Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Volume 25, Issue 8
Displaying 1-11 of 11 articles from this issue
  • Yujiro Asada, Atsushi Yamashita, Yuichiro Sato, Kinta Hatakeyama
    2018 Volume 25 Issue 8 Pages 653-664
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: June 09, 2018

    Ischemic cardiovascular disease is a major cause of morbidity and mortality worldwide and thrombus formation on disrupted atherosclerotic plaques is considered to trigger its onset. Although the activation of platelets and coagulation pathways has been investigated intensively, the mechanisms of thrombus formation on disrupted plaques have not been understood in detail. Platelets are thought to play a central role in the formation of arterial thrombus because of rapid flow conditions; however, thrombus that develops on disrupted plaques consistently includes large amounts of fibrin in addition to aggregated platelets. While, thrombus does not always become large enough to completely occlude the vascular lumen, indicating that the propagation of thrombus is also critical for the onset of cardiovascular events. Various factors, such as vascular wall thrombogenicity, altered blood flow and imbalanced blood hemostasis, modulate thrombus formation and propagation on disrupted plaques. Pathological findings derived from humans and experimental animal models of atherothrombosis have identified important factors that affect thrombus formation and propagation, namely platelets, extrinsic and intrinsic coagulation factors, proinflammatory factors, plaque hypoxia and blood flow alteration. These findings might provide insight into the mechanisms of thrombus formation and propagation on disrupted plaques that lead to the onset of cardiovascular events.

    Download PDF (1632K)
  • Long Jiang, Lu-Ya Wang, Xiao-shu Cheng
    2018 Volume 25 Issue 8 Pages 665-673
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: June 13, 2018

    Familial hypercholesterolemia (FH) is an autosomal-dominant disorder that is characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and an increased risk of cardiovascular disease. Despite the use of high-dose statins and the recent addition of proprotein convertase subtilisin/kexin type 9 inhibitors as a treatment option, many patients with homozygous FH fail to achieve optimal reductions of LDL-c levels. Gene therapy has become one of the most promising research directions for contemporary life sciences and is a potential treatment option for FH. Recent studies have confirmed the efficacy of a recombinant adeno-associated virus 8 vector expressing the human LDL-c receptor gene in a mouse model, and this vector is currently in phase 2 clinical trials. Much progress has also been achieved in the fields of antisense oligonucleotide- and small interfering RNA-based gene therapies, which are in phase 1–2 clinical trials. In addition, novel approaches, such as the use of minicircle DNA vectors, microRNAs, long non-coding RNAs, and the CRISPR/Cas9 gene-editing system, have shown great potential for FH therapy. However, the delivery system, immunogenicity, accuracy, and specificity of gene therapies limit their clinical applications. In this article, we discuss the current status of gene therapy and recent advances that will likely affect the clinical application of gene therapy for the treatment of FH.

    Download PDF (507K)
Original Article
  • Jessica Ristorto, Nathan Messas, Benjamin Marchandot, Marion Kibler, S ...
    2018 Volume 25 Issue 8 Pages 674-689
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: February 08, 2018

    Aim: In percutaneous coronary intervention (PCI)-treated acute coronary syndrome (ACS) patients on clopidogrel therapy, high on-treatment platelet adenosine diphosphate (ADP) reactivity was observed in numerous studies, with significant increases in non-fatal myocardial infarction, definite/probable stent thrombosis, or cardiovascular mortality. Compared to clopidogrel, prasugrel and ticagrelor provide more potent platelet inhibition. Whether new P2Y12 inhibitors reduce thrombotic events in a similar manner compared to the rate observed with appropriate P2Y12 inhibition by clopidogrel must still be determined. This study sought to compare long-term outcomes between clopidogrel responders (platelet reactivity index [PRI] vasodilator-stimulated phosphoprotein [VASP] <61%) and patients under prasugrel or ticagrelor therapy following PCI-treated ACS.

    Methods: 730 ACS patients undergoing urgent PCI were prospectively enrolled into two groups: clopidogrel responders (n=448) and those under ticagrelor or prasugrel therapy (n=282). The primary endpoint was a composite of cardiovascular death, myocardial infarction, stent thrombosis, and stroke; the secondary endpoint comprised major hemorrhagic events.

