Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

POPDC2 a novel susceptibility gene for conduction disorders.

Despite recent progress in the understanding of cardiac ion channel function and its role in inherited forms of ventricular arrhythmias, the molecular basis of cardiac conduction disorders often remains unresolved. We aimed to elucidate the genetic background of familial atrioventricular block (AVB) using a whole exome sequencing (WES) approach. In monozygotic twins with a third-degree AVB and in another, unrelated family with first-degree AVB, we identified a heterozygous nonsense mutation in the POPDC2 gene causing a premature stop at position 188 (POPDC2W188⁎), deleting parts of its cAMP binding-domain. Popeye-domain containing (POPDC) proteins are predominantly expressed in the skeletal muscle and the heart, with particularly high expression of POPDC2 in the sinoatrial node of the mouse. We now show by quantitative PCR experiments that in the human heart the POPDC-modulated two-pore domain potassium (K2P) channel TREK-1 is preferentially expressed in the atrioventricular node. Co-expression studies in Xenopus oocytes revealed that POPDC2W188⁎ causes a loss-of-function with impaired TREK-1 modulation. Consistent with the high expression level of POPDC2 in the murine sinoatrial node, POPDC2W188⁎ knock-in mice displayed stress-induced sinus bradycardia and pauses, a phenotype that was previously also reported for POPDC2 and TREK-1 knock-out mice. We propose that the POPDC2W188⁎ loss-of-function mutation contributes to AVB pathogenesis by an aberrant modulation of TREK-1, highlighting that POPDC2 represents a novel arrhythmia gene for cardiac conduction disorders.

A Mutation in the G-Protein Gene GNB2 Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction.

RATIONALE: Familial sinus node and atrioventricular conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue, and syncope because of a temporarily or permanently reduced heart rate. To date, only a few genes for familial sinus and atrioventricular conduction dysfunction are known, and the majority of cases remain pathogenically unresolved. OBJECTIVE: We aim to identify the disease gene in a large 3-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and atrioventricular block (AVB) and to characterize the mutation-related pathomechanisms in familial SND+AVB. METHODS AND RESULTS: Genome-wide linkage analysis mapped the SND+AVB disease locus to chromosome 7q21.1-q31.1 (2-point logarithm of the odds score: 4.64; θ=0); in this region, targeted exome sequencing identified a novel heterozygous mutation (p.Arg52Leu) in the GNB2 gene that strictly cosegregated with the SND+AVB phenotype. GNB2 encodes the ß2 subunit (Gß2) of the heterotrimeric G-protein complex that is being released from G-protein-coupled receptors on vagal stimulation. In 2 heterologous expression systems (HEK-293T cells and Xenopus laevis oocytes), an enhanced activation of the G-protein-activated K+ channel (GIRK; Kir3.1/Kir3.4) was shown when mutant Gß2 was coexpressed with Gγ2; this was in contrast to coexpression of mutant Gß2-Gγ2 with other cardiac ion channels (HCN4, HCN2, and Cav1.2). Molecular dynamics simulations suggested a reduced binding property of mutant Gß2 to cardiac GIRK channels when compared with native Gß2. CONCLUSIONS: A GNB2 gene mutation is associated with familial SND+AVB and leads to a sustained activation of cardiac GIRK channels, which is likely to hyperpolarize the myocellular membrane potential and thus reduces their spontaneous activity. Our findings describe for the first time a role of a mutant G-protein in the nonsyndromic pacemaker disease because of GIRK channel activation.

Estradiol regulates human QT-interval: acceleration of cardiac repolarization by enhanced KCNH2 membrane trafficking.

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.

Corneal Densitometry as a Novel Technique for Monitoring Amiodarone Therapy.

