BACKGROUND: Dysfunction of the gap junction channel protein connexin 43 (Cx43) contributes to myocardial ischemia/reperfusion (I/R)-induced ventricular arrhythmias. Cx43 can be regulated by small ubiquitin-like modifier (SUMO) modification. Protein inhibitor of activated STAT Y (PIASy) is an E3 SUMO ligase for its target proteins. However, whether Cx43 is a target protein of PIASy and whether Cx43 SUMOylation plays a role in I/R-induced arrhythmias are largely unknown. METHODS: Male Sprague-Dawley rats were infected with PIASy short hairpin ribonucleic acid (shRNA) using recombinant adeno-associated virus subtype 9 (rAAV9). Two weeks later, the rats were subjected to 45 min of left coronary artery occlusion followed by 2 h reperfusion. Electrocardiogram was recorded to assess arrhythmias. Rat ventricular tissues were collected for molecular biological measurements. RESULTS: Following 45 min of ischemia, QRS duration and QTc intervals statistically significantly increased, but these values decreased after transfecting PIASy shRNA. PIASy downregulation ameliorated ventricular arrhythmias induced by myocardial I/R, as evidenced by the decreased incidence of ventricular tachycardia and ventricular fibrillation, and reduced arrythmia score. In addition, myocardial I/R statistically significantly induced PIASy expression and Cx43 SUMOylation, accompanied by reduced Cx43 phosphorylation and plakophilin 2 (PKP2) expression. Moreover, PIASy downregulation remarkably reduced Cx43 SUMOylation, accompanied by increased Cx43 phosphorylation and PKP2 expression after I/R. CONCLUSION PIASy downregulation inhibited Cx43 SUMOylation and increased PKP2 expression, thereby improving ventricular arrhythmias in ischemic/reperfused rats heart.
Rats ; Male ; Animals ; Myocardial Reperfusion Injury/metabolism* ; Connexin 43/genetics* ; Sumoylation ; Down-Regulation ; Rats, Sprague-Dawley ; Arrhythmias, Cardiac/drug therapy* ; Myocardial Ischemia/metabolism* ; RNA, Small Interfering/metabolism*

Arrhythmias, Cardiac ; Genetic Diseases, X-Linked/genetics* ; Gigantism/genetics* ; Heart Defects, Congenital/genetics* ; Humans ; Intellectual Disability/genetics* ; Male ; Neuroblastoma

Studies have demonstrated that the occurrence of a variety of arrhythmias presents an obvious circadian rhythm,which may be regulated by circadian rhythm genes.Circadian cycle and light stimulation can affect circadian rhythm genes and proteins,which constitute a transcription-translation loop that can regulate the ion channels in myocardial cell membrane through nervous-humoral regulation and changes in central clock-sub-clock gene expression,thereby modulating arrhythmia.This article reviews the molecular basis,mechanism,and performance of circadian rhythm in regulating arrhythmia.
Humans ; Circadian Rhythm/genetics* ; Myocytes, Cardiac ; Arrhythmias, Cardiac

Due to the negative autopsy and without cardiac structural abnormalities, unexpected sudden cardiac death （USCD） is always a tough issue for forensic pathological expertise. USCD may be associated with parts of fatal arrhythmic diseases. These arrhythmic diseases may be caused by disorders of cardiac ion channels or channel-related proteins. Caveolin can combine with multiple myocardial ion channel proteins through its scaffolding regions and plays an important role in maintaining the depolarization and repolarization of cardiac action potential. When the structure and function of caveolin are affected by gene mutations or abnormal protein expression, the functions of the regulated ion channels are correspondingly impaired, which leads to the occurrence of multiple channelopathies, arrhythmia or even sudden cardiac death. It is important to study the effects of caveolin on the functions of ion channels for exploring the mechanisms of malignant arrhythmia and sudden cardiac death.
Arrhythmias, Cardiac/physiopathology* ; Autopsy ; Caveolins/metabolism* ; Channelopathies/genetics* ; Death, Sudden, Cardiac/pathology* ; Forensic Pathology ; Humans ; Ion Channels/metabolism* ; Mutation ; Myocardium

The early cardiac biological pacemaker studies were mostly around HCN channel, and how to build a biological pacemaker through the enhanced If current. In recent years, however, people found that the genes of Tbx3 could play an important role in the development of cardiac conduction system, especially in processes of the maturity of the sinoatrial node and maintenance of its function. And the Tbx3 can further optimize the biological pacemaker. Therefore, it could be a new therapeutic focus in biological pacemaker and treatment of cardiac conduction system disease. This paper summarizes some of the latest research progress of the Tbx3 in biological pacemaker in recent years. We hope that this review could provide theoretical basis for the clinical applications of Tbx3.
Arrhythmias, Cardiac ; genetics ; Biological Clocks ; Brugada Syndrome ; Cardiac Conduction System Disease ; Heart ; physiopathology ; Heart Conduction System ; abnormalities ; Humans ; Sinoatrial Node ; T-Box Domain Proteins ; genetics

