Publications by authors named "Britt-Maria Beckmann"

31 Publications

Molecular Mechanism of Autosomal Recessive Long QT-Syndrome 1 without Deafness.

Int J Mol Sci 2021 Jan 23;22(3). Epub 2021 Jan 23.

Institute for Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, 35037 Marburg, Germany.

encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current , which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in result in long QT syndrome, called Romano-Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in oocytes, are in agreement with an autosomal recessive disorder, since the reduction was only observed in homomeric mutants, but not in heteromeric channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment.
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http://dx.doi.org/10.3390/ijms22031112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865240PMC
January 2021

Characterization of an N-terminal Na1.5 channel variant - a potential risk factor for arrhythmias and sudden death?

BMC Med Genet 2020 11 19;21(1):227. Epub 2020 Nov 19.

Institute of Legal Medicine, Goethe University of Frankfurt, Kennedyallee 104, 60596, Frankfurt am Main, Germany.

Background: Alterations in the SCN5A gene encoding the cardiac sodium channel Na1.5 have been linked to a number of arrhythmia syndromes and diseases including long-QT syndrome (LQTS), Brugada syndrome (BrS) and dilative cardiomyopathy (DCM), which may predispose to fatal arrhythmias and sudden death. We identified the heterozygous variant c.316A > G, p.(Ser106Gly) in a 35-year-old patient with survived cardiac arrest. In the present study, we aimed to investigate the functional impact of the variant to clarify the medical relevance.

Methods: Mutant as well as wild type GFP tagged Na1.5 channels were expressed in HEK293 cells. We performed functional characterization experiments using patch-clamp technique.

Results: Electrophysiological measurements indicated, that the detected missense variant alters Nav1.5 channel functionality leading to a gain-of-function effect. Cells expressing S106G channels show an increase in Na1.5 current over the entire voltage window.

Conclusion: The results support the assumption that the detected sequence aberration alters Na1.5 channel function and may predispose to cardiac arrhythmias and sudden cardiac death.
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http://dx.doi.org/10.1186/s12881-020-01170-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678220PMC
November 2020

Left-ventricular innervation assessed by I-SPECT/CT is associated with cardiac events in inherited arrhythmia syndromes.

Int J Cardiol 2020 08 6;312:129-135. Epub 2020 Mar 6.

Department of Cardiology and Vascular Medicine, West-German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany; Department of Medicine I, University Hospital Munich, Ludwig-Maximilians University, Munich, Germany; German Cardiovascular Research Center (DZHK), Munich Heart Alliance, Munich, Germany. Electronic address:

Aims: Impaired myocardial sympathetic innervation assessed by Iodine-Metaiodobenzylguanidine (I-MIBG) scintigraphy is associated with cardiac events. Since regional disparities of structural abnormalities are common in inherited arrhythmia syndromes (iAS), a chamber-specific innervation assessment of the right (RV) and left ventricle (LV) could provide important insights for a patient-individual therapy. Aim of this study was to evaluate chamber-specific patterns of autonomic innervation by Single-photon emission computed tomography/computed tomography (SPECT/CT) in patients with iAS with respect to clinical outcome regarding cardiac events.

Methods And Results: We assessed ventricular sympathetic innervation (LV, RV and planar heart/mediastinum-ratios, and washout-rates) by I-MIBG-SPECT/CT in 48 patients (arrhythmogenic right ventricular cardiomyopathy [ARVC], n = 26; laminopathy, n = 8; idiopathic ventricular fibrillation [iVF], n = 14) in relation to a composite clinical endpoint (ventricular arrhythmia; cardiac death; cardiac hospitalization). RV tracer uptake was lower in patients with ARVC than in laminopathy and iVF patients (1.7 ± 0.4 vs. 2.1 ± 0.7 and 2.1 ± 0.5, respectively). Over a median follow-up of 2.2 years, the combined endpoint was met in 18 patients (n = 12 ventricular tachyarrhythmias, n = 5 hospitalizations, n = 1 death). LV, but not RV H/M ratio was associated with the combined endpoint (hazard-ratio 2.82 [1.30-6.10], p < 0.01). After adjustment for LV and RV function, LV H/M-ratio still remained a significant predictor for cardiac events (hazard-ratio 2.79 [1.06-7.35], p = 0.04).

