Progressive Conduction Disease Research Articles

NKX2.5 coding exons sequencing reveals novel non-synonymous mutations in patients with sporadic congenital heart diseases among the Tanzanian population

BackgroundThe evolutionally conserved homeobox transcription factor NKX2-5 has been at the forefront in the field of cardiac biology, providing molecular insights into the mechanisms of cardiac development and disease. This homodomain transcription factor is a central regulator of cardiac development and is expressed in both the first and second heart fields (FHF and SHF). Mutations in the NKX2-5 gene have been linked to sporadic cases of congenital heart disease (CHD), making it a significant target for research and study. While several studies have been conducted on Caucasian populations, there is a dearth of knowledge on the effects of NKX2-5 gene mutations in other settings, underscoring the need for further investigation. Due to differences in geographical and ancestral origin, we hypothesize that mutations may vary across different populations. Understanding the genetic factors that cause CHD is essential for providing effective genetic counseling and developing strategies for risk reduction. Additionally, identification of NKX2-5 mutations in individuals with CHDs is crucial because patients with CHDs are at a higher risk of progressive conduction disease and sudden cardiac death, and genetic information is taken into consideration while making decisions regarding pacemakers and implantable cardiac defibrillators. To determine the risk of congenital heart disease among infants, we conducted a study where we sequenced the exon 1 and exon 2 of NKX 2.5 in patients with sporadic CHDs, with the aim of identifying mutations in the NKX2.5 gene.ResultsIn this study, a novel frame-shift disease-causing mutation was discovered in patients with atrial-ventricular septal defect. The mutation, identified as c95_95 del A; cDNA.369–369 delA; g 369–369 delA, resulted in the substitution of phenylalanine to leucine (F295L), which in turn caused a truncated NKX2.5 protein. In addition, a non-synonymous mutation, g 316C > T; cDNA 316C > T leucine to arginine (L37R) substitution, was found in a patient with the tetralogy of Fallot, affecting protein function. Furthermore, a novel non-synonymous mutation identified as g 2295–2298; cDNA 755–758 delins AGGG, was predicted by mutation taster to be disease-causing in a ventricular septal defect. It is worth noting that none of these mutations were found among the control subjects, highlighting their potential significance in the pathogenesis of these cardiac defects.ConclusionMutations in the NKX2.5 gene are associated with congenital heart diseases and provide molecular insight into the pathogenesis of congenital heart diseases. We recommend that patients with NKX2.5 mutations have periodic screening for cardiac conduction abnormalities and be evaluated for potential implanted cardiac defibrillators and pacemakers.

Abstract 14926: Case of Severe Myocarditis Associated With Nivolumab-Relatlimab

Introduction: Immune checkpoint inhibitors (ICIs) are the standard of care for cancer but can cause immune-related adverse events (irAEs). Nivolumab/Relatlimab combination was approved in March 2022 for unresectable or metastatic melanoma. Cardiac toxicity associated with ICIs is rare but can be fatal. Prompt recognition is key. Description: We present a case of an 84-year-old with no cardiac history who experienced worsening fatigue a week after Nivolumab/Relatlimab infusion. This was followed by myalgia, double vision, shortness of breath, and chest heaviness. Her symptoms worsened, and she sought medical care. Tests showed elevated high-sensitivity troponin T and total creatine kinase levels of 1100 and 6000, respectively. Her first EKG revealed first degree AV block. Within hours, she developed a complete AV block. Her initial LVEF was 75%. She was diagnosed with “triple M" syndrome (myositis, myocarditis, and myasthenia) and received pulse-dose steroids and IV immunoglobulin. She developed myasthenic crisis with respiratory failure requiring intubation. Repeat echocardiogram revealed a drop in LVEF to 43% with new regional wall motion abnormalities attributed to worsening myocarditis. Considering fast progression and poor prognosis, the patient and her family chose comfort measures over escalation of care. Discussion: Myocarditis is a known but rare irAE with reported incidence of less than 1%. It can be associated with myositis and/or myasthenia. Clinical presentation varies, but rapidly progressive conduction disease is one of the most commonly described conditions. Direct T-cell cytotoxicity is the proposed mechanism. Cardiac irAEs can fully resolve if treated early. However, mortality remains elevated. Conclusion: This is one of the few reported cases of severe myocarditis from Nivolumab/Relatlimab. As the combination is still in phase IV development, more cases may emerge in the future and early recognition is vital.

