Key Molecule of Aggravation of Hypertensive Organ Damage by Large Blood Pressure Variability

• Project/Area Number: 24591104
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Kurume University
• Principal Investigator: KAI Hisashi 久留米大学, 医学部, 准教授 (60281531)
• Co-Investigator(Kenkyū-buntansha): UCHIWA Hiroki 久留米大学, 医学部, 助教 (30624506) ; KAJIMOTO Hidemi 久留米大学, 医学部, 助教 (50349700) ; AOKI Yuji 久留米大学, 医学部, 助教 (80597419)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 血圧変動 / 高血圧 / 心肥大 / 線維化 / 炎症 / 心臓リモデリング / 血管リモデリング

Outline of Final Research Achievements

The aim of this study was to determine the key molecule of aggravation of hypertensive organ damage by large blood pressure (BP) variability. First, using a model of a combination of hypertension and large BP variability, large BP variability activated mineralocortioid receptor (MR), Rac, and PAK in medial smooth muscle of the intramyocardial arterioles. A sub-depressure dose of selective MR inhibitor, eplerenone prevented chronic inflammatory changes, cardiac hypertrophy, myocardial fibrosis, and LV systolic dysfunction. Accordingly, it was suggested that the Rac-PAK-MR system plays a role in the aggravation of the large BP variability-induced aggravation of hypertensive organ damages. Currently, further investigation using genetically engineered mice is on-going to determine the causal relation between MR system and large BP variability-induced aggravation of hypertensive organ damages.

Research Products

• [Journal Article] Benefit of losartan/hydrochlorthizide-fixed dose combination treatment for isolated morning hypertension: the MAPPY study (2015)
  • Author(s): Kai H, Ueda T, Uchiwa H, Iwamoto Y, Anegawa T, Fukuda K, Fukumoto Y, Imaizumi T.
  • Journal Title: Clinical and Experimental Hypertension Volume: ePub Issue: 6 Pages: 1-9
  • DOI: 10.3109/10641963.2015.1013118
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 「バイオマーカーと臓器障害」血圧変動と臓器障害 (2015)
  • Author(s): 甲斐久史
  • Journal Title: 循環器Plus Volume: 15 Pages: 10-12
• [Journal Article] BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease (2014)
  • Author(s): Kajimoto, H. Kai, H. Aoki, H. Uchiwa, H. Aoki, Y. Yasuoka, S. Anegawa, T. Mishina, Y. Suzuki, A. Fukumoto, Y. Imaizumi, T.
  • Journal Title: Kidney international Volume: 87 Issue: 1 Pages: 128-36
  • DOI: 10.1038/ki.2014.223
  • Peer Reviewed
• [Journal Article] Large Blood Pressure Variability Aggravates Arteriolosclerosis and Cortical Sclerotic Changes in the Kidney in Hypertensive Rats (2014)
  • Author(s): Aoki Y, Kai H, Kajimoto H, Kudo H, Takayama N, Yasuoka S, Anegawa T, Iwamoto Y, Uchiwa H, Fukuda K, Kage M, Kato S, Fukumoto Y, Imaizumi T.
  • Journal Title: Circulation Journal Volume: 78 Issue: 9 Pages: 2284-2291
  • DOI: 10.1253/circj.CJ-14-0027
  • NAID: 130004677614
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanism of aggravation of hypertensive organ damages by short-term blood pressure variability. (2014)
  • Author(s): Kai H, Kudo H, Takayama N, Yasuoka S, Aoki Y, Imaizumi T.
  • Journal Title: Current Hypertension Reviews Volume: 10 Issue: 3 Pages: 125-133
  • DOI: 10.2174/1573402111666141217112655
  • Peer Reviewed / Open Access
• [Journal Article] 血圧変動による臓器障害の機序：RASの関与 (2014)
  • Author(s): 甲斐久史
  • Journal Title: Angiotensin Research Volume: 11 Pages: 144-149
• [Journal Article] Report of the Salt Reduction Committee of the Japanese Society of Hypertension(1) Role of salt in hypertension and cardiovascular diseases. (2013)
  • Author(s): Ando K, Kawarazaki H, Miura K, Matsuura H, Watanabe Y, Yoshita K, Kawamura M, Kusaka M, Kai H, Tsuchihashi T, Kawano Y.
