Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Volume 26 , Issue 2
Showing 1-12 articles out of 12 articles from the selected issue
  • Yoko Yoshida, Hideki Kato, Yoichiro Ikeda, Masaomi Nangaku
    2019 Volume 26 Issue 2 Pages 99-110
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: November 02, 2018

    Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy (TMA) defined by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. aHUS is caused by uncontrolled complement activation in the alternative pathway (AP). A variety of genetic defects in complement-related factors or acquired autoantibodies to the complement regulators have been found in 50 to 60% of all cases. Recently, however, the classification and diagnosis of aHUS are becoming more complicated. One reason for this is that some factors, which have not been regarded as complement-related factors, have been reported as predisposing factors for phenotypic aHUS. Given that genotype is highly correlated with the phenotype of aHUS, careful analysis of underlying genetic abnormalities or acquired factors is needed to predict the prognosis or to decide an optimal treatment for the disease. Another reason is that complement dysregulation in the AP have also been found in a part of other types of TMA such as transplantation-related TMA and pregnancy-related complication. Based on these findings, it is now time to redefine aHUS according to the genetic or acquired background of abnormalities.

    Here, we review the pathogeneses and the corresponding phenotypes of aHUS and complement-related TMAs.

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  • Ryuji Toh
    2019 Volume 26 Issue 2 Pages 111-120
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: December 12, 2018

    While there is a controversy regarding the causal relationship between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD), recent studies have demonstrated that the cholesterol efflux capacity (CEC) of HDL is associated with the incidence of CVD. However, there are several limitations to current assays of CEC. First, CEC measurements are not instantly applicable in clinical settings, because CEC assay methods require radiolabeled cholesterol and cultured cells, and these procedures are time consuming. Second, techniques to measure CEC are not standardized. Third, the condition of endogenous cholesterol donors would not be accounted for in the CEC assays. Recently, we established a simple, high-throughput, cell-free assay system to evaluate the capacity of HDL to accept additional cholesterol, which is herein referred to as “cholesterol uptake capacity (CUC)”. We demonstrated that CUC represents a residual cardiovascular risk in patients with optimal low-density lipoprotein cholesterol control independently of traditional risk factors, including HDL-C. Establishing reproducible approaches for the cholesterol removal capacity of HDL is required to validate the impact of dysfunctional HDL on cardiovascular risk stratification in the “real world”.

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  • Yasushi Ishigaki, Naoki Kawagishi, Yutaka Hasegawa, Shojiro Sawada, Hi ...
    2019 Volume 26 Issue 2 Pages 121-127
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: December 15, 2018

    Pharmacological treatments to decrease low-density lipoprotein (LDL) cholesterol (LDL-C) have limited effects on patients with homozygous familial hypercholesterolemia (HoFH). Since LDL receptors are located mainly in the liver, liver transplantation is considered to be the only way to correct the hepatic cholesterol metabolism abnormalities in HoFH. Liver transplantations, including those combined with heart transplantation, for HoFH have been increasing since 1984, making this a globally established therapeutic option for HoFH. Plasma LDL-C is reported to be dramatically lowered, by 80%, after transplantation, with the rapid regression of cutaneous and tendinous xanthomas. However, long-term cardiovascular benefits remain unclear. The major concerns about liver transplantation include surgical complications, the need for lifelong immunosuppressive therapy, and rejection. In addition, organ transplantations from deceased donors are extremely rare in Japan. We experienced two pediatric siblings with HoFH who received living-donor liver transplantations from their heterozygous parents. Their plasma LDL-C levels decreased immediately and stabilized at approximately 200 mg/dL. Both developed normally with the administration of lipid-lowering medications and have been free of severe problems for more than 10 years, to date, since transplantation. In Japan, where the shortage of deceased donors is critical, the combination of living-donor liver transplant from a heterozygous donor, that is, usually a parent, and medication is regarded as a valid therapeutic option for HoFH. Further studies and clinical experience are required to establish liver transplantation as a safe and effective treatment for HoFH.

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Original Article
  • Yihui Liu, Jiang Xu, Wanyun Tao, Rong Yu, Xinjiang Zhang
    2019 Volume 26 Issue 2 Pages 136-144
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: June 15, 2018

    Aim: Dyslipidemia is the most common lipid metabolism disorder in humans, and its etiology remains elusive. Hypertriglyceridemia (HTG) is a type of dyslipidemia that contributes to atherosclerosis and coronary heart disease. Previous studies have demonstrated that mutations in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1(LMF1), and glycerol-3 phosphate dehydrogenase 1 (GPD1) are responsible for HTG by using genomic microarrays and next-generation sequencing. The aim of this study was to identify genetic lesions in patients with HTG.

