Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
早期公開論文
早期公開論文の109件中1~50を表示しています
  • Tomonori Sugiura, Yasuaki Dohi, Yasuyuki Takagi, Takashi Yokochi, Naof ...
    原稿種別: Original Article
    論文ID: 59857
    発行日: 2020年
    [早期公開] 公開日: 2020/11/25
    ジャーナル オープンアクセス 早期公開

    Aims: Small arteries can be visualized in the ocular fundus, and findings of retinopathy based on Scheie classification are often applied to evaluate the impact of hypertension and atherosclerosis. However, the relationship between damage in the large and small arteries has not been investigated sufficiently, especially in the early stages. The present study investigated possible associations between large artery atherosclerosis and small artery retinopathy in untreated middle-aged individuals.

    Methods: Untreated middle-aged workers undergoing periodic health check-ups (n=7,730, 45±8 years) were enrolled in this study. The absence or presence and extent of retinopathy were characterized by ophthalmologists as hypertensive (H0-4) and atherosclerotic grades (S0-4) based on Scheie classification. Large artery atherosclerosis was examined based on functional assessment of the cardio-ankle vascular index (CAVI) and morphological assessment of the carotid intima-media thickness (IMT) by ultrasound.

    Results: We found significant differences in CAVI and carotid IMT between individuals with and without hypertensive or atherosclerotic retinopathy. Multivariable regression analysis showed that the presence of hypertensive and atherosclerotic retinopathy was significantly associated with CAVI and carotid IMT. Logistic regression analysis with the endpoint of a hypertensive or atherosclerotic lesion revealed that CAVI and carotid IMT are independent determinants of retinopathy.

    Conclusions: CAVI and carotid IMT were significantly associated with the presence of retinopathy based on Scheie classification in untreated middle-aged subjects, implying that atherosclerotic examination in large arteries could reveal early-stage small artery retinopathy.

  • Masayasu Yoneda, Mitsunobu Kubota, Hiroshi Watanabe, Genshi Egusa
    原稿種別: Review
    論文ID: RV17046
    発行日: 2020年
    [早期公開] 公開日: 2020/11/25
    ジャーナル オープンアクセス 早期公開

    Japanese Americans include Japanese individuals migrating from Japan to the United States (first-generation Japanese Americans [JA-1]) and their offspring (second- or later-generation Japanese Americans [JA-2]). Although Japanese Americans share their genetic predisposition with the Japanese, their lifestyles have been westernized rapidly and extensively. We conducted a medical survey for atherosclerosis among Japanese Americans living in Hawaii and Los Angeles and native Japanese living in Hiroshima for 50 years since 1970 (the Hawaii–Los Angeles–Hiroshima Study) and obtained the following results:

    (1)In the 1990s, a westernized lifestyle induced hyperlipidemia among Japanese Americans, and based on the evaluation of the carotid artery intima-media wall thickness (IMT), atherosclerosis was apparently more advanced in Japanese Americans than in native Japanese. In addition, the advancement of atherosclerosis corresponded to the degree of westernization of lifestyles in JA-1 and JA-2.

    (2) In the 2010s, the serum total cholesterol and low-density lipoprotein cholesterol levels in native Japanese were significantly higher than those in Japanese Americans, and the difference in the progression of carotid artery IMT was smaller between native Japanese and Japanese Americans.

    (3)Maintaining a healthy Japanese lifestyle since childhood may suppress future worsening of risk factors for atherosclerosis (such as obesity and diabetes mellitus) and contribute to atherosclerosis prevention in the Japanese.

  • Hayato Tada, Soichiro Usui, Kenji Sakata, Masayuki Takamura, Masa-aki ...
    原稿種別: Review
    論文ID: 60087
    発行日: 2020年
    [早期公開] 公開日: 2020/11/21
    ジャーナル オープンアクセス 早期公開

    Precision or personalized medicine is currently gaining a lot of attention. Clinical evidence for its effectiveness has been established based on randomized clinical trials accounting for classical risk factors, such as hypertension, diabetes, and serum lipids. However, besides such classical risk factors, the genetic background should be considered, at least for heritable traits, including atherosclerotic cardiovascular disease (ASCVD). Such classical risk factors are almost always incidents that have already occurred in which it may be too late to start treatment, instead of indicators of presymptomatic state. Human genome information is associated with most traits, including ASCVD. Two methods of implementing precision medicine for ASCVD using human genome information are currently being investigated: the use of rare genetic variations that have large effect sizes and polygenic risk scores that are composed of multiple common genetic variations. This review article emphasizes the importance of clinical as well as genetic diagnoses when implementing precision medicine. Precision medicine should be considered based on comprehensive genetic analyses, encompassing rare to common genetic variations.

  • Ken-ichi Hirata
    原稿種別: Editorial
    論文ID: ED155
    発行日: 2020年
    [早期公開] 公開日: 2020/11/21
    ジャーナル オープンアクセス 早期公開
  • Takamitsu Nakamura, Manabu Uematsu, Takeo Horikoshi, Toru Yoshizaki, T ...
    原稿種別: Original Article
    論文ID: 57562
    発行日: 2020年
    [早期公開] 公開日: 2020/11/20
    ジャーナル オープンアクセス 早期公開

    Aim: To examine whether improvement in flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery and brachial-ankle pulse wave velocity (baPWV) has an additive effect on achieving optimal goals of traditional risk factors to reduce cardiovascular risk in patients with coronary artery disease (CAD).

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

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

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

  • Takuya Tsujimura, Mitsuyoshi Takahara, Osamu Iida, Shun Kohsaka, Yoshi ...
    原稿種別: Original Article
    論文ID: 60053
    発行日: 2020年
    [早期公開] 公開日: 2020/11/20
    ジャーナル オープンアクセス 早期公開

    Aim: The aim of the current study was to describe the clinical profile, frequency of in-hospital complications, and predictors of adverse events in patients undergoing endovascular therapy (EVT) for acute limb ischemia (ALI), and to compare them with those of patients undergoing EVT for chronic symptomatic peripheral artery disease (PAD).

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

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

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

  • Daisuke Kitano, Suguru Migita, Yuxin Li, Rie Takahashi, Yoshiki Tanigu ...
    原稿種別: Original Article
    論文ID: 56549
    発行日: 2020年
    [早期公開] 公開日: 2020/11/18
    ジャーナル オープンアクセス 早期公開

    Aim: According to recent clinical trials, a combination of direct oral anticoagulants with antiplatelet drugs is often recommended for atrial fibrillation patients who receive drug-eluting stents (DESs). Although the optimal combination comprises direct factor Xa inhibitors and a P2Y12 receptor antagonist (or aspirin), their influence on vascular responses to DESs remains unclear.

    Methods: Pigs were given either aspirin and clopidogrel (dual antiplatelet therapy [DAPT] group), aspirin and rivaroxaban (AR group), or clopidogrel and rivaroxaban (CR group), followed by everolimus-eluting stent (Promus Element) implantation into the coronary artery. Stented coronary arteries were evaluated via intravascular optical coherence tomography (OCT) and histological analysis at 1 and 3 months.

    Results: OCT revealed lower neointimal thickness in the DAPT group and comparable thickness among all groups at 1 and 3 months, respectively. Histological analyses revealed comparable neointimal area among all groups and the smallest neointimal area in the CR group at 1 and 3 months, respectively. In the DAPT and AR groups, the neointima continued to grow from 1 to 3 months. A shortened time course for neointima growth was observed in the CR group, with rapid growth within a month (maintained for 3 months). A higher incidence of in-stent thrombi was observed in the AR group at 1 month; no thrombi were found in either group at 3 months. More smooth muscle cells with contractile features were found in the CR group at both 1 and 3 months.

    Conclusions: Our results proved the noninferiority of the combination of rivaroxaban with an antiplatelet drug, particularly the dual therapy using rivaroxaban and clopidogrel, compared to DAPT after DES implantation.

