TY - JOUR
T1 - Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events
T2 - Implications for mutation-specific response to β-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 G.
AU - Qi, Ming
AU - Towbin, Jeffrey A.
AU - Vincent, G. Michael
AU - Lopes, Coeli M.
PY - 2012/4/24
Y1 - 2012/4/24
N2 - Background-β-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 β-adrenergic stimulation and clinical response to β-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). β-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 β-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 β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
AB - Background-β-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 β-adrenergic stimulation and clinical response to β-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). β-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 β-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 β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
KW - adrenergic beta-antagonists
KW - ion channels
KW - long QT syndrome
KW - mutation
UR - http://www.scopus.com/inward/record.url?scp=84860210760&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.111.048041
DO - 10.1161/CIRCULATIONAHA.111.048041
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 22456477
AN - SCOPUS:84860210760
SN - 0009-7322
VL - 125
SP - 1988
EP - 1996
JO - Circulation
JF - Circulation
IS - 16
ER -
