A novel homozygous SCN5A variant detected in sick sinus syndrome.

Sick sinus syndrome (SSS) is a group of disorders characterized by an abnormal cardiac impulse formation or propagation from the sinoatrial node. Mutated SCN5A has been reported in SSS, however, homozygosity of SCN5A is exceedingly rare. Here, we report a consanguineous family with four affected children with SSS. Symptomatic bradycardia necessitated implanting a pacemaker in all of them. Sequencing SCN5A revealed a novel homozygous variant (p.Cys1850Arg), which was predicted to interfere with protein folding. Our report describes the phenotype of a novel homozygous SCN5A variant and contributes to the compendium of molecular pathology of inherited arrhythmias in consanguineous populations.

A homozygous SCN5A mutation associated with atrial standstill and sudden death.

BACKGROUND: Atrial standstill is an arrhythmogenic condition characterized by the absence of spontaneous electrical and mechanical atrial activity or in response to stimulation. There are few reported familial cases which have been associated with SCN5A mutations cosegregating with GJA5 or RYR2; however, isolated SCN5A mutations are rare. OBJECTIVE: The purpose of this study was to determine the clinical and biophysical consequence of a novel SCN5A mutation identified in a family with progressive atrial standstill and sudden death. METHODS: The family of a sporadic case of congenital atrial standstill underwent genetic screening. Human Embryonic Kidney 293 cells were transfected with wild-type (WT) or mutant SCN5A cDNAs. Biophysical properties were studied using whole-cell using patch clamp methods. RESULTS: A novel homozygous SCN5A mutation, p.V1340L, was identified in the proband and her sister. The proband had complete atrial standstill whereas the sister had partial atrial standstill. Heterozygous mutations were identified in the mother, father, and brother. All three had normal sinus rhythm and were asymptomatic. The mutant Nav1.5(V1340L) reduced Nav1.5 current density as well as showed a depolarizing shift in the voltage-dependent steady-state activation (WT: -35.3 ± 1.62 mV; V1340L: -22.4 ± 2.59 mV; P  =  0.001). CONCLUSIONS: A homozygous loss-of-function SCN5A mutation likely results in atrial standstill and sudden death due to suppression of initiation of action potential.

Sinus Node and Atrial Arrhythmias.

Although sinus node dysfunction (SND) and atrial arrhythmias frequently coexist and interact, the putative mechanism linking the 2 remain unclear. Although SND is accompanied by atrial myocardial structural changes in the right atrium, atrial fibrillation (AF) is a disease of variable interactions between left atrial triggers and substrate most commonly of left atrial origin. Significant advances have been made in our understanding of the genetic and pathophysiologic mechanism underlying the development and progression of SND and AF. Although some patients manifest SND as a result of electric remodeling induced by periods of AF, others develop progressive atrial structural remodeling that gives rise to both conditions together. The treatment strategy will thus vary according to the predominant disease phenotype. Although catheter ablation will benefit patients with predominantly AF and secondary SND, cardiac pacing may be the mainstay of therapy for patients with predominant fibrotic atrial cardiomyopathy. This contemporary review summarizes current knowledge on sinus node pathophysiology with the broader goal of yielding insights into the complex relationship between sinus node disease and atrial arrhythmias.

Electrophysiological Effects of Selective Atrial Coronary Artery Occlusion in Humans.

BACKGROUND: The arrhythmogenesis of ventricular myocardial ischemia has been extensively studied, but models of atrial ischemia in humans are lacking. This study aimed at describing the electrophysiological alterations induced by acute atrial ischemia secondary to atrial coronary branch occlusion during elective coronary angioplasty. METHODS AND RESULTS: Clinical data, 12-lead ECG, 12-hour Holter recordings, coronary angiography, and serial plasma levels of high-sensitivity troponin T and midregional proatrial natriuretic peptide were prospectively analyzed in 109 patients undergoing elective angioplasty of right or circumflex coronary arteries. Atrial coronary branches were identified and after the procedure patients were allocated into two groups: atrial branch occlusion (ABO, n=17) and atrial branch patency (non-ABO, n=92). In comparison with the non-ABO, patients with ABO showed: (1) higher incidence of periprocedural myocardial infarction (20% versus 53%, P=0.01); (2) more frequent intra-atrial conduction delay (19% versus 46%, P=0.03); (3) more marked PR segment deviation in the Holter recordings; and (4) higher incidence of atrial tachycardia (15% versus 41%, P=0.02) and atrial fibrillation (0% versus 12%, P=0.03). After adjustment by a propensity score, ABO was an independent predictor of periprocedural infarction (odds ratio, 3.4; 95% confidence interval, 1.01-11.6, P<0.05) and atrial arrhythmias (odds ratio, 5.1; 95% confidence interval, 1.2-20.5, P=0.02). CONCLUSIONS: Selective atrial coronary artery occlusion during elective percutaneous transluminal coronary angioplasty is associated with myocardial ischemic damage, atrial arrhythmias, and intra-atrial conduction delay. Our data suggest that atrial ischemic episodes might be considered as a potential cause of atrial fibrillation in patients with chronic coronary artery disease.

