Congenital Sick Sinus Syndrome Research Articles

КЛИНИЧЕСКИЕ И МОЛЕКУЛЯРНО-ГЕНЕТИЧЕСКИЕ ОСНОВЫ ВНЕЗАПНОЙ СЕРДЕЧНОЙ СМЕРТИ ПРИ ПЕРВИЧНЫХ ЭЛЕКТРИЧЕСКИХ ЗАБОЛЕВАНИЯХ СЕРДЦА У ДЕТЕЙ

Primary electrical heart diseases (PEHDs) are hereditary orphan life-threatening conditions leading to a sudden cardiac death in young adults in the absence of structural heart disease. Among the most common and studied diseases of this group are: long QT syndrome (LQTS), catecholaminergic ventricular tachycardia, Brugada syndrome, short QT syndrome, early ventricular repolarization syndrome. Also, this group of diseases includes congenital sick sinus syndrome, progressive cardiac conduction defect, idiopathic ventricular fibrillation, familial atrial fibrillation and a number of cases (from 5 to 10%) of the sudden cardiac death syndrome in infants. The total prevalence of PEHDs in the pediatric population is quite high and is about 1:2000, mainly due to long QT syndrome. PEHDs are poorly identified by the standard clinical approach, at the same time a delay in diagnosing and prescribing specific therapy may lead to fatal consequences and sudden cardiac death of the child at the first-ever syncope. The vast majority of PEHDs genes identified to date encode subunits of cardiac ion channels or proteins, which interact with ion channels and regulate their functions. The advent of the next generation sequencing led to a shift in most DNA diagnostics laboratories from screening single genes or small gene panels to examining of whole exome or whole genome data. These diseases, especially LQTS, have become unique cardiological models for clinical and genetic studies, analysis of genotype-phenotype correlations and the development of a modern strategy of multi-level hybrid therapy and the prevention of sudden cardiac death (SCD) in people of young age. The most PEHDs can and should be diagnosed in childhood, which now makes it possible to effectively prevent life-threatening arrhythmias. More and more patients are surviving into adulthood, as yet, and patients are interacting with traditional risk factors and obviously should have higher cardiovascular risks. Due to the high prevalence in the population, the association with the SCD, the polymorphism of clinical and genetic manifestations, high technology medicine, the research of PEHDs has become one of the priority places in both pediatric and adult cardiology, and the diseases have now become models for development of gene therapies. The paper outlines the clinical and genetic characteristics, the basics of diagnostics and up-to-date therapeutic, interventional and surgical technologies for the treatment of the most common PEHDs in childhood.

Genetics of Sudden Cardiac Death, the Channelopathies: Today's Perspective and the Future

Channelopathy constitute significant proportion of SCD worldwide (around 10% or 370000 deaths annually). Besides LQTS, the channelopathies include Brugada syndrome (BrS), short QT syndrome, Early Repolarization Syndrome (ERS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and congenital sick sinus syndrome. It was constituting a mysterious group of disease until the second half of the last century when Anton Jervell and Fred Lange-Nielsen described Jervell Lange-Nielsen syndrome in 1957.It was late until 1995 where genetic characterization commenced. Later on, the massive genetic information obtained in the field with discovery of genetic heterogeneity and allelic heterogeneity were all part of our new understanding and clues to solve the historical conundrum of channelopathies. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels. Diving deep into the genetic details of those syndromes enable us to improve our knowdelege and decode the pathophysiology of those malignant arrhythmias. The ultimate ambition is prevention of channelopathy based sudden cardiac death and associated disorders in human.

HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node.

