Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to β-blocker therapy in type 1 long-QT syndrome

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, Jørgen 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 - Adolescent

KW - Adrenergic beta-Antagonists

KW - Adult

KW - Child

KW - Female

KW - Genetic Predisposition to Disease

KW - Heart Arrest

KW - Humans

KW - KCNQ1 Potassium Channel

KW - Male

KW - Mutation

KW - Risk

KW - Romano-Ward Syndrome

KW - Treatment Outcome

KW - Young Adult

U2 - 10.1161/CIRCULATIONAHA.111.048041

DO - 10.1161/CIRCULATIONAHA.111.048041

M3 - Journal article

C2 - 22456477

SN - 0009-7322

VL - 125

SP - 1988

EP - 1996

JO - Circulation

JF - Circulation

IS - 16

ER -