Conclusion: We demonstrated that chamber-specific MIBG-SPECT/CT imaging is feasible and that reduced LV sympathetic innervation was associated with worse outcome in iAS. These findings provide novel insights into the potential role of regional autonomic nervous system heterogeneity for the evolution of life-threatening cardiac events in iAS.
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http://dx.doi.org/10.1016/j.ijcard.2020.03.013DOI Listing
August 2020

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

Eur Heart J 2019 09;40(35):2964-2975

Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.

Aims: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.

Methods And Results: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.

Conclusion: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.
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http://dx.doi.org/10.1093/eurheartj/ehz311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748747PMC
September 2019

Sudden unexpected death in the young - Value of massive parallel sequencing in postmortem genetic analyses.

Forensic Sci Int 2018 Dec 26;293:70-76. Epub 2018 Oct 26.

Institute of Legal Medicine, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.

Cases of sudden cardiac death (SCD) in young and apparently healthy individuals represent a devastating event in affected families. Hereditary arrhythmia syndromes, which include primary electrical heart disorders as well as cardiomyopathies, are known to contribute to a significant number of these sudden death cases. We performed postmortem genetic analyses in young sudden death cases (aged <45years) by means of a defined gene panel using massive parallel sequencing (MPS). The data were evaluated bioinformatically and detected sequence variants were assessed using common databases and applying in silico prediction tools. In this study, we identified variants with likely pathogenic effect in 6 of 9 sudden unexpected death (SUD) cases. Due to the detection of numerous unknown and unclassified variants, interpretation of the results proved to be challenging. However, by means of an appropriate evaluation of the findings, MPS represents an important tool to support the forensic investigation and implies great progress for relatives of young SCD victims facilitating adequate risk stratification and genetic counseling.
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http://dx.doi.org/10.1016/j.forsciint.2018.09.034DOI Listing
December 2018

Characterization of a novel KCNJ2 sequence variant detected in Andersen-Tawil syndrome patients.

BMC Med Genet 2017 10 10;18(1):113. Epub 2017 Oct 10.

Institute of Legal Medicine, University Hospital Frankfurt, Goethe University, Kennedyallee 104, D-60596, Frankfurt, Germany.

Background: Mutations in the KCNJ2 gene encoding the ion channel Kir2.1 have been linked to the Andersen-Tawil syndrome (ATS). Molecular genetic screening performed in a family exhibiting clinical ATS phenotypes unmasked a novel sequence variant (c.434A > G, p.Y145C) in this gene. The aim of this study was to investigate the effect of this variant on Kir2.1 ion channel functionality.

Methods: Mutant as well as wild type GFP tagged Kir2.1 channels were expressed in HEK293 cells. In order to examine the effect of the new variant, electrophysiological measurements were performed using patch clamp technique. Cellular localization of the mutant in comparison to the wild type ion channel was analyzed by confocal laser scanning microscopy.

Results: The currents of cells expressing only mutant channels or a mixture of wild type and mutant were significantly reduced compared to those expressing wild type (WT) channels (p < 0.01). Whereas WT expressing cells exhibited at -120 mV an averaged current of -4.5 ± 1.9 nA, the mutant generates only a current of -0.17 ± 0.07 nA. A co-expression of mutant and WT channel generates only a partial rescue of the WT current. Confocal laser scanning microscopy indicated that the novel variant is not interfering with synthesis and/or protein trafficking.

Conclusions: The detected sequence variant causes loss-of-function of the Kir2.1 channel and explains the clinical phenotypes observed in Andersen-Tawil syndrome patients.
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http://dx.doi.org/10.1186/s12881-017-0472-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634867PMC
October 2017

Relevance of molecular testing in patients with a family history of sudden death.

Forensic Sci Int 2017 Jul 13;276:18-23. Epub 2017 Apr 13.

Kerckhoff Heart and Thorax Center, Benekestraße 2, 61231 Bad Nauheim, Germany.

