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Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
Sahlgrenska Akademin Göteborgs Universitet.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
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2013 (English)In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 115, no 10, 1423-1432 p.Article in journal (Refereed) Published
Abstract [en]

Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.

Place, publisher, year, edition, pages
American Physiological Society , 2013. Vol. 115, no 10, 1423-1432 p.
Keyword [en]
electrocardiography, electrophysiology, long QT syndrome, diagnosis, arrhythmia, genes, mutation
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:umu:diva-80102DOI: 10.1152/japplphysiol.00665.2013OAI: oai:DiVA.org:umu-80102DiVA: diva2:646503
Funder
Swedish Heart Lung Foundation
Available from: 2013-09-09 Created: 2013-09-09 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Long QT syndrome: studies of diagnostic methods
Open this publication in new window or tab >>Long QT syndrome: studies of diagnostic methods
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: The Long QT Syndrome (LQTS) is a hereditary heart disease with risk of malignant ventricular arrhythmia and sudden cardiac death. Despite our increased knowledge about genotype and phenotype correlation we still rely on the 12-lead ECG for assessment of the QT interval and the T-wave morphology for diagnosis and risk stratification. Intra- and -inter individual variability in manually QT measurement and, e.g., difficulties in defining the end of the T-wave may impair the diagnosis of LQTS. Increased heterogeneity in ventricular repolarization (VR) may be an important factor in the arrhythmogenicity in cases of LQTS. In a LQTS founder population the same mutation is carried by numerous individuals in many families which provide a unique opportunity to study diagnostic methods, risk assessment, VR and the correlation between genotype and phenotype.

Methods: Resting 12-lead ECG and vectorcardiogram (VCG) were recorded in 134 LQTS mutation carriers and 121 healthy controls, to investigate the capability and precision in measuring the QT interval. For assessment of the VR, VCG was compared in individuals with mutations in the KCNQ1 and KCNH2 gene. Genealogical and geographic studies were performed in 37 index cases and their relatives to determine if Swedish carriers of the Y111C mutation in the KCNQ1 gene constitute a founder population. To confirm kinship, haplotype analysis was performed in 26 of the 37 index cases. The age and prevalence of the Y111C mutation were calculated in families sharing a common haplotype.

Results: VCG by automatic measurement of the QT interval provided the best combination of sensitivity (90%) and specificity (89%) in the diagnosis of LQTS. VCG showed no consistent pattern of increased VR heterogeneity among KCNQ1 and KCNH2 mutation carriers. Living carriers of the Y111C mutation shared a common genetic (haplotype), genealogic and geographic origin. The age of the Y111C mutation was approximately 600 years. The prevalence of living carriers of the Y111C mutation in the mid-northern Sweden was estimated to 1:1,500-3,000.

Conclusion: We have shown that VCG provides a valuable contribution to the diagnosis and risk assessment of LQTS in adults and children. No consistent pattern of increased VR heterogeneity was found among the LQTS mutation carriers. The identified Swedish LQTS founder population will be a valuable source to future LQTS research and may contribute to increase our understanding of LQTS and the correlation of phenotype, genotype and modifying factors.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. 67 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1583
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-80103 (URN)978-91-7459-693-9 (ISBN)
Public defence
2013-10-04, Hörsal D, Unod T 9, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
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Available from: 2013-09-12 Created: 2013-09-09 Last updated: 2013-09-12Bibliographically approved

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