electrophysiological-assessment-murine-atria-with-high-resolution

Electrophysiological Assessment of Murine Atria with High-Resolution Optical Mapping

Recent genome-wide association studies targeting atrial fibrillation (AF) have indicated a strong association between the genotype and ...

Tokyo Medical and Dental University

Coexistent idiopathic left ventricular tachycardia and atrial fibrillation induced by maintained VA conduction during ventricular tachycardia.

The aim of this study was to assess the spatial distribution of the origins of adenosine triphosphate (ATP) sensitive focal atrial tachycardias (AT) that have their earliest activation recorded in the His bundle (HB) catheter.

Distribution of the origin of adenosine triphosphatesensitive atrial tachycardias with the earliest activation recorded in the His bundle catheter: are they limited to the immediate vicinity of the His bundle?

Dabigatran has demonstrated promising results for the prevention of strokes in patients with non-valvular atrial fibrillation (NVAF). However, there have been episodes of major bleeding, especially in elderly patients or those with renal dysfunction. The purpose of this study was to retrospectively examine the relationship between the bleeding events and activated partial thromboplastin time (APTT) values under dabigatran usage in the everyday clinical practice. Moreover, we investigated which factors would contribute to the APTT values.

Bleeding events and activated partial thromboplastin time with dabigatran in clinical practice.

Amiodarone-induced thyrotoxicosis (AIT) may develop long after amiodarone withdrawal. This study sought to determine the incidence and clinical characteristics of AIT after amiodarone withdrawal.

Amiodarone-induced thyrotoxicosis late after amiodarone withdrawal.

Lifestyle-related diseases, such as obesity and dyslipidemia are important risk factors for atrial fibrillation (AF). However, the underlying mechanism linking these diseases and AF has not been fully investigated.

High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b.

Calcium ion (Ca(2+)) signaling is a typical phenomenon mediated through immune receptors, such as the B-cell antigen receptor (BCR), and it is important for their biological activities. To analyze the signaling of immune receptors together with their in vivo dynamics, we generated stable transgenic mice with the Föster/fluorescence resonance energy transfer (FRET)-based Ca(2+) indicator yellow cameleon 3.60 (YC3.60), based on the Cre/loxP system (YC3.60(flox)). We successfully obtained mice with specific YC3.60 expression in immune or nerve cells as well as mice with ubiquitous expression of this indicator. We established five-dimensional (5D) (x, y, z, time, and Ca(2+)) intravital imaging of lymphoid tissues, including the bone marrow. Furthermore, in autoimmune-prone models, the CD22(-/-) and C57BL/6- lymphoproliferation (lpr)/lpr mouse, Ca(2+) fluxes were augmented, although they did not induce autoimmune disease. Intravital imaging of Ca(2+) signals in lymphocytes may improve assessment of the risk of autoimmune diseases in model animals.

Intravital imaging of Ca(2+) signals in lymphocytes of Ca(2+) biosensor transgenic mice: indication of autoimmune diseases before the pathological onset.

Morbidity and mortality caused by cardiac arrhythmias are a major issue in developed countries. Although conventional therapeutic options including pharmacological therapy, catheter ablation, and implantable devices have shown extensive advances to help reduce morbidity and mortality, a certain segment of these arrhythmias is still refractory to treatment. Therefore, gene therapy was explored as a potential additional or alternative therapy. Gene therapy trials have been developed for bradycardia, atrial fibrillation, and ventricular tachycardia. For the treatment of bradycardia, "biological pacemaker" attempts have been examined utilizing virus vectors to eliminate inward rectifier potassium current, or to overexpress the If current to convert quiescent myocytes into spontaneously active cells. These gene therapy attempts were soon followed by gene and cell hybrid therapies, and cell transplantation therapies utilizing pacemaker cells derived from stem cells. For the treatment of tachycardia, two major strategies were conceived: 1) to increase the effective refractory period, or 2) to recover the conduction velocity. The establishment of a selective and highly efficient gene transfer method would enable us to apply these concepts into the atrial fibrillation and ventricular tachycardia models. Both concepts resulted in an elimination or reduction of tachyarrhythmias in large animal models. Although these trials proved the concept of gene therapy as an adjuvant or alternative approach for the treatment of cardiac arrhythmias, the limitation of these studies is the long-term efficacy and safety. Consequently, an improvement in the gene delivery method is required to overcome these issues.

Gene Therapy for Cardiac Arrhythmias.

Genome-wide association study has identified that the genetic variations at NOS1AP (neuronal nitric oxide synthase-1 adaptor protein) were associated with QT interval and sudden cardiac death (SCD). However, the mechanism linking a genetic variant of NOS1AP and SCD is poorly understood. We used Nos1ap knockout mice (Nos1ap(-/-)) to determine the involvement of Nos1ap in SCD, paying special attention to oxidative stress.At baseline, a surface electrocardiogram (ECG) and ultrasound echocardiography (UCG) showed no difference between Nos1ap(-/-) and wild-type (WT) mice. Oxidative stress was induced by a single injection of doxorubicin (Dox, 25 mg/kg). After Dox injection, Nos1ap(-/-) showed significantly higher mortality than WT (93.3 versus 16.0% at day 14, P < 0.01). ECG showed significantly longer QTc in Nos1ap(-/-) than WT, and UCG revealed significant reduction of fractional shortening (%FS) only in Nos1ap(-/-) after Dox injection. Spontaneous ventricular tachyarrhythmias were documented by telemetry recording after Dox injection only in Nos1ap(-/-). Ex vivo optical mapping revealed that the action potential duration (APD)90 was prolonged at baseline in Nos1ap(-/-), and administration of Dox lengthened APD90 more in Nos1ap(-/-) than in WT. The expression of Bnp and the H2O2 level were higher in Nos1ap(-/-) after Dox injection. Nos1ap(-/-) showed a reduced amplitude of calcium transient in isolated cardiomyocytes after Dox injection. Administration of the antioxidant N-acetyl-L-cysteine significantly reduced mortality of Nos1ap(-/-) by Dox injection, accompanied by prevention of QT prolongation and a reduction in %FS.Although Nos1ap(-/-) mice have apparently normal hearts, oxidative stress evokes ventricular tachyarrhythmia and heart failure, which may cause sudden cardiac death.

Koji Sugiyama

Department of Bio-informational Pharmacology,
Medical Research Institute,
Department of Bio-informational Pharmacology, Medical Research Institute

Tokyo Medical and Dental University

Electrophysiological Assessment of Murine Atria with High-Resolution Optical Mapping

Koji Sugiyama

Department of Bio-informational Pharmacology,Medical Research Institute,Department of Bio-informational Pharmacology, Medical Research Institute

Tokyo Medical and Dental University

Electrophysiological Assessment of Murine Atria with High-Resolution Optical Mapping

Department of Bio-informational Pharmacology,
Medical Research Institute,
Department of Bio-informational Pharmacology, Medical Research Institute