Linkage analysis of novel biomarkers for the construction of preventive and therapeutic strategies in cardiovascular diseases

• Project/Area Number: 24591077
• 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: Nippon Medical School
• Principal Investigator: SEINO Yoshihiko 日本医科大学, 医学部, 教授 (10163073)
• Co-Investigator(Renkei-kenkyūsha): TAKANO Masamichi 日本医科大学, 医学部, 准教授 (40287719) ; KOBAYASHI Nobuaki 日本医科大学, 医学部, 助教 (80366674) ; INAMI Toru 日本医科大学, 医学部, 助教 (00468753) ; KURIHARA Osamu 日本医科大学, 医学部, 助教 (00614794) ; KITAMURA Mitsunobu 日本医科大学, 医学部, 助教 (90557464) ; OTSUKA Toshiaki 日本医科大学, 医学部, 准教授 (80339374)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: バイオマーカー / 心不全 / 潜在性心筋傷害 / 不安定プラーク / 睡眠時無呼吸 / 高感度トロポニン / sLOX-1 / MMP-9 / 心血管バイオマーカー / 高血圧症 / 睡眠時無呼吸症候群 / 新規リスクマーカー / 心血管カテーテル治療 / 冠動脈疾患 / 高血圧 / 粥状動脈硬化 / プラーク / 心筋傷害 / 臨床心血管病態学 / 糖尿病 / BNP / 冠動脈内視鏡

Outline of Final Research Achievements

To construct preventive and therapeutic strategy in cardiovascular diseases, we have applied linkage analyses in novel cardiovascular biomarkers in stage A or B and C patients. Even in patients with stable coronary artery disease, severity of SAS (AHI) significantly correlated with elevation of Hs-TnT, BNP, and sLOX-1 (detection of minor myocardial injury : MMI and silent vulnerable plaque). Elevation of sLOX-1 was characterized by ruptured thin-cap fibroatheroma. Strong statin therapy lowered Hs-TnT (deterrent of MMI) and attenuated periprocedural myocardial injury following PCI. Concerning the MMI in chronic heart failure, we revealed cross-talk between MMI and serum cholesterol levels and production of monocyte pro-inflammatory cytokines. It is important to select and set the high-precision surrogate biomarkers according to the heart failure stages and construct the comprehensive therapeutic strategies.

Research Products

• [Journal Article] Effects of adaptive servo-ventilation therapy on cardiac function and remodeling in patients with chronic heart failure (SAVIOR-C): study protocol for a randomized controlled trial (2015)
  • Author(s): Seino Yoshihiko, Shin-ichi Momomura, Kihara Yasuki, Adachi Hitoshi, Yasumura Yoshio, Yokoyama Hiroyuki
  • Journal Title: Trials Volume: 16 Issue: 1 Pages: 1-7
  • DOI: 10.1186/s13063-014-0530-z
  • Peer Reviewed / Open Access
• [Journal Article] Adaptive Servo-Ventilation Therapy for Patients With Chronic Heart Failure in a Confirmatory, Multicenter, Randomized, Controlled Study (2015)
  • Author(s): Momomura Shin-ichi, SeinovYoshihiko, Kihara Yasuki, Adachi Hitoshi, Yasumura Yoshio, Yokoyama Hiroyuki, Wada Hiroshi, Ise Takayuki, Tanaka Koichi
  • Journal Title: Circulation Journal Volume: 79 Issue: 5 Pages: 981-990
  • DOI: 10.1253/circj.CJ-15-0221
  • NAID: 130005066288
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Coronary atherosclerosis is already ongoing in pre-diabetic status: Insight from intravascular imaging modalities. (2015)