Sudden cardiac death (SCD) is a major cause of death in industrial countries. Although SCD occurs mainly in adults, it may also affect young persons, where genetic cardiac disorders comprise at least half of these cases. This includes primary arrhythmogenic disorders such as long QT syndrome and inherited cardiomyopathies. However, in many cases, postmortem examinations provide no conclusive results explaining the cause of death. Since family members of the deceased may eventually have inherited the same disease, they are at risk of SCD. In the present study, 28 patients with a family history of sudden unexplained death (SUD), of survived cardiac arrest and with a clinical diagnosis of an inherited cardiac disease were screened using phenotype-guided molecular analysis of genes associated with arrhythmogenic cardiac diseases. In 64% of the cases, gene variants with potentially pathogenic cardiac effects were detected suggesting that an arrhythmia syndrome may have caused the death of the deceased family member. Therefore, we recommend that relatives of SUD victims should undergo extended cardiac examination and, depending on the clinical diagnosis, a targeted genetic analysis should follow, which is crucial to identify family members at risk.
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http://dx.doi.org/10.1016/j.forsciint.2017.04.001DOI Listing
July 2017

Electrophysiological characterization of a large set of novel variants in the SCN5A-gene: identification of novel LQTS3 and BrS mutations.

Pflugers Arch 2016 08 11;468(8):1375-87. Epub 2016 Jun 11.

Institute of Physiology and Pathophysiology, Vegetative Physiology, Philipps-University of Marburg, Deutschhausstraße 1-2, 35037, Marburg, Germany.

SCN5A encodes for the α-subunit of the cardiac voltage-gated sodium channel Nav1.5. Gain-of-function mutations in SCN5A are related to congenital long QT syndrome (LQTS3) characterized by delayed cardiac repolarization, leading to a prolonged QT interval in the ECG. Loss-of-function mutations in SCN5A are related to Brugada syndrome (BrS), characterized by an ST-segment elevation in the right precordial leads (V1-V3). The aim of this study was the characterization of a large set of novel SCN5A variants found in patients with different cardiac phenotypes, mainly LQTS and BrS. SCN5A variants of 13 families were functionally characterized in Xenopus laevis oocytes using the two-electrode voltage-clamp technique. We found in most of the cases, but not all, that the electrophysiology of the variants correlated with the clinically diagnosed phenotype. A susceptibility to develop LQTS can be suggested in patients carrying the variants S216L, K480N, A572D, F816Y, and G983D. However, taking the phenotype into account, the presence of the variants in genomic data bases, the mutational segregation, combined with our in vitro and in silico experiments, the variants S216L, S262G, K480N, A572D, F816Y, G983D, and T1526P remain as variants of unknown significance. However, the SCN5A variants R568H and A993T can be classified as pathogenic LQTS3 causing mutations, while R222stop and R2012H are novel BrS causing mutations.
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http://dx.doi.org/10.1007/s00424-016-1844-3DOI Listing
August 2016

Early repolarization pattern is the strongest predictor of arrhythmia recurrence in patients with idiopathic ventricular fibrillation: results from a single centre long-term follow-up over 20 years.

Europace 2016 May 11;18(5):718-25. Epub 2016 Jan 11.

Department of Medicine I, University Hospital Munich, Ludwig Maximilians University, Munich, Germany Deutsches Zentrum für Herz-Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.

Aims: Idiopathic ventricular fibrillation (iVF) accounts for up to 14% of VF incidence. Data regarding long-term outcome and clinical risk markers of arrhythmia recurrence are scarce. The objective of our study was to describe a long-term follow-up (FU) of a cohort of iVF survivors in our centre during the past 20 years, and to investigate the influence of clinical parameters, e.g. presence of an early repolarization pattern (ERP), on recurrence rate of arrhythmias.

Methods And Results: Thirty-five iVF survivors were identified and retrospectively analysed regarding recurrent implantable cardioverter-defibrillator (ICD) interventions and covariates potentially influencing arrhythmia recurrence. Appropriate ICD interventions occurred in 15 patients (43%) after a median of 6.6 years during a median FU period of 8.8 years. Two patients (13%) received the first appropriate therapy after an assumed average ICD battery longevity of 7 years, while in all other patients, the first therapy occurred within the first ICD period. Appropriate interventions were observed more often and earlier in patients with ERP (HR 3.9; 1.4-11.0; P = 0.01), whereas all other covariates failed to predict subsequent events. A high incidence of inappropriate ICD therapies (67 interventions in 14 patients) could be attributed to the occurrence of atrial fibrillation (66% of all inappropriate therapies).

