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Long QT syndrome: studies of diagnostic methods
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
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: urn:nbn:se:umu:diva-80103ISBN: 978-91-7459-693-9 (print)OAI: oai:DiVA.org:umu-80103DiVA: diva2:646532
Public defence
2013-10-04, Hörsal D, Unod T 9, Norrlands Universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-09-12 Created: 2013-09-09 Last updated: 2013-09-12Bibliographically approved
List of papers
1. Two automatic QT algorithms compared with manual measurement in identification of long QT syndrome
Open this publication in new window or tab >>Two automatic QT algorithms compared with manual measurement in identification of long QT syndrome
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2010 (English)In: Journal of Electrocardiology, ISSN 0022-0736, E-ISSN 1532-8430, Vol. 43, no 1, 25-30 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Long QT syndrome (LQTS) is an inherited disorder that increases the risk of syncope and malignant ventricular arrhythmias, which may result in sudden death.

METHODS: We compared manual measurement by 4 observers (QT(manual)) and 3 computerized measurements for QT interval accuracy in the diagnosis of LQTS: 1. QT measured from the vector magnitude calculated from the 3 averaged orthogonal leads X, Y, and Z (QTVCG) and classified using the same predefined QTc cut-points for classification of QT prolongation as in manual measurements; 2. QT measured by a 12-lead electrocardiogram (ECG) program (QTECG) and subsequently classified using the same cut-points as in (1) above; 3. The same QT value as in (2) above, automatically classified by a 12-lead ECG program with thresholds for QT prolongation adjusted for age and sex (QTinterpret). The population consisted of 94 genetically confirmed carriers of KCNQ1 (LQT1) and KCNH2 (LQT2) mutations and a combined control group of 28 genetically confirmed noncarriers and 66 unrelated healthy volunteers.

RESULTS: QT(VCG) provided the best combination of sensitivity (89%) and specificity (90%) in diagnosing LQTS, with 0.948 as the area under the receiver operating characteristic curve. The evaluation of QT measurement by the 4 observers revealed a high interreader variability, and only 1 of 4 observers showed acceptable level of agreement in LQTS mutation carrier identification (kappa coefficient >0.75).

CONCLUSION: Automatic QT measurement by the Mida1000/CoroNet system (Ortivus AB, Danderyd, Sweden) is an accurate, efficient, and easily applied method for initial screening for LQTS.

Keyword
Long QT syndrome, QT interval, Automatic measurement, Vectorcardiography, Mutation analysis
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-32965 (URN)10.1016/j.jelectrocard.2009.09.008 (DOI)20005993 (PubMedID)
Available from: 2010-03-31 Created: 2010-03-31 Last updated: 2017-12-12Bibliographically approved
2. Vectorcardiographic recordings of the Q-T interval in a pediatric long Q-T syndrome population
Open this publication in new window or tab >>Vectorcardiographic recordings of the Q-T interval in a pediatric long Q-T syndrome population
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2013 (English)In: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 34, no 2, 245-249 p.Article in journal (Refereed) Published
Abstract [en]

Measurements of the Q-T interval are less reliable in children than in adults. Identification of superior diagnostic tools is warranted. This study aimed to investigate whether a vectorcardiogram (VCG) recorded from three orthogonal leads (X, Y, Z) according to Frank is superior to a 12-lead electrocardiogram (ECG) in providing a correct long Q-T syndrome (LQTS) diagnosis in children. This LQTS group consisted of 35 genetically confirmed carriers of mutations in the KCNQ1 (n = 29) and KCNH2 (n = 6) genes. The control group consisted of 35 age- and gender-matched healthy children. The mean age was 7 years in the LQTS group and 6.7 years in the control group (range, 0.5-16 years). The corrected Q-T interval (QT(c)) was measured manually (QT(man)) by one author (A.W.). The 12-lead ECG automatic measurements (QT(ECG)) and interpretation (QT(Interpret)) of QT(c) were performed with the Mac5000 (GE Medical System), and the VCG automatic measurements (QT(VCG)) were performed with the Mida1000, CoroNet (Ortivus AB, Sweden). By either method, a QT(c) longer than 440 ms was considered prolonged and indicative of LQTS. Of the 35 children with genetically confirmed LQTS, 30 (86 %) received a correct diagnosis using QT(VCG), 29 (82 %) using QT(man), 24 (69 %) using QT(ECG), and 17 (49 %) using QT(Interpret). Specificity was 0.80 for QT(VCG), 0.83 for QT(man), 0.77 for QT(ECG), and 0.83 for QT(Interpret). The VCG automatic measurement of QT(c) seems to be a better predictor of LQTS than automatic measurement and interpretation of 12-lead ECG.

Keyword
Children, Electrocardiogram, Long QT syndrome, QT, Vectorcardiogram
National Category
Cardiac and Cardiovascular Systems Pediatrics
Identifiers
urn:nbn:se:umu:diva-67401 (URN)10.1007/s00246-012-0425-2 (DOI)000315036500007 ()
Available from: 2013-04-09 Created: 2013-03-18 Last updated: 2017-12-06Bibliographically approved
3. Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene
Open this publication in new window or tab >>Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene
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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
Keyword
electrocardiography, electrophysiology, long QT syndrome, diagnosis, arrhythmia, genes, mutation
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:umu:diva-80102 (URN)10.1152/japplphysiol.00665.2013 (DOI)
Funder
Swedish Heart Lung Foundation
Available from: 2013-09-09 Created: 2013-09-09 Last updated: 2017-12-06Bibliographically approved
4. Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation
Open this publication in new window or tab >>Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation
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2011 (English)In: Heart Rhythm, ISSN 1547-5271, E-ISSN 1556-3871, Vol. 8, no 4, 541-547 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro albeit a benign clinical phenotype in a Swedish Long QT Syndrome population.

OBJECTIVE: To investigate the origin (genealogic, geographic, genetic and age) of the Y111C/KCNQ1 mutation in Sweden.

METHODS: We identified 170 carriers of the Y111C/KCNQ1 mutation in 37 Swedish proband families. Genealogical investigation was performed in all families. Haplotype analysis was performed in 26 probands, 21 family members and 84 healthy Swedish controls, using 15 satellite markers flanking the KCNQ1 gene. Mutation age was estimated using the ESTIAGE and DMLE computer softwares and regional population demographics data.

RESULTS: All probands were traced back to a northern river valley region. A founder couple born in 1605/1614 connected 26/37 families. Haplotyped probands shared 2-14 (median 10) uncommon alleles, with frequencies ranging between 0.01-0.41 (median 0.16) in the controls. The age of the mutation was estimated to 24 generations (95% CI 18; 34), i.e. 600 years (95% CI 450; 850) if assuming 25 years per generation. The number of now living Swedish Y111C mutation-carriers was estimated to ~200-400 individuals for the mutation age span 22-24 generations and population growth rates 25-27%.

CONCLUSIONS: The Y111C/KCNQ1 mutation is a Swedish LQTS founder mutation, introduced in the northern population approximately 600 years ago. The enrichment of the mutation was enabled by a mild clinical phenotype and strong regional founder effects during the population development of the northern inland. The Y111C/KCNQ1 founder population constitutes an important asset for future genetic and clinical studies.

Place, publisher, year, edition, pages
Elsevier, 2011
Keyword
Dominant-negative mutation, Founder mutation, Gene mutation, Ion channel, Long QT syndrome
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-39709 (URN)10.1016/j.hrthm.2010.11.043 (DOI)21129503 (PubMedID)
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2017-12-11Bibliographically approved

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