  • Author(s): Kurihara Osamu, Takano Masamichi, Seino Yoshihiko, Wataru Shimizu, Mizuno Kyoichi
  • Journal Title: World Journal of Diabetes Volume: 6 Issue: 1 Pages: 184-191
  • DOI: 10.4239/wjd.v6.i1.184
  • Peer Reviewed / Open Access
• [Journal Article] Expanding the role of cardiac biomarkers—natriuretic peptides and troponins—further in pre-Stage A (2015)
  • Author(s): Seino Yoshihiko, Otsuka Toshiaki
  • Journal Title: Hypertension Research Volume: 38 Issue: 1 Pages: 11-12
  • DOI: 10.1038/hr.2014.145
  • Peer Reviewed
• [Journal Article] Relationships between the Serum Cholesterol Levels, Production of Monocyte Proinflammatory Cytokines and Long-term Prognosis in Patients with Chronic Heart Failure (2014)
  • Author(s): Nakagomi Akihiro, Seino Yoshihiko, Noma Satsuki, Kohashi Keiichi, Kosugi Munenori, Kato Katsuhito, Kusama Yoshiki
  • Journal Title: Internal Medicine Volume: 53 Issue: 21 Pages: 2415-2424
  • DOI: 10.2169/internalmedicine.53.2672
  • NAID: 130004704951
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Heart-type fatty acid-binding protein is a novel prognostic marker in patients with essential hypertension (2014)
  • Author(s): Setsuta Koichi, Seino Yoshihiko, Mizuno Kyoichi
  • Journal Title: International Journal of Cardiology Volume: 176 Issue: 3 Pages: 1323-1325
  • DOI: 10.1016/j.ijcard.2014.07.150
  • Peer Reviewed / Open Access
• [Journal Article] Serum Cystatin C, Creatinine-Based Estimated Glomerular Filtration Rate, and the Risk of Incident Hypertension in Middle-Aged Men (2014)
  • Author(s): Otsuka T, Kato K, Kachi Y, Ibuki C, Seino Y, Kodani E, Kawada T
  • Journal Title: American Journal of Hypertension Volume: 27 Issue: 4 Pages: 596-602
  • DOI: 10.1093/ajh/hpt164
  • Peer Reviewed
• [Journal Article] Impact of Prediabetic Status on Coronary Atherosclerosis: A multivessel angioscopic study (2013)
  • Author(s): Kurihara O, Takano M, Yamamoto M, Shirakabe A, Kimata N, Inami T, Kobayashi N, Munakata R, Murakami D, Inami S , Okamatsu K , Ohba T, Ibuki C, Hata N, Seino Y
  • Journal Title: Diabetes Care Volume: 36 Issue: 3 Pages: 729-733
  • DOI: 10.2337/dc12-1635
  • Peer Reviewed
• [Journal Article] High-sensitivity cardiac troponin T for earlier diagnosis of acute myocardial infarction in patients with initially negative troponin T test-Comparison between cardiac markers (2013)
  • Author(s): Kitamura M, Hata N, Takayama T, Hirayama A, Ogawa M, Yamashina A, Mera H, Yoshino H, Nakamura F, Seino Y
  • Journal Title: Journal of Cardiology Volume: 62 Issue: 6 Pages: 336-342
  • DOI: 10.1016/j.jjcc.2013.06.005
  • Peer Reviewed
• [Journal Article] Soluble lectin-like oxidized LDL receptor-1 (sLOX-1) as a valuable diagnostic marker for rupture of thin-cap fibroatheroma: Verification by optical coherence tomography (2013)
  • Author(s): Kobayashi N, Takano M, Hata N, Kume N, Yamamoto M, Yokoyama S, Shinada T, Tomita K, Shirakabe A, Otsuka T, Seino Y, Mizuno K
