Progressive Cardiac Conduction Disease Research Articles

Phenotype of a patient with contiguous deletion of TBX5 and TBX3: Expanding the disease spectrum

The important roles that T-box genes play in the morphogenesis of the heart and its conduction system has long been established, and a number of disorders are linked to mutations in these T-box genes. Holt-Oram syndrome (HOS), the classic heart and hand syndrome, is clinically typified by radial ray upper limb abnormalities and cardiac malformations, and is caused by mutations involving TBX5. Another member of the T-box gene family, TBX3, is found in close proximity to TBX5 on chromosome 12q24. Mutations in TBX3 cause ulnar-mammary syndrome (UMS), which is distinguished by upper limb malformations affecting the ulnar ray, apocrine, and mammary gland hypoplasia, and genital defects. While disorders involving isolated mutations of TBX5 and TBX3 have been well described, contiguous deletions of these T-box genes remain exceptional. We report on a patient with features of both HOS and UMS consisting of bilateral symmetric limb malformations, congenital cardiac defects, and rapidly progressive cardiac conduction disease.

Ion channel complex disease in long QT syndrome

Sixty years have passed since the first report of congenital long syndrome (LQTS). The pathogenesis of LQTS was speculated to be ion channel dysfunction in the early 1990s, 1 and mutations in cardiac ion channels were found one after another at the end of the 20th century. 2‐4 Since mutations in cardiac ion channels induced various diseases, including LQTS, Brugada syndrome, and progressive cardiac conduction disease, these inherited arrhythmic diseases were named “ion channel diseases” or “channelopathies.” 5 At first, mutations found in inherited arrhythmia diseases were all mutations in a-subunits of the channels, which are the main components of the ion channels, the mutations in the b-subunit, an auxiliary subunit of the channel, were later reported in Jervell and Lange-Nielsen syndrome, a phenotype of LQTS. 6 It was then shown that the regulation of channels depends not only on its a- and b-subunits but also on multiple cytoskeletal and membrane proteins and that mutations in these protein genes can also cause inherited arrhythmia syndromes. For example, the a-subunit of the cardiac sodium channel (NaV1.5) encoded by the SCN5A gene composes a main channel protein and conducts cardiac sodium current. Some auxiliary proteins interact with NaV1.5 and control its transport to the sarcolemma, cellular location, and gating properties by phosphorylation or dephosphorylation, and anchor NaV1.5 to the cytoskeleton. Mutations in some of these auxiliary proteins showed clinical phenotypes similar to type 3 LQTS (gain of function) or Brugada syndrome (loss of function). Thus, the recent concept of “channelopathy” should not be limited to mutations in the channel protein itself but should be expanded to mutations in the adaptor proteins. Cardiac potassium currents that contribute to ventricular repolarization consist of a rapid activation component (IKr) and a slow activation component (IKs). IKs is activated at phases 2 and 3 of action potential, and it terminates the

Transgenic models of cardiac arrhythmias and sudden death

Transgenic models of cardiac arrhythmias and sudden death

Prognostic Implications of Progressive Cardiac Conduction Disease

Progressive cardiac conduction disease (PCCD), characterized by temporal increase in PR interval and QRS duration, may be attributed to diverse pathophysiological mechanisms. This study aimed to investigate whether PCCD is associated with increased risk of cardiovascular morbidity and mortality. Digital analysis of 12-lead ECG was performed to select patients with PCCD from among a database containing 359,737 ECGs. Long-term prognosis of PCCD was assessed in a large hospital-based population: 458 patients (341 males; mean age, 57.9 ± 14.7 years) with PCCD were enrolled. During a mean follow-up of 13.3 ± 6.4 years, 109 patients were hospitalized for heart failure (HF), and there were 16 and 59 deaths from cardiovascular diseases and all causes, respectively. Multivariate Cox proportional hazards analysis confirmed (1) a significant association of temporal incremental rate of PR interval (≥ 2 ms/year) and QRS duration (≥ 3 ms/year) with HF hospitalization (hazard ratio [HR], 2.34; 95% confidence interval [CI], 1.36-4.05; P=0.002 and HR, 2.08; 95% CI, 1.25-3.53; P=0.01, respectively) and (2) a significant association of temporal incremental rate of PR interval (≥ 4 ms/year) and QRS duration (≥ 5 ms/year) with cardiovascular mortality (HR, 6.9; 95% CI, 1.47-36.96; P=0.02 and HR, 4.31; 95% CI, 1.19-16.5; P=0.03, respectively). The severity of PCCD was independently and significantly associated with HF hospitalization and cardiovascular mortality.

