Target triglycerides to prevent cardiovascular events

• Project/Area Number: 19K17599
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Hiroshima University
• Principal Investigator: Kajikawa Masato 広島大学, 病院(医), 助教 (80777293)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 中性脂肪 / 血管内皮機能 / 脳心血管疾患 / 残余リスク

Outline of Research at the Start

脳心血管疾患は日本人の死因の約25%を占め、発症すると重篤な障害や死亡につながるためその予防は切実な課題である。LDLコレステロールは心血管疾患発症の危険因子として確立しているが、LDLコレステロールに対する薬物治療を行っても心血管疾患発症リスクが残存する。これまでの研究で中性脂肪が心血管疾患発症の危険因子であることが示唆され、中性脂肪は脂質異常症治療の次のターゲットとして注目されている。本研究は、①中性脂肪と心血管疾患発症リスクの調査、②動脈硬化マーカーによる心血管疾患発症リスクが増大する閾値の解析、を通じて心血管疾患の発症を抑制するための中性脂肪の目標値を明らかにすることを目的としている。

Outline of Final Research Achievements

A total of 679 patients aged 30-88 years who had been diagnosed with cardiovascular disease were enrolled. Serum triglyceride levels more than 100 mg/dL were significantly associated with an increased risk of first major cardiovascular events compared with the serum triglyceride levels <100 mg/dL.
Next, a total of 7047 subjects who underwent health-screening examinations with agreement for measurement of vascular function were enrolled. We investigated cross-sectional associations between serum triglyceride levels and endothelial function assessed by measurement of flow-mediated vasodilation (FMD). FMD was significantly higher in subjects with triglyceride levels of <50 mg/dL than in subjects with triglyceride levels of more than 50 mg/dL.

Academic Significance and Societal Importance of the Research Achievements

日本や外国における脂質異常症ガイドラインは、中性脂肪が150 mg/dL以下を正常と定義している。しかし、適切な中性脂肪治療の目標値について十分な根拠がなく、どこまで介入すればよいのか指針はない。本研究の成果により、中性脂肪が正常高値であるの100-150 mg/dLの群で、既に血管内皮機能が障害され、心血管疾患発症リスクが高いことが示された。さらに血管内皮機能と中性脂肪との関係に関する研究結果から、中性脂肪はより低い値を目標に治療を行うことで心筋梗塞、脳梗塞などの血管合併症発症の抑制につながることが示唆された。

