Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Advance online publication
Showing 1-50 articles out of 55 articles from Advance online publication
  • Hiroyuki Daida, Tomotaka Dohi, Yoshifumi Fukushima, Hirotoshi Ohmura, ...
    Type: Review
    Article ID: 48603
    Published: 2019
    [Advance publication] Released: May 21, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Enormous effort has been put into the prevention of atherosclerosis through risk modification, especially with lipid-lowering therapies. Regression, that is, the reversal of the atherosclerosis process, has long been a goal of atherosclerosis research among basic and clinical investigators. Intravascular ultrasound (IVUS) was developed in the 1990s as an intracoronary imaging technique to observe the details of the vessel walls and to measure the vessel lumen and plaque area with high reproducibility. Compared with the coronary angiogram, IVUS provides far more detailed information on the vessel wall. In this article, we review lipid-lowering trials that have used IVUS and discuss the current understanding of the effectiveness of aggressive lipid-lowering therapy, which inhibits atherosclerotic progression and induces regression and plaque stabilization.

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  • Yuichi Sasaki, Yoshiyuki Ikeda, Takahiro Miyauchi, Yoshihiro Uchikado, ...
    Type: Original Article
    Article ID: 47993
    Published: 2019
    [Advance publication] Released: May 18, 2019
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    Aim: Menopause causes arterial senescence and atherosclerotic development through decrease of estrogen. Recently, histone deacetylase SIRT1 has been reported to have protective effects against arterial senescence and atherosclerosis. However, the relationship between estrogen and SIRT1 in the context of menopause-induced arterial senescence is not well understood. The present study aims to investigate whether SIRT1 is involved in the etiology of menopause-induced arterial senescence and atherosclerotic development.

    Methods: Twelve-week old female apolipoprotein E-knockout (ApoE-KO) mice underwent ovariectomy (OVX) or sham surgery.

    Results: SIRT1 expression and endothelial nitric oxide synthase (eNOS) activation in the aorta were significantly lower in OVX mice than they were in sham mice (OVX vs. sham, n=5 per group). Senescence-associated β-galactosidase activity, protein expression of Ac-p53 and PAI-1, and aortic atherosclerosis lesions were significantly greater in OVX mice than they were in sham mice. Administration of 17β-estradiol (E2) for eight weeks to OVX mice restored aortic SIRT1 expression, activated eNOS, and retarded OVX-induced arterial senescence and atherosclerotic development (E2 vs. control, n=5 per group). The effects of E2 on SIRT1 upregulation, anti-senescence and anti-atherosclerosis were attenuated by administration of a SIRT1 inhibitor, sirtinol. In vitro experiment using human endothelial cells demonstrated that E2 also increased SIRT1 expression and retarded oxidized low density lipoprotein-induced premature senescence, which were also abolished by sirtinol. These results suggested that estrogen modulated arterial senescence and atherosclerosis through SIRT1. Additionally a selective estrogen receptor modulator (SERM), bazedoxifene, also augmented SIRT1 and inhibited arterial senescence and atherosclerotic development (SERM vs. control, n=3 per group).

    Conclusions: Downregulation of SIRT1 causes OVX-induced arterial senescence and atherosclerosis in ApoE-KO mice. Administration of estrogen or SERM enables OVX mice to restore these alterations by SIRT1 induction.

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  • Hayato Tada, Tamami Nakagawa, Hirofumi Okada, Takuya Nakahashi, Mika M ...
    Type: Original Article
    Article ID: 49551
    Published: 2019
    [Advance publication] Released: May 18, 2019
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    Aim: Carotid plaque score (cPS) reflecting throughout the carotid artery plaque burden may be a better marker than carotid intima–media thickness (cIMT) is. We aimed to compare the prognostic utility of these measurements in patients with atherosclerotic cardiovascular disease (ASCVD).

    Methods: We retrospectively examined 2,035 Japanese patients with ASCVD who underwent carotid ultrasonography between January 2008 and December 2015 at Kanazawa University Hospital. Median follow-up period was 4 years. We used Cox models that adjusted for established risk factors of ASCVD, including age, gender, hypertension, diabetes, smoking, and serum lipids to assess the association of cIMT as well as cPS with major adverse cardiac events (MACE). MACE was defined as all-cause mortality or rehospitalization for a cardiovascular-related illness.

    Results: During follow-up, 243 participants experienced MACE. After adjustment for established risk factors, cPS was associated with MACE (hazard ratio [HR]=3.38 for top quintile vs. bottom quintile of cPS; 95% confidence interval [CI] 1.82–6.27; P trend <0.001), while cIMT was not (HR=0.88, P=0.57). Addition of the cPS to established risk factors significantly improved risk discrimination (C-index 0.726 vs. 0.746; P=0.017).

    Conclusion: These results suggest that cPS, rather than cIMT may be a better marker to identify increased risk for recurrence of MACE among patients with secondary prevention setting.

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  • Yuyan Liu, Akira Fujiyoshi, Hisatomi Arima, Aya Kadota, Sayaka Kadowak ...
    Type: Original Article
    Article ID: 47977
    Published: 2019
    [Advance publication] Released: May 15, 2019
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    Aim: Computed tomography (CT) can directly provide information on body compositions and distributions, compared to anthropometric indices. It has been shown that various obesity indices are associated with carotid intima-media thickness (IMT). However, whether CT-based obesity indices are stronger than anthropometric indices in association with atherosclerosis remains to be determined in a general population.

    Methods: We cross-sectionally assessed carotid IMT using ultrasound in 944 community-dwelling Japanese men free of stroke and myocardial infarction. CT image at the L4–L5 level was obtained to compute areas of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Anthropometric measures assessed included body mass index (BMI), waist circumference, and waist-to-hip ratio. Using multivariable linear regression, slopes of IMT per 20th to 80th percentile of each index were compared. We also compared the slope of index with simultaneous adjustment for BMI in the same model.

    Results: Areas of VAT and SAT were positively associated with IMT, but not stronger than those of anthropometric indices in point estimates. Among all obesity indices, BMI was strongest in association with IMT after adjusting for age and lifestyle factors or further adjusting for metabolic factors. In simultaneous adjustment models, BMI, but not CT-based indices, remained significant and showed the strongest association.

    Conclusions: In community-dwelling Japanese men, anthropometric obesity indices, BMI in particular, were more strongly associated with carotid atherosclerosis than CT-based obesity indices. The association of general obesity with carotid atherosclerosis was strong and adding CT-based obesity measure did not considerably influence in the association.

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  • Kazuki Ueda, Eriko Morishita, Hironaga Shiraki, Shunzo Matsuoka, Shins ...
    Type: Case Report
    Article ID: 48819
    Published: 2019
    [Advance publication] Released: May 15, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Thrombophilia increases the risk of venous thrombosis, but is rarely responsible for aortic thrombosis. Aortic mural thrombus (AMT) may be associated with a protein C deficiency. However, it is necessary to determine whether the protein C deficiency is congenital/hereditary or secondary/acquired (consumption of protein C during the process of thrombus formation). This study describes a 77-year-old Japanese woman with incidentally diagnosed AMT, who had a protein C deficiency (activity 54%, antigen 42%). Sequencing of the protein C gene revealed a heterozygous mutation of c.1268delG, p.Gly423Valfs82 in exon 9, indicating a congenital protein C deficiency. These findings indicate that very late onset AMT can occur in an adult with congenital protein C deficiency.

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  • Jun-Hyuk Lee, Ji-Won Lee, Young-Jae Lee
    Type: Original Article
    Article ID: 48942
    Published: 2019
    [Advance publication] Released: May 15, 2019
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    Aim: Serum alkaline phosphatase (ALP), a useful marker of hepatobiliary or bone disorders, has recently been found to be associated with cardiovascular diseases. This study aimed to examine the association of serum ALP level with arterial stiffness, as measured by brachial-ankle pulse wave velocity.

    Methods: This cross-sectional study included 2476 participants (1486 men and 990 women) aged ≥ 20 years who underwent a medical examination. Pearson correlation analyses were conducted to examine the bivariate correlations between baPWV and clinical variables. To examine the independent relationship between serum ALP and baPWV, a multiple linear regression analysis was conducted with baPWV as the dependent variable in a sex-specific manner.

    Results: After adjusting for age, body mass index, current smoking, alcohol drinking, regular exercise, hypertension, type 2 diabetes, dyslipidemia, chronic kidney disease, log-transformed AST, log-transformed ALT, and log-transformed GGT levels, log-transformed serum ALP level was positively and independently associated with baPWV (β=78.6 for men, P=0.001; and β=85.3 for women, P<0.001).

    Conclusions: Serum ALP level was positively and independently associated with baPWV in men and women, suggesting that an elevated ALP level may be a useful surrogate marker for arterial stiffness in adult men and women.

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  • Masakatsu Nishikawa, Yoshihiro Takeda, Naoei Isomura, Takashi Tanigawa ...
    Type: Original Article
    Article ID: 48934
    Published: 2019
    [Advance publication] Released: May 14, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Although high on-treatment platelet reactivity (HTPR) with dual antiplatelet therapy (DAPT) correlates with long-term adverse outcomes in patients undergoing percutaneous coronary intervention, the correlation in Japanese patients remains unclear. Therefore, we examined the relationship between platelet reactivity during DAPT with aspirin and clopidogrel and 1-year clinical outcomes following successful coronary stent implantation.

    Methods: A prospective, multicenter registry study (j-CHIPS) was conducted in patients undergoing coronary stenting and receiving aspirin and clopidogrel at 16 hospitals in Japan. A VerifyNow point-of-care assay was used to assess platelet reactivity, and a cutoff value to define HTPR was established.

    Results: Between February 2011 and May 2013, 1047 patients were prospectively enrolled, of which 854 patients with platelet function evaluation at 12–24 h after PCI were included in the final analysis. After 1 year of follow-up, the incidence of the primary endpoint (a composite of all-cause mortality, myocardial infarction, stent thrombosis, and ischemic stroke) was significantly higher in patients with HTPR than in those without (5.9% vs. 1.5%, p=0.008), and HTPR showed a modest ability to discriminate between patients who did and did not experience major adverse cardiac and cerebrovascular events (area under the curve, 0.60; 95% confidence interval, 0.511–0.688, p=0.039). HTPR status did not identify patients at risk for major or minor bleeding events.