Conclusion: The recurrence rate of ventricular arrhythmias in iVF survivors is high and recurrence might occur delayed (>7 years after the initial event). ERP seems to be highly predictive with respect to early arrhythmia recurrence. Our results highlight that better pathophysiologic understanding of ERP might facilitate a better risk stratification before and an optimal treatment after an iVF event. The high rate of AF and ERP in iVF survivors might indicate an underlying heart disease or myocardial electrical disorder not apparent at the index event.
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http://dx.doi.org/10.1093/europace/euv301DOI Listing
May 2016

Early repolarization pattern: a marker of increased risk in patients with catecholaminergic polymorphic ventricular tachycardia.

Europace 2016 Oct 23;18(10):1587-1592. Epub 2015 Dec 23.

University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.

Aims: The early repolarization pattern (ERP) has been shown to be associated with arrhythmias in patients with short QT syndrome, Brugada syndrome, and ischaemic heart disease. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome and related to malignant ventricular tachyarrhythmias in a structurally normal heart. The aim of this study was to evaluate the prevalence of ERP and clinical events in patients with CPVT.

Methods And Results: Digitalized resting 12-lead ECGs of patients were analysed for ERP and for repolarization markers (QT and T-T interval). The ERP was diagnosed as 'notching' or 'slurring' at the terminal portion of QRS with ≥0.1 mV elevation in at least two consecutive inferior (II, III, aVF) and/or lateral leads (V4-V6, I, aVL). Among 51 CPVT patients (mean age 36 ± 15 years, 11 males), the ERP was present in 23 (45%): strictly in the inferior leads in 9 (18%) patients, in the lateral leads in 9 (18%) patients, and in infero-lateral leads in 5 (10%) patients. All patients with ERP were symptomatic at presentation (23 of 23 patients with ERP vs. 19 of 28 patients without ERP, P = 0.003). Syncope was also more frequent in patients with ERP (18 of 23 patients with ERP vs. 11 of 28 patients without ERP, P = 0.005).

Conclusion: A pathologic ERP is present in an unexpected large proportion (45%) of patients and is associated with an increased frequency of syncope. In patients with unexplained syncope and ERP at baseline, exercise testing should be performed to detect CPVT.
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http://dx.doi.org/10.1093/europace/euv357DOI Listing
October 2016

Purkinje-related ventricular fibrillation associated with a homozygous H558R polymorphism in the sodium channel SCN5A gene.

Europace 2016 Jun 17;18(6):896. Epub 2015 Jun 17.

Medizinische Klinik I, Klinikum Grosshadern, Ludwig-Maximilians Universität München, DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.

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http://dx.doi.org/10.1093/europace/euv134DOI Listing
June 2016

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Nat Genet 2014 Aug 22;46(8):826-36. Epub 2014 Jun 22.

Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated institute of the University of Lübeck, Lübeck, Germany).

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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http://dx.doi.org/10.1038/ng.3014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124521PMC
August 2014

Novel calmodulin mutations associated with congenital arrhythmia susceptibility.

Circ Cardiovasc Genet 2014 Aug 10;7(4):466-74. Epub 2014 Jun 10.

Background: Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations.

Methods And Results: We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity.

Conclusions: CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140998PMC
August 2014

Clinical utility gene card for: long-QT syndrome (types 1-13).

Eur J Hum Genet 2013 Oct 20;21(10). Epub 2013 Mar 20.

Department of Medicine 1, University Hospital of the Ludwig Maximilians University-Campus Grosshadern, Munich, Germany.

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http://dx.doi.org/10.1038/ejhg.2013.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778358PMC
October 2013

Calmodulin mutations associated with recurrent cardiac arrest in infants.

Circulation 2013 Mar 6;127(9):1009-17. Epub 2013 Feb 6.

Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Background: Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause.

Methods And Results: We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity.

Conclusions: Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.001216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834768PMC
March 2013

[Genetic testing in hereditary arrythmia syndromes today and in the future].

Herzschrittmacherther Elektrophysiol 2012 Sep 20;23(3):161-6. Epub 2012 Sep 20.

Medizinische Klinik und Poliklinik I, Ludwig-Maximilians-Universität München, D-81377, München, Germany.

Genetic testing already has a substantial impact in identifying hereditary arrhythmia syndromes after sudden death in young patients. This report provides information on current developments, available options and reasonable approaches in the clinical setting. In addition the limitations of genetic testing are discussed. Genetic testing is only useful for patients in the context of clinical findings interpreted by an experienced cardiogenetics team.
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http://dx.doi.org/10.1007/s00399-012-0230-xDOI Listing
September 2012

A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern.