Ventricular myocardial non-compaction has been recognized and defined as a genetic cardiomyopathy by American Heart Association since 2006. The argument on the nomenclature and pathogenesis of this kind of ventricular myocardial non-compaction characterized by regional ventricular wall thickening and deep trabecular recesses often complicated with chronic heart failure, arrhythmia and thromboembolism and usually overlap the genetics and phenotypes of other kind of genetic or mixed cardiomyopathy still exist. The proper classification and correct nomenclature of the non-compact ventricles will contribute to the precisely and completely understanding of etiology and its related patho-physiological mechanism for a better risk stratification and more personalized therapy of the disease individually. All of the genetic heterogeneity and phenotypical overlap and the variety in histopathological, electromechanical and clinical presentation indicates that some of the cardiomyopathies might just be the different consequence of myocardial development variations related to gene mutation and phenotype of one or group genes induced by the interacted and disturbed process of gene modulation at different links of gene function expression and some other etiologies. This review aims to establish a new concept of "ventricular non-compaction syndrome" based on the demonstration of the current findings of etiology, epidemiology, histopathology and echocardiography related to the disorder of ventricular myocardial compaction and myocardial electromechanical function development.
American Heart Association ; Arrhythmias, Cardiac ; Cardiomyopathies* ; Classification ; Echocardiography ; Epidemiology ; Genetic Heterogeneity ; Genetics ; Heart Failure ; Humans ; Phenotype ; Thromboembolism

BACKGROUNDMonosodium L-glutamate (MSG) is a food flavour enhancer and its potential harmfulness to the heart remains controversial. We investigated whether MSG could induce cardiac arrhythmias and apoptosis via the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.

METHODSMyocardial infarction (MI) was created by ligating the coronary artery and ventricular arrhythmias were monitored by electrocardiogram in the rat in vivo. Neonatal rat cardiomyocytes were isolated and cultured. Cell viability was estimated by 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay. Calcium mobilization was monitored by confocal microscopy. Cardiomyocyte apoptosis was evaluated by acridine orange staining, flow cytometry, DNA laddering, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.

RESULTSMSG (i.v.) decreased the heart rate at 0.5 g/kg and serious bradycardia at 1.5 g/kg, but could not induce ventricular tachyarrhythmias in normal rats in vivo. In rats with acute MI in vivo, however, MSG (1.5 g/kg, i.v.) induced ventricular tachyarrhythmias and these arrhythmias could be prevented by blocking the AMPA and N-methyl-d-aspartate (NMDA) receptors. Selectively activating the AMPA or NMDA receptor induced ventricular tachyarrhythmias in MI rats. At the cellular level, AMPA induced calcium mobilization, oxidative stress, mitochondrial dysfunction and apoptosis in cultured cardiomyocytes, especially when the AMPA receptor desensitization were blocked by cyclothiazide. The above toxic cellular effects of AMPA were abolished by AMPA receptor blockade or by H2O2 scavengers.

CONCLUSIONSMSG induces bradycardia in normal rats, but triggers lethal tachyarrhythmias in myocardial infarcted rats probably by hindering AMPA receptors. AMPA receptor overstimulation also induces cardiomyocyte apoptosis, which may facilitate arrhythmia.

Animals ; Apoptosis ; drug effects ; Arrhythmias, Cardiac ; chemically induced ; Calcium ; metabolism ; Cell Survival ; drug effects ; Cells, Cultured ; DNA Fragmentation ; drug effects ; Glutamic Acid ; toxicity ; Male ; Microscopy, Confocal ; Myocardial Infarction ; chemically induced ; Rats ; Rats, Wistar ; Receptors, AMPA ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sodium Glutamate ; toxicity ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid ; toxicity

OBJECTIVEMitochondrial disease is a group of energy metabolic disorders, characterized by involvement of multisystem with high energy requirements. Encephalomyopathies are common clinical findings of the mitochondrial diseases. However, mitochondrial cardiac damage is not rare. In this study, the clinical, biological, and genetic analyses were performed in three patients with mitochondrial cardiac damage, in order to understand the characteristics of mitochondrial diseases.

METHODThree girls presented with arrhythmia and cardiac enlargement from the age of 3, 4 and 8 years respectively. They were admitted into the Peking University First Hospital. Infection, autoimmune diseases, aminoacidopathies, organic acidurias, mitochondrial-fatty acid oxidation defects, and lysosomal storage disease were excluded by routine laboratory examinations and metabolic analysis for blood amino acids, acylcarnitines, urinary organic acids, and lysosome activity assay. Peripheral leukocytes mitochondrial respiratory chain enzyme I to V activities were measured by spectrophotometry. The entire sequence of the mitochondrial DNA was analyzed.

