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Cardiovascular Journal of Africa 2021Atrial standstill is an uncommon but serious clinical entity that is often unrecognised in the clinical setting. Its diagnosis and treatment should be swift as malignant...
Atrial standstill is an uncommon but serious clinical entity that is often unrecognised in the clinical setting. Its diagnosis and treatment should be swift as malignant arrhythmias and thromboembolic complications can arise. We present a 79-year-old man brought to our emergency department with acute confusion, heart failure and severe bradycardia in the context of diabetic ketoacidosis, and discuss the diagnosis and management of this arrhythmic condition.
Topics: Aged; Arrhythmias, Cardiac; Bradycardia; Diabetic Ketoacidosis; Electrocardiography; Heart Atria; Humans; Male
PubMed: 34143176
DOI: 10.5830/CVJA-2020-026 -
Molecular Genetics & Genomic Medicine May 2021We examined the genetic background of a Chinese Han family in which some members presented with complex arrhythmias including sick sinus syndrome, progressive conduction...
BACKGROUND
We examined the genetic background of a Chinese Han family in which some members presented with complex arrhythmias including sick sinus syndrome, progressive conduction block, atrial fibrillation, atrial standstill and Brugada syndrome. The possible underlying mechanism associated with the genetic mutation was explored.
METHODS
Targeted capture sequencing was conducted in the probands in the coding and splicing regions of genes implicated in inherited arrhythmias. Stable cell lines overexpressing wild type (WT) or mutant SCN5A were generated in HEK293T cells. Whole-cell recording was performed to evaluate the functional changes in sodium channels.
RESULTS
The rare heterozygous linkage mutations, SCN5A R965C and R1309H, were found in these patients with complex familial arrhythmias. Compared to WT, R965C or R1309H, the peak current of sodium channel was dramatically reduced in HEK293T cell with linkage R965C-R1309H mutation when testing potentials ranging from -45 to 15 mV. Notably, the maximum peak current of sodium channels with R1309H and linkage R965C-R1309H displayed significant decreases of 31.5% and 73.34%, respectively, compared to WT. Additionally, compared to R965C or R1309H alone, the linkage mutation R965C-R1309H demonstrated not only a more obvious depolarisation-shifted activation and hyperpolarisation-shifted inactivation, but also a more significant alteration in the time constant, V and the slope factor of activation and inactivation.
CONCLUSIONS
The linkage mutation SCN5A R965C-R1309H led to a more dramatically reduced current density, as well as more significant depolarisation-shifted activation and hyperpolarisation-shifted inactivation in sodium channels than R965C or R1309H alone, which potentially explain this complex familial arrhythmia syndrome.
Topics: Action Potentials; Arrhythmias, Cardiac; Female; HEK293 Cells; Heterozygote; Humans; Ion Channel Gating; Male; Mutation, Missense; NAV1.5 Voltage-Gated Sodium Channel; Pedigree; Protein Domains; Young Adult
PubMed: 33764691
DOI: 10.1002/mgg3.1613 -
Journal of Clinical Medicine Feb 2021Cardiac involvement in patients with muscular dystrophy associated with Lamin A/C mutations () is characterized by atrioventricular conduction abnormalities and...
INTRODUCTION
Cardiac involvement in patients with muscular dystrophy associated with Lamin A/C mutations () is characterized by atrioventricular conduction abnormalities and life-threatening cardiac arrhythmias. Little is known about cardiac involvement in patients with emerin mutation (). The aim of our study was to describe and compare the prevalence and time distribution of cardiac arrhythmias at extended follow-up.
PATIENTS AND METHODS
45 consecutive patients affected by muscular dystrophy associated to laminopathy or emerinopathy were examined. All patients underwent clinical evaluation, 12-lead surface electrocardiogram (ECG), 24 h electrocardiographic monitoring, and cardiac implanted device interrogation.
