Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias

Peter J. Schwartz, Silvia G. Priori, Carla Spazzolini, Arthur J. Moss, G. Michael Vincent, Carlo Napolitano, Isabelle Denjoy, Pascale Guicheney, Günter Breithardt, Mark T. Keating, Jeffrey Towbin, Alan H. Beggs, Paul Brink, Arthur A.M. Wilde, Lauri Toivonen, Wojciech Zareba, Jennifer L. Robinson, Katherine W. Timothy, Valerie Corfield, Duangrurdee WattanasirichaigoonClive Corbett, Wilhelm Haverkamp, Eric Schulze-Bahr, Michael H. Lehmann, Ketty Schwartz, Philippe Coumel, Raffaella Bloise

Research output: Contribution to journalArticle

1241 Citations (Scopus)

Abstract

Background - The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. Methods and Results - We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498,497, and 506 ms, respectively). The percent of patients who were free of recurrence with β-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Conclusions - Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

Original languageEnglish (US)
Pages (from-to)89-95
Number of pages7
JournalCirculation
Volume103
Issue number1
DOIs
StatePublished - Jan 9 2001

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Long QT Syndrome
Genetic Association Studies
Cardiac Arrhythmias
Genes
Sleep
Exercise
Mutation
Genotype
Sudden Cardiac Death
Syncope
Arousal
Heart Arrest
Ion Channels
Genetic Therapy
Emotions
Recurrence
Mortality

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Schwartz, P. J., Priori, S. G., Spazzolini, C., Moss, A. J., Michael Vincent, G., Napolitano, C., ... Bloise, R. (2001). Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation, 103(1), 89-95. https://doi.org/10.1161/01.CIR.103.1.89

Genotype-phenotype correlation in the long-QT syndrome : Gene-specific triggers for life-threatening arrhythmias. / Schwartz, Peter J.; Priori, Silvia G.; Spazzolini, Carla; Moss, Arthur J.; Michael Vincent, G.; Napolitano, Carlo; Denjoy, Isabelle; Guicheney, Pascale; Breithardt, Günter; Keating, Mark T.; Towbin, Jeffrey; Beggs, Alan H.; Brink, Paul; Wilde, Arthur A.M.; Toivonen, Lauri; Zareba, Wojciech; Robinson, Jennifer L.; Timothy, Katherine W.; Corfield, Valerie; Wattanasirichaigoon, Duangrurdee; Corbett, Clive; Haverkamp, Wilhelm; Schulze-Bahr, Eric; Lehmann, Michael H.; Schwartz, Ketty; Coumel, Philippe; Bloise, Raffaella.

In: Circulation, Vol. 103, No. 1, 09.01.2001, p. 89-95.

Research output: Contribution to journalArticle

Schwartz, PJ, Priori, SG, Spazzolini, C, Moss, AJ, Michael Vincent, G, Napolitano, C, Denjoy, I, Guicheney, P, Breithardt, G, Keating, MT, Towbin, J, Beggs, AH, Brink, P, Wilde, AAM, Toivonen, L, Zareba, W, Robinson, JL, Timothy, KW, Corfield, V, Wattanasirichaigoon, D, Corbett, C, Haverkamp, W, Schulze-Bahr, E, Lehmann, MH, Schwartz, K, Coumel, P & Bloise, R 2001, 'Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias', Circulation, vol. 103, no. 1, pp. 89-95. https://doi.org/10.1161/01.CIR.103.1.89
Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Michael Vincent G, Napolitano C et al. Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation. 2001 Jan 9;103(1):89-95. https://doi.org/10.1161/01.CIR.103.1.89
Schwartz, Peter J. ; Priori, Silvia G. ; Spazzolini, Carla ; Moss, Arthur J. ; Michael Vincent, G. ; Napolitano, Carlo ; Denjoy, Isabelle ; Guicheney, Pascale ; Breithardt, Günter ; Keating, Mark T. ; Towbin, Jeffrey ; Beggs, Alan H. ; Brink, Paul ; Wilde, Arthur A.M. ; Toivonen, Lauri ; Zareba, Wojciech ; Robinson, Jennifer L. ; Timothy, Katherine W. ; Corfield, Valerie ; Wattanasirichaigoon, Duangrurdee ; Corbett, Clive ; Haverkamp, Wilhelm ; Schulze-Bahr, Eric ; Lehmann, Michael H. ; Schwartz, Ketty ; Coumel, Philippe ; Bloise, Raffaella. / Genotype-phenotype correlation in the long-QT syndrome : Gene-specific triggers for life-threatening arrhythmias. In: Circulation. 2001 ; Vol. 103, No. 1. pp. 89-95.
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title = "Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias",
abstract = "Background - The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ({"}triggers{"}) associated with cardiac events may in large part be gene specific. Methods and Results - We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62{\%}) during exercise, and only 3{\%} occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13{\%}) and more likely to have events during rest/sleep (29{\%} and 39{\%}). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498,497, and 506 ms, respectively). The percent of patients who were free of recurrence with β-blocker therapy was higher and the death rate was lower among LQT1 patients (81{\%} and 4{\%}, respectively) than among LQT2 (59{\%} and 4{\%}, respectively) and LQT3 (50{\%} and 17{\%}, respectively) patients. Conclusions - Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.",
author = "Schwartz, {Peter J.} and Priori, {Silvia G.} and Carla Spazzolini and Moss, {Arthur J.} and {Michael Vincent}, G. and Carlo Napolitano and Isabelle Denjoy and Pascale Guicheney and G{\"u}nter Breithardt and Keating, {Mark T.} and Jeffrey Towbin and Beggs, {Alan H.} and Paul Brink and Wilde, {Arthur A.M.} and Lauri Toivonen and Wojciech Zareba and Robinson, {Jennifer L.} and Timothy, {Katherine W.} and Valerie Corfield and Duangrurdee Wattanasirichaigoon and Clive Corbett and Wilhelm Haverkamp and Eric Schulze-Bahr and Lehmann, {Michael H.} and Ketty Schwartz and Philippe Coumel and Raffaella Bloise",
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T1 - Genotype-phenotype correlation in the long-QT syndrome

T2 - Gene-specific triggers for life-threatening arrhythmias

AU - Schwartz, Peter J.

AU - Priori, Silvia G.

AU - Spazzolini, Carla

AU - Moss, Arthur J.

AU - Michael Vincent, G.

AU - Napolitano, Carlo

AU - Denjoy, Isabelle

AU - Guicheney, Pascale

AU - Breithardt, Günter

AU - Keating, Mark T.

AU - Towbin, Jeffrey

AU - Beggs, Alan H.

AU - Brink, Paul

AU - Wilde, Arthur A.M.

AU - Toivonen, Lauri

AU - Zareba, Wojciech

AU - Robinson, Jennifer L.

AU - Timothy, Katherine W.

AU - Corfield, Valerie

AU - Wattanasirichaigoon, Duangrurdee

AU - Corbett, Clive

AU - Haverkamp, Wilhelm

AU - Schulze-Bahr, Eric

AU - Lehmann, Michael H.

AU - Schwartz, Ketty

AU - Coumel, Philippe

AU - Bloise, Raffaella

PY - 2001/1/9

Y1 - 2001/1/9

N2 - Background - The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. Methods and Results - We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498,497, and 506 ms, respectively). The percent of patients who were free of recurrence with β-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Conclusions - Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

AB - Background - The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. Methods and Results - We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498,497, and 506 ms, respectively). The percent of patients who were free of recurrence with β-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Conclusions - Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

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