PURPOSE: The clinical efficacy and toxicity of amiodarone may be determined more effectively by tissue deposition than by levels of the agent in serum. Therefore, corneal densitometry might be useful for therapeutic monitoring. The aim of the study is to evaluate Scheimpflug corneal densitometry in patients with amiodarone keratopathy (AK). DESIGN: Comparative case series. PARTICIPANTS: Sixty-six patients receiving amiodarone therapy and 66 healthy controls were consecutively enrolled in this study. METHODS: Patients were examined using the Oculus Pentacam (Wetzlar, Germany). MAIN OUTCOME MEASURES: Densitometry data from different corneal layers and different annuli were extracted, analyzed, and compared with densitometry values of healthy controls. Duration of treatment, cumulative dose, Orlando stage (slit-lamp biomicroscopy), and serum concentrations of amiodarone and N-desethylamiodarone also were determined, and the correlation to different densitometry data was evaluated. RESULTS: The total corneal light backscatter at total corneal thickness and at total diameter was significantly higher in the amiodarone group compared with the control group (AK group: 28.3±5.2; control group: 24.4±4.2; P < 0.001). Upon dividing the corneal surface into different layers at total thickness, the differences were significant in all layers (P < 0.001). The serum concentrations of the metabolite N-desethylamiodarone correlate with densitometry values, especially in the 0- to 2-mm annulus in the anterior layer (r = 0.419; P = 0.001), whereas the cumulative dose and duration of treatment correlate significantly with the densitometry values in the 0- to 2-mm annulus at total thickness (P = 0.014 and P = 0.022, respectively). CONCLUSIONS: Corneal densitometry is a useful, objective method for quantifying AK and can help in monitoring amiodarone therapy. The serum concentration of the active metabolite N-desethylamiodarone correlates with the extent of keratopathy in the anterior layer, whereas chronic changes in the stroma correlate with the cumulative dose and duration of treatment.

Tpeak-Tend interval and Tpeak-Tend/QT ratio in patients with Brugada syndrome.

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 Tpeak-Tend 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.

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

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 Tpeak-Tend 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.

Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.

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.

Non dominant-negative KCNJ2 gene mutations leading to Andersen-Tawil syndrome with an isolated cardiac phenotype.

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.

Mutational spectrum in the Ca(2+)--activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.

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 syndromes. In eight probands with atrioventricular block or right bundle branch block--five familial cases and three sporadic 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.

Overlapping cardiac phenotype associated with a familial mutation in the voltage sensor of the KCNQ1 channel.

BACKGROUND: Cardiac action potential repolarisation is determined by K(+) currents including I(Ks). I(Ks) channels are heteromeric channels composed of KCNQ1 and KCNE E-subunits. Mutations in KCNQ1 are associated with sinus bradycardia, familial atrial fibrillation (fAF) and/or short QT syndrome as a result of gain-of-function, and long QT syndrome (LQTS) due to loss-of-function in the ventricles. Here, we report that the missense mutation R231C located in S4 voltage sensor domain is associated with a combined clinical phenotype of sinus bradycardia, fAF and LQTS. We aim to understand the molecular basis of the complex clinical phenotype. METHODS: We expressed and functionally analyzed the respective channels kinetics in Xenopus laevis oocytes. The molecular nature of the residue R231 was studied by homology modeling and molecular dynamics simulation. RESULTS: As a result, the mutation reduced voltage sensitivity of channels, possibly due to neutralization of the positive charge of the arginine side chain substituted by cysteine. Modeling suggested that the charge carrying side chain of R231 is positioned suitably to transfer transmembrane voltages into conformational energy. Further, the mutation altered the functional interactions with KCNE subunits. CONCLUSION: The mutation acted in a E-subunit dependent manner, suggesting I(Ks) function altered by the presence of different KCNE subunits in sinus node, atria and ventricles as the molecular basis of sinus bradycardia, fAF and LQTS in mutation carriers.

Role of implantable cardioverter defibrillator therapy in patients with acquired long QT syndrome: a long-term follow-up.

AIMS: The use of implantable cardioverter defibrillators (ICD) in patients with torsade de pointes (TdP) and ventricular fibrillation in the presence of acquired long QT syndrome (aLQTS) is under debate, partly due to the fact that aLQTS is potentially reversible and currently no long-term follow-up data are available. We aimed to evaluate the long-term follow-up of patients with acquired long QT syndrome (aLQTS) who had received an implantable cardioverter defibrillator (ICD) for secondary prevention of sudden cardiac arrest (SCA). METHOD AND RESULTS: Over a 10 year period, 43 patients with an ICD after survived cardiac arrest (SCA) due to an aLQTS were included [female n= 27 (63%); mean age 61 ± 16 years]. There was no clinical evidence for congenital LQTS (Schwartz score 1.25 ± 0.8). Structural heart disease was present in 29 patients (47%; ischaemic n= 13; dilated cardiomyopathy n= 9; mean EF 41%± 12). The most common proarrhythmic trigger happened to be antiarrhythmic drugs (n= 34; 79%). Other triggers included contrast agent (n= 1), haloperidol (n= 2), severe hypokalaemia (n= 2), drug abuse/alcohol (n= 2), and mere severe bradycardia (n= 2). Under trigger QTc interval measured 536 ± 58 vs. 438 ± 33 ms without trigger (P< 0.001). During a mean follow-up of 84 ± 55 months, appropriate shocks occurred in 19 patients (44%); inappropriate shocks in 13 patients (30%; only inappropriate n= 3). Appropriate shocks were almost as common in patients without as in those with structural heart disease (35 vs. 48%; P= 0.32). None of the patients were re-exposed to the initial trigger during the follow-up period. Beta-blocker medication did not prevent ICD shocks (12 of 19 vs. 11 of 24 on medication). CONCLUSION: Appropriate ICD shocks are a common finding in patients with aLQTS and SCA irrespective of the underlying cause or structural heart disease. Thus, even in the presence of relevant acquired proarrhythmia ICD may be beneficial.

