Sudden unexpected cardiac death and postmortem identification of a novel RYR2 gene mutation.

A 13-year-old female was found lifeless at home. The autopsy and consecutive histological and toxicological examinations showed blood-rich and edematous lungs and foamy bloody content in the airways. No morphologic pathological findings were seen, especially no bleeding sources. Toxicological findings were unremarkable. The specific cause of death remained unclear. Due to reported losses of consciousness, a moleculargenetic postmortem testing was performed. A so far undescribed mutation in the cardiac ryanodine receptor gene RyR2 was detected. This mutation is suitable to explain the case history as well as the morphological findings. The cardiac ryanodine receptor gene RyR2 encodes the ryanodine receptor type 2, an ion channel in the cardiomyocytes. The ion channel regulates the influx of calcium ions and thus influences myocardial activity. Mutations in this channel may result in the catecholaminergic polymorphic ventricular tachycardia (CPVT), a cardiac arrhythmia that can lead to syncope and sudden cardiac death. This case demonstrates the usefulness and need of molecular autopsy, in particular to identify and treat possibly affected family members.

[Genetic testing to prevent sudden cardiac death]. / Genetische Diagnostik zur Vermeidung des plötzlichen Herztods.

Successfully incorporating genetic testing into clinical practice to prevent sudden cardiac death (SCD) requires (1) appropriate recognition of an inherited cardiovascular condition, (2) identification of appropriate family members at risk and for genetic testing, (3) selection of the appropriate genetic test and information about the expected diagnostic yield, (4) understanding the complexity of result interpretation and distinct handling of incidental findings and (5) providing effective communication and medical advice regarding the genetic and medical results and implications to the patient and his family. Molecular autopsy in SCD victims will be of future importance to determine the cause of death. Interdisciplinary patient care should be provided in specialized centers with a high level of cardiogenetic expertise and is recommended to provide precise and individualized patient management.

Molecular genetic diagnostics for ventricular arrhythmias and sudden cardiac death syndromes.

Inherited forms of ventricular arrhythmias are rare diseases, but a major cause for severe cardiac events, sudden unexplained death syndromes, and death in young adults, infants, and children. Each disorder is genetically heterogeneous (5-20 genes per disease) and molecular testing may include both core genes and less common disease genes as well. Owing to the rapid development and feasibility of sequencing technologies enabling a parallel analysis of several hundred genes up to a whole exome, disease mutations can be identified very efficiently, but have to be seen in the complexity and natural variance of the human genome. Precise phenotypic knowledge and advanced gene variant interpretation are important to ensure adequate patient diagnostics and management. This article focuses on the genetic causes of inherited arrhythmia forms predisposing patients to sudden cardiac death and discusses practical issues and skills for molecular testing.

[Cardiogenetics in Germany- a view and review]. / Kardiogenetik in Deutschland ­ ein (Rück­)Blick.

The development of the cardiogenetics field in Germany has been increasing since the mid-1990s with many national contributions, some of them were really important and groundbreaking. The starting point was and still is the patient and his family, e.g. with a familial form of arrhythmia or cardiomyopathy, the clarification of the genetic cause and the personalized treatment of those being affected. The scientific, always translationally oriented interest in identifying a causative gene and uncovering the underlying pathomechanisms has led to notable contributions for Brugada syndrome, short QT syndrome and cardiac conduction disorders or sinus node dysfunction, but also in DCM or ARVC. What is important, however, is always the way back (bench > bed side): implementation of national and international recommendations for cardiogenetic diagnostics in daily cardiological routine and the personalized care and therapy of those being affected.

Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry.

BACKGROUND: Brugada syndrome is characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD). Fundamental questions remain on the best strategy for assessing the real disease-associated arrhythmic risk, especially in asymptomatic patients. The aim of the present study was to evaluate the prognosis and risk factors of SCD in Brugada syndrome patients in the FINGER (France, Italy, Netherlands, Germany) Brugada syndrome registry. METHODS AND RESULTS: Patients were recruited in 11 tertiary centers in 4 European countries. Inclusion criteria consisted of a type 1 ECG present either at baseline or after drug challenge, after exclusion of diseases that mimic Brugada syndrome. The registry included 1029 consecutive individuals (745 men; 72%) with a median age of 45 (35 to 55) years. Diagnosis was based on (1) aborted SCD (6%); (2) syncope, otherwise unexplained (30%); and (3) asymptomatic patients (64%). During a median follow-up of 31.9 (14 to 54.4) months, 51 cardiac events (5%) occurred (44 patients experienced appropriate implantable cardioverter-defibrillator shocks, and 7 died suddenly). The cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients. Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events, whereas gender, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events. CONCLUSIONS: In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low. Inducibility of ventricular tachyarrhythmia and family history of SCD were not predictors of cardiac events.