Forever Young

Mutations in the α subunit of the cardiac sodium channel, encoded by SCN5A , have been identified in a broad range of cardiac rhythm disorders that include long QT3 (LQT3), Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, atrial fibrillation, and dilated cardiomyopathy. Since the identification of the first SCN5A mutation in long QT syndrome in 1995, more than 200 mutations have now been reported.1 Initially, it was assumed that each arrhythmic phenotype was attributable to a specific SCN5A mutation; however, overlap syndromes, where single individuals exhibit clinical features of Brugada syndrome and LQT3, are now well characterized.2 The broad phenotypic range of SCN5A mutations underscores the importance of tight sodium channel regulation in maintaining normal rhythmicity. (SELECT FULL TEXT TO CONTINUE)

Pathophysiological Mechanisms of Sino-Atrial Dysfunction and Ventricular Conduction Disease Associated with SCN5A Deficiency: Insights from Mouse Models

Genetically modified mice provide a number of models for studying cardiac channelopathies related to cardiac Na+ channel (SCN5A) abnormalities. We review key pathophysiological features in these murine models that may underlie clinical features observed in sinus node dysfunction and progressive cardiac conduction disease, thereby providing insights into their pathophysiological mechanisms. We describe loss of Na+ channel function and fibrotic changes associated with both loss and gain-of-function Na+ channel mutations. Recent reports further relate the progressive fibrotic changes to upregulation of TGF-β1 production and the transcription factors, Atf3, a stress-inducible gene, and Egr1, to the presence of heterozygous Scn5a gene deletion. Both changes are thus directly implicated in the clinically observed disruptions in sino-atrial node pacemaker function, and sino-atrial and ventricular conduction, and their progression with age. Murine systems with genetic modifications in Scn5a thus prove a useful tool to address questions concerning roles of genetic and environmental modifiers on human SCN5A disease phenotypes.

Defining the Disconnect Between In Vitro Models and Human Arrhythmogenic Disease

Understanding the pathogenetic chain of events between genotype and phenotype is critical to the appropriate diagnosis and treatment of heritable diseases. Although our knowledge of the molecular substrate of many diseases continues to increase, identifying the mechanistic links between a susceptibility variant and disease expression remains a major challenge. A minority of mendelian diseases display complete clinical penetrance in individuals harboring known disease-causing mutations, with rare examples such as achondroplasia and Huntington disease. Even in the most well-characterized hereditary arrhythmia syndrome, the long-QT syndrome (LQTS), in which genotype-phenotype relationships and gene-specific management strategies1 exist for the most common molecular subtypes (LQTS 1 to 3), the reasons for incomplete penetrance and variable expression in this disease remain largely unknown. In fact, LQTS has relatively low penetrance; however, in those LQTS genotype-positive individuals who do exhibit symptoms, the initial presentation can be catastrophic, and all too often, families come to clinical attention as a result of aborted cardiac arrest or sudden cardiac death. Therefore, identification of disease-associated mutations in individuals at risk for heritable arrhythmogenic disorders is imperative for subsequent risk reduction in their family members and them. Article see p 1001 Over the past 10 to 15 years, it has been shown that mutations in SCN5A , the gene encoding the α subunit of the human cardiac sodium channel (Na v 1.5), have pleiotropic effects, including risk for type 3 LQTS, Brugada syndrome, progressive cardiac conduction disease, atrial fibrillation, sick sinus syndrome, sudden infant death syndrome, and dilated cardiomyopathy. This phenotypic plasticity is not unique to SCN5A , but is also observed with other cardiovascular disease–associated genes. For example, mutations in the cardiac ryanodine receptor gene, RYR2 , are associated with catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia/cardiomyopathy. In the current issue of Circulation , Watanabe et al …

