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Andrew Mathias,
Arthur J Moss,
Coeli M Lopes,
Alon Barsheshet,
Scott McNitt,
Wojciech Zareba,
Jennifer L Robinson,
Emanuela H Locati,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Pyotr G Platonov,
Ming Qi,
Wataru Shimizu,
Jeffrey A Towbin,
G Michael Vincent,
Arthur A M Wilde,
Li Zhang,
Ilan Goldenberg
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Individual QTc may vary widely among carriers of the same LQTS mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. OBJECTIVES: We hypothesized that assessment of QTc variance in patients with congenital long QT syndrome (LQTS) who carry the same mutation provides incremental prognostic information to the patient-specific QTc. METHODS: The study population comprised 1206 LQTS patients with 95 different mutations and ≥5 individuals per mutation. Multivariate Cox proportional hazards regression modeling 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 msec). Multivariate analysis showed that each 20 msec increment in QTcSD was associated with a significant 33% (p=0.002) increase in the risk for cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among LQT1 patients (HR=1.55 per 20 msec increment [p<0.001]), whereas among LQT2 patients the risk associated with QTcSD was not statistically significant (HR=0.99 [p=0.95]; p-value for QTcSD-by-genotype interaction = 0.002). CONCLUSIONS: Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk for cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the LQT1 genotype.
Heart rhythm: the official journal of the Heart Rhythm Society 01/2013; · 4.56 Impact Factor
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Jamie Mullally,
Ilan Goldenberg,
Arthur J Moss,
Coeli M Lopes,
Michael J Ackerman,
Wojciech Zareba,
Scott McNitt,
Jennifer L Robinson, Jesaia Benhorin,
Elizabeth S Kaufman,
Jeffrey A Towbin,
Alon Barsheshet
[show abstract]
[hide abstract]
ABSTRACT: 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<0.001). 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.
Heart rhythm: the official journal of the Heart Rhythm Society 11/2012; · 4.56 Impact Factor
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Jason Costa,
Coeli M Lopes,
Alon Barsheshet,
Arthur J Moss,
Dmitriy Migdalovich,
Gregory Ouellet,
Scott McNitt,
Slava Polonsky,
Jennifer L Robinson,
Wojciech Zareba,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Pyotr G Platonov,
Wataru Shimizu,
Jeffrey A Towbin,
G Michael Vincent,
Arthur A M Wilde,
Ilan Goldenberg
[show abstract]
[hide abstract]
ABSTRACT: Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events.
We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene.
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).
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.
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.
Heart rhythm: the official journal of the Heart Rhythm Society 01/2012; 9(6):892-8. · 4.56 Impact Factor
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Alon Barsheshet,
Arthur J Moss,
Scott McNitt,
Slava Polonsky,
Coeli M Lopes,
Wojciech Zareba,
Jennifer L Robinson,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Jeffrey A Towbin,
G Michael Vincent,
Ming Qi,
Ilan Goldenberg
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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.
Circulation Cardiovascular Genetics 08/2011; 4(5):491-9. · 6.11 Impact Factor
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Alon Barsheshet,
Derick R Peterson,
Arthur J Moss,
Peter J Schwartz,
Elizabeth S Kaufman,
Scott McNitt,
Slava Polonsky,
Jonathan Buber,
Wojciech Zareba,
Jennifer L Robinson,
Michael J Ackerman, Jesaia Benhorin,
Jeffrey A Towbin,
G Michael Vincent,
Li Zhang,
Ilan Goldenberg
[show abstract]
[hide abstract]
ABSTRACT: 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.
This study hypothesized that risk assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate.
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).
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).
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.
Heart rhythm: the official journal of the Heart Rhythm Society 03/2011; 8(8):1207-13. · 4.56 Impact Factor
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Dimitry Migdalovich,
Arthur J Moss,
Coeli M Lopes,
Jason Costa,
Gregory Ouellet,
Alon Barsheshet,
Scott McNitt,
Slava Polonsky,
Jennifer L Robinson,
Wojciech Zareba,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Pyotr G Platonov,
Wataru Shimizu,
Jeffrey A Towbin,
G Michael Vincent,
Arthur A M Wilde,
Ilan Goldenberg
[show abstract]
[hide abstract]
ABSTRACT: 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.
