Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study

Arthur A M Wilde; Arthur J Moss; Elizabeth S Kaufman; Wataru Shimizu; Derick R Peterson; Jesaia Benhorin; Coeli Lopes; Jeffrey A Towbin; Carla Spazzolini; Lia Crotti; Wojciech Zareba; Ilan Goldenberg; Jørgen K Kanters; Jennifer L Robinson; Ming Qi; Nynke Hofman; David J Tester; Connie R Bezzina; Mariëlle Alders; Takeshi Aiba; Shiro Kamakura; Yoshihiro Miyamoto; Mark L Andrews; Scott McNitt; Bronislava Polonsky; Peter J Schwartz; Michael J Ackerman

doi:10.1161/CIRCULATIONAHA.116.021823

Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study

Arthur A M Wilde, Arthur J Moss, Elizabeth S Kaufman, Wataru Shimizu, Derick R Peterson, Jesaia Benhorin, Coeli Lopes, Jeffrey A Towbin, Carla Spazzolini, Lia Crotti, Wojciech Zareba, Ilan Goldenberg, Jørgen K Kanters, Jennifer L Robinson, Ming Qi, Nynke Hofman, David J Tester, Connie R Bezzina, Mariëlle Alders, Takeshi AibaShiro Kamakura, Yoshihiro Miyamoto, Mark L Andrews, Scott McNitt, Bronislava Polonsky, Peter J Schwartz, Michael J Ackerman

Physiology of circulation, kidney and lung

90 Citations (Scopus)

Abstract

Background: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a large LQT3 population. Methods: The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. Results: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome-related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β-blocker therapy was associated with an 83% reduction in CEs in females (P=0.015) but not in males (who had many fewer events), with a significant sex × β-blocker interaction (P=0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events (P<0.02). Conclusions: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, β-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events.

Original language	English
Journal	Circulation
Volume	134
Issue number	12
Pages (from-to)	872-882
ISSN	0009-7322
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.116.021823
Publication status	Published - 20 Sept 2016

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10.1161/CIRCULATIONAHA.116.021823

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Wilde, A. A. M., Moss, A. J., Kaufman, E. S., Shimizu, W., Peterson, D. R., Benhorin, J., Lopes, C., Towbin, J. A., Spazzolini, C., Crotti, L., Zareba, W., Goldenberg, I., Kanters, J. K., Robinson, J. L., Qi, M., Hofman, N., Tester, D. J., Bezzina, C. R., Alders, M., ... Ackerman, M. J. (2016). Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. Circulation, 134(12), 872-882. https://doi.org/10.1161/CIRCULATIONAHA.116.021823

Wilde, AAM, Moss, AJ, Kaufman, ES, Shimizu, W, Peterson, DR, Benhorin, J, Lopes, C, Towbin, JA, Spazzolini, C, Crotti, L, Zareba, W, Goldenberg, I, Kanters, JK, Robinson, JL, Qi, M, Hofman, N, Tester, DJ, Bezzina, CR, Alders, M, Aiba, T, Kamakura, S, Miyamoto, Y, Andrews, ML, McNitt, S, Polonsky, B, Schwartz, PJ & Ackerman, MJ 2016, 'Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study', Circulation, vol. 134, no. 12, pp. 872-882. https://doi.org/10.1161/CIRCULATIONAHA.116.021823

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title = "Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study",

abstract = "Background: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a large LQT3 population. Methods: The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. Results: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome-related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β-blocker therapy was associated with an 83% reduction in CEs in females (P=0.015) but not in males (who had many fewer events), with a significant sex × β-blocker interaction (P=0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events (P<0.02). Conclusions: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, β-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events.",

author = "Wilde, {Arthur A M} and Moss, {Arthur J} and Kaufman, {Elizabeth S} and Wataru Shimizu and Peterson, {Derick R} and Jesaia Benhorin and Coeli Lopes and Towbin, {Jeffrey A} and Carla Spazzolini and Lia Crotti and Wojciech Zareba and Ilan Goldenberg and Kanters, {J{\o}rgen K} and Robinson, {Jennifer L} and Ming Qi and Nynke Hofman and Tester, {David J} and Bezzina, {Connie R} and Mari{\"e}lle Alders and Takeshi Aiba and Shiro Kamakura and Yoshihiro Miyamoto and Andrews, {Mark L} and Scott McNitt and Bronislava Polonsky and Schwartz, {Peter J} and Ackerman, {Michael J}",

year = "2016",

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doi = "10.1161/CIRCULATIONAHA.116.021823",

language = "English",

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pages = "872--882",

journal = "Circulation",

issn = "0009-7322",

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TY - JOUR

T1 - Clinical Aspects of Type 3 Long-QT Syndrome

T2 - An International Multicenter Study

AU - Wilde, Arthur A M

AU - Moss, Arthur J

AU - Kaufman, Elizabeth S

AU - Shimizu, Wataru

AU - Peterson, Derick R

AU - Benhorin, Jesaia

AU - Lopes, Coeli

AU - Towbin, Jeffrey A

AU - Spazzolini, Carla

AU - Crotti, Lia

AU - Zareba, Wojciech

AU - Goldenberg, Ilan

AU - Kanters, Jørgen K

AU - Robinson, Jennifer L

AU - Qi, Ming

AU - Hofman, Nynke

AU - Tester, David J

AU - Bezzina, Connie R

AU - Alders, Mariëlle

AU - Aiba, Takeshi

AU - Kamakura, Shiro

AU - Miyamoto, Yoshihiro

AU - Andrews, Mark L

AU - McNitt, Scott

AU - Polonsky, Bronislava

AU - Schwartz, Peter J

AU - Ackerman, Michael J

PY - 2016/9/20

Y1 - 2016/9/20

N2 - Background: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a large LQT3 population. Methods: The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. Results: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome-related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β-blocker therapy was associated with an 83% reduction in CEs in females (P=0.015) but not in males (who had many fewer events), with a significant sex × β-blocker interaction (P=0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events (P<0.02). Conclusions: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, β-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events.

AB - Background: Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a large LQT3 population. Methods: The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years. Results: Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome-related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β-blocker therapy was associated with an 83% reduction in CEs in females (P=0.015) but not in males (who had many fewer events), with a significant sex × β-blocker interaction (P=0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events (P<0.02). Conclusions: Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, β-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events.

U2 - 10.1161/CIRCULATIONAHA.116.021823

DO - 10.1161/CIRCULATIONAHA.116.021823

M3 - Journal article

C2 - 27566755

SN - 0009-7322

VL - 134

SP - 872

EP - 882

JO - Circulation

JF - Circulation

IS - 12

ER -

Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study

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