Progressive Cardiac Conduction Disease Research Articles

Abstract Mo079: Analyzing the Predicted Impact of Published SCN5A Variants in Juvenile-Onset Sick Sinus Syndrome

Background: Sick sinus syndrome (SSS) is a cardiac condition caused by sinoatrial node dysfunction, leading to arrhythmias due to the inability to transmit signals properly to the upper chambers of the heart. While age-related degeneration of the sinoatrial node is the most common contributing factor to SSS, congenital disorders involving genetic variants can also lead to its development, even in pediatric patients. To explore the genetic basis of SSS in the pediatric population (age < 19 years), we conducted a comprehensive review of case reports to identify associated genetic variants. Our focus centered on variants reported in the sodium channel protein type 5 subunit alpha ( SCN5A ) gene, which has been reported to contribute to various ventricular arrhythmias, including SSS. Methods: A comprehensive literature review of case reports of juvenile-onset SSS was conducted using PubTator/PubMed and the Online Mendelian Inheritance in Man (OMIM) database to identify SCN5A variants. Case reports were selected if they met the following criteria: at least one patient diagnosed with SSS at or under the age of 19 with a detected variant in the SCN5A gene. The structural effects of identified variants were assessed using the HOPE web service. Results: Data compiled from the literature review provided a total of 53 cases related to juvenile-onset SSS and the SCN5A gene. Among the reported patients, many exhibited multiple arrhythmogenic phenotypes alongside SSS, including progressive cardiac conduction disease, idiopathic ventricular tachycardia, and Brugada syndrome. The majority of identified variants were missense, although truncating and insertion/deletion variants were also documented. All three inheritance variations - heterozygous, homozygous, and compound heterozygous - were observed in this set of patients. Although many of the variants had some functional studies performed to determine their pathogenicity, some of the variants did not have a predicted impact. For these variants, we characterized the location and biochemical properties of the variants, comparing them to the variants with known functional impact. Conclusion: Future studies will explore the functional impact associated with the predicted variants through modeling specific mutations in SCN5A , using cardiomyocytes in vitro . Additionally, using further published studies and surveying the protein structure analysis of SCN5A variants will aid in characterizing those that are specific to SSS.

Systematic analysis of SCN5A variants associated with inherited cardiac diseases

BackgroundSCN5A variants are associated with a spectrum of cardiac electrical disorders with clear phenotypes. However, they may also be associated with complex phenotypic traits like overlap syndromes or pleiotropy, which have not been systematically described. In addition, the involvement of SCN5A in dilated cardiomyopathies (DCMs) remains controversial. ObjectiveWe aimed to evaluate the different phenotypes associated with pathogenic (P)/likely pathogenic (LP) SCN5A variants and to determine the prevalence of pleiotropy in a large multicentric cohort of P/LP SCN5A variant carriers. MethodsThe DNA of 13,510 consecutive probands (9960 with cardiomyopathies) was sequenced with a custom panel of genes. Individuals carrying a heterozygous single P/LP SCN5A variant were selected and phenotyped. ResultsThe study included 170 P/LP variants found in 495 patients. Of them, 119 (70%) were exclusively associated with a single well-established phenotype: 91 with Brugada syndrome, 15 with type 3 long QT syndrome, 6 with progressive cardiac conduction disease, 4 with multifocal ectopic Purkinje-related premature contractions, and 3 with sick sinus syndrome. Thirty-two variants (19%) were associated with overlap syndromes or pleiotropy. The 19 remaining variants (11%) were associated with atypical or unclear phenotypes. Of those, 8 were carried by 8 patients presenting with DCM with a debatable causative genotype/phenotype link. ConclusionMost P/LP SCN5A variants were found in patients with primary electrical disorders, mainly Brugada syndrome. Nearly 20% were associated with overlap syndromes or pleiotropy, underscoring the need for comprehensive phenotypic evaluation. The concept of SCN5A variants causing DCM is extremely rare (8/9960) if not questionable.