    Conclusion: HTPR was significantly associated with adverse ischemic outcomes at 1 year after PCI in Japanese patients receiving maintenance DAPT, indicating its potential as a prognostic indicator of clinical outcomes in this high-risk patient population.

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  • Maki Tsujita, Nobukatsu Akita, Tomo Yokota, Fumihiko Kobayashi, Shinji ...
    Type: Original Article
    Article ID: 48967
    Published: 2019
    [Advance publication] Released: May 14, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Probucol is a controversial drug to inhibit ATP-binding cassette transporter A1 (ABCA1) and to exhibit some positive clinical effects such as regression of xanthomas. It reportedly rescues female infertility in scavenger receptor BI-deficient mice. Here, we investigated the effect of probucol on propagation in HDL-deficient mice as alternative models for impaired HDL-mediated cholesterol delivery.

    Methods: Propagation of ABCA1-deficient (Abca1-/-) mice and lecithin: cholesterol acyltransferase (LCAT)-deficient (Lcat-/-) mice were quantitatively observed under the probucol treatment.

    Results: Abca1-/- and Lcat-/- mice appear with negligible plasma HDL concentration. Upon backcrossing Abc1+/- with the Abc1-/- mice and cross-breeding between Abc1+/- mice, the numbers of Abc1-/- weaned pups were reduced to 54.7% and to 57.1% from those expected by Mendelian genetics, respectively. Similarly, Lcat-/- weaned pups decreased to 67.7% and to 35.9% but only in the male. Probucol severely reduced plasma HDL-cholesterol to 5% in the wild-type mice, but showed no effects on their propagation. Probucol corrected the deflections of the genotype distribution in the weaned pups recovery in the LCAT-deficient mice propagation but not in the ABCA1-deficient mice while plasma HDL was kept negligible. Probucol had no effect on cholesterol content in the steroidogenic organs of the HDL-deficient mice, while it somewhat increased plasma corticosterone and expression of adrenal cortex HMG-CoA reductase, StAR, cytochrome P450scc, and VKORC1 indicating increase in the synthesis of cholesterol and steroid hormones and in vitamin K turn-over. However, no evident mechanistic background was indicated.

    Conclusions: Probucol corrected deflection of genotype distribution in propagation of the LCAT-deficient mice but not the ABCA1-deficient mice at the weaning stage, apparently not through normalization of hypoalphalipoproteinemia.

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  • Kohji Shirai, Kenji Suzuki, Shinichi Tsuda, Kazuhiro Shimizu, Masanobu ...
    Type: Original Article
    Article ID: 48314
    Published: 2019
    [Advance publication] Released: May 09, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The cardio–ankle vascular index (CAVI) represents the blood pressure-independent arterial stiffness from the origin of the aorta to the ankle. CAVI0 has been proposed as a variant index. We aimed to clarify the difference between CAVI and CAVI0 among large populations, and to explore reasons of the difference.

    Methods: The subjects were 5,293 Japanese healthy and 3,338 hypertensive people. Simple and multiple regression analyses were performed using age, sex, body mass index, systolic, and diastolic blood pressure (Pd) as variables. Sub-group analysis was performed by sex and age. The CAVI values with and without adjustment by reference pressure were also compared.

    Results: CAVI had a positive correlation with Pd, while CAVI0 had a negative correlation with Pd in the healthy population. The CAVI values of the hypertensive group were higher than those of healthy group in both men and women, but the CAVI0 values in women of the hypertensive group in the 30–39 age group was significantly lower than that of the corresponding healthy group. Differences of CAVI values with or without modification using the reference pressure were 1.09%±1.38% for the healthy group and 3.68%±1.66% for the hypertensive group.

    Conclusion: CAVI showed the expected values, but CAVI0 showed inexplicable results in the healthy and hypertensive populations. The differences were due to the strong dependency of CAVI0 on Pd. Differences of CAVI values with or without reference pressure were negligible. These results indicate that CAVI obtained by the VaSera system is appropriate, but CAVI0 is not.

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  • Hirofumi Tomiyama
    Subject Area: Editorial
    Article ID: ED110
    Published: 2019
    [Advance publication] Released: May 09, 2019
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  • Hiroshi Sonoda, Koshi Nakamura, Akiko Tamakoshi
    Type: Original Article
    Article ID: 47779
    Published: 2019
    [Advance publication] Released: April 30, 2019
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    Aims: The ankle-brachial index (ABI) can be a prognostic marker for chronic kidney disease (CKD) in Western populations. Since there is little relevant evidence for Asian populations, we investigated the relationship between ABI and the risk of incident CKD in a general Japanese population.

    Methods: The cohort included 5,072 participants aged 30–79 without a history of renal disease or cerebro-cardiovascular disease. Incident CKD, defined as an estimated glomerular filtration rate <60 (mL/min/1.73 m2) and/or proteinuria (≥ 1+ on urine dipstick), was compared among participants grouped according to baseline ABI: 0.90–0.99, 1.00–1.09, 1.10–1.19, 1.20–1.29, and 1.30–1.39. Hazard ratios for incident CKD were estimated using a Cox proportional hazards model, with the ABI 1.10–1.19 group serving as the reference.

    Results: The CKD incidence rate (/100 person-years) was 1.80 during the mean follow-up period of 5.1 years. The CKD incidence rate was 3.04 in the ABI category 0.90–0.99, 1.58 in ABI 1.00–1.09, 1.72 in ABI 1.10–1.19, 2.01 in ABI 1.20–1.29, and 3.33 in ABI 1.30–1.39. The hazard ratios for developing CKD were 2.14 (95% confidence interval 1.16–3.92) in ABI 0.90–0.99, 1.08 (0.83–1.41) in ABI 1.00–1.09, 1.03 (0.83–1.29) in ABI 1.20–1.29, and 1.37 (0.77–2.47) in ABI 1.30–1.39, after adjusting for age, sex, systolic blood pressure, diabetes, and other confounding factors.

    Conclusions: In a general Japanese population, an ABI of 0.90–0.99 was associated with an increased risk of incident CKD, independent of traditional cardiovascular risk factors.

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  • Hayato Tada, Masayuki Takamura, Masa-aki Kawashiri
    Type: Review
    Article ID: RV17034
    Published: 2019
    [Advance publication] Released: April 30, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Lipoprotein(a) [Lp(a)], discovered in 1963, has been associated with atherosclerotic cardiovascular disease (ASCVD) independent of other traditional risk factors, including LDL cholesterol. Lp(a) is an apolipoprotein B (apoB)-containing lipoprotein, which contains an LDL-like particle. Unlike LDL, which is a primary therapeutic target to decrease ASCVD, current guidelines recommend measuring Lp(a) for risk assessments because there is no clear evidence demonstrating the clinical benefit of decreasing Lp(a) using classical drugs such as niacin. However, recent Mendelian randomization studies indicate that Lp(a) causally correlates with ASCVD. In addition, novel drugs, including PCSK9 inhibitors, as well as antisense oligonucleotide for apo(a), have exhibited efficacy in decreasing Lp(a) substantially, invigorating a discussion whether Lp(a) could be a novel therapeutic target for further ASCVD risk reduction. This review aims to provide current understanding, and future perspectives, of Lp(a), which is currently considered a mere biomarker but may emerge as a novel therapeutic target in future clinical settings.

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  • Mustafa Umut Somuncu, Tunahan Akgun, Mustafa Ozan Cakır, Ferit Akgul ...
    Type: Original Article
    Article ID: 48413
    Published: 2019
    [Advance publication] Released: April 18, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The primary percutaneous procedure resulted in a significant improvement in the prognosis of myocardial infarction. However, no-reflow phenomenon restrains this benefit of the process. There are studies suggesting that soluble suppression of tumorigenicity (sST2) can be valuable in the diagnosis and progression of heart failure and myocardial infarction. In this study, we aimed to investigate the effect of sST2 on no-reflow phenomenon in ST-elevated myocardial infarction (STEMI).

    Method: This study included 379 patients (258 men; mean age, 60±11 years) who underwent primary percutaneous treatment for STEMI. sST2 levels were measured from blood samples taken at admission. Patients were divided into two groups according to Thrombolysis in Myocardial Infarction(TIMI) flow grade: group 1 consists of TIMI 0,1,2, accepted as no-reflow, and group 2 consists of TIMI 3, accepted as reflow.

    Results: No-reflow phenomenon occurred in 60 patients (15.8%). The sST2 level was higher in the no-reflow group (14.2±4.6 vs. 11.3±5.0, p=0.003). Moreover, regression analysis indicated that diabetes mellitus, lower systolic blood pressure, multivessel vascular disease, high plaque burden, and grade 0 initial TIMI flow rate were other independent predictors of the no-reflow phenomenon in our study. Besides, when the patients were divided into high and low sST2 groups according to the cut-off value from the Receiver operating characteristics analysis, being in the high sST2 group was associated with 2.7 times increased odds for no-reflow than being in the low sST2 group.

    Conclusion: sST2 is one of the independent predictors of the no-reflow phenomenon in STEMI patients undergoing primary percutaneous coronary intervention.

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  • Kiyonori Nanto, Osamu Iida, Masahiko Fujihara, Yoshiaki Yokoi, Yusuke ...
    Type: Original Article
    Article ID: 45617
    Published: 2019
    [Advance publication] Released: April 16, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Although current guidelines recommend surgical revascularization as the first-line therapy for chronic total occlusion of the abdominal aorta (Leriche syndrome), endovascular therapy (EVT) has been increasingly utilized because of the development of new technologies and techniques. EVT has demonstrated durable midterm outcomes for aortoiliac occlusive disease (AIOD). Nonetheless, little is known regarding their long-term outcomes and predictors of restenosis.

    Methods: We retrospectively analyzed a multicenter database of 64 consecutive patients (age, 73±10 years; 64% male; 22% critical limb ischemia) undergoing EVT for aortoiliac occlusive disease between September 2005 and March 2016. The outcome measures were primary and secondary patency, following EVT, calculated using the Kaplan–Meier method. Independent predictors associated with restenosis were assessed using Cox proportional hazard regression model.

    Results: Technical success was achieved in 61 patients (95%). In total, 214 stents (192 self-expandable stents, 22 balloon-expandable stents) were implanted. During the follow-up of 33±28 months, 11 patients experienced loss of patency. The primary patency rates were 88%, 70%, and 70% at 1, 3, and 5 years, respectively. The secondary patency rates were 98%, 87%, and 77% at 1, 3, and 5 years, respectively. In Cox regression analysis, E-Luminexx stent use (in 29 patients, 48%) was associated with restenosis [hazard ratio, 4.41, P=0.038].