Abstract 17852: A Right Atrial Mass(querader) Causing Complete Heart Block in an Otherwise Healthy Female

Introduction: Right atrial masses are ominous and have a broad differential including thrombus, primary cardiac tumors such as myxoma vs sarcoma, metastatic processes like lymphoma, and, rarely, autoimmune etiologies. In this case, an apple watch notification of bradycardia was a simple start to a complicated course of rapidly progressive conduction disease arising from an unusual presentation of cardiac sarcoidosis. Case Presentation: A 45-year-old previously healthy female originally presented to clinic with a one-month history of exertional dyspnea and palpitations with bradycardia noted on her Apple Watch and an ongoing event monitor revealing transient type II second-degree atrioventricular block. In the office, she was normotensive but bradycardic at 33 beats per minute with electrocardiogram revealing complete heart block with junctional escape. She was admitted for additional work-up with transesophageal echocardiogram (TEE) which was unrevealing. Cardiac magnetic resonance imaging (cMRI) identified two 2 x 2 cm right atrial masses that appeared hypermetabolic on cardiac fluorodeoxyglucose positron emission tomography (FDG cPET) in addition to bilateral hilar lymph nodes. A temporary-permanent pacemaker equipped with a lead capable of floating atrial bipolar sensing was placed while biopsy plans were arranged. Transbronchial ultrasound guided biopsy of the hilar lymph node returned benign. She then underwent two different attempts at transcatheter biopsy of the right atrial masses - one TEE guided, another intracardiac echo (ICE) guided - with most samples unrevealing except one with an inconclusive amount of spindle cells raising concerns for sarcoma. The decision was made to pursue cardiothoracic surgical resection of the right atrial masses with pathology returning with granulomatous lesions consistent with sarcoidosis. Discussion: Cardiac involvement is present in 25% of cases of sarcoidosis and most commonly manifests as conduction abnormalities, ventricular arrhythmia, and/or heart failure. Only a few cases of atrial masses are reported in the literature and its presence in this woman with heart block confounded the picture before a diagnostic biopsy of this treatable condition could be obtained.

Adverse Outcomes With Cardiac Sarcoid: New Zealand Experience in the Modern Era

Diagnosis of cardiac sarcoidosis (CS) has increased with availability of multi-modal imaging yet presenting phenotype and natural history of the disease remain highly variable. This study evaluated experience in the Auckland/Northland regions between 2004 and 2022. A retrospective observational study of patients with CS defined according to Heart Rhythm Society (HRS) criteria. Demographics, diagnostic presentation, and adverse clinical outcomes were evaluated, including heart failure, ventricular arrhythmia (VA), device therapy, transplant, and death. Ninety-nine patients met diagnostic criteria for CS; median age was 55±11 years and 52% were male. Clinical presentations included symptomatic conduction disease in 53%, new heart failure in 24%, in VA 16%, and incidental in 6%. Diagnosis was confirmed by imaging studies: cardiac MRI in 85 patients (86%) and/or positive computed tomography-positron emission tomography (CT-PET) in 47 (47%), and positive cardiac biopsy in 24 (24%). Devices were implanted in 84 (85%) patients, with defibrillator capability in 67 (80%). Seventy (71%) patients experienced 158 adverse events: death in 13%, heart failure in 28%, VA in 27%, device therapies in 21%, progressive conduction disease in 7%, atrial arrhythmias in 3%, stroke in 1%, and transplant in 6%. Twenty-two patients (26%) did not meet Class I indications for implantable cardioverter defibrillator, but more than one-third required device therapy. A regimen of high-dose steroid (>30 mg prednisone) with a tapering regimen was used in 65% of patients, with additional steroid sparing agents in 55%. Complete disease suppression was assessed by repeat PET at 3 months was observed in 55%. Adverse cardiovascular events are common with CS. Over 50% of patients experience cardiac arrhythmia and consideration of appropriate device therapy is important at diagnosis.