  • Journal Title: International Journal of Cardiology Volume: 168 Issue: 4 Pages: 3217-3223
  • DOI: 10.1016/j.ijcard.2013.04.110
  • Peer Reviewed
• [Journal Article] Identification of high-risk plaques associated with peri-procedural myocardial injury following elective percutaneous coronary intervention: Assessment by high-sensitivity troponin-T measurements and optical coherence tomography (2013)
  • Author(s): Yamamoto M, Seino Y, Otsuka T, Kurihara O, Negishi K, Murakami D, Takano M, Mizuno K
  • Journal Title: International Journal of Cardiology Volume: 168 Issue: 3 Pages: 2860-2862
  • DOI: 10.1016/j.ijcard.2013.03.134
  • Peer Reviewed
• [Journal Article] Detection of acute aortic dissection by extremely high soluble lectin-like oxidized LDL receptor-1 (sLOX-1) and low troponin T levels in blood (2013)
  • Author(s): Kobayashi N, Hata N, Kume N, Yokoyama S, Takano M, Shinada T, Tomita K, Shirakabe A, Inami T, Seino Y, Mizuno K
  • Journal Title: International Journal of Cardiology Volume: 165 Issue: 3 Pages: 557-559
  • DOI: 10.1016/j.ijcard.2012.09.001
  • Peer Reviewed
• [Journal Article] Prediction of atrial fibrillation after ischemic stroke using P-wave signal averaged electrocardiography (2013)
  • Author(s): Yodogawa K, Seino Y, Ohara T, Hayashi M, Miyauchi Y, Katoh T, Mizuno K
  • Journal Title: Journal of Cardiology Volume: 61 Issue: 1 Pages: 49-52
  • DOI: 10.1016/j.jjcc.2012.08.013
  • Peer Reviewed
• [Journal Article] Oscillometric measurement of brachial artery cross-sectional area and its relationship with cardiovascular risk factors and arterial stiffness in a middle-aged male population (2013)
  • Author(s): Otsuka T, Munakata R, Kato K, Kodani E, Ibuki C, Kusama Y, Seino Y, Kawada T
  • Journal Title: Hypertension Research Volume: 36 Issue: 10 Pages: 910-915
  • DOI: 10.1038/hr.2013.56
  • Peer Reviewed
• [Journal Article] 血管炎症のバイオマーカーをみる (2013)
  • Author(s): 清野 精彦
  • Journal Title: Vascular Medicine Volume: 9 Pages: 54-58
• [Journal Article] 不安定プラークマーカーとその読みかた (2013)
  • Author(s): 清野 精彦
  • Journal Title: Medical Practice Volume: 30 Pages: 875-980
• [Journal Article] 不安定プラークとバイオマーカー (2013)
  • Author(s): 清野精彦、小林宣明、高野雅充
  • Journal Title: 循環器 Volume: 3 Pages: 29-34
  • Peer Reviewed
• [Journal Article] Links between sleep disordered breathing, coronary atherosclerotic burden, and cardiac biomarkers in patients with stable coronary artery disease. (2012)
  • Author(s): Inami T, SeinoY, Otsuka T, Yamamoto M, Kimata M, Murakami D, Takano M, Ohba T, Ibuki C , Mizuno K
  • Journal Title: Journal of Cardiology Volume: 60 Issue: 3 Pages: 180-186
  • DOI: 10.1016/j.jjcc.2012.03.003
  • Peer Reviewed
• [Journal Article] Malondialdehyde-Modified Low-Density Lipoprotein Is a Useful Marker to Identify Patients With Vulnerable Plaque (2012)
  • Author(s): Tajika K, Okamatsu K, Takano M, Inami S, Yamamoto M, Murakami D, Kobayashi N, Ohba T, Hata N, Seino Y, Mizuno K