Brugada-like cardiac disease in myotonic dystrophy type 2: report of two unrelated patients.

BACKGROUND: Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystem disorder caused by CCTG repeat expansions within intron 1 of the ZNF9 gene on chromosome 3q. Cardiac conduction disturbances, supraventricular arrhythmias, and cardiomyopathy are described in DM2 but Brugada-like features have not yet been reported. Brugada syndrome (BS) is a genetically heterogeneous cardiac conduction disorder which is characterized by a significant ST-segment elevation upon ECG evaluations and bears an increased risk for sudden cardiac death. CASE REPORTS: We report two unrelated patients with genetically confirmed DM2 who developed clinical relevant cardiac arrhythmias with syncopal events from 35 (patient 1) and 47 years (patient 2). Brugada-like ECG findings were present in both patients. Family history was negative for BS, but the mothers of both index patients were also affected by DM2 and had different ventricular rhythm disturbances. SCN5A gene sequencing revealed an unknown genetic variant c.4140 C > A, p.N1380K, in patient 1, while no mutation was detected in patient 2. DISCUSSION: Our observations may suggest that Brugada-like cardiac arrhythmias can occur in DM2, as this seems also to be the case in DM1. The chance association of two independent inherited disorders has to be considered and cannot be excluded in one of our patients. However, on statistical grounds, this possibility cannot explain all observed cases of DM with Brugada-like cardiac disease.

[Totally subcutaneous cardioverter-defibrillator (S-ICD®) : recent experience and future perspectives]. / Komplett subkutaner Kardioverter-Defibrillator (S-ICD®) : Aktuelle Erfahrungen und Ausblick.

The implantable cardioverter defibrillator (ICD) is an established therapy for patients at risk of sudden cardiac death. Nevertheless the endocardial electrode in conventional systems plays a major role in long-term complications (difficult removal, risk of endocarditis, etc.). The totally subcutaneous ICD (S-ICD®, Cameron Health, San Clemente, CA, USA) represents a new and particularly significant development in ICD therapy which, since it requires no electrode in or on the heart, results in significantly fewer perioperative and long-term complications (e.g., thromboembolism and endocarditis risk). Although we see an indication for primary and secondary prevention, patients need to be informed about the limited data from randomized trials with the S-ICD®. As there is no permanent pacing option, patients in whom a pacemaker is indicated are not appropriate candidates for S-ICD®. In addition, patients with ventricular tachycardias that can be terminated by antitachycardic pacing are not recommended for the device. In the present article, we report our initial experience with the 18 patients implanted with the S-ICD® to date, comment on the available studies and offer a critical perspective.

Diagnosis and treatment of cardiac amyloidosis: position statement of the German Cardiac Society (DGK).

Systemic forms of amyloidosis affecting the heart are mostly light-chain (AL) and transthyretin (ATTR) amyloidoses. The latter is caused by deposition of misfolded transthyretin, either in wild-type (ATTRwt) or mutant (ATTRv) conformation. For diagnostics, specific serum biomarkers and modern non-invasive imaging techniques, such as cardiovascular magnetic resonance imaging (CMR) and scintigraphic methods, are available today. These imaging techniques do not only complement conventional echocardiography, but also allow for accurate assessment of the extent of cardiac involvement, in addition to diagnosing cardiac amyloidosis. Endomyocardial biopsy still plays a major role in the histopathological diagnosis and subtyping of cardiac amyloidosis. The main objective of the diagnostic algorithm outlined in this position statement is to detect cardiac amyloidosis as reliably and early as possible, to accurately determine its extent, and to reliably identify the underlying subtype of amyloidosis, thereby enabling subsequent targeted treatment.

Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease.

Heterozygous mutations in the human transcription factor gene NKX2.5 are associated with either isolated or combined congenital heart disease (CHD), primarily secundum atrial septal defect-II (ASD-II), ventricular septal defect (VSD) or tetralogy of Fallot (TOF). Thus, NKX2.5 has an important role at different stages of cardiac development. The frequency of NKX2.5 mutations in a broader phenotypic spectrum of CHD is not completely determined. Here, we report the identification of two novel mutations in the NKX2.5 gene in a screening of 121 patients with a broad spectrum of CHDs. However, mutations were only associated with familial ASD-II and in both, patients also showed atrioventricular (AV) block. We found one missense mutation (R190L) in two siblings with ASD-II and a frame-shift mutation (A255fsX38) at the C-terminus in a mother and daughter. In addition, a single patient with hypoplastic left heart syndrome (HLHS) had the reported sequence variant R25C. Importantly, sporadic cases of CHD that share phenotypic aspects of NKX2.5 mutation carriers were negative for genetic analysis. Thus, even important for cardiac development, germline mutations in NKX2.5 are rare in patients with sporadic CHD and genetic and/or pathophysiologic heterogeneity is likely for sporadic forms of CHD.