PO-03-224 ELECTROPHYSIOLOGY STUDY WITH VENTRICULAR STIMULATION DOES NOT ADEQUATELY RISK STRATIFY PATIENTS WITH MYOTONIC DYSTROPHY

Myotonic dystrophy (MD) types 1 and 2 frequently are associated with progressive conduction disease. Furthermore, patients are at risk ventricular arrhythmias (VAs), although prediction of this remains difficult. The 2021 HRS Guidelines give a IIb recommendation to the use of electrophysiology study (EPS) with ventricular stimulation (v-stim) to risk stratify patients for VAs. The utility of EPS in predicting the development of VAs, however, has not been explored in this patient population. To examine the natural history of MD patients with positive and negative v-stim during EPS. Patients with a history of MD undergoing EPS with associated v-stim from 2007 to present were retrospectively identified. EPS included measurement of baseline conduction intervals. Ventricular stimulation was performed from two sites, most commonly the right ventricular apex and the right ventricular outflow tract, with delivery of up to three ventricular extra-stimuli with a drive cycle length of 600 ms and 400 ms. V-stim was deemed positive when sustained monomorphic ventricular tachycardia (VT) was present or required intervention (pace termination or cardioversion) due to hemodynamic compromise. From 2007-2022, 26 consecutive patients with confirmed type 1 or type 2 myotonic dystrophy presented for EPS with v-stim. Mean age was 51 +/- 12.6 years and mean LV ejection fraction of 63 +/- 9.4%. Eight (31%) v-stim protocols utilized Isoproterenol. Four v-stim protocols were positive for sustained or hemodynamically significant VT, one of which was induced with 600 doubles, the others with triple extra-stimuli. 22 of 26 subjects received a device implant, with 18 receiving pacemakers (PPM) and 4 intracardiac defibrillators (ICD). All four of the patients with positive v-stims underwent ICD implant. After a mean of 5.7 years of follow up, 7 patients with pacemakers had sustained VT, 6 of whom had negative v-stims. Of the 4 patients with positive v-stims, only 1 developed sustained VT in follow-up. In this single center, observational study, v-stim in patients with myotonic dystrophy was not useful in predicting the subsequent development of clinical VAs as a vast majority of MD patients who developed VAs had negative v-stims. Given the changing ventricular substrate in patients with MD, implantation of a dual chamber ICD should be considered without performing an EP study with ventricular stimulation.

Cardiac Manifestations of Myotonic Dystrophy in a Pediatric Cohort.

Myotonic dystrophy type 1 (DM1) is the most prevalent inherited neuromuscular dystrophy in adults. It is a multisystem disease with cardiac manifestations. Whilst these are well-defined in adults, there are scarce published data in the pediatric population. This study aimed to investigate the yield and progression of cardiac disease in pediatric DM1 patients, focusing on congenital DM1 (cDM1).MethodsA retrospective observational study of all pediatric DM1 patients referred to our center (December 2000-November 2020) was conducted. Patients were classified into DM1 forms according to age of symptom onset and disease severity. Patients underwent clinical and cardiac evaluation with 12-lead ECG, transthoracic echocardiography and 24-h ECG Holter monitoring.Results67 DM1 pediatric patients were included: 56 (83.6%) cDM1 and 11 (16.4%) non-cDM1. Median follow-up time of cDM1 patients was 8.0 [3.25–11.0] years. 49 (87.5%) cDM1 patients had baseline 12-lead ECG and 44 (78.6%) had a follow-up 12-lead-ECG, with a median follow-up time from diagnosis to baseline ECG of 2.8 [1.0–8.5] years and to follow-up ECG of 10.9 [5.7–14.2] years. Overall, 43 (87.8%) presented ECG abnormalities, most commonly in the form of asymptomatic conduction disease (n = 23, 46.9%), of which 21 (42.9%) had first degree atrioventricular block (1st AVB). There was an increase of prevalence from baseline to follow-up ECG in low QRS voltage (16.7%), poor R wave progression (13.9%), abnormal repolarisation (11.9%) and 1st AVB (7.6%). one patient (1.8%) underwent pacemaker implantation for syncope in the context of progressive conduction disease. No patients developed left ventricular systolic dysfunction. 4 (7.1%) cDM1 patients died during follow up, including three who died suddenly with no clear cause of death.ConclusionsThis study is the first to analyse the prevalence and progression of ECG abnormalities in cDM1 pediatric patients. The high prevalence of abnormal findings, progressive changes and number of potentially associated events (1 pacemaker implantation and 3 unexplained sudden deaths) stresses the importance of systematic and continued cardiac evaluation of these patients.