  • Journal Title: Circulation Journal Volume: 76 Issue: 9 Pages: 2211-2217
  • DOI: 10.1253/circj.CJ-12-0183
  • NAID: 10030696874
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] オシロメトリック法による上腕動脈面積測定の再現性および正確性に関する検討 (2012)
  • Author(s): 宗像亮、大塚俊昭、梅田宗紀、加藤活人、雪吹周生、清野精彦
  • Journal Title: THERAPEUTIC RESEARCH Volume: 33 Pages: 1701-1709
  • Peer Reviewed
• [Journal Article] Switching to Pitavastatin inStatin-Treated Low HDL-C Patients Further Improves the Lipid Profile and Attenuates Minute Myocardial Damage (2012)
  • Author(s): Ibuki C, Seino Y, Otsuka T, Kimata N, Inami T, Murakami D, Mizuno K
  • Journal Title: Journal of Clinical Medicine Research Volume: 4(6) Pages: 385-392
  • DOI: 10.4021/jocmr1108w
  • Peer Reviewed
• [Journal Article] 急性冠症候群の血液生化学診断 (2012)
  • Author(s): 清野精彦
  • Journal Title: 日本医師会雑誌 Volume: 141 Pages: 2639-2643
  • Peer Reviewed
• [Presentation] Effects of ASV Therapy on Cardiac Function and Remodeling in Systolic Heart Failure Outpatients from a Randomized Controlled Study (SAVIOR-C) (2015)
  • Author(s): Momomura Shin-ichi, Seino Yoshihiko, Kihara Yasuki, Yasumura Yoshio, Adachi Hitoshi, Yokoyama Hiroyuki
  • Organizer: 日本循環器学会学術集会
  • Place of Presentation: ABCホール（大阪）
  • Year and Date: 2015-04-26
• [Presentation] No Need of Implantable Cardioverter-Defibrillator in Patients with a History of Fatal Ventricular Arrhythmia following Pure Refractory Vasospastic Angina (2015)
  • Author(s): Murakami Daisuke, Takano Masamichi, Shimura Tetsuro, Uetake Shunsuke, Yamamoto Teppei, Munakata Ryo, Maruyama Mitsunori, Ohba Takayoshi, Seino Yoshihiko, Mizuno Kyoichi, Shimizu Wataru
  • Organizer: 日本循環器学会学術j集会
  • Place of Presentation: グランフロント大阪（大阪）
  • Year and Date: 2015-04-26
• [Presentation] Appropriate Blood Pressure Control Suppresses Minor Myocardial Injury in Patients with Essential Hypertension (2015)
  • Author(s): Setsuta Koichi, Seino Yoshihiko, Shimizu Wataru
  • Organizer: 日本循環器学会学術j集会
  • Place of Presentation: グランフロント大阪（大阪）
  • Year and Date: 2015-04-25
• [Presentation] Combination of Several Calcium-channel-Blockers improves a Prognosis for the Patients of Refractory Vasospastic Angina with Appropriate Judgment of Drug Efficacy (2015)
  • Author(s): Murakami Daisuke, Takano Masamichi, Shimura Tetsuro, Kurihara Osamu, Munakata Ryo, Ohba Takayoshi, Seino Yoshihiko, Mizuno Kyoichi, Shimizu Wataru
  • Organizer: 日本循環器学会学術j集会
  • Place of Presentation: グランフロント大阪（大阪）
  • Year and Date: 2015-04-25
• [Presentation] SAS-CHSARC Network: The Chiba-Hokusoh Sleep Apnea Regional Collaborative (CHSARC) Network for the Earlier Diagnosis and Treatment of Sleep Apnea Syndrome (2015)
  • Author(s): Seino Yoshihiko, Inami Toru, Munakata Ryo, Shimura Tetsuro, Uchiyama Saori, Maruyama Mitsunori, Takano Masamichi, Ohba Takayoshi, Shimizu Wataru
  • Organizer: 日本循環器学会学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪）
  • Year and Date: 2015-04-24