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Variations in the gene encoding for the major sodium channel (Na(v)1.5) in the heart, SCN5A, has been shown to cause a number of arrhythmia syndromes (with or without structural changes in the myocardium), including the long-QT syndrome (type 3), Brugada syndrome, (progressive) cardiac conduction disease, sinus node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy. Of equal importance are variations in genes encoding for various subunits and regulatory proteins interacting with the α-subunit Na(v)1.5 and modifying its function. Based on detailed studies of genotype-phenotype relationships in these disease entities, on detailed studies of the basic electrophysiological phenotypes (heterologous expressed wild-type and mutant sodium channels and their interacting proteins), and on attempts to integrate the obtained knowledge, the past 15 years has witnessed an explosion of knowledge about these disease entities.

A Complex Double Deletion in LMNA Underlies Progressive Cardiac Conduction Disease, Atrial Arrhythmias, and Sudden Death

Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death. We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication. We identified for the first time a complex LMNA gene rearrangement involving a double deletion in a 4-generation Dutch family with progressive conduction system disease. Our findings underscore the fact that if conventional polymerase chain reaction-based direct sequencing approaches for LMNA analysis are negative in suggestive pedigrees, mutation detection techniques capable of detecting gross genomic lesions involving deletions and insertions should be considered.

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.

Cardiac sodium channelopathies.

Cardiac sodium channel are protein complexes that are expressed in the sarcolemma of cardiomyocytes to carry a large inward depolarizing current (INa) during phase 0 of the cardiac action potential. The importance of INa for normal cardiac electrical activity is reflected by the high incidence of arrhythmias in cardiac sodium channelopathies, i.e., arrhythmogenic diseases in patients with mutations in SCN5A, the gene responsible for the pore-forming ion-conducting α-subunit, or in genes that encode the ancillary β-subunits or regulatory proteins of the cardiac sodium channel. While clinical and genetic studies have laid the foundation for our understanding of cardiac sodium channelopathies by establishing links between arrhythmogenic diseases and mutations in genes that encode various subunits of the cardiac sodium channel, biophysical studies (particularly in heterologous expression systems and transgenic mouse models) have provided insights into the mechanisms by which INa dysfunction causes disease in such channelopathies. It is now recognized that mutations that increase INa delay cardiac repolarization, prolong action potential duration, and cause long QT syndrome, while mutations that reduce INa decrease cardiac excitability, reduce electrical conduction velocity, and induce Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, or combinations thereof. Recently, mutation-induced INa dysfunction was also linked to dilated cardiomyopathy, atrial fibrillation, and sudden infant death syndrome. This review describes the structure and function of the cardiac sodium channel and its various subunits, summarizes major cardiac sodium channelopathies and the current knowledge concerning their genetic background and underlying molecular mechanisms, and discusses recent advances in the discovery of mutation-specific therapies in the management of these channelopathies.

Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies

Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed. We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype. We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with <or=90% (M(active)) or >90% (M(inactive)) peak I(Na) reduction were analyzed separately. The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group. In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.

Increased Myocardial Collagen Turnover in Patients with Progressive Cardiac Conduction Disease