  • Toru Miyoshi
    原稿種別: Editorial
    論文ID: ED148
    発行日: 2020年
    [早期公開] 公開日: 2020/11/18
    ジャーナル オープンアクセス 早期公開
  • Hyun Goo Kang, Chan-Hyuk Lee, Byoung-Soo Shin, Gyung Ho Chung, Hyo Sun ...
    原稿種別: Original Article
    論文ID: 58214
    発行日: 2020年
    [早期公開] 公開日: 2020/11/15
    ジャーナル オープンアクセス 早期公開

    Aim: Arterial narrowing associated with the progression of atherosclerosis leads to serious conditions such as stroke, coronary artery disease, or even death. High-resolution magnetic resonance imaging (HR-MRI) is better for detecting arterial wall status and discriminating tissue characteristics than conventional imaging. We used HR-MRI to investigate the frequency of patients with basilar artery (BA) stenosis observed distinctively on routine angiography and identify the clinical features associated with this imaging. We analyzed the nature of the vessel wall causing the basal artery stenosis by HR-MRI, and related clinical factors.

    Methods: Patients with BA stenosis underwent HR-MRI. The association between atherosclerosis (with or without intraplaque hemorrhage [IPH]) and dissection was analyzed. High signal intensity within a BA plaque on magnetization-prepared rapid acquisition with gradient echo was defined as an area with a signal intensity >200% that of the adjacent muscle.

    Results: Fifteen patients were diagnosed with BA dissection on HR-MRI. IPH was identified in 14 patients. Patients with BA plaque with IPH were older and had higher prevalence of hypertension and hyperlipidemia than the other patients. The frequencies of alcohol drinking and number of current smokers were higher in the dissection group than in the other groups. Hyperlipidemia was identified as an influencing factor for IPH development in atherosclerotic plaque. Young age was identified as the influencing factor for the occurrence of BA dissection.

    Conclusions: The etiology of stenosis or occlusion was unclear until the development of HR-MRI. With HR-MRI, stroke etiology is better understood, and factors affecting each etiology can be identified. Further studies that clarify the etiology of posterior circulation stroke are required.

  • Minami Imai, Mari Kawamura, Ikoi Kochi, Tetsuro Matsuoka, Shinji Kihar ...
    原稿種別: Original Article
    論文ID: 58784
    発行日: 2020年
    [早期公開] 公開日: 2020/11/15
    ジャーナル オープンアクセス 早期公開

    Aims: Cardiovascular diseases (CVD) are a global leading cause of mortality. However, few biomarkers are available to predict future coronary plaque rupture. We have recently demonstrated that low levels of anti-apolipoprotein B-100 autoantibody (anti-apo B-100 Ab) correlated with an increased CVD risk in Japanese patients with diabetes. In the present study, we examined the relationship between serum anti-apo B-100 Ab levels and coronary plaque characteristics in patients undergoing elective percutaneous coronary intervention (PCI).

    Methods: We conducted iMAP®-intravascular ultrasound (IVUS) in 88 Japanese male patients undergoing elective PCI, and the five consecutive slices of IVUS images at the center of the most stenotic culprit lesion were used for identifying the plaque characteristics. The serum levels of anti-apo B-100 Ab against synthetic peptides (p45 or p210) were measured using a homemade enzyme-linked immunosorbent assay.

    Results: Serum IgG levels of anti-apo B-100 Ab against both native p45 and p210 (IgGN-p45 and IgGN-p210) and malondialdehyde (MDA)-modified p45 and p210 (IgGMDA-p45 or IgGMDA-p210) showed a negative correlation with plaque burden in total male patients undergoing elective PCI. Additionally, both IgGN-p45 and IgGN-p210, but neither IgGMDA-p45 nor IgGMDA-p210, correlated negatively with necrotic and positively with fibrotic components of iMAP®-IVUS plaque characteristics in the patients with <1 month statin treatment before elective PCI (“statin-untreated” group). There was no significant correlation between anti-apo B-100 Ab and any plaque characteristics in the patients with statin treatment for 1 month or more before elective PCI (“statin-treated” group).

    Conclusion: Measuring serum levels of anti-apo B-100 Ab might be helpful in the evaluation of unstable coronary plaque in male CVD patients without statin treatment.

  • Makoto Fujita, Hiroyasu Yamamoto, Nao Yoshida, Runa Ono, Tetsuro Matsu ...
    原稿種別: Original Article
    論文ID: 58875
    発行日: 2020年
    [早期公開] 公開日: 2020/11/15
    ジャーナル オープンアクセス 早期公開

    Aim: Adiponectin (APN) exhibits different atheroprotective effects, and we have previously reported that APN function is modulated by its binding proteins, E-selectin ligand 1, Mac-2 binding protein, and cystatin C. In the present study, we aimed to identify a novel atheroprotective mechanism of APN via C-C motif chemokine 2 (CCL2).

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

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

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

  • Qi Zhao, Ting-Yu Zhang, Yu-Jing Cheng, Yue Ma, Ying-Kai Xu, Jia-Qi Yan ...
    原稿種別: Original Article
    論文ID: 59840
    発行日: 2020年
    [早期公開] 公開日: 2020/11/13
    ジャーナル オープンアクセス 早期公開

    Aim: The triglyceride-glucose index (TyG index) is proposed as a surrogate parameter for insulin resistance (IR) and, when elevated, is related to increased cardiovascular risks. Whether the TyG index is of great value in predicting adverse prognosis for individuals diagnosed with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), who received elective percutaneous coronary intervention (PCI), and without recognized diabetes remains unclear.

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

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

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

  • Takashi Hisamatsu
    原稿種別: Editorial
    論文ID: ED150
    発行日: 2020年
    [早期公開] 公開日: 2020/11/13
    ジャーナル オープンアクセス 早期公開
  • Meng-Huan Lei, Yu-Lin Wu, Sheng-Liang Chung, Chao-Chin Chen, Wei-Cheng ...
    原稿種別: Original Article
    論文ID: 59386
    発行日: 2020年
    [早期公開] 公開日: 2020/11/07
    ジャーナル オープンアクセス 早期公開

    Aims: Type 2 diabetes mellitus (T2DM) is no longer regarded as a coronary risk equivalent, and heterogeneity of cardiovascular risk exists, suggesting that further risk stratification should be mandatory. This study aimed to determine the prevalence and clinical predictors of coronary artery calcium (CAC) score, and evaluate the CAC score as a predictor of cardiovascular outcome in a large asymptomatic T2DM cohort.

    Methods: A total of 2,162 T2DM patients were recruited from a Diabetes Shared Care Network and the CAC score was measured. Cardiovascular outcomes were obtained for 1,928 patients after a follow-up of 8.4 years. Multiple regression analysis and Cox proportional hazard regression were applied to identify clinical predictors of CAC and calculate the incidence and hazard ratios (HRs) for all-cause mortality and cardiovascular events by CAC category.

    Results: Of the recruited patients, 96.8% had one or more risk factors. The distribution of CAC scores was as follows: CAC=0 in 24.2% of the patients, 0 <CAC ≤ 100 in 41.5%, 100 <CAC ≤ 400 in 20.3%, CAC >400 in 14.7%. The multivariable predictor of increased CAC included age (years) (odds ratio, 1.07; 95% confidence interval, 1.06–1.08), male sex (1.82; 1.54–2.17), duration (years) of T2DM (1.07; 1.05–1.09), and multiple risk factors (1.94; 1.28–2.95). Increasing severity of CAC was associated with higher all-cause or cardiac mortality and higher incident cardiovascular events. The HRs for cardiac death or major cardiac events in CAC >400 vs CAC=0 were 8.67 and 10.52, respectively (p<0.001)

    Conclusion: CAC scoring provides better prognostication of cardiovascular outcome than traditional risk factors in asymptomatic T2DM patients, and may allow identifying a high-risk subset for enhancing primary prevention.

  • Hisashi Adachi
    原稿種別: Editorial
    論文ID: ED149
    発行日: 2020年
    [早期公開] 公開日: 2020/11/07
    ジャーナル オープンアクセス 早期公開
  • A Report from the Asian Pacific Society of Atherosclerosis and Vascular Disease Asia-Pacific Peripheral Artery Disease Consensus Statement Project Committee
    Maria Teresa B Abola, Jonathan Golledge, Tetsuro Miyata, Seung-Woon Rh ...
    原稿種別: Erratum
    論文ID: ER53660
    発行日: 2020年
    [早期公開] 公開日: 2020/11/07
    ジャーナル オープンアクセス 早期公開
  • Chang-Mo Oh, Sung Keun Park, Ju Young Jung, Joong-Myung Choi, Eunhee H ...
    原稿種別: Original Article
    論文ID: 56143
    発行日: 2020年
    [早期公開] 公開日: 2020/11/06
    ジャーナル オープンアクセス 早期公開

    Aims: Although chronic kidney disease is recognized as an independent risk factor for cerebrovascular disease, its association with hemorrhagic and ischemic stroke remains controversial.

