Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
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Review
  • Yuya Nakano
    Type: Review
    2020 Volume 27 Issue 5 Pages 397-405
    Published: May 01, 2020
    Released: May 01, 2020
    [Advance publication] Released: December 20, 2019
    JOURNALS FREE ACCESS

    Low birth weight (LBW) infants have higher risk of developing insulin resistance and its comorbidities later in life. The concept of “developmental origins of health and disease” suggests that intrauterine and postnatal environments have an important role in increasing these risks. The risk of such adult-onset diseases in LBW infants might be associated with adipose tissue maldevelopment including altered body composition and increased amount of visceral fat, which is the same mechanism as that in children and adults with metabolic syndrome. However, LBW infants often have different characteristics: they are not always overweight or obese over their life course. The inconsistency might be associated with the thrifty phenotype, which is produced in response to impaired growth potential and decreased lean body mass. LBW infants tend to be obese within the limits of impaired growth potential. Through our previous investigations evaluating longitudinal changes in adiponectin levels at an early stage of life, we speculated that probably, the intrauterine life of term infants or the period up to term-equivalent age in preterm infants might be the key age for the development of adipose tissues including fat cells. Because of that, we hypothesized that the smaller number of adipocytes in LBW infants might be associated with overloading of single adipocytes and impaired adipose tissue expandability. The possible mechanisms are discussed from the perspective of adipose tissue maldevelopment in LBW infants.

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Editorial
Original Article
  • Hiroshi Yoshida, Hayato Tada, Kumie Ito, Yoshimi Kishimoto, Hidekatsu ...
    Type: Original Article
    2020 Volume 27 Issue 5 Pages 409-417
    Published: May 01, 2020
    Released: May 01, 2020
    [Advance publication] Released: September 05, 2019
    JOURNALS FREE ACCESS

    Aims: The present study was conducted to establish a practical method for measuring non-cholesterol sterols and reference intervals of serum levels.

    Methods: Healthy subjects (109 men and 151 women), four patients with sitosterolemia, and 10 heterozygous mutation carriers of ABCG5/ABCG8 genes were investigated. Then, three non-cholesterol sterols (sitosterol, campesterol, and lathosterol) of fasting serum samples were measured via a practical and highly sensitive gas chromatography (GC) method with 0.2 µg/mL as the lower limit of quantification. The coefficient of variation (CV) values for within-run reproducibility were 3.06%, 1.89%, and 1.77% for lathosterol, campesterol, and sitosterol, respectively. The CV values for between-run reproducibility were 2.81%, 2.06%, and 2.10% for lathosterol, campesterol, and sitosterol, respectively.

    Results: The serum levels of sitosterol and campesterol were significantly higher in women than in men, whereas the serum levels of lathosterol were significantly higher in men than in women. Because of these gender difference, the determination of reference intervals of the three sterol values was performed by considering gender. The reference intervals of sitosterol, campesterol, and lathosterol were 0.99–3.88, 2.14–7.43, and 0.77–3.60 µg/mL in men and 1.03–4.45, 2.19–8.34, and 0.64–2.78 µg/mL in women, respectively. The serum levels of sitosterol and campesterol were higher in patients with sitosterolemia (94.3±47.3 and 66.3±36.6 µg/mL, respectively) than in healthy subjects.

    Conclusion: These results demonstrate a practical and highly sensitive GC method to measure non-cholesterol sterol levels and gender-segregated reference intervals of sitosterol, campesterol, and lathosterol in Japanese healthy subjects.

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  • Zhibin Li, Chunmei He, Yongwen Liu, Dongmei Wang, Mingzhu Lin, Changqi ...
    Type: Original Article
    2020 Volume 27 Issue 5 Pages 418-428
    Published: May 01, 2020
    Released: May 01, 2020
    [Advance publication] Released: September 13, 2019
    JOURNALS FREE ACCESS

    Aim: We aimed to explore the independent associations of serum Fetuin-B and common genetic variants in FETUB locus with subclinical atherosclerosis.

    Methods: A cross-sectional study of 1,140 obese adults, who underwent serum Fetuin-B testing, hepatic ultrasonography scanning, genotyping on four tagging single nucleotide polymorphisms (SNPs) in FETUB locus and atherosclerosis detection, was conducted in Xiamen, China.

    Results: Increasing tertiles of brachial ankle pulse wave velocity (ba-PWV) were significantly associated with higher prevalence of nonalcoholic fatty liver disease (NAFLD) (48.8%, 61.5%, and 70.5% for tertiles of 1–3, respectively, p<0.001) and serum Fetuin-B (3.85±1.39, 4.09±1.40, and 4.27±1.46 µg/ml, p=0.047). Multivariable linear regression analyses with adjustment for potential confounding factors, even NAFLD per se, showed that serum Fetuin-B were significantly and positively associated with ba-PWV, with standardized regression coefficients (β) ranging from 0.055 to 0.075 (all p-values <0.05) in different models. However, the significant relationship between serum Fetuin-B and ba-PWV disappeared with further adjustment for insulin resistance. Serum Fetuin-B was not significantly associated with ankle-brachial index (ABI). All genotypes of the four tested FETUB tagging SNPs were not significantly associated with either ba-PWV or ABI with adjustment for potential confounding factors.