Research Products

• [Journal Article] Serum Potassium Levels of 4.5 to Less Than 5.0 mmol/L Are Associated with Better Vascular Function (2022)
  • Author(s): Maruhashi T, Kajikawa M, Kishimoto S, Takaeko Y, Yamaji T, Harada T, Hashimoto Y, Han Y, Aibara Y, Yusoff FM, Nakano Y, Chayama K, Nakashima A, Goto C, Yoshimura K, Higashi Y.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 29 Issue: 11 Pages: 1588-1602
  • DOI: 10.5551/jat.63285
  • NAID: 130008132408
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2022-11-01
  • Peer Reviewed / Open Access
• [Journal Article] Self-reported total sitting time on a non-working day is associated with blunted flow-mediated vasodilation and blunted nitroglycerine-induced vasodilation (2022)
  • Author(s): Yamaji T, Harada T, Hashimoto Y, Nakano Y, Kajikawa M, Yoshimura K, Chayama K, Goto C, Han Y, Mizobuchi A, Yusoff FM, Kishimoto S, Maruhashi T, Nakashima A, Higashi Y.
  • Journal Title: Sci Rep Volume: 12(1) Issue: 1 Pages: 6366-6366
  • DOI: 10.1038/s41598-022-10242-8
  • Peer Reviewed / Open Access
• [Journal Article] Implantation of Hypoxia-Induced Mesenchymal Stem Cell Advances Therapeutic Angiogenesis (2022)
  • Author(s): Yusoff FM, Nakashima A, Kawano KI, Kajikawa M, Kishimoto S, Maruhashi T, Ishiuchi N, Abdul Wahid SFS, Higashi Y.
  • Journal Title: Stem Cells Int Volume: - Pages: 6795274-6795274
  • DOI: 10.1155/2022/6795274
  • Peer Reviewed / Open Access
• [Journal Article] Poor tooth brushing behavior is associated with high risk of cardiovascular events: A prospective observational study (2022)
  • Author(s): Matsui S, Maruhashi T, Kishimoto S, Kajikawa M, Yusoff FM, Nakashima A, Taguchi A, Higashi Y.
  • Journal Title: Int J Cardiol . Volume: 350 Pages: 111-117
  • DOI: 10.1016/j.ijcard.2021.12.056
  • Peer Reviewed
• [Journal Article] Isolated diastolic hypertension is not associated with endothelial dysfunction (2022)
  • Author(s): Han Y, Maruhashi T, Kajikawa M, Kishimoto S, Yamaji T, Harada T, Hashimoto Y, Yusoff FM, Nakano Y, Chayama K, Nakashima A, Goto C, Yoshimura K, Higashi Y.
  • Journal Title: Hypertens ResInt Volume: 45(4) Issue: 4 Pages: 698-707
  • DOI: 10.1038/s41440-022-00854-y
  • Peer Reviewed / Open Access
• [Journal Article] Vascular Dysfunction Predicts Future Deterioration of Left Ventricular Ejection Fraction in Patients with Heart Failure with Mildly Reduced Ejection Fraction (2022)
  • Author(s): Kishimoto S, Maruhashi T, Kajikawa M, Harada T, Yamaji T, Han Y, Mizobuchi A, Hashimoto Y, Yoshimura K, Nakano Y, Chayama K, Goto C, Yusoff FM, Nakashima A, Higashi Y.
  • Journal Title: J Clin Med Volume: 10(24) Issue: 24 Pages: 5980-5980
  • DOI: 10.3390/jcm10245980
  • Peer Reviewed / Open Access
• [Journal Article] Short stature is associated with low flow-mediated vasodilation in Japanese men (2022)
  • Author(s): Harada T, Kajikawa M, Maruhashi T, Kishimoto S, Yamaji T, Han Y, Mizobuchi A, Hashimoto Y, Yoshimura K, Nakano Y, Chayama K, Goto C, Yusoff FM, Nakashima A, Higashi Y.
  • Journal Title: Hypertens Res Volume: 45(2) Issue: 2 Pages: 308-314
  • DOI: 10.1038/s41440-021-00785-0
  • Peer Reviewed
