Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome.

Aims: Gain-of-function mutations in RYR2, encoding the cardiac ryanodine receptor channel (RyR2), cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Whereas, genotype-phenotype correlations of loss-of-function mutations remains unknown, due to a small number of analysed mutations. In this study, we aimed to investigate their genotype-phenotype correlations in patients with loss-of-function RYR2 mutations.

Electrophysiological Analysis of hiPSC-Derived Cardiomyocytes Using a Patch-Clamp Technique.

Electrophysiological analysis of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using a patch-clamp technique enables the most precise evaluation of electrophysiological properties in single cells. Compared to multielectrode array (MEA) and membrane voltage imaging, patch-clamp recordings offer quantitative measurements of action potentials, and the relevant ionic currents which are essential for the research of disease modeling of inherited arrhythmias, safety pharmacology, and drug discovery using hiPSC-CMs. In this chapter, we describe the detail flow of patch-clamp recordings in hiPSC-CMs.

Propranolol Attenuates Late Sodium Current in a Long QT Syndrome Type 3-Human Induced Pluripotent Stem Cell Model.

Background: Long QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the gene, which encodes the α subunit of the cardiac voltage-gated sodium channel. LQT3 patients present bradycardia and lethal arrhythmias during rest or sleep. Further, the efficacy of β-blockers, the drug used for their treatment, is uncertain.

Gene-Based Risk Stratification for Cardiac Disorders in Mutation Carriers.

Background: Mutations in (), which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance, atrial fibrillation, and malignant ventricular arrhythmias. Although the type of mutations have been reported to be associated with susceptibility to malignant ventricular arrhythmias, the gene-based risk stratification for cardiac complications remains unexplored.

Methods And Results: The multicenter cohort included 77 mutation carriers from 45 families; cardiac disorders were retrospectively analyzed.

Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of SCN5A-D1275N-Related Cardiac Sodium Channelopathy.

Background: TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, Na1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced Na1.

Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation.

Calmodulin is a ubiquitous Ca2+ sensor molecule encoded by three distinct calmodulin genes, CALM1-3. Recently, mutations in CALM1-3 have been reported to be associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism through which heterozygous calmodulin mutations lead to severe LQTS remains unknown, particularly in human cardiomyocytes.

Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia.

Introduction: Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies.

Electrocardiography as the First Step for the Further Examination of Cardiac Involvement in Myasthenia Gravis.

Introduction: Cardiac involvement of myasthenia gravis (MG) accompanies a poor prognosis. In the present study, we aimed to investigate the relationship between ECG abnormality and cardiac involvement.

Methods: Of 178 patients diagnosed with MG between 2001 and 2013 at our hospital, we retrospectively analyzed consecutive 58 patients who underwent both ECG and echocardiography and without underlying cardiovascular disease.

Impact of renal function deterioration on adverse events during anticoagulation therapy using non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.

Renal function is crucial for patients with non-valvular atrial fibrillation (NVAF) using non-vitamin K antagonist oral anticoagulants (NOAC). The incidence of renal function deterioration during anticoagulation therapy and its impact of adverse events are unknown. In 807 consecutive NVAF patients treated with NOAC and with estimated creatinine clearance (eCCr) ≥ 50 ml/min (mean age 68 ± 11 years, mean CHADS2 score = 1.

Identification of a nuclear localization signal in mouse polycomb protein, M33.

The mouse Polycomb group (PcG) protein M33 forms nuclear complexes with the products of other PcG members and maintains repressed states of developmentally important genes, including homeotic genes. In this context, nuclear localization is a prerequisite for M33 to exert its function. However, we previously found that M33 in mouse liver shuttles dynamically between the nucleus and the cytoplasm, depending on the proliferative states of cells, coupled with phosphorylation and dephosphorylation of M33 protein.

Evidence for the involvement of double-strand breaks in heat-induced cell killing.

To identify critical events associated with heat-induced cell killing, we examined foci formation of gammaH2AX (histone H2AX phosphorylated at serine 139) in heat-treated cells. This assay is known to be quite sensitive and a specific indicator for the presence of double-strand breaks. We found that the number of gammaH2AX foci increased rapidly and reached a maximum 30 minutes after heat treatment, as well as after X-ray irradiation.