  • Journal Title: Hypertension Research Volume: 36 Issue: 12 Pages: 1009-1019
  • DOI: 10.1038/hr.2013.102
  • Peer Reviewed
• [Journal Article] Report of the Salt Reduction Committee of the Japanese Society of Hypertension(2) Goal and strategies of dietary salt reduction in the management of hypertension. (2013)
  • Author(s): Miura K, Ando K, Tsuchihashi T, Yoshita K, Watanabe Y, Kawarazaki H, Matsuura H, Kusaka M, Kai H, Kawamura M, Kawano Y.
  • Journal Title: Hypertension Research Volume: 36 Issue: 12 Pages: 1020-1025
  • DOI: 10.1038/hr.2013.105
  • Peer Reviewed
• [Journal Article] Report of the Salt Reduction Committee of the Japanese Socieety of Hypertension (3) Assessment and application of salt intake in the management of hypertension (2013)
  • Author(s): Tsuchihashi T, Kai H, Kusaka M, et al.
  • Journal Title: Hypertension Research Volume: 36 Issue: 12 Pages: 1026-1031
  • DOI: 10.1038/hr.2013.103
  • Peer Reviewed
• [Journal Article] 血圧変動と臓器障害 (2013)
  • Author(s): 甲斐久史
  • Journal Title: Annual Review循環器2013 Volume: N/A Pages: 193-201
• [Journal Article] 二次予防としての血圧管理 (2013)
  • Author(s): 青木裕司、岩元美子、打和大幹、甲斐久史
  • Journal Title: Cardiac Practice Volume: 24 Pages: 139-144
• [Journal Article] Reduction in Morning Blood Pressure Is a Key Factor for Ameliorating Urinary Albumin Excretion in Patients With Morning Hypertension Irrespective of Treatment Regimen (2013)
  • Author(s): Kai H, Kaneyuki M, Shihara M, Toyama Y, Mitsutake Y, Umei H, Kusaba K, Ueda T, Adachi H, Imaizumi T
  • Journal Title: Circulation Journal Volume: 77 Issue: 6 Pages: 1551-1557
  • DOI: 10.1253/circj.CJ-12-1102
  • NAID: 10031158886
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Blood Pressure Variability Activates Cardiac Mineralocorticoid Receptor and Induces Cardiac Remodeling in Hypertensive Rats (2013)
  • Author(s): Yasuoka S, Kai H, Kajimoto H, Anegawa T
  • Journal Title: Circulation Journal Volume: 77 Issue: 6 Pages: 1474-1481
  • DOI: 10.1253/circj.CJ-12-1253
  • NAID: 10031158877
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Respiratory variation of vertebral arterial flow in a patient scheduled for coronary artery bypass graft surgery - Lesson from atypical subclavian steel phenomenon - (2013)
  • Author(s): Anegawa T, Kai H, Fukuda K, Iwamoto Y, Tsuru T, Itaya N, Koiwaya H, Takeuchi T, Toyama Y, Oba T, Mawatari K, Takeuchi Y, Morioka M, Tanaka H, Ueno T, Imaizumi T
  • Journal Title: Circulation Journal Volume: 77
  • Peer Reviewed
• [Journal Article] マイクロコンベックス型探触子を用いた経口腔頚部血管超音波検査法（modified TOCU） (2013)
  • Author(s): 1. 姉川敬裕、福田賢治、甲斐久史、崎間洋邦、矢坂正弘、梶本英美、岩元美子、安岡逸、青木裕司、打和大幹、岡田靖、今泉勉
  • Journal Title: 脳卒中 Volume: 35 Pages: 1-4
  • Peer Reviewed
• [Journal Article] Losartan/hydrochlorothiazide combination versus high dose losartan in patients with morning hypertension - A prospective, randomized, open-labeled, parallel-group, multicenter trial - (2012)