• [Journal Article] Relationship between hemoglobin A1c level and flow-mediated vasodilation in patients with type 2 diabetes mellitus receiving antidiabetic drugs (2022)
  • Author(s): Yamaji T, Harada T, Hashimoto Y, Nakano Y, Kajikawa M, Yoshimura K, Aoki G, Chayama K, Goto C, Mizobuchi A, Han Y, Yusoff FM, Kishimoto S, Maruhashi T, Nakashima A, Higashi Y.
  • Journal Title: J Diabetes Investig Volume: 13(4) Issue: 4 Pages: 677-686
  • DOI: 10.1111/jdi.13705
  • Peer Reviewed / Open Access
• [Journal Article] Promising Assessment of Vascular Function for Future Cardiovascular Events (2021)
  • Author(s): Kajikawa M, Higashi Y.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 11 Pages: 1123-1125
  • DOI: 10.5551/jat.ED154
  • NAID: 130008110122
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-11-01
  • Peer Reviewed
• [Journal Article] Volume Elastic Modulus, Vascular Function, and Vascular Structure in Patients with Cardiovascular Risk Factors (2021)
  • Author(s): Maruhashi T, Kajikawa M, Kishimoto S, Takaeko Y, Yamaji T, Harada T, Hashimoto Y, Han Y, Aibara Y, Mohamad Yusoff F, Chayama K, Nakashima A, Goto C, Nakano Y, Higashi Y.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 9 Pages: 963-973
  • DOI: 10.5551/jat.59261
  • NAID: 130008082092
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-09-01
  • Peer Reviewed
• [Journal Article] Falsely normalized ankle-brachial index despite the presence of lower-extremity peripheral artery disease: two case reports (2021)
  • Author(s): Maruhashi T, Matsui S, Yusoff FM, Kishimoto S, Kajikawa M, Higashi Y.
  • Journal Title: J Med Case Rep Volume: 15(1) Issue: 1 Pages: 622-622
  • DOI: 10.1186/s13256-021-03155-z
  • Peer Reviewed / Open Access
• [Journal Article] A body shape index is associated with endothelial dysfunction in both men and women (2021)
  • Author(s): Kajikawa M, Maruhashi T, Kishimoto S, Yamaji T, Harada T, Hashimoto Y, Han Y, Mizobuchi A, Aoki G, Yoshimura K, Chayama K, Goto C, Yusoff FM, Nakashima A, Higashi Y.
  • Journal Title: Sci Rep Volume: 11(1) Issue: 1 Pages: 17873-17873
  • DOI: 10.1038/s41598-021-97325-0
  • Peer Reviewed / Open Access
• [Journal Article] Upstroke time as a marker of atherosclerosis in patients with diabetes mellitus who have a normal ankle-brachial index (2021)
  • Author(s): Maruhashi T, Kajikawa M, Kishimoto S, Takaeko Y, Yamaji T, Harada T, Hashimoto Y, Han Y, Yusoff FM, Nakano Y, Chayama K, Nakashima A, Goto C, Yoshimura K, Higashi Y.
  • Journal Title: J Diabetes Complications Volume: 35(11) Issue: 11 Pages: 108044-108044
  • DOI: 10.1016/j.jdiacomp.2021.108044
  • Peer Reviewed
• [Journal Article] Low-intensity pulsed ultrasound decreases major amputation in patients with critical limb ischemia: 5-year follow-up study (2021)
  • Author(s): Mohamad Yusoff F, Kajikawa M, Yamaji T, Takaeko Y, Hashimoto Y, Mizobuchi A, Han Y, Kishimoto S, Maruhashi T, Nakashima A, Higashi Y.
  • Journal Title: PLoS One Volume: 16(8) Issue: 8 Pages: e0256504-e0256504
  • DOI: 10.1371/journal.pone.0256504
  • Peer Reviewed / Open Access
• [Journal Article] Stair climbing activity and vascular function in patients with hypertension (2021)