Heart Rhythm 2012 Oct 6;9(10):1627-34. Epub 2012 Jun 6.

Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.

Background: The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases.

Objective: To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP.

Methods: We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages.

Results: Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance.

Conclusions: In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.
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http://dx.doi.org/10.1016/j.hrthm.2012.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459269PMC
October 2012

A large candidate gene survey identifies the KCNE1 D85N polymorphism as a possible modulator of drug-induced torsades de pointes.

Circ Cardiovasc Genet 2012 Feb 18;5(1):91-9. Epub 2011 Nov 18.

Department of Medicine I, University Hospital Munich, Campus Grosshadern, Ludwig-Maximilians University, Munich, Germany.

Background: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS.

Methods And Results: In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects.

Conclusions: This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.
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http://dx.doi.org/10.1161/CIRCGENETICS.111.960930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288202PMC
February 2012

Inherited cardiac arrhythmias: diagnosis, treatment, and prevention.

Dtsch Arztebl Int 2011 Sep 16;108(37):623-33; quiz 634. Epub 2011 Sep 16.

Medizinische Klinik und Poliklinik 1, Ludwig-Maximilians-Universität München.

Background: The incidence of sudden cardiac death in persons under age 40 is roughly 3 per 100 000 persons per year in Germany and North America. Many of these deaths are found to be due to hereditary heart diseases, often a primary structural heart disease associated with arrhythmia or else a primary arrhythmia syndrome in a structurally normal heart. Such diseases are usually of autosomal dominant inheritance, often affect otherwise healthy persons, and can generally be well treated if recognized early. Patients commonly have affected relatives who are still asymptomatic.

Methods: This review is based on articles up to May 2010 that were retrieved by a selective search of the Medline database via PubMed, with additional consideration of the relevant European and American guidelines and the German Law on Genetic Diagnosis.

Results And Conclusion: Hereditary arrhythmia syndromes are now found in more than half of all initially unexplained cases of sudden cardiac death in young persons. Among such cases, the hereditary arrhythmia syndrome is primary in 70% and caused by an arrhythmogenic structural heart disease in 30%. In addition to autopsy findings, a thorough family history, relevant medical findings obtained during life (if available), the examination of relatives, and directed molecular testing where appropiate enabled establishing the diagnosis. Arrthymia syndromes that can cause sudden death are often detectable during life if physicians and the public are appropriately sensitized.
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http://dx.doi.org/10.3238/arztebl.2011.0623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187620PMC
September 2011

Recurrent torsades de pointes after catheter ablation of incessant ventricular bigeminy in combination with QT prolongation.

Europace 2012 Feb 8;14(2):299-300. Epub 2011 Sep 8.

Medizinische Klinik I, Klinikum München Pasing, Akademisches Lehrkrankenhaus der Universität München, Steinerweg 5, 81241 München, Germany.

A 45-year-old woman, who had received a single-chamber implantable cardioverter defibrillator (ICD) due to ventricular fibrillation 5 years ago, was admitted for catheter ablation of incessant right ventricular outflow tract bigeminy. After successful ablation recurrent torsades de pointes associated with a prolonged corrected QT (QTc) interval were initiated by polymorphic premature ventricular complexes. Genetic testing revealed a heterozygous missense mutation in the SCN5A-gene (p.Arg190Gln, Exon 5), consistent with long QT-syndrome 3. DDDR pacing following implantation of an atrial lead prevented further ventricular tachyarrhythmias.
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http://dx.doi.org/10.1093/europace/eur278DOI Listing
February 2012

Lack of replication in polymorphisms reported to be associated with atrial fibrillation.

Heart Rhythm 2011 Mar 4;8(3):403-9. Epub 2010 Nov 4.

Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany.

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia and has a substantial heritable component. Numerous associations between single nucleotide polymorphisms (SNPs) and AF have been described, but few have been replicated.

Objective: We sought to systematically replicate SNPs that are reported to be associated with AF in two large study samples of European descent.

Methods: We searched PubMed for studies reporting associations between SNPs and AF published before July 1, 2007. SNPs were genotyped in two independent case-control samples from Germany and the United States. Associations between SNPs and AF were assessed using logistic regression models adjusting for age, sex, and hypertension. A meta-analysis of the results from the two studies was performed.