    Conclusion: In this retrospective study, EVT for AIOD demonstrated favorable 5-year patency. E-Luminexx stent implantation was associated with restenosis in this population.

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  • Takeo Horikoshi, Jun-ei Obata, Takamitsu Nakamura, Daisuke Fujioka, Yo ...
    Type: Original Article
    Article ID: 48249
    Published: 2019
    [Advance publication] Released: April 16, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Although coronary endothelial vasomotor dysfunction predicts future coronary events, there are few human studies showing the relationship between endothelial vasomotor dysfunction and atheroma plaque progression in the same coronary artery. This study examined whether endothelial vasomotor dysfunction is related to atheroma plaque progression in the infarct-related coronary artery of ST-segment elevation myocardial infarction (STEMI) survivors using serial assessment of coronary plaque size with intravascular ultrasound (IVUS) and coronary vasomotor responses to acetylcholine (ACh).

    Methods: This study included 50 patients with a first acute STEMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy with percutaneous coronary intervention (PCI). IVUS and vasomotor response to ACh in the LAD were measured within two weeks of acute myocardial infarction (AMI) (1st test) and repeated six months (2nd test) after AMI under optimal anti-atherosclerotic therapies.

    Results: Percent atheroma volume (PAV) and total atheroma volume (TAV) in the LAD progressed over six months of follow-up in 18 and 14 patients, respectively. PAV and TAV progression was significantly associated with persistent impairment of epicardial coronary artery dilation and coronary blood flow increase in response to ACh at both the 1st and 2nd tests. PAV and TAV progression had no significant association with traditional risk factors, PCI-related variables, medications, and the coronary vasomotor responses to sodium nitroprusside, an endothelium-independent vasodilator.

    Conclusions: Persistent impairment of endothelial vasomotor function in the conduit arterial segment and the resistance arteriole was related to atheromatous plaque progression in the infarct-related coronary arteries of STEMI survivors.

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  • Akira Fujiyoshi
    Type: Editorial
    Article ID: ED109
    Published: 2019
    [Advance publication] Released: April 16, 2019
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  • Akira Asai, Yuki Shuto, Mototsugu Nagao, Momoyo Kawahara, Teruo Miyaza ...
    Type: Original Article
    Article ID: 48223
    Published: 2019
    [Advance publication] Released: April 11, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Although metformin treatment has been reported to reduce the risk of cardiovascular events in patients with type 2 diabetes, the underlying mechanisms have not been elucidated fully. Here we assessed atherosclerotic lesion formation in newly established 2 mouse lines with different blood glucose levels (Oikawa-Nagao Diabetes-Prone [ON-DP] and -Resistant [ON-DR]) to evaluate the effect of metformin on early-stage atherosclerosis.

    Methods: Mildly hyperglycemic ON-DP and normoglycemic ON-DR female mice fed an atherogenic diet for 20 weeks (8–28 weeks of age). During the feeding period, one group of each mouse line received metformin in drinking water (0.1%), while another group received water alone as control. Atherosclerotic lesion formation in the aortic sinus was quantitively analyzed from the oil red O-stained area of the serial sections.

    Results: Metformin treatment did not affect food intake, body weight, and casual blood glucose levels within each mouse line during the 20-week feeding period. Nevertheless, metformin treatment significantly reduced atherosclerotic lesion formation in the ON-DP mice (59% of control), whereas no significant effect of metformin was observed in the lesion size of the ON-DR mice.

    Conclusion: Metformin can attenuate early-stage atherogenesis in mildly hyperglycemic ON-DP mice. Pleiotropic effects of metformin, beyond its glucose-lowering action, may contribute to the antiatherogenic property in the early-stage atherosclerosis.

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  • Akemi Kakino, Yoko Usami, Sayaka Horiuchi, Yoshiko Fujita, Kazuhiko Ko ...
    Type: Original Article
    Article ID: 47183
    Published: 2019
    [Advance publication] Released: April 03, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aims: A functional abnormality in high-density lipoprotein (HDL) particles rather than a quantitative abnormality in HDL cholesterol levels has been suggested to promote atherosclerosis. The modification of HDL may underlie functional changes to HDL such as gaining the ability to bind and activate the lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1). We aimed to develop a novel method for measuring modified HDL on the basis of its binding to LOX-1.

    Methods: We designed a LOX-1 binding–based enzyme-linked immunosorbent assay (ELISA) with recombinant LOX-1 and anti-apoAI antibody. A lipid-free standard was devised by making a chimeric fusion protein containing anti-LOX-1 antibody and human apoAI fragment. We used this system to detect modified HDL, designated as LOX-1 ligand containing apoAI (LAA).

    Results: With our ELISA system, we detected HDL modified by copper oxidation, hypochlorous acid, 4-hydroxynonenal, and potassium cyanate, but not native HDL. Upon oxidation, HDL showed increased LOX-1 binding activity and decreased cholesterol efflux and paraoxonase-1 activities. In the ELISA, the chimeric fusion protein standard showed minimal variation in reference binding curves in contrast to copper-oxidized HDL preparations, suggesting better quality control of the chimeric fusion protein as the standard for measuring modified HDL activity. LAA was detectable in the plasma of healthy individuals and of mice fed a high-fat diet.

    Conclusion: We have developed a novel ELISA by using recombinant LOX-1 and anti-apoAI antibody to measure the activity of modified HDL in plasma.

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  • Barbora Czippelova, Zuzana Turianikova, Jana Krohova, Radovan Wiszt, Z ...
    Type: Original Article
    Article ID: 47530
    Published: 2019
    [Advance publication] Released: March 30, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Motivated by the paradoxical and differing results of the early atherosclerosis related indices – Cardio-Ankle Vascular Index (CAVI) reflecting arterial stiffness and Reactive Hyperemia Index (RHI) evaluating endothelium dependent flow-induced vasodilation – in obesity, we aimed to assess CAVI and RHI in obese adolescents and young adults in the context of differences in systemic vascular resistance (SVR).

    Methods: We examined 29 obese (14f, 15.4 [12.3–18.5] y; BMI: 33.2±4.4 kg.m2) and 29 non-obese gender and age matched adolescents and young adults (BMI: 21.02±2.3 kg.m2). CAVI and RHI were measured using VaSera VS-1500 (Fukuda Denshi, Japan) and Endo-PAT 2000 (Itamar Medical, Israel), respectively. Hemodynamic measures were recorded using volume-clamp plethysmography (Finometer Pro, FMS, Netherlands) and impedance cardiography (CardioScreen 2000, Medis GmbH, Germany). SVR and sympathetic activity related indices – Velocity Index (VI) and Heather Index (HI), and LFSAP (spectral power in low frequency band of systolic blood pressure oscillations) were determined.

    Results: In obese group, CAVI (4.59±0.88 vs. 5.18±0.63, p=0.002) and its refined version CAVI0 (6.46±1.39 vs.7.33±0.99, p=0.002) were significantly lower. No significant difference in RHI was found. SVR and sympathetic activity indices were all significantly lower in the obese group than in the non-obese group. RHI correlated positively with SVR (r=0.390, p=0.044) in obese subjects.

    Conclusion: Our results indicate that both indices used for the detection of early atherosclerotic changes are influenced by vascular tone. Vascular resistance could influence CAVI and RHI results impairing their interpretation.

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  • Bum Joon Kim, Hyun Young Kim, Wonho Jho, Young Seo Kim, Seong-Ho Koh, ...
    Article ID: 47365
    Published: 2019
    [Advance publication] Released: March 27, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Development of atherosclerotic plaques is affected by vascular geometry and hemodynamics. Hemodynamics in the basilar artery (BA) is unique as the flow converges from vertebral arteries (VAs). Here, we investigated the characteristics of BA plaque based on VA and BA geometry.

    Methods: Consecutive patients evaluated using high-resolution magnetic resonance imaging (MRI) at a general health center were screened. Geometric characteristics of VA (VA dominancy and VA-BA angles) and BA (BA convexity and BA angles) were assessed. The burden of BA plaques was investigated in each wall (anterior, posterior, left, and right lateral). The characteristics of BA plaques were compared according to VA dominancy (right vs. left), BA angle of lateral view (lateral mid-BA angle; dichotomized), and total plaque burden (divided by tertiles).

    Results: Of the 1029 subjects, BA plaques were observed in 98 (9.5%) patients, and were more frequently located at the anterior wall (32.4%) and posterior wall (35.0%) than the right wall (15.3%) and left lateral wall (17.6%). Right and left lateral plaques were more frequent in the left and right convex BA, respectively (p=0.009 and p=0.024, respectively). Anterior plaques were more frequently observed in low lateral mid-BA angle (p= 0.043). BA plaques were predominant in anterior and posterior walls in patients with lower plaque burden, whereas they were predominant in right and left lateral walls in patients with higher plaque burden (p=0.001 and p=0.025, respectively).

    Conclusions: Asymptomatic BA plaque location was associated with BA convexity and lateral mid-BA angle. The anteriorly and posteriorly located BA plaques may extend to the lateral walls as the plaque burden increases.

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  • Keisuke Kojima, Shigeki Kimura, Kazuto Hayasaka, Masafumi Mizusawa, To ...
    Article ID: 48181
    Published: 2019
    [Advance publication] Released: March 27, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Knowledge of subclinical plaque morphology and plaque distribution in the aorta in vivo remains unclear. This study aimed to increase the body of knowledge in this area.

    Methods: We enrolled 37 consecutive patients with stable angina pectoris patients who underwent non-obstructive angioscopy for both the coronary artery and aorta immediately after percutaneous coronary intervention. We evaluated the presence of aortic plaques and the distribution of plaque instability. Patients were allocated into two groups according to the number of vulnerable plaques in whole aorta (a low [0–11] and high [≥ 12] group). We evaluated the relationships between the two groups in terms of cardiovascular risk factors.

    Results: Aortic plaques were identified using non-obstructive angioscopy in all patients, and the greatest number of plaques was found at the infrarenal abdominal aorta (IAA) (the aortic arch, the descending thoracic aorta, the suprarenal abdominal aorta, the IAA, and common iliac artery; 65%, 76%, 65%, 95%, and 49%, respectively; p<0.001). The maximum yellow grade, and the number of intense yellow plaques, ruptured plaques, and thrombi were highest at the IAA (p<0.001). The prevalence of diabetes mellitus and peripheral arterial disease was higher in the high vulnerable plaque group (83.3% vs. 40.0%, p=0.010, 50.0% vs. 8.0%, p=0.005, respectively).