    Results: The median follow-up was 260±186 days. Clopidogrel patients were older and more likely to present non-ST segment elevation myocardial infarction, cardiovascular risk factors, atrial fibrillation, or prior vascular disease. After propensity score matching, the primary endpoint was met in 7.1% of the clopidogrel group and 4.1% of the prasugrel/ticagrelor group (p=0.43). Minor bleeding events were significantly reduced in the clopidogrel group (1.1% vs. 3%; p=0.03). In a multivariate analysis, the antiplatelet treatment strategy was not an independent primary endpoint predictor.

    Conclusion: In PCI-treated ACS patients, clopidogrel therapy and PRI VASP <61% were not associated with increased risks of thrombotic events compared to prasugrel or ticagrelor therapy.

    Download PDF (383K)
  • Hiroshi Komoda, Aya Shiraki, Jun-ichi Oyama, Toshiyuki Nishikido, Koic ...
    2018 Volume 25 Issue 8 Pages 690-697
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: February 03, 2018

    Aim: Recently, calcium channel blockers (CCBs) have been reported to reduce atherosclerosis with anti-inflammatory or antiatherosclerotic effects in vivo. It is well established that monocytes and macrophages play important roles in promoting atherosclerosis. However, the effects of CCBs on macrophage activation remain unclear. The aim of this study was to evaluate the effects of azelnidipine, a dihydropyridine L-type CCB, on the activation of macrophages and to clarify the mechanisms of the effects of CCBs on atherosclerosis.

    Methods: THP-1 monocytes, a human leukemic cell line, were stimulated with 50 ng/mL of phorbol-12-myristate-13-acetate (PMA) 1 h after pretreatment with 10 μM azelnidipine or dimethyl sulfoxide (DMSO), and harvested.

    Results: Azelnidipine blocked the expression of intercellular adhesion molecule-1 quantified by FACS analysis. The expression levels of Apo E and MMP9, which are markers of macrophage differentiation, were inhibited by azelnidipine as evaluated by quantitative RT-PCR. The level of LOX-1 mRNA, a scavenger receptor, was also reduced significantly by pretreatment with 10 μM azelnidipine. Azelnidipine also lowered the uptake of acetylated LDL. The expression of the L-type calcium channel Cav1.2 was 10-fold higher after 24 h of PMA stimulation. A knockdown of the CACNA1C gene, which encodes Cav1.2 protein in humans, with siRNA blocked the effect of reducing adhesion by azelnidipine, indicating that the effects of azelnidipine on macrophage differentiation were expressed through the CACNA1C gene.

    Conclusion: Our results suggest that azelnidipine has potent antiatherosclerotic properties by inhibition of macrophage activation through Cav1.2.

    Download PDF (1216K)
  • Yusuke Takahara, Tomotake Tokunou, Toshihiro Ichiki
    2018 Volume 25 Issue 8 Pages 698-708
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: January 10, 2018

    Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels through inhibition of incretin degradation, which stimulates insulin secretion. Recent studies reported that DPP-4 inhibitors suppressed atherogenesis in apolipoprotein E-knockout (ApoEKO) mice. In this study, we investigated whether teneligliptin, a DPP-4 inhibitor, affects the development of abdominal aortic aneurysms (AAA) in ApoEKO mice.

    Methods: ApoEKO mice were fed a high-fat diet (HFD) and infused with angiotensin (Ang) II by osmotic mini pumps for 4 weeks to induce AAA with (DPP-4i group) or without (control group) teneligliptin administered orally from 1 week before HFD and Ang II infusion to the end of the experiment. Confluent rat vascular smooth muscle cells (VSMCs) were serum-starved for 48 hours, then incubated with or without teneligliptin for another 24 hours and stimulated with Ang II.

    Results: Treatment with teneligliptin significantly reduced the AAA formation rate (30.7% vs. 71.4% vs. control, P<0.05), aortic dilatation (1.32±0.09 mm vs. 1.76±0.18 mm in the control, P<0.05) and severity score (0.75±0.28 vs. 1.91±0.4 in the control, P<0.05). Elastin degradation grade was also attenuated in DPP-4i group (2.83±0.17 vs. 3.45±0.16 in the control, P<0.05). The number of macrophages infiltrating into the abdominal aorta was decreased in the DPP-4i group (51.8± 29.8/section vs. 219.5±78.5/section in the control, P<0.05). Teneligliptin attenuated Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and mRNA expression of monocyte chemoattractant protein-1 in VSMCs.

    Conclusion: Treatment with teneligliptin suppressed AAA formation in ApoEKO mice with HFD and Ang II infusion. Suppression of macrophage infiltration by teneligliptin may be involved in the inhibition of AAA formation.