Histopathologically, progressive cardiac conduction disease (PCCD) is characterized by progressive fibrosis and sclerodegenerative changes in the proximal and distal conduction system of the heart. Therefore, we sought to determine the serum levels of myocardial collagen turnover markers, extracellular matrix components, transforming growth factor beta(1) (TGFbeta(1)), and bone morphogenic protein-7 (BMP-7) in this population. Study population included 20 patients (6 M/14 F, mean age 76 +/- 8 years) with acquired, permanent 2:1, or complete atrioventricular block and compared with age- and sex-matched, asymptomatic, healthy control subjects (n = 18, 6 M/12 F, mean age 75 +/- 7 years). Serum myocardial collagen turnover markers:matrix metalloproteinases (MMP-1, 2, 9), tissue inhibitor of matrix metalloproteinase (TIMP-1), amino-terminal propeptide of procollagen type I (PINP) and type III (PIIINP), carboxy-terminal telopeptide of collagen type I (CITP), and carboxy-terminal propeptide of procollagen type I (PICP), serum extracellular matrix components (laminin and fibronectin), TGFbeta(1), and BMP-7 levels were measured in both groups. Serum PICP (849 +/- 396 vs 631 +/- 294 ng/mL, P = 0.04), PIIINP (3.7 +/- 1.3 vs 3 +/- 1 mug/L, P = 0.03), CITP (0.68 +/- 0.35 vs 0.48 +/- 0.25 ng/mL, P = 0.037), and plasma MMP-9 (58.8 +/- 56 vs 25.9 +/- 17.3 ng/mL, P = 0.006) levels were higher in patient population compared to control subjects. Serum MMP-1 (24.1 +/- 20.5 vs 13.6 +/- 7.5 ng/mL, P = 0.045) and MMP-2 (1310 +/- 139 vs 1186 +/- 163 ng/mL, P = 0.01) levels were higher in control subjects compared to patient population. There was no difference in serum TIMP-1, PINP, laminin, fibronectin, TGFbeta(1), and BMP-7 levels between two groups. Our findings demonstrate the presence of increased myocardial collagen turnover and active fibrotic process in patients with PCCD compared to control subjects.

Penetrance of monogenetic cardiac conduction diseases. A matter of conduction reserve?

See article by Tan et al. [3] (pages 409–417) in this issue. Loss-of-function mutations in the SCN5a gene coding for the human Nav1.5 cardiac sodium channel, which lead to decreased peak sodium current, are associated with cardiac conduction defects (CCD), progressive cardiac conduction disease [1] or Brugada syndrome [2]. However, despite the strong linkage of sodium channel mutations to the disease in probands, the same mutation is often found in non-affected family members. The study by Tan and coworkers in this issue describes a SCN5a mutation leading to a C-terminal truncation (L1821fs/10) that was found in a patient with sick sinus syndrome, CCD and ventricular tachycardia [3]. This particular mutation was shown to lead to an almost complete loss of channel function and thus to haploinsufficiency of the peak sodium current. Interestingly, the same mutation was found in 6 family members of which 2 had very mild symptoms and … *Corresponding author. Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, The Netherlands. Tel.: +31 30 253 8900; fax: +31 30 253 9036. h.v.m.vanrijen{at}med.uu.nl

Progressive Cardiac Conduction Defect is the Prevailing Phenotype in Carriers of a Brugada Syndrome SCN5A Mutation

Loss-of-function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenègre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome. Families were included in the study if a SCN5A mutation was identified in a BS proband and if at least two family members were mutation carriers. Sixteen families met the study criteria, representing 78 carriers. Resting ECG showed a spontaneous BS ECG pattern in 28 of 78 (36%) gene carriers. Intraventricular conduction anomalies were identified in 59 of 78 gene carriers including complete (17) or incomplete (24) right bundle branch block, right bundle branch block plus hemiblock (6), left bundle branch block (1), hemiblock (1), and parietal block (10). PR and QRS duration were longer in the gene carrier cohort in comparison with their relatives carrying no mutation. Finally, in the gene carrier cohort conduction defect progressively aggravated with aging leading in five occasions to pacemaker implantations. The present study shows that the most common phenotype of gene carriers of a BS-type SCN5A mutation is progressive cardiac conduction defects similar to the Lenègre disease phenotype. In consequence, we propose that carriers of a SCN5A mutation need a clinical and ECG follow-up because of the risk associated with severe conduction defects.

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.

Functional Characterization of a Trafficking-defective HCN4 Mutation, D553N, Associated with Cardiac Arrhythmia

Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.

Hereditary progressive cardiac conduction and muscle disease: Clinical staging

Hereditary progressive cardiac conduction and muscle disease: Clinical staging