Results: We identified 21 SNPs and the angiotensin-converting enzyme insertion/deletion polymorphism that were reported to be associated with AF in the literature. Nine of these genetic variants were not represented on common genome-wide SNP arrays. We successfully genotyped 21 of these 22 variants in 2,145 cases with AF from the German Competence Network for Atrial Fibrillation and 4,073 controls from the KORA S4 study and 16 variants in 790 cases and 1,330 controls from the Massachusetts General Hospital. None of the SNPs replicated in independent populations with AF.

Conclusion: Our results suggest that previously reported associations to AF were likely false positives and highlight the need for systematic replication of genetic associations in large, independent cohorts to accurately detect variants associated with disease.
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http://dx.doi.org/10.1016/j.hrthm.2010.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068750PMC
March 2011

Association of early repolarization pattern on ECG with risk of cardiac and all-cause mortality: a population-based prospective cohort study (MONICA/KORA).

PLoS Med 2010 Jul 27;7(7):e1000314. Epub 2010 Jul 27.

University Hospital Munich, Campus Grosshadern, Medical Department I, Ludwig-Maximilians University Munich, Munich, Germany.

Background: Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent.

Methods And Findings: Electrocardiograms of 1,945 participants aged 35-74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05-3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21-5.83, p = 0.015) for men between 35-54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58-6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90-9.61, p<0.001) for men between 35-54 y. HRs for all-cause mortality were weaker but reached significance.

Conclusions: We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors' Summary.
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http://dx.doi.org/10.1371/journal.pmed.1000314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910598PMC
July 2010

Usefulness of short-term variability of QT intervals as a predictor for electrical remodeling and proarrhythmia in patients with nonischemic heart failure.

Am J Cardiol 2010 Jul;106(2):216-20

Department of Medicine I, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany.

The high incidence of sudden cardiac death in heart failure (HF) reflects electrophysiologic changes in response to myocardial failure. We previously showed that short-term variability of QT intervals (STV(QT)) identifies latent repolarization disorders in patients with drug-induced or congenital long QT syndrome. This study sought to determine (1) if STV(QT) is increased in patients with dilated cardiomyopathy (DC) and moderate congestive HF and (2) if increased STV(QT) is associated with ventricular arrhythmia in patients with HF. Sixty patients (53 +/- 12 years of age, 14 women) with DC and moderate HF (New York Heart Association classes II to III) were compared to matched controls. Twenty patients had implantable cardiac defibrillators secondary to a history of ventricular tachycardia (VT). Two cardiologists blinded to diagnosis manually measured QT intervals. Beat-to-beat variability of repolarization was determined from Poincaré plots of 30 consecutive QT intervals as was STV(QT). QTc intervals were comparable in patients and controls (419 +/- 36 vs 415 +/- 32 ms, respectively, p >0.05), whereas STV(QT) was significantly higher in patients with HF (7.8 +/- 3 vs 4.1 +/- 2 ms, respectively, p <0.05). STV(QT) was more increased in patients with a history of VT compared to those without VT (10.1 +/- 2 vs 6.6 +/- 2 ms, respectively, p <0.05). Increased STV(QT) and decreased ejection fraction were associated with a history of VT; however, STV(QT) was the strongest indicator. In conclusion, the present study demonstrates for the first time that STV(QT) is increased in patients with DC with HF. Patients with DC and HF and implantable cardiac defibrillators for secondary prevention had the highest STV(QT). Thus, increased STV(QT) in the context of moderate HF may reflect a latent repolarization disorder and increased susceptibility to sudden death in patients with DC, which is not identified by a prolonged QT interval.
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http://dx.doi.org/10.1016/j.amjcard.2010.02.033DOI Listing
July 2010

Laminopathy presenting as familial atrial fibrillation.

Int J Cardiol 2010 Nov 15;145(2):394-396. Epub 2010 May 15.

Department of Medicine I, Klinikum Grosshadern of the Ludwig Maximilians University of Munich, Germany.

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http://dx.doi.org/10.1016/j.ijcard.2010.04.024DOI Listing
November 2010

Spontaneous Brugada electrocardiogram patterns are rare in the German general population: results from the KORA study.

Europace 2009 Oct 4;11(10):1338-44. Epub 2009 Aug 4.

Department of Medicine I, University Hospital Munich, Campus Grosshadern, Munich, Germany.