Totally subcutaneous implantable cardioverter defibrillator with an alternative, right parasternal, electrode placement.

The totally subcutaneous implantable cardioverter-defibrillator (S-ICD) is an entirely novel defibrillation device that avoids the direct contact of device electrodes with the heart and the cardiovascular system. Here, we present a particular case of a young woman with congenital long-QT syndrome in which we implanted the electrode alternatively, right parasternally. This decision was based on the thoracic anatomy of the patient and on findings of a model of S-ICD electrodes in an adult torso. In conclusion, in some patients an alternative subcutaneous electrode position may be carefully considered but should not be taken to outweigh the standard left-sided placement.

Genes causing inherited forms of cardiomyopathies. A current compendium.

Cardiomyopathies (diseases of the heart muscle) are a relevant but heterogeneous group of cardiac diseases. The underlying structural myocardial alterations, detectable with contemporary cardiac imaging modalities and also on twelve-lead surface ECG, embody both linkage and differentiation of the respective clinical forms. Most of these are defined to the heart, however, cardiac involvement is also known in the presence of specific metabolic or muscular systemic diseases. In many of the known cardiomyopathies, a genetic background has been elucidated thus indicating a potential familial disease. This, in turn, also harbors the risk that more family members may be affected besides the index patient.

Familial Sinus Node Disease Caused by a Gain of GIRK (G-Protein Activated Inwardly Rectifying K+ Channel) Channel Function.

BACKGROUND: Inherited forms of sinus node dysfunction (SND) clinically include bradycardia, sinus arrest, and chronotropic incompetence and may serve as disease models to understand sinus node physiology and impulse generation. Recently, a gain-of-function mutation in the G-protein gene GNB2 led to enhanced activation of the GIRK (G-protein activated inwardly rectifying K+ channel). Thus, human cardiac GIRK channels are important for heart rate regulation and subsequently, genes encoding their subunits Kir3.1 and Kir3.4 ( KCNJ3 and KCNJ5) are potential candidates for inherited SND in human. METHODS: We performed a combined approach of targeted sequencing of KCNJ3 and KCNJ5 in 52 patients with idiopathic SND and subsequent whole exome sequencing of additional family members in a genetically affected patient. A putative novel disease-associated gene variant was functionally analyzed by voltage-clamp experiments using various heterologous cell expression systems (Xenopus oocytes, CHO cells, and rat atrial cardiomyocytes). RESULTS: In a 3-generation family with SND we identified a novel variant in KCNJ5 which leads to an amino acid substitution (p.Trp101Cys) in the first transmembrane domain of the Kir3.4 subunit of the cardiac GIRK channel. The identified variant cosegregated with the disease in the family and was absent in the Exome Variant Server and Exome Aggregation Consortium databases. Expression of mutant Kir3.4 (±native Kir3.1) in different heterologous cell expression systems resulted in increased GIRK currents ( IK,ACh) and a reduced inward rectification which was not compensated by intracellular spermidine. Moreover, in silico modeling of heterotetrameric mutant GIRK channels indicates a structurally altered binding site for spermine. CONCLUSIONS: For the first time, an inherited gain-of-function mutation in the human GIRK3.4 causes familial human SND. The increased activity of GIRK channels is likely to lead to a sustained hyperpolarization of pacemaker cells and thereby reduces heart rate. Modulation of human GIRK channels may pave a way for further treatment of cardiac pacemaking.