  • Author(s): Ueda T, Kai H, Imaizumi T
  • Journal Title: Hypertension Research Volume: 35 Issue: 7 Pages: 708-712
  • DOI: 10.1038/hr.2012.27
  • Peer Reviewed
• [Journal Article] Is low diastolic blood pressure an independent risk for cardiovascular events in patients with manifest atherosclerotic disease? (2012)
  • Author(s): Kai H, Ueno T, Kimura T, Adachi H, Imaizumi T
  • Journal Title: Hypertension Volume: 59 Issue: 4
  • DOI: 10.1161/hypertensionaha.111.190264
  • Peer Reviewed
• [Journal Article] Stent-anchored coil embolotherapy; Novel treatment procedure for huge pulmonary arterio-venous malformation in hereditary hemorrhagic telangiectasia- (2012)
  • Author(s): Koiwaya H, Kai H, Ueno T, Niiyama H, Takeuchi T, Ueda S-I, Gondo T, Kumagai E, Miyamoto M, Yokoyama S, Sasaki K-I, Toyama Y, Ohtsuka M, Mitsutake Y, Anegawa T, Suda K, Imaizumi T
  • Journal Title: International Journal of Cardiology Volume: 157 Issue: 1 Pages: 122-124
  • DOI: 10.1016/j.ijcard.2012.03.049
  • Peer Reviewed
• [Journal Article] Selective gene expression analysis of muscular and vascular components in hearts using laser microdissection method. (2012)
  • Author(s): Ikeda A, Kai H, Kajimoto H, Yasuoka S
  • Journal Title: Int J Vasc Med Volume: Article ID 863410 Pages: 2012-2012
  • DOI: 10.1155/2012/863410
  • Peer Reviewed
• [Presentation] Japan-Korea Joint Symposium: “Challenges to the classic paradigm of the hypertensive heart disease” Fibro-inflammatory changes during progression of systolic/diastolic dysfunction in hypertensive heart (2014)
  • Author(s): Kai H
  • Organizer: 58th Korean Society of Cardiology Annual Scientific Meeting
  • Place of Presentation: Goyang, Korea
  • Year and Date: 2014-11-28
  • Invited
• [Presentation] 血栓薬服用中の冠動脈疾患における血圧レベルが脳出血発症に及ぼす影響：JCADサブ解析 (2014)
  • Author(s): 甲斐久史、興梠貴英、福田賢治、福本義弘、山崎力、永井良三
  • Organizer: 第37回日本高血圧学会学術集会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2014-10-18
• [Presentation] 高齢者の早朝高血圧に対するロサルタン/ヒドロクロロチアジド配合剤と高用量ロサルタンの比較-MAPPY研究サブ解析の結果より- (2014)
  • Author(s): 打和大幹、甲斐久史、福田賢治、上田集宣、姉川敬裕、青木裕司、岩元美子、今泉勉、福本義弘
  • Organizer: 第61回日本心臓病学会学術集会
  • Place of Presentation: 宮城県仙台市
  • Year and Date: 2014-09-27
• [Presentation] Within-individual day-by-day blood pressure variability during subacute stage predicts functional and long-term survival outcomes in ischemic stroke patients: Fukuoka Stroke Registry. (2014)
  • Author(s): Fukuda K, Kai H, Kamouchi M, Hata J, Ago T, Imaizumi T, Kitazono T
  • Organizer: European Society of Cardiology Congress 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-09-01
• [Presentation] Effects of systolic blood pressure levels on risk for strokes in coronary artery disease patients receiving anti-thrombotic combination therapy: JCAD study (2014)