    Method: Our study included a family of seven members from Jiangsu province across three generations. The proband was diagnosed with severe HTG, with a plasma triglyceride level of 38.70 mmol/L. Polymerase chain reaction (PCR) and Sanger sequencing were performed to explore the possible causative gene mutations for this patient. Furthermore, we measured the post-heparin LPL and hepatic lipase (HL) activities using an antiserum inhibition method.

    Results: A compound heterozygous mutation in the LMF1 gene (c.257CT/p.P86L and c.1184CT/p.T395I) was identified and co-segregated with the affected patient in this family. Both mutations were predicted to be deleterious by three bioinformatics programs (Polymorphism Phenotyping-2, Sorting Intolerant From Tolerant, and MutationTaster). The levels of the plasma post-heparin LPL and HL activities in the proband (57 and 177 mU/mL) were reduced to 24% and 75%, respectively, compared with those assayed in the control subject with normal plasma triglycerides.

    Conclusion: A compound heterozygous mutation of LMF1 was identified in the presenting patient with severe HTG. These findings expand on the spectrum of LMF1 mutations and contribute to the genetic diagnosis and counseling of families with HTG.

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  • Chika Okada, Hironori Imano, Kazumasa Yamagishi, Renzhe Cui, Mitsumasa ...
    2019 Volume 26 Issue 2 Pages 145-153
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: June 13, 2018

    Aims: The frequency of breakfast intake has been reported to be inversely associated with the risk of cardiovascular events; however, it is uncertain what the impact of the energy and nutrient intakes from breakfast are. We assessed the association between these intakes from breakfast and the risk of stroke prospectively.

    Methods: In a baseline survey of four Japanese communities between 1981 and 1990, we enrolled 3 248 residents (1 662 men and 1 586 women) aged 40–59 years who were free from stroke and heart disease and who responded to the 24-hour dietary recall survey. We assessed the dietary intake at breakfast, lunch, dinner, and other times separately.

    Results: During the median 25-year follow-up, 230 individuals (147 men and 83 women) developed stroke. After adjustment for age, community, other dietary intakes, and lifestyle and physiological factors, the multivariable-adjusted hazard ratios (95% confidence intervals) of intracerebral hemorrhage for the highest versus lowest quartiles of energy intake from breakfast were 0.38 (0.15–0.99) in men and 1.36 (0.36–5.10) in women. For the major nutrients, a higher saturated or monounsaturated fat intake at breakfast was associated with a reduced risk of intracerebral hemorrhage in men, and remained statistically significant after further adjustment for intake of other major nutrients from breakfast.

    Conclusions: A higher intake of energy from breakfast, primarily saturated or monounsaturated fat, was associated with a reduced risk of intracerebral hemorrhage in Japanese men.

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  • Shizuya Yamashita, Daisaku Masuda, Hidenori Arai, Yuji Matsuzawa
    2019 Volume 26 Issue 2 Pages 154-169
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: May 18, 2018

    Aims: To gain a more accurate understanding of the current real-world management of dyslipidemia in Japan, an online survey was conducted in a variety of physicians from five medical fields.

    Methods: A web-based survey with online questionnaire was designed, and members of an on-line information service for physicians were invited to participate. The survey enrolled 500 physicians, 100 in each of five categories: cardiology; diabetes, metabolism and endocrinology; neurology/neurosurgery/stroke medicine; general internal medicine (hospitals ≥20 beds), and general internal medicine (self-employed practitioners at clinics or small hospitals ≤19 beds).

    Results: Regardless of their specialties, most physicians recognized high low density lipoprotein cholesterol level as an important risk for atherosclerotic cardiovascular disease. Physicians with expertise in cardiology, diabetes, metabolism and endocrinology were most in favor of drug-based cholesterol lowering. Specialists in neurology/neurosurgery/stroke medicine and in general internal medicine were more concerned about statin safety and aggressive lipid-lowering therapy than those in cardiology and diabetes, metabolism and endocrinology, and tended to treat fewer patients with familial hypercholesterolemia (FH). Especially, those in general internal medicine (self-employed practitioners at clinics or small hospitals ≤19 beds) made less use of techniques for diagnosing FH.

    Conclusions: Awareness of target values for lipid management and of adverse reactions to drug therapy appears to vary somewhat depending on the participant's medical specialty. We also found that FH is probably underdiagnosed in Japan today. Further educations on proper diagnosis and management of dyslipidemia are required for physicians who are not specialized in cardiovascular health.

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  • Yukiko Okami, Hirotsugu Ueshima, Yasuyuki Nakamura, Nagako Okuda, Hide ...
    2019 Volume 26 Issue 2 Pages 170-182
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: June 09, 2018

    Aim: The positive relationship between dietary cholesterol and serum cholesterol has been questioned by a set of recent cohort studies. This study aimed to investigate how employment status and education years relate to the association between dietary cholesterol and serum low-density lipoprotein cholesterol (LDL-C) in a Japanese population.

