Basic Research for Biological Pacemaker

• Project/Area Number: 16590672
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Nagoya University
• Principal Investigator: INDEN Yasuya Nagoya University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (10359747)
• Co-Investigator(Kenkyū-buntansha): MUROHARA Toyoaki Nagoya University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (90299503) ; KONDO Takahisa Nagoya University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (00303644) ; TAKADA Yasunobu Nagoya University, University Hospital, Research Associate, 医学部附属病院, 助手 (80378067)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000); Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: pacemaker cell / ionic channel / gene therapy

Research Abstract

As for the treatment to the bradyarrhythmia, a cardiac pacemaker is generally implanted. And now, the prognosis and QOL of the bradyarrhythmia patient are improving by the artificial pacemaker therapy. However there are some problems in pacemaker therapy. The artificial cardiac pacemaker is very expensive and the battery life is limited. The patients need reoperation for the battery exchange and receive the operative-stress. Therefore as the regeneration medicine to the bradyarrhythmia, making the biological pacemaker cell, which has an automaticity as same as the sinus nodal cell, is tried by the gene introduction. It is because the 4th phase diastolic depolarization happens due to the lack of the inward rectifie K+ channel and the existence of the hyperpolarization-activated inward current channel that the sinus nodal cell has automaticity. This hyperpolarization-activated inward current channel is prescribed by the HCN gene family and it needs the extraction of HCN2 and the HCN4 gene in this HCN gene family to create the pacemaker cell. We evaluated bradyarrhythmia in klotho mutant mice, ageing model. We found that klotho gene expression is essential for the sinoatrial node. We got the HCN4 from the human heart cDNA by the technique of PCR and inserted the HCN4 full length arrangement in the plasmid pcDMA3.1. After the confirmation the full length arrangement of the HCN4-plaemid, we confirmed protein manifestation by Western blot using the human kidney cell. To create the recombinant adenovirus which contained a gotten gene, the HCN4-plaemid was introduced to cosmid-vector pAxCAwtit2. Which means the There is possibility to create the biological pacemaker cell which has automaticity through the diastolic depolarization by introducing the HCN4 gene into the cardiomyocyte using the recombinant adenovirus.

Research Products

• [Journal Article] Computerized three-dimensional potential mapping with a multielectrode basket catheter can be useful for pulmonary vein electrical disconnection (2005)
  • Author(s): Yamada T
  • Journal Title: Interv Card Electrophysiol 12・1 Pages: 23-33
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Computerized three-dimensional potential mapping with a multielectrode basket catheter can be useful for pulmonary vein electrical disconnection. (2005)
  • Author(s): Yamada T, Murakami Y, Muto M, Okada T, Okamoto M, Shimizu T, Toyama J, Yoshida Y, Tsuboi N, Ito T, Kondo T, Inden Y, Hirai M, Murohara T.
  • Journal Title: J Interv Card Electrophysiol. 12(1) Pages: 23-33
  • NAID: 10012840692
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Use of an artificial neural network to localize accessory pathways of Wolff-Parkinson-White syndrome with12-lead electrocardiogram (2005)
  • Author(s): Huang D
  • Journal Title: Med Inform Internet Med 30・4 Pages: 277-286
• [Journal Article] Increased expression of plasminogen activator inhibitor-1 in cardiomyocytes contributes to cardiac fibrosis after myocardial infarction (2004)
  • Author(s): Takeshita K
  • Journal Title: Am J Pathol. 164・2 Pages: 449-56
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of the amino acid residues of the platelet glycoprotein Ib (GPIb) essential for the von Willebrand factor binding by clustered charged-to-alanine scanning mutagenesis (2004)
  • Author(s): Shimizu A
  • Journal Title: J Biol Chem 279・16 Pages: 16285-94
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression (2004)
  • Author(s): Takeshita K
  • Journal Title: Circulation 109・14 Pages: 1776-82
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers (2004)
  • Author(s): Kondo T
  • Journal Title: Arterioscler Thromb Vasc Biol 24・8 Pages: 1442-7
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Electrophysiologic characteristics of atrial tachycardia orginating the right atrium : from the right pulmonary veins or posterior rigt artrium : double potentials obtained from the posterior wall of the right atrium can be useful to predict foci of atrial tachycardia in right pulmonary veins or posterior right atrium (2004)
  • Author(s): Yamada T
  • Journal Title: J Cardiovasc Electrophysiol. 15・7 Pages: 745-51
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased expression of plasminogen activator inhibitor-1 in cardiomyocytes contributes to cardiac fibrosis after myocardial infarction. (2004)
  • Author(s): Takeshita K, Hayashi M, Iino S, Kondo T, Inden Y, Iwase M, Kojima T, Hirai M, Ito M, Loskutoff DJ, Saito H, Murohara T, Yamamoto K.
  • Journal Title: Am J Pathol. 164(2) Pages: 449-456
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of the amino acid residues of the platelet glycoprotein Ib (GPIb) essential for the von Willebrand factor binding by clustered charged-to-alanine scanning mutagenesis. (2004)
  • Author(s): Shimizu A, Matsushita T, Kondo T, Inden Y, Kojima T, Saito H, Hirai M.
  • Journal Title: J Biol Chem. 279(16) Pages: 16285-16294
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. (2004)
  • Author(s): Takeshita K, Fujimori T, Kurotaki Y, Honjo H, Tsujikawa H, Yasui K, Lee JK, Kamiya.K, Kitaichi K, Yamamoto K, Ito M, Kondo T, Iino S, Inden Y, Hirai M, Murohara T, Kodama I, Nabeshima Y.
  • Journal Title: Circulation. 109(14) Pages: 1776-1782
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers. (2004)
  • Author(s): Kondo T, Hayashi M, Takeshita K, Numaguchi Y, Kobayashi K, Iino S, Inden Y, Murohara T.
  • Journal Title: Arterioscler Thromb Vase Biol. 24(8) Pages: 1442-1447
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Electrophysiologic characteristics of atrial tachycardia originating from the right pulmonary veins or posterior right atrium : double potentials obtained from the posterior wall of the right atrium can be useful to predict foci of atrial tachycardia in right pulmonary veins or posterior right atrium. (2004)
  • Author(s): Yamada T, Murakami Y, Muto M, Okada T, Okamoto M, Toyama J, Yoshida Y, Tsuboi N, Ito T, Kondo T, Inden Y, Hirai M, Murohara T.
  • Journal Title: J Cardiovasc Electrophysiol. 15(7) Pages: 745-751
  • Description: 「研究成果報告書概要(欧文)」より