Atrial standstill in sinus node disease due to extensive atrial fibrosis: impact on dual chamber pacemaker implantation.

AIMS: Atrial standstill is characterized by the absence of atrial activity. We report about a series of cases, in which conventional atrial pacemaker lead implantation in patients with symptomatic sinus node disease failed due to lack of excitable right atrial tissue, thus, prompting the diagnosis of atrial standstill. We hypothesized that mapping of the atria with subsequent identification of myocardium still amenable to atrial pacing would allow dual chamber pacemaker implantation. METHODS AND RESULTS: In four patients, atrial lead implantation failed. In these patients, spontaneous or fibrillatory electrical activity was absent but the atria could not be captured despite high stimulation voltages at conventional atrial sites. We suspected partial or complete atrial standstill and subsequently confirmed this hypothesis by conventional (n = 1) or electroanatomical mapping (n = 3). Areas of fibrotic tissue were present in all patients as identified by lack of spontaneous electrical activity and inability of local electrical capture via the mapping catheter. Surviving atrial tissue, which could be electrically captured with subsequent conduction of activity to the atrioventricular (AV) node, was present in three patients. Successful targeted atrial lead implantation at these sites was achieved in all these patients. Isolated sinus node activity without conduction to the atria was found in one patient. CONCLUSION: Partial atrial standstill may be present and prevent atrial lead implantation in patients with sinus node disease. In these patients, recognition of partial atrial standstill and identification of surviving muscular islets with connection to the AV node by mapping studies may still allow synchronous AV sequential pacing.

Pediatric and Familial Genetic Arrhythmia Syndromes: SCN5A-Related Disorders When It Is Not Long QT Type 3: Clinical Signs and Symptoms.

The following case series presents three different pediatric patients with SCN5A-related disease. In addition, family members are presented to demonstrate the variable penetrance that is commonly seen. Identifying features of this disease is important, because even in the very young, SCN5A disorders can cause lethal arrhythmias and sudden death.

Atrial Standstill in the Pediatric Population: A Multi-Institution Collaboration.

BACKGROUND: Atrial standstill (AS) is a rare condition characterized by absence of electrical activity within the atria. Studies to date have been limited. OBJECTIVES: The authors sought to describe the clinical characteristics, genetics, and outcomes of patients with AS. METHODS: This was a retrospective multicenter study of patients <18 years at AS diagnosis, defined as absence of atrial activity documented during an electrophysiology study, device placement, or noninvasive rhythm tracings and confirmed by echocardiogram. Patients with acquired disorders were excluded. Clinical details and genetic variants were recorded and analyzed. RESULTS: Twenty patients were diagnosed at a median age of 6.6 years (IQR: 2.9-10.8 years). Arrhythmias included 16 (80%) with atrial/supraventricular arrhythmias and 8 (40%) with ventricular tachycardia, including 4 with cardiac arrests. A type 1 Brugada pattern was documented in 4. Pacemakers were implanted in 18 (90%). Although atrial leads were attempted in 15, only 4 achieved pacing at implantation. During a median follow-up of 6.9 years (IQR: 1.2-13.3 years), 7 (35%) had thromboembolic events. Of these, none had atrial pacing, 6 were not on anticoagulation, and 1 was on aspirin. Genetic testing identified SCN5A variants in 13 patients (65%). Analyses suggest SCN5A loss-of-function may be one mechanism driving AS. Ventricular arrhythmias and cardiac arrest were more commonly seen in patients with biallelic SCN5A variants. CONCLUSIONS: AS may be associated with loss-of-function SCN5A variants. Patients demonstrate atrial and ventricular arrhythmias, and may present challenges during device placement. Patients without the capacity for atrial pacing are at risk for thromboembolic events and warrant anticoagulation.

