Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Volume 28 , Issue 11
Showing 1-14 articles out of 14 articles from the selected issue
Review
  • Yukinori Tamura
    Subject area: Review
    2021 Volume 28 Issue 11 Pages 1109-1122
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: June 19, 2021
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    Zinc is an essential micronutrient for human health and is involved in various biological functions, such as growth, metabolism, and immune function. In recent years, research on intracellular zinc dynamics has progressed, and it has become clear that zinc transporters strictly control intracellular zinc localization, zinc regulates the functions of various proteins and signal transduction pathways as a second messenger similar to calcium ions, and intracellular zinc dyshomeostasis is associated with impaired insulin synthesis, secretion, sensitivity, lipid metabolism, and vascular function. Numerous animal and human studies have shown that zinc deficiency may be associated with the risk factors for diabetes and cardiovascular diseases (CVDs) and zinc administration might be beneficial for the prevention and treatment of these diseases. Therefore, an understanding of zinc biology may help the establishment of novel strategies for the prevention and treatment of diabetes and CVDs. This review will summarize the current knowledge on the role of zinc homeostasis in the pathogenesis of diabetes and atherosclerosis and will discuss the potential of zinc in the prevention of these diseases.

Editorial
Original Article
  • Takamitsu Nakamura, Manabu Uematsu, Takeo Horikoshi, Toru Yoshizaki, T ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1133-1144
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: November 20, 2020
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    Aim: To examine whether improvement in flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery and brachial-ankle pulse wave velocity (baPWV) has an additive effect on achieving optimal goals of traditional risk factors to reduce cardiovascular risk in patients with coronary artery disease (CAD).

    Methods: We assessed 323 patients with CAD and impaired vascular function, defined as an impaired FMD of the brachial artery (<5.5%) and increased baPWV (>1,440 cm/sec). After FMD and baPWV measurements at 24 weeks of optimal medical treatment (OMT), the study patients were followed up for <60 months or until a composite of cardiac death, nonfatal myocardial infarction (MI), unstable angina, or ischemic stroke occurs.

    Results: During the median follow-up period of 35 months, cardiovascular events occurred in 72 patients. Multivariate Cox hazards analysis showed that patients with an improvement in FMD and baPWV had the lowest probability of future cardiovascular events. In addition, the improvement in FMD and baPWV had a significant incremental effect on the predictive value of the achievement of optimal goals for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) using net reclassification improvement (NRI) and integrated discrimination improvement (IDI).

    Conclusions: The improvement in FMD and baPWV had additive effects on risk reduction of the achievement of the optimal goals of traditional risk factors in patients with CAD. Thus, serial measurements of FMD and baPWV may be useful for identifying CAD patients at residual risk for adverse cardiovascular events following OMT.

  • Takuya Tsujimura, Mitsuyoshi Takahara, Osamu Iida, Shun Kohsaka, Yoshi ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1145-1152
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: November 20, 2020
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    Aim: The aim of the current study was to describe the clinical profile, frequency of in-hospital complications, and predictors of adverse events in patients undergoing endovascular therapy (EVT) for acute limb ischemia (ALI), and to compare them with those of patients undergoing EVT for chronic symptomatic peripheral artery disease (PAD).

    Methods: The current study compared 2,398 cases of EVT for ALI with 74,171 cases of EVT for chronic symptomatic PAD performed between January 2015 and December 2018 in Japan. We first compared the clinical profiles of ALI patients with those of PAD patients. We then evaluated the proportion of in-hospital complications and investigated their risk factors in the ALI patients. The association of clinical characteristics with the risk of in-hospital complications was analyzed via logistic regression modeling.

    Results: Patients with ALI were older and had a higher prevalence of female sex, impaired mobility, and history of cerebrovascular disease, but a lower prevalence of cardiovascular risk factors and history of coronary artery disease. The proportion of in-hospital EVT-related complications in ALI was 6.1% and was significantly higher compared with those in chronic symptomatic PAD patients (2.0%, P<0.001). Bedridden status (adjusted odds ratio [aOR], 1.74 [1.14 to 2.66]; P=0.010), history of coronary artery disease (aOR, 1.80 [1.21 to 2.68]; P=0.004), and a suprapopliteal lesion (aOR, 1.70 [1.05 to 2.74]; P=0.030) were identified as independent risk factors for in-hospital complications.