    Methods: We conducted a retrospective cohort study using the National Health Insurance Service-National Sample Cohort, which is representative of the Korean population. A total of 195,772 Koreans who were not diagnosed with stroke before 2009 were included in this study from 2009 to 2013. The eGFR was divided into six categories (≥ 90, 75–89, 60–74, 45–59, 30–44, <30 mL/min/1.73 m2). The Kaplan–Meier plot was illustrated to compare the incidence of stroke. Cox proportional hazard model was used to estimate the hazard ratio (HR) of eGFR for risk of ischemic and hemorrhagic stroke by sex.

    Results: During an average of 4.36 years of follow-up period, 2,236 and 668 people were diagnosed with newly ischemic and hemorrhagic stroke, respectively. Age-adjusted incidence rate for ischemic stroke among people with eGFR <45 mL/min/1.73 m2 was higher than those with eGFR ≥ 90 mL/min/1.73 m2, whereas that for hemorrhagic stroke among people with eGFR ≥ 90 mL/min/1.73 m2 was higher than those with eGFR <45 mL/min/1.73 m2. After adjusting for multiple covariates, the adjusted HR for ischemic stroke increased with decreasing eGFR in men (p for trend <0.001), but not in women (p for trend=0.48). On the other hand, there was no significant relationship between eGFR and risk of hemorrhagic stroke in both men and women.

    Conclusions: Reduced glomerular filtration rate less than 45 mL/min/1.73 m2 was associated with an increased risk of ischemic stroke, especially in men.

  • Yoshimi Kishimoto, Masayuki Aoyama, Emi Saita, Yukinori Ikegami, Reiko ...
    原稿種別: Original Article
    論文ID: 59899
    発行日: 2020年
    [早期公開] 公開日: 2020/10/30
    ジャーナル オープンアクセス 早期公開

    Aim: Kinin B1 receptor (KB1R) was shown to be up-regulated in human carotid atherosclerotic lesions. Serum KB1R levels were also reported to be high in patients with stroke. However, KB1R deficiency increased atherosclerotic lesions. Therefore, the role of KB1R in atherosclerosis remains unclear. Moreover, no study has reported blood KB1R levels in patients with coronary artery disease (CAD).

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

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

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

  • Marie Nakamura, Yasushi Yamamoto, Wataru Imaoka, Toshio Kuroshima, Ryo ...
    原稿種別: Original Article
    論文ID: 56838
    発行日: 2020年
    [早期公開] 公開日: 2020/10/28
    ジャーナル オープンアクセス 早期公開

    Aims: Smoking is a major risk factor for cardiovascular disease (CVD), a leading cause of death and disability. Other CVD risk factors include age, gender, hypertension, diabetes, increased low-density lipoprotein cholesterol (LDL-C) and decreased high-density lipoprotein cholesterol (HDL-C). Our goal was to assess relationships between smoking status and CVD risk factors, with a focus on direct LDL-C, HDL-C, triglycerides (TG) and small dense LDL-C (sdLDL-C).

    Methods: A total of 34,497 Japanese men and women, mean age 51 years, had their CVD risk factors including fasting serum total cholesterol, TG, HDL-C, sdLDL-C, and direct LDL-C assessed. One-way ANOVA and multiple linear regression analyses were carried to assess the interrelationships of these parameters with smoking.

    Results: In both men and women, current smokers had significantly (p<0.001) higher median TG (+19.6%, +16.9%) and sdLDL-C levels (+12.7%, +4.2%) levels, and significantly (p<0.001) lower HDL-C levels (-7.3%, -4.3%) than non-smokers. They were also significantly (p<0.05) more likely to have TG values >150 mg/dL (+56.8%, +116.3%), sdLDL-C >40.1 mg/dL (+28.8%, +44.9%), and HDL-C <40 mg/dL (+89.8%, +114.3%). Ex-smokers generally had lipid values that were intermediate between non-smokers and current smokers. Multivariate analysis confirmed the significance of these relationships.

    Conclusion: Our data indicate that current cigarette smoking is associated with increased TG and sdLDL-C levels, as well as decreased HDL-C levels. Furthermore, smoking effect on lipid profiles remain after cessation. These data provide further justification for smoking cessation.

  • Masaki Hayakawa, Keisuke Takano, Michinori Kayashima, Kei Kasahara, Hi ...
    原稿種別: Case Report
    論文ID: 58362
    発行日: 2020年
    [早期公開] 公開日: 2020/10/28
    ジャーナル オープンアクセス 早期公開

    Patients with severe COVID-19 often experience complications including coagulopathy and fatal thrombosis. COVID-19 pneumonia sometimes leads to acute respiratory distress syndrome, requiring extracorporeal membrane oxygenation (ECMO), during which thrombosis and bleeding are major causes of death. Anticoagulation such as heparin is essential for COVID-19 patients on ECMO; however, bleeding might be caused by not only heparin, but also acquired von Willebrand syndrome (AVWS). To date, no study has examined ECMO-related bleeding and AVWS in COVID-19 patients.

    We report a COVID-19 patient who experienced bleeding from AVWS in addition to disseminated intravascular coagulation (DIC) during ECMO. The level of high–molecular weight VWF multimers decreased during ECMO therapy, and these findings promptly improved after discontinuation of ECMO. Plasma levels of VWF antigen were extremely high, probably due to endothelial cell damage caused by COVID-19. On the other hand, plasma levels of ADAMTS13 activity were moderately reduced, to 20–30% of normal. The patient was successfully treated with cryoprecipitate in bleeding during ECMO without a reduction in heparin, which might have induced thromboembolism. Bleeding found in this patient might be caused by AVWS and DIC.

    Severe COVID-19 patients are in a thrombotic state and need to receive anticoagulant therapy. However, once they receive ECMO therapy, bleeding symptoms could be observed. In such cases, physicians should think of AVWS in addition to the side effect of heparin and DIC.

  • Tatsuya Maruhashi, Masato Kajikawa, Shinji Kishimoto, Yuji Takaeko, Ta ...
    原稿種別: Original Article
    論文ID: 59261
    発行日: 2020年
    [早期公開] 公開日: 2020/10/23
    ジャーナル オープンアクセス 早期公開

    Aims: Volume elastic modulus (VE), an index of arterial elasticity, and arterial diameter of the brachial artery can be automatically measured by a newly developed oscillometric device. We investigated the associations of VE with flow-mediated vasodilation (FMD), an index of endothelium-dependent vasodilation, nitroglycerine-induced vasodilation (NID), an index of endothelium-independent vasodilation, and intima-media thickness (IMT) of the brachial artery and association of oscillometrically measured brachial artery diameter with ultrasonographically measured brachial artery diameter in patients with cardiovascular risk factors.

    Methods: Oscillometric measurements of VE and brachial artery diameter and ultrasound measurements of brachial artery diameter, FMD, NID, and IMT of the brachial artery were performed in 50 patients with cardiovascular risk factors.

    Results: The mean values were 2.1±0.4 mmHg/% for VE, 0.31±0.05 mm for brachial IMT, 4.48±0.70 mm for oscillometric brachial artery diameter, and 4.30±0.55 mm for ultrasound brachial artery diameter. VE significantly correlated with brachial IMT (r=0.51, P<0.001), whereas there was no significant correlation of VE with FMD (r=-0.08, P=0.58) or NID (r=0.07, P=0.61). Multivariate analysis revealed that VE was significantly associated with brachial IMT (β=0.33, P=0.04). Oscillometric brachial artery diameter significantly correlated with ultrasound brachial artery diameter (r=0.79, P<0.001). The Bland-Altman plot showed good agreement between oscillometric brachial artery diameter and ultrasound brachial artery diameter (mean difference, -0.17 mm; limits of agreement, -1.03 mm to 0.69 mm).

