis as well as for a variety of additional cardiac and coronary structural abnormalities.

Improving clinical practice guidelines for practicing cardiologists.

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.

Prospective study of bacteremia after cardiac catheterization.

Nine hundred sixty consecutive cardiac catheterization procedures were studied prospectively for the presence of periprocedural bacteremia. Overall, among 960 procedures, only 4 were associated with clinically significant bacteremia. All 4 were related to the intravenous line and none to the cardiac procedure itself. Clinically nonsignificant bacteremias were correlated with procedural duration, multiple skin punctures, use of multiple balloons, and obesity.

Quantification of Atherosclerotic Burden in the Descending Aorta by Transesophageal Echocardiography: Inter- and Intraobserver Variability.

Atherosclerotic plaques had been imaged but not quantitated in the thoracic aorta using transesophageal echocardiography. The aim of this study was to describe a method for measuring the atherosclerotic plaque area in the descending aorta by transesophageal echocardiography (TEE) and to evaluate its reproducibility. TEE examinations were performed by two independent sonographers, in 21 patients with angiographically proven coronary artery disease. Two hundred fifty-six transverse segments (mean 12 +/- 3 patient) of the descending aorta were adequately recorded. In each segment the plaque and the lumen areas in the half of the aortic segment distant from the transesophageal probe were measured by one reader in the two studies (intersonographer reproducibility). Interreader reproducibility was also evaluated. The correlation coefficient between the first and second study (intersonographer reproducibility) was 0.81. The standard deviation of the difference between examinations equaled 0.137 cm(2) and the mean absolute difference between examinations was 0.003 cm(2) (95% CI: -0.015; 0.021; P = 0.75). The correlation coefficient between the two readers was 0.86, the standard deviation of the difference between readers was 0.175 cm(2) and the mean absolute difference was 0.006 cm(2) (95% CI: -0.029; 0.018; P = 0.63). A method for quantitative measurement of aortic atherosclerotic plaque area was evaluated and found to have high intersonographer and intereader reproducibilities. This method might be used in the future for noninvasive evaluation of regression or progression of aortic atherosclerosis.

Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations.

BACKGROUND: Patients with long QT syndrome (LQTS) who harbor multiple mutations (i.e. ≥ 2 mutations in ≥ 1 LQTS-susceptibility gene) may experience increased risk for life-threatening cardiac events. OBJECTIVES: The present study was designed to compare the clinical course of LQTS patients with multiple mutations to those with a single mutation. METHODS: The risk for life-threatening cardiac events (comprising aborted cardiac arrest, implantable defibrillator shock, or sudden cardiac death) from birth through age 40 years, by the presence of multiple vs. single mutations, was assessed among 403 patients from the LQTS Registry. RESULTS: Patients with multiple mutations (n=57) exhibited a longer QTc at enrollment compared with those with a single mutation (mean ± SD: 506 ± 72 vs. 480 ± 56 msec, respectively; P=0.003) and had a higher rate of life threatening cardiac events during follow-up (23% vs. 11%, respectively; p=0.031). Consistently, multivariate analysis demonstrated that patients with multiple mutations had a 2.3-fold (P=0.015) increased risk for life threatening cardiac events as compared to patients with a single mutation. The presence of multiple mutations in a single LQTS gene was associated with a 3.2-fold increased risk for life threatening cardiac events (P=0.010) whereas the risk associated with multiple mutation status involving >1 LQTS gene was not significantly different from the risk associated with a single mutation (HR 1.7, P=0.26). CONCLUSIONS: LQTS patients with multiple mutations have a greater risk for life-threatening cardiac events as compared to patients with a single mutation.

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.

Senior academic physicians and retirement considerations.

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.

The phenomenon of "QT stunning": the abnormal QT prolongation provoked by standing persists even as the heart rate returns to normal in patients with long QT syndrome.

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.

Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome.

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.

Risk of syncope in family members who are genotype-negative for a family-associated long-QT syndrome mutation.

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.

Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome.

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/RR°·8) than LQTS type 2 patients (improved QTc = QT/RR°·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.