    Conclusion: The current study demonstrated that ALI patients with significant comorbidities show a higher proportion of in-hospital complications after EVT.

  • Yusuke Tomoi, Mitsuyoshi Takahara, Yoshimitsu Soga, Masahiko Fujihara, ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1153-1160
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: January 22, 2021
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    Aim: Originally developed for predicting the risk of stroke in patients with atrial fibrillation (AF), the CHA2DS2-VASc score also has the potential to predict the risk of other cardiovascular disease. This study aimed to investigate the prognostic value of the CHA2DS2-VASc score in patients with peripheral artery disease (PAD) requiring Femoral popliteal (FP) endovascular therapy (EVT).

    Methods: This multicenter, retrospective study analyzed the clinical database of 2190 patients who underwent FP EVT for symptomatic PAD (Rutherford categories 2–4) between January 2010 and December 2018. We calculated the CHA2DS2-VASc score and then investigated the association between the score, as well as AF, and their prognosis. Outcome measures were major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs).

    Results: During a median follow-up of 3.0 years (interquartile range, 1.5–5.0 years), 532 MACEs and 562 MALEs occurred. The CHA2DS2-VASc score and AF were independently associated with an increased risk of MACEs; their adjusted hazard ratios [95% confidence intervals] were 1.28 [1.20–1.36] (P<0.001) per 1-point increase and 1.49 [1.06–2.09] (P=0.022), respectively. The CHA2DS2-VASc score was almost linearly associated with MACEs, without any clear threshold point. On the other hand, these variables were not associated with MALEs risk (P=0.32 and 0.48).

    Conclusion: The CHA2DS2-VASc score and AF were independently associated with the increased risk of MACEs but not of MALEs in patients with symptomatic PAD who underwent FP EVT. The score might be useful in stratifying the MACEs risk in this type of patients.

  • Teruo Sekimoto, Shinji Koba, Hiroyoshi Mori, Rikuo Sakai, Taito Arai, ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1161-1174
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: February 05, 2021
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    Aim: This study investigated whether the small dense low-density lipoprotein cholesterol (sd-LDL-c) level is associated with the rapid progression (RP) of non-culprit coronary artery lesions and cardiovascular events (CE) after acute coronary syndrome (ACS).

    Methods: In 142 consecutive patients with ACS who underwent primary percutaneous coronary intervention for the culprit lesion, the sd-LDL-c level was measured using a direct homogeneous assay on admission for ACS and at the 10-month follow-up coronary angiography. RP was defined as a progression of any pre-existing coronary stenosis and/or stenosis development in the initially normal coronary artery. CEs were defined as cardiac death, myocardial infarction, stroke, or coronary revascularization.

    Results: Patients were divided into two groups based on the presence (n=29) or absence (n=113) of RP after 10 months. The LDL-c and sd-LDL-c levels at baseline were equivalent in both the groups. However, the sd-LDL-c, triglyceride, remnant lipoprotein cholesterol (RL-c), and apoC3 levels at follow-up were significantly higher in the RP group than in the non-RP group. The optimal threshold values of sd-LDL-c, triglyceride, RL-c, and apoC3 for predicting RP according to receiver operating characteristics analysis were 20.9, 113, 5.5, and 9.7 mg/dL, respectively. Only the sd-LDL-c level (≥ 20.9 mg/dL) was significantly associated with incident CEs at 31±17 months (log-rank: 4.123, p=0.043).

    Conclusions: The sd-LDL-c level on treatment was significantly associated with RP of non-culprit lesions, resulting in CEs in ACS patients. On-treatment sd-LDL-c is a residual risk and aggressive reduction of sd-LDL-c might be needed to prevent CEs.

  • Qi Zhao, Ting-Yu Zhang, Yu-Jing Cheng, Yue Ma, Ying-Kai Xu, Jia-Qi Yan ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1175-1194
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: November 13, 2020
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    Aim: The triglyceride-glucose index (TyG index) is proposed as a surrogate parameter for insulin resistance (IR) and, when elevated, is related to increased cardiovascular risks. Whether the TyG index is of great value in predicting adverse prognosis for individuals diagnosed with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), who received elective percutaneous coronary intervention (PCI), and without recognized diabetes remains unclear.