RESULTS
At the end of 11 (5.0-16.6) years of follow-up, 89% of the patients showed cardiac arrhythmias. The most prevalent was atrial standstill (AS) (31%), followed by atrial fibrillation/flutter (AF/Afl) (29%) and ventricular tachycardia (22%). patients presented more frequently AF/AFl compared to (50% vs. 20%, ). Half of the patients presented with AS, whilst there was no occurrence of such in the ( = 0.001). Ventricular arrhythmias were found in 60% of patients with laminopathy compared to 3% in patients with emerinopathy ( < 0.001). The age of AVB occurrence was higher in the group (32.8 +/- 10.6 vs. 25.1 +/- 9.1, = 0.03).
CONCLUSIONS
Atrial arrhythmias are common findings in patients with muscular dystrophy associated with / mutations; however, they occurred earlier in patients. Ventricular arrhythmias were very common (60%) in and occurred definitely earlier compared to the group.
PubMed: 33673224
DOI: 10.3390/jcm10040732 -
Journal of Comparative Pathology Oct 2020The hearts of three dogs, clinically diagnosed as having persistent atrial standstill syndrome (PAS), were studied post mortem. The most significant gross findings in...
The hearts of three dogs, clinically diagnosed as having persistent atrial standstill syndrome (PAS), were studied post mortem. The most significant gross findings in the hearts of all three dogs were dilatation and marked reduction in the thickness of both atrial walls. Histopathologically, all three had widespread progressive loss of the atrial myocardium with replacement by fatty or fibrofatty tissue, consistent with atrial myopathy. The lesion mainly affected the upper half of both atria and was more severe in the epimyocardium and midmyocardium than in the endomyocardium. On the basis of these observations, it is proposed that the atrial myopathy commences in the upper regions of both atria and progresses downwards, as has been demonstrated electrophysiologically in PAS in humans, and extends from the epicardium towards the endocardium.
Topics: Animals; Cardiomyopathies; Dog Diseases; Dogs; Genetic Diseases, Inborn; Heart Atria; Heart Block
PubMed: 33222880
DOI: 10.1016/j.jcpa.2020.08.005 -
Frontiers in Cell and Developmental... 2020Voltage-gated sodium (Na) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. Na channel β subunits have been widely...
Voltage-gated sodium (Na) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. Na channel β subunits have been widely studied due to their modulatory role. Mice null for , which encodes Na β1 and β1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality. A mutation in exon 3 of , c.308A>T leading to β1_p.D103V and β1b_p.D103V, was previously found in a patient with a history of proarrhythmic conditions with progressive atrial standstill as well as cognitive and motor deficits accompanying structural brain abnormalities. We investigated whether β1 or β1b subunits carrying this mutation affect Na1.5 and/or Na1.1 currents using a whole cell patch-clamp technique in tsA201 cells. We observed a decrease in sodium current density in cells co-expressing Na1.5 or Na1.1 and β1 compared to β1. Interestingly, β1b did not affect Na1.1 sodium current density but induced a positive shift in the voltage dependence of inactivation and a faster recovery from inactivation compared to β1b. The β1b isoform did not affect Na1.5 current properties. Although the _c.308A>T mutation may not be the sole cause of the patient's symptoms, we observed a clear loss of function in both cardiac and brain sodium channels. Our results suggest that the mutant β1 and β1b subunits play a fundamental role in the observed electrical dysfunction.
PubMed: 33134290
DOI: 10.3389/fcell.2020.528742 -
Circulation. Arrhythmia and... Oct 2020
Topics: Cardiomyopathies; Genetic Diseases, Inborn; Heart Atria; Heart Block; Humans; Phenotype; Stroke; X-Linked Emery-Dreifuss Muscular Dystrophy
PubMed: 33079577
DOI: 10.1161/CIRCEP.120.009338 -
Pacing and Clinical Electrophysiology :... Feb 2021Sick sinus syndrome (SSS) is a group of disorders characterized by an abnormal cardiac impulse formation or propagation from the sinoatrial node. Mutated SCN5A has been...
Sick sinus syndrome (SSS) is a group of disorders characterized by an abnormal cardiac impulse formation or propagation from the sinoatrial node. Mutated SCN5A has been reported in SSS, however, homozygosity of SCN5A is exceedingly rare. Here, we report a consanguineous family with four affected children with SSS. Symptomatic bradycardia necessitated implanting a pacemaker in all of them. Sequencing SCN5A revealed a novel homozygous variant (p.Cys1850Arg), which was predicted to interfere with protein folding. Our report describes the phenotype of a novel homozygous SCN5A variant and contributes to the compendium of molecular pathology of inherited arrhythmias in consanguineous populations.
