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, Marielle Alders, Takeshi AibaShiro Kamakura, Yoshihiro Miyamoto, Mark L. Andrews, Scott McNitt, Bronislava Polonsky, Peter J. Schwartz, Michael John Ackerman

Research output: Contribution to journalArticle

57 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 languageEnglish (US)
Pages (from-to)872-882
Number of pages11
JournalCirculation
Volume134
Issue number12
DOIs
StatePublished - Sep 20 2016
Externally publishedYes

Fingerprint

Multicenter Studies
Syncope
Heart Arrest
Regression Analysis
Long QT Syndrome
Sodium Channels
Sudden Cardiac Death
Therapeutics
Sudden Death
Long QT syndrome type 3
Population
Registries
Mutation

Keywords

  • arrhythmia
  • cardiac
  • cardiac
  • death
  • genetic testing
  • human
  • long-QT syndrome
  • risk assessment
  • SCN5A protein
  • sudden

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Wilde, A. A. M., Moss, A. J., Kaufman, E. S., Shimizu, W., Peterson, D. R., Benhorin, J., ... 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

Clinical Aspects of Type 3 Long-QT Syndrome : An International Multicenter Study. / Wilde, Arthur A M; Moss, Arthur J.; Kaufman, Elizabeth S.; Shimizu, Wataru; Peterson, Derick R.; Benhorin, Jesaia; Lopes, Coeli; Towbin, Jeffrey A.; Spazzolini, Carla; Crotti, Lia; Zareba, Wojciech; Goldenberg, Ilan; Kanters, Jørgen K.; Robinson, Jennifer L.; Qi, Ming; Hofman, Nynke; Tester, David J.; Bezzina, Connie R.; Alders, Marielle; Aiba, Takeshi; Kamakura, Shiro; Miyamoto, Yoshihiro; Andrews, Mark L.; McNitt, Scott; Polonsky, Bronislava; Schwartz, Peter J.; Ackerman, Michael John.

In: Circulation, Vol. 134, No. 12, 20.09.2016, p. 872-882.

Research output: Contribution to journalArticle

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
Wilde AAM, Moss AJ, Kaufman ES, Shimizu W, Peterson DR, Benhorin J et al. Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. Circulation. 2016 Sep 20;134(12):872-882. https://doi.org/10.1161/CIRCULATIONAHA.116.021823
Wilde, Arthur A M ; Moss, Arthur J. ; Kaufman, Elizabeth S. ; Shimizu, Wataru ; Peterson, Derick R. ; Benhorin, Jesaia ; Lopes, Coeli ; Towbin, Jeffrey A. ; Spazzolini, Carla ; Crotti, Lia ; Zareba, Wojciech ; Goldenberg, Ilan ; Kanters, Jørgen K. ; Robinson, Jennifer L. ; Qi, Ming ; Hofman, Nynke ; Tester, David J. ; Bezzina, Connie R. ; Alders, Marielle ; Aiba, Takeshi ; Kamakura, Shiro ; Miyamoto, Yoshihiro ; Andrews, Mark L. ; McNitt, Scott ; Polonsky, Bronislava ; Schwartz, Peter J. ; Ackerman, Michael John. / Clinical Aspects of Type 3 Long-QT Syndrome : An International Multicenter Study. In: Circulation. 2016 ; Vol. 134, No. 12. pp. 872-882.
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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.",
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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, Marielle

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 John

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.

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KW - cardiac

KW - cardiac

KW - death

KW - genetic testing

KW - human

KW - long-QT syndrome

KW - risk assessment

KW - SCN5A protein

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