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

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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. / Barsheshet, Alon; Goldenberg, Ilan; O-Uchi, Jin; Moss, Arthur J.; Jons, Christian; Shimizu, Wataru; Wilde, Arthur A.; McNitt, Scott; Peterson, Derick R.; Zareba, Wojciech; Robinson, Jennifer L.; Ackerman, Michael J.; Cypress, Michael; Gray, Daniel A.; Hofman, Nynke; Kanters, Jorgen K.; Kaufman, Elizabeth S.; Platonov, Pyotr; Qi, Ming; Towbin, Jeffrey A.; Vincent, G. Michael; Lopes, Coeli M.

I: Circulation, Vol. 125, Nr. 16, 2012, s. 1988.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Barsheshet, A, Goldenberg, I, O-Uchi, J, Moss, AJ, Jons, C, Shimizu, W, Wilde, AA, McNitt, S, Peterson, DR, Zareba, W, Robinson, JL, Ackerman, MJ, Cypress, M, Gray, DA, Hofman, N, Kanters, JK, Kaufman, ES, Platonov, P, Qi, M, Towbin, JA, Vincent, GM & Lopes, CM 2012, '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', Circulation, vol. 125, nr. 16, s. 1988. https://doi.org/10.1161/CIRCULATIONAHA.111.048041

APA

CBE

Barsheshet A, Goldenberg I, O-Uchi J, Moss AJ, Jons C, Shimizu W, Wilde AA, McNitt S, Peterson DR, Zareba W, Robinson JL, Ackerman MJ, Cypress M, Gray DA, Hofman N, Kanters JK, Kaufman ES, Platonov P, Qi M, Towbin JA, Vincent GM, Lopes CM. 2012. 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. Circulation. 125(16):1988. https://doi.org/10.1161/CIRCULATIONAHA.111.048041

MLA

Vancouver

Author

Barsheshet, Alon ; Goldenberg, Ilan ; O-Uchi, Jin ; Moss, Arthur J. ; Jons, Christian ; Shimizu, Wataru ; Wilde, Arthur A. ; McNitt, Scott ; Peterson, Derick R. ; Zareba, Wojciech ; Robinson, Jennifer L. ; Ackerman, Michael J. ; Cypress, Michael ; Gray, Daniel A. ; Hofman, Nynke ; Kanters, Jorgen K. ; Kaufman, Elizabeth S. ; Platonov, Pyotr ; Qi, Ming ; Towbin, Jeffrey A. ; Vincent, G. Michael ; Lopes, Coeli M. / 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. I: Circulation. 2012 ; Vol. 125, Nr. 16. s. 1988.

RIS

TY - JOUR

T1 - 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

AU - Barsheshet, Alon

AU - Goldenberg, Ilan

AU - O-Uchi, Jin

AU - Moss, Arthur J.

AU - Jons, Christian

AU - Shimizu, Wataru

AU - Wilde, Arthur A.

AU - McNitt, Scott

AU - Peterson, Derick R.

AU - Zareba, Wojciech

AU - Robinson, Jennifer L.

AU - Ackerman, Michael J.

AU - Cypress, Michael

AU - Gray, Daniel A.

AU - Hofman, Nynke

AU - Kanters, Jorgen K.

AU - Kaufman, Elizabeth S.

AU - Platonov, Pyotr

AU - Qi, Ming

AU - Towbin, Jeffrey A.

AU - Vincent, G. Michael

AU - Lopes, Coeli M.

PY - 2012

Y1 - 2012

N2 - 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.)

AB - 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.)

KW - adrenergic beta-antagonists

KW - ion channels

KW - long QT syndrome

KW - mutation

U2 - 10.1161/CIRCULATIONAHA.111.048041

DO - 10.1161/CIRCULATIONAHA.111.048041

M3 - Article

VL - 125

SP - 1988

JO - Circulation

JF - Circulation

SN - 1524-4539

IS - 16

ER -