Genotype-Phenotype Correlation in the Long-QT Syndrome: Gene-Specific Triggers for Life-Threatening Arrhythmias
Open accessAbstract
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 ss-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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AF prevalence in long QT syndrome is 5-10%.
“Long QT syndrome KCNQ1 KCNH2 SCN5A ANK2 others IKs IKr INa INa,K Various effects 5-10% 846-850”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [850]
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- Authors
- Schwartz, P. J., Priori, S. G., Spazzolini, C., Moss, A. J., Vincent, G. M., Napolitano, C., Denjoy, I., Guicheney, P., Breithardt, G., Keating, M. T., Towbin, J. A., Beggs, A. H., Brink, P., Wilde, A. A. M., Toivonen, L., Zareba, W., Robinson, J. L., Timothy, K. W., Corfield, V., Wattanasirichaigoon, D., Corbett, C., Haverkamp, W., Schulze-Bahr, E., Lehmann, M. H., Schwartz, K., Coumel, P., & Bloise, R.
- Affiliations
- University of Utah (US)
- From the Department of Cardiology (P.J.S., C.S., R.B.), Policlinico S. Matteo IRCCS and University of Pavia, Pavia, Italy; Molecular Cardiology Laboratories (S.G.P., C.N.), IRCCS Fondazione “S. Maugeri,” Pavia, Italy; Department of Medicine (A.J.M., W.Z., J.L.R.), University of Rochester School of Medicine and Dentistry, Rochester, NY; Department of Medicine (M.V., K.W.T.), University of Utah School of Medicine (Salt Lake City); Service de Cardiologie (I.D., P.C.), Hôpital Lariboisière, Paris,...
- ORCID
- Venue
- Circulation
- Published
- 2001-01-02
- Volume
- 103
- Issue
- 1
- Pages
- 89-95
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2097912415
- Cited by
- 1,779
- References
- 23
- Citations by year
- 2026: 41 · 2025: 39 · 2024: 52 · 2023: 40 · 2022: 62 · 2021: 63 · 2020: 81 · 2019: 42 · 2018: 63 · 2017: 78 · 2016: 78 · 2015: 69 · 2014: 63 · 2013: 86 · 2012: 96
- FWCI
- 55.51
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute (HL 33843, HL 51618, R01HL051618, R01HL033843)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Keywords
- long QT syndrome, genotype-phenotype correlation, LQT1, long QT syndrome type 2, long QT syndrome type 3, cardiac ion channel mutations, exercise-induced arrhythmia, sudden cardiac death, syncope, cardiac arrest, beta-blocker therapy, QTc interval, arrhythmia triggers
- MeSH terms
- Adrenergic beta-Antagonists, Adult, Arrhythmias, Cardiac, Electrocardiography, Emotions, Female, Genotype, Humans, Ion Channels, Long QT Syndrome, Male, Phenotype, Sex Factors, Sleep, Syncope, Exercise, Survival Rate, Death, Sudden, Cardiac
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