Topics: Adolescent; Female; Homozygote; Humans; Infant; Male; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Pacemaker, Artificial; Pedigree; Sick Sinus Syndrome; Young Adult
PubMed: 32965045
DOI: 10.1111/pace.14077 -
Compound Heterozygous Mutations in Severe Sodium Channelopathy With Brugada Syndrome: A Case Report.Frontiers in Cardiovascular Medicine 2020Brugada syndrome (BrS) is an inherited cardiac arrhythmia with an increased risk for sudden cardiac death (SCD). About 20% of BrS cases are explained by mutations in...
Brugada syndrome (BrS) is an inherited cardiac arrhythmia with an increased risk for sudden cardiac death (SCD). About 20% of BrS cases are explained by mutations in the gene, encoding the main cardiac sodium Na1.5 channel. Here we present a severe case of cardiac sodium channelopathy with BrS caused by compound heterozygous mutations. We performed a genetic analysis of in a male proband who collapsed during cycling at the age of 2 years. Because of atrial standstill, he received a pacemaker, and at the age of 3 years, he experienced a collapse anew with left-sided brain stroke. A later ECG taken during a fever unmasked a characteristic BrS type-1 pattern. The functional effect of the detected genetic variants was investigated. Next-generation sequencing allowed the detection of two variants in : c.4813+3_4813+6dupGGGT-a Belgian founder mutation-and c.4711 T>C, p.Phe1571Leu. A familial segregation analysis showed the presence of the founder mutation in the proband's affected father and paternal aunt and the occurrence of the p.Phe1571Leu. The functional effect of the founder mutation was previously described as a loss-of-function. We performed a functional analysis of the p.Phe571Leu variant in HEK293 cells alone or co-expressed with the β-subunit. Compared to the wild type, p.Phe1571Leu displayed a hyperpolarizing shift in the voltage dependence of inactivation (loss-of-function), while the activation parameters were unaffected. Using the peptide toxin nemertide α-1, the variant's loss-of-function effect could be restored due to a toxin-dependent reduction of channel inactivation. This is the first report providing support for the pathogenicity of the p.Phe1571Leu variant which, together with the c.4813+3_4813+6dupGGGT founder mutation, explains the severity of the phenotype of cardiac sodium channelopathy with BrS in the presented case.
PubMed: 32850980
DOI: 10.3389/fcvm.2020.00117 -
Circulation. Arrhythmia and... Oct 2020Mutations in the nuclear envelope genes encoding and are responsible for Emery-Dreifuss muscular dystrophy. However, mutations often manifest dilated cardiomyopathy...
Cardiac Emerinopathy: A Nonsyndromic Nuclear Envelopathy With Increased Risk of Thromboembolic Stroke Due to Progressive Atrial Standstill and Left Ventricular Noncompaction.
BACKGROUND
Mutations in the nuclear envelope genes encoding and are responsible for Emery-Dreifuss muscular dystrophy. However, mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with mutations.
METHODS
Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51).
RESULTS
We identified 3 X-linked recessive mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with has never been reported, we further genetically screened 102 LVNC patients and found a frameshift mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC.
CONCLUSIONS
Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.
Topics: Adolescent; Adult; Aged; Cardiac Conduction System Disease; Cardiomyopathies; Child; Female; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Heart Atria; Heart Block; Humans; Isolated Noncompaction of the Ventricular Myocardium; Male; Membrane Proteins; Middle Aged; Mutation; Nuclear Proteins; Phenotype; Sick Sinus Syndrome; Stroke; Thromboembolism; X-Linked Emery-Dreifuss Muscular Dystrophy; Young Adult
PubMed: 32755394
DOI: 10.1161/CIRCEP.120.008712 -
Journal of the American Society of... Jul 2020
Topics: Atrial Fibrillation; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Genetic Diseases, Inborn; Heart Atria; Heart Block; Humans; Interatrial Block
PubMed: 32359950
DOI: 10.1016/j.echo.2020.02.014