    Conclusions: In patients with cardiovascular risk factors, VE may represent atherosclerotic structural alterations of the vascular wall but not vascular function. The accuracy of oscillometric measurement of brachial artery diameter is acceptable.

  • Amane Kozuki, Mitsuyoshi Takahara, Masahiro Shimizu, Yoichi Kijima, Ry ...
    原稿種別: Original Article
    論文ID: 59774
    発行日: 2020年
    [早期公開] 公開日: 2020/10/23
    ジャーナル オープンアクセス 早期公開

    Aim: The predictors of restenosis after endovascular therapy (EVT) with paclitaxel drug-coated balloons (DCBs) have not been clearly established. The present study aimed to investigate the association of post-procedural dissection, as evaluated using intravascular ultrasound (IVUS), with the risk of restenosis following femoropopliteal EVT with paclitaxel DCBs.

    Methods: In the present single-center retrospective study, 60 de novo femoropopliteal lesions (44 patients) that underwent EVT with DCBs, without bail-out stenting, were enrolled. The primary outcome was 1-year primary patency. Risk factors for restenosis were evaluated using a Cox proportional hazards regression model and random survival forest analysis.

    Results: The 1-year primary patency rate was 57.2% [95% confidence interval, 45%–72%]. IVUS-evaluated post-procedural dissection was significantly associated with the risk of restenosis (P=0.002), with the best cutoff point of 64º [range, 39º–83º]. The random survival forest analysis showed that the variable importance measure of IVUS-evaluated dissection was significantly lower than that of the reference vessel diameter (P<0.001), not different from that of the lesion length (P=0.41), and significantly higher than that of any other clinical feature (all P<0.05).

    Conclusion: IVUS-evaluated post-procedural dissection was associated with 1-year restenosis following femoropopliteal EVT with DCB.

  • Kazuki Uemura, Minoru Yamada, Masafumi Kuzuya, Hiroshi Okamoto
    原稿種別: Original Article
    論文ID: 58354
    発行日: 2020年
    [早期公開] 公開日: 2020/10/19
    ジャーナル オープンアクセス 早期公開

    Aim: We examined the effects of active learning education on arterial stiffness and physical activity of community-dwelling older adults with low health literacy.

    Methods: This study is a secondary analysis of randomized controlled trial of 60 participants aged 65 and older with low health literacy. The intervention group (n=30) participated in a weekly 90-minute active learning program session for 24 weeks, which addressed health promotion in older age. The control group (n=30) attended a 90-minute health education class in a didactic manner. The outcomes were measured at baseline and in week 24. The degree of arterial stiffness was assessed based on the cardio-ankle vascular index (CAVI) using the VS-1500 device (Fukuda Denshi Co., Ltd., Tokyo, Japan). The shortened version of the self-reported International Physical Activity Questionnaire was used to assess the amount of total physical activity determined by the metabolic equivalent hours per week. We used analysis by intention-to-treat, with multiple imputation for missing data.

    Results: Seven participants (11.7%) dropped out prior to the post-intervention assessment. The multiple imputation analysis revealed that the intervention group showed significant improvement in CAVI [between-groups difference (95% confidence interval)=-0.78 (-1.25 to -0.31), Cohen's d=0.82] and physical activity [32.5 (0.3 to 64.7), Cohen's d=0.57] as compared with the control group. The sensitivity analysis for the complete cases showed similar results.

    Conclusion: Active learning health education may be effective in improving arterial stiffness and physical activity in older adults with low health literacy.

  • Takeshi Okada, Mizuki Sumida, Tohru Ohama, Yuki Katayama, Ayami Saga, ...
    原稿種別: Original Article
    論文ID: 56887
    発行日: 2020年
    [早期公開] 公開日: 2020/10/06
    ジャーナル オープンアクセス 早期公開

    Aims: HDL particles have various anti-atherogenic functions, whereas HDL from atherosclerotic patients was demonstrated to be dysfunctional. One possible mechanism for the formation of dysfunctional HDL is the oxidation of its components. However, oxidized HDLs (Ox-HDLs) remain to be well investigated due to lack of reliable assay systems.

    Methods: We have developed a novel sandwich enzyme-linked immunosorbent assay (ELISA) for Ox-HDL by using the FOH1a/DLH3 antibody, which can specifically recognize oxidized phosphatidylcholine, a major component of HDL phospholipid (HDL-PL). We defined forced oxidation of 1 mg/L HDL-PL as 1 U/L Ox-HDL. We assessed serum Ox-HDL levels of normolipidemic healthy subjects (n=94) and dyslipidemic patients (n=177).

    Results: The coefficients of variation of within-run and between-run assays were 12.5% and 13.5%. In healthy subjects, serum Ox-HDL levels were 28.5±5.0 (mean±SD) U/L. As Ox-HDL levels were moderately correlated with HDL-PL (r=0.59), we also evaluated the Ox-HDL/HDL-PL ratio, which represents the proportion of oxidized phospholipids in HDL particles. In dyslipidemic patients, Ox-HDL levels were highly variable and ranged from 7.2 to 62.1U/L, and were extremely high (50.4±13.3U/L) especially in patients with hyperalphalipoproteinemia due to cholesteryl ester transfer protein deficiency. Regarding patients with familial hypercholesterolemia, those treated with probucol, which is a potent anti-oxidative and anti-hyperlipidemic drug, showed significantly lower Ox-HDL (16.2±5.8 vs. 30.2±5.4, p<0.001) and Ox-HDL/HDL-PL ratios (0.200±0.035 vs. 0.229±0.031, p=0.015) than those without probucol.

    Conclusion: We have established a novel sandwich ELISA for Ox-HDL, which might be a useful and easy strategy to evaluate HDL functionality, although the comparison study between this Ox-HDL ELISA and the assay of HDL cholesterol efflux capacity remains to be done. Our results indicated that probucol treatment may be associated with lower Ox-HDL levels.

  • Kazunori Shimada, Hiroaki Morinaga, Takashi Kiyanagi, Tetsuro Miyazaki ...
    原稿種別: Original Article
    論文ID: 58297
    発行日: 2020年
    [早期公開] 公開日: 2020/10/15
    ジャーナル オープンアクセス 早期公開

    Aim: Pneumococcal and influenza infections can cause serious morbidity and mortality in patients with cardiovascular diseases. The purpose of this study was to investigate the safety and efficacy of simultaneous inoculations of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and trivalent influenza vaccine (TIV) in patients with coronary artery disease (CAD).

    Methods: This was a prospective, randomized, single-blind, placebo-controlled study. A total of 40 patients with CAD were randomly assigned to the TIV+PPSV23 (simultaneous inoculations of TIV and PPSV23) and TIV+Placebo (inoculations of TIV and placebo) groups. Primary outcomes were the safety of simultaneous vaccinations and the changing of circulating cardiovascular biomarkers before, at 4-, and at 12-weeks after vaccinations.

    Results: The baseline characteristics between the two groups were identical. The prevalence of injection-site pain, swelling, and reddening were 47%, 37%, and 37% in the TIV+PPSV23 group, and 10%, 5%, and 0% in the TIV+Placebo group, respectively. All reactions were self-limited. Body temperature >37.0℃ or serious injection-related reaction was not observed. The levels of white blood cells, high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, pentraxin-3, and malondialdehide-modified low-density lipoprotein (LDL), were not significantly different between the two groups before and after vaccinations. The levels of anti-oxidized LDL were significantly and step-wisely decreased from baseline, to 4-, and 12-weeks vaccinations in the both groups. No significant changes of other markers were observed in both groups at each time point.

    Conclusion: Simultaneous inoculations of TIV and PPSV23 were safety in patients with CAD, suggesting that dual vaccinations can be considered even in patients with CAD.