    Conclusion: Serum Fetuin-B was positively associated with ba-PWV and may link liver fat accumulation to subclinical atherosclerosis via insulin resistance.

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  • Yongin Cho, Hyangkyu Lee, Hyun Ki Park, Eun Yeong Choe, Hye Jin Wang, ...
    Type: Original Article
    2020 Volume 27 Issue 5 Pages 429-440
    Published: May 01, 2020
    Released: May 01, 2020
    [Advance publication] Released: September 13, 2019
    JOURNALS FREE ACCESS

    Aim: Most statins increase the risk of new-onset diabetes. Unlike other statins, pitavastatin is reported to exert neutral effects on serum glucose level, but the precise mechanism is unknown.

    Methods: Eight-week-old male C57BL/6J mice (n=26) were fed high-fat diet (HFD, 45% fat) with 0.01% placebo, rosuvastatin, or pitavastatin for 12 weeks. Cultured HepG2, C2C12, and 3T3-L1 cells and visceral adipocytes from HFD-fed mice were treated with vehicle or 10 µM statins for 24 h. The effects of pitavastatin and rosuvastatin on intracellular insulin signaling and glucose transporter 4 (GLUT4) translocation were evaluated.

    Results: After 12 weeks, the fasting blood glucose level was significantly lower in pitavastatin-treated group than in rosuvastatin-treated group (115.2±7.0 versus 137.4±22.3 mg/dL, p=0.024). Insulin tolerance significantly improved in pitavastatin-treated group as compared with rosuvastatin-treated group, and no significant difference was observed in glucose tolerance. Although plasma adiponectin and insulin levels were not different between the two statin treatment groups, the insulin-induced protein kinase B phosphorylation was weakly attenuated in pitavastatin-treated adipocytes than in rosuvastatin-treated adipocytes. Furthermore, minor attenuation in insulin-induced GLUT4 translocation to the plasma membrane of adipocytes was observed in pitavastatin-treated group.

    Conclusion: Pitavastatin showed lower diabetogenic effects than rosuvastatin in mice that may be mediated by minor attenuations in insulin signaling in adipocytes.

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  • Ivo N. SahBandar, Lishomwa C. Ndhlovu, Katelyn Saiki, Lindsay B. Koho ...
    Type: Original Article
    2020 Volume 27 Issue 5 Pages 441-448
    Published: May 01, 2020
    Released: May 01, 2020
    [Advance publication] Released: October 04, 2019
    JOURNALS FREE ACCESS

    Aims: Cardiovascular disease (CVD) remains the leading cause of death worldwide despite improvements in the treatment of atherosclerosis, an inflammatory disease and major underlying cause of CVD. Monocytes, an innate immune cell type, are linked to CVD progression; however, given their heterogeneity, the association between distinct monocyte subsets and increased risk of CVD remains unclear. This study investigated the association between peripheral monocyte subpopulation numbers and carotid intima-media thickness (cIMT), a sensitive measure of CVD risk, in a cohort of adults recruited from the general population.

    Methods: We used clinical data and peripheral blood mononuclear cell (PBMC) specimens from 67 individuals. cIMT was measured by high-resolution, B-mode, ultrasound images of the right carotid artery. PBMCs were stained with conjugated monoclonal antibodies to define monocyte subpopulations based on CD14 and CD16 co-expressions into classical (CD14++CD16), intermediate/inflammatory (CD14++CD16), and non-classical/patrolling (CD14low/+CD16++) monocytes.

    Results: We found a higher intermediate monocyte count was significantly correlated with increased right common carotid artery (RCCA) and right carotid bifurcation (RBIF) intima-media thickness (IMT) (p=0.004 and 0.006,respectively), even after adjusting for CVD-associated clinical data (p=0.006 and 0.004, respectively).

    Conclusion: Our study demonstrated a strong correlation between inflammatory monocyte counts and cIMT. These results suggest that, in the general population, there is a relationship between intermediate monocyte expansion and elevated predictors for CVD risk, and intermediate monocytes may be involved in the development of atherosclerosis and metabolic diseases. Strategies targeting inflammatory monocytes may be needed to slow CVD progression.

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  • Naohisa Hosomi, Kazuo Kitagawa, Yoji Nagai, Yoko Nakagawa, Shiro Aoki, ...
    Type: Original Article
    2020 Volume 27 Issue 5 Pages 449-460
    Published: May 01, 2020
    Released: May 01, 2020
    [Advance publication] Released: September 18, 2019
    JOURNALS FREE ACCESS

    Aims: To understand the different influences of statins on the incidence rate of each stroke subtype in association with low-density lipoprotein (LDL) cholesterol levels, we performed a post hoc analysis on the data from the Japan Statin Treatment Against Recurrent Stroke (J-STARS) study.

    Methods: Subjects (n=1,578) were divided into three groups according to their mean postrandomized LDL cholesterol level (<100, 100–120, and ≥ 120 mg/dL) until the last observation before the event or the end of follow-up. A Cox proportional hazard model for time to events was used for calculating adjusted hazard ratios, 95% confidence intervals, and the trend tests.

