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PloS One 2022The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to...
The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF.
Topics: AMP-Activated Protein Kinases; Animals; Atrial Fibrillation; Atrial Flutter; Atrial Function, Left; Atrial Remodeling; Carbachol; Cardiac Pacing, Artificial; Disease Models, Animal; Electrocardiography; Mice; Mice, Inbred C57BL; Myocardium; Myocytes, Cardiac; Tachycardia, Ventricular
PubMed: 34995278
DOI: 10.1371/journal.pone.0256512 -
Journal of Cardiology Cases Sep 2021The use of leadless trans-catheter pacemakers is increasing particularly in the elderly population. However, its indication for those with anatomical anomaly remains...
The use of leadless trans-catheter pacemakers is increasing particularly in the elderly population. However, its indication for those with anatomical anomaly remains unknown. We had a 75-year-old woman with atrial standstill and ventricular escape. Micra leadless pacemaker (Medtronic, Inc, Minneapolis, MN, USA) failed to be deployed due to too enlarged right atrium accompanied by atrial septal deficiency, followed by successful implantation of transvenous pacemaker lead by using SelectSecure lead (Medtronic) with a C315 delivery catheter that enhanced back-up force toward the ventricular septum against significant tricuspid regurgitation. The Micra is a promising system, but we should understand its limitations as well as alternative systems particularly for such an anatomical anatomy. < A Micra leadless trans-catheter pacemaker is a promising system with less invasiveness, particularly for elderly patients, but we should understand its technical limitation and consider alternative systems if necessary, particularly for those with enlarged right heart.>.
PubMed: 34466178
DOI: 10.1016/j.jccase.2021.02.015 -
ESC Heart Failure Oct 2021Giant cell myocarditis (GCM) is a rare condition. Its association with SARS-CoV-2 has not been described before. The 46-year-old female patient was admitted to the...
Giant cell myocarditis (GCM) is a rare condition. Its association with SARS-CoV-2 has not been described before. The 46-year-old female patient was admitted to the clinic on September 2020. She had 7 year adrenal insufficiency history and infarct-like debut of myocardial disease in November 2019. After COVID-19 in April 2020, cardiac disease progressed. The examination showed low QRS voltage, QS complexes in V -V leads, atrial standstill, left ventricular systolic and restrictive dysfunction, elevated anti-heart antibodies, and subepicardial late gadolinium enhancement by magnetic resonance imaging. Endomyocardial biopsy and pacemaker implantation were performed, but the patient died suddenly due to ventricular tachycardia or ventricular fibrillation (the resuscitation was ineffective). The autopsy revealed GCM, SARS-CoV-2, and Parvovirus B19 were detected in the myocardium. The role of SARS-CoV-2 in the pathogenesis of autoimmune myocarditis is discussed.
Topics: COVID-19; Cardiomyopathies; Contrast Media; Death, Sudden, Cardiac; Female; Gadolinium; Genetic Diseases, Inborn; Giant Cells; Heart Atria; Heart Block; Humans; Middle Aged; SARS-CoV-2
PubMed: 34327860
DOI: 10.1002/ehf2.13520 -
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 -
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 -
HeartRhythm Case Reports Jun 2019
PubMed: 31285994
DOI: 10.1016/j.hrcr.2019.03.008