| 1. |
- Goldenberg, Ilan, et al.
(author)
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Risk for Life-Threatening Cardiac Events in Patients With Genotype-Confirmed Long-QT Syndrome and Normal-Range Corrected QT Intervals
- 2010
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 57:1, s. 51-59
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Journal article (peer-reviewed)abstract
- Objectives This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) intervals. Background Current data regarding the outcome of patients with concealed LQTS are limited. Methods Clinical and genetic risk factors for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) from birth through age 40 years were examined in 3,386 genotyped subjects from 7 multinational LQTS registries, categorized as LQTS with normal-range QTc (<= 440 ms [n = 469]), LQTS with prolonged QTc interval (>440 ms [ n = 1,392]), and unaffected family members (genotyped negative with <= 440 ms [ n = 1,525]). Results The cumulative probability of ACA or SCD in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (p < 0.001) but higher than in unaffected family members (0.4%) (p < 0.001). Risk factors ACA or SCD in patients with normal-range QTc intervals included mutation characteristics (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1: LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3: LQTS type 2, hazard ratio: 8.04; p = 0.07), whereas clinical factors, including sex and QTc duration, were associated with a significant increase in the risk for ACA or SCD only in patients with prolonged QTc intervals (female age >13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002). Conclusions Genotype-confirmed patients with concealed LQTS make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for ACA or SCD in this overall lower risk LQTS subgroup. (J Am Coll Cardiol 2011;57:51-9) (C) 2011 by the American College of Cardiology Foundation
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| 2. |
- Barsheshet, Alon, et al.
(author)
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Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events Implications for Mutation-Specific Response to beta-Blocker Therapy in Type 1 Long-QT Syndrome
- 2012
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In: Circulation. - 1524-4539. ; 125:16, s. 1988-1988
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Journal article (peer-reviewed)abstract
- Background-beta-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to beta-adrenergic stimulation and clinical response to beta-blocker therapy according to mutation location. Methods and Results-The study sample comprised 860 patients with genetically confirmed mutations in the KCNQ1 channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations = 2.75; 95% confidence interval, 1.29-5.86; P=0.009). beta-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02-0.73; P=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31-2.13; P=0.68, respectively; P for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to beta-adrenergic stimulation. Conclusions-Patients with C-loop missense mutations in the KCNQ1 channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with beta-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations. (Circulation. 2012; 125: 1988-1996.)
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| 3. |
- Costa, Jason, et al.
(author)
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Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome
- 2012
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In: Heart Rhythm. - : Elsevier BV. - 1547-5271. ; 9:6, s. 892-898
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Journal article (peer-reviewed)abstract
- 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.
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| 4. |
- Migdalovich, Dimitry, et al.
(author)
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Mutation and gender-specific risk in type 2 long QT syndrome: Implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome
- 2011
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In: Heart Rhythm. - : Elsevier BV. - 1547-5271. ; 8:10, s. 1537-1543
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Journal article (peer-reviewed)abstract
- BACKGROUND Men and women with type 2 long QT syndrome (LQT2) exhibit time-dependent differences in the risk for cardiac events. We hypothesized that data regarding the location of the disease-causing mutation in the KCNH2 channel may affect gender-specific risk in LQT2. OBJECTIVE This study sought to risk-stratify LQT2 patients for life-threatening cardiac events based on clinical and genetic information. METHODS The risk for life-threatening cardiac events from birth through age 40 years (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) was assessed among 1,166 LQT2 male (n = 490) and female (n = 676) patients by the location of the LQTS-causing mutation in the KCNH2 channel (prespecified in the primary analysis as pore-loop vs. non-pore-loop). RESULTS During follow-up, the cumulative probability of life-threatening cardiac events years was significantly higher among LQT2 women (26%) as compared with men (14%; P <.001). Multivariate analysis showed that the risk for life-threatening cardiac events was not significantly different between women with and without pore-loop mutations (hazard ratio 1.20; P = .33). In contrast, men with pore-loop mutations displayed a significant > 2-fold higher risk of a first ACA or SCD as compared with those with non-pore-loop mutations (hazard ratio 2.18; P = .01). Consistently, women experienced a high rate of life-threatening events regardless of mutation location (pore-loop: 35%, nonpore-loop: 23%), whereas in men the rate of ACA or SCD was high among those with pore-loop mutations (28%) and relatively low among those with non-pore-loop mutations (8%). CONCLUSION Combined assessment of clinical and mutation-specific data can be used for improved risk stratification for life-threatening cardiac events in LQT2.
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| 5. |
- Hoefen, Ryan, et al.