    Download PDF (766K)
  • Takuya Nakahashi, Hayato Tada, Kenji Sakata, Akihiro Nomura, Miho Ohir ...
    2018 Volume 25 Issue 8 Pages 709-719
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: January 26, 2018

    Aim: To assess whether combining measurements obtained from carotid ultrasonography in addition to the age, creatinine, and ejection fraction (ACEF) score would improve the predictive ability of outcome in patients with acute coronary syndrome (ACS).

    Methods: We examined 264 patients with ACS (194 men; mean age: 68±11 years) who underwent percutaneous coronary intervention. The carotid plaque score (cPS) and intima–media thickness (cIMT) were determined by carotid ultrasonography. The modified ACEF score was calculated using the following formula: (age/left ventricular ejection fraction) +1 point for every 10 mL/min reduction in creatinine clearance below 60 mL/min per 1.73 m2. The endpoint of this study was major adverse cardiovascular and cerebrovascular events (MACEs), defined as all-cause death, myocardial infarction, stoke, and target vessel revascularization.

    Results: During the median 4-year follow-up, there were 121 incidents of MACEs. Multivariate Cox proportional hazard regression analysis revealed that cPS ≥9.8 (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.01–2.31) and ACEF score ≥1.20 (HR, 1.62; 95% CI, 1.11–2.39) were significantly associated with MACEs, whereas cIMT was not. When the new combined risk score was calculated by multiplying the cPS by the modified ACEF score, the freedom from MACEs at 5 years was 71% and 31% for the lower and higher scores, respectively (p<0.001). The area under the receiver-operating characteristic curve for MACEs for the ACEF score, cPS, and combined risk score were 0.65, 0.66, and 0.71, respectively (p<0.05).

    Conclusion: The cPS offers an incremental predictive value when combined to the simple ACEF score in ACS.

    Download PDF (623K)
  • Wei Sun, Guangsheng Li, Xiangjun Zeng, Zhaohui Lai, Mingqi Wang, Yi Ou ...
    2018 Volume 25 Issue 8 Pages 720-732
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: June 05, 2018

    Aims: Nonvalvular atrial fibrillation often occurs in combination with carotid atherosclerosis, but less is known about it in combination with cerebral artery stenosis. This study investigated the characteristics of cerebral infarction in patients with nonvalvular atrial fibrillation with or without cerebral artery stenosis.

    Methods: A retrospective analysis was conducted on 172 cerebral infarction patients with nonvalvular atrial fibrillation hospitalized at the Affiliated Ganzhou Hospital of Nanchang University between December 2011 and January 2016. The patients were divided into two groups (stenosis and non-stenosis groups) based on whether the cerebral infarction was combined with cerebral artery stenosis or not. Clinical characteristics, related supplementary examination, and the imaging characteristics of cerebral infarction lesions were compared between the groups.

    Results: Mean age [(75.73±8.46) years vs. (63.44±9.95) years], National Institute of Health stroke scale (NIHSS) score [(8.66±6.73) vs. (4.59±3.51)], CHA2DS2-VASc score [(2.93±1.40) vs. (0.96±0.98)], history of hypertension (74.4% vs. 30.0%), and history of stroke/ transient ischemic attack (TIA) (55.8% vs. 13.3%) were higher in the stenosis group (n=107) than in the non-stenosis group (n=65) (P<0.01). In the stenosis group, there were different types of cerebral infarction lesions, including multiple infarction (multifocal type), massive infarction, watershed infarction, and lacunar infarction; in the non-stenosis group, the 60.0% lesions were multiple infarction (multifocal type), a significantly higher proportion than the stenosis group (26.2%, P<0.05). NIHSS score was an independent risk factor for worse prognosis at follow-up (OR (95%CI) 1.251–1.674, P<0.001).

    Conclusions: Advanced age, hypertension, and stroke/TIA were increased in patients with cerebral infarction with nonvalvular atrial fibrillation combined with cerebral artery stenosis.

    Download PDF (1854K)
  • Hongyan Wu, Yuan Yang, Zhangxue Hu
    2018 Volume 25 Issue 8 Pages 733-740
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: February 02, 2018

    Aims: Lipoprotein glomerulopathy (LPG) is a rare inherited renal disease. Several apolipoprotein E (apoE) mutations have been reported to be related to LPG. Herein, we report a case of a LPG patient with a novel apoE mutation.

    Methods: A 45-year-old Chinese female was diagnosed as LPG by renal biopsy. APOE gene was sequenced. Clinical and genetic studies were conducted.