• [Presentation] Upregulation of Monocyte Proinflammatory Cytokines Production by C-Reactive Protein Predicts Poor Outcomes in Patients with Chronic Heart Failure (2014)
  • Author(s): Nakagomi A , Noma S, Kohashi K, Kosugi M, E Ikuko, K Naomi, E, Yasumi, K, Yoshiki, Seino Y, Atarashi Hi, Shimizu W
  • Organizer: 日本循環器学会学術集会（第78回）
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] Coronary Atherosclerosis and Risk of Acute Coronary Syndromes in Chronic Kidney Disease (2014)
  • Author(s): Kurihara O, Kimata N, Inami T, Murakami D,Munakata R, Ohba T, Takano M, Seino Y, Mizuno K
  • Organizer: 日本循環器学会学術集会（第78回）
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] Drug-on Acetylcholine Provocation Test is Most Useful for Assessment of Therapeutic Efficacy in Patients of Refractory Vasospastic Angina (2014)
  • Author(s): Murakami D, Takano M, Kano S, Shimura T, Kurihara O, Kimata N, Inami T, Munakata R, Ohba T, Seino Y, Mizuno K, Shimizu W
  • Organizer: 日本循環器学会学術集会（第78回）
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] Influence of Backgroud Risk Factors and Prescibed Medications on the Release-kinetics of Plaque-related Biomarkers Following PTA in Patients with ASO (2014)
  • Author(s): Kimata N, Seino Y, Kano S, Hada T, Shimura T, Kurihara O, Inami T, Munakata R, Murakami D, Takano M, Ohba T, Shimizu W
  • Organizer: 日本循環器学会学術集会（第78回）
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] Clinical Feasibility of High-sensitive Troponin T in Patients with Acute Coronary Syndrome―A Sub-analysis of iNET Study― (2014)
  • Author(s): Takayama T, Hirayama A, Kitamura M, H, Ogawa M, Yamashina A, Mera H, Yoshino H , Nakamura F, Seino Y
  • Organizer: 日本循環器学会学術集会（第78回）
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] Impact of Pre-Diabetic Status on Coronary Atherosclerosis -A Multivessel Angioscopic Study- (2013)
  • Author(s): Kurihara O, Takano M, Yamamoto M, Kano S, Shimura T, Kimata N, Inami T, Munakata R, Murakami D, Ohba , Ibuki C, Seino Y, Mizuno K
  • Organizer: 日本心血管インターベンション治療学会学術集会（第22回）
  • Place of Presentation: 神戸国際展示場(兵庫県神戸市)
• [Presentation] 冠動脈における早期動脈硬化進行の特徴とは：ＯＣＴ所見からの考察 (2013)
  • Author(s): Murakami D, Takano M, Yamamoto M, Kurihara O, Kimata N, Inami T, Munakata R, Ohba T, Seino Y, Mizuno K
  • Organizer: 日本心血管インターベンション治療学会学術集会（第22回）
  • Place of Presentation: 神戸国際展示場(兵庫県神戸市)
• [Presentation] Troponin T as a predictor for the responsiveness to the conventional therapy during a short-term prognostic factor in acute decompensated heart failure patients associated with severe aortic stenosis (2013)
  • Author(s): Munakata R, Yamamoto T, Shirakabe A, Inami T, Hosokawa Y, Akutsu K, Sato N, Hata N, Seino Y, Tanaka K
  • Organizer: Acute Cardiac Care 2013
  • Place of Presentation: Hotel Auditorium(スペイン マドリード)
• [Presentation] 上腕動脈コンプライアンス指標による冠動脈狭窄病変の存在予測－脳波伝播速度との比較－ (2013)
  • Author(s): 宗像 亮, 大塚 俊昭, 稲見 徹, 小谷 英太郎, 雪吹 周生, 清野 精彦, 清水 渉
  • Organizer: 日本心臓病学会学術集会（第61回）
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