    Results: The event rates for atherothrombotic stroke did not decrease in accordance with the postrandomized LDL cholesterol level subgroups of either the control or the pravastatin group (p=0.15 and 0.33 for the trend, respectively). In the control group, however, no atherothrombotic stroke event was observed in the subgroup of the low postrandomized LDL cholesterol level (less than 100 mg/dL). The event rates for atherothrombotic stroke were lower in the middle postrandomized LDL cholesterol level subgroup (100–120 mg/dL) of the pravastatin group than that of the control group. The event rates for lacunar stroke decreased in the lower postrandomized LDL cholesterol level subgroup of the control group but not of the pravastatin group (p=0.004 and 0.06 for the trend, respectively).

    Conclusions: Statins showed different influences on the risks of atherothromobotic and lacunar stroke according to postrandomized LDL cholesterol levels.

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  • Sung Keun Park, Min-Ho Kim, Eunhee Ha, Ju Young Jung, Chang-Mo Oh, Joo ...
    Type: Original Article
    2020 Volume 27 Issue 5 Pages 461-470
    Published: May 01, 2020
    Released: May 01, 2020
    [Advance publication] Released: September 27, 2019
    JOURNALS FREE ACCESS

    Aim: Chronic kidney disease, evaluated by the estimated glomerular filtration rate (eGFR), is an established risk factor for cardiovascular disease. However, the association between renal function stratified by the eGFR and the risk of incident ischemic heart disease (IHD) in a community-based Asian population is still inconclusive. Study design: Retrospective longitudinal observational study.

    Method: In data from 206,919 Korean patients registered in the National Health Insurance Corporation (NHIC), we analyzed the risk of incident IHD according to the quartiles (Q) of eGFR (ml/min/1.73 m2) (Q1 <71.07, Q2: 71.07–83.16, Q3: 83.17–95.49, Q4 >95.50). The identification of IHD was based on the International Classification of Diseases (ICD) for IHD (ICD code: I20–I25) registered in the NHIC. The Cox proportional hazards model was used to calculate the adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for IHD according to quartile groups of eGFR levels.

    Results: Q1 had the more unfavorable baseline metabolic conditions than the other quartile groups. Considering Q4 as the reference, the unadjusted HRs (95% CIs) for IHD increased significantly in the order of Q3 (1.42 [1.29–1.56]), Q2 (1.51 [1.38–1.67]), and Q1 (2.11 [1.93–2.30]), and fully adjusted HRs (95% CIs) increased significantly from Q2 (1.15 [1.04–1.27]) to Q1 (1.31 [1.18–1.44]).

    Conclusion: The risk of IHD increased significantly from individuals with an eGFR ≤ 83.16. Mildly decreased renal function is a potential risk factor for IHD.

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  • Shinji Koba, Ikuo Inoue, Marcoli Cyrille, Chen Lu, Hyoe Inomata, Junic ...
    Type: Original Article
    2020 Volume 27 Issue 5 Pages 471-484
    Published: May 01, 2020
    Released: May 01, 2020
    [Advance publication] Released: November 21, 2019
    JOURNALS FREE ACCESS

    Aim: In patients with hyperlipidemia, intolerance to statins presents a challenge in reducing the risk of events associated with cardiovascular disease. This phase 3, randomized, double-blind trial in Japanese patients with statin intolerance aimed to evaluate the efficacy and safety of evolocumab vs. ezetimibe in lowering low-density lipoprotein-cholesterol (LDL-C).

    Methods: This study was conducted in a 12-week, double-blind period followed by an open-label extension designed to characterize 1 year of evolocumab treatment. Statin intolerance was defined as failure of two or more statins due to myalgia, myositis, or rhabdomyolysis. Eligible patients were randomized at 2:2:1:1 into four groups: 420 mg evolocumab every 4 weeks (Q4W)+oral placebo daily, 140 mg evolocumab every 2 weeks (Q2W)+oral placebo daily, subcutaneous (SC) placebo Q4W+10 mg ezetimibe daily, and SC placebo Q2W+ 10 mg ezetimibe daily.

    Results: Sixty-one patients were randomized to evolocumab (n=40) or ezetimibe (n=21). For the co-primary endpoints of percent change from the baseline in mean LDL-C to the mean of weeks 10 and 12 and to week 12, the evolocumab-ezetimibe treatment differences were −39.4% (95% CI, −47.2% to −31.5%) and −40.1% (95% CI, −48.7% to −31.6%), respectively (adjusted p<0.0001). The most common adverse events were diarrhea (9.5%) and nasopharyngitis (12.5%) in the ezetimibe and evolocumab groups, respectively, during the double-blind period and nasopharyngitis (29%) during the open-label extension.

    Conclusion: Evolocumab was superior to ezetimibe in reducing LDL-C during the 12-week double-blind period in this population of Japanese patients with statin intolerance, with efficacy and safety results maintained for 1 year.

    Trial registration: ClinicalTrials.gov, NCT02634580

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