    Results: The patient presented with nephrotic syndrome and hypertension. A fasting lipid panel showed mild hyperlipidemia and elevated serum apoE (5.6 mg/dL). Renal biopsy revealed typical LPG lesions with whorled, mesh-like material in dilated glomerular capillary lumens that stained positive for Sudan Ⅲ and apoE. apoE gene analysis revealed a T-to-C point mutation at amino acid 173 that caused a substitution of a proline residue for a leucine residue, which has not been reported previously. We named this mutation apoE Chengdu (c.518T>C, p.L173P). Two of five of the family members carried this mutation, including the patient's brother who was receiving hemodialysis, and her sister, whose urine protein levels were normal. All mutation carriers were heterozygotes with the apoE genotype ε3/ε3. This mutation was not found among 200 of the local people. Fenofibrate treatment for one year induced clinical improvement.

    Conclusions: ApoE Chengdu (p.L173P) is a novel mutation causing LPG. This case supports the hypothesis that the substitution of proline in or near the LDL receptor-binding area contributes to the development of LPG. The detailed mechanism of action of this variant remains to be elucidated.

    Download PDF (1527K)
Study Profile
  • Akihiro Nomura, Hayato Tada, Atsushi Nohara, Masa-aki Kawashiri, Masak ...
    2018 Volume 25 Issue 8 Pages 741-746
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: January 20, 2018

    Aim: Sitosterolemia is an extremely rare, autosomal recessive disease characterized by high plasma cholesterols and plant sterols because of increased absorption of dietary cholesterols and sterols from the intestine, and decreased excretion from biliary tract. Previous study indicated that sitosterolemic patients might be vulnerable to post-prandial hyperlipidemia, including high remnant-like lipoprotein particles (RLP) level. Here we evaluate whether a loading dietary fat increases a post-prandial RLP cholesterol level in sitosterolemic patients compared to heterozygous familial hypercholesterolemic patients (FH).

    Methods: We recruit total of 20 patients: 5 patients with homozygous sitosterolemia, 5 patients with heterozygous sitosterolemia, and 10 patients with heterozygous FH as controls from May 2015 to March 2018 at Kanazawa University Hospital, Japan. All patients receive Oral Fat Tolerance Test (OFTT) cream (50 g/body surface area square meter, orally only once, and the cream includes 34% of fat, 74 mg of cholesterol, and rich in palmitic and oleic acids. The primary endpoint is the change of a RLP cholesterol level after OFTT cream loading between sitosterolemia and FH. We measure them at baseline, and 2, 4, and 6 hours after the oral fat loading.

    Results: This is the first study to evaluate whether sitosterolemia patients have a higher post-prandial RLP cholesterol level compared to heterozygous FH patients.

    Conclusion: The result may become an additional evidence to restrict dietary cholesterols for sitosterolemia. This study is registered at University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000020330).

    Download PDF (149K)
  • Mariko Harada-Shiba, Hidenori Arai, Yasushi Ishigaki, Shun Ishibashi, ...
    2018 Volume 25 Issue 8 Pages 751-770
    Published: August 01, 2018
    Released on J-STAGE: August 01, 2018
    Advance online publication: June 07, 2018


    1. Familial hypercholesterolemia (FH) is an autosomal hereditary disease with the 3 major clinical features of hyper-LDL-cholesterolemia, premature coronary artery disease and tendon and skin xanthomas. As there is a considerably high risk of coronary artery disease (CAD), in addition to early diagnosis and intensive treatment, family screening (cascade screening) is required (Recommendation level A)

    2. For a diagnosis of FH, at least 2 of the following criteria should be satisfied:

    ① LDL-C ≥180 mg/dL, ② Tendon/skin xanthomas, ③ History of FH or premature CAD within 2nd degree blood relatives (Recommendation level A)

    3. Intensive lipid-lowering therapy is necessary for the treatment of FH. First-line drug should be statins. (Recommendation level A, Evidence level 3)

    4. Screening for CAD as well as asymptomatic atherosclerosis should be conducted periodically in FH patients. (Recommendation level A)

    5. For homozygous FH, consider LDL apheresis and treatment with PCSK9 inhibitors or MTP inhibitors. (Recommendation level A)

    6. For severe forms of heterozygous FH who have resistant to drug therapy, consider PCSK9 inhibitors and LDL apheresis. (Recommendation level A)

    7. Refer FH homozygotes as well as heterozygotes who are resistant to drug therapy, who are children or are pregnant or have the desire to bear children to a specialist. (Recommendation level A)

    Download PDF (1464K)