Aims: The Brugada syndrome is a rare, potentially fatal primary cardiomyopathy. Patients are identified by symptoms and typical electrocardiogram (ECG) patterns. Prevalence of spontaneous Brugada ECG patterns in the general population is unknown.

Methods And Results: We analysed 12-lead resting ECGs of 4149 men and women aged 25-74 years from the population-based KORA Study. Computer-assisted analysis identified ECGs with J-point elevation in leads V1-V3 and QRS duration
Conclusion: Spontaneous Brugada ECG patterns are rare in the general population and may hence constitute a relevant biological signal. Computer-aided analysis can help to identify abnormal ECGs.
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http://dx.doi.org/10.1093/europace/eup205DOI Listing
October 2009

Relation of increased short-term variability of QT interval to congenital long-QT syndrome.

Am J Cardiol 2009 May 18;103(9):1244-8. Epub 2009 Mar 18.

Department of Medicine I, Klinikum Grosshadern, Ludwig Maximilians University Munich, Munich, Germany.

Apart from clinical symptoms the diagnosis and risk stratification in long-QT syndrome (LQTS) is usually based on the surface electrocardiogram. Studies have indicated that not only prolongation of the QT interval but also an increased short-term variability of QT interval (STV(QT)) is a marker for a decreased repolarization reserve in patients with drug-induced LQTS. The aims of this study were to determine if STV(QT) (1) is higher in patients with LQTS compared with controls, (2) if this effect is more pronounced in a high-risk LQTS population, and (3) could increase the diagnostic power of the surface electrocardiogram in identifying mutation carriers. Forty mutation carriers were compared with age- and gender-matched control subjects in the absence of beta-receptor-blocking agents. Lead II or V(5) RR and QT intervals from 30 consecutive beats were manually measured. STV(QT) was determined from Poincaré plots of QT intervals (STV(QT) = Sigma|QTn + 1 - QTn|/[30 x radical2]). Compared with controls, patients with LQTS had a prolonged QTc interval (449 +/- 41 vs 411 +/- 32 ms, p = 0.00049) and increased STV(QT) (6.4 +/- 3.2 vs 4.1 +/- 1.6 ms, p = 0.005). In patients with the highest risk of clinical events, defined as a QTc interval >500 ms or symptoms before beta-blocker therapy, STV(QT) was 9 +/- 4 ms. QTc interval had a sensitivity of 43% and a specificity of 97% in identifying mutation carriers (thresholds 450 ms for men and 460 ms for women). Receiver operator characteristic analysis showed that an STV(QT) of 4.9 ms was the optimal cut-off value to predict mutation carriers. When incorporating an STV(QT) >4.9 ms for those whose QTc interval was within the normal limits, sensitivity to distinguish mutation carriers increased to 83% with a specificity of 68%, so that another 15 mutation carriers could be identified. In conclusion, these are the first results in humans showing that STV(QT) is increased in congenital LQTS, this effect is increased in patients with symptoms before therapy, and, hence, STV(QT) could prove to be a useful noninvasive additive marker for diagnostic screening to bridge the gap before results of genetic testing are available.
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http://dx.doi.org/10.1016/j.amjcard.2009.01.011DOI Listing
May 2009

Atrial Arrhythmias in long-QT syndrome under daily life conditions: a nested case control study.

J Cardiovasc Electrophysiol 2009 Apr 27;20(4):401-7. Epub 2008 Oct 27.

Department of Cardiology and Angiology, Hospital of the University of Münster, Germany.

Background: The long-QT syndromes (LQTS) are inherited electrical cardiomyopathies characterized by prolonged ventricular repolarization and ventricular arrhythmias. Several genetic reports have associated defects in LQTS-causing genes with atrial fibrillation (AF). We therefore studied whether atrial arrhythmias occur in patients with LQTS under daily-life conditions.

Methods: We systematically assessed atrial arrhythmias in LQTS patients and matched controls using implanted defibrillators or pacemakers as monitors of atrial rhythm in a nested case-control study. Twenty-one LQTS patients (3 male; 39 +/- 18 years old; 18 on beta blocker, ICD therapy duration 6.3 +/- 2.7 years; 4 LQT1, 6 LQT2, 2 LQT3) were matched to 21 control subjects (13 male; 50 +/- 19 years old; 3 on beta blocker; pacemaker therapy duration 8.5 +/- 5.5 years; 19 higher-degree AV block, 2 others). LQTS patients were identified by a systematic search of the LQTS patient databases in Münster and Munich.