QT interval prolongation and risk for cardiac events in genotyped LQTS-index children.

Congenital long-QT syndrome (LQTS) is an inherited cardiac disorder with a disturbance in repolarization characterized by a prolonged QT interval on the surface electrocardiogram and life-threatening ventricular tachycardia. Publications from the International LQTS Registry have provided information that the cardiac risk may be influenced by gender, genotype, exposure to arrhythmia triggers, and previous cardiac events. In children, early-onset of disease, changes in life style, and medical treatment is a sensitive issue and significant, gender-related differences of a first life-threatening event were reported. Thus, we investigated the clinical features of a large genotyped population of LQTS-index children (age < or =16 years) upon a single-center experience and determined risk factors for symptoms. Of 83 children [mean corrected QT interval (QTc) 510 +/- 74 ms], 89% had LQT1, -2, or -3. Nine patients (11%) were identified as having Jervell and Lange-Nielsen syndrome. Among symptomatic children (n = 51, 61%), syncope was the most prevalent symptom at initial presentation (49%); however, aborted cardiac arrest (ACA) occurred in 33% and sudden cardiac death (SCD) in 18%, respectively, as the initial manifestation. During a mean follow-up period of 5.9 +/- 4.7 years, 31% of the children developed symptoms while on therapy (86% syncope, 9% ACA, 5% SCD). Statistical analyses of risk factors for cardiac events showed that the QTc >500 ms was a strong and significant predictor for cardiac events during follow-up (p = 0.02). Furthermore, a prior syncope [hazard ratio (HR), 4.05; 95% confidence interval (CI), 1.1 to 15.0; p = 0.03] or an ACA (HR, 11.7; 95% CI, 3.1 to 43.4; p = <0.001) identified children with an increased risk for recurrent cardiac events compared to asymptomatic LQT children. LQTS-index children manifest with a high percentage of severe symptoms. Among presently validated risk factors for LQTS, a QTc interval >500 ms and a history of prior syncope or ACA were strong predictors for recurrent cardiac events.

Biventricular myocardial strain analysis using cardiac magnetic resonance feature tracking (CMR-FT) in patients with distinct types of right ventricular diseases comparing arrhythmogenic right ventricular cardiomyopathy (ARVC), right ventricular outflow-tract tachycardia (RVOT-VT), and Brugada syndrome (BrS).

OBJECTIVES: As underlying heart diseases of right ventricular tachyarrhythmias, ARVC causes wall-motion abnormalities based on fibrofatty myocardial degeneration, while RVOT-VT and BrS are thought to lack phenotypic MR characteristics. To examine whether cardiac magnetic resonance (CMR) feature tracking (FT) in addition to ARVC objectively facilitates detection of myocardial functional impairments in RVOT-VT and BrS. METHODS: Cine MR datasets of four retrospectively enrolled, age-matched study groups [n = 65; 16 ARVC, 26 RVOT-VT, 9 BrS, 14 healthy volunteers (HV)] were independently assessed by two distinctly experienced investigators regarding myocardial function using CMR-FT. Global strain (%) and strainrate (s-1) in radial and longitudinal orientation were assessed at RVOT as well as for left (LV) and right (RV) ventricle at a basal, medial and apical section with the addition of a biventricular circumferential orientation. RESULTS: RV longitudinal and radial basal strain (%) in ARVC (- 12.9 ± 4.2; 11.4 ± 5.1) were significantly impaired compared to RVOT-VT (- 18.0 ± 2.5, p ≤ 0.005; 16.4 ± 5.2, p ≤ 0.05). Synergistically, RVOT endocardial radial strain (%) in ARVC (33.8 ± 22.7) was significantly lower (p ≤ 0.05) than in RVOT-VT (54.3 ± 14.5). For differentiation against BrS, RV basal and medial radial strain values (%) (13.3 ± 6.1; 11.8 ± 2.9) were significantly reduced when compared to HV (21.0 ± 6.9, p ≤ 0.05; 20.1 ± 6.6, p ≤ 0.005), even in case of a normal RV ejection fraction (EF) (> 45%; n = 6) (12.0 ± 2.7 vs. 20.1 ± 6.6, p ≤ 0.05). CONCLUSIONS: CMR-FT facilitates relevant differentiation in patients with right ventricular tachyarrhythmias: between ARVC against RVOT-VT and HV as well as between BrS with even a preserved EF against HV.