Outcomes of cardiac pacing in patients with myotonic dystrophy type 1: A single specialist centre study

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Cardiac conduction disease and sudden cardiac death is known to be associated with Myotonic Dystrophy type 1 (MD). Patients often require device implantation to prevent sudden cardiac death. It is not known how frequently device implantation occurs and how quickly conduction disease progresses. Objective To define the rate and type of device implantation, rate of pacing and outcome in MD patients managed in a single specialist centre. Method Retrospective analysis of pacing and outcome data on consecutive MD patients managed at Specialist Centre in the UK between 2011 and 2021. Results 24/119 MD patients were implanted with a cardiac device. Male:Female 13:11. At implant, patients had a mean age of 56 (95% CI 52 to 59), mean PR interval 217 ms (95% CI 203 to 230), mean QRSd 123ms (95% CI 109 to 137). Devices implanted included 16 DDDR, 4 CRT-D, 1 CRT-P, 1- ICD and 2 VVI pacemakers. 10 (42%) died during follow up of 10 years. 12 out of 19 (63%) with an atrial pacing lead required a mean increase in atrial pacing of 15% (95% CI 5 to 25) during follow up. 12 out of 24 (50%) of patients required mean increase of 13% (95% CI 5 to 22) in Ventricular pacing. 7 (88%) patients who died had evidence of progressive conduction disease prior to death. Conclusion In our cohort of myotonic dystrophy patients 20% required device implantation. There was a higher incidence of progressive atrial rather than ventricular pacing, despite the known concern about progressive AV block. Despite pacing, mortality remained high and was more frequent in patients with progressive conduction disease. Increases in pacing demand could be early indicator of disease progression.

Generation of an iPSC cell line (USFi003-A) from a patient with dilated cardiomyopathy carrying a heterozygous mutation in LMNA (p.R541C)

Mutations in the gene that encodes the nuclear envelope proteins lamin A/C (LMNA) are considered to be a prominent cause of Dilated cardiomyopathy (DCM), a leading cause of heart failure and a prevalent indication for heart transplant. Here we described the generation of induced pluripotent stem cells (iPSCs) from a 53-year-old female with DCM plus progressive conduction disease who carry a heterozygous mutation in LMNA (c.1621C > T, p.R541C). PBMCs isolated from the patient were reprogrammed with Yamanaka factors KOS, KLF4, and c-MYC by the non-integrating sendai virus vector system. The obtained iPSC lines demonstrated normal karyotype and pluripotent identity.

Cardiac Implantable Electronic Devices: A Window Into the Evolution of Conduction Disease in CardiacAmyloidosis.

This study characterized the relationship between conduction disease and cardiac amyloidosis (CA) through longitudinal analysis of cardiac implantable electronic device (CIED) data. Bradyarrhythmias and tachyarrhythmias are commonly reported in CA and may precede a CA diagnosis, although the natural history of conduction disease in CA is not well-described. Patients with CA (transthyretin amyloidosis cardiomyopathy [ATTR-CM] and light-chain amyloidosis [AL-CA]) and a CIED were identified within the Duke University Health System. Patient characteristics at the time of implantation, including demographics and data relevant to CA diagnosis, cardiac imaging, and CIED were recorded. CIED interrogations were analyzed for pacing and atrial fibrillation (AF) burden, activity level, lead parameters, and ventricular arrhythmia incidence and/or therapy. Thirty-four patients with CA (7 with AL-CA, 27 with ATTR-CM [78% with wild-type]; 82% men) with median age of 75 years and a mean ejection fraction of 42 ± 13% had a CIED implanted for bradycardia (65%) or prevention of sudden cardiac death (35%). CIED implantation preceded CA diagnosis in 14 patients (41%). Over a mean follow-up of 3.1± 4.0 years, right ventricular sensing amplitudes decreased but did not result in device malfunction; lead impedances and capture thresholds remained stable. Between post-implantation years 1 and 5, mean ventricular pacing increased from 56 ± 9% to 96 ± 1% (p=0.003) and AF burden increased from 2 ± 1.3 to 17 ± 3 h/day (p=0.0002). Ventricular arrhythmias were common (mean episodes per patient per year: 6.7 ± 2.3 [ATTR-CM] and 5.1 ± 3.2 [AL-CA]) but predominately nonsustained; only 1 patient with AL-CA required implantable cardioverter-defibrillator therapy. Longitudinal analysis of CIED data in patients with CA revealed progressive conduction disease, with high AF burden and eventual dependence on ventricular pacing, although lead parameters remained stable. Ventricular arrhythmias were common but predominantly nonsustained, particularly in ATTR-CM.