Demographics, clinical features and genetics of inherited arrhythmias in Oman

Abstract Background Inherited arrhythmia syndromes (IAS) are a group of rare disorders that result from genetic mutations in several genes encoding ion channels causing disruption in its structure and function and predispose affected individuals to various symptoms including sudden cardiac death (SCD). They include congenital long QT syndrome, Brugada syndrome (BrS), progressive cardiac conduction disease, short QT syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). There have been few reports of long QT syndrome from the Arabian Gulf region but this is the first comprehensive review of multiple inherited arrhythmia syndromes in the region. Objectives Our objective are to describe the demographics of children and adults with inherited arrhythmia syndromes, report the presenting clinical features, genetic mutations and management strategies. Also, to report some unique and rare genetic findings in our population. Methods This is a descriptive retrospective study that included children and adults with inherited arrhythmia syndromes diagnosed and treated at a national heart center over 16 years, between 2006 to 2022. Data collected included patient demographics, geographical distribution, clinical features, genetic reports and management strategies. Result One hundred and six patients were included in the analysis. Sixty-six (62.3%) were males, and 68 (64.2%) were adults and 38 (35.8%) were children. Three inherited arrhythmia syndromes were found in our population that included Long QT, Brugada and catecholaminergic polymorphic ventricular tachycardia (CPVT), which accounted for 58 (54.7%), 39 (36.8%) and 9 (8.5%), respectively. Seventy-six (71.7%) of the patients were reported to be from consanguineous families. Most children, 31 (91.4%) had long QT, whereas most adults, 39(54.9%) had Brugada. The clinical features varied based on the type of arrhythmia. There were 28(26.4%) asymptomatic individuals who were diagnosed incidentally. Syncope was the most common presenting symptom in patients with Long QT, 24(41.4%) and Brugada syndrome, 20(51.3%). Palpitations, 4(44.4%) and bradycardia, 4(44.4%) were the predominant presenting features in patients with CPVT. The treatment modalities included beta blockers and antiarrhythmics, implantable cardioversion defibrillators(ICDs), pacemakers, and left sympathetic ganglionectomy(LSGs). We identified 36 individuals with pathogenic or likely pathogenic variants and 12 VOUS(variants of uncertain significance) in different genes of IAS. Conclusion This is the first comprehensive study on the inherited arrhythmia syndromes in Oman and the Arabian Peninsula. We provided insights about demographics, clinical, genetic profile and the treatment strategies of the most common IAS in the region. Tis study hat will help in early detection of the different types of arrhythmias and early intervention to prevent sudden cardiac death in patients and their relatives.

Biophysical mechanisms of myocardium sodium channelopathies.

Genetic variants of gene SCN5A encoding the alpha-subunit of cardiac voltage-gated sodium channel Nav1.5 are associated with various diseases, including long QT syndrome (LQT3), Brugada syndrome (BrS1), and progressive cardiac conduction disease (PCCD). In the last decades, the great progress in understanding molecular and biophysical mechanisms of these diseases has been achieved. The LQT3 syndrome is associated with gain-of-function of sodium channels Nav1.5 due to impaired inactivation, enhanced activation, accelerated recovery from inactivation or the late current appearance. In contrast, BrS1 and PCCD are associated with the Nav1.5 loss-of-function, which in electrophysiological experiments can be manifested as reduced current density, enhanced fast or slow inactivation, impaired activation, or decelerated recovery from inactivation. Genetic variants associated with congenital arrhythmias can also disturb interactions of the Nav1.5 channel with different proteins or drugs and cause unexpected reactions to drug administration. Furthermore, mutations can affect post-translational modifications of the channels and their sensitivity to pH and temperature. Here we briefly review the current knowledge on biophysical mechanisms of LQT3, BrS1 and PCCD. We focus on limitations of studies that use heterologous expression systems and induced pluripotent stem cells (iPSC) derived cardiac myocytes and summarize our understanding of genotype-phenotype relations of SCN5A mutations.

Prevalence and Clinical Significance of Electrocardiographic Complete Right Bundle Branch Block in Young Individuals.

