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Europace : European Pacing,... Oct 2018Cardiac atrial arrhythmias are the most common type of heart rhythm disorders. Its genetic elucidation remains challenging with poor understanding of cellular and...
AIMS
Cardiac atrial arrhythmias are the most common type of heart rhythm disorders. Its genetic elucidation remains challenging with poor understanding of cellular and molecular processes. These arrhythmias usually affect elderly population but in rare cases, young children may also suffer from such electrical diseases. Severe complications, including stroke, are commonly age related. This study aims to identify a genetic link between electro-mechanic atrial dysfunction and stroke in children.
METHODS AND RESULTS
In two unrelated boys of 11 and 14 years with both stroke and atrial arrhythmias, the clinical phenotype was determined through a complete physical examination, electrocardiogram (ECG), Holter ECG, and computed tomography. The genetic testing was performed on a large 95 genes panel implicated in myocardial electrical imbalance, using the next generation sequencing method. The panel also includes the genes usually associated with the development of cardiomyopathies. In one child, a left atrial dilation was observed. The 2nd boy suffered from atrial standstill. Both suffered from atrial bradycardia, flutter, and fibrillation. The complete genetic testing revealed the SCN5A c.3823G>A (p.D1275N) mutation in the first family, c.1141-2A>G and c.3157G>A (p.E1053K) mutations in the second family.
CONCLUSION
Our results strengthen the association between Nav1.5 mutations and the occurrence of stroke in young patients. It emphasizes the need to look for atrial myopathy in the decision process for anticoagulation in young patients with atrial arrhythmic events.
Topics: Adolescent; Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Flutter; Atrial Function, Left; Bradycardia; Cardiomyopathies; Child; Electrocardiography; Genetic Diseases, Inborn; Heart Atria; Heart Block; Humans; Male; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Phenotype; Stroke
PubMed: 29579189
DOI: 10.1093/europace/euy041 -
HeartRhythm Case Reports Nov 2017
PubMed: 29387541
DOI: 10.1016/j.hrcr.2017.07.014 -
Europace : European Pacing,... Oct 2018Unexplained scar-related atrial tachycardia (AT) has been frequently encountered in clinical practice. We hypothesized that idiopathic, isolated fibrotic atrial...
AIMS
Unexplained scar-related atrial tachycardia (AT) has been frequently encountered in clinical practice. We hypothesized that idiopathic, isolated fibrotic atrial cardiomyopathy (ACM) underlies this rhythm disorder. This study was aimed to characterize the underlying substrate and to explore the aetiology of this unexplained scar-related AT.
METHODS AND RESULTS
Twenty-six (11 men, aged 46 ± 13 years) of 52 non-surgical scar-related AT patients identified by three-dimensional voltage mapping were enrolled in this prospective observational study. Multimodality image examinations (echocardiography, cardiac magnetic resonance, 99Tc single-photon emission computed tomography), ventricular voltage mapping, and intracardiac pressure curve recording ruled out ventricular involvement. Catheter ablation was acutely successful for all the patients, and pacemaker implantation was performed in seven patients who presented sinus node dysfunction or atrial standstill after termination of the AT. In three patients with multiple AT recurrences, the diseased areas of the right atrium were resected and dechannelled via mini-invasive surgical interventions. Histological examinations revealed profound fibrosis without amyloidosis or adipose deposition. Viral and familial investigations yielded negative results. Fibrosis progression over a median of 45 (5-109) months of follow-up manifested as atrial arrhythmia recurrence in seven patients and atrial lead non-capture due to newly developed atrial standstill in two patients. Two patients suffered four ischaemic stroke events before receiving anticoagulation treatment.
CONCLUSION
Isolated, fibrotic ACM may underlie the idiopathic scar-related ATs. This novel cardiomyopathy has unique clinical characteristics with high morbidity including stroke and warrants specific therapeutic strategies. Further investigations are required to determine the aetiology and mechanism.
Topics: Adult; Cardiac Pacing, Artificial; Cardiomyopathies; Catheter Ablation; Cicatrix; Disease Progression; Echocardiography; Electrophysiologic Techniques, Cardiac; Female; Fibrosis; Genetic Diseases, Inborn; Heart Atria; Heart Block; Humans; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Sick Sinus Syndrome; Tachycardia, Supraventricular; Tomography, Emission-Computed, Single-Photon
PubMed: 29293999
DOI: 10.1093/europace/eux340 -
Journal of the American Heart... Oct 2017There is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a...