This study sought to risk-stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information.
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).
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%).
Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2.
Heart rhythm: the official journal of the Heart Rhythm Society 03/2011; 8(10):1537-43. · 4.56 Impact Factor
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Judy F Liu,
Christian Jons,
Arthur J Moss,
Scott McNitt,
Derick R Peterson,
Ming Qi,
Wojciech Zareba,
Jennifer L Robinson,
Alon Barsheshet,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Emanuela H Locati,
Carlo Napolitano,
Silvia G Priori,
Peter J Schwartz,
Jeffrey Towbin,
Michael Vincent,
Li Zhang,
Ilan Goldenberg
[show abstract]
[hide abstract]
ABSTRACT: We aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS).
Data regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited.
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.
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.
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.
Journal of the American College of Cardiology 02/2011; 57(8):941-50. · 14.16 Impact Factor
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Ilan Goldenberg,
Samuel Horr,
Arthur J Moss,
Coeli M Lopes,
Alon Barsheshet,
Scott McNitt,
Wojciech Zareba,
Mark L Andrews,
Jennifer L Robinson,
Emanuela H Locati, [......],
Carlo Napolitano,
Pyotr G Platonov,
Silvia G Priori,
Ming Qi,
Peter J Schwartz,
Wataru Shimizu,
Jeffrey A Towbin,
G Michael Vincent,
Arthur A M Wilde,
Li Zhang
[show abstract]
[hide abstract]
ABSTRACT: 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.
Current data regarding the outcome of patients with concealed LQTS are limited.
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]).
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).
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.
Journal of the American College of Cardiology 12/2010; 57(1):51-9. · 14.16 Impact Factor
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Judy F Liu,
Arthur J Moss,
Christian Jons, Jesaia Benhorin,
Peter J Schwartz,
Carla Spazzolini,
Lia Crotti,
Michael J Ackerman,
Scott McNitt,
Jennifer L Robinson,
Ming Qi,
Ilan Goldenberg,
Wojciech Zareba
[show abstract]
[hide abstract]
ABSTRACT: 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.
The American journal of cardiology 01/2010; 105(2):210-3. · 3.58 Impact Factor
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Carla Spazzolini,
Jamie Mullally,
Arthur J Moss,
Peter J Schwartz,
Scott McNitt,
Gregory Ouellet,
Thomas Fugate,
Ilan Goldenberg,
Christian Jons,
Wojciech Zareba, [......],
Michael J Ackerman, Jesaia Benhorin,
Lia Crotti,
Elizabeth S Kaufman,
Emanuela H Locati,
Ming Qi,
Carlo Napolitano,
Silvia G Priori,
Jeffrey A Towbin,
G Michael Vincent
[show abstract]
[hide abstract]
ABSTRACT: 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).
The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously.
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.
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.
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.
Journal of the American College of Cardiology 08/2009; 54(9):832-7. · 14.16 Impact Factor
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Elizabeth S Kaufman,
Scott McNitt,
Arthur J Moss,
Wojciech Zareba,
Jennifer L Robinson,
W Jackson Hall,
Michael J Ackerman, Jesaia Benhorin,
Emanuela T Locati,
Carlo Napolitano,
Silvia G Priori,
Peter J Schwartz,
Jeffrey A Towbin,
G Michael Vincent,
Li Zhang
[show abstract]
[hide abstract]
ABSTRACT: 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.
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.
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).
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.
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).
Heart rhythm: the official journal of the Heart Rhythm Society 07/2008; 5(6):831-6. · 4.56 Impact Factor
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Ilan Goldenberg,
Arthur J Moss,
Derick R Peterson,
Scott McNitt,
Wojciech Zareba,
Mark L Andrews,
Jennifer L Robinson,
Emanuela H Locati,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Carlo Napolitano,
Silvia G Priori,
Ming Qi,
Peter J Schwartz,
Jeffrey A Towbin,
G Michael Vincent,
Li Zhang
[show abstract]
[hide abstract]
ABSTRACT: 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.
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).
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.