  • Takayasu Ohtake, Shuzo Kobayashi
    原稿種別: Editorial
    論文ID: ED146
    発行日: 2020年
    [早期公開] 公開日: 2020/10/15
    ジャーナル オープンアクセス 早期公開
  • Ai Ikeda, Andrew Steptoe, Eric J Brunner, Koutatsu Maruyama, Kiyohide ...
    原稿種別: Original Article
    論文ID: 53926
    発行日: 2020年
    [早期公開] 公開日: 2020/10/10
    ジャーナル オープンアクセス 早期公開

    Aims: Stress is known to be a potential contributor to the development of diabetes and hypertension. However, the biological mechanisms underlying the association between cardiometabolic risk markers and the biological stress response have not yet been determined. Therefore, we examined salivary alpha-amylase and heart rate variability in relation to cardiometabolic status in a sample of healthy Japanese men and women.

    Methods: Participants (473 men and 1,029 women aged 30-84) underwent a 75 g oral glucose tolerance test after a 10-hr fast. The homeostasis model assessment index for insulin resistance was based on fasting and 2-hr postload glucose and insulin concentrations. Sitting blood pressure was measured twice after rest. A saliva sample was collected in the morning and salivary alpha-amylase was assayed. A 5-min heart rate variability recording was evaluated using time-domain indices of standard deviations of normal-to-normal intervals and root mean square of successive differences. Multivariate linear regression models were used to estimate associations between salivary alpha-amylase and each outcome measure.

    Results: Salivary alpha-amylase was associated with fasting glucose (β=0.008; 95% CI=0.002, 0.014), 2-hr postload glucose (β=0.023; 95% CI=0.004, 0.041), homeostasis model assessment index for insulin resistance (β=0.032; 95%CI=0.000, 0.064), systolic (β=1.603; 95% CI=0.479, 2.726) and diastolic (β=0.906; 95% CI=0.212, 1.600) blood pressures among women. These associations remained significant after further adjustment for heart rate variability measures.

    Conclusions: The elevation of salivary alpha-amylase may reflect a dysfunction of the sympathetic nervous system associated with cardiometabolic abnormalities in women.

  • Yuanying Li, Hiroshi Yatsuya, Sachiko Tanaka, Hiroyasu Iso, Akira Okay ...
    原稿種別: Original Article
    論文ID: 58958
    発行日: 2020年
    [早期公開] 公開日: 2020/10/10
    ジャーナル オープンアクセス 早期公開

    Aims: We aimed to develop and validate risk prediction models to estimate the absolute 10-year risk of death from coronary heart disease (CHD), stroke, and cardiovascular disease (CVD).

    Methods: We evaluated a total of 44,869 individuals aged 40–79 years from eight Japanese prospective cohorts to derive coefficients of risk equations using cohort-stratified Cox proportional hazard regression models. Discrimination (C-index) of the equation was examined in each cohort and summarised using random-effect meta-analyses. Calibration of the equation was assessed using Hosmer-Lemeshow chi-squared statistic.

    Results: Within a median follow-up of 12.7 years, we observed 765 deaths due to CVD (276 CHDs and 489 strokes). After backward selection, age, sex, current smoking, systolic blood pressure (SBP), proteinuria, prevalent diabetes mellitus, the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDLC), interaction terms of age by SBP, and age by current smoking were retained as predictors for CHD. Sex was excluded in the stroke equation. We did not consider TC/HDLC as a risk factor for the stroke and CVD equations. The pooled C-indices for CHD, stroke, and CVD were 0.83, 0.80, and 0.81, respectively, and the corresponding p-values of the Hosmer-Lemeshow tests were 0.18, 0.003, and 0.25, respectively.

    Conclusions: Risk equations in the present study can adequately estimate the absolute 10-year risk of death from CHD, stroke, and CVD. Future work will evaluate the system as an education and risk communication tool for primary prevention of CHD and stroke.

  • Masaaki Miyata
    原稿種別: Editorial
    論文ID: ED147
    発行日: 2020年
    [早期公開] 公開日: 2020/10/10
    ジャーナル オープンアクセス 早期公開
  • Makoto Kuro-o
    原稿種別: Review
    論文ID: RV17045
    発行日: 2020年
    [早期公開] 公開日: 2020/10/08
    ジャーナル オープンアクセス 早期公開

    During the evolution of skeletons, terrestrial vertebrates acquired strong bones made of calcium–phosphate. By keeping the extracellular fluid in a supersaturated condition regarding calcium and phosphate ions, they created the bone when and where they wanted simply by providing a cue for precipitation. To secure this strategy, they acquired a novel endocrine system to strictly control the extracellular phosphate concentration. In response to phosphate intake, fibroblast growth factor–23 (FGF23) is secreted from the bone and acts on the kidney through binding to its receptor Klotho to increase urinary phosphate excretion, thereby maintaining phosphate homeostasis. The FGF23–Klotho endocrine system, when disrupted in mice, results in hyperphosphatemia and vascular calcification. Besides, mice lacking Klotho or FGF23 suffer from complex aging-like phenotypes, which are alleviated by placing them on a low-phosphate diet, indicating that phosphate is primarily responsible for the accelerated aging. Phosphate acquires the ability to induce cell damage and inflammation when precipitated with calcium. In the blood, calcium–phosphate crystals are adsorbed by serum protein fetuin-A and prevented from growing into large precipitates. Consequently, nanoparticles that comprised calcium–phosphate crystals and fetuin-A, termed calciprotein particles (CPPs), are generated and dispersed as colloids. CPPs increase in the blood with an increase in serum phosphate and age. Circulating CPP levels correlate positively with vascular stiffness and chronic non-infectious inflammation, raising the possibility that CPPs may be an endogenous pro-aging factor. Terrestrial vertebrates with the bone made of calcium–phosphate may be destined to age due to calcium–phosphate in the blood.

  • Keisuke Kojima, Takafumi Hiro, Yutaka Koyama, Akihito Ohgaku, Hidesato ...
    原稿種別: Original Article
    論文ID: 56598
    発行日: 2020年
    [早期公開] 公開日: 2020/10/02
    ジャーナル オープンアクセス 早期公開

    Aims: Wall shear stress (WSS) has been considered a major determinant of aortic atherosclerosis. Recently, non-obstructive general angioscopy (NOGA) was developed to visualize various atherosclerotic pathologies, including in vivo ruptured plaque (RP) in the aorta. However, the relationship between aortic RP and WSS distribution within the aortic wall is unclear. This study aimed to investigate the relationship between aortic NOGA-derived RP and the stereographic distribution of WSS by computational fluid dynamics (CFD) modeling using three-dimensional computed tomography (3D-CT) angiography.

    Methods: We investigated 45 consecutive patients who underwent 3D-CT before coronary angiography and NOGA during coronary angiography. WSS in the aortic arch was measured by CFD analysis based on the finite element method using uniform inlet and outlet flow conditions. Aortic RP was detected by NOGA.

    Results: Patients with a distinct RP showed a significantly higher maximum WSS value in the aortic arch than those without aortic RP (56.2±30.6 Pa vs 36.2±19.8 Pa, p=0.017), no significant difference was noted in the mean WSS between those with and without aortic RP. In a multivariate logistic regression analysis, the presence of a maximum WSS value more than a specific value was a significant predictor of aortic RP (odds ratio 7.21, 95% confidence interval 1.78-37.1, p=0.005).

    Conclusions: Aortic RP detected by NOGA was strongly associated with a higher maximum WSS in the aortic arch derived by CFD using 3D-CT. The maximum WSS value may have an important role in the underlying mechanism of not only aortic atherosclerosis, but also aortic RP.

  • Daiki Yoshii, Takenobu Nakagawa, Yoshihiro Komohara, Hiroaki Kawaguchi ...
    原稿種別: Original Article
    論文ID: 57703
    発行日: 2020年
    [早期公開] 公開日: 2020/10/02
    ジャーナル オープンアクセス 早期公開

    Aim: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders associated with metabolic syndrome, and its prevalence has been on the rise. The pathogenesis of NAFLD has not yet been sufficiently elucidated due to the multifactorial nature of the disease, although the activation of macrophages/Kupffer cells is considered to be involved. We previously reported an animal model of NAFLD using MicrominipigsTM (µMPs) fed high-fat diets containing cholesterol with or without cholic acid. The aim of this study was to investigate the phenotypic changes of macrophages that occur during the development of NAFLD.

    Methods: Immunohistochemistry of macrophages, lymphocytes, and stellate cells was performed using liver samples, and the density of positive cells was analyzed.