    Conclusions: Aortic atherosclerosis was the most severe at the IAA, and aortic plaque vulnerability and distribution were associated with the prevalence of diabetes mellitus and peripheral artery disease in patients with stable angina pectoris. Non-obstructive angioscopy may identify patients at high risk of future aortic events.

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  • Megumi Yano, Akira Matsunaga, Sadako Harada, Bo Zhang, Emi Kawachi, Mi ...
    Article ID: 47191
    Published: 2019
    [Advance publication] Released: March 19, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The purpose of this study was to compare two homogeneous assays of low-density lipoprotein-cholesterol (LDL-C) with a modified beta quantification reference measurement for LDL-C (BQ-LDL), fractions of chylomicron (CM), very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) by quantitative ultracentrifugation in patients with hypertriglyceridemia.

    Methods: Two homogeneous LDL-C assays (LDL-C(K), Kyowa Medex and LDL-C(S), Sekisui Medical) were used to measure 198 samples of fresh anonymized leftover sera with hypertriglyceridemia (≥ 150 mg/dL). Of these, 32 samples with discrepant LDL-C levels or hypertriglyceridemia (≥ 400 mg/dL) were used for further analysis. Quantitative ultracentrifugation was used to separate samples.

    Results: The two homogeneous LDL-C assays had a strong correlation with each other for the samples from 198 patients with hypertriglyceridemia. LDL-C(K) and LDL-C(S) in 32 selected samples were strongly correlated with BQ-LDL. In both homogeneous assays, cholesterol in the CM and VLDL fractions was measured as part of the LDL-C. A weak correlation was found between cholesterol in the VLDL fraction and LDL-C using the two homogeneous assays, but no correlation was found with cholesterol in the CM fraction. Cholesterol in the IDL fraction was also measured as part of the LDL-C in both assays.

    Conclusion: Both homogeneous assays partially detected cholesterol in the chylomicron and VLDL fractions, but LDL-C measured by both homogeneous assays correlated with BQ-LDL.

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  • Yusuke Todate, Ikuko Uwano, Satoshi Yashiro, Ai Chida, Yutaka Hasegawa ...
    Article ID: 48553
    Published: 2019
    [Advance publication] Released: March 15, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: It remains unclear whether elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for cerebral vascular disease. Familial hypercholesterolemia (FH) is the most appropriate model for understanding the effects of excess LDL-C because affected individuals have inherently high levels of circulating LDL-C. To clarify the effects of hypercholesterolemia on cerebral small vessel disease (SVD), we investigated cerebrovascular damage in detail due to elevated LDL-C using high resolution brain magnetic resonance imaging (MRI) in patients with FH.

    Methods: Twenty-eight patients with FH and 35 healthy controls underwent 7T brain MRI. The prevalence of SVD and arterial structural changes were determined in each group.

    Results: The prevalence of periventricular hyperintensity (PVH) was significantly higher (control, 0% vs. FH, 14.2%, p=0.021) and deep white matter intensity tended to be more frequent in FH patients than in controls. The prevalence of SVD in patients with forms of cerebral damage, such as lacunar infarction, PVH, deep white matter hyperintensities (DWMH), microbleeding, and brain atrophy, was significantly higher among FH patients (control, n=2, 5.7% vs. FH, n=7, 25.0%, p<0.001, chi-square test). The tortuosity of major intracranial arteries and the signal intensity of lenticulostriate arteries were similar in the two groups. In FH patients, as the grade of PVH progressed, several atherosclerosis risk factors, such as body mass index, blood pressure, and triglyceride level, showed ever worsening values.

    Conclusion: These results obtained from FH patients revealed that persistently elevated LDL-C leads to cerebral PVH. It is necessary in the management of FH to pay attention not only to the development of coronary heart disease but also to the presence of cerebral SVD.

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  • Hiroyasu Yamamoto, Mari Kawamura, Ikoi Kochi, Minami Imai, Yukie Murat ...
    Article ID: 46797
    Published: 2019
    [Advance publication] Released: March 14, 2019
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    Aim: In the pathogenesis of atherosclerosis, autoantibodies have two-facedness of progression and protection. Previous reports have indicated that low autoantibody levels against apolipoprotein B-100 (apo B-100) could increase the risk of atherosclerotic cardiovascular diseases (CVD) in healthy subjects. In this study, we investigated the relationship between circulating anti-apo B-100 autoantibodies and the clinical parameters in Japanese diabetic patients with or without CVD.

    Methods: We measured the serum levels of anti-apo B-100 autoantibodies against native and malondialdehyde (MDA)-modified p45 or p210 epitopes, as well as anti-apo E autoantibodies, using enzyme-linked immunosorbent assay.

    Results: In patients with CVD, the circulating levels of IgG against native p45, MDA-modified p45, and MDA-modified p210 (IgGN-45, IgGMDA-45, and IgGMDA-210) were significantly lower than those in patients without CVD, whereas no difference was observed in anti-apo E autoantibody levels. In addition, IgMN-45, IgMMDA-45, and IgGMDA-45 were negatively correlated with LDL-C levels, whereas IgGN-45 and IgGN-210 were positively correlated with HbA1c levels. No correlation was observed between autoantibody levels and diabetic microangiopathy. In the statin-treated subgroup, IgGMDA-45 and IgGMDA-210 were significantly lower in patients with CVD than in those without CVD.

    Conclusion: Measurement of serum anti-apo B-100 autoantibodies can be useful for the evaluation of CVD risk in patients with diabetes receiving statin treatment.

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  • Jingyi Liu, Makoto Nishida, Hiroyasu Inui, Jiuyang Chang, Yinghong Zhu ...
    Article ID: 48405
    Published: 2019
    [Advance publication] Released: March 14, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: A direct oral anti-coagulant, FXa inhibitor, has been applied to the clinical treatment of myocardial infarction (MI). Experimental studies in mice indicated that FXa inhibitors reduced atherosclerosis and prevented cardiac dysfunction after coronary ligation. These studies suggested that protease-activated receptor (PAR) 2, a major receptor of activated FX, may play an important role in atherosclerosis and cardiac remodeling.

    Methods: The effects of a FXa inhibitor, rivaroxaban, were investigated in a new murine model of ischemic cardiomyopathy (ICM) using SR-BI KO/ApoeR61h/h mice (Hypo E mice) that developed MI by high-fat diet loading.

    Results: Hypo E mice were fed rivaroxaban-containing (n=49) or control chow diets (n=126) after the induction of MI. The survival curve of the rivaroxaban-treated group 2 weeks after the induction of MI was improved significantly as compared with the non-treatment group (survival rate: 75.5% vs. 47.4%, respectively, p=0.0012). Echocardiography and the expression of BNP showed that rivaroxaban attenuated heart failure. Histological analyses revealed that rivaroxaban reduced aortic atherosclerosis and coronary occlusion, and markedly attenuated cardiac fibrosis. Rivaroxaban treatment decreased cardiac PAR2 levels and pro-inflammatory genes. In vitro, rivaroxaban application demonstrated the increase of cell viability against hypoxia in cardiac myocytes and the reduction of hypoxia-induced inflammation and fibrosis-related molecules in cardiac fibroblasts. The effects of the PAR2 antagonist against hypoxia-induced inflammation were comparable to rivaroxaban in cardiac fibroblasts.

    Conclusions: Rivaroxaban treatment just after MI in Hypo E mice prevented the progression of ICM by attenuating cardiac remodeling, partially through the suppression of the PAR2-mediated inflammatory pathway.

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  • Yong Zhu, Chengping Hu, Yu Du, Jianwei Zhang, Jinxing Liu, Guojie Chen ...
    Article ID: 47043
    Published: 2019
    [Advance publication] Released: March 09, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Omentin-1, as a novel adipocytokine, ameliorates obesity-associated disorders and suppresses the development of atherosclerotic lesions. The present research investigated the correlation between serum omentin-1 and post-infarction myocardial function.

    Methods: A total of 52 patients with first anterior ST-segment elevation myocardial infarction (STEMI) were recruited into this study. Participants were divided into two subgroups according to median admission omentin-1 concentration. δ1 was defined as (admission omentin-1 level) - (serum omentin-1 at 24 hours after admission) and δ2 was defined as (admission omentin-1 level) - (serum omentin-1 at 72 hours after admission). The change in left ventricular ejection fraction (LVEF) was regarded as (LVEF at 3 months post-STEMI)–(LVEF at 2 days post-STEMI).

    Results: Admission omentin-1 level was the highest, while omentin-1 decreased over the following 3 days. The high admission omentin-1 group had lower peak muscle brain fraction of creatine kinase (CK–MB). Additionally, the change in LVEF and the global LVEF at 3 months post-STEMI all ameliorated significantly in the high admission omentin-1 group. For the time-dependent change in omentin-1, there were negative associations among δ1, δ2, and peak CK–MB. δ1 and δ2 also correlated positively with LVEF at 3 months post-STEMI. Most importantly, δ1 (r =0.346, p=0.012) and δ2 (r =0.439, p=0.001) also correlated positively with the change in LVEF. After multivariate linear regression analysis, δ1 (Beta=0.026, 95% CI 0.011 to 0.041, p=0.001) and δ2 (Beta=0.024, 95% CI 0.009 to 0.038, p=0.003) also remained associated with the change in LVEF.

    Conclusions: The admission omentin-1 and time-dependent change in omentin-1 level all have a significant correlation with the early improvement of post-infarction myocardial function. While only the time-dependent change in omentin-1 (δ1 and δ2) remained associated with the early improvement of post-infarction myocardial function after multivariate linear regression analysis. The present research indicated that omentin-1 represents a promising adipocytokine to retard negative cardiac remodeling after STEMI.

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  • Enric Sánchez, Àngels Betriu, Andree Yeramian, Elvira Fernández, Franc ...
    Article ID: 47498
    Published: 2019
    [Advance publication] Released: March 06, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Advanced glycation end-products (AGEs) have been involved in the atherogenic process in the high-risk population. The goal of this study was to demonstrate that AGEs are related to subclinical atheromatous disease in subjects with low to moderate vascular risk.