    Methods: A population-based, random sample, cross-sectional study (INTERLIPID) was performed. Among 1,145 Japanese individuals aged 40-59 years, 106 were excluded because of special diets, use of lipid-lowering drugs, hormone replacement, and missing data, leaving 1,039 individuals (533 men and 506 women). Dietary cholesterol was assessed from four 24-h dietary recalls, and LDL-C was measured enzymatically with an auto-analyzer. A standard questionnaire inquired about employment status and education years.

    Results: In men, a 1 standard deviation (SD) higher dietary cholesterol was associated with 3.16 mg/dL lower serum LDL-C (P=0.009; unadjusted model). After adjustment for covariates, higher serum LDL-C was estimated per 1 SD higher intake of dietary cholesterol in nonemployed men [self-employed, homemakers, farmers, fishermen, and retired employees; β=+9.08, 95% confidence interval (CI)=+0.90-+17.27] and less educated men (β=+4.46, 95% CI=-0.97-+9.90), whereas an inverse association was observed in employed men (β=-3.02, 95% CI=-5.49--0.54) and more educated men (β=-3.66, 95% CI=-6.25--1.07).

    Conclusions: In men who were nonemployed and less educated, a higher intake of dietary cholesterol was associated with elevated concentrations of serum LDL-C, whereas an inverse association was observed in men who were employed and more educated.

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  • Hiroyuki Takahashi, Takashi Nomiyama, Yuichi Terawaki, Takako Kawanami ...
    2019 Volume 26 Issue 2 Pages 183-197
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: June 30, 2018

    Aims: Recently, incretin therapy has attracted increasing attention because of its potential use in tissue-protective therapy. Neuron-derived orphan receptor 1 (NOR1) is a nuclear orphan receptor that regulates vascular smooth muscle cell (VSMC) proliferation. In the present study, we investigated the vascular-protective effect of Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, by inhibiting NOR1 expression in VSMCs.

    Methods: We classified 7-week-old male 129X1/SvJ mice into control group and Ex-4 low- and high-dose-treated groups fed normal or high-fat diets, respectively. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by the evaluation of neointima formation at 12 weeks of age. To evaluate VSMC proliferation, bromodeoxyuridine incorporation assay and cell cycle distribution analysis were performed. NOR1 and cell cycle regulators were detected using immunohistochemistry, western blotting, quantitative reverse-transcription polymerase chain reaction, and luciferase assays.

    Results: Ex-4 treatment reduced vascular injury-induced neointima formation compared with controls. In terms of VSMCs occupying the neointima area, VSMC numbers and NOR1-expressing proliferative cells were significantly decreased by Ex-4 in a dose-dependent manner in both diabetic and non-diabetic mice. In vitro experiments using primary cultured VSMCs revealed that Ex-4 attenuated NOR1 expression by reducing extracellular signal-regulated kinase-mitogen-activated protein kinase and cAMP-responsive element-binding protein phosphorylations. Furthermore, in the cell cycle distribution analysis, serum-induced G1–S phase entry was significantly attenuated by Ex-4 treatment of VSMCs by inhibiting the induction of S-phase kinase-associated protein 2.

    Conclusion: Ex-4 attenuates neointima formation after vascular injury and VSMC proliferation possibly by inhibiting NOR1 expression.

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  • Ayako Kurihara, Tomonori Okamura, Daisuke Sugiyama, Aya Higashiyama, M ...
    2019 Volume 26 Issue 2 Pages 198-206
    Published: February 01, 2019
    Released: February 01, 2019
    [Advance publication] Released: August 09, 2018

    Aim: To examine the relationship between the intake of dietary vegetable protein and CVD mortality in a 15-year follow-up study of a representative sample of the Japanese population.

    Methods: A total of 7,744 participants aged 30 years or older (3,224 males and 4,520 females) who were free of CVD at baseline were included in this analysis. Vegetable protein intake (% energy) was assessed using a three-day semi-weighed dietary record at baseline. Multivariable-adjusted hazard ratios (HRs) were calculated using Cox's proportional hazards model after adjusting for confounding factors.

    Results: The total person-years studied were 107,988 with a mean follow-up period of 13.9 years. There were 1,213 deaths during the follow-up period, among which 354 (29.2%) were due to CVD. Vegetable protein intake was associated inversely with CVD and cerebral hemorrhage mortality, with the HRs for a 1% energy increment in vegetable protein intake being 0.86 (95% CI, 0.75–0.99) and 0.58 (95% CI, 0.35–0.95), respectively. In the subgroup analysis of participants with or without hypertension, the inverse association between vegetable protein intake and CVD mortality was more evident in the nonhypertensive group, with the HRs for CVD and stroke being 0.68 (95% CI, 0.50–0.94) and 0.50 (95% CI, 0.30–0.84), respectively.

    Conclusions: Vegetable protein intake may prevent future CVD, particularly in nonhypertensive subjects in the Japanese population. However, further studies are necessary to examine the biological mechanisms of this effect.

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