  • Author(s): Yamaji T, Harada T, Hashimoto Y, Nakano Y, Kajikawa M, Yoshimura K, Chayama K, Goto C, Han Y, Mizobuchi A, Yusoff FM, Kishimoto S, Maruhashi T, Nakashima A, Higashi Y.
  • Journal Title: Hypertens Res Volume: 44(10) Issue: 10 Pages: 1274-1282
  • DOI: 10.1038/s41440-021-00697-z
  • Peer Reviewed
• [Journal Article] Inconvenient relationship of haemoglobin A1c level with endothelial function in type 2 diabetes in a cross-sectional study (2021)
  • Author(s): Yamaji T, Harada T, Hashimoto Y, Takaeko Y, Kajikawa M, Han Y, Maruhashi T, Kishimoto S, Hashimoto H, Kihara Y, Hida E, Chayama K, Goto C, Yusoff FM, Nakashima A, Higashi Y.
  • Journal Title: BMJ Open Volume: 11(6) Issue: 6 Pages: e045415-e045415
  • DOI: 10.1136/bmjopen-2020-045415
  • Peer Reviewed
• [Journal Article] Lower triglyceride levels are associated with better endothelial function (2021)
  • Author(s): Takaeko Y, Maruhashi T, Kajikawa M, Kishimoto S, Yamaji T, Harada T, Hashimoto Y, Han Y, Kihara Y, Chayama K, Goto C, Yusoff FM, Yoshimura K, Nakashima A, Higashi Y.
  • Journal Title: J Clin Lipidol Volume: 15(3) Issue: 3 Pages: 500-511
  • DOI: 10.1016/j.jacl.2021.04.004
  • Peer Reviewed
• [Journal Article] Spontaneous renal hemorrhage in acquired cystic kidney disease (2021)
  • Author(s): Kajikawa M, Tanji H, Higashi Y.
  • Journal Title: J Gen Fam Med Volume: 22(2) Issue: 2 Pages: 94-95
  • DOI: 10.1002/jgf2.400
  • Peer Reviewed
• [Journal Article] Smoking status and endothelial function in Japanese men (2021)
  • Author(s): Hashimoto H, Maruhashi T, Yamaji T, Harada T, Han Y, Takaeko Y, Kihara Y, Chayama K, Goto C, Aibara Y, Yusoff FM, Kishimoto S, Kajikawa M, Nakashima A, Higashi Y.
  • Journal Title: Sci Rep Volume: 11(1) Issue: 1 Pages: 95-95
  • DOI: 10.1038/s41598-020-80012-x
  • Peer Reviewed / Open Access
• [Journal Article] Association of Body Mass Index with Endothelial Function in Asian Men (2021)
  • Author(s): Kajikawa Masato、Maruhashi Tatsuya、Kishimoto Shinji、Hashimoto Haruki、Takaeko Yuji、Yamaji Takayuki、Harada Takahiro、Hashimoto Yu、Han Yiming、Kihara Yasuki、Hida Eisuke、Chayama Kazuaki、Goto Chikara、Yusoff Farina Mohamad、Nakashima Ayumu、Higashi Yukihito
  • Journal Title: International Journal of Cardiology Volume: 324 Pages: 186-192
  • DOI: 10.1016/j.ijcard.2020.09.029
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial function is preserved in light to moderate alcohol drinkers but is impaired in heavy drinkers in women: Flow-mediated Dilation Japan (FMD-J) study (2020)
  • Author(s): Oda Nozomu、Kajikawa Masato、Maruhashi Tatsuya、Kishimoto Shinji、Yusoff Farina Mohamad、Goto Chikara、Nakashima Ayumu、Tomiyama Hirofumi、Takase Bonpei、Yamashina Akira、Higashi Yukihito
  • Journal Title: PLOS ONE Volume: 15 Issue: 12 Pages: e0243216-e0243216
  • DOI: 10.1371/journal.pone.0243216
  • Peer Reviewed / Open Access
• [Journal Article] Low Levels of Low-Density Lipoprotein Cholesterol and Endothelial Function in Subjects without Lipid-Lowering Therapy (2020)
  • Author(s): Takaeko Yuji、Kajikawa Masato、Kishimoto Shinji、Yamaji Takayuki、Harada Takahiro、Han Yiming、Kihara Yasuki、Hida Eisuke、Chayama Kazuaki、Goto Chikara、Aibara Yoshiki、Yusoff Farina Mohamad、Maruhashi Tatsuya、Nakashima Ayumu、Higashi Yukihito