    Methods: A cross-sectional study in which 2,568 non-diabetic subjects of both sexes without cardiovascular disease were included. Subcutaneous content of AGEs was assessed by skin autofluorescence (SAF) and subclinical atheromatous disease was measured by assessing the atheromatous plaque burden in carotid and femoral regions using ultrasonography. In addition, serum pentosidine, carboxymethyl-lysine (CML) and AGE receptors (RAGE) were assessed in a nested case-control study with 41 subjects without plaque and 41 individuals subjects with generalized disease.

    Results: Patients with atheromatous plaque had a higher SAF than those with no plaque (1.9 [1.7 to 2.3] vs. 1.8 [1.6 to 2.1] arbitrary units (AU), p0.001). The SAF correlated with the total number of affected regions (r= 0.171, p<0.001), increasing progressively from 1.8 [1.6 to 2.1] AU in those without atheromatous disease to 2.3 [1.9 to 2.7] AU in patients with ≥ 8 plaques (p0.001). A correlation was also observed between SAF and the total plaque area (r=0.113, p<0.001). The area under the Receiver Operating Characteristic curve was 0.65 (0.61 to 0.68) for identifying male subjects with atheromatous disease. The multivariable logistic regression model showed a significant and independent association between SAF and the presence of atheromatous disease. However, no significant differences in serum pentosidine, CML, and RAGE were observed.

    Conclusions: Increased subcutaneous content of AGEs is associated with augmented atheromatous plaque burden. Our results suggest that SAF may provide clinically relevant information to the current strategies for the evaluation of cardiovascular risk, especially among the male population.

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  • Takuya Tsujimura, Mitsuyoshi Takahara, Osamu Iida, Seiichi Hiramori, N ...
    Article ID: 47399
    Published: 2019
    [Advance publication] Released: March 05, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Although the InnovaTM self-expanding nitinol stent (Boston Scientific, Marlborough, MA) exhibits acceptable performance in long-term safety and efficacy when used for the treatment of femoropopliteal (FP) lesions, clinical outcomes following its implantation have not been systematically studied in real-world settings. We investigated the one-year clinical outcomes after implantation of InnovaTM self-expanding nitinol stents for the treatment of FP lesions in real-world settings.

    Methods: In this multicenter study, 481 lesions in 453 consecutive patients with peripheral artery disease (PAD) (74±9 years; male, 70%; diabetes mellitus, 61%; dialysis, 27%; critical limb ischemia, 37%) who underwent endovascular therapy with the implantation of InnovaTM self-expanding nitinol stents for FP lesions were analyzed from February 2016 to April 2017. The primary endpoint was one-year restenosis, whereas the secondary endpoints included one-year major adverse limb events and predictors for one-year restenosis.

    Results: The mean lesion length was 18±10 cm. One-year restenosis and major adverse limb event rates were 36% and 18%, respectively. Multivariate analysis revealed that the presence of diabetes mellitus (odds ratio [OR]: 1.83; 95% confidence interval [CI]: 1.07–3.13), distal reference vessel diameter (OR: 1.86; 95% CI: 1.09–3.16), spot stenting (OR: 2.27; 95% CI: 1.27–4.06), and lack of one-year cilostazol treatment (OR: 0.58; 95% CI: 0.33–1.00) were independent risk factors for one-year restenosis.

    Conclusion: The current study demonstrated one-year clinical outcomes after InnovaTM self-expanding nitinol stent placement for the treatment of FP lesions, including challenging cases in real-world settings.

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  • Jing Song, Xia Jiang, Yaying Cao, Juan Juan, Tao Wu, Yonghua Hu
    Article ID: 46615
    Published: 2019
    [Advance publication] Released: March 01, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: ATP-binding cassette A1 (ABCA1) plays an important role in reducing the risk of stroke. Egg is the major source of dietary cholesterol and is known to be associated with the risk of stroke and atherosclerosis. We aimed to assess the effects of interaction between an ABCA1 variant (rs2066715) and egg consumption on the risk of ischemic stroke (IS), carotid plaque, and carotid-intima media thickness (CIMT) in the Chinese population.

    Methods: In total, 5869 subjects (including 1213 IS cases) across 1128 families were enrolled and divided into two groups based on the median egg consumption (4 eggs per week). In the analyses for the presence of carotid plaque and CIMT, 3171 out of 4656 IS-free controls without self-reported history of coronary heart disease and lipid-lowering medications were included. Multilevel logistic regression models were used to model the genetic association of rs2066715 with the risk of IS, and mixed-effect linear regression for the genetic association of rs2066715 with carotid plaque, and CIMT. The gene-by-egg cross-product term was included in the regression model for interaction analysis.

    Results: We found that rs2066715 was associated with the increased risk of carotid plaque among those who consumed <4 eggs per week after adjustment (odds ratio [95% confidence interval]: 1.61 [1.08, 2.39], P =0.019). A significant effect of interaction between rs2066715 and egg consumption on the risk of carotid plaque was identified (P =0.011).

    Conclusion: rs2066715 was found to interact with egg consumption in modifying the risk of carotid plaque in the Chinese population.

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  • Ce Zhang, Jian Tian, Lin Jiang, Lianjun Xu, Junhao Liu, Xueyan Zhao, X ...
    Article ID: 47324
    Published: 2019
    [Advance publication] Released: March 01, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: To evaluate the prognostic value of plasma big endothelin-1 level in the context of three-vessel disease (TVD) with heavy atherosclerotic burden.

    Methods: A total of 6,150 patients with TVD and available big endothelin-1 data were included in the study. Participants were divided into two groups according to the optimal cutoff value of big endothelin-1 for mortality prediction. The primary endpoint was all-cause death. C-index, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to evaluate the added prognostic value of plasma big endothelin-1 level beyond the SYNTAX score Ⅱ.

    Results: On the basis of the optimal cutoff value of 0.79 pmol/L, 1,984 patients were assigned to the high big endothelin-1 group. During a median follow-up of 6.8 years, 818 patients experienced all-cause death. Plasma big endothelin-1 level was significantly higher in patients who died than in patients who survived. Multivariable analysis found that high big endothelin-1 level was independently associated with an increased risk of mortality (hazard ratio: 1.36, 95% confidence interval: 1.18–1.57, P0.001). The association of big endothelin-1 with all-cause death was relatively consistent across subgroups with no significant interactions. The predictive ability of the SYNTAX score Ⅱ was significantly enhanced by addition of plasma big endothelin-1 level (C-index: 0.723 vs.0.715, P =0.029; NRI: 0.304, P0.001; IDI: 0.009, P0.001).

    Conclusions: Plasma big endothelin-1 level is an independent predictor of long-term mortality in patients with TVD. It can improve the discrimination and reclassification of the SYNTAX score Ⅱ for mortality prediction.

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  • Junji Kobayashi
    Article ID: ED108
    Published: 2019
    [Advance publication] Released: February 27, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION
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  • Elko Randrianarisoa, Angela Lehn-Stefan, Anja Hieronimus, Roderich Rie ...
    Article ID: 47274
    Published: 2019
    [Advance publication] Released: February 19, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The visceral adiposity index (VAI) has been proposed as an estimate of visceral adipose tissue (VAT) mass and as an indicator of VAT dysfunction. Both parameters are associated with cardiometabolic risk, including insulin resistance. In this study, we investigated whether VAI is associated with subclinical atherosclerosis in subjects who were free of cardiovascular disease but were at risk of developing diabetes mellitus.

    Methods: A total of 731 adults with a median age of 47 years old without diabetes mellitus were included in this cross-sectional study. The anthropometric data, blood pressure, and lipid profiles of 398 women and 333 men were measured. All subjects underwent an oral glucose tolerance test, and carotid intima–media thickness (cIMT) was evaluated by ultrasound. Insulin resistance was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR).

    Results: VAI and HOMA-IR (ßst=0.44, p<0.0001), VAI and cIMT (ßst=0.17, p<0.0001), and HOMA-IR and cIMT (ßst=0.09, p=0.0127) were correlated with each other. After adjusting for cofounding variables, VAI is still correlated with HOMA-IR (ßst=0.42, p<0.0001). Furthermore, VAI (ßst=0.07, p=0.0392) but not HOMA-IR (ßst=0.03, p=0.37) was correlated with cIMT independently of other established cardiovascular risk factors.

    Conclusion: The calculation of VAI may provide a better estimation of subclinical atherosclerosis than the calculation of HOMA-IR.

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  • Yu Du, Yingxin Zhao, Yong Zhu, Chenping Hu, Jianwei Zhang, Qingwei Ji, ...
    Article ID: 47019
    Published: 2019
    [Advance publication] Released: February 15, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Several members of secreted frizzled-related protein (SFRP) are involved in the process of myocardial ischemia–reperfusion injury. However, little is known about the role of SFRP5 in patients with acute ST-segment elevation myocardial infarction (STEMI).

    Methods: In this cross-sectional study, 85 patients with first-time anterior STEMI who underwent timely primary percutaneous coronary intervention (PCI) and 35 patients without coronary artery disease (CAD) were enrolled. Serum SFRP5 levels were measured using an enzyme-linked immunosorbent assay kit. Patients with STEMI were divided into low-SFRP5 and high-SFRP5 groups according to their median baseline serum SFRP5 levels. To evaluate cardiac function and structure after infarction, the left ventricular ejection fraction (LVEF) and left ventricular end-diastolic volume (LVEDV) were measured using echocardiography. The associations between changes in LVEF and reduced LVEF (≤ 50%) and clinical variables were determined by univariate and multivariate analyses.

    Results: Baseline serum SFRP5 levels were significantly higher in patients with STEMI than in those without CAD (23.3 ng/mL vs 19.8 ng/mL, P=0.008), although they decreased over time. Also, baseline serum SFRP5 levels were inversely correlated with peak hypersensitive cardiac troponin I (hs-cTnI) levels (r=−0.234, P=0.025) and peak hypersensitive C-reactive protein (hs-CRP) levels (r=−0.262, P=0.015). A multivariate linear regression model showed that changes in LVEF were positively correlated with serum SFRP5 levels at baseline (β= 0.249, 95% confidence interval (CI) 0.018–0.245, P=0.024) and 24 h after admission (β=0.220, 95% CI 0.003–0.264, P=0.045). At 3 months, LVEF in patients with high SFRP5 levels was significantly improved over baseline [(60.8±7.1) % vs (56.1±7.5) %, P=0.001]. LVEF was also significantly higher in patients with high SFRP5 levels than in those with low at the 3-month follow-up [(60.8±7.1) % vs (56.8±8.9) %, P=0.028]. Consequently, high serum SFRP5 levels at baseline were associated with a decreased risk of reduced LVEF at 3 months, independent of peak hs-cTnI and baseline cardiac function (hazard ratio 0.190, 95% CI 0.036–0.996; P=0.049).