Juvenile-onset multifocal atrial arrhythmias, atrial standstill and compound heterozygosity of genetic variants in TAF1A: sentinel event for evolving dilated cardiomyopathy-a case report.

Background: Juvenile onset of extensive atrial electromechanical failure, including atrial standstill, is a rare disease entity that may precede ventricular cardiomyopathy. Genetic variants associated with early-onset atrioventricular (AV) cardiomyopathy are increasingly recognized. Case summary: A 16-year-old patient presented with atrial brady- and tachyarrhythmias and concomitant impaired atrial electromechanical function (atrial standstill). The atrial phenotype preceded the development of a predominantly right-sided AV dilated cardiomyopathy with pronounced myocardial fibrosis. A His-bundle pacemaker was installed for high-degree AV conduction block and sinus arrest. Using familial-based whole-exome sequencing, a missense mutation and a copy number variant deletion (compound heterozygosity) of the TAF1A gene (involved in ribosomal RNA synthesis) were identified. Discussion: Juvenile onset of severe atrial electromechanical failure with atrial arrhythmias should prompt deep pheno- and genotyping and calls for vigilance for downstream cardiomyopathic deterioration.

Atrial standstill associated with lamin A/C mutation: A case report.

The case report shares evidence for a better understanding of atrial standstill. This being a rare arrhythmogenic condition. This is a 46-year-old woman presented with multiple sites of arterial embolism, including lower extremity arteries, coronary artery, and cerebral artery. Unexpectedly, multiple arterial embolization in the patient was due to atrial standstill by transthoracic echocardiography and cardiac electrophysiological study. An additional family investigation revealed that the patient's brother and sister also suffered from this disease. In search of further understanding the case, we carried out the genetic testing of the family and a frame shift double-G insertion mutation at c.1567 in the LMNA gene was found in all the three individuals. The patient recovered well after anticoagulation therapy and left bundle branch area pacing. This report remarks on the importance of multiple sites of arterial embolism which should be wary of family atrial standstill.

Novel pathogenic variant in LMNA gene identified in a six-generation family causing atrial cardiomyopathy and associated right atrial conduction arrhythmias.

Objective: To characterize the cardiac phenotype associated with the novel pathogenic variant (c.1526del) of LMNA gene, which we identified in a large, six-generation family. Methods and Results: A family tree was constructed. The clinical data of living and deceased family members were collected. DNA samples from 7 family members were analyzed for LMNA mutations using whole-exome high-throughput sequencing technology. The clinical presentation of pathogenic variant carriers was evaluated. In this six-generation family (n = 67), one member experienced sudden death at the age of 40-years-old. Three pathogenic variant carriers were identified to possess a novel heterozygous deletion mutation in LMNA gene (HGVS: NM_170707.4, c.1526del) located at exon 9 of LMNA chr1:156137145, which creates a premature translational stop signal (p.Pro509Leufs*39) in the LMNA gene and results in an mutant lamin A protein product. The main symptoms of the pathogenic variant carriers were palpitation, fatigue, and syncope, which typically occurred around 20-years-old. AV-conduction block and non-sustained ventricular tachycardia were the first signs of disease and would rapidly progress to atrial standstill around 30-years-old. Significant right atrial enlargement and bicuspid aortic valve malformation was also commonly seen in patients who carried this pathogenic variant. Conclusion: The pathogenic variant of c.1526del p.P509Lfs*39 was a frameshift deletion located at exon 9 of LMNA chr1:156137145 and causes severe right atrial enlargement, sick sinus syndrome, atrial standstill, ventricular tachycardia, and bicuspid aortic valve malformation. Our findings expand the phenotypic spectrum of novel LMNA gene mutations.

Persistent Atrium Standstill Post Atrial Fibrillation Ablation Therapy.

Atrial standstill is a rare condition in which the atrium loses its mechanical contraction with or without losing the electrical conduction. In this report, we discuss a case of a 64-year-old male patient with a history of hypertrophic cardiomyopathy (HCM) and persistent refractory atrial fibrillation (AF). He underwent ablation therapy with a successful return to sinus rhythm. However, post-procedure echocardiography imaging showed the absence of left atrium mechanical activity. We aim to highlight the importance of assessing atrial mechanical activity by imaging after sinus cardioversion in order to treat any preventable complications promptly.

Left Bundle Branch Area Pacing in a Giant Atrium With Atrial Standstill: A Case Report and Literature Review.