    Methods: Overall, 1,510 subjects diagnosed with NSTE-ACS, who received elective PCI, and without recognized diabetes were enrolled in the current study. All participants received a routine follow-up after discharge. The TyG index was obtained from the following equation: napierian logarithmic (ln) [fasting triglyceride (TG, mg/dL)×fasting blood glucose (FBG, mg/dL)/2]. Adverse cardiovascular events included all-cause death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and ischemia-driven revascularization, composite of which was defined as the primary endpoint.

    Results: Overall, 316 (20.9%) endpoint events were documented during a 48-month follow-up. Despite adjusting for confounding variates, the TyG index remains to be a significant risk predictor for the primary endpoint, with a hazard ratio (HR) [95% confidence interval (CI)] of 2.433 (1.853-3.196) (P<0.001). A significant enhancement on the predictive performance for the primary endpoint emerged when adding the TyG index into a baseline model [area under the receiver-operating characteristic (ROC) curve (AUC), 0.835 for baseline model vs. 0.853 for baseline model+TyG index, P<0.001; net reclassification improvement (NRI), 0.194, P<0.001; integrated discrimination improvement (IDI), 0.023, P=0.007].

    Conclusions: The TyG index is an independent risk predictor for adverse cardiovascular events in nondiabetic subjects diagnosed with NSTE-ACS and who received elective PCI. Further prospective studies are needed to verify these findings.

  • Yoshimi Kishimoto, Masayuki Aoyama, Emi Saita, Yukinori Ikegami, Reiko ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1195-1203
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: October 30, 2020
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    Aim: Kinin B1 receptor (KB1R) was shown to be up-regulated in human carotid atherosclerotic lesions. Serum KB1R levels were also reported to be high in patients with stroke. However, KB1R deficiency increased atherosclerotic lesions. Therefore, the role of KB1R in atherosclerosis remains unclear. Moreover, no study has reported blood KB1R levels in patients with coronary artery disease (CAD).

    Methods: We measured plasma KB1R levels in 375 patients undergoing coronary angiography. The severity of CAD was represented as the numbers of >50% stenotic vessels and segments and the severity score.

    Results: CAD was found in 197 patients, of whom 89 had 1-vessel disease (1-VD), 62 had 2-VD, and 46 had 3-VD. Plasma KB1R levels were higher in 197 patients with CAD than in 178 without CAD (median 83.3 vs. 73.7 pg/mL, p<0.01). A stepwise increase in KB1R levels was found depending on the number of stenotic vessels: 77.1 in 1-VD, 87.8 in 2-VD, and 88.5 pg/mL in 3-VD (p<0.025). A high KB1R level (>90.0 pg/mL) was present in 30% of patients with CAD(-), 39% of 1-VD, 50% of 2-VD, and 48% of 3-VD (p<0.025). KB1R levels correlated with the number of stenotic segments and the severity score (r=0.14 and r=0.17, p<0.01). In multivariate analysis, KB1R levels were an independent factor associated with CAD. Odds ratio for CAD was 1.62 (95%CI=1.02-2.58) for high KB1R level >90.0 pg/mL.

    Conclusion: Plasma KB1R levels in patients with CAD were high and were associated with the presence and severity of CAD independent of atherosclerotic risk factors.

  • Makoto Fujita, Hiroyasu Yamamoto, Nao Yoshida, Runa Ono, Tetsuro Matsu ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1204-1213
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: November 15, 2020
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    Aim: Adiponectin (APN) exhibits different atheroprotective effects, and we have previously reported that APN function is modulated by its binding proteins, E-selectin ligand 1, Mac-2 binding protein, and cystatin C. In the present study, we aimed to identify a novel atheroprotective mechanism of APN via C–C motif chemokine 2 (CCL2).

    Methods: We conducted iMAP®-intravascular ultrasound (IVUS) in 111 Japanese male patients with stable angina. The plaque characteristics were determined where “plaque burden” [(EEM CSA − lumen CSA)/(EEM CSA)×100 (%)] >50%, and their correlation with serum CCL2 and APN levels was analyzed. Using western blot analysis, the effects of APN on the biological effects of CCL2 were examined in their mutual binding by co-immunoprecipitation assay, the monocyte migration, and the phosphorylation of MAP kinases.