    Conclusions: High serum SFRP5 levels measured during the acute phase of STEMI were significantly associated with promoting myocardial recovery at an early phase following primary PCI, suggesting that SFRP5 is a potential therapeutic target in acute STEMI.

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  • Hung Hsu, Powen Hsu, Ming-Hui Cheng, Yasuki Ito, Eiichiro Kanda, Ernst ...
    Article ID: 48330
    Published: 2019
    [Advance publication] Released: February 07, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aims: Prediabetes and diabetes are associated with increased insulin resistance and decreased insulin production, dyslipidemia, and increased cardiovascular disease (CVD) risk. Our goals were to assess lipoprotein subfractions using novel assays in such subjects.

    Methods: Fasting normal, prediabetic, and diabetic Taiwanese men and women (n=2,049) had their serum glucose, glycosylated hemoglobin, insulin, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), HDL3-C, apolipoprotein E-HDL-C, direct low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), LDL-TG, and remnant lipoprotein cholesterol (RLP-C) levels measured using novel assays. HDL2-C, LDL-C, and large-buoyant LDL-C (lbLDL-C) were calculated.

    Results: Prediabetic male and female subjects had significantly higher levels of TG, RLP-C, sdLDL-C, the sdLDL-C/LDL-C ratio, and LDL-TG than normal subjects, and statin treatment abolished this effect in men, but not in women. Diabetic male and female subjects had significantly higher TG and sdLDL-C/LDL-C ratios, and significantly lower levels of HDL-C, HDL2-C, HDL3-C, and apoE HDL-C than normal subjects, as did prediabetic women. Median direct LDL-C levels were >100 mg/dL in all groups, even in those receiving statin therapy. Calculated LDL-C significantly underestimated direct LDL-C by >10% in diabetic subjects.

    Conclusions: Our data indicate that prediabetic subjects were more likely to have significantly elevated RLP-C, sdLDL-C, and LDL-TG, while diabetic subjects were more likely to have significantly decreased HDL-C, HDL2-C, HDL3-C, and apoE HDL-C than normal subjects, and calculated LDL-C significantly underestimated their direct LDL-C. In our view, direct LDL-C and sdLDL-C should be measured and optimized in both diabetic and prediabetic subjects to reduce CVD risk.

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  • Qi Kong, Xin Ma, Chen Wang, Wuwei Feng, Bruce Ovbiagele, Yuren Zhang, ...
    Article ID: 47464
    Published: 2019
    [Advance publication] Released: February 06, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Coronary artery stenosis (CAS) ≥ 50% frequently coexists in patients with acute ischemic cerebrovascular disease (AICVD), which portends unfavorable outcomes. We sought to examine whether patients with AICVD with CAS had more severe and more diffused cervicocephalic atherosclerosis (CA).

    Methods: Patients with AICVD were consecutively enrolled and underwent simultaneous computed tomography angiography (CTA) of the coronary and cervicocephalic arteries. A total of 140 patients were divided into “AICVD+CAS” and “AICVD only” groups according to whether CTA showed stenosis of ≥ 50% in at least one coronary arterial segment. The relationship of the presence of CAS with the severity and extent of CA were examined.

    Results: The CA severity characteristics, including the presence of stenosis ≥ 50% and the grade of the most severe stenotic segment, were not significantly different between the two groups. Regarding the extent of CA, the presence of stenosis ≥ 50% in both sides (adjusted odds ratio [OR]: 4.29, 95% confidence interval [CI]: 1.67–10.98), both extracranial and intracranial (adjusted OR: 5.26, 95% CI: 2.24–12.35), both anterior and posterior circulation (adjusted OR: 5.29, 95% CI: 2.22–12.64), and the number of stenotic segments ≥ 50% in cervicocephalic arteries (adjusted OR: 1.58, 95% CI: 1.28–1.96) were associated with CAS in patients with AICVD, independently of clinical demographics and CA severity characteristics.

    Conclusion: CA was similarly severe in patients with AICVD with and without CAS, but those with CAS had significantly more diffused CA. The extent of CA and CAS were mutual indicators in patients with AICVD, irrespective of CA severity.

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  • Miki Sakamoto, Naoki Edo, Satoshi Takahashi, Erina Okamura, Kenji Uno, ...
    Article ID: 47597
    Published: 2019
    [Advance publication] Released: February 06, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aims: The proper management of atherosclerotic risk factors (ARFs) and attainment of target levels (TLs) for ARFs are crucial in preventing atherosclerotic cardiovascular disease (ASCVD). In this study, utilizing data from the “Specific Health Check and Guidance in Japan,” which was conducted from 2008 to 2011, we examined TL attainment status of low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) and prescription status of dyslipidemia and hypertension in patients with diabetes undergoing medical treatment, and analyzed the factors that affected prescription status.

    Methods: Subjects receiving medical treatment for diabetes were selected from the database. Subjects were classified by prescription status for dyslipidemia and hypertension, and TL attainment status was assessed for each ARF.

    Results: The percentage of subjects who did not attain TLs and were not under medication was higher for LDL-C than for BP. The un-prescribed rates among non-TL-attained subjects were 60%–75% for LDL-C, and around 30%–40% for BP. The un-prescribed rates to those who were qualified for prescription therapy were also higher for LDL-C than for BP. Logistic regression analyses revealed that the subjects who were prescribed for dyslipidemia had the following characteristics compared with the un-prescribed non-TL-attained subjects: older age, higher body mass index, lower estimated glomerular filtration rate, previous heart or cerebrovascular disease, and higher medication rate for other ARFs.

    Conclusions: The present study revealed that, in Japan, the adequate prescription rate for dyslipidemia was lower than that for hypertension in patients with diabetes, suggesting the proper prescription therapy for dyslipidemia should be pursued to further prevent ASCVD.

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  • Yoko Nishida, Yasuhiko Kubota, Hiroyasu Iso, Akiko Tamakoshi, the JACC ...
    Article ID: 46383
    Published: 2019
    [Advance publication] Released: January 31, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Previous studies suggested a positive association between eczema and cardiovascular disease (CVD), probably through enhanced systemic inflammation. However, several studies reported null findings about eczema and CVD, so the evidence is still controversial.

    Methods: We asked 85,099 participants (35,489 men and 49,610 women), aged 40 to 79 years, without a history of CVD or cancer at baseline between 1988 and 1990, to complete a lifestyle questionnaire, including information eczema frequency (seldom, sometimes or often).

    Results: During the 6,389,818 person-years of follow-up, there were 1,174 deaths from coronary heart disease (CHD), 979 from heart failure, 366 from cardiac arrhythmia, 2,454 from total stroke, 1,357 from ischemic stroke, 1,013 from hemorrhagic stroke, and 201 from aortic aneurysm or dissection. The multivariable-adjusted model showed that individuals who “sometimes” or “often” had eczema had 0.82 (95%confidence interval (CI): 0.69–0.97) or 1.26 (95%CI: 1.01–1.56) times the risk of mortality from CHD, respectively, compared to those who “seldom” did. Individuals who “often” had 1.30 (95%CI: 1.05–1.61) times the risk of mortality from CHD, compared to those who “seldom or sometimes” did. There was no association of eczema with mortality from other CVD, or no interaction between eczema and sex or age, in relation to any CVD mortality risk.

    Conclusions: Self-reported frequent eczema was associated with increased risk of mortality from CHD, but not other major CVD, in a Japanese general population. Since steroid usage was not considered, future studies should include it as a potential confounding factor.

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  • Ran Lee, Hye-Ran Ahn, Min-Ho Shin, Hee-Nam Kim, Young-Hoon Lee, Seong- ...
    Article ID: 47167
    Published: 2019
    [Advance publication] Released: January 23, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: To elucidate the role of pentraxin-3 (PTX3) in atherosclerosis, we evaluated lipid and cardiovascular risk profiles according to the plasma PTX3 levels in subjects from the general population.

    Methods: A sub-cohort of 2,000 subjects was randomly sampled from a Korean community-based cohort study. After excluding those with a medication history for dyslipidemia, 1,747 subjects (902 men and 845 women) were included in the final analyses. Linear and logistic regressions with adjustment for appropriate variables were performed.

    Results: The PTX3 level was positively associated with the high-density lipoprotein cholesterol (HDL-C) level and negatively associated with the log-transformed triglyceride (TG) level, total cholesterol/HDL-C ratio, and low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio (p0.05). Subjects with the highest PTX3 levels (≥ 1.17 ng/dl) exhibited a lower risk of metabolic syndrome (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.57-0.94), overweight/obesity (OR 0.65, 95% CI 0.50-0.83), increased TG level (OR 0.66, 95% CI 0.51-0.86), and increased HDL-C level (OR 0.67, 95% CI 0.51-0.88) compared to those with the lowest PTX3 level (0.7 ng/dl).

    Conclusion: The circulating PTX3 level was inversely associated with metabolic syndrome, overweight/obesity, and parameters of dyslipidemia, suggesting a cardioprotective role of PTX3 in atherosclerosis.

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  • Xian Fu, Xianliang Li, Li Xiong, Xuelong Li, Ruxun Huang, Qingchun Gao
    Article ID: 46573
    Published: 2019
    [Advance publication] Released: January 19, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Carotid–cerebral pulse wave velocity (ccPWV) reflects the segment (C-M segment) stiffness between the common carotid artery and ipsilateral middle cerebral artery. C-M segment atherosclerosis (CMSA) is regarded the most frequent cause of anterior circulation ischemic stroke. We aimed to evaluate the association of ccPWV with early stage CMSA in this study.

    Methods: Eighty-one acute ischemic stroke (AIS) patients with 154 C-M segments who were successfully evaluated with digital subtraction angiography, ccPWV, carotid intima–media thickness (cIMT), and brachial–ankle pulse wave velocity were enrolled into this study. Patient demographics and clinical data were retrieved from our AIS databases.

