-
Frontiers in Physiology 2013Slowed myocardial conduction velocity (θ) is associated with an increased risk of re-entrant excitation, predisposing to cardiac arrhythmia. θ is determined by the ion...
Slowed myocardial conduction velocity (θ) is associated with an increased risk of re-entrant excitation, predisposing to cardiac arrhythmia. θ is determined by the ion channel and physical properties of cardiac myocytes and by their interconnections. Thus, θ is closely related to the maximum rate of action potential (AP) depolarization [(dV/dt)max], as determined by the fast Na(+) current (I Na); the axial resistance (r a) to local circuit current flow between cells; their membrane capacitances (c m); and to the geometrical relationship between successive myocytes within cardiac tissue. These determinants are altered by a wide range of pathophysiological conditions. Firstly, I Na is reduced by the impaired Na(+) channel function that arises clinically during heart failure, ischemia, tachycardia, and following treatment with class I antiarrhythmic drugs. Such reductions also arise as a consequence of mutations in SCN5A such as those occurring in Lenègre disease, Brugada syndrome (BrS), sick sinus syndrome, and atrial fibrillation (AF). Secondly, r a, may be increased due to gap junction decoupling following ischemia, ventricular hypertrophy, and heart failure, or as a result of mutations in CJA5 found in idiopathic AF and atrial standstill. Finally, either r a or c m could potentially be altered by fibrotic change through the resultant decoupling of myocyte-myocyte connections and coupling of myocytes with fibroblasts. Such changes are observed in myocardial infarction and cardiomyopathy or following mutations in MHC403 and SCN5A resulting in hypertrophic cardiomyopathy (HCM) or Lenègre disease, respectively. This review defines and quantifies the determinants of θ and summarizes experimental evidence that links changes in these determinants with reduced myocardial θ and arrhythmogenesis. It thereby identifies the diverse pathophysiological conditions in which abnormal θ may contribute to arrhythmia.
PubMed: 23825462
DOI: 10.3389/fphys.2013.00154 -
The Journal of Physiology Sep 2013Over 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)... (Review)
Review
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.
Topics: Action Potentials; Animals; Brugada Syndrome; Channelopathies; Humans; Long QT Syndrome; Mutation; NAV1.5 Voltage-Gated Sodium Channel
PubMed: 23818691
DOI: 10.1113/jphysiol.2013.256461 -
Circulation Aug 2011The D1275N SCN5A mutation has been associated with a range of unusual phenotypes, including conduction disease and dilated cardiomyopathy, as well as atrial and...
BACKGROUND
The D1275N SCN5A mutation has been associated with a range of unusual phenotypes, including conduction disease and dilated cardiomyopathy, as well as atrial and ventricular tachyarrhythmias. However, when D1275N is studied in heterologous expression systems, most studies show near-normal sodium channel function. Thus, the relationship of the variant to the clinical phenotypes remains uncertain.
METHODS AND RESULTS
We identified D1275N in a patient with atrial flutter, atrial standstill, conduction disease, and sinus node dysfunction. There was no major difference in biophysical properties between wild-type and D1275N channels expressed in Chinese hamster ovary cells or tsA201 cells in the absence or presence of β1 subunits. To determine D1275N function in vivo, the Scn5a locus was modified to knock out the mouse gene, and the full-length wild-type (H) or D1275N (DN) human SCN5A cDNAs were then inserted at the modified locus by recombinase mediated cassette exchange. Mice carrying the DN allele displayed slow conduction, heart block, atrial fibrillation, ventricular tachycardia, and a dilated cardiomyopathy phenotype, with no significant fibrosis or myocyte disarray on histological examination. The DN allele conferred gene-dose-dependent increases in SCN5A mRNA abundance but reduced sodium channel protein abundance and peak sodium current amplitudes (H/H, 41.0±2.9 pA/pF at -30 mV; DN/H, 19.2±3.1 pA/pF, P<0.001 vs. H/H; DN/DN, 9.3±1.1 pA/pF, P<0.001 versus H/H).
CONCLUSIONS
Although D1275N produces near-normal currents in multiple heterologous expression experiments, our data establish this variant as a pathological mutation that generates conduction slowing, arrhythmias, and a dilated cardiomyopathy phenotype by reducing cardiac sodium current.
Topics: Animals; Atrial Flutter; CHO Cells; Cardiomyopathy, Dilated; Cricetinae; Cricetulus; Defibrillators, Implantable; Electrocardiography; Humans; Male; Mice; Mice, Transgenic; Mutation, Missense; Myocardial Contraction; NAV1.5 Voltage-Gated Sodium Channel; Sick Sinus Syndrome; Sodium Channels; Treatment Outcome; Young Adult
PubMed: 21824921
DOI: 10.1161/CIRCULATIONAHA.110.987248 -
The Journal of Tehran Heart Center 2011We introduce a 32-year-old man who was evaluated for a dizziness and headache of unknown origin for at least two months and was referred to our center after ECG...