Results: One-third (7 of 21) of the LQTS patients developed self-terminating atrial arrhythmias (atrial cycle lengths <250 ms). Only one control patient developed a single episode of postoperative AF (P < 0.05 vs LQTS).

Conclusions: LQTS patients at high risk for ventricular arrhythmias may develop short-lasting atrial arrhythmias under daily-life conditions, suggesting that prolonged atrial repolarization may contribute to the initiation of AF.
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http://dx.doi.org/10.1111/j.1540-8167.2008.01339.xDOI Listing
April 2009

The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG).

Eur Heart J 2008 Apr 25;29(7):907-14. Epub 2008 Jan 25.

Department of Medicine I, Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Marchioninistr. 15, Munich D-81377, Germany.

Aims: Atrial fibrillation (AF) is the most frequent arrhythmia in humans. Rare familial forms exist. Recent evidence indicates a genetic susceptibility to common forms of AF. The alpha-subunit of the myocardial I(Kr)-channel, encoded by the KCNH2 gene, is crucial to ventricular and atrial repolarization. Patients with mutations in KCNH2 present with higher incidence of AF. Common variants in KCNH2 have been shown to modify ventricular repolarization. We intended to investigate, whether such variants may also modulate atrial repolarization and predispose to AF.

Methods And Results: In a two-stage association study we analysed 1207 AF-cases and 2475 controls. In stage I 40 tagSNPs (single nucleotide polymorphisms) from the KCNH2 genomic region were genotyped in 671 AF-cases and 694 controls. Of five associated variants, the common K897-allele of the KCNH2-K897T variant was replicated in n = 536 independent AF cases and n = 1781 controls in stage II [overall odds ratio 1.25, 95% confidence interval 1.11-1.41, P = 0.00033]. This association remained significant after adjustment for gender and age.

Conclusion: We report a genetic association finding including positive replication between the K897-allele and higher incidence of AF. This provides a molecular correlate for complex genetic predispositions to AF. The consequences of the K897T variant at the atrial level will require further functional investigations.
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http://dx.doi.org/10.1093/eurheartj/ehm619DOI Listing
April 2008

Beat-to-beat variability of QT intervals is increased in patients with drug-induced long-QT syndrome: a case control pilot study.

Eur Heart J 2008 Jan 22;29(2):185-90. Epub 2007 Dec 22.

Department of Medicine I, Klinikum Grosshadern, Ludwig Maximilians University Munich, Marchioninistrasse 15, D-81366 Munich, Germany.

Aims: Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT intervals. Here, we evaluate variability of QT intervals in patients with a history of drug-induced long QT syndrome (dLQTS) and TdP in absence of a mutation in any of the major LQTS genes.

Methods And Results: Twenty patients with documented TdP under drugs with QT-prolonging potential were compared with 20 matched control individuals. An observer blinded to diagnosis manually measured lead-II, RR, and QT intervals from 30 consecutive beats. BVR was determined from Poincaré plots of QT intervals as short-term variability (STV(QT) = Sigma|QT(n)(+1) - QT(n)|/[30 x radical2]). QRS interval and cycle length was comparable between study groups and controls. No difference was found in QTc between dLQTS and controls (428 +/- 25 vs. 421 +/- 34 ms, P = 0.26), whereas STV(QT) was significantly higher in dLQTS when compared with controls (8.1 +/- 3.7 vs. 3.6 +/- 1.3 ms, P = 0.001). Proarrhythmic predictive power of STV(QT) was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI: 0.79-0.99 vs. 0.39-0.75).

Conclusion: In the absence of QTc prolongation, baseline STV(QT) characterized patients with documented drug-induced proarrhythmia. STV(QT) could prove to be a useful non-invasive, easily obtainable parameter aiding the identification of the patient at risk for potentially life threatening arrhythmia in the context of drugs with QT prolonging potential.
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http://dx.doi.org/10.1093/eurheartj/ehm586DOI Listing
January 2008

Seizures on hearing the alarm clock.

Lancet 2007 Dec;370(9605):2172

Department of Neurology, Klinikum Grosshadern, University of Munich, Germany.

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http://dx.doi.org/10.1016/S0140-6736(07)61913-8DOI Listing
December 2007