    Results: Multivariate analyses showed that CMSA was independently associated with higher systolic BP, ccPWV, and cIMT. ccPWV and cIMT presented good diagnostic values for evaluating early stage CMSA in the receiver operating characteristic curve analyses. The areas under the curve (AUCs) of ccPWV were significantly higher than that of cIMT (Z=2.204, P=0.007). The AUC, sensitivity, specificity, Youden index, and cutoff of ccPWV for detecting early stage CMSA were 0.815 (P<0.001), 86%, 70.7%, 0.567, and 5.4 m/s, respectively. Furthermore, ccPWV was significantly correlated with the stenosis of CMSA at the early stage in Spearman’s correlation analyses (r=0.877, P<0.001) and fractional polynomial plot with 95% confidence intervals.

    Conclusions: Cerebral arterial stiffness has the potential to be a new marker of early stage atherosclerosis of the cerebral large artery. This finding may help us prevent the occurrence of stroke and decrease the burden of society from stroke patients.

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  • Xiaolan Yu, Jianping Lu, Jingjing Li, Wen Guan, Shaorong Deng, Qing De ...
    Article ID: 46821
    Published: 2019
    [Advance publication] Released: January 17, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Endothelial lipase (EL), hepatic lipase (HL), and lipoprotein lipase (LPL) are all triglyceride lipases and are associated with coronary artery disease (CAD). However, whether they can be simultaneous independent risk factors for CAD is unknown. In the present study, we investigated whether the three lipases can be independent risk factors simultaneously for CAD and whether combining these lipases could provide greater predictive power than high-density lipoprotein cholesterol (HDL-c) for the development of CAD.

    Methods: Eighty-six patients with CAD and 65 healthy controls were enrolled in the study. Additionally, 38 patients who underwent one-year follow-up angiography after percutaneous coronary intervention with stent implantation were collected to investigate in-stent restenosis. Serum EL, HL, and LPL concentrations were measured and compared with other coronary risk factors.

    Results: Serum EL and HL concentrations were both significantly increased in patients with CAD or in-stent restenosis, whereas serum LPL concentration was reduced significantly in patients with CAD. Multivariate logistic regression analysis indicated that the three lipases were simultaneous independent risk factors for CAD. However, only serum EL concentration was considered an independent risk factor for in-stent restenosis. Importantly, the receiver operating characteristic curve showed that the combined measurement of the three lipases displayed better predictive power than HDL-c or any one of the three lipases for CAD.

    Conclusions: Serum EL concentration was an independent risk factor for both CAD and in-stent restenosis. Moreover, the combined assessment of serum EL, HL, and LPL concentrations as multiple risk factors provided potent predictive power for CAD.

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  • Hao Wang, Dongyuan Liu, Hongbing Zhang
    Article ID: 45963
    Published: 2019
    [Advance publication] Released: January 15, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The study aimed to identify the underlying differentially expressed genes (DEGs) and mechanism of macrophage-enriched rupture atherosclerotic plaque using bioinformatics methods.

    Methods: GSE41571, which includes six stable samples and five ruptured atherosclerotic samples, was downloaded from the GEO database. After preprocessing, DEGs between ruptured and stable atherosclerotic samples were identified using LIMMA. Gene Ontology biological process (GO_BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed using the Database for Annotation, Visualization, and Integration Discovery (DAVID) online tool. Based on the STRING database, protein-protein interactions (PPIs) network among DEGs were constructed. Regulatory relationships between miRNAs/transcriptional factors (TFs) and target genes were predicted using Enrichr, and regulatory networks were visualized using Cytoscape.

    Results: A total of 268 DEGs (64 up-regulated and 204 down-regulated DEGs) were identified between ruptured and stable samples. In the PPI network, collagen type III alpha 1 chain (COL3A1), collagen type I alpha 2 chain (COL1A2), and asporin (ASPN) were more than 15 interaction degrees. In the miRNA-target network, miR21 was highlighted with highest degrees and ASPN could be targeted by miR21. Functional enrichment analysis showed that COL3A1 and COL1A2 were significantly enriched in extracellular matrix organization and cell adhesion GO_BP terms. Pre-platelet basic protein (PPBP) was the most significantly up-regulated gene in ruptured atherosclerotic samples and enriched in immune response and inflammatory response GO_BP terms.

    Conclusions: Down-regulated COL3A1, COL1A2 and ASPN, and up-regulated PPBP might perform critical promotional roles in atherosclerotic plaque rupture. Furthermore, miR21 might be potential target to prevent atherosclerotic rupture.

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  • Mingming Lu, Yuanyuan Cui, Peng Peng, Huiyu Qiao, Jianming Cai, Xihai ...
    Article ID: 47449
    Published: 2019
    [Advance publication] Released: January 09, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The present study aimed to investigate the association between shape and location of atherosclerotic plaques and intraplaque hemorrhage (IPH) in carotid arteries using magnetic resonance (MR) imaging.

    Methods: Overall, 114 symptomatic patients (mean age: 64.9±10.9 years; 81 males) who underwent MR imaging and had advanced carotid plaques were included in analysis. IPH presence and carotid plaque shape and location (below and above bifurcation) were evaluated. The plaque shape was defined as follows: type-I: the arc-length of plaque is greater in the upstream; type-II: the arc-length of plaque in downstream and upstream is equal; and type-III: the arc-length of plaque is greater in downstream. The plaque shape and location were compared between plaques with and without IPH and their associations with IPH were determined.

    Results: Of 181detectedplaques, 57 (31.5%) had IPH. Compared with plaques without IPH, those with IPH had higher incidence of the plaque shape of type-I (66.7% vs. 32.2%, P0.001), lower incidence of plaque shape of type-III (24.6% vs. 50.0%, P=0.001), and were more likely located above carotid bifurcation (71.9% vs. 48.4%, P=0.003). The plaque shape of type-I (OR, 4.01; 95%CI, 1.36–11.83; P=0.012) and location above bifurcation (OR, 3.21; 95%CI, 1.07–9.61; P=0.037) of carotid plaques were significantly associated with IPH after adjusting for confounder factors.

    Conclusions: Carotid plaque shape and location are significantly associated with the occurrence of IPH. Our findings could provide new insights for the pathogenesis of IPH and vulnerably plaques.

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  • Naofumi Yoshida, Kengo Sasaki, Daisuke Sasaki, Tomoya Yamashita, Hajim ...
    Article ID: 47415
    Published: 2018
    [Advance publication] Released: December 27, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Bacteroides vulgatus and B. dorei have a protective effect against atherosclerosis, suggesting that expansion of these species in the gut microbiota could help patients with coronary artery disease (CAD). This study aimed to investigate the effect of resistant starch (RS) on the gut microbiota and its metabolites in fecal sample cultures from patients with CAD and individuals without CAD, using a single-batch fermentation system.

    Methods: Fecal samples from 11 patients with CAD and 10 individuals without CAD were fermented for 30 h with or without RS in the Kobe University Human Intestinal Microbiota Model (KUHIMM). Gut microbiota and the abundance of B. vulgatus and B. dorei were analyzed using 16S ribosomal ribonucleic acid (rRNA) gene sequencing and the quantitative polymerase chain reaction. Short-chain fatty acids were analyzed using high-performance liquid chromatography.

    Results: Gut microbial analysis showed significantly lower levels of B. vulgatus and B. dorei in the original fecal samples from patients with CAD, which was simulated after 30 h of fermentation in the KUHIMM. Although RS significantly increased the absolute numbers of B. vulgatus and B. dorei, and butyrate levels in CAD fecal sample cultures, the numbers varied among each patient.

    Conclusions: The effect of RS on gut microbiota and its metabolites in the KUHIMM varied between CAD and non-CAD fecal sample cultures. The KUHIMM may be useful for preclinical evaluations of the effects of RS on the gut microbiota and its metabolites.

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  • Sandy Huey-Jen Hsu, Men-Hwang Jang, Pao-Ling Torng, Ta-Chen Su
    Article ID: 43968
    Published: 2018
    [Advance publication] Released: December 26, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aims: Recent studies suggest elevated levels of small dense low-density lipoprotein cholesterol (sdLDL-C) can predict the risk of incident coronary heart disease (CHD), even in individuals considered to be at low risk for cardiovascular disease(CVD) based on their LDL-C levels. This study aims to prospectively investigate the association between sdLDL-C concentration and traditional and nontraditional CHD risk markers to explore the underlying roles of sdLDL-C in atherogenic processes.

    Methods: Between 2009 and 2011, 594 healthy volunteers aged 35–65 years were recruited as control subjects in a study of work-related risk factors and acute CHD. All participants fasted for 12–14 h, and venous blood samples were collected in the morning to measure serum lipid profiles and other CHD-related markers. A standard oral glucose tolerance test was performed on all participants to assess their subclinical diabetes and prediabetes status.

    Results: There were significantly positive associations between sdLDL-C concentration and traditional (age, smoking and alcohol drinking habit, blood pressure, body mass index (BMI), serum lipid profiles, and diabetes status) and nontraditional risk factors (complete blood counts, (CBC), fibrinogen, high-sensitivity C-reactive protein, and subclinical diabetes status) for CVD. After adjusting for confounding variables which include age, gender, BMI, hypertension, household income, and smoking and alcohol drinking habits, all atherosclerotic risk markers except D-dimer were significantly and positively associated with sdLDL-C.

    Conclusions: Our data indicated sdLDL-C is strongly associated with atherosclerotic risk markers, such as inflammation, thrombosis, hematological markers, and prediabetes. This study supports the hypothesis that sdLDL-C is a promising CVD risk biomarker.

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  • Takashi Yamaguchi, Kohji Shirai, Daiji Nagayama, Shoko Nakamura, Rena ...
    Article ID: 45799
    Published: 2018
    [Advance publication] Released: December 22, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Cardio-ankle vascular index (CAVI) reflects arterial stiffness and has been established as a useful surrogate marker of atherosclerosis. Contrary to the abundant data indicating slower progression of atherosclerosis with statins, studies on fibrates remain scarce. The aim of this study was thus to clarify the effect of bezafibrate on CAVI as well as on oxidative stress.

    Methods: A randomized, open-label, controlled study was performed. 66 hypertriglyceridemic patients with type 2 diabetes were assigned to two groups: bezafibrate (400 mg/day) group and eicosapentaenoic acid (EPA 1.8 g/day) group. Patients were administered the respective treatment for 12 weeks. CAVI, glycolipid metabolic parameters, and diacron-reactive oxygen metabolites (d-ROMs) were evaluated before and after the study period.