Polymorphisms in the cardiac sodium channel promoter displaying variant in vitro expression activity.

Variable transcription of the cardiac sodium channel gene is a candidate mechanism determining arrhythmia susceptibility. We have previously cloned and characterized the core promoter and flanking region of SCN5A, encoding the cardiac sodium channel. Loss-of-function mutations in this gene have been reported in approximately 20% of patients with Brugada syndrome, an inherited cardiac electrical disorder associated with a high incidence of life-threatening arrhythmias. In this study, we identified DNA variants in the proximal 2.8 kb promoter region of SCN5A and determined their frequency in 1,121 subjects. This population consisted of 88 Brugada syndrome patients with no SCN5A coding region mutation, and 1,033 anonymized subjects from various ethnicities. Variant promoter activity was assayed in CHO cells and neonatal cardiomyocytes by transient transfection of promoter-reporter constructs. Single-nucleotide polymorphisms (SNPs) were identified at approximately 1/200 base pairs which are: 11 in the 5'-flanking region, 1 in exon 1, and 5 in intron 1. In addition, a haplotype consisting of two SNPs in complete linkage disequilibrium was identified. Minor allele frequencies were >5% in at least one ethnic panel at 5/19 polymorphic sites. In vitro functional analysis in cardiomyocytes identified four variants with significantly (P<0.05) reduced reporter activity (up to 63% reduction). The largest changes were seen with c.-225-1790 G>A, which reduced reporter activity by 62.8% in CHO cells and 55% in cardiomyocytes. From these results, we can conclude that the SCN5A core promoter includes multiple DNA polymorphisms with altered in vitro activity, further supporting the concept of interindividual variability in transcription of this cardiac ion channel gene.

De novo mutation in the SCN5A gene associated with early onset of sudden infant death.

BACKGROUND: Congenital long QT syndrome (LQTS), a cardiac ion channel disease, is an important cause of sudden cardiac death. Prolongation of the QT interval has recently been associated with sudden infant death syndrome, which is the leading cause of death among infants between 1 week and 1 year of age. Available data suggest that early onset of congenital LQTS may contribute to premature sudden cardiac death in otherwise healthy infants. METHODS AND RESULTS: In an infant who died suddenly at the age of 9 weeks, we performed mutation screening in all known LQTS genes. In the surface ECG soon after birth, a prolonged QTc interval (600 ms(1/2)) and polymorphic ventricular tachyarrhythmias were documented. Mutational analysis identified a missense mutation (Ala1330Pro) in the cardiac sodium channel gene SCN5A, which was absent in both parents. Subsequent genetic testing confirmed paternity, thus suggesting a de novo origin. Voltage-clamp recordings of recombinant A1330P mutant channel expressed in HEK-293 cells showed a positive shift in voltage dependence of inactivation, a slowing of the time course of inactivation, and a faster recovery from inactivation. CONCLUSIONS: In this study, we report a de novo mutation in the sodium channel gene SCN5A, which is associated with sudden infant death. The altered functional characteristics of the mutant channel was different from previously reported LQTS3 mutants and caused a delay in final repolarization. Even in families without a history of LQTS, de novo mutations in cardiac ion channel genes may lead to sudden cardiac death in very young infants.

Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.

BACKGROUND: The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. METHODS AND RESULTS: We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. CONCLUSIONS: Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.

A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype.

Mutations in the human minK gene KCNE1 have been linked to autosomal dominant and autosomal recessive long-QT (LQT) syndrome, a cardiac condition predisposing to ventricular arrhythmias. minK and KvLQT1, the LQT1 gene product, form a native cardiac K+ channel that regulates the slowly delayed rectifier potassium current I(Ks). We used single-strand conformation polymorphism and sequencing techniques to identify novel KCNE1 mutations in patients with a congenital LQT syndrome of unknown genetic origin. In 150 unrelated index patients a missense mutation (V109I) was identified that significantly reduced the wild-type I(Ks) current amplitude (by 36%) when coexpressed with KvLQT1 in Xenopus oocytes. Other biophysical properties of the I(Ks) channel were not altered. Since we observed incomplete penetrance (only one of two mutation carriers could be diagnosed by clinical criteria), and the family's history was unremarkable for sudden cardiac death, the 109I allele most likely causes a mild phenotype. This finding may have implications for the occurrence of "acquired" conditions for ventricular arrhythmias and thereby the potential cardiac risk for asymptomatic mutation carriers still remains to be determined.