    Results: The number of Iba-1-positive macrophages increased with increasing cholesterol content in the diet. The numbers of CD163-positive macrophages and CD204-positive macrophages also increased with increasing cholesterol content in the diet; however, the proportion of CD204-positive macrophages among Iba-1-positive macrophages was significantly reduced by cholic acid supplementation.

    Conclusion: The results suggest that lipid accumulation induced macrophage recruitment in swine livers, and that the number of M2-like macrophages increased at the early stage of NAFLD, while the number of M1-like macrophages increased at the late stage of NAFLD, resulting in a liver condition like non-alcoholic steatohepatitis. We provide evidence of the phenotypic changes that occur in macrophages during the development of NAFLD that has never been reported before using µMPs.

  • Hiroto Yabushita, Shinichi Goto, Sunao Nakamura, Hideki Oka, Masamitsu ...
    原稿種別: Original Article
    論文ID: 59675
    発行日: 2020年
    [早期公開] 公開日: 2020/10/02
    ジャーナル オープンアクセス 早期公開

    Aim: The clinically meaningful coronary stenosis is diagnosed by trained interventional cardiologists. Whether artificial intelligence (AI) could detect coronary stenosis from CAG video is unclear.

    Methods: The 199 consecutive patients who underwent coronary arteriography (CAG) with chest pain between December 2018 and May 2019 was enrolled. Each patient underwent CAG with multiple view resulting in total numbers of 1,838 videos. A multi-layer 3-dimensional convolution neural network (CNN) was trained as an AI to detect clinically meaningful coronary artery stenosis diagnosed by the expert interventional cardiologist, using data from 146 patients (resulted in 1,359 videos) randomly selected from the entire dataset (training dataset). This training dataset was further split into 109 patients (989 videos) for derivation and 37 patients (370 videos) for validation. The AI developed in derivation cohort was tuned in validation cohort to make final model.

    Results: The final model was selected as the model with best performance in validation dataset. Then, the predictive accuracy of final model was tested with the remaining 53 patients (479 videos) in test dataset. Our AI model showed a c-statistic of 0.61 in validation dataset and 0.61 in test dataset, respectively.

    Conclusion: An artificial intelligence applied to CAG videos could detect clinically meaningful coronary atherosclerotic stenosis diagnosed by expert cardiologists with modest predictive value. Further studies with improved AI at larger sample size is necessary.

  • Tamaki Kobayashi, Makoto Kurano, Mai Nanya, Tomo Shimizu, Ryunosuke Oh ...
    原稿種別: Original Article
    論文ID: 55699
    発行日: 2020年
    [早期公開] 公開日: 2020/10/01
    ジャーナル オープンアクセス 早期公開

    Aim: Recently, it has been established that most of the pleiotropic effects of high-density lipoprotein (HDL) are attributed to sphingosine 1-phosphate (S1P), which rides on HDL via apolipoprotein M (ApoM). In subjects with diabetes mellitus, both the pleiotropic effects of HDL and its role in reverse cholesterol transport are reported to be impaired. To elucidate the mechanisms underlying the impaired pleiotropic effects of HDL in subjects with diabetes, from the aspects of S1P and ApoM.

    Methods: The incubation of HDL in a high-glucose condition resulted in the dimerization of ApoM. Moreover, the treatment of HDL with methylglyoxal resulted in the modulation of the ApoM structure, as suggested by the results of western blot analysis, isoelectric focusing electrophoresis, and two-dimensional gel electrophoresis, which was reversed by treatment with anti-glycation reagents.

    Results: The glycation of HDL resulted in impaired binding of the glycated HDL to S1P, and the S1P on glycated HDL degraded faster. In the case of human subjects, on the other hand, although both the serum ApoM levels and the ApoM content in HDL were lower in subjects with diabetes, we did not observe the polymerization of ApoM.

    Conclusions: Modulation of the quantity and quality of ApoM might explain, at least in part, the impaired functions of HDL in subjects with diabetes mellitus. ApoM might be a useful target for laboratory testing and/or the treatment of diabetes mellitus.

  • Tomoya Yamashita, Naofumi Yoshida, Takuo Emoto, Ken-ichi Hirata
    原稿種別: Editorial
    論文ID: ED142
    発行日: 2020年
    [早期公開] 公開日: 2020/10/01
    ジャーナル オープンアクセス 早期公開
  • Isao Muraki
    原稿種別: Editorial
    論文ID: ED144
    発行日: 2020年
    [早期公開] 公開日: 2020/10/01
    ジャーナル オープンアクセス 早期公開
  • Chao Zhang, Xin Chen, Ju-Kun Wang, Yu Li, Shi-Jun Cui, Zhonggao Wang, ...
    原稿種別: Original Article
    論文ID: 55343
    発行日: 2020年
    [早期公開] 公開日: 2020/09/25
    ジャーナル オープンアクセス 早期公開

    Aim: During the development of atherosclerosis, the vascular smooth muscle cells (SMCs) undergo phenotypic switching from contractile phenotype to synthetic phenotype. This study aimed at examining the role of DNA modification mediated by the oxidative stress dependent ten eleven translocation enzymes (TETs) expression at early stage of phenotypic switching.

    Methods: Based on the in vitro SMCs calcification model, DNA damage, phenotypic switching and 5-hydroxymethylcytosine (5hmC) were examined by comet assay, alkaline DNA unwinding assay, immunofluorescence staining, Dot blotting and Western blotting. Then Western blotting and qRT-PCR were performed to analyze the TETs expression and the relationship between the activity of poly(ADP-ribose) polymerase 1 (PARP1) and TETs expression. We further alter 5hmC modification by inhibition of TET1 or PARP1 to rescue the phenotypic switching of SMCs using immunofluorescence staining, Dot blotting and qRT-PCR. We performed immunochemistry staining to examine the activated PARP1-TET1 pathway in vivo.

    Results: The phenotypic switching was observed in the SMCs cultured with calcification medium as the expression of the cell markers of contractile SMCs decreased and cell proliferation increased. In contrast, PAR and 5hmC were markedly increased in SMCs with calcification due to DNA damage. Our study further demonstrated that oxidative stress-activated PARP1, promotes TET1 expression and 5hmC increase during the phenotypic switching. Inhibition of TET1 or PARP1 can rescue the phenotypic switching of SMCs with calcification.

    Conclusion: Our study demonstrated the important role of PARylation dependent 5hmC, in SMCs phenotypic switching. It raises the possibility to target TET1 and PARP1 for atherosclerosis treatment.

  • Yusuke Sato, Hiroyasu Uzui, Tetsuji Morishita, Yoshitomo Fukuoka, Kana ...
    原稿種別: Original Article
    論文ID: 57653
    発行日: 2020年
    [早期公開] 公開日: 2020/09/25
    ジャーナル オープンアクセス 早期公開

    Aim: The aim of this study was to examine the effects of evolocumab on favorable limb events in patients with chronic limb-threatening ischemia (CLTI).

    Methods: A single-center, prospective observational study was performed on 30 patients with CLTI. The subjects were divided into 2 groups based on evolocumab administration: evolocumab-treated (E) group (n=14) and evolocumab non-treated (non-E) group (n=16). The primary outcome was 12-month freedom from major amputation. The secondary outcomes were 12-month amputation-free survival (AFS), overall survival (OS), and wound-free limb salvage. The mean follow-up period was 18±11 months.

    Results: No significant difference was detected between the two groups for the 12-month freedom from major amputation (log-rank p=0.15), while the 12-month AFS rate was significantly higher in the E group than that in the non-E group (log-rank p=0.02). The 12-month OS rate in the E group was shown a tendency for improvement, as compared with that in the non-E group (log-rank p=0.056). Evolocumab administration was not associated with a significant change in freedom from major amputation (HR, 0.23, 95% CI, 0.03-2.07, p=0.19). However, evolocumab administration was related to a tendency for improvement of AFS and OS (HR, 0.13, 95% CI, 0.02-1.06, p=0.056; HR, 0.16, 95% CI, 0.02-1.37, p=0.09, respectively). Moreover, The E group had a higher proportion of wound-free limb salvage at 12 months (92% vs. 42%, p=0.03).

