Research Projects
Elucidation of Genetic and Electrophysiological Basis of
Hereditary Lethal Arrhythmias
Hereditary lethal arrhythmias predispose young or middle-aged affected individuals to sudden death. Defining its pathophysiology and establishing effective strategies for the prophylaxis of sudden death are therefore urgent issues in public health. Recent advances in genetic technologies have elucidated the genetic basis of hereditary arrhythmias. Especially in congenital long QT syndrome (LQTS), mutations have been identified in dozens of cardiac ion channel genes that affect action potential configuration and the impulse propagation. Since the diagnostic probability of identifying the gene mutation is reasonably high, it is feasible to provide LQTS family members with presymptomatic genetic testing and prophylactic treatment based on the genetic information. Accordingly, genetic testing of LQTS is now reimbursed by medical insurance in Japan. In contrast, molecular studies of other mutations have identified only a small proportion of affected individuals. Such yet-to-be-defined diseases include Brugada syndrome, one form of idiopathic ventricular fibrillation predominantly observed in Asian countries, and progressive cardiac conduction defect, a disorder of the cardiac conduction system and a major cause of pacemaker implantation worldwide.
This project is aimed at elucidating the molecular basis of sudden death in hereditary lethal arrhythmias and ultimately developing new prophylactic approaches that potentially replace the implantable devices. The project goals will be achieved by close collaboration among clinical and research institutes around the world, and exploiting cutting-edge technologies such as iPS cells (induced pluripotent stem cells).
1. Genetic screening and electrophysiological analysis of hereditary lethal arrhythmias
Hereditary lethal arrhythmias are generally rare, and the available family members are too few to perform linkage analysis. In order to identify the genetic basis of lethal arrhythmias, we need to collect larger numbers of cases/families and analyze their clinical phenotypes and genetic information. This will be accomplished by close collaboration among both clinical and research institutes around the world. Genetic screening of each case and the resulting mutations will allow us to perform functional evaluation using basic electrophysiological techniques, such as patch clamp, that will elucidate the pathophysiological mechanisms responsible for hereditary lethal arrhythmias.
2. Electrophysiological analysis of human iPS cell-derived cardiomyocytes from patients with hereditary lethal arrhythmias
Human cardiomyocytes are generally hard to obtain because of both ethical and technical limitations; therefore, functional and electrophysiological evaluations of patientsﾕ cardiomyocytes are virtually impossible. Importantly, Professor Fukudaﾕs group at Keio University has recently developed an innovative strategy to establish human iPS-derived cardiomyocytes in collaboration with Professor Yamanaka at Kyoto University. Human iPS cells, established from skin fibroblast cells, were induced to differentiate into functional cardiomyocytes. Nagasaki University, in collaboration with other national institutions, will carry out functional and electrophysiological analysis using human cardiomyocytes derived from both healthy individuals and lethal arrhythmias patients. This project will allow us to develop novel treatments for lethal arrhythmias as well as discover new drugs, which in turn may lead to the development of custom, mutation-specific therapies for hereditary lethal arrhythmias.
3. Computer simulation to delineate the basis mechanisms of hereditary lethal arrhythmias
Functional outcomes of the genetic defects in hereditary lethal arrhythmias have been most commonly evaluated in cultured cell lines by means of heterologous expression. To understand the mechanisms underlying the initiation of lethal arrhythmias and clinical manifestations, further functional studies at the level of multicellular cardiac muscle preparations or the whole heart are required. To this end, we will perform computer simulation studies (e.g., multicellular Luo-Rudy models) as part of a collaborative effort between engineering and medical sciences.
4. Establishment of genetically-engineered animals relevant to hereditary lethal arrhythmias and functional analysis in vivo
Investigations using the aforementioned techniques will provide important information to better understand the genetic, molecular, and cellular basis of hereditary lethal arrhythmias. To further explore the pathophysiological mechanisms underlying hereditary lethal arrhythmias, genetically-engineered animals, such as transgenic mice, will be established and their functional or electrophysiological abnormalities will be characterized in vivo.