Atrial standstill (AS) is a rare condition defined by the lack of atrial electrical and mechanical activities. It is usually clinically manifested as symptomatic bradycardia, which requires permanent pacemaker (PPM) implantation. Traditional right ventricular apical pacing causes electrical and mechanical dyssynchrony resulting in left ventricular dysfunction, heart failure, and arrhythmias. As a novel physiological pacing strategy, left bundle branch area pacing (LBBaP) has demonstrated effectiveness and safety in recent years, but its application in exceptional conditions is rarely reported. We report the case of a 47-year-old female, who was diagnosed with AS complicated with a giant atrium, and successfully received a single-chamber PPM with LBBaP.

Severe bradycardia caused by diabetic ketoacidosis.

Atrial standstill is an uncommon but serious clinical entity that is often unrecognised in the clinical setting. Its diagnosis and treatment should be swift as malignant arrhythmias and thromboembolic complications can arise. We present a 79-year-old man brought to our emergency department with acute confusion, heart failure and severe bradycardia in the context of diabetic ketoacidosis, and discuss the diagnosis and management of this arrhythmic condition.

Progressive chronic SARS-CoV-2-positive giant cell myoendocarditis with atrial standstill and sudden cardiac death.

Giant cell myocarditis (GCM) is a rare condition. Its association with SARS-CoV-2 has not been described before. The 46-year-old female patient was admitted to the clinic on September 2020. She had 7 year adrenal insufficiency history and infarct-like debut of myocardial disease in November 2019. After COVID-19 in April 2020, cardiac disease progressed. The examination showed low QRS voltage, QS complexes in V1 -V5 leads, atrial standstill, left ventricular systolic and restrictive dysfunction, elevated anti-heart antibodies, and subepicardial late gadolinium enhancement by magnetic resonance imaging. Endomyocardial biopsy and pacemaker implantation were performed, but the patient died suddenly due to ventricular tachycardia or ventricular fibrillation (the resuscitation was ineffective). The autopsy revealed GCM, SARS-CoV-2, and Parvovirus B19 were detected in the myocardium. The role of SARS-CoV-2 in the pathogenesis of autoimmune myocarditis is discussed.

Pathological Features of Persistent Atrial Standstill Syndrome in Three Dogs.

The hearts of three dogs, clinically diagnosed as having persistent atrial standstill syndrome (PAS), were studied post mortem. The most significant gross findings in the hearts of all three dogs were dilatation and marked reduction in the thickness of both atrial walls. Histopathologically, all three had widespread progressive loss of the atrial myocardium with replacement by fatty or fibrofatty tissue, consistent with atrial myopathy. The lesion mainly affected the upper half of both atria and was more severe in the epimyocardium and midmyocardium than in the endomyocardium. On the basis of these observations, it is proposed that the atrial myopathy commences in the upper regions of both atria and progresses downwards, as has been demonstrated electrophysiologically in PAS in humans, and extends from the epicardium towards the endocardium.

Indications for permanent pacing in dogs and cats.

Pacemaker implantation is considered as a standard procedure for treatment of symptomatic bradycardia in both dogs and cats. Advanced second-degree and third-degree atrioventricular blocks, sick sinus syndrome, persistent atrial standstill, and vasovagal syncope are the most common rhythm disturbances that require pacing to either alleviate clinical signs or prolong survival. Most pacemakers are implanted transvenously, using endocardial leads, but rarely epicardial leads may be necessary. To decide whether a patient is a candidate for pacing, as well as which pacing modality should be used, the clinician must have a clear understanding of the etiology, the pathophysiology, and the natural history of the most common bradyarrhythmias, as well as what result can be achieved by pacing patients with different rhythm disturbances. The goal of this review was, therefore, to describe the indications for pacing by evaluating the available evidence in both human and veterinary medicine. We described the etiology of bradyarrhythmias, clinical signs and electrocardiographic abnormalities, and the choice of pacing modality, taking into account how different choices may have different physiological consequences to selected patients. It is expected that this review will assist veterinarians in recognizing arrhythmias that may require permanent pacing and the risk-benefit of each pacing modality and its impact on outcome.

Atrial standstill in suspected isolated cardiac sarcoidosis.

Most of the abnormal cardiac conduction system findings are atrial tachyarrhythmias in cardiac sarcoidosis. However, atrial standstill as a sick-sinus syndrome could be complicated in the case of diffuse atrial fibrosis. Herein, we present an interesting and valuable case of atrial standstill with suspected isolated cardiac sarcoidosis. .