We introduce a 32-year-old man who was evaluated for a dizziness and headache of unknown origin for at least two months and was referred to our center after ECG findings. He was finally diagnosed as a case of idiopathic, familial, diffuse, persistent atrial standstill, which is a rare arrhythmogenic condition characterized by the absence of electrical and mechanical activity in the atria. He successfully received a single-chamber permanent pacemaker.
PubMed: 23074623
DOI: No ID Found -
Journal of Cardiology Cases Aug 2010We report two cases of idiopathic atrial dilatation in two adult siblings, a brother and a sister. The first patient was a 36-year-old man who was referred to our...
We report two cases of idiopathic atrial dilatation in two adult siblings, a brother and a sister. The first patient was a 36-year-old man who was referred to our institution for evaluation of atrial fibrillation and syncopes. Transthoracic echocardiography revealed an enlarged right atrium accompanied by a severe tricuspid regurgitation associated with annular dilatation. The diagnosis of idiopathic atrial enlargement was made after all other lesions known to produce it have been excluded. The patient did not consent to the proposed cardiothoracic surgical treatment so he remained on conservative therapy. On electrocardiography, atrial standstill was noted, resulting in the implantation of a VVI cardiac pacemaker one year later. After an asymptomatic period, the patient suffered sudden death at the age of 40 years. His 45-year-old sister suffering from the same symptoms was also referred for examination, also to be diagnosed with idiopathic atrial dilatation and severe tricuspid regurgitation. Idiopathic dilatation of the right atrium, although a rare disorder, should not be forgotten as differential diagnosis for enlarged right atrium. Transthoracic echocardiography is the most commonly used technique and in our cases it was sufficient for establishing the diagnosis.
PubMed: 30546704
DOI: 10.1016/j.jccase.2010.02.001 -
The Canadian Veterinary Journal = La... Dec 2009Primary persistent atrial standstill due to atrioventricular muscle dystrophy is a rare familial disease in dogs. The diagnosis of this disorder in a 5-month-old English...
Primary persistent atrial standstill due to atrioventricular muscle dystrophy is a rare familial disease in dogs. The diagnosis of this disorder in a 5-month-old English springer spaniel is the earliest in dogs that have been presented at the Ontario Veterinary College.
Topics: Animals; Animals, Newborn; Breeding; Dog Diseases; Dogs; Fatal Outcome; Male; Muscular Dystrophy, Animal
PubMed: 20190980
DOI: No ID Found -
Yonsei Medical Journal Feb 2009We report a 55-year-old female patient who presented with no P waves but with a wide QRS complex escape rhythm at 44 beats/min and prolonged QTc of 0.55 seconds on ECG....
We report a 55-year-old female patient who presented with no P waves but with a wide QRS complex escape rhythm at 44 beats/min and prolonged QTc of 0.55 seconds on ECG. The patient had recurrence of ventricular fibrillations and loss of consciousness, and underwent defibrillation and cardiopulmonary resuscitation (CPR) several times because of cardiac arrest. The transthoracic echocardiography showed dilated cardiomyopathy and enlargement of both atria. The Doppler echocardiography documented the absence of A wave in the tricuspid and mitral valve flow. An electrophysiologic study demonstrated electrical inactivity in the right and left atria. Atrial pacing with maximum output did not capture the atria. These findings together with her electrocardiographic finding indicated atrial standstill. Sudden cardiac death was her first clinical manifestation of ventricular arrhythmia. The patient remained asymptomatic after receiving a single chamber implantable cardioverter-defibrillator (ICD) with VVI pacemaker function.
Topics: Bradycardia; Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Female; Heart Atria; Humans; Middle Aged; Ventricular Fibrillation
PubMed: 19259364
DOI: 10.3349/ymj.2009.50.1.156 -
Progress in Biophysics and Molecular... 2008Both gain- and loss-of-function mutations in the SCN5A gene, which encodes the alpha-subunit of the cardiac voltage-gated Na+ channel Na(v)1.5, are well established to... (Review)
Review
Both gain- and loss-of-function mutations in the SCN5A gene, which encodes the alpha-subunit of the cardiac voltage-gated Na+ channel Na(v)1.5, are well established to underlie hereditary arrhythmic syndromes (cardiac channelopathies) such as the type 3 long QT syndrome, cardiac conduction diseases, Brugada syndrome, sick sinus syndrome, atrial standstill and numerous overlap syndromes. Although patch-clamp studies in heterologous expression systems have provided important information to understand the genotype-phenotype relationships of these diseases, they could not clarify how mutations can be responsible for such a large spectrum of diseases, the late age of onset or the progressiveness of some of them, and for the overlapping syndromes. Genetically modified mice rapidly appeared as promising tools for understanding the pathophysiological sequence of cardiac SCN5A-related channelopathies and several mouse models have been established. Here, we review the results obtained on these models that, for most of them, convincingly recapitulate the clinical phenotypes of the patients but that also have their own limitations. Mouse models turn out to be powerful tools to elucidate the pathophysiological mechanisms of SCN5A-related diseases and offer the opportunity to investigate the cellular consequences of SCN5A mutations such as the remodelling of other gene expression that might participate in the overall phenotype and explain some of the differences among patients. Finally, they also constitute useful tools for future studies addressing as yet unanswered questions, such as the role of genetic and environmental modifiers on cardiac conduction and repolarisation.