    Results: In a clinical study, we found that the percentage of plaque in the culprit lesion was correlated positively with serum CCL2 and negatively with serum APN levels, with significance. We identified CCL2 as a novel APN-binding serum protein using immunoprecipitation and western blot analysis. CCL2-induced phosphorylation of MAP kinases and monocyte migration was significantly attenuated by APN in vitro.

    Conclusion: The opposite association of APN and CCL2 on the percentage of coronary plaque might be caused by their direct interaction and competitive functions on monocyte migration.

  • Masanori Nishimura, Atsushi Yamashita, Yunosuke Matsuura, Junichi Okut ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1214-1240
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: December 10, 2020
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    Aims: Inflammation and hypertension contribute to the progression of atherosclerotic aneurysm in the aorta. Vascular cell metabolism is regarded to modulate atherogenesis, but the metabolic alterations that occur in atherosclerotic aneurysm remain unknown. The present study aimed to identify metabolic pathways and metabolites in aneurysmal walls and examine their roles in atherogenesis.

    Methods: Gene expression using microarray and metabolite levels in the early atherosclerotic lesions and aneurysmal walls obtained from 42 patients undergoing aortic surgery were investigated (early lesion n=11, aneurysm n=35) and capillary electrophoresis–time-of-flight mass spectrometry (early lesion n=14, aneurysm n=38). Using immunohistochemistry, the protein expression and localization of the identified factors were examined (early lesion n=11, non-aneurysmal advanced lesion n=8, aneurysm n=11). The roles of the factors in atherogenesis were analyzed in macrophages derived from human peripheral blood mononuclear cells.

    Results: Enrichment analysis using 35 significantly upregulated genes (log2 ratio, >3) revealed the alteration of the kynurenine pathway. Metabolite levels of tryptophan, kynurenine, and quinolinic acid and the kynurenine-to-tryptophan ratio were increased in the aneurysmal walls. Gene and protein expression of kynureninase and kynurenine 3-monooxygenase were upregulated and localized in macrophages in the aneurysmal walls. The silencing of kynureninase in the cultured macrophages enhanced the expression of interleukin-6 and indoleamine 2,3-dioxygenase 1.

    Conclusion: Our study suggests the upregulation of the kynurenine pathway in macrophages in aortic atherosclerotic aneurysm. Kynureninase may negatively regulate inflammation via the kynurenine pathway itself in macrophages.

  • Chikao Miyazaki, Kazuhiro Shimizu, Yoshinobu Nagasawa, Tatsuo Chiba, K ...
    Subject area: Original Article
    2021 Volume 28 Issue 11 Pages 1241-1249
    Published: November 01, 2021
    Released: November 01, 2021
    [Advance publication] Released: January 20, 2021
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    Aim: Stroke is well known to lead to hypertension; nevertheless, the role of vascular function in hypertension remains unclear. In this study, we aimed to clarify the mechanism underlying increased arterial stiffness following stroke.

    Methods: The cardio-ankle vascular index (CAVI) was measured in five New Zealand White rabbits. Under general anesthesia, intracranial pressure (ICP) was increased by injecting saline (15 mL) into the cisterna magna. ICP was monitored using a catheter inserted into the subarachnoid space via right frontal bone craniotomy. Blood pressure (BP), CAVI, and common carotid flow (CCF) were evaluated, and the responses of these parameters to increased ICP were analyzed.

    Results: Saline injection into the cisterna magna increased the ICP by over 20 mmHg. Both BP and CAVI increased from 63.2±4.84 to 128.8±14.68 mmHg and from 4.02±0.28 to 4.9±0.53, respectively. Similarly, BP and CCF increased. When hexamethonium was administered before the increase in ICP, the increase in BP (132.2±9.41 mmHg with 10 mg/kg hexamethonium vs. 105.6±11.01 mmHg with 100 mg/kg hexamethonium) and CAVI (5.02±0.64 with 10 mg/kg hexamethonium vs. 4.82±0.42 with 100 mg/kg hexamethonium) were suppressed in a dose-dependent manner.

    Conclusion: Increased ICP causes an increase in BP and CAVI, suggesting that enhanced stiffness of the muscular arteries contributes to high BP. Blocking the autonomic nervous system with hexamethonium suppresses the increase in BP and CAVI, indicating that these increases are mediated by activation of the autonomic nervous system.

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