    Conclusion: Evolocumab administration was associated with a better AFS outcome in patients with CLTI. Long-term administration of evolocumab over 12 months contributed to improving proportion of wound-free limb salvage.

  • Yu Sato, Akiomi Yoshihisa, Yasuhiro Ichijo, Koichiro Watanabe, Yu Hots ...
    原稿種別: Original Article
    論文ID: 58727
    発行日: 2020年
    [早期公開] 公開日: 2020/09/25
    ジャーナル オープンアクセス 早期公開

    Aim: We aimed to evaluate the significance of the cardio-ankle vascular index (CAVI) to predict stroke in patients with heart failure (HF).

    Methods: This was a prospective observational study, which recruited clinical data from a total of 557 patients who had been hospitalized for HF and undergone CAVI. According to the receiver operating characteristic curve analysis, the accurate cut-off value of CAVI in predicting post-discharge stroke was 9.64. We divided the patients into two groups: the high-CAVI group (HF patients with CAVI ≥ 9.64, n=111, 19.9%) and the low-CAVI group (HF patients with CAVI <9.64, n=446, 80.1%). We compared the patients' characteristics and post-discharge prognosis. The primary endpoint was stroke.

    Results: The high-CAVI group was older (73.0 vs. 65.5 years old, P<0.001). Male sex (73.9% vs. 61.4%, P=0.015), coronary artery disease (47.7% vs. 36.1%, P=0.024), and diabetes mellitus (54.1% vs. 37.4%, P=0.001) were more prevalent in the high-CAVI group. In contrast, there was no difference in left ventricular ejection fraction, and prevalence of hypertension and dyslipidemia. The Kaplan-Meier analysis demonstrated that post-discharge stroke rate was higher in the high-CAVI group than in the low-CAVI group (log-rank P=0.005). In multivariate Cox proportional hazard analysis, high CAVI was found to be an independent predictor of stroke, with an adjusted hazard ratio of 3.599, compared to low CAVI.

    Conclusion: CAVI independently predicts stroke in patients with HF.

    The trial registration number: UMIN000029132

  • Atsushi Hozawa
    原稿種別: Editorial
    論文ID: ED143
    発行日: 2020年
    [早期公開] 公開日: 2020/09/25
    ジャーナル オープンアクセス 早期公開
  • Hideki Fujii
    原稿種別: Editorial
    論文ID: ED145
    発行日: 2020年
    [早期公開] 公開日: 2020/09/25
    ジャーナル オープンアクセス 早期公開
  • Shinichiro Uchiyama, Takao Hoshino, Hugo Charles, Kenji Kamiyama, Taiz ...
    原稿種別: Original Article
    論文ID: 58552
    発行日: 2020年
    [早期公開] 公開日: 2020/09/17
    ジャーナル オープンアクセス 早期公開

    Aims: We have previously reported 5-year follow-up data on the TIAregistry.org, an international prospective cohort in patients with transient ischemic attack (TIA) or minor stroke. We conducted a Japanese subgroup analysis because outcomes and predictors might differ according to ethnicities and regions. In this study, we compared the baseline and 5-year follow-up data of Japanese and non-Japanese patients with TIA or minor stroke.

    Methods: Patients with TIA or minor ischemic stroke within 7 days after the onset were classified into two groups based on ethnicity, Japanese (n=345) and non-Japanese (n=3502); further, 5-year event rates were compared between the two groups. We also determined predictors of 5-year stroke for both groups.

    Results: Vascular death and death from any cause were identified to be less prevalent, unlike stroke and intracranial hemorrhage, which was determined to be more prevalent in Japanese than in non-Japanese patients. Five-year rate of stroke was significantly higher in Japanese patients. Cumulative stroke and major cardiovascular event rates did not decline but instead linearly increased from 1 to 5 years in both groups. Baseline risk factors for 5-year stroke were as follows: age, diabetes, history of stroke or TIA, and congestive heart failure in Japanese patients. Independent predictors of 5-year stroke were large artery atherosclerosis, congestive heart failure, diabetes, and age in Japanese patients.

    Conclusions: Recurrent stroke and intracranial hemorrhage were determined to be more prevalent at 5 years after TIA or minor stroke in Japanese patients than in non-Japanese patients. Strategies to mitigate the long-term risks of stroke, aside from adherence to current guidelines, should take Japanese-patient-specific residual risks into account.

  • Shin-ichiro Katsuda, Yuko Fujikura, Yuko Horikoshi, Akihiro Hazama, Ts ...
    原稿種別: Original Article
    論文ID: 57364
    発行日: 2020年
    [早期公開] 公開日: 2020/09/11
    ジャーナル オープンアクセス 早期公開

    Aim: The mechanism underlying the stiffness of the aorta and iliofemoral artery that is required to maintain blood pressure (BP) is unclear. A new stiffness index of the aorta (aBeta) and iliac-femoral arteries (ifBeta) was defined by applying the cardio-ankle vascular index (CAVI). We compared changes in stiffness of the two arteries in response to reduced BP, due to the non-selective α adrenergic blocker phentolamine and the β1 adrenergic blocker atenolol, in rabbits.

    Methods: Pressure waves at the origin (oA) and distal ends of the aorta (dA) and the distal end of the left femoral artery (fA) were recorded simultaneously using three pressure sensors in 25 anesthetized rabbits. Phentolamine (50 µg/kg/min) and atenolol (10 mg/kg/min) were infused for 2 min. The pulse wave velocity (PWV) in each artery was determined; aBeta, ifBeta, and whole Beta (aifBeta) were calculated by the following formula; Beta=2ρ/PP×ln(SBP/DBP)×PWV2 (ρ: blood density; SBP, SBP, and PP: systolic, diastolic, and pulse pressures, respectively).

    Results: SBP and DBP at oA, dA, and fA decreased by the administration of phentolamine and atenolol, with and without decreased total peripheral vascular resistance. After phentramine infusion, cardiac output (CO), aBeta, and aifBeta increased, while ifBeta decreased. After infusion of atenolol, CO decreased, while aBeta, ifBeta, and aifBeta remained unchanged.

    Conclusion: The contradictory reactions of aBeta and ifBeta to phentolamine suggest that the stiffness of the aorta and ilio-femoral artery is regulated separately during decreased BP induced by phentolamine, but not by atenolol.

  • Maria Pina Dore, Michele Portoghese, Giovanni Mario Pes
    原稿種別: Original Article
    論文ID: 56531
    発行日: 2020年
    [早期公開] 公開日: 2020/09/10
    ジャーナル オープンアクセス 早期公開

    Aim: Recent studies suggest that glucose-6-phosphate dehydrogenase (G6PD) deficiency, a genetically inherited condition causing hemolytic anemia, may be a risk factor for cardiovascular disease (CVD). We aimed to perform a retrospective case–control study in Sardinia taking advantage from clinical records of patients undergoing upper digestive endoscopy and screened for H. pylori infection.

    Methods: A total of 9,604 patients with a known G6PD status and a complete clinical history, including CVD, and leading CVD risk factors, including H. pylori infection, undergoing upper endoscopy between 2002 and 2017 were enrolled in this study.

    Results: Multivariate logistic regression analysis confirmed an increased CVD risk in subjects with G6PD deficiency [odd ratio (OR), 3.24; 95% confidence interval (CI) 2.44–4.30] after adjusting for potential confounders and effect modifiers, including H. pylori infection. Cardiovascular risk was similar in subjects with and without G6PD deficiency before age 60 (OR, 1.26; 95% CI 0.78–2.04, P=0.562), whereas it increased after age 60 in the former group (OR, 3.05; 95% CI 2.22–4.19, P<0.0001) especially in males (OR 3.67; 95% CI 2.19–6.14) than in females (OR, 2.96; 95% CI 1.89–4.64) by sex-specific logistic regression analysis.

    Conclusion: The risk of CVD was greater in G6PD-deficient subjects after age 60, both in males and females, than those with normal enzyme activity, after adjusting for conventional CVD risk factors and H. pylori infection. The reduction of important protective mechanisms against oxidative stress in elderly might explain the study findings.