There is limited information on the clinical significance of complete right bundle branch block (CRBBB) in young individuals. The aim of this study was to determine the prevalence and significance of CRBBB in a large cohort of young individuals aged 14-35 years old. From 2008 to 2018, 104,369 consecutive individuals underwent a cardiovascular assessment with a health questionnaire, electrocardiogram, clinical consultation, and selective echocardiography. Follow-up was obtained via direct telephone consultations. Mean follow-up was 7.3 ± 2.7 years. CRBBB was identified in 154 (0.1%) individuals and was more prevalent in males compared with females (0.20% vs. 0.06%; p<0.05) and in athletes compared with non-athletes (0.25% vs. 0.14%; p<0.05). CRBBB-related cardiac conditions were identified in 7 (5%) individuals (4 with atrial septal defect, 1 with Brugada syndrome, 1 with progressive cardiac conduction disease and 1 with atrial fibrillation). Pathology was more frequently identified in individuals with non-isolated CRBBB compared with individuals with isolated CRBBB (14% vs 1%; p < 0.05) and in individuals with a QRS duration of ≥130 milliseconds (ms) compared with individuals with a QRS of <130ms (10% vs 1%; p<0.05). The prevalence of CRBBB in young individuals was 0.1% and was more prevalent in males and athletes. CRBBB-related conditions were identified in 5% of individuals and were more common in individuals with non-isolated CRBBB and more pronounced intraventricular conduction delay (QRS duration of ≥130ms). Secondary evaluation should be considered for young individuals with CRBBB with symptoms, concerning family history, additional electrocardiographic anomalies or significant QRS prolongation (≥130ms).

Генетически детерминированное прогрессирующее заболевание проводящей системы сердца у ребенка с вариантами гена SCN5A

Progressive cardiac conduction disease (PCCD) refers to a group of genetic disorders that are extremely rare and can be caused by mutations in various genes, including SCN5A. In addition to PCCD, genetic variants of SCN5A can have other diverse phenotypic manifestations in forms of sick sinus syndrome, also known as sinus node dysfunction (SND), atrial fibrillation (AF), Brugada syndrome, long QT syndrome etc. Authors present a clinical case of genetically determined PCCD that had combination of SND (tachy-bradycardia syndrome), AF and intraventricular conduction disorders in a child with histologically confirmed atria fibrosis. Two variants in SCN5A were revealed in the female pediatric patient in a compound heterozygous state during a molecular genetic study. The patient was implanted with a permanent pacemaker, but further progression of the disease led to the manifestation of ventricular tachyarrhythmias and her death. Histological examination confirmed significant replacement of the atrial myocardium with fibrous tissue. Further accumulation of knowledge about the pathogenesis, the course and prognosis of genetically determined cardiac arrhythmias would help identify patients with life-threatening disorders among all children with SCN5A misregulations.

PO-653-06 RISK FACTORS ASSOCIATED WITH INCIDENT CARDIAC CONDUCTION DISEASE

Progressive cardiac conduction disease can lead to syncope, heart failure, and death. The only available therapy is pacemaker implantation, with no established prevention strategies. While a few immutable characteristics have been shown to presage conduction disease, research to identify modifiable risk factors has been scant.

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts.

Sodium voltage-gated channel α subunit 5 (SCN5A)-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with SCN5A-disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one SCN5A pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives. Fifteen patients (88.2%) were male, and sixteen independent variants were found (twelve missense, three truncating and one complex inframe deletion/insertion). The frequency of compound heterozygosity was remarkably high (3/17, 17.6%), with early childhood onset and severe disease. Overall, 70.6% of pediatric patients presented with overlap syndrome, 11.8% with isolated sick sinus syndrome, 11.8% with isolated Brugada syndrome (BrS) and 5.9% with isolated type 3 long QT syndrome (LQTS). A total of 24/45 SCN5A mutation carriers were affected (overall penetrance 53.3%), and penetrance was higher in males (63.3%, 19 affected/30 mutation carriers) than in females (33.3%, 5 affected/15 carriers). In conclusion, pediatric patients with SCNA-disease causing variants presented mainly as overlap syndrome, with predominant loss-of-function phenotypes of sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD) and ventricular arrhythmias.

Left bundle branch area pacing in a young athlete with progressive cardiac conduction (Lev-Lenegre) disease

We present the case of a professional soccer player affected by right bundle branch block and symptomatic 2:1 atrio-ventricular block during effort, due to progressive cardiac conduction disease (Lev-Lenegre disease), who received successful left bundle branch area pacing after a failed attempt at His bundle pacing. The electrocardiographic outcome of paced QRS was consistent with a rapid electrical activation of the left ventricle through the Purkinje system. The pursue of physiological pacing was preferred over conventional, given the young age of our patient and the expectedly high burden of stimulation, to reduce the long-term risk of pacing-induced cardiomyopathy.

Impact of the DSP-H1684R Genetic Variant on Ion Channels Activity in iPSC-Derived Cardiomyocytes.