Key points The contribution of HCN4 pacemaker channels in the autonomic regulation of the sino‐atrial node (SAN) has been a matter of debate.The transgenic overexpression of HCN4 did not induce tachycardia, but reduced heart rate variability, while the conditional knockdown of HCN4 gave rise to sinus arrhythmia.The response of the SAN to β‐adrenergic stimulation was not affected by overexpression or knockdown of HCN4 channels.When HCN4 channels were knocked down, the parasympathetic response examined by cervical vagus nerve stimulation (CVNS) was enhanced; the CVNS induced complete sinus pause. The overexpression of HCN4 attenuated bradycardia induced by CVNS only during β‐adrenergic stimulation.We concluded that HCN4 pacemaker channels stabilize the spontaneous firing by attenuating the parasympathetic response of the SAN. The heart rate is dynamically controlled by the sympathetic and parasympathetic nervous systems that regulate the sinoatrial node (SAN). HCN4 pacemaker channels are the well‐known causative molecule of congenital sick sinus syndrome. Although HCN4 channels are activated by cAMP, the sympathetic response of the SAN was preserved in patients carrying loss‐of‐function mutations of the HCN4 gene. In order to clarify the contribution of HCN4 channels in the autonomic regulation of the SAN, we developed novel gain‐of‐function mutant mice in which the expression level of HCN4 channels could be reversibly changed from zero to ∼3 times that in wild‐type mice, using tetracycline transactivator and the tetracycline responsive element. We recorded telemetric ECGs in freely moving conscious mice and analysed the heart rate variability. We also evaluated the response of the SAN to cervical vagus nerve stimulation (CVNS). The conditional overexpression of HCN4 did not induce tachycardia, but reduced heart rate variability. The HCN4 overexpression also attenuated bradycardia induced by the CVNS only during the β‐adrenergic stimulation. In contrast, the knockdown of HCN4 gave rise to sinus arrhythmia, and enhanced the parasympathetic response; complete sinus pause was induced by the CVNS. In vitro, we compared the effects of acetylcholine on the spontaneous action potentials of single pacemaker cells, and found that similar phenotypic changes were induced by genetic manipulation of HCN4 expression both in the presence and absence of β‐adrenergic stimulation. Our study suggests that HCN4 channels attenuate the vagal response of the SAN, and thereby stabilize the spontaneous firing of the SAN.

Congenital sick sinus syndrome: Prenatal diagnosis and postnatal follow-up

Congenital sick sinus syndrome: Prenatal diagnosis and postnatal follow-up

A Functional Assay for Sick Sinus Syndrome Genetic Variants

Background/Aims: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na⁺/K⁺ current (I_f), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. Methods: To determine the function of hcn4 in zebrafish, embryos were either bathed in the I_f -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). Results: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. Conclusions: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information.

Congenital Sick Sinus Syndrome With Atrial Inexcitability and Coronary Sinus Flutter

Congenital sick sinus syndrome has been described sporadically. The syndrome may comprise various components of sinus bradycardia, atrial fibrillation, and right atrial inexcitability.1–7 In the current case, detailed electrophysiological evaluation was undertaken with electroanatomic mapping of the right atrium and coronary sinus (CS) and of associated supraventricular arrhythmias. ### Case A 37-year-old asymptomatic male physician from Mexico without any previous medical problems was referred after routine physical examination for evaluation of atrial fibrillation with a slow ventricular rate. Arrhythmia duration was unknown. He stated that bradycardia had been consistently noted on previous clinical examinations and had been attributed to competitive long-distance running since childhood. Heart rates in the “40s” had been noted since age 10 to 11 years when he had been informed of a “heart murmur.” Subsequent echocardiographic examination had been normal. The patient denied any family history of sudden death or arrhythmias. He had no siblings and no children. His prior records (and those of his parents) were unavailable. Physical examination was normal except for a regular bradycardia of 45 beats/min. Twelve-lead ECG showed fixed R-R intervals. No clear P-wave activity was identified. However, there was small-amplitude baseline electric activity of debatable origin, interpreted variously by experienced electrocardiographers as standstill, artifact, or atrial fibrillation waves (Figure 1A). A transthoracic echocardiogram showed normal ventricular volume and function (left ventricular end-diastolic diameter, 52 mm; left ventricle end-systolic diameter, 34 mm) and mild tricuspid regurgitation with estimated pulmonary artery systolic pressure of 40 mm Hg. Both atria were severely enlarged (left atrial volume index, 58 mL; right atrial area, 41 cm2). Doppler echocardiographic examination of both tricuspid and mitral atrioventricular (AV) inflow showed complete absence of A waves, indicating lack of left and right atrial contractile activity (Figure 2). A transesophageal echocardiogram did not reveal any evidence of …

The Cardiac Conduction System

The human heart beats 2.5 billion times during a normal lifespan, a feat accomplished by cells of the cardiac conduction system (CCS). The functional components of the CCS can be broadly divided into the impulse-generating nodes and the impulse-propagating His-Purkinje system. Human diseases of the conduction system have been identified that alter impulse generation, impulse propagation, or both. CCS dysfunction is primarily due to acquired conditions such as myocardial ischemia/infarct, age-related degeneration, procedural complications, and drug toxicity. Inherited forms of CCS disease are rare, but each new mutation provides invaluable insight into the molecular mechanisms governing CCS development and function. Applying a multidisciplinary approach, which includes human genetic screening, biophysical analysis, and transgenic mouse technology, has yielded a broad array of gene families involved in maintaining normal CCS physiology (Figure 1). In this review, we discuss gene families that have been implicated in human CCS diseases of rhythm, conduction block, accessory conduction, and development (Table). We also investigate evolving therapeutic strategies that may serve as adjuvant or replacement therapy to current implantable pacemakers. Figure 1. Cardiac conduction system cell. Genes identified in human cardiac conduction system disease are highlighted. View this table: Table. Genetic Basis of Conduction System Disease The human sinoatrial node (SAN) is a crescent-shaped, intramural structure with its head located subepicardially at the junction of the right atrium and the superior vena cava and its tail extending 10 to 20 mm along the crista terminalis.26 The SAN has complex 3-dimensional tissue architecture with central and peripheral components made up of distinct ion channel and gap junction expression profiles.27 Central and peripheral cells have different action potential characteristics and conduction properties (Figure 2).27 Experimental and computational models have demonstrated that SAN heterogeneity is necessary to maintain normal automaticity and impulse conduction.28,–,30 Figure 2. Electrophysiological heterogeneity of the …