P3443Myotonic dystrophy type 1 in childhood: benign from a cardiac perspective?

Abstract Introduction/Purpose Patients with myotonic dystrophy (DM1) have an increased risk of cardiac conduction disease and ventricular tachycardia associated with sudden cardiac death. Whilst this is well-established in adults, there is little published data on cardiac abnormalities in paediatric patients. To our knowledge this is the largest described cohort of children with DM1. The aim of this study is to better understand the prevalence and type of cardiac abnormalities in paediatric patients with DM1. Methods We retrospectively studied consecutive patients referred to our paediatric quaternary institution between 31 December 2000 and 31 January 2019. The electronic patient record was reviewed for the presence of cardiac manifestations, including clinical assessment in clinic, echocardiogram, 12 lead ECG and 24-hour ECG. Results 60 children were identified with a diagnosis of DM1, 56 (93%) with the congenital form of the disease. The median age at diagnosis was 2.4 (IQR 1.2–24, n=52) months. 51 (85%) were under regular formal cardiac follow up. Cardiac symptoms (syncope, palpitations or chest pain) were present in 6 (10%). 12 lead ECGs were available in 50 (83%) and there was at least one echocardiogram performed in 57 (95%). There were 3 deaths (5%), 2 sudden and unexplained (aged 11 and 6.5 years old). 1 child (2%) underwent pacemaker implantation due to the presence of syncope and evidence of progressive conduction disease (Mobitz II AV block). During the period of follow-up, 37 (62%) patients had evidence of conduction disease on 12 lead ECG or Holter: 1st degree or higher AV block (35%, n=21), trifascicular block (6.7%, n=4), intraventricular conduction delay (32%, n=19), prolonged QTc (15%, n=9) and junctional rhythm (5% n=3). In addition to abnormalities of conduction, 27 (45%) patients had axis deviation and 12 (20%) abnormal repolarisation. Abnormalities were present in 8 (14%) of those with an echocardiogram. 2 (3.5%) had hypertrophic cardiomyopathy. Other abnormalities included bicuspid aortic valve, aortic root dilatation, dyskinetic septal motion, pericardial effusion, mitral valve thickening and perimembranous VSD. 24 (40%) patients had a signal averaged ECG of which 14 (58%) were positive in 1 or more vector. 3 (5%) patients had an exercise test with no arrhythmia or progression of conduction abnormalities. 1 patient had an invasive EP study showing a prolonged HV interval but no inducible ventricular tachycardia. Conclusions There appears to be a high incidence of cardiac involvement in children with DM1. Adverse events (death and pacemaker implantation) are represented in our cohort. More studies are required in order to establish how we might better identify those at risk of progression of conduction disease and ventricular arrhythmia. Regular and lifelong cardiac follow up is advisable but risk stratification and device implantation remains challenging.

Functional characterization of TRPM4 variants identified in sudden unexpected natural death

