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Background--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. Methods and Results--We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)- interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 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 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; and rs2880058, P=8.6×10-7) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3×10-4) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5×10-4). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus 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 with patients in the other quartiles combined (P=0.039). Conclusions--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 of long-QT syndrome. [ABSTRACT FROM AUTHOR]

Very recently, mutations in the TRPM4 gene have been identified in four pedigrees as the cause of an autosomal dominant form of cardiac conduction disease. To determine the role of TRPM4 gene variations, the relative frequency of TRPM4 mutations and associated phenotypes was assessed in a cohort of 160 unrelated patients with various types of inherited cardiac arrhythmic syndro-mes. In eight probands with atrioventricular block or right bundle branch block-five familial cases and three spora-dic cases-a total of six novel and two published TRPM4 mutations were identified. In patients with sinus node dysfunction, Brugada syndrome, or long-QT syndrome, no mutations were found. The novel mutations include six amino acid substitutions and appeared randomly distributed through predicted TRPM4 protein. In addition, eight polymorphic sites including two in-frame deletions were found. Mutations separated from polymorphisms by absence in control individuals and familial cosegregation in some families. In summary, TRPM4 gene mutations appear to play a major role in cardiac conduction disease but not for other related syndromes so far. The phenotypes are variable and clearly suggestive of additional factors modulating the disease phenotype in some patients. Hum Mutat 33:109-117, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aims: Brugada syndrome (BrS) is characterized by a typical electrocardiogram (ECG) pattern in right precordial leads (V1-V3; so-called type 1 ECG) and an increased risk of sudden cardiac death due to ventricular fibrillation. Annual cardiac event rates vary from 0.5% in asymptomatic to 7.7% in high-risk patients. So far, spontaneous occurrence of the type 1 ECG, survived cardiac arrest, and/or documented ventricular arrhythmias are main risk predictors, whereas other factors (e.g. family history or genotype) are not applicable for risk stratification. In this study, we investigated the relationship between T peak -T end intervals (TpTe) as a novel ECG parameter for the occurrence of cardiac arrhythmias., Methods and Results: Clinical and genetic data of 78 unrelated BrS patients (male: n = 57, age: 45 ± 14 years) were retrospectively analysed for medical history, gene mutation, and ECG parameters (in particular heart rate, PQ, QRS, QT, and TpTe) as obtained after digital measurements. TpTe in ECG lead V1 (87 ± 30 vs. 71 ± 27 ms; P = 0.017) and the TpTe/QT ratio (0.24 vs. 0.19; P = 0.018) were significantly higher in high-risk BrS patients than in other BrS patients. In the other right precordial leads typically indicative for BrS, no significant difference was noted., Conclusion: Assessment of the TpTe interval or the TpTe/QT ratio in lead V1 is potentially useful as a non-invasive risk marker for BrS patients with life-threatening arrhythmias., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

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 peak -T end 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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

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.

Patients with an implantable cardioverter defibrillator (ICD) may experience loss of consciousness. Electromagnetic interference (EMI) may trigger undesired or inhibit necessary therapy in patients with an ICD. Therefore, questions about personal or professional activities for ICD patients arise. Restricting driving or other personal activities has adverse effects on the patient's quality of life. The national Societies of Cardiology provide recommendations for ICD patients concerning driving of motor vehicles. Patients with an ICD that is implanted prophylactically do not have to refrain from driving after recovery from the implantation procedure. Patients with arrhythmias are classified into different groups depending on the risk of recurrence of tachycardias and symptoms. Commercial driving is not allowed for patients with an ICD in Germany except for those with a prophylactic indication without a history of arrhythmias. Those patients may drive small cars but no trucks or busses. Guidelines for medical fitness in commercial or military flying are regulated by the Joint Aviation Authorities (JAA) and ventricular tachycardias are a contraindication for both. Fortunately, loss of consciousness is not dangerous in most jobs. Strong sources of EMI can occur at special workplaces. Patients have to be advised and tested individually concerning their risk for EMI at their employment site before returning safely. Modern life exposes to an increasing amount of EMI. Intact household devices usually do not interfere with ICDs. Mobile phones may interfere with implanted devices. Interaction can be minimized by special precautions like maintaining a distance of minimum 10 cm between mobile phone and ICD. Electronic surveillance systems work differently and have the potential to interact with devices. Patients should be advised to pass those systems with avoiding longer exposure. The presence of an ICD is presently a contraindication for undergoing magnetic resonance imaging (MRI) because of a high risk of destruction of the system with even potential harm to the patient. High-frequency application for electrocautery devices or ablation is possible under certain precautions that have to be planned before. There is a high sensitivity of ICD systems to ionizing radiation with defect of the devices after a cumulative dose > 5 Gy.