Dysfunction of Myosin Light-Chain 4 (MYL4) Leads to Heritable Atrial Cardiomyopathy With Electrical, Contractile, and Structural Components: Evidence From Genetically-Engineered Rats.
BACKGROUND
There is increasing interest in the concept of atrial cardiomyopathy, but the underlying molecular and mechanistic determinants remain poorly defined. We identified a family with heritable atrial cardiomyopathy manifesting as progressive atrial-selective electromechanical dysfunction, tachyarrhythmias, and bradyarrhythmias requiring pacemaker implantation. Myosin light-chain 4 (), encoding the atrial-selective essential myosin light chain, was identified as a candidate gene. We used genetically modified rat models to investigate the role of in atrial cardiomyopathy.
METHODS AND RESULTS
Exome sequencing and systematic bioinformatic analyses identified a rare missense variant of (c.31G>A []) in a large multiplex atrial cardiomyopathy family pedigree. The mutation cosegregated with atrial standstill (selected as the principal presenting trait) with a logarithm of the odds score of 5.3. The phenotype of rats with mutation knock-in confirmed the causative role of the mutation. knockout rats showed a similar atrial cardiomyopathy phenotype, whereas rats with an adjacent 4-amino-acid deletion showed no phenotype. Both knock-in rats and knockout rats showed progressive atrial electrophysiological, contractile, and fibrotic abnormalities, similar to affected patients. Biochemical analyses of mutation rats showed activation of proapoptotic and profibrotic signaling, along with increased atrial-cardiomyocyte terminal deoxynucleotidyl transferase dUTP nick end labeling staining, suggesting enhanced apoptotic cell death, findings that were mimicked by in vitro adenoviral transfer of the mutant gene to neonatal-rat cardiomyocytes.
CONCLUSIONS
Loss-of-function gene variants cause progressive atrial cardiomyopathy in humans and rats. Our findings identify as a key gene required for atrial contractile, electrical and structural integrity. These results improve our understanding of the molecular basis of atrial cardiomyopathy and introduce new models for further mechanistic analysis.
Topics: Action Potentials; Adult; Animals; Apoptosis; Arrhythmias, Cardiac; Atrial Remodeling; Cardiomyopathies; Disease Models, Animal; Female; Fibrosis; Genetic Predisposition to Disease; Heart Atria; Heart Conduction System; Heart Rate; Heredity; Humans; Male; Mutation, Missense; Myocardial Contraction; Myocytes, Cardiac; Myosin Light Chains; Phenotype; Rats, Transgenic; Signal Transduction; Young Adult
PubMed: 29080865
DOI: 10.1161/JAHA.117.007030 -
Internal Medicine (Tokyo, Japan) 2017Objective Supraventricular arrhythmias are commonly detected in patients with anti-mitochondrial antibody M2 (AMA-M2)-associated myopathy. However, the prevalence of...
Objective Supraventricular arrhythmias are commonly detected in patients with anti-mitochondrial antibody M2 (AMA-M2)-associated myopathy. However, the prevalence of supraventricular arrhythmias in unselected AMA-M2-positive patients and the impact of AMA-M2 on supraventricular arrhythmias have yet to be fully investigated. Methods We analyzed 384 patients (116 men; age, 60 [48-69] years), who underwent AMA-M2 testing following the detection of elevated hepatobiliary enzymes. Supraventricular arrhythmias involving atrial fibrillation, atrial flutter, atrial tachycardia, sick sinus syndrome, and atrial standstill were confirmed by a 12-lead electrocardiogram, 24-hour ambulatory monitoring, and physician-assigned diagnoses within the three years before and two years after the AMA-M2 test. Results Seventy-seven (20%) patients were positive for AMA-M2. The prevalence of supraventricular arrhythmias among AMA-M2-positive patients was higher than that among AMA-M2-negative patients (14% vs. 6%, p=0.008). A univariate analysis showed that supraventricular arrhythmias were associated with AMA-M2 positivity, aging, congestive heart failure, and the CHADS score. The multivariate analysis determined that AMA-M2 positivity was an independent risk factor for supraventricular arrhythmias (odds ratio 3.52, p=0.011). Among the AMA-M2-positive patients, the AMA-M2 titer did not differ to a statistically significant extent, regardless of the presence or absence of supraventricular arrhythmias. Multiple supraventricular arrhythmias with extremely low atrial deflections was a characteristic finding in AMA-M2-positive patients with supraventricular arrhythmias. Conclusion AMA-M2 enhances the risk of supraventricular arrhythmias, indicating the possible involvement of the atrial myocardium and the formation of an arrhythmogenic substrate. The results highlight the need for clinical attention to supraventricular arrhythmias in AMA-M2-positive patients.
