This laboratory focuses on understanding pathogenesis of intractable and common cardiovascular diseases using multidisciplinary approach (patch-clamp, cell biology, optical recording, genetic analysis, and computational analysis). Our ultimate goal is to improve diagnosis and management of intractable and common cardiovascular diseases.

#B1. Gender-specific medicine (GSM) for cardiovascular diseases#BR
In the past few years, we have shown that non-genomic regulation of cardiac ion channels by sex hormones underlies, at least in part, gender difference in cardiac electrophysiology, and thus susceptibility to arrhythmias. This year, we used FRET imaging and LC/MS technology to show that non-genomic regulation of cardiac ion channels by sex hormones cross-talks with adrenergic receptor signaling specifically in the raft micro-domain.

#B2. Pathogenesis of atrial fibrillation (AF)#BR
Atrial fibrillation (AF) is the most frequent arrhythmias, reaching more than 1 million patients in Japan. Associated cerebral infarction due to cardiogenic thrombosis (250,000 patients /year in Japan) and higher incidence of cognitive impairment cause reduced QOL and are main causes of bedridden old people. Thus, establishment of therapeutic strategy for AF is an urgent requirement.
#B(1) GWAS for AF#BR
We had carried out most extensive GWAS (genome-wide association study) in Japan to determine gene polymorphisms associated with AF. Since 2011, we have participated in the international Meta-analysis called as CHARGE study. CHARGE study found 10 SNPs associated with AF: among them, 6 SNPs were associated with both European/American and Japanese, and 4 with European/American but not with Japanese.
#B(2) Functional analysis of AF associated genes#BR
One of the sales-points of GWAS is the identification of novel pathogenic pathways and therapeutic targets due to its comprehensibility. We carried out functional analysis for 6 genes associated with Japanese AF patients, and found a novel pathway generating abnormal automaticity in the pulmonary vein myocardium, which is the main triggering factor of atrial fibrillation.
#B(3) Risk stratification#BR
Another sales-point of GWAS is the risk stratification of the diseases and its use for future personalized medicine. Based on GWAS data, we calculated AF risk score and classified them into 4 quartile groups. The highest risk group has 5.5 higher risk of AF development relative to the lowest risk group (left panel in Figure 1). The risk stratification yielded around 60% sensitivity and specificity (right panel in Figure 1), which are not enough for personalized medicine, and further studies to increase odds ratio are needed.

#B3. Pathogenesis of ventricular fibrillation (VF) and sudden cardiac death#BR
Despite extensive effort by many researchers for years, VF remains the main cause of sudden death, and the biggest challenge in arrhythmia research. Last year, we showed that genetic deletion of the His-Purkinje system-specific transcription factor in mice exhibited exercise-related ventricular tachyarrhythmias. This year, we searched for genetic disturbance of this transcription factor in patients with idiopathic VF, and found that the mutations of this factor are responsible for idiopathic VF, and a common variant is a modifier of causative gene mutations for idiopathic VF.

#B4. Use of iPS cells for arrhythmia research#BR
In the past few years, we have aimed to use human iPS-derived cardiomyocytes (hiPS-CMs) for drug screening. hiPS-CMs include various types of cardiomyocytes, such as atrial, ventricular, and nodal types of cardiomyocytes, and exhibit relatively immature electrophysiological properties of cardiac cells, hindering high-quality drug screening. In order to generate mature ventricular-like hiPS-CMs, we over-expressed a gene into hiPS-CMs. The genetically-altered hiPS-CMs exhibited mature forms of action potentials and drug sensitivity. Our novel technique would be useful for evaluation of drug-induced alternation of repolarization processes in the human cardiomyocytes.

#B5. Use of state-of-art technology for cardiovascular research#BR
#B(1) Use of motion vector technology for in vitro analysis of cardiac contraction#BR
Motion vector technology created by Sony Co. (Dr. Matsui E. et al.) is the in vitro system to assay non-invasively contraction and relaxation speed of cardiac myocytes. We have tried to broaden its application to screening of cardiac toxicity of drugs. This year, we applied to examine cardiac toxicity of anti-cancer drugs.
#B(2) Use of 3-D cardiac simulator (UT-heart) for screening of cardiac toxicity of drugs#BR
Prof. Hisada T. et al. in the University of Tokyo have developed 3-D cardiac simulator (UT-heart). We have tried to broaden its application to screening of cardiac toxicity of drugs. This year, we examined 10 standard drugs (high risk, intermediate risk, and no risk).

School of Medicine
　2nd grade Introduction to Neurophysiology (2 units)
　2nd grade Physiology (6 units)
　3rd grade Cardiology (1 unit)
　4th grade Project semester
School of Health Care Medicine
　3rd/4th grade Cardiac physiology (8 units)