Mutations of desmosomal genes are known to cause arrhythmogenic cardiomyopathy characterized by arrhythmias and sudden cardiac death. Previously, we described a novel genetic variant H1684R in desmoplakin gene (DSP), associated with a progressive cardiac conduction disease (PCCD). In the present study, we aimed to investigate an effect of the DSP-H1684R genetic variant on the activity of ion channels. We used cardiomyocytes derived from induced pluripotent stem cells (iPSC cardiomyocytes) from a patient with DSP-H1684R genetic variant and from two healthy donors. Immunofluorescent staining and western blot analyses were used to characterize patient-specific cardiomyocytes. By the whole-cell voltage-clamp technique we estimated the activity of voltage-gated sodium, calcium, and potassium channels that are responsible for action potential generation and its shape. Action potentials' parameters were measured using whole-cell current-clamp technique. In patient-specific cardiomyocytes we observed both lower amplitudes of currents through sodium Nav1.5 channels and L-type calcium channels, but higher amplitude of current through transient-outward potassium channels in comparison to donor cardiomyocytes. Current-clamp measurements revealed shortening of action-potential in DSP-H1684R-carrying iPSC cardiomyocytes. Therefore, observed alterations in the channels activity might have a great impact on the properties of action potential and development of PCCD. Our results show that desmoplakin genetic variants, besides conduction slowing caused by structural heart remodeling, could affect multiple ion channel activity aggravating arrhythmia manifestation in PCCD.

Gap-134, a Connexin43 activator, prevents age-related development of ventricular fibrosis in Scn5a+/− mice

Down-regulation of Connexin43 (Cx43) has often been associated with the development of cardiac fibrosis. We showed previously that Scn5a heterozygous knockout mice (Scn5a+/−), which mimic familial progressive cardiac conduction defect, exhibit an age-dependent decrease of Cx43 expression and phosphorylation concomitantly with activation of TGF-β pathway and fibrosis development in the myocardium between 45 and 60 weeks of age. The aim of this study was to investigate whether Gap-134 prevents Cx43 down-regulation with age and fibrosis development in Scn5a+/− mice.We observed in 60-week-old Scn5a+/− mouse heart a Cx43 expression and localization remodeling correlated with fibrosis. Chronic administration of a potent and selective gap junction modifier, Gap-134 (danegaptide), between 45 and 60 weeks, increased Cx43 expression and phosphorylation on serine 368 and prevented Cx43 delocalization. Furthermore, we found that Gap-134 prevented fibrosis despite the persistence of the conduction defects and the TGF-β canonical pathway activation.In conclusion, the present study demonstrates that the age-dependent decrease of Cx43 expression is involved in the ventricular fibrotic process occurring in Scn5a+/− mice. Finally, our study suggests that gap junction modifier, such as Gap-134, could be an effective anti-fibrotic agent in the context of age-dependent fibrosis in progressive cardiac conduction disease.

Generation of two iPSC lines (FAMRCi004-A and FAMRCi004-B) from patient with familial progressive cardiac conduction disorder carrying genetic variant DSP p.His1684Arg.

Human iPSC cell lines (FAMRCi004-A and FAMRCi004-B) were generated from patient with progressive cardiac conduction disease and sick sinus syndrome carrying DSP p.His1684Arg genetic variant. Patient-specific adipose tissue-derived mesenchymal multipotent stromal cells were reprogrammed using non-integrative Sendai viruses. Established iPSC lines showed normal karyotype, expressed pluripotent markers and were able to differentiate toward three germ layers in vitro. The reported iPSC lines could be useful tool for in vitro modeling of progressive cardiac conduction disease associated with mutations in desmosomal genes.

Atrial Flutter as the First Manifestation of Progressive Cardiac Conduction Disease in a Young Apparently Healthy Patient: А Case Report

Abstract We reported a case of a twenty-one-year-old man with an atrial flutter as the first manifestation of progressive cardiac conduction disease. The patient was admitted to the cardiology department due to complaints of shortness of breath and a decrease in exercise tolerance, which had happened after physical exercises (running). During ambulatory ECG monitoring persistent AFL was observed with atrial rate 262-297 bpm and ventricular rate 26-136 bpm (average 56 bpm). AV conduction was very variable – 4:1-14:1. The results of ambulatory ECG monitoring during the whole period of recording indicated signs of atrioventricular conduction disturbances. After cardioversion sinus rhythm was restored additional rhythm and conduction disorders were revealed. Ambulatory ECG monitoring was performed two weeks after the initial one, and throughout this recording were registered sinus rhythm on the background of first-degree AV block; transient Mobitz I AV block; and type 2 second-degree sinoatrial block. Trans-esophageal electrophysiology study was performed. During pharmacological denervation of the heart, signs of slowing of the atrioventricular conduction and sinus node recovery time persisted. These changes along with right bundle branch block were regarded as a progressive cardiac conduction disease with an apparently hereditary cause.