Topics: Aged; Antibodies; Atrial Fibrillation; Atrial Flutter; Electrocardiography; Enzymes; Humans; Male; Middle Aged; Mitochondria; Multivariate Analysis; Prevalence; Risk Factors; Tachycardia, Supraventricular
PubMed: 28717071
DOI: 10.2169/internalmedicine.56.8183 -
Journal of the American College of... Jul 2017Inherited cardiac conduction disease is a rare bradyarrhythmia associated with mutations in various genes that affect action potential propagation. It is often...
BACKGROUND
Inherited cardiac conduction disease is a rare bradyarrhythmia associated with mutations in various genes that affect action potential propagation. It is often characterized by isolated conduction disturbance of the His-Purkinje system, but it is rarely described as a syndromic form.
OBJECTIVES
The authors sought to identify the genetic defect in families with a novel bradyarrhythmia syndrome associated with bone malformation.
METHODS
The authors genetically screened 15 European cases with genotype-negative de novo atrioventricular (AV) block and their parents by trio whole-exome sequencing, plus 31 Japanese cases with genotype-negative familial AV block or sick sinus syndrome by targeted exon sequencing of 457 susceptibility genes. Functional consequences of the mutation were evaluated using an in vitro cell expression system and in vivo knockout mice.
RESULTS
The authors identified a connexin-45 (Cx45) mutation (p.R75H) in 2 unrelated families (a de novo French case and a 3-generation Japanese family) who presented with progressive AV block, which resulted in atrial standstill without ventricular conduction abnormalities. Affected individuals shared a common extracardiac phenotype: a brachyfacial pattern, finger deformity, and dental dysplasia. Mutant Cx45 expressed in Neuro-2a cells showed normal hemichannel assembly and plaque formation. However, Lucifer yellow dye transfer and gap junction conductance between cell pairs were severely impaired, which suggested that mutant Cx45 impedes gap junction communication in a dominant-negative manner. Tamoxifen-induced, cardiac-specific Cx45 knockout mice showed sinus node dysfunction and atrial arrhythmia, recapitulating the intra-atrial disturbance.
CONCLUSIONS
Altogether, the authors showed that Cx45 mutant p.R75H is responsible for a novel disease entity of progressive atrial conduction system defects associated with craniofacial and dentodigital malformation.
Topics: Adolescent; Adult; Animals; Atrioventricular Block; Child; Child, Preschool; Connexins; DNA; DNA Mutational Analysis; Dentofacial Deformities; Disease Models, Animal; Disease Progression; Electrocardiography; Female; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Mutation; Pedigree; Phenotype; Young Adult
PubMed: 28705318
DOI: 10.1016/j.jacc.2017.05.039 -
Journal of Veterinary Cardiology : the... Jun 2017To evaluate survival time in dogs with persistent atrial standstill after pacemaker implantation and to compare the survival times for cardiac-related vs. non-cardiac...
OBJECTIVES
To evaluate survival time in dogs with persistent atrial standstill after pacemaker implantation and to compare the survival times for cardiac-related vs. non-cardiac deaths. Secondary objectives were to evaluate the effects of breed and the presence of congestive heart failure (CHF) at the time of diagnosis on survival time.
ANIMALS
Twenty dogs with persistent atrial standstill and pacemaker implantation.
METHODS
Medical records were searched to identify dogs diagnosed with persistent atrial standstill based on electrocardiogram that underwent pacemaker implantation. Survival after pacemaker implantation was analyzed using the Kaplan-Meier method.
RESULTS
The median survival time after pacemaker implantation for all-cause mortality was 866 days. There was no significant difference (p=0.573) in median survival time for cardiac (506 days) vs. non-cardiac deaths (400 days). The presence of CHF at the time of diagnosis did not affect the survival time (P=0.854). No difference in median survival time was noted between breeds (P=0.126).