    Results: Serum triglycerides (TG), remnant-like particle cholesterol (RLP-C), fasting plasma glucose, HbA1c and d-ROMs decreased, while HDL-cholesterol increased significantly in the bezafibrate group but did not change in the EPA group. The decreases in TG, RLP-C, HbA1c and d-ROMs were significantly greater in the bezafibrate group than in the EPA group. CAVI decreased significantly only in the bezafibrate group and the decrease was significantly greater in bezafibrate group than in EPA group. Simple regression analysis showed no significant relationship between the change in CAVI and changes in other variables. Multivariate logistic regression analysis identified high baseline CAVI, low HDL-cholesterol level, and bezafibrate administration as significant independent predictors of CAVI decrease.

    Conclusion: Bezafibrate treatment ameliorates arterial stiffness accompanied by improvement of glycolipid metabolism and oxidative stress. These effects potentially have important beneficial health consequences in hypertriglyceridemic patients with type 2 diabetes.

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  • Ruka Yoshida, Hideki Ishii, Itsuro Morishima, Akihito Tanaka, Yasuhiro ...
    Article ID: 47654
    Published: 2018
    [Advance publication] Released: December 22, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Patients undergoing percutaneous coronary intervention (PCI) who require both oral anticoagulant (OAC) and antiplatelet therapy (APT) are exposed to a serious risk of bleeding. The aim of this study was to clarify the relationship among nutritional and inflammation status and long-term bleeding in patients requiring both OACs and APT after PCI.

    Methods: We performed PCI in 3,718 consecutive patients between April 2011 and March 2017, 302 of whom were treated with both OACs and APT. Patients were followed for up to 3 years for bleeding events, defined as the Bleeding Academic Research Consortium (BARC) class ≥3 bleeding. We retrospectively evaluated the ability of the Geriatric Nutritional Risk Index (GNRI) and high-sensitivity C-reactive protein (hs-CRP) to detect bleeding events.

    Results: During a median follow-up of 1,080 days, bleeding events were observed in 53 (17.5%) patients. Bleeding events were associated with a low GNRI (≤98) (hazard ratio [HR], 3.16; 95% confidence interval [CI], 1.84-5.45; p<0.0001) and hs-CRP level ≥2.5 mg/L (HR, 2.75; 95% CI, 1.61-4.78; p=0.0003). A low GNRI+high hs-CRP showed a 5.12-fold increase in the incidence of BARC class ≥3 bleeding (95% CI, 2.68-9.91; p<0.0001) compared with a normal GNRI+low hs-CRP. The addition of the GNRI and hs-CRP to the PRECISE-DAPT score improved C-statistics from 0.67 to 0.71 and enhanced the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI, 0.36, p<0.0001; IDI, 0.066, p<0.0001).

    Conclusions: The GNRI and hs-CRP were novel predictors of the long-term bleeding risk in patients requiring both OACs and APT after PCI.

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  • Tsuyoshi Nozue, Takeshi Takamura, Kazuki Fukui, Kiyoshi Hibi, Satoru K ...
    Article ID: 47621
    Published: 2018
    [Advance publication] Released: December 20, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Coronary computed tomography angiography (CCTA)-derived fractional flow reserve (FFRCT) accurately diagnoses ischemic lesions of intermediate stenosis severity. However, significant determinants of FFRCT have not been fully evaluated.

    Methods: This was a sub-analysis of the Treatment of Alogliptin on Coronary Atherosclerosis Evaluated by Computed Tomography-Based Fractional Flow Reserve trial. Thirty-nine diabetic patients (117 vessels) with intermediate coronary artery stenosis [percent diameter stenosis (%DS) <70%] in whom FFRCT was measured were included in this study. CCTA-defined, vessel-based volumetric and morphological characteristics of plaques were examined to determine their ability to predict FFRCT.

    Results: Patient-based, multivariate linear regression analysis showed that hemoglobinA1c, triglycerides, and the estimated glomerular filtration rate were significant independent factors associated with FFRCT. Vessel-based, univariate linear regression analysis showed that the total atheroma volume (r=−0.233, p=0.01) and the percentage atheroma volume (PAV) (r=−0.284, p=0.002) as well as %DS (r=−0.316, p=0.006) were significant determinants of FFRCT. Among the plaque components, significant negative correlations were observed between FFRCT and low- (r=−0.248, p=0.007) or intermediate-attenuation plaque volume (r=−0.186, p=0.045), whereas calcified plaque volume was not associated with FFRCT. In the left anterior descending coronary artery (LAD), the plaque volume of each component was associated with FFRCT.

    Conclusions: Plaque volume, PAV, and %DS were significant determinants of FFRCT. Plaque morphology, particularly in LAD, was associated with FFRCT in diabetic patients with intermediate coronary artery stenosis.

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  • Xuesen Cheng, Aimin Dang, Naqiang Lv, Tong Zhao
    Article ID: 45351
    Published: 2018
    [Advance publication] Released: December 15, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: This study was designed to analyze microparticles (MPs) from endothelial cells (EMPs) and immune cells from healthy individuals and paitents with Takayasu arteritis (TA), and any possible relationships between MPs and TA acitivity.

    Methods: MPs derived from the plasma of 51 subjects were analyzed, including 32 patients with TA and 19 healthy individuals. Flow cytometry was performed with Annexin (Anx)-V and antibodies against surface markers of endothelial cells (CD144), T cells (CD3), B cells (CD19), and monocytes (CD14).

    Results: The concentrations of total EMPs, AnxV+ EMPs and AnxV- EMPs were significantly increased when comparing patients with TA and healthy controls (54×103 vs. 32×103 MPs /ml, P=0.0004; 22×103 vs. 12×103 MPs /ml, P=0.0006; and 31×103 vs. 19×103 MPs /ml, P=0.0005), and comparing active TA patients with remission ones (85×103 vs. 45×103 MPs /ml, P=0.016; 39×103 vs. 14×103 MPs /ml, P=0.0092; and 47×103 vs.29×103 MPs /ml, P=0.0371). In addition, the concentrations of total EMPs (odds ratio [OR]=1.024, 95% confidence interval [CI]: 1.001 to 1.048, P=0.037), AnxV+(OR=1.089, 95%CI: 1.011 to 1.172, P=0.024), and AnxV- EMPs (OR=1.029, 95% CI: 1.002 to 1.056, P=0.034) were positively related to TA activity. With multiple linear regression analysis, platelet was associated with both total and AnxV- EMP concentrations independently, while erythrocyte sedimentation rate was independently correlated with AnxV+EMPs.

    Conclusion: Concentrations of endothelial microparticles are correlated with inflammation in Takayasu arteritis and may be useful markers to assess disease activity.

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  • Masato Nakamura, Junya Ako, Hidenori Arai, Atsushi Hirayama, Yoshitaka ...
    Article ID: 45583
    Published: 2018
    [Advance publication] Released: December 04, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aims: The EXPLORE-J study aimed to assess lipid management in patients hospitalized for acute coronary syndrome (ACS) and their cardiovascular risk despite undergoing standard therapy. Here, we focused on background characteristics of patients in the EXPLORE-J study to elucidate the current lipid-lowering therapy and its issues in Japan.

    Methods: In this multicenter, prospective, observational study (UMIN000018946), consecutive Japanese ACS patients who required hospitalization were registered between April 2015 and August 2016. Background and lipid profile data collected within 14 days of hospitalization were analyzed according to risk factors such as diabetes mellitus status.

    Results: In total, 1944 patients were analyzed (80.3% male). The mean and standard deviation (SD) age and body mass index of all patients were 66.0 years (SD: 12.2) and 24.24 kg/m2 (SD: 3.59), respectively. The most common lipid-modifying medication used at the time of ACS was statins (27.3%). The low-density lipoprotein cholesterol (LDL-C) level (first measurement after hospitalization) of patients overall was 121.3 mg/dL (SD: 40.0); 30.3% had an LDL-C level 100 mg/dL (current target level for secondary prevention of cardiovascular events in Japan), compared with 52.1% of patients with a previous history of coronary artery disease (CAD), and 57.2% of patients with a history of diabetes.

    Conclusions: Many patients were not meeting Japanese LDL-C target levels at the time of ACS, and a large proportion of patients meeting target levels developed ACS; therefore, more stringent management and further evaluation of the target LDL-C levels is warranted in high-risk patients and those with previous history of CAD.

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  • Hanako Niki, Yoshimi Kishimoto, Susumu Ibe, Emi Saita, Kenji Sasaki, K ...
    Article ID: 46508
    Published: 2018
    [Advance publication] Released: December 04, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Betatrophin, a recently identified circulating adipokine, affects lipid and glucose metabolism. However, association between plasma betatrophin levels and atherosclerotic diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD), has not been elucidated.

    Methods: We investigated plasma betatrophin levels in 457 patients undergoing elective coronary angiography who also had ankle-brachial index (ABI) test for PAD screening.

    Results: Of the 457 study patients, CAD was present in 241 patients (53%) (1-vessel [1-VD], n=99; 2-vessel [2-VD], n=71; 3-vessel disease [3-VD], n=71). Compared to 216 patients without CAD, 241 with CAD had higher betatrophin levels (median 1120 vs. 909 pg/mL, p<0.001). A stepwise increase in betatrophin levels was found depending on the number of >50% stenotic coronary vessels: 909 in CAD(-), 962 in 1-VD, 1097 in 2-VD, and 1393 pg/ml in 3-VD (p<0.001). Betatrophin levels correlated with the number of >25% stenotic segments (r=0.24,p<0.001). PAD (ABI<0.9) was found in 41 patients (9%). Plasma betatrophin levels were also significantly higher in 41 patients with PAD than in 416 without PAD (1354 vs. 981 pg/mL, p<0.001). In the multivariate analysis, betatrophin levels were not a factor for CAD, but they were a significant factor for 3-VD and PAD independent of atherosclerotic risk factors. The odds ratios for 3-VD and PAD were 1.06 (95%CI=1.01-1.11) and 1.07 (95%CI=1.01-1.13) for a 100-pg/mL increase in betatrophin levels, respectively (p<0.05).

    Conclusion: Plasma betatrophin levels were associated with the presence and severity of CAD and PAD, suggesting betatrophin has a role in atherosclerosis.

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