(author)
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In Silico Cardiac Risk Assessment in Patients With Long QT Syndrome Type 1: Clinical Predictability of Cardiac Models
- 2012
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 60:21, s. 2182-2191
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Journal article (peer-reviewed)abstract
- Objectives The study was designed to assess the ability of computer-simulated electrocardiography parameters to predict clinical outcomes and to risk-stratify patients with long QT syndrome type 1 (LQT1). Background Although attempts have been made to correlate mutation-specific ion channel dysfunction with patient phenotype in long QT syndrome, these have been largely unsuccessful. Systems-level computational models can be used to predict consequences of complex changes in channel function to the overall heart rhythm. Methods A total of 633 LQT1-genotyped subjects with 34 mutations from multinational long QT syndrome registries were studied. Cellular electrophysiology function was determined for the mutations and introduced in a 1-dimensional transmural electrocardiography computer model. The mutation effect on transmural repolarization was determined for each mutation and related to the risk for cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) among patients. Results Multivariate analysis showed that mutation-specific transmural repolarization prolongation (TRP) was associated with an increased risk for cardiac events (35% per 10-ms increment [p < 0.0001]; >= upper quartile hazard ratio: 2.80 [p < 0.0001]) and life-threatening events (aborted cardiac arrest/sudden cardiac death: 27% per 10-ms increment [p = 0.03]; >= upper quartile hazard ratio: 2.24 [p = 0.002]) independently of patients' individual QT interval corrected for heart rate (QTc). Subgroup analysis showed that among patients with mild to moderate QTc duration (<500 ms), the risk associated with TRP was maintained (36% per 10 ms [p < 0.0001]), whereas the patient's individual QTc was not associated with a significant risk increase after adjustment for TRP. Conclusions These findings suggest that simulated repolarization can be used to predict clinical outcomes and to improve risk stratification in patients with LQT1, with a more pronounced effect among patients with a lower-range QTc, in whom a patient's individual QTc may provide less incremental prognostic information. (J Am Coll Cardiol 2012;60:2182-91) (C) 2012 by the American College of Cardiology Foundation
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| 6. |
- Mathias, Andrew, et al.
(author)
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Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome
- 2013
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In: Heart Rhythm. - : Elsevier BV. - 1547-5271. ; 10:5, s. 720-725
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Journal article (peer-reviewed)abstract
- BACKGROUND Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LOTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. OBJECTIVES To hypothesize that the assessment of QTc variance in patients with congenital LOTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. METHODS The study population comprised 1206 patients with LOTS with 95 different mutations and >= 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. RESULTS Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P=.002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P<.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P=.95; P value for QTcSD-by-genotype interaction=.002). CONCLUSIONS Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype.
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| 7. |
- Holmqvist, Fredrik, et al.
(author)
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Abnormal P-Wave Morphology Is a Predictor of Atrial Fibrillation Development and Cardiac Death in MADIT II Patients
- 2010
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In: Annals of Noninvasive Electrocardiology. - 1082-720X. ; 15:1, s. 63-72
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Journal article (peer-reviewed)abstract
- Background: Several ECG-based approaches have been shown to add value when risk-stratifying patients with congestive heart failure, but little attention has been paid to the prognostic value of abnormal atrial depolarization in this context. The aim of this study was to noninvasively analyze the atrial depolarization phase to identify markers associated with increased risk of mortality, deterioration of heart failure, and development of atrial fibrillation (AF) in a high-risk population with advanced congestive heart failure and a history of acute myocardial infarction. Methods: Patients included in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) with sinus rhythm at baseline were studied (n = 802). Unfiltered and band-pass filtered signal-averaged P waves were analyzed to determine orthogonal P-wave morphology (prespecified types 1, 2, and 3/atypical), P-wave duration, and RMS20. The association between P-wave parameters and data on the clinical course and cardiac events during a mean follow-up of 20 months was analyzed. Results: P-wave duration was 139 +/- 23 ms and the RMS20 was 1.9 +/- 1.1 mu V. None of these parameters was significantly associated with poor cardiac outcome or AF development. After adjustment for clinical covariates, abnormal P-wave morphology was found to be independently predictive of nonsudden cardiac death (HR 2.66; 95% CI 1.41-5.04, P = 0.0027) and AF development (HR 1.75; 95% CI 1.10-2.79, P = 0.019). Conclusion: Abnormalities in P-wave morphology recorded from orthogonal leads in surface ECG are independently predictive of increased risk of nonsudden cardiac death and AF development in MADIT II patients. Ann Noninvasive Electrocardiol 2010;15(1):63-72
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