From rare events to systematic data collection: the RESCUED registry for sudden cardiac death in the young in Germany.

BACKGROUND: Approximately one-third of sudden cardiac deaths in the young (SCDY) occur due to a structural cardiac disease. Forty to fifty percent of SCDY cases remain unexplained after autopsy (including microscopic and forensic-toxicological analyses), suggesting arrhythmia syndromes as a possible cause of death. Due to the possible inheritability of these diseases, blood relatives of the deceased may equally be carriers of the causative genetic variations and therefore may have an increased cardiac risk profile. A better understanding of the forensic, clinical, and genetic data might help identify a subset of the general population that is at increased risk of sudden cardiac death. STUDY DESIGN: The German registry RESCUED (REgistry for Sudden Cardiac and UnExpected Death) comprises information about SCDY fatalities and clinical and genetic data of both the deceased and their biological relatives. The datasets collected in the RESCUED registry will allow for the identification of leading causes of SCDY in Germany and offer unique possibilities of scientific analyses with the aim of detecting unrecognized trends, risk factors, and clinical warning signs of SCDY. In a pilot phase of 24 months, approximately 180 SCDY cases (< 50 years of age) and 500 family members and clinical patients will be included. CONCLUSION: RESCUED is the first registry in Germany collecting comprehensive data of SCDY cases and clinical data of the biological relatives reviewed by cardiac experts. RESCUED aims to improve individual risk assessment and public health approaches by directing resources towards early diagnosis and evidence-based, personalized therapy and prevention in affected families. Trial registration number (TRN): DRKS00033543.

[Postmortem genetic analysis following sudden cardiac death : Background, approach, and future]. / Postmortale Genetik nach einem plötzlichen Herztod : Hintergründe, Vorgehen und Zukunft.

BACKGROUND: Sudden cardiac death (SCD) is defined as an unexpected, nontraumatic death with a possible cardiac or unknown cause. The lowest incidence is observed in infancy and childhood (1 per 100,000), and the incidence is approximately 50 per 100,000 in the middle-aged population, reaching a plateau around the age of 80 (200 per 100,000). While most SCD cases occur in older people with coronary artery disease, there is a predominance of monogenetic and polygenetic diseases in the young. METHODS: Postmortem genetic analysis (molecular autopsy) using next-generation sequencing reveals a definite pathogenic genetic alteration, which can explain SCD of young patients in near 20% of the cases. Hence, postmortem genetic analysis has become an important tool to unravel the inheritable cause of death. Furthermore, early identification of a pathogenic genetic sequence variant in the deceased is crucial to reduce risk in relatives due to preventive personalized measures. RESULTS AND CONCLUSION: Postmortem genetic analysis forms together with the clinical assessment the basis for early identification of at-risk relatives. A new guideline for the management of ventricular arrhythmias and prevention of sudden death was recently published by the European Society of Cardiology. The new recommendations give genetic testing, also in deceased patients a much higher priority reflecting increasing relevance of genetic testing for diagnostic evaluation, risk stratification and prevention.

Catalytic antibodies in arrhythmogenic cardiomyopathy patients cleave desmoglein 2 and N-cadherin and impair cardiomyocyte cohesion.