Molecular and genetic insights into progressive cardiac conduction disease.

Progressive cardiac conduction disease (PCCD) is often a primarily genetic disorder, with clinical and genetic overlaps with other inherited cardiac and metabolic diseases. A number of genes have been implicated in PCCD pathogenesis with or without structural heart disease or systemic manifestations. Precise genetic diagnosis contributes to risk stratification, better selection of specific therapy and allows familiar cascade screening. Cardiologists should be aware of the different phenotypes emerging from different gene-mutations and the potential risk of sudden cardiac death. Genetic forms of PCCD often overlap or coexist with other inherited heart diseases or manifest in the context of multisystem syndromes. Despite the significant advances in the knowledge of the genetic architecture of PCCD and overlapping diseases, in a measurable fraction of PCCD cases, including in familial clustering of disease, investigations of known cardiac disease-associated genes fail to reveal the underlying substrate, suggesting that new causal genes are yet to be discovered. Here, we provide insight into genetics and molecular mechanisms of PCCD and related diseases. We also highlight the phenotypic overlaps of PCCD with other inherited cardiac and metabolic diseases, present unmet challenges in clinical practice, and summarize the available therapeutic options for affected patients.

Preprodynorphin gene mutation causes progressive cardiac conduction disease: A whole-exome analysis of a pedigree

AimsProgressive cardiac conduction disease (PCCD) is a rare heart disease that usually shows familial inheritance. Potential genetic risk factors for PCCD have been mostly limited to genes that encode ion channels, cardiac transcription factors, T-box transcription factors, gap junction proteins, energy metabolism regulators and structural proteins. Main methodsSubjects in the present study came from a family who exhibited the autosomal dominant inheritance of PCCD. The primary proband had syncope and an electrocardiogram typical for PCCD, which started in the left bundle branch block, and passed to the atrioventricular block. The patient received a permanent pacemaker in 2013. Pathogenic mutations in the proband's family were identified using whole-exome sequencing and Sanger sequencing. Key findingsThe results for the family members were verified using Sanger sequencing, while the results for healthy unrelated individuals were verified using SNaPShot. All patients in the family shared two adjacent missense mutations in the preprodynorphin (PDYN) gene (c.581A > T, c.580G > C; p.D194L). SignificanceThe PDYN double mutation c.581A > T and c.580G > C (p.D194L) may be linked to the onset of familial PCCD. The effects of these mutations on electrophysiology require further investigation.

Drug-induced fatal arrhythmias: Acquired long QT and Brugada syndromes

Since the early 1990s, the concept of primary "inherited" arrhythmia syndromes or ion channelopathies has evolved rapidly as a result of revolutionary progresses made in molecular genetics. Alterations in genes coding for membrane proteins such as ion channels or their associated proteins responsible for the generation of cardiac action potentials (AP) have been shown to cause specific malfunctions which eventually lead to cardiac arrhythmias. These arrhythmic disorders include congenital long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, short QT syndrome, progressive cardiac conduction disease, etc. Among these, long QT and Brugada syndromes are the most extensively studied, and drugs cause a phenocopy of these two diseases. To date, more than 10 different genes have been reported to be responsible for each syndrome. More recently, it was recognized that long QT syndrome can be latent, even in the presence of an unequivocally pathogenic mutation (silent mutation carrier). Co-existence of other pathological conditions in these silent mutation carriers may trigger a malignant form of ventricular arrhythmia, the so called torsade de pointes (TdP) that is most commonly brought about by drugs. In analogy to the drug-induced long QT syndrome, Brugada type 1 ECG can also be induced or unmasked by a wide variety of drugs and pathological conditions; so physicians may encounter patients with a latent form of Brugada syndrome. Of particular note, Brugada syndrome is frequently associated with atrial fibrillation whose therapeutic agents such as Vaughan Williams class IC drugs can unmask the dormant and asymptomatic Brugada syndrome. This review describes two types of drug-induced arrhythmias: the long QT and Brugada syndromes.