  • Masayuki Suzuki, Kohei Furuya, Misato Ozawa, Kumiko Miura, Tadashi Oza ...
    原稿種別: Original Article
    論文ID: 58339
    発行日: 2020年
    [早期公開] 公開日: 2020/09/10
    ジャーナル オープンアクセス 早期公開

    Aim: Aortic arch atherosclerosis, particularly complex aortic arch plaques (CAPs), is an important source of cerebral emboli. CAPs and atrial fibrillation (AF) often co-exist; however, the prevalence and risk of CAPs in acute ischemic stroke patients with AF is unclear.

    Methods: In patients with acute ischemic stroke with non-valvular AF admitted to Jichi Medical University Hospital during April 2016 to September 2019, we retrospectively evaluated the presence of CAPs on transesophageal echocardiography (TEE).

    Results: CAPs were observed in 41 (38.7 %) of 106 patients with non-valvular AF. Older age, diabetes mellitus, chronic kidney disease, low high-density lipoprotein cholesterol (HDL-C) levels, higher levels of glycohemoglobin A1c (HbA1c), higher CHADS2 and CHA2DS2-VASc scores, and intracranial or carotid artery stenosis were more frequently observed in CAPs-positive than in CAPs-negative patients. In multivariable analyses, older age (odds ratio [OR]: 1.2 per year increase; 95% confidence interval [CI]: 1.07–1.24; P<0.0001), diabetes mellitus (OR: 4.7; 95%CI: 1.27-17.35; P<0.05), and low HDL-C (OR: 0.95 per 1 mg/dl increase; 95%CI: 0.92-0.99; P <0.01) were independent risk factors for CAPs. The prevalence of CAPs was age-dependent, and there was a significantly higher risk in patients aged either 75–84 years or >84 years than in those aged <65 (OR: 7.6; 95%CI: 1.50-38.62, and OR: 32.1; 95%CI: 5.14-200.11, respectively).

    Conclusions: Even in patients with ischemic stroke with non-valvular AF, concomitant CAPs should be considered in older individuals and those who have diabetes or low HDL-C.

  • Shojiro Sawada
    原稿種別: Editorial
    論文ID: ED140
    発行日: 2020年
    [早期公開] 公開日: 2020/09/10
    ジャーナル オープンアクセス 早期公開
  • Yasushi Honda
    原稿種別: Editorial
    論文ID: ED141
    発行日: 2020年
    [早期公開] 公開日: 2020/09/10
    ジャーナル オープンアクセス 早期公開
  • Jianan Li, Hong Qiu, Lirong Yan, Tingting Guo, Yong Wang, Yang Li, Jia ...
    原稿種別: Original Article
    論文ID: 57265
    発行日: 2020年
    [早期公開] 公開日: 2020/09/08
    ジャーナル オープンアクセス 早期公開

    Aim: The efficacy and safety of ticagrelor and clopidogrel in patients with stable coronary artery disease (SCAD) undergoing percutaneous coronary intervention (PCI) remain uncertain. Thus, this study aimed to compare the efficacy and safety of ticagrelor and clopidogrel in patients with SCAD treated with PCI.

    Methods: A total of 9,379 patients with SCAD undergoing PCI who received dual antiplatelet therapy (DAPT) were consecutively enrolled in two groups, namely, ticagrelor (n=1,081) and clopidogrel (n=8,298) groups. Major adverse cardiovascular and cerebrovascular events (MACCEs) and bleeding events according to ticagrelor or clopidogrel use were compared.

    Results: After propensity matching (n=1,081 in each group), ticagrelor was associated with fewer MACCEs compared with clopidogrel (3.6% vs. 5.7%, hazard ratio [HR]=0.62, 95% confidence interval [CI] 0.41–0.93, p=0.019), and the difference between ticagrelor and clopidogrel for bleeding events was nonsignificant (1.7% vs. 1.2%, HR=1.39, 95% CI 0.68–2.85, p=0.366). On the other hand, the difference between ticagrelor and clopidogrel for net adverse clinical events was significant (4.1% vs. 6.0%, HR=0.67, 95% CI 0.46–0.98, p=0.039). In a multivariate analysis, the use of ticagrelor, number of stents, previous history of diabetes, previous history of smoking, and ACC/AHA type B2 or C lesions were considered independent predictors of MACCEs, while radial artery access, previous history of stroke, and weight <60kg were independent predictors of bleeding events.

    Conclusions: Ticagrelor was associated with a lower incidence of MACCEs without an increased risk of bleeding events in patients with SCAD receiving PCI.

  • Makoto Utsunomiya, Mitsuyoshi Takahara, Masahiko Fujihara, Tatsuya Shi ...
    原稿種別: Original Article
    論文ID: 57927
    発行日: 2020年
    [早期公開] 公開日: 2020/09/08
    ジャーナル オープンアクセス 早期公開

    Aim: This study aims to elucidate the effects of early application of target lesion revascularization (TLR) to restenosis lesions of the superficial femoral artery (SFA) without recurrence of symptoms. Despite recent improvements in endovascular therapy (EVT) for the SFA, restenosis remains to be a problem. However, restenosis is not always associated with the recurrence of limb symptoms. Although early application of TLR is not generally approved for restenosis lesions of the SFA without recurred symptoms, it is expected to contribute to long-term patency and other favorable outcomes. Nonetheless, its effectiveness remains to be determined.

    Methods: We retrospectively analyzed 616 patients who developed restenosis after undergoing femoro-popliteal EVT for claudication (Rutherford category 1 to 3) due to de novo femoro-popliteal lesions between January 2010 and December 2016 at 11 centers in Japan. Recurred symptoms were defined as symptoms of the same or higher Rutherford categories than those immediately before the initial EVT.

    Results: Of the patients, 291 (47 %) lacked recurred symptoms; 69 (24 %) underwent TLR for restenosis. After propensity matching, the risk of occlusion was determined to be not significantly different between the TLR and observation groups; the 3-year occlusion-free rate was 68 % and 62 %, respectively (P=0.84). The risk of recurring symptoms, critical limb ischemia, and all-cause death was also found to be comparable between groups. The incidence of target vessel revascularization was significantly higher in the TLR than in the observation group (1.55 [95 % confidence interval: 1.25–1.93] vs. 0.59 [0.41–0.85] per 3 person-years).

    Conclusions: In patients with SFA restenosis without recurred symptoms, early application of TLR showed no advantages.

  • Itaru Hisauchi, Tetsuya Ishikawa, Makoto Ayaori, Harumi Uto-Kondo, Yur ...
    原稿種別: Original Article
    論文ID: 59279
    発行日: 2020年
    [早期公開] 公開日: 2020/09/08
    ジャーナル オープンアクセス 早期公開

    Aim: We examined the impact of baseline high-density lipoprotein cholesterol efflux capacity (CEC) on major cardiac adverse events (MACE) in patients with coronary artery disease (CAD) during a long-term secondary prevention.

    Method: CEC was measured using a cell-based efflux system in (3)[H]-cholesterol-labeled J774 macrophages in apolipoprotein B-depleted plasma between January 2011 and January 2013. Patients with CAD were divided into 2 groups as a boundary CEC value of 1: 0.19 ≤ CEC <1 (impaired CEC group, mean CEC of 0.76±0.16, n=136), and 1 ≤ CEC ≤ 2.08 (enhanced CEC group, 1.20±0.19, n=44). MACE, comprised the incidence of cardiac death, non-fatal myocardial infarction, and any revascularizations (RV) without restenosis approximately 1 year after vascularization, was retrospectively investigated at September 2019. Impact of enhanced CEC on MACE among 22 variables was examined by applying a Cox proportional hazard model.

    Result: The frequency of MACE in impaired CEC group (16.9%, mean observational interval of 2111±888 days) was significantly higher than that in enhanced CEC group (2.3%, 2,252±685, p=0.013), largely driven by the significantly higher RV incidence (14.0 % versus 2.3 %, p=0.032). Enhancement of CEC was the significant predictor of MACE (hazard ratio: 0.11; 95% CI: 0.013-0.879; p=0.038).

    Conclusion: A baseline CEC level of more than 1 in patients with CAD brought favorable long-term clinical outcomes, suggesting that CEC is a useful prognostic and therapeutic surrogate for secondary prevention of CAD.

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