  • Journal Title: Journal of Clinical Medicine Volume: 9 Issue: 12 Pages: 3796-3796
  • DOI: 10.3390/jcm9123796
  • Peer Reviewed / Open Access
• [Journal Article] Relationship between high-density lipoprotein cholesterol levels and endothelial function in women: a cross-sectional study (2020)
  • Author(s): Takaeko Yuji、Matsui Shogo、Kajikawa Masato、Maruhashi Tatsuya、Yamaji Takayuki、Harada Takahiro、Han Yiming、Hashimoto Haruki、Kihara Yasuki、Hida Eisuke、Chayama Kazuaki、Goto Chikara、Aibara Yoshiki、Yusoff Farina Mohamad、Kishimoto Shinji、Nakashima Ayumu、Higashi Yukihito
  • Journal Title: BMJ Open Volume: 10 Issue: 7 Pages: e038121-e038121
  • DOI: 10.1136/bmjopen-2020-038121
• [Journal Article] Target of Triglycerides as Residual Risk for Cardiovascular Events in Patients With Coronary Artery Disease ― Post Hoc Analysis of the FMD-J Study A ― (2019)
  • Author(s): Kajikawa Masato、Noma Kensuke、Nakashima Ayumu、Tomiyama Hirofumi、Takase Bonpei、Kohro Takahide、Suzuki Toru、Ishizu Tomoko、Ueda Shinichiro、Yamazaki Tsutomu、Furumoto Tomoo、Kario Kazuomi、Inoue Teruo、Koba Shinji、Watanabe Kentaro、Takemoto Yasuhiko、Hano Takuzo、Sata Masataka et al.
  • Journal Title: Circulation Journal Volume: 83 Issue: 5 Pages: 1064-1071
  • DOI: 10.1253/circj.CJ-18-1082
  • NAID: 130007636980
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-04-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Relationship between a Body Shape Index and Endothelial Function: FMD-Japan Registry (2022)
  • Author(s): Masato Kajikawa, Tatsuya Maruhashi, Shinji Kishimoto, Takayuki Yamaji, Takahiro Harada, Yu Hashimoto, Yiming Han, Farina Mohamad Yusoff, Ayumu Nakashima, Yukihito Higashi
  • Organizer: 第86回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] Body Mass Index (BMI)と血管内皮機能との関係 (2022)
  • Author(s): 梶川 正人、丸橋 達也、岸本 真治、山路 貴之、原田 崇弘、橋本 悠、Farina Mohamad Yusoff、Yiming Han、中島 歩、東 幸仁
  • Organizer: 第7回日本血管不全学会学術集会
• [Presentation] Relationship between body mass index and endothelial function in men: FMD-Japan registry (2021)
  • Author(s): Masato Kajikawa, Tatsuya Maruhashi, Shinji Kishimoto, Yuji Takaeko, Takayuki Yamaji, Takahiro Harada, Yu Hashimoto, Yiming Han, Farina Mohamad Yusoff, Ayumu Nakashima, Yukihito Higashi
  • Organizer: 第85回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] 改良型ezFMDで評価した血管内皮機能による新規イベント発症リスクの層別化 (2021)
  • Author(s): 梶川 正人、森本 陽香、橋本 悠、山路 貴之、原田 崇弘、岸本 真治、丸橋 達也、Farina Mohamad Yusoff、Yiming Han、中島 歩、辻 敏夫、東 幸仁
  • Organizer: 第6回日本血管不全学会学術集会
• [Presentation] 骨折リスクと血管機能との関係 (2021)
  • Author(s): 梶川 正人、橋本 悠、高永甲 有司、山路 貴之、原田 崇弘、岸本 真治、丸橋 達也、Farina Mohamad Yusoff、Yiming Han、中島 歩東 幸仁
  • Organizer: 第74回日本酸化ストレス学会第21回日本NO学会合同学術集会
• [Presentation] High-normal Triglycerides are Associated with Increased Cardiovascular Events in Patients with Coronary Artery Disease (2020)
  • Author(s): Masato Kajikawa, Tatsuya Maruhashi, Shinji Kishimoto, Haruki Hashimoto, Yuji Takaeko, Takayuki Yamaji, Takahiro Harada, Yu Hashimoto, Farina Mohamad Yusoff, Yasuki Kihara, Kensuke Noma, Ayumu Nakashima, Yukihito Higashi, FMD-J Investigators
  • Organizer: 第84回日本循環器学会学術集会
  • Int'l Joint Research
• [Presentation] 中性脂肪が血管内皮機能や心血管疾患発症に与える影響とその閾値について (2020)
  • Author(s): 梶川正人
  • Organizer: SPPARM Expo