Circulation 04/2008; 117(17):2184-91. · 14.74 Impact Factor
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Ilan Goldenberg,
Arthur J Moss,
James Bradley,
Slava Polonsky,
Derick R Peterson,
Scott McNitt,
Wojciech Zareba,
Mark L Andrews,
Jennifer L Robinson,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Emanuela H Locati,
Carlo Napolitano,
Silvia G Priori,
Ming Qi,
Peter J Schwartz,
Jeffrey A Towbin,
G Michael Vincent,
Li Zhang
[show abstract]
[hide abstract]
ABSTRACT: 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.
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).
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.
Circulation 04/2008; 117(17):2192-201. · 14.74 Impact Factor
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Rahul Seth,
Arthur J Moss,
Scott McNitt,
Wojciech Zareba,
Mark L Andrews,
Ming Qi,
Jennifer L Robinson,
Ilan Goldenberg,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Emanuela H Locati,
Carlo Napolitano,
Silvia G Priori,
Peter J Schwartz,
Jeffrey A Towbin,
G Michael Vincent,
Li Zhang
[show abstract]
[hide abstract]
ABSTRACT: This study was designed to investigate the clinical course of women with long QT syndrome (LQTS) throughout their potential childbearing years.
Only limited data exist regarding the risks associated with pregnancy in women with LQTS.
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.
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).
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.
Journal of the American College of Cardiology 03/2007; 49(10):1092-8. · 14.16 Impact Factor
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Andrew J Sauer,
Arthur J Moss,
Scott McNitt,
Derick R Peterson,
Wojciech Zareba,
Jennifer L Robinson,
Ming Qi,
Ilan Goldenberg,
Jenny B Hobbs,
Michael J Ackerman, Jesaia Benhorin,
W Jackson Hall,
Elizabeth S Kaufman,
Emanuela H Locati,
Carlo Napolitano,
Silvia G Priori,
Peter J Schwartz,
Jeffrey A Towbin,
G Michael Vincent,
Li Zhang
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ABSTRACT: 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.
The clinical course and risk factors for cardiac events in genotype-confirmed adult patients with LQTS have not been previously investigated.
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.
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.
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.
Journal of the American College of Cardiology 02/2007; 49(3):329-37. · 14.16 Impact Factor
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Jenny B Hobbs,
Derick R Peterson,
Arthur J Moss,
Scott McNitt,
Wojciech Zareba,
Ilan Goldenberg,
Ming Qi,
Jennifer L Robinson,
Andrew J Sauer,
Michael J Ackerman, Jesaia Benhorin,
Elizabeth S Kaufman,
Emanuela H Locati,
Carlo Napolitano,
Silvia G Priori,
Jeffrey A Towbin,
G Michael Vincent,
Li Zhang
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ABSTRACT: 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.
To identify risk factors associated with aborted cardiac arrest and sudden cardiac death during adolescence in patients with clinically suspected LQTS.
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.
Aborted cardiac arrest or LQTS-related sudden cardiac death; follow-up ended on February 15, 2005.
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).
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.
JAMA The Journal of the American Medical Association 09/2006; 296(10):1249-54. · 30.03 Impact Factor
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Ilan Goldenberg,
Jehu Mathew,
Arthur J Moss,
Scott McNitt,
Derick R Peterson,
Wojciech Zareba, Jesaia Benhorin,
Li Zhang,
G Michael Vincent,
Mark L Andrews,
Jennifer L Robinson,
Brian Morray
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ABSTRACT: We evaluated the incremental prognostic information provided by multiple corrected QT (QTc) measurements on serial electrocardiograms (ECGs) in patients with the inherited long QT syndrome (LQTS).
A baseline QTc of > or =500 ms has been shown to be associated with increased risk of cardiac events among LQTS patients. However, the value of QTc measurements on follow-up ECGs in risk assessment has not been determined.
The risk of a first LQTS-related cardiac event during adolescence was assessed in 375 patients enrolled in the International LQTS Registry for whom serial follow-up ECGs were recorded before age 10.
The mean +/- SD difference between the minimum and maximum QTc values on serial ECGs recorded in study patients was 47 +/- 40 ms. The maximum QTc interval recorded before age 10 was the strongest predictor of cardiac events during adolescence (adjusted hazard ratio [HR] = 2.74; p < 0.001). Other follow-up QTc measures, including the baseline, the mean, and the most recent QTc interval recorded before age 10, were less significant risk factors. After adjusting for the maximum QTc value during follow-up, no significant association remained between the baseline QTc value and the risk of subsequent cardiac events (HR = 1.04; p = 0.91).