SCN5A Missense Mutation from a Patient with Complex Cardiac Rhythm and Conduction Disorder Requires the Common Polymorphism H558R on the Same Allele for Arrhythmogenic Biophysical Phenotype

Background: Mutations in SCN5A that decrease peak INa cause several arrhythmogenic syndromes such as type 1 Brugada syndrome (BrS1), cardiac conduction disease (CCD), and congenital sick sinus syndrome (SSS). Here, we report a novel missense mutation (V240M) in SCN5A, in the presence of the common polymorphism H558R that perturbs cardiac rhythm and conduction. Methods and results: A 10-year-old boy had atrial fibrillation and sinus pauses up to 6 seconds during 24h Holter monitoring. Nine months after pacemaker implantation, monomorphic ventricular tachycardia (VT) was recorded during exercise. He was diagnosed clinically with SSS, CCD and VT. Comprehensive open reading frame/splice site mutational analysis of SCN5A was performed using DHPLC and DNA sequencing. A missense mutation (V240M), localized between the DI-S4 and DI-S5 region of the sodium channel, and the common polymorphism H558R were found on the same allele. The double mutation was engineered by site direct mutagenesis and expressed in HEK cells for voltage clamp study. After 24h of transfection, the current densities of SCN5A-V240M were reduced compared with WT channels (-175 ± 27 pA/pF for V240M and -417 ± 100 pA/pF for WT), after 48h of incubation, the current densities of SCN5A-V240M were comparable to WT levels. However, SCN5A-V240M/H558R had current densities dramatically reduced (-34 ± 17 pA/pF). In addition, gating kinetic analysis showed a 10 mV negative shift of inactivation and slower time constants of recovery, all of which would tend to reduce peak INa. Conclusion: The profound biophysical phenotype with loss of function could account for the severity of the clinical phenotype. The requirement for H558R represents another example, and a dramatic one, of phenotype modification by this common polymorphism.

Dilated Cardiomyopathy due to Sodium Channel Dysfunction

The cardiac sodium channel mediates the rapid upstroke of the cardiac action potential and thereby constitutes a critical determinant of cardiac excitability and conduction. Mutations in the SCN5A gene encoding the α-subunit of this channel have been linked to a broad clinical spectrum of arrhythmia disorders, including long QT syndrome, Brugada syndrome, sick sinus syndrome, conduction disease, and most recently, atrial fibrillation.1,2 These primary arrhythmia syndromes were originally considered pure electrical entities occurring in the absence of structural heart disease, and the presence of myocardial abnormalities in these disorders was originally actually excluded by definition. Evidence is now accumulating, however, that sodium channelopathy can also be associated with the development of cardiac fibrosis, dilatation, and hypertrophy.3–8 Such structural changes within the myocardium may in turn further predispose to the development of ventricular arrhythmias. These findings have led to reevaluation of the initial view that mutations in a cardiac ion channel would only lead to pure electrical dysfunction and raised the intriguing possibility that the structural alterations could be a direct consequence of sodium channel dysfunction rather than a consequence of long-standing arrhythmia. The mechanism by which a dysfunctional sodium channel leads to structural changes in myocardial tissue, however, remains unclear. Article p 83 In this issue of Circulation: Arrhythmia and Electrophysiology , Ge et al8 report on a novel SCN5A mutation (A1180V) linked to dilated cardiomyopathy (DCM), expanding the repertoire of SCN5A mutations associated with DCM. Previously, the D1275N mutation was discovered independently by McNair et al5 and Olson et al6 in the same large family with the syndrome of DCM, atrial arrhythmias, sinus node dysfunction, and conduction disease. This family had been originally described by Greenlee et al9 in 1986. The D1275N mutation has also been associated with mild ventricular structural alterations in …

Association of Congenital, Diffuse Electrical Disease in Children with Normal Heart: Sick Sinus Syndrome, Intraventricular Conduction Block, and Monomorphic Ventricular Tachycardia

