Sven Zumhagen

University of Münster, Muenster, North Rhine-Westphalia, Germany

Are you Sven Zumhagen?

Claim your profile

Publications (34)173.33 Total impact


  • No preview · Article · Dec 2015 · Europace
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, P<0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, P<0.001) and LQT3 (57%, P=0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, P<0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction.European Journal of Human Genetics advance online publication, 16 December 2015; doi:10.1038/ejhg.2015.257.
    No preview · Article · Dec 2015 · European journal of human genetics: EJHG
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Modulation of cardiac repolarization by sexual hormones is controversial and hormonal effects on ion channels remain largely unknown. In the present translational study, we therefore assessed the relationship between QTc duration and gonadal hormones and studied underlying mechanisms. Methods and results: We measured hormone levels and QTc intervals in women during clomiphene stimulation for infertility and women before, during, and after pregnancy. Three heterozygous LQT-2 patients (KCNH2-p.Arg752Pro missense mutation) and two unaffected family members additionally were studied during their menstrual cycles. A comprehensive cellular and molecular analysis was done to identify the mechanisms of hormonal QT-interval regulation. High estradiol levels, but neither progesterone nor estradiol/progesterone ratio, inversely correlated with QTc. Consistent with clinical data, in vitro estradiol stimulation (60 pmol/L, 48 h) enhanced IKCNH2. This increase was mediated by estradiol receptor-α-dependent promotion of KCNH2-channel trafficking to the cell membrane. To study the underlying mechanism, we focused on heat-shock proteins. The heat-shock protein-90 (Hsp90) inhibitor geldanamycin abolished estradiol-induced increase in IKCNH2. Geldanamycin had no effect on KCNH2 transcription or translation; nor did it affect expression of estradiol receptors and chaperones. Estradiol enhanced the physical interaction of KCNH2-channel subunits with heat-shock proteins and augmented ion-channel trafficking to the membrane. Conclusion: Elevated estradiol levels were associated with shorter QTc intervals in healthy women and female LQT-2 patients. Estradiol acts on KCNH2 channels via enhanced estradiol-receptor-α-mediated Hsp90 interaction, augments membrane trafficking and thereby increases repolarizing current. These results provide mechanistic insights into hormonal control of human ventricular repolarization and open novel therapeutic avenues.
    No preview · Article · Aug 2015 · European Heart Journal
  • [Show abstract] [Hide abstract]
    ABSTRACT: The totally subcutaneous implantable defibrillator (S-ICD) was introduced as a new alternative to conventional implantable defibrillators and is employed worldwide. This system is especially attractive for young patients. However, in patients with hypertrophic cardiomyopathy (HCM), T-wave oversensing may occur. To address the question whether the S-ICD system is suitable for HCM patients, the data of a standard of care prospective single-center S-ICD registry were evaluated. In the present study, 18 HCM patients who received an S-ICD for primary (n = 14) or secondary prevention (n = 4) and a minimal follow-up duration of 6 months were analyzed. The mean follow-up duration was 31.7 ± 15.4 months. Ventricular arrhythmias were adequately detected in 4 patients (22 %). In 7 patients (39 %), T-wave oversensing was noticed and led to at least one inappropriate shock in 4 patients (22 %). Further adverse events included surgical revision due to a mobile sensing electrode and resulting noise detection as well as one case of early battery failure requiring pulse generator change. Patients with HCM and S-ICD systems have an increased risk of T-wave oversensing and inappropriate shock delivery. Thorough monitoring as well as exercise tests may help to improve device settings and thereby prevent T-wave oversensing.
    No preview · Article · Aug 2015 · Clinical Research in Cardiology