In LQTS patients, there is a considerable variability in QTc measures in serial follow-up ECGs. The maximum QTc interval provides incremental prognostic information beyond the baseline measurement. We suggest that risk stratification in LQTS patients should include follow-up ECG data.
Journal of the American College of Cardiology 09/2006; 48(5):1047-52. · 14.16 Impact Factor
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ABSTRACT: To describe the clinical, genetic, and electrophysiologic characteristics of a new PAS-domain HERG mutation (M124R) that has been identified in a single large Jewish family with Long QT syndrome (LQTS).
Many previously reported HERG mutations causing LQTS are located either in the C-terminus, or in the pore region. Relatively fewer clinical data are available on N-terminus (PAS-domain) mutation carriers.
Clinical data were available in 76 family members (aged 1-93 years, 69 alive) over 18 years of follow-up, while electrocardiographic data were available in 57, and genetic data in 45 family members. Cellular electrophysiology was assessed in transfected Chinese Hamster Ovary (CHO) cells using the whole-cell patch-clamp technique.
Thirty-six family members were phenotypically categorized as nonaffected, 3 as equivocal, and 20 as affected. Mean QTc was 410+/-23, 440+/-10, and 498+/-41 ms, respectively, in these three subgroups. Eight out of 20 affected family members were symptomatic: five had only syncope, two had aborted cardiac arrest, and one sudden death. Genetic analyses identified the M124R point mutation in all affected members tested (n=16), while all those tested with nonaffected (n=26) and equivocal (n=3) phenotype did not carry the mutation. The M124R mutation reduced the HERG tail-current density by 65%, significantly accelerated the deactivation kinetics, and caused a negative shift in the voltage dependence of activation.
A new PAS-domain HERG mutation (M124R) was identified as causing LQTS in a large Jewish family, with high penetrance and frequent disease-related symptoms. This mutation markedly decreased the tail-current density and accelerated the deactivation kinetics of the HERG channel in transfected CHO cells.
Annals of Noninvasive Electrocardiology 08/2005; 10(3):334-41. · 1.10 Impact Factor
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ABSTRACT: 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.
A risk factor-based formula may predict the likelihood that patients referred for coronary angiography will have 3VD or LMD.
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.
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.
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.
Clinical Cardiology 07/2005; 28(6):288-92. · 2.15 Impact Factor
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Wojciech Zareba,
Arthur J Moss,
Gloria Sheu,
Elizabeth S Kaufman,
Silvia Priori,
G Michael Vincent,
Jeffrey A Towbin, Jesaia Benhorin,
Peter J Schwartz,
Carlo Napolitano,
W Jackson Hall,
Mark T Keating,
Ming Qi,
Jennifer L Robinson,
Mark L Andrews
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ABSTRACT: Recent data showed that long QT syndrome (LQTS) patients with mutations in the pore region of the HERG (LQT2) gene have significantly higher risk of cardiac events than subjects with mutations in the non-pore region. The aim of this study was to determine whether there is an association between the location of mutations in the KCNQ1 gene and cardiac events in LQT1 patients.
The study population consisted of 294 LQT1 patients with KCNQ1 gene mutations. Demographic, clinical, and follow-up information was compared among subjects with different locations of KCNQ1 mutations defined as pre-pore region including N-terminus (1-278), pore region (279-354), and post-pore region including C-terminus (>354). Cardiac events observed during follow-up from birth until age of last contact or age 40 years were defined as syncope, cardiac arrest, or sudden death. There were 164 (56%) LQT1 patients with pre-pore mutations, 101 (34%) with pore mutations, and 29 (10%) with post-pore mutations. QTc duration did not differ significantly among the three subgroups (mean QTc = 494, 487, and 501 ms, respectively). There was no significant difference between groups with regard to the risk of cardiac events by age 40 years.
There are no significant differences in clinical presentation, ECG parameters, and cardiac events among LQT1 patients with different locations of KCNQ1 mutations. These findings indicate that factors other than location of mutation influence clinical phenotype in patients with LQT1 mutations.
Journal of Cardiovascular Electrophysiology 11/2003; 14(11):1149-53. · 3.06 Impact Factor