Molecular analysis at the Harvey Ras-1 gene in patients with long QT syndrome.

Patients with long QT syndrome (LQTS; MIM 1921500) frequently suffer from syncope and are threatened by sudden cardiac death due to ventricular arrhythmias, typically of the torsade de pointes type. Initial progress in revealing the molecular basis of the disease was made by the observation of genetic linkage of the disease locus to the Harvey Ras-1 gene (HRAS 1) on chromosome 11p15.5. More recently loci on chromosomes 3, 4, and 7 have also been found to be linked to LQTS, thus demonstrating heterogeneity in the causes for this disease. The present study performed sequence analysis on the HRAS 1 gene in patients with congenital and acquired LQTS to determine the frequency of HRAS 1 mutations in patients with this disease. In neither group were no mutations identified in the coding regions or in the splice donor and acceptor sites. Alleles characterized by a T to C transition in exon 1 and an insertion/deletion polymorphism upstream of exon 1 showed no significant difference in their frequencies between LQTS patients and normal controls. No quantitative influence of the such characterized genotypes on the QT duration was observed. These results demonstrate that structural mutations in the HRAS 1 gene are not a frequent cause of LQTS. Also, since there was no association of different alleles at the HRAS 1 locus with changes in QT duration, it appears unlikely that this gene is a major contributor to this disease.

[Right ventricular tachyarrhythmias--diagnostics and therapy]. / Rechtsventrikuläre Tachyarrhythmien--Diagnostik und Therapie.

Ventricular tachyarrhythmias originating from the right ventricle frequently occur in young, apparently healthy patients with rare underlying cardiac diseases. Among these are arrhythmogenic right ventricular cardiomyopathy (ARVC), idiopathic right ventricular outflow-tract tachycardia (RVOVT), and Brugada syndrome (BrS). All harbor the risk of sudden cardiac death, whereas they differ substantially as to diagnosis, therapy and prognosis. This is the reason why detailed investigations are an essential prerequisite for further efficient individualized management strategies which are mainly directed to prevent sudden cardiac death and to minimize the risk of arrhythmia recurrences in affected patients, respectively. Both antiarrhythmic drug therapy, catheter ablation, and the implantation of an automatic cardioverter defibrillator may, therefore, be a first-line therapeutic option in tailored treatment regimens. This review is a summary of the available literature on pathogenesis, diagnosis, treatment, and prognosis of such diseases associated with right ventricular tachyarrhythmias.

[Atrial flutter after orthotopic heart transplantation due to recipient-to-donor transatrial conduction]. / Vorhofflattern in der Frühphase nach orthotoper Herztransplantation.

A few weeks after orthotopic heart transplantation, a male adolescent developed atrial arrhythmias of the donor heart due to an atypical recipient atrial flutter with a recipient-to-donor transatrial conduction resulting in an absolute arrhythmia. Under medication with propafenone, the atrial flutter of the donor heart could be terminated with cardioversion.

Gene-specific differences in the circadian variation of ventricular repolarization in the long QT syndrome: a key to sudden death during sleep?

BACKGROUND: In the long QT syndrome (LQTS) most life-threatening cardiac events occur in association with physical or emotional stress. However, a minority of patients dies suddenly during sleep; intriguingly, these sleep-related sudden deaths tend to cluster in families. The mechanism(s) underlying this phenomenon and the reason why it occurs in few selected families are unknown. Recently, some of the LQTS genes have been identified leading to three main subgroups (LQT1, LQT2, LQT3) associated respectively with mutations affecting the following ionic currents involved in the control of ventricular repolarization: I(Ks), I(Kr), I(Na). We have recently observed that cardiac events nighttime are rare in LQT1 and frequent in LQT3 patients. METHODS: We studied 26 LQTS patients all genotyped (11 LQT1, 9 LQT2, 6 LQT3) and 26 healthy controls matched by age and gender. Using a specific software, 24-hour ambulatory ECG recordings were performed and the QT interval was measured in order to allow comparison between QTc nighttime and daytime. RESULTS: The main finding is that while LQT1 patients show a trend for modest QTc shortening and LQT2 patients a trend for modest lengthening nighttime versus daytime, LQT3 patients show clear lengthening of the QTc nighttime. These changes are not explained by heart rate changes or by the use of beta-blockers. CONCLUSIONS: The marked tendency for further QT prolongation nighttime, which clearly increases arrhythmic risk, present among LQT3 patients and absent among LQT1 patients, provides an explanation for the gene-specific higher risk for sudden death during sleep for LQT3 compared to LQT1 patients.