  • No preview · Article · Jul 2015 · Clinical Research in Cardiology

  • No preview · Conference Paper · Apr 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: -Considerable interest exists in the identification of genetic modifiers of disease severity in the Long QT Syndrome (LQTS) as their identification may contribute to refinement of risk stratification. -We searched for single nucleotide polymorphisms (SNPs) that modulate the QTc-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1,201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies (GWAS) in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, p=9.5×10(-8); rs12143842, p=4.8×10(-7); rs2880058, p=8.6×10(-7)) were strongly associated with the QTc-interval with marked effects (>12ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454, OR=1.85 [95% CI, 1.32-2.59], p=3×10(-4)) and KCNQ1 (rs12576239; OR=1.84 [95% CI, 1.31-2.60], p=5×10(-4)). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multi-locus genetic risk score (GRSNOS1AP) uncovered a strong linear relationship between GRSNOS1AP and the QTc-interval (p=4.2×10(-7)). Furthermore, patients with a GRSNOS1AP in the lowest quartile had a lower relative risk of cardiac events compared to patients in the other quartiles combined (p=0.039). -We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time we linked common genetic variation at KCNQ1 with risk for LQTS.
    No preview · Article · Mar 2015 · Circulation Cardiovascular Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gain-of-function mutations in CACNA1C, encoding the L-type Ca(2+) channel Cav1.2, cause Timothy syndrome (TS), a multi-systemic disorder with dysmorphic features, long-QT syndrome (LQTS) and autism spectrum disorders. TS patients have heterozygous mutations (G402S and G406R) located in the alternatively spliced exon 8, causing a gain-of-function by reduced voltage-dependence of inactivation. Screening 540 unrelated patients with non-syndromic forms of LQTS, we identified six functional relevant CACNA1C mutations in different regions of the channel. All these mutations caused a gain-of-function combining different mechanisms, including changes in current amplitude, rate of inactivation and voltage-dependence of activation or inactivation, similar as in TS. Computer simulations support the theory that the novel CACNA1C mutations prolong action potential duration. We conclude that genotype-negative LQTS patients should be investigated for mutations in CACNA1C, as a gain-of-function in Cav1.2 is likely to cause LQTS and only specific and rare mutations, i.e. in exon 8, cause the multi-systemic TS. Copyright © 2015 International Society for Heart Research. Published by Elsevier Ltd. All rights reserved.
    Full-text · Article · Jan 2015 · Journal of Molecular and Cellular Cardiology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by recurrent syncopes and sudden cardiac death triggered by sympathetic activation in young individuals without structural heart disease and a normal baseline electrocardiogram. There is reason to question whether the current expert consensus treatment recommendation, maximal tolerated β-blockade alone or in combination with low-dose flecainide, is the optimal antiarrhythmic treatment strategy in CPVT, as high doses of β-blockers may eventually lead to adverse side effects and β-blocker discontinuation. Indeed, β-blocker non-compliance accounts for around 5% of sudden cardiac deaths in CPVT patients. Case report Differing from the current recommendation, we present the first report of a CPVT patient successfully treated with high-dose flecainide and minimal β-blockade. This combination resulted in complete suppression of ventricular arrhythmias during exercise stress tests and Holter monitoring and was well tolerated without any side effects. We review the current literature on β-blocker non-compliance-related sudden cardiac death in CPVT, summarize the in vitro and in vivo data on flecainide therapy in CPVT, and discuss the rationale of our antiarrhythmic approach. <Learning objective: This case illustrates typical features of CPVT including the therapeutic management of a young CPVT patient with poor β-blocker tolerance at normal dosages. In this setting, high-dose flecainide combined with minimal β-blockade may (1) result in complete antiarrhythmic response and may (2) improve the antiarrhythmic drug-compliance thereby reducing the risk of non-compliance-related sudden cardiac death.
    No preview · Article · Sep 2014 · Journal of Cardiology Cases
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Analyzing a patient with progressive and severe cardiac conduction disorder combined with idiopathic ventricular fibrillation (IVF), we identified a splice site mutation in the sodium channel gene SCN5A. Due to the severe phenotype, we performed whole-exome sequencing (WES) and identified an additional mutation in the KCNK17 gene encoding the K2P potassium channel TASK-4. The heterozygous change (c.262G>A) resulted in the p.Gly88Arg mutation in the first extracellular pore loop. Mutant TASK-4 channels generated threefold increased currents, while surface expression was unchanged, indicating enhanced conductivity. When co-expressed with wild-type channels, the gain-of-function by G88R was conferred in a dominant-active manner. We demonstrate that KCNK17 is strongly expressed in human Purkinje cells and that overexpression of G88R leads to a hyperpolarization and strong slowing of the upstroke velocity of spontaneously beating HL-1 cells. Thus, we propose that a gain-of-function by TASK-4 in the conduction system might aggravate slowed conductivity by the loss of sodium channel function. Moreover, WES supports a second hit-hypothesis in severe arrhythmia cases and identified KCNK17 as a novel arrhythmia gene.