  • Author(s): Kai H, Kohro T, Fukuda K, Fukumoto Y, Yamasaki T, Nagai R
  • Organizer: European Society of Cardiology Congress 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30
• [Presentation] 血圧変動による高血圧性臓器障害増悪のメカニズムとは (2014)
  • Author(s): 甲斐久史
  • Organizer: 第18回日本適応医学会学術集会
  • Place of Presentation: 東京都千代田区
  • Year and Date: 2014-06-21
• [Presentation] 心疾患合併高血圧 (2014)
  • Author(s): 甲斐久史
  • Organizer: 第3回臨床高血圧フォーラム
  • Place of Presentation: 広島県広島市
  • Year and Date: 2014-05-24
• [Presentation] トピックス「血圧変動性高血圧への治療戦略」Short-term Blood Pressure Variability and Cardiovascular Damages – Clinical Aspects and Molecular Mechanism – (2014)
  • Author(s): 甲斐久史
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Large blood pressure variability aggravates arteriolosclerosis and ischemic changes in the kidney in hypertensive rats. (2013)
  • Author(s): Aoki Y, Kai H, Kajimoto H, Kudo H, Takayama N, Yasuoka S, Anegawa T, Iwamoto Y, Uchiwa H, Fukuda K, Kage M, Kato S, Fukumoto Y, Imaizumi T
  • Organizer: High Blood Pressure Research 2013 Scientific Session
  • Place of Presentation: New Orleans, La, USA
• [Presentation] パネルディスカッション“血圧変動と家庭血圧、24時間血圧：最新の知見” 血圧変動と臓器障害―機序 (2013)
  • Author(s): 甲斐久史
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 大阪
• [Presentation] “Diabetes Controversy 4：糖尿病患者における降圧薬は？―ARB or ACE阻害薬” 糖尿病合併高血圧の治療―ACE阻害薬再考 (2013)
  • Author(s): 甲斐久史
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] 高血圧ラットの腎臓において血圧変動増大は細動脈硬化および虚血性病変を増加させる (2013)
  • Author(s): 青木裕司、甲斐久史、梶本英美、工藤博司、高山成政、安岡 逸、姉川敬裕、岩元美子、打和大幹、福田賢治、鹿毛政義、加藤誠也、福本義弘、今泉勉
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 大阪
• [Presentation] 脳梗塞患者の急性期・亜急性期における血圧の再現性に関する検討 ： Fukuoka Stroke Registry（FSR） (2013)
  • Author(s): 福田賢治，甲斐久史，鴨打正浩，石束光司，姉川敬裕，岩元美子，中根博，今泉勉，北園孝成
  • Organizer: 第2回臨床高血圧フォーラム
  • Place of Presentation: 東京
• [Presentation] BMP type I receptor inhibition reduces endothelial dysfunction and vascular osteogenic differentiation in mice with chronic kidney disease. (2013)
  • Author(s): Kajimoto H, Kai H, Aoki H, Uchiwa H, Aoki Y, Iwamoto Y, Angawa T, Fukuda K, Imaizumi T
  • Organizer: American Heart Association’s Scientific Sessions 2013
  • Place of Presentation: Dallas, TX, USA
• [Presentation] Candesartan-based Treatment for Variability Lowering of Individual Blood Pressure and Heart Rate at Home Study: CAVALIER at HOME (2013)
  • Author(s): Kai H, Imaizumi T
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Large Blood Pressure Variability Aggravates Arteriolosclerosis and Interstitial Ischemic Changes in the Kidney in Hypertensive Rats (2013)
  • Author(s): Aoki Y, Kai H, Kudo H, Takayama N, Yasuoka S, Anegawa T, Iwamoto Y, Uchiwa H, Fukuda K, Kato S, Imaizumi T