Transforming growth factor β receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease.

Loss-of-function mutations in SCN5A, the gene encoding NaV1.5 channel, have been associated with inherited progressive cardiac conduction disease (PCCD). We have proposed that Scn5a heterozygous knock-out (Scn5a+/-) mice, which are characterized by ventricular fibrotic remodelling with ageing, represent a model for PCCD. Our objectives were to identify the molecular pathway involved in fibrosis development and prevent its activation. Our study shows that myocardial interstitial fibrosis occurred in Scn5a+/- mice only after 45 weeks of age. Fibrosis was triggered by transforming growth factor β (TGF-β) pathway activation. Younger Scn5a+/- mice were characterized by a higher connexin 43 expression than wild-type (WT) mice. After the age of 45 weeks, connexin 43 expression decreased in both WT and Scn5a+/- mice, although the decrease was larger in Scn5a+/- mice. Chronic inhibition of cardiac sodium current with flecainide (50 mg/kg/day p.o) in WT mice from the age of 6 weeks to the age of 60 weeks did not lead to TGF-β pathway activation and fibrosis. Chronic inhibition of TGF-β receptors with GW788388 (5 mg/kg/day p.o.) in Scn5a+/- mice from the age of 45 weeks to the age of 60 weeks prevented the occurrence of fibrosis. However, current data could not detect reduction in QRS duration with GW788388. Myocardial fibrosis secondary to a loss of NaV1.5 is triggered by TGF-β signalling pathway. Those events are more likely secondary to the decreased NaV1.5 sarcolemmal expression rather than the decreased Na+ current per se. TGF-β receptor inhibition prevents age-dependent development of ventricular fibrosis in Scn5a+/- mouse.

Cardiac Arrhythmias Related to Sodium Channel Dysfunction.

The voltage-gated cardiac sodium channel (Nav1.5) is a mega-complex comprised of a pore-forming α subunit and 4 ancillary β-subunits together with numerous protein partners. Genetic defects in the form of rare variants in one or more sodium channel-related genes can cause a loss- or gain-of-function of sodium channel current (INa) leading to the manifestation of various disease phenotypes, including Brugada syndrome, long QT syndrome, progressive cardiac conduction disease, sick sinus syndrome, multifocal ectopic Purkinje-related premature contractions, and atrial fibrillation. Some sodium channelopathies have also been shown to be responsible for sudden infant death syndrome (SIDS). Although these genetic defects often present as pure electrical diseases, recent studies point to a contribution of structural abnormalities to the electrocardiographic and arrhythmic manifestation in some cases, such as dilated cardiomyopathy. The same rare variants in SCN5A or related genes may present with different clinical phenotypes in different individuals and sometimes in members of the same family. Genetic background and epigenetic and environmental factors contribute to the expression of these overlap syndromes. Our goal in this chapter is to review and discuss what is known about the clinical phenotype and genotype of each cardiac sodium channelopathy, and to briefly discuss the underlying mechanisms.

Progressive cardiac conduction disease associated with a DSP gene mutation

Progressive cardiac conduction disease associated with a DSP gene mutation

Atrial Fibrillation and SCN5A Variants.

Although atrial fibrillation (AF) is clinically and genetically a highly heterogeneous disease, recent studies suggest that the arrhythmia may arise because of interactions between genetic and acquired risk factors - the so called "double-hit" hypothesis. Genome-wide association studies have identified common AF susceptibility loci, and linkage analysis and candidate gene approaches have identified mutations in genes that encode for cardiac ion channels and signaling proteins; however, most of the heritability of AF still remains unexplained. The voltage-dependent cardiac sodium channel, encoded by SCN5A, conducts the main cardiac inward sodium current (INa) and is responsible for the upstroke of the atrial action potential. Mutations in SCN5A, which encodes the α-subunit of the NaV1.5 channel, have been linked with increased susceptibility to not only AF but also ventricular arrhythmias (long QT syndrome, Brugada syndrome), progressive cardiac conduction disease, and overlap syndromes with mixed arrhythmia phenotypes. Over the last decade, functional characterization of SCN5A mutations by expressing the channel in heterologous expression systems and applying cellular electrophysiological techniques has not only advanced our understanding of molecular mechanisms of AF but also potentially identified a mechanism-based approach to treating this common and morbid condition.