RESULTIn two patients (case 1 and case 3), hypertrophic cardiomyopathy and grade I to grade II of cardiac function were found. One patient (case 2) was diagnosed with arrhythmia and grade I of cardiac function. Increased creatine phosphokinase and creatine kinase isoenzyme MB were observed. Mitochondrial respiratory chain complex deficiencies were indentified in the three patients. Patient 1 had combined deficiencies of complex III and V. The activity of complex I+III was 18.7 nmol/(min·mg mitochondrial protein) (control 84.4 ± 28.5). The activity of complex V was 20.4 nmol/(min·mg mitochondrial protein) (control 103.7 ± 29.2). In her mitochondrial gene, A14693G on tRNA(Glu) and T16519C on D-loop were found. Patient 2 had an isolated complex I deficiency. The activity was 22.0 nmol/(min·mg mitochondrial protein) (control 44.0 ± 5.4). A16183C, T16189C and G15043A mutations on D-loop were found. Patient 3 had a combined deficiency of complex IV and V. The activity of complex IV was 21.0 nmol/(min·mg mitochondrial protein) (control 54.1 ± 12.3). The activity of complex V was 23.2 nmol/(min·mg mitochondrial protein) (control 103.7 ± 29.2). C253T and C16187T mutations on D-loop were detected. Haplotype analysis showed that three patients belong to H2a2a. Improvement was observed after the treatment with L-carnitine, coenzyme Q10, vitamin C and E. At present, the patients are 7, 5 and 8 years old. Although excise intolerance still persists, they had a good general condition with normal school life.

CONCLUSIONThe mitochondrial diseases with cardiac damage show cardiomyopathy, arrhythmia and exercise intolerance. Many kinds of mitochondrial respiratory chain deficiency were observed. A14693G in mitochondrial tRNA(Glu) gene is probably one of the causes in China.

Arrhythmias, Cardiac ; diagnosis ; genetics ; metabolism ; Biomarkers ; blood ; urine ; Cardiomyopathy, Hypertrophic ; diagnosis ; genetics ; metabolism ; Child ; Child, Preschool ; DNA Mutational Analysis ; DNA, Mitochondrial ; genetics ; Electron Transport Chain Complex Proteins ; deficiency ; genetics ; metabolism ; Female ; Humans ; Male ; Mitochondria, Heart ; enzymology ; pathology ; Mitochondrial Diseases ; diagnosis ; genetics ; metabolism ; Mutation

Arrhythmias, Cardiac ; diagnosis ; genetics ; pathology ; Brugada Syndrome ; diagnosis ; genetics ; pathology ; Channelopathies ; diagnosis ; genetics ; pathology ; DNA Mutational Analysis ; Electrocardiography ; Genetic Testing ; Heart Conduction System ; physiopathology ; Humans ; Infant ; Long QT Syndrome ; diagnosis ; genetics ; pathology ; Muscle Proteins ; genetics ; Mutation ; NAV1.5 Voltage-Gated Sodium Channel ; genetics ; Sodium Channels ; genetics ; Sudden Infant Death ; etiology

Mutation or common intronic variants in cardiac ion channel genes have been suggested to be associated with sudden cardiac death caused by idiopathic ventricular tachyarrhythmia. This study aimed to find mutations in cardiac ion channel genes of Korean sudden cardiac arrest patients with structurally normal heart and to verify association between common genetic variation in cardiac ion channel and sudden cardiac arrest by idiopathic ventricular tachyarrhythmia in Koreans. Study participants were Korean survivors of sudden cardiac arrest caused by idiopathic ventricular tachycardia or fibrillation. All coding exons of the SCN5A, KCNQ1, and KCNH2 genes were analyzed by Sanger sequencing. Fifteen survivors of sudden cardiac arrest were included. Three male patients had mutations in SCN5A gene and none in KCNQ1 and KCNH2 genes. Intronic variant (rs2283222) in KCNQ1 gene showed significant association with sudden cardiac arrest (OR 4.05). Four male sudden cardiac arrest survivors had intronic variant (rs11720524) in SCN5A gene. None of female survivors of sudden cardiac arrest had SCN5A gene mutations despite similar frequencies of intronic variants between males and females in 55 normal controls. Common intronic variant in KCNQ1 gene is associated with sudden cardiac arrest caused by idiopathic ventricular tachyarrhythmia in Koreans.
Adolescent ; Adult ; Aged ; Arrhythmias, Cardiac/genetics ; *Death, Sudden, Cardiac ; Ether-A-Go-Go Potassium Channels/genetics ; Female ; Genetic Markers ; Genetic Predisposition to Disease ; Genetic Variation ; Heart/physiology ; Heart Conduction System/abnormalities ; Humans ; KCNQ1 Potassium Channel/*genetics ; Male ; Middle Aged ; NAV1.5 Voltage-Gated Sodium Channel/*genetics ; Republic of Korea ; Tachycardia, Ventricular/*genetics ; Ventricular Fibrillation/*genetics ; Young Adult