• [Presentation] 経皮的冠動脈インターベンション時の心筋傷害とN-Terminal Pro-B-Type Natriuetic Peptide上昇の関係 (2013)
  • Author(s): 高野 仁司, 大場 崇芳, 山本 英世, 宮地 秀樹, 乾 恵輔, 川中 秀和, 高橋 保裕, 菊池 有史, 田邊 潤, 稲見 茂信, 田中 邦夫, 草間 芳樹, 清野 精彦, 水野 杏一, 清水 渉
  • Organizer: 日本心臓病学会学術集会（第61回）
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
• [Presentation] Heart-type fatty acid-binding protein is a novel prognostic marker in patients with essential hypertension. (2013)
  • Author(s): Setsuta K, Nishizawa A, Kitahara Y, Seino Y, Mizuno K
  • Organizer: ESC Congress 2013
  • Place of Presentation: Amsterdam RAI(オランダ アムステルダム)
• [Presentation] Early diagnostic and prognostic value of cTnT hs and NT-proBNP in cardiac emergency rooms (2013)
  • Author(s): Seino Y
  • Organizer: ProCardio Symposium
  • Place of Presentation: Steigenberger Airport Hotel Amsterdam(オランダ アムステルダム)
  • Invited
• [Presentation] Drug-Acetylcholline Provocation Test for Assessment of Therapeutic Efficacy in Patients with Refractory Vasospastic Angina-Importance of CCB Combinatioｎ Ｔｈｅｒａｐｙ (2013)
  • Author(s): Murakami D
  • Organizer: 日本循環器学会学術集会（第７７回） "
  • Place of Presentation: 横浜
• [Presentation] Untreated Obstructive Sleep Apnoea as a Therapeutic Target in Acute Dissection " (2013)
  • Author(s): Seino Y
  • Organizer: 日本循環器学会学術集会(第７７回) "
  • Place of Presentation: 横浜
• [Presentation] Characteristic Features of Disordered Breathing in the Convalescent Phase Dissection-Comparative Analysis with Stable Coronary Artery Disease- (2013)
  • Author(s): Seino Y
  • Organizer: 日本循環器学会学術集会(第77回） "
  • Place of Presentation: 横浜
• [Presentation] Identification of High-Risk Plaques Associatedwith Peri-procedural Myocardial Injury Following Elective Percutaneoous Coronary Intervention (2013)
  • Author(s): Yamamoto M
  • Organizer: 日本循環器学会学術集会(第77回）
  • Place of Presentation: 横浜
• [Presentation] 低HDL-C患者におけるPitavastatinへのスタチン変更はさらなる脂質プロファイル改善と微小心筋傷害軽減をもたらす (2012)
  • Author(s): 雪吹周生
  • Organizer: 日本心臓病学会（第60回）
  • Place of Presentation: 金沢
• [Presentation] 中年男性集団における高血圧発症予測因子としての血清シスタチンCと推算糸球体濾過量の比較 (2012)
  • Author(s): 大塚俊昭
  • Organizer: 日本高血圧学会（第35回）
  • Place of Presentation: 名古屋
• [Presentation] Links between sleep disordered breathing and the type of acute aortic dissection in the acute phase:differences in patent versus thrombosed false lumen (2012)
  • Author(s): Inami T
  • Organizer: Canadian Cardiovascular Congress 2012
  • Place of Presentation: Toronto
• [Presentation] Impact of Prediabetic Status on Coronary Atherosclerosis: A multivessel angioscopic study (2012)
  • Author(s): Kurihara O
  • Organizer: American Heart Association Scientific Sessions 2012
  • Place of Presentation: Los Angeles
• [Presentation] 前糖尿病と冠動脈硬化：血管内視鏡からの検討 (2012)
  • Author(s): 栗原理
  • Organizer: 日本冠疾患学会（第26回）
  • Place of Presentation: 横浜
• [Book] 循環器疾患 最新の治療 2014-2015 (分担執筆：循環器領域におけるバイオマーカーの新展開:不安定プラークに迫る) (2014)
  • Author(s): 清野 精彦 (分担執筆)
  • Total Pages: 528
  • Publisher: 南江堂