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- Barsheshet, Alon, et al.
(författare)
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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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Ingår i: Circulation. - 1524-4539. ; 125:16, s. 1988-1988
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Costa, Jason, et al.
(författare)
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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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Ingår i: Heart Rhythm. - : Elsevier BV. - 1547-5271. ; 9:6, s. 892-898
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Tidskriftsartikel (refereegranskat)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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