  • Organizer: 第77回日本循環器学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Morning blood pressure lowering rather than treatment regimen is important for reducing urinary albumin excretion in patients with morning hypertension (2012)
  • Author(s): Kai H, Ueda T, Imaizumi T
  • Organizer: The 24th Scietific Meeting of the International Society of Hypertension
  • Place of Presentation: Sydney, Austraria
• [Presentation] Increased phosphatase and tensin homolog plays a crucial role in endothelial dysfunction in mice with renal failure (2012)
  • Author(s): Kajimoto H, Kai H, Aoki H, Uchiwa H, Aoki Y, Anegawa T, Imaizumi T
  • Organizer: American Heart Association’s Scientific Sessions 2012
  • Place of Presentation: Los Angeles, USA
• [Presentation] 循環器治療領域における高血圧専門医取得のメリット (2012)
  • Author(s): 甲斐 久史
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 名古屋
• [Presentation] 急性期脳梗塞患者の日間血圧変動と予後の関係：Fukuoka Stroke Registry（FSR） (2012)
  • Author(s): 福田 賢治、甲斐 久史、鴨打 正浩、石束 光司、姉川 敬裕、岩元 美子、中根 博、北園 孝成、今泉 勉
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 名古屋
• [Presentation] 血圧変動増大はPAK-MR系を介して高血圧性臓器障害を助長する (2012)
  • Author(s): 甲斐久史、安岡 逸、梶本英美、工藤博司、高山成政、今泉 勉
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 京都
• [Presentation] 左椎骨動脈血流波形が呼気時に逆行、吸気時に順行と呼吸性変動を示した左鎖骨下動脈盗血現象の一例 (2012)
  • Author(s): 姉川敬裕、福田賢治、甲斐久史、岩元美子、津留智子、青木裕司、打和大幹、竹内靖治、森岡基浩、今泉 勉
  • Organizer: 第37回日本脳卒中学会総会
  • Place of Presentation: 福岡
• [Presentation] 急性期脳梗塞患者の入院中血圧変動が予後に及ぼす影響: Fukuoka Stroke Registry(FSR) (2012)
  • Author(s): 福田賢治、甲斐久史、鴨打正浩、石束光司、姉川敬裕、岩元美子、中根 博、今泉 勉、北園孝成
  • Organizer: 第37回日本脳卒中学会総会
  • Place of Presentation: 福岡
• [Presentation] Inhibition of CaMKII/ERK-mediated eNOS phosphorylation impairs endothelial function in renal failure mice: New effect of asymmetric dimethylarginine (2012)
  • Author(s): Kajimoto H, Kai H, Aoki H, Uchiwa H, Aoki Y, Imaizumi T
  • Organizer: 第16回日本心不全学会学術集会
  • Place of Presentation: 仙台
• [Presentation] Exaggerated Blood Pressure Variability Aggravates Arteriolosclerosis and Interstitial Ischemic Lesions in the Kidney of Hypertensive Rats (2012)
  • Author(s): Aoki Y, Kai H, Kudo H, Takayama N, Yasuoka S, Anegawa T, Iwamoto Y, Uchiwa H, Fukuda K, Kage M, Kato S, Imaizumi T
  • Organizer: 第16回日本心不全学会学術集会
  • Place of Presentation: 仙台
• [Presentation] 非弁膜性心房細動を有する脳梗塞患者からみたCHADS2スコア、CHA2DS2-VAScスコア (2012)
  • Author(s): 姉川 敬裕、福田 賢治、甲斐 久史、岩元 美子、青木 裕司、打和 大幹、梶本 英美、矢坂 正弘、岡田 靖、今泉 勉
  • Organizer: 第36回日本心臓病学会学術集会
  • Place of Presentation: 金沢
• [Presentation] マイクロコンベックス型探触子を用いた経口腔頸部血管超音波検査法（modified TOCU） (2012)
  • Author(s): 姉川敬裕、甲斐久史、福田賢治、矢坂正弘、崎間洋邦、湧川佳幸、齊藤正樹、岩元美子、田原敦子、梶本英美、安岡逸、青木裕司、打和大幹、岡田 靖、今泉 勉
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 名古屋
• [Presentation] MAPPY Study Investigators: 降圧治療による尿中アルブミン減少の規定因子は何か？―早朝高血圧患者における検討― (2012)
  • Author(s): 甲斐久史、上田集宣、今泉勉
  • Organizer: 第36回日本高血圧学会総会
  • Place of Presentation: 名古屋