    Full-text · Article · Jun 2014 · EMBO Molecular Medicine
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genetisch bedingte (monogene) Herzerkrankungen bedürfen einer sorgsamen klinischen, genetischen und familiären Diagnostik, da die Erkrankungen mit einem hohen kardiovaskulären Risiko in jungen Jahren assoziiert sein können. Es handelt sich zumeist um Erkrankungen durch Ionenkanalgenmutationen, die genetisch heterogen und von einer unterschiedlichen Sensitivität in der Mutationsdetektion (pro Erkrankung oder Ionenkanalgen) gekennzeichnet sind. In Analogie zu anderen Ionenkanalerkrankungen besteht oft ein episodisches Auftreten von Symptomen, das durch Trigger (meist erhöhte Herzfrequenz bei körperlicher und/oder physischer Belastung) gefördert werden kann. Bei diesen relativ seltenen Erkrankungen ist eine frühzeitige Diagnostik und interdisziplinäre Betreuung durch Kardiologen, Kinderkardiologen und Humangenetikern (und ggf. Psychologen) sinnvoll. Mittlerweile existieren erste internationale Empfehlungen, wann eine Genotypisierung aus diagnostischer, therapeutischer oder prognostischer Sicht durchzuführen ist.
    No preview · Article · Dec 2013 · Medizinische Genetik
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of pharmacologic agents for the treatment of diseases is still challenging, especially in rare inherited arrhythmia syndromes like long and short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia. The underling pathophysiologic mechanism of these inherited diseases is in most cases either a gain- or a loss-of-function due to mutations in ion channel genes. Although the biophysical properties of mutant channel subunits are well studied, little is known aboutthe targeting effect of specific pharmacologic agents. In this review, we focus on the therapeutic (in vivo) and the experimental (in vitro) approaches in the most common inherited forms.
    No preview · Article · Nov 2013 · Current Medicinal Chemistry
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p = 3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p = 3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.
    Full-text · Article · Nov 2013 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: Distinguishing pathogenic mutations from benign amino acid alterations is a challenge in genetic diagnostic. Currently, next generation sequencing will lead to an increasing number of variants in LQT genes to be ascertained for pathogenicity. Several online available pathogenicity prediction programs (PPT) have been developed to assess the impact of a gene variation on protein function. These programs differ in the weighting of parameters used for prediction and an evaluation of PPTs using data sets of variants with known functionality is important. Methods and results: We tested the performance of 7 pathogenicity prediction tools (PPT) (KvSNP, MutPred, PolyPhen2, SIFT, SNAP, SNPs & Go and PMUT) in a set of 354 amino acid substitutions in the LQT genes 1-3. Variants were obtained from in-house and external LQTS databases and separated into pathogenic mutations (MUT, n=244) and benign polymorphism (POLY, n=110) with respect to their clinical phenotype and familial and/or database occurrence. The amount of correctly and incorrectly predicted MUT and POLY (tp, tn, fp, fn) and the performance parameters accuracy (fn+fp/all), sensitivity (tp/tp+fn) and specificity (tn/tn+fp) were calculated. The quality of the PPTs differed significantly also with regard to the gene being analyzed. MutPred revealed the overall best sensitivity (<0.97, fn=2.9%) and accuracy (0.83) and PolyPhen2 the best specificity (0.69, fp=30.9%). With regard to each gene the Kv channel specific PPT KvSNP performed best for KCNH2 and KCNQ1 (accuracy: 0.89 and 0.94). For SCN5A all PPTs revealed a strikingly worse performance. Here the best sensitivity (0.96, fn=3.7%) and accuracy (0.78) was observed for MutPred. The most confident prediction (fn=2%, fp=18.2%) can be obtained using a combination of 2 or 3 best performing PPTs and considering only those substitutions as pathogenic or benign which show a concordant result. Applying this prediction strategy on 18 not reported, rare (MAF<0.05 in EVS) variants in LQT 1-3 10 variants were concordantly predicted to be pathogenic and 4 as neutral and this prediction results fit well with the clinical phenotype observed. The remaining 4 variants that differed in prediction result were considered to be variants of uncertain significance (VUS). Conclusion: A combined analysis by well performing PPT can be supportive to evaluate the potential pathogenicity of variants in LQT 1-3 genetic analysis. In addition, correlation with clinical data (disease expression, familial cosegregation) and presence in LSMD/control databases is essential for a correct genetic diagnosis.
    Preview · Article · Aug 2013 · European Heart Journal