Impact of presynaptic sympathetic imbalance in long-QT syndrome by positron emission tomography.

OBJECTIVE: We investigated the impact of cardiac presynaptic norepinephrine recycling in patients with long-QT syndrome (LQTS) using positron emission tomography (PET) with 11C-meta-hydroxyephedrine ([11C]mHED-PET). METHODS: [11C]mHED-PET was performed in 25 patients with LQTS (LQT1: n=14; LQT2: n=11) and 20 healthy controls and correlated with clinical parameters. [11C]mHED-PET images were analysed for global and regional retention indices (RI) and washout rates (WO) reflecting dynamic parameters of the tracer activity. RESULTS: Global and regional RI values were similar between patients with LQTS and controls. Although the global WO rates were similar between these groups, regional WO rates were on average higher in the lateral left ventricle (LV) wall in patients with LQTS (dose, mean ±SD; 0.08±0.14 vs 0.00%±0.09% min-1; p=0.033). In addition, patients with LQTS with a longer QTc interval showed a higher global WO rate. Clinical symptoms correlated with higher global WO rates. In the presence of normal global WO rates, asymptomatic LQTS patients showed higher global RI values. CONCLUSION: The increased regional WO rate of [11C]mHED in the lateral LV suggests an imbalance of presynaptic catecholamine reuptake and release, resulting in a higher synaptic catecholamine concentration, in particular in LQT1 patients. This might enhance ß-adrenoceptor signalling and thereby aggravate inherited ion channel dysfunction and may facilitate occurrence of ventricular tachyarrhythmias. Detection of regional differences in LV sympathetic nervous function may modify disease expression and potentially serve as a non-invasive risk marker in congenital LQTS. TRIAL REGISTRATION NUMBER: 2006-002767-41;Results.

Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia.

In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch-activated K2P potassium channel TREK-1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK-1. In addition, mutant channels exhibit a hypersensitivity to stretch-activation, suggesting that the selectivity filter is directly involved in stretch-induced activation and desensitization. Increased sodium permeability and stretch-sensitivity of mutant TREK-1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT We present a pharmacological strategy to rescue the selectivity defect of the TREK-1 pore. Our findings provide important insights for future studies of K2P channel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.

Long-term follow-up of subcutaneous ICD systems in patients with hypertrophic cardiomyopathy: a single-center experience.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.

Improved Clinical Risk Stratification in Patients with Long QT Syndrome? Novel Insights from Multi-Channel ECGs.

BACKGROUND: We investigated whether multichannel ECG-recordings are useful to risk-stratify patients with congenital long-QT syndrome (LQTS) for risk of sudden cardiac death under optimized medical treatment. METHODS: In 34 LQTS-patients (11 male; age 31±13 years, QTc 478±51ms; LQT1 n = 8, LQT2 n = 15) we performed a standard 12-channel ECG and a 120-channel body surface potential mapping. The occurrence of clinical events (CE; syncope, torsade de pointes (TdP), sudden cardiac arrest (SCA)) was documented and correlated with different ECG-parameters in all lead positions. RESULTS: Seven patients developed TdP, four survived SCA and 12 experienced syncope. 12/34 had at least one CE. CE was associated with a longer QTc-interval (519±43ms vs. 458±42ms; p = 0.001), a lower T-wave integral (TWI) on the left upper chest (-1.2±74.4mV*ms vs. 63.0±29.7mV*ms; p = 0.001), a lower range of T-wave amplitude (TWA) in the region of chest lead V8 (0.10±0.08mV vs. 0.18±0.07mV; p = 0.008) and a longer T-peak-T-end time (TpTe) in lead V1 (98±23ms vs. 78±26ms; p = 0.04). Receiver-operating-characteristic (ROC) analyses revealed a sensitivity of 96% and a specificity of 75% (area under curve (AUC) 0.89±0.06, p = 0.001) at a cut-off value of 26.8mV*ms for prediction of CE by TWI, a sensitivity of 86% and a specificity of 83% at a cut-off value of 0.11mV (AUC 0.83±0.09, p = 0.002) for prediction of CE by TWA and a sensitivity of 83% and a specificity of 73% at a cut-off value of 87ms (AUC 0.80±0.07, p = 0.005) for prediction of CE by TpTe. CONCLUSIONS: Occurrence of CE in LQTS-patients seems to be associated with a prolonged, low-amplitude T-wave.