Topics: Animals; Arrhythmias, Cardiac; Brugada Syndrome; Disease Models, Animal; Humans; Long QT Syndrome; Mice; Mice, Knockout; Mice, Mutant Strains; Mice, Transgenic; Muscle Proteins; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Sodium Channels; Voltage-Gated Sodium Channel beta-1 Subunit
PubMed: 19041666
DOI: 10.1016/j.pbiomolbio.2008.10.012 -
Journal of Veterinary Internal Medicine 2006We reviewed the indications for age and breeds of dogs who received transvenous endocardial artificial pacemaker (AP) implantation (n = 105) and complications and...
We reviewed the indications for age and breeds of dogs who received transvenous endocardial artificial pacemaker (AP) implantation (n = 105) and complications and survival thereafter at a single institution over a 6-year period. A third-degree atrioventricular (AV) block (59%) and sick sinus syndrome (SSS; 27%) were the most common indications, along with a high-grade second-degree AV block (9%) and atrial standstill (5%). The most common breeds identified were Labrador Retriever (n = 16; 11 with a third-degree AV block), American Cocker Spaniel (n = 14; 10 with SSS), and Miniature Schnauzer (n = 13; all with SSS). Common presenting complaints were syncope (n = 66) and exercise intolerance or lethargy (n = 25). Half of the dogs (n = 52) had a history of acute onset of clinical signs (<2 weeks). Mean survival time for the 60 dogs who died during the study period was 2.2 years (range, 0.1-5.8 years). Major complications occurred in 13% of dogs and included lead displacement (n = 7), sensing problems that led to syncope (n = 3), infection at the pacemaker site (n = 1), bleeding (n = 1), and ventricular fibrillation during implantation (n = 1; successfully defibrillated). Minor complications occurred in 11 dogs (11%). The success rate of transvenous AP implantation was comparatively high (all dogs survived the first 48 hours), and the complication rate was comparatively low when compared with a previous multicenter study, most likely because of how commonly the procedure was performed and supervisory experience.
Topics: Animals; Dog Diseases; Dogs; Female; Heart Block; Male; Pacemaker, Artificial; Sick Sinus Syndrome; Time Factors; Treatment Outcome
PubMed: 16955812
DOI: 10.1892/0891-6640(2006)20[877:acaoot]2.0.co;2 -
Heart Rhythm Oct 2005Congenital atrial standstill has been linked to SCN5A. Incomplete penetrance observed in atrial standstill has been attributed in part to the digenic inheritance of...
BACKGROUND
Congenital atrial standstill has been linked to SCN5A. Incomplete penetrance observed in atrial standstill has been attributed in part to the digenic inheritance of polymorphisms in the atrial-specific gap junction connexin 40 (Cx40) in conjunction with an SCN5A mutation.
OBJECTIVES
The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation identified in a family with atrial standstill.
METHODS
Family members of an apparently sporadic case of atrial standstill underwent genetic screening of SCN5A and atrial-specific genes including Cx40. Biophysical properties of the wild-type (WT) and mutant SCN5A channels in a heterologous expression system were studied using the whole-cell patch clamp technique.
RESULTS
The novel SCN5A mutation L212P was identified in the proband (age 11 years) and his father. The father was in normal sinus rhythm. The proband had no P waves on surface ECG, and his right atrium could not be captured by pacing. The recombinant L212P Na channel showed a large hyperpolarizing shift in both the voltage dependence of activation (WT: -48.1 +/- 0.9 mV; L212P: -63.5 +/- 1.5 mV; P < .001) and inactivation (WT: -86.6 +/- 0.9 mV; L212P: -95.6 +/- 0.8 mV; P < .001) and delayed recovery from inactivation. Further screenings for genetic variations that might mitigate L212P dysfunction revealed that the proband, but not his father, carries Cx40 polymorphisms inherited from his asymptomatic mother.
CONCLUSION
These results suggest that genetic defects in SCN5A most likely underlie atrial standstill. Coinheritance of Cx40 polymorphisms is a possible genetic factor that modifies the clinical manifestation of this inherited arrhythmia.
Topics: Alleles; Atrial Fibrillation; Atrial Function; Bradycardia; Child, Preschool; Connexins; DNA Mutational Analysis; Electrocardiography; Family Health; Female; Genetic Predisposition to Disease; Genetic Testing; Heart Atria; Heart Rate; Humans; Male; Muscle Proteins; Mutation, Missense; NAV1.5 Voltage-Gated Sodium Channel; Pedigree; Phenotype; Polymorphism, Genetic; Sodium Channels; Gap Junction alpha-5 Protein
PubMed: 16188595
DOI: 10.1016/j.hrthm.2005.06.032