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: WES is an emerging strategy to identify disease causing mutations. In patients with a pronounced phenotype and the potential of multiple variants it might be of particular use. In a pilot study we performed WES in a patient with a severe form of progressive cardiac conduction defect (PCCD) and idiopathic ventricular fibrillation (IVF). Subsequently, the functional effects of novel mutant genes were investigated. Methods and results: For variant analysis and prioritization of WES data all variants with a reliable confidence (coverage >20x) were taken into account (n=76,713 in 19,135 genes). Next, variants not being present in 388 genes relevant for cardiac function were excluded (remaining n=1,590 in 278 genes). Within this group of selected genes only alterations with serious consequences (non-synonymous coding (nsSNV), essential splice site, frame shift coding, stop gained or stop lost, complex indel variations) were further analyzed (n=92). Hereafter, variants annotated in Exome Variant Server (EVS), dbSNP 137 and GeneCards v3 (MAF>0.01%) were excluded and remaining variants confirmed by direct Sanger sequencing (n=8: 4 nsSNV, 3 indels, 1 splice site). The pathogenic impact of verified variants was determined using several pathogenicity prediction tools (PPT). Alterations with a concordantly predicted "deleterious effect" were further analyzed. Following this prioritization scheme two heterozygous variants were filtered out. A novel essential splice site mutation in the SCN5A gene (c.3963+1G>A, p.?), most likely to cause a loss of function, was identified. As a novelty a very rare amino acid substitution in the two pore domain potassium channel (K2P) gene KCNK17 (c.262G>A, p.G88R) encoding the TASK-4 channel was found. This gene is unlinked to an inherited disorder so far. Heterologous expression of TASK-4_G88R channels revealed a gain-of-function by generating three-fold increased outward currents in two-electrode voltage-clamp recordings. This effect was not due to an increased channel density at the cell surface (chemiluminescence assay, live cell imaging) or an altered pH-sensitivity. Though, two other TASK-4 mutations (G88E, G88K) resulted in a similar gain-of-function implicating that the particular residue 88 (glycine) is important for normal gating behavior. Coexpression of TASK-4_G88R with wild type channels showed a dominant-active effect. Conclusions: In a patient with a severe arrhythmia phenotype WES helped to identify disease causing and modifying mutations. This approach identified KCNK17 a novel disease gene and may support a second hit-hypothesis.
    Preview · Article · Aug 2013 · European Heart Journal
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10(-68); rs9388451, P = 5.1 × 10(-17)) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10(-14)). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10(-81)). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.
    Full-text · Article · Jul 2013 · Nature Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome. In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation). In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.
    Full-text · Article · Jun 2013 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: Andersen-Tawil syndrome (ATS) is characterized by dysmorphic features, periodic paralyses and abnormal ventricular repolarization. After genotyping a large set of patients with congenital long-QT syndrome, we identified two novel, heterozygous KCNJ2 mutations (p.N318S, p.W322C) located in the C-terminus of the Kir2.1 subunit. These mutations have a different localization than classical ATS mutations which are mostly located at a potential interaction face with the slide helix or at the interface between the C-termini. Mutation carriers were without the key features of ATS, causing an isolated cardiac phenotype. While the N318S mutants regularly reached the plasma membrane, W322C mutants primarily resided in late endosomes. Co-expression of N318S or W322C with wild-type Kir2.1 reduced current amplitudes only by 20-25 %. This mild loss-of-function for the heteromeric channels resulted from defective channel trafficking (W322C) or gating (N318S). Strikingly, and in contrast to the majority of ATS mutations, neither mutant caused a dominant-negative suppression of wild-type Kir2.1, Kir2.2 and Kir2.3 currents. Thus, a mild reduction of native Kir2.x currents by non dominant-negative mutants may cause ATS with an isolated cardiac phenotype.
    No preview · Article · May 2013 · Archiv für Kreislaufforschung
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inherited long QT syndrome (LQTS) is characterized by a prolonged ventricular repolarization (QTc interval) and symptoms (syncope, sudden cardiac arrest) due to polymorphic ventricular arrhythmias. As of today, 13 different cardiac ion channel genes have been associated with congenital LQTS. The most common ones are due to KCNQ1 (LQT-1), KCNH2 (LQT-2), and SCN5A (LQT-3) gene mutations and account for up to 75 % of cases. Typical clinical findings are an increased QT interval on the surface electrocardiogram, specifically altered T wave morphologies, polymorphic ventricular arrhythmias, or an indicative family history. Recently, in the HRS/EHRA expert consensus statement, comprehensive genetic testing of major LQTS genes was recommended for index patients for whom there is a strong clinical suspicion of LQTS. Overall, antiadrenergic therapy, in particular β-receptor blockers, has been the mainstay of therapy and has significantly reduced cardiac events. For high-risk patients, an implantable cardioverter defibrillator (ICD) is recommended. Importantly, lifestyle modification and avoidance of arrhythmia triggers are additional important approaches.
    No preview · Article · Sep 2012 · Herzschrittmachertherapie & Elektrophysiologie
  • Article: EKG-Quiz

    No preview · Article · Sep 2012 · Herzschrittmachertherapie & Elektrophysiologie