AIMS: Arrhythmogenic cardiomyopathy (AC) is a severe heart disease predisposing to ventricular arrhythmias and sudden cardiac death caused by mutations affecting intercalated disc (ICD) proteins and aggravated by physical exercise. Recently, autoantibodies targeting ICD proteins, including the desmosomal cadherin desmoglein 2 (DSG2), were reported in AC patients and were considered relevant for disease development and progression, particularly in patients without underlying pathogenic mutations. However, it is unclear at present whether these autoantibodies are pathogenic and by which mechanisms show specificity for DSG2 and thus can be used as a diagnostic tool. METHODS AND RESULTS: IgG fractions were purified from 15 AC patients and 4 healthy controls. Immunostainings dissociation assays, atomic force microscopy (AFM), Western blot analysis and Triton X-100 assays were performed utilizing human heart left ventricle tissue, HL-1 cells and murine cardiac slices. Immunostainings revealed that autoantibodies against ICD proteins are prevalent in AC and most autoantibody fractions have catalytic properties and cleave the ICD adhesion molecules DSG2 and N-cadherin, thereby reducing cadherin interactions as revealed by AFM. Furthermore, most of the AC-IgG fractions causing loss of cardiomyocyte cohesion activated p38MAPK, which is known to contribute to a loss of desmosomal adhesion in different cell types, including cardiomyocytes. In addition, p38MAPK inhibition rescued the loss of cardiomyocyte cohesion induced by AC-IgGs. CONCLUSION: Our study demonstrates that catalytic autoantibodies play a pathogenic role by cleaving ICD cadherins and thereby reducing cardiomyocyte cohesion by a mechanism involving p38MAPK activation. Finally, we conclude that DSG2 cleavage by autoantibodies could be used as a diagnostic tool for AC.

Manual vs. automatic assessment of the QT-interval and corrected QT.

AIMS: Sudden cardiac death (SCD) is challenging to predict. Electrocardiogram (ECG)-derived heart rate-corrected QT-interval (QTc) is used for SCD-risk assessment. QTc is preferably determined manually, but vendor-provided automatic results from ECG recorders are convenient. Agreement between manual and automatic assessments is unclear for populations with aberrant QTc. We aimed to systematically assess pairwise agreement of automatic and manual QT-intervals and QTc. METHODS AND RESULTS: A multi-centre cohort enriching aberrant QTc comprised ECGs of healthy controls and long-QT syndrome (LQTS) patients. Manual QT-intervals and QTc were determined by the tangent and threshold methods and compared to automatically generated, vendor-provided values. We assessed agreement globally by intra-class correlation coefficients and pairwise by Bland-Altman analyses and 95% limits of agreement (LoA). Further, manual results were compared to a novel automatic QT-interval algorithm. ECGs of 1263 participants (720 LQTS patients; 543 controls) were available [median age 34 (inter-quartile range 35) years, 55% women]. Comparing cohort means, automatic and manual QT-intervals and QTc were similar. However, pairwise Bland-Altman-based agreement was highly discrepant. For QT-interval, LoAs spanned 95 (tangent) and 92 ms (threshold), respectively. For QTc, the spread was 108 and 105 ms, respectively. LQTS patients exhibited more pronounced differences. For automatic QTc results from 440-540 ms (tangent) and 430-530 ms (threshold), misassessment risk was highest. Novel automatic QT-interval algorithms may narrow this range. CONCLUSION: Pairwise vendor-provided automatic and manual QT-interval and QTc results can be highly discrepant. Novel automatic algorithms may improve agreement. Within the above ranges, automatic QT-interval and QTc results require manual confirmation, particularly if T-wave morphology is challenging.

Functional Characterization of a Spectrum of Novel Romano-Ward Syndrome KCNQ1 Variants.

The KCNQ1 gene encodes the α-subunit of the cardiac voltage-gated potassium (Kv) channel KCNQ1, also denoted as Kv7.1 or KvLQT1. The channel assembles with the ß-subunit KCNE1, also known as minK, to generate the slowly activating cardiac delayed rectifier current IKs, a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function variants in KCNQ1 cause the congenital Long QT1 (LQT1) syndrome, characterized by delayed cardiac repolarization and a QT interval prolongation in the surface electrocardiogram (ECG). Autosomal dominant loss-of-function variants in KCNQ1 result in the LQT syndrome called Romano-Ward syndrome (RWS), while autosomal recessive variants affecting function, lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. The aim of this study was the characterization of novel KCNQ1 variants identified in patients with RWS to widen the spectrum of known LQT1 variants, and improve the interpretation of the clinical relevance of variants in the KCNQ1 gene. We functionally characterized nine human KCNQ1 variants using the voltage-clamp technique in Xenopus laevis oocytes, from which we report seven novel variants. The functional data was taken as input to model surface ECGs, to subsequently compare the functional changes with the clinically observed QTc times, allowing a further interpretation of the severity of the different LQTS variants. We found that the electrophysiological properties of the variants correlate with the severity of the clinically diagnosed phenotype in most cases, however, not in all. Electrophysiological studies combined with in silico modelling approaches are valuable components for the interpretation of the pathogenicity of KCNQ1 variants, but assessing the clinical severity demands the consideration of other factors that are included, for example in the Schwartz score.