Rhythm disturbances in children with structurally normal hearts are usually associated with abnormalities in cardiac ion channels. The phenotypic expression of these abnormalities ("channelopathies") includes: long and short QT syndromes, Brugada syndrome, congenital sick sinus syndrome, catecholaminergic polymorphic ventricular tachycardia, Lènegre-Lev disease, and/or different degrees of cardiac conduction disease. The study group consisted of three male patients with sick sinus syndrome, intraventricular conduction disease, and monomorphic sustained ventricular tachycardia. Clinical data and results of electrocardiography, Holter monitoring, electrophysiology, and echocardiography are described. In all patients, the ECG during sinus rhythm showed right bundle branch block and long QT intervals. First-degree AV block was documented in two subjects, and J point elevation in one. A pacemaker was implanted in all cases due to symptomatic bradycardia (sick sinus syndrome). Atrial tachyarryhthmias were observed in two patients. The common characteristic ventricular arrhythmia was a monomorphic sustained ventricular tachycardia, inducible with ventricular stimulation and sensitive to lidocaine. In one patient, radiofrequency catheter ablation was successfully performed. No structural abnormalities were found in echocardiography in the study group. Common clinical and ECG features suggest a common pathophysiology in this group of patients with congenital severe electrical disease.

A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia

Individual mutations in the SCN5A-encoding cardiac sodium channel alpha-subunit cause single cardiac arrhythmia disorders, but a few cause multiple distinct disorders. Here we report a family harboring an SCN5A mutation (L1821fs/10) causing a truncation of the C-terminus with a marked and complex biophysical phenotype and a corresponding variable and complex clinical phenotype with variable penetrance. A 12-year-old male with congenital sick sinus syndrome (SSS), cardiac conduction disorder (CCD), and recurrent monomorphic ventricular tachycardia (VT) had mutational analysis that identified a 4 base pair deletion (TCTG) at position 5464-5467 in exon 28 of SCN5A. The mutation was also present in six asymptomatic family members only two of which showed mild ECG phenotypes. The deletion caused a frame-shift mutation (L1821fs/10) with truncation of the C-terminus after 10 missense amino acid substitutions. When expressed in HEK-293 cells for patch-clamp study, the current density of L1821fs/10 was reduced by 90% compared with WT. In addition, gating kinetic analysis showed a 5-mV positive shift in activation, a 12-mV negative shift of inactivation and enhanced intermediate inactivation, all of which would tend to reduce peak and early sodium current. Late sodium current, however, was increased in the mutated channels. The L1821fs/10 mutation causes the most severe disruption of SCN5A structure for a naturally occurring mutation that still produces current. It has a marked loss-of-function and unique phenotype of SSS, CCD and VT with incomplete penetrance.

Stroke complicating congenital sick sinus syndrome

We report the case of a patient with congenital sick sinus syndrome complicated by atrial fibrillation and embolic stroke 23 years after the initial diagnosis, at the age of 34 years. Treatment with a dual-chamber pacemaker and oral anticoagulation were initiated; further follow-up was uneventful but pacemaker diagnostics constantly documented asymptomatic recurrences of paroxysmal atrial fibrillation.

Expression defects of the common polymorphisms S524Y and H558R in the Q1077 SCN5A variant can be rescued by mexiletine

The cardiac Na channel encoded by SCN5A underlies excitability in the heart. “Loss of function” has been implicated in heritable arrhythmia syndromes such as Brugada syndrome, progressive cardiac conduction disease, and congenital sick sinus syndrome. The polymorphism H558R is very common with minor allelic frequency of 9.2% to 29% in different ethnic groups, and S524Y is common in the black population with a minor allelic frequency of 3.3%. Two splice variants of human SCN5A, one lacking a glutamine at position 1077 (Q1077del) and one containing Q1077, exist in every human in a 2:1 mRNA transcript ratio.

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A).

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the alpha subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.

Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to sinus node dysfunction and diagnosed by electrocardiographic demonstration of sinus bradycardia or sinus arrest. Although frequently associated with underlying heart disease and seen most often in the elderly, SSS may occur in the fetus, infant, and child without apparent cause. In this setting, SSS is presumed to be congenital. Based on prior associations with disorders of cardiac rhythm and conduction, we screened the α subunit of the cardiac sodium channel (SCN5A) as a candidate gene in ten pediatric patients from seven families who were diagnosed with congenital SSS during the first decade of life. Probands from three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrate loss of function or significant impairments in channel gating (inactivation) that predict reduced myocardial excitability. Our findings reveal a molecular basis for some forms of congenital SSS and define a recessive disorder of a human heart voltage-gated sodium channel.