BackgroundThe TRPM4 gene encodes the subunit of the Ca2+-activated nonselective cation channel, which is enriched in the specialized cardiac conduction system and Purkinje fibers. To date, several putative disease-causing variants in TRPM4 have been reported to be associated with cardiac arrhythmia and progressive conduction disease. Here, we report the functional effects of previously uncharacterized variants of uncertain significance (VUS) that we have found while performing a “genetic autopsy” in individuals who have suffered sudden unexpected death (SUD) in the New York City area. Methods and ResultsWe have identified thirteen uncommon missense VUS in TRPM4 by testing 95 targeted genes implicated in channelopathy and cardiomyopathy in 330 cases of SUD. In several cases there were co-existing VUS in one or more other genes that were tested. We selected four TRPM4 VUS (C20S, A380V, L595V and I1082S) for functional characterization, since these cases lacked detectable variants in other genes of our testing panel. Two of the cases were infants, one was a child and one an adult. RNA-seq data analysis showed that the longer TRPM4b splice variant is predominantly expressed in adult and fetal human heart. We therefore used site-directed mutagenesis to introduce these variants in a TRPM4b cDNA. HEK293 cells were transfected with the cDNAs and patch clamping was performed to assess the functional consequences of the TRPM4 mutants. The TRPM4 current was recorded in excised patches and was significantly reduced by each of the mutants. The total protein level of TRPM4-C20S was markedly decreased, whereas the A380V and L595V mutants exhibited decreased surface expression. The TRPM4-A380V current rapidly desensitized following patch excision. ConclusionsEach of the VUS tested caused a defect in TRPM4 channel function via distinctly different mechanisms, hence, it lays the foundation for further co-segregation family studies and animal studies of the TRPM4 variants.

GW28-e1208 SCN5A Mutants Associated with Familial Cardiac Sodium Overlap Syndrome Characterized as Sick Sinus Syndrome, Atrial Fibrillation, Brugada Syndrome, and Progressive Conduction Disease

GW28-e1208 SCN5A Mutants Associated with Familial Cardiac Sodium Overlap Syndrome Characterized as Sick Sinus Syndrome, Atrial Fibrillation, Brugada Syndrome, and Progressive Conduction Disease

GW28-e0741 SCN5A Mutants Associated with Familial Cardiac Sodium Overlap Syndrome Characterized as Sick Sinus Syndrome, Atrial Fibrillation, Brugada Syndrome, and Progressive Conduction Disease

GW28-e0741 SCN5A Mutants Associated with Familial Cardiac Sodium Overlap Syndrome Characterized as Sick Sinus Syndrome, Atrial Fibrillation, Brugada Syndrome, and Progressive Conduction Disease

Missed opportunity for anticoagulation in a patient with AL cardiac amyloidosis and rapidly progressive heart failure

A previously healthy 65-year-old woman presented with progressive symptoms of heart failure. Low-voltage ECG and findings on echocardiography were concerning for infiltrative cardiomyopathy. Cardiac MRI showed biventricular late gadolinium enhancement,...

A Case of Giant Cell Myocarditis Presenting with Rapidly Progressive Conduction Disease and Heart Failure

A Case of Giant Cell Myocarditis Presenting with Rapidly Progressive Conduction Disease and Heart Failure

Progressive conduction disease late after adriamycin treatment of lymphoma, despite normalised ejection fraction

Progressive conduction disease late after adriamycin treatment of lymphoma, despite normalised ejection fraction

Novel and highly lethal NKX2.5 missense mutation in a family with sudden death and ventricular arrhythmia.

To date, several disease-related mutations in NKX2-5, a cardiac-specific homeobox gene, have been documented in patients with a variety of congenital heart diseases (CHDs). The most commonly reported phenotypes are secundum atrial septal defect (ASD) and atrioventricular conduction disease (AVCD). Reports of sudden cardiac death (SCD) have been attributed to progressive conduction disease preventable with pacemaker therapy. A retrospective chart review of individuals from three generations of a family with a novel NKX2-5 mutation associated with CHD, ventricular arrhythmias, and SCD despite pacemaker therapy was conducted. The review documented NKX2-5 Gln181His missense mutation in 11 phenotypically affected members of a single family with a strong family history of SCD, CHD, and AVCD. Before genotyping, four family members died suddenly, two despite pacemaker therapy. The ages at SCD were respectively 23, 29, 44, and 45 years. Observed phenotypic characteristics of genotype-positive patients included ASD, ventricular septal defect, aortic coarctation, tricuspid atresia, supraventricular tachycardia, progressive AVCD, and ventricular tachycardia documented on implantable cardiac defibrillator (ICD) recording. The age at presentation ranged from 5 months to 44 years, and AVCD was seen as early as infancy. Four phenotypically unaffected family members tested negative for the mutation. The findings of this review strongly suggest a new association of this NKX2-5 mutation with SCD from ventricular arrhythmia. This observation has significant implications for the choice of therapy for affected individuals, specifically the use of ICDs, and broadens the observed phenotypic spectrum of NKX2-5 mutations.

Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects

Over the last two decades, an increasing number of SCN5A mutations have been described in patients with long QT syndrome type 3 (LQT3), Brugada syndrome, (progressive) conduction disease, sick sinus syndrome, atrial standstill, atrial fibrillation, dilated cardiomyopathy, and sudden infant death syndrome (SIDS). Combined genetic, electrophysiological and molecular studies have provided insight into the dysfunction and dysregulation of the cardiac sodium channel in the setting of SCN5A mutations identified in patients with these inherited arrhythmia syndromes. However, risk stratification and patient management is hindered by the reduced penetrance and variable disease expressivity in sodium channelopathies. Furthermore, various SCN5A-related arrhythmia syndromes are known to display mixed phenotypes known as cardiac sodium channel overlap syndromes. Determinants of variable disease expressivity, including genetic background and environmental factors, are suspected but still largely unknown. Moreover, it has become increasingly clear that sodium channel function and regulation is more complicated than previously assumed, and the sodium channel may play additional, as of yet unrecognized, roles in cardiac structure and function. Development of cardiac structural abnormalities secondary to SCN5A mutations has been reported, but the clinical relevance and underlying mechanisms are unclear. Increased insight into these issues would enable a major next step in research related to cardiac sodium channel disease, ultimately enabling improved diagnosis, risk stratification and treatment strategies.

Pacemaker and Implantable Cardioverter-Defibrillator Use in a US Myotonic Dystrophy Type 1 Population

We assessed implant rates, indications, characteristics, and outcomes in patients with the neuromuscular disease, myotonic dystrophy type 1 (DM1) receiving a pacemaker or an implantable cardioverter-defibrillator (ICD). Device use was evaluated in a prospective, multicenter registry of 406 genetically confirmed adult patients followed for 9.5 ± 3.2 years. Forty-six (11.3%) had or received a pacemaker and 21 (5.2%) received an ICD. Devices were primarily implanted for asymptomatic conduction abnormalities and left ventricular (LV) systolic dysfunction. However, 7 (15.2%) pacemakers were implanted for third-degree atrioventricular block and 6 (28.6%) ICDs were implanted for ventricular tachyarrhythmias (ventricular tachycardia [VT] or fibrillation [VF]). Patients receiving devices were older and more frequently had heart failure, LV systolic dysfunction, atrial tachyarrhythmias, and ECG conduction abnormalities compared to nondevice patients. Five (10.9%) pacemaker patients underwent upgrade to an ICD, 3 for LV systolic dysfunction, 1 for VT/VF, and 1 for progressive conduction disease. Seventeen (27.4%) of the 62 patients with devices were pacemaker-dependent at last follow-up. Three (14.3%) ICD patients had appropriate therapies. Twenty-four (52.2%) pacemaker patients died including 13 of respiratory failure and 7 of sudden death. Seven (33.3%) ICD patients died including 2 of respiratory failure and 3 of sudden death. The patients with ICDs and sudden death all had LV systolic dysfunction and 1 death was documented due to inappropriate therapies. DM1 patients commonly receive antiarrhythmia devices. The risk of VT/VF and sudden death suggests that ICDs rather than pacemakers should be considered for these patients.

Progressive Conduction Diseases.

Progressive cardiac conduction disease (PCCD), a source of considerable morbidity, comprises a heterogeneous group of conditions resulting from genetic predisposition, environmental modifiers, and other physiologic determinants, including aging. The genetic factors include numerous mutations and variants within the cardiac sodium channel gene, SCN5A. The electrocardiographic phenotype has variable penetrance and is associated with appearances ranging from an isolated conduction disorder to an association with tachyarrhythmias and clinically significant cardiomyopathy. A heterozygotic Scn5a mouse model provides evidence that PCCD may lead to cardiac remodeling consistent with clinical observations in addition to slowing of intracardiac conduction. PCCD has also been associated with the altered expression of genes encoding other proteins involved in impulse propagation, including those responsible for Ca2+- activated ion channels and cytoskeletal components, both in the presence or absence of structural abnormalities.