Telemedical monitoring in patients with inborn cardiac disease - experience of a tertiary care centre.

BACKGROUND: The number of cardiologically relevant genetic findings will continue to increase. This is due to the use of high-throughput sequencing techniques and the critical role of incidental findings in cardiac disease genes. Telemedicine can be a useful diagnostic tool to monitor the heart rhythm of patients with inborn cardiac diseases. METHODS: Patients were screened once they had been referred to our outpatient department for rare cardiac diseases between January 2020 and May 2022. Those patients who underwent genetic testing and were consequently diagnosed with a genetic disorder were included in this study. Their medical records were evaluated regarding implanted cardiac electronic devices and findings in the telemedical monitoring. RESULTS: 304 patients were seen in our outpatient department for rare cardiac diseases in the mentioned period. In 100 cases, genetic testing was performed. 10 patients (10%) with an identified inborn cardiac disease were monitored via telemedicine until the end of May 2022. 4 patients were monitored by implantable loop recorders (ILR), 4 patients were monitored by Implantable Cardioverter Defibrillators (ICD), and 2 patients received both devices. Clinical relevant arrhythmias making medical intervention necessary were identified in 4 cases. In two cases, data interpretation was hampered by sinus tachycardia caused by physical exercise. DISCUSSION: Telemonitoring of the heart rhythm by medical devices is beneficial for patients with monogenic heart diseases. Especially, when the indication for an ICD is not clear, implantation of a telemonitored ILR can be a suitable choice. However, rhythm analysis can be challenging in young patients who are physically active.

Fetal Bradycardia Caused by Monogenic Disorders-A Review of the Literature.

Introduction: The standard obstetric definition of fetal bradycardia is a sustained fetal heart rate < 110 bpm over at least 10 min. Fetal bradycardia can be the first and only prenatal presentation of a heart disease. We present an overview on different genetic disorders that should be taken into consideration in case of diagnosed fetal bradycardia. Methods: A literature review was conducted using a PubMed- and OMIM-based search for monogenetic disorders causing fetal bradycardia in September 2022. Results: The review on the literature identified nine monogenic diseases that could lead to fetal bradycardia. Four of these disorders can be associated with extracardiac findings. Discussion: Genetic testing should be considered in cases with fetal bradycardia, especially in cases of additional extracardiac findings. Broad sequencing techniques and improved prenatal phenotyping could help to establish a diagnosis in an increasing number of cases.

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

KCNQ1 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 IKs, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 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 KCNQ1 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 KCNQ1 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 Xenopus laevis oocytes, are in agreement with an autosomal recessive disorder, since the IKs reduction was only observed in homomeric mutants, but not in heteromeric IKs channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant IKs 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.

Characterization of an N-terminal Nav1.5 channel variant - a potential risk factor for arrhythmias and sudden death?

BACKGROUND: Alterations in the SCN5A gene encoding the cardiac sodium channel Nav1.5 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 Nav1.5 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 Nav1.5 current over the entire voltage window. CONCLUSION: The results support the assumption that the detected sequence aberration alters Nav1.5 channel function and may predispose to cardiac arrhythmias and sudden cardiac death.

Left-ventricular innervation assessed by 123I-SPECT/CT is associated with cardiac events in inherited arrhythmia syndromes.

AIMS: Impaired myocardial sympathetic innervation assessed by 123Iodine-Metaiodobenzylguanidine (123I-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 123I-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 123MIBG-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.

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

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.

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

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.

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

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.

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

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.

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

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.

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.

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.

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.

Novel calmodulin mutations associated with congenital arrhythmia susceptibility.

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 ß-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.