CONCLUSIONS
Dogs with persistent atrial standstill have a median survival time of 866 days with pacemaker implantation, though a wide range of survival times was observed. There was no difference in the median survival time for dogs with cardiac-related deaths and those without. Patient breed and the presence of CHF before pacemaker implantation did not affect median survival time.
Topics: Animals; Cardiomyopathies; Dog Diseases; Dogs; Genetic Diseases, Inborn; Heart Atria; Heart Block; Pacemaker, Artificial; Survival Analysis; Treatment Outcome
PubMed: 28578822
DOI: 10.1016/j.jvc.2017.03.003 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Apr 2017To explore the clinical features of atrial flutter (AFL) and evaluate the efficacy of radiofrequency catheter ablation (RFCA) for AFL in children. Data were collected...
To explore the clinical features of atrial flutter (AFL) and evaluate the efficacy of radiofrequency catheter ablation (RFCA) for AFL in children. Data were collected and analyzed on 50 consecutive pediatric AFL patients (male 37/female 13) who underwent electrophysiology study and RFCA from February 2009 to November 2016 in a case observational study. The average age was (6.2±3.5) years and body weight was (23.7±13.5) kg. Heart structure was normal in 26 patients. Twenty-four patients had congenital heart disease (CHD) and among them 22 patients underwent repaired surgery before. Patients were followed-up for 1 month to 7 years after RFCA. Clinical features and the outcomes of RFCA in AFL patients were analyzed. The average onset age was (4.2±3.3) years. Of these patients, 84% had persistent AFL and 16% paroxysmal AFL. AFL with sick sinus syndrome (SSS) occurred in 36% patients without statistically significant difference between the groups with and without CHD (38.9%(7/18) . 61.1%(11/18), respectively, =0.239 5); 49 patients underwent RFCA except one case with atrial standstill during the procedure. The total acute success rate was 96%. The follow-up recurrence rate was 8%.No complication of the procedures was observed. The cavotricuspid isthmus-dependent AFL occurred in all patients without CHD. However, in the children with CHD after the repair surgery 10 (45%) cases were with cavotricuspid isthmus-dependent AFL, 4 (8%) with atrial scars-dependent AFL, and 8(16%) with both cavotricuspid isthmus and atrial scars-dependent AFL. RFCA was effective and safe for pediatric AFL. There is no difference on the acute success rate, the follow-up AFL recurrence rate, as well as occurrence of SSS between the groups with and without CHD. AFL patients with CHD included the cavotricuspid isthmus-dependent AFL, atrial scars-dependent AFL or both.
Topics: Atrial Flutter; Cardiomyopathies; Catheter Ablation; Child; Child, Preschool; Cicatrix; Female; Follow-Up Studies; Genetic Diseases, Inborn; Heart Atria; Heart Block; Heart Defects, Congenital; Humans; Male; Middle Aged; Recurrence; Treatment Outcome
PubMed: 28441822
DOI: 10.3760/cma.j.issn.0578-1310.2017.04.007 -
Journal of Veterinary Cardiology : the... Jun 2017Persistent atrial standstill is a rare arrhythmia in both human and veterinary patients. In recent decades, cases of partial atrial standstill have been recognized in...
Persistent atrial standstill is a rare arrhythmia in both human and veterinary patients. In recent decades, cases of partial atrial standstill have been recognized in humans. We describe a case of presumptive partial atrial standstill in a Greyhound, in which there was disparate left and right atrial electromechanical function and rapid progression to congestive heart failure over the span of fourteen weeks. An atrial cardiomyopathy characterized by severe, diffuse, fibrofatty replacement of the atrial myocardium was identified histologically.
Topics: Animals; Arrhythmias, Cardiac; Cardiomyopathies; Dog Diseases; Dogs; Electrocardiography; Fatal Outcome; Female; Genetic Diseases, Inborn; Heart Atria; Heart Block
PubMed: 28314614
DOI: 10.1016/j.jvc.2017.01.003 -
International Journal of Cardiology Dec 2016
Topics: Adult; Atrial Appendage; Cardiomyopathies; Coronary Disease; Genetic Diseases, Inborn; Heart Atria; Heart Block; Humans; Intracranial Embolism; Male; Septal Occluder Device; Treatment Outcome
PubMed: 27723534
DOI: 10.1016/j.ijcard.2016.09.130