Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Advance online publication
Showing 1-50 articles out of 56 articles from Advance online publication
  • Yoshihiro Kokubo, Makoto Watanabe, Aya Higashiyama, Kyoko Honda-Kohmo
    Type: Editorial
    Article ID: ED134
    Published: 2020
    [Advance publication] Released: May 29, 2020
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  • Haizhao Yan, Manabu Niimi, Chuan Wang, Yajie Chen, Huanjin Zhou, Fumik ...
    Type: Original Article
    Article ID: 55244
    Published: 2020
    [Advance publication] Released: May 23, 2020
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    Aim: Endothelial lipase (EL) plays an important role in lipoprotein metabolism. Our recent study showed that increased hepatic expression of EL attenuates diet-induced hypercholesterolemia, thus subsequently reducing atherosclerosis in transgenic (Tg) rabbits. However, it is yet to be determined whether increased EL activity itself per se is anti-atherogenic or whether the anti-atherogenic effect of EL is exclusively dependent on its lipid-lowering effect.

    Methods: To determine the mechanisms underlying EL-mediated anti-atherogenic effect, we fed Tg and non-Tg rabbits diets containing different amounts of cholesterol to make their plasma cholesterol levels similarly high. Sixteen weeks later, we examined their lipoprotein profiles and compared their susceptibility to atherosclerosis.

    Results: With Tg and non-Tg rabbits having hypercholesterolemia, the plasma lipids and lipoprotein profiles were observed to be similar, while pathological examinations revealed that lesion areas of both aortic and coronary atherosclerosis of Tg rabbits were not significantly different from non-Tg rabbits. Moreover, Tg rabbits exhibited faster clearance of DiI-labeled β-VLDLs than non-Tg rabbits.

    Conclusion: The results of our study suggest that the enhancement of β-VLDL catabolism is the major mechanism for atheroprotective effects of EL in Tg rabbits.

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  • Hirofumi Tomiyama, Kazuki Shiina
    Type: Review
    Article ID: RV17041
    Published: 2020
    [Advance publication] Released: May 23, 2020
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    The brachial-ankle pulse wave velocity (brachial-ankle PWV), which is measured simply by wrapping pressure cuffs around the four extremities, is a simple marker to assess the stiffness of the medium- to large- sized arteries. The accuracy and reproducibility of its measurement have been confirmed to be acceptable. Risk factors for cardiovascular disease, especially advanced age and high blood pressure, are reported to be associated with an increase of the arterial stiffness. Furthermore, arterial stiffness might be involved in a vicious cycle with the development/progression of hypertension, diabetes mellitus and chronic kidney disease. Increase in the arterial stiffness is thought to contribute to the development of cardiovascular disease via pathophysiological abnormalities induced in the heart, brain, kidney, and also the arteries themselves. A recent independent participant data meta-analysis conducted in Japan demonstrated that the brachial-ankle PWV is a useful marker to predict future cardiovascular events in Japanese subjects without a previous history of cardiovascular disease, independent of the conventional model for the risk assessment. The cutoff point may be 16.0 m/s in individuals with a low risk of cardiovascular disease (CVD), and 18.0 m/s in individuals with a high risk of CVD and subjects with hypertension. In addition, the method of measurement of the brachial-ankle PWV can also be used to calculate the inter-arm systolic blood pressure difference and ankle-brachial pressure index, which are also useful markers for cardiovascular risk assessment.

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  • Daisaku Masuda, Arihiro Kiyosue, Atsushi Hirayama, Junichiro Shimauchi ...
    Type: Original Article
    Article ID: 54353
    Published: 2020
    [Advance publication] Released: May 20, 2020
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    Aims: Profiling of lipoproteins can predict risk of cardiovascular disease; gel permeation high-performance liquid chromatography (HPLC) improves prediction accuracy by providing detailed data for specific lipoprotein subclasses. This study applied HPLC to examine the effects of evolocumab, which effectively treats hyperlipidemia and mixed dyslipidemia, on lipoprotein subclasses, specifically the number and size of lipoprotein particles.

    Methods: This post-hoc analysis used patient blood samples from YUKAWA-2, a phase 3 trial evaluating the efficacy of evolocumab in Japanese adult patients with hyperlipidemia or mixed dyslipidemia and at high risk for cardiovascular disease. We used HPLC to assess observed values and percent change from baseline in cholesterol and triglyceride (TG) concentrations, number of particles in lipoprotein subclasses to week 12, and mean observed values and mean percent change from baseline in variables to weeks 10 and 12. HPLC was also compared with conventional methods in assessing low-density lipoprotein (LDL) cholesterol (LDL-C) values.

    Results: Data for all 404 patients were analyzed. Evolocumab significantly decreased cholesterol and TG concentrations, and total particle count, in very low-density lipoprotein (VLDL) and LDL subclasses. Particle size increased slightly in LDL, high-density lipoprotein (HDL), and VLDL, but data varied widely. At very low LDL-C, HPLC measurements were higher than those from conventional methods.

    Conclusion: This research used HPLC to assess the effects of evolocumab in 20 lipid subclasses. By lowering lipid content and improving the lipid profile, evolocumab may reduce atherogenicity. This reduction is better quantified by HPLC than by conventional methods in the very low LDL-C range.

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  • Koichiro Fujisue, Kenshi Yamanaga, Suguru Nagamatsu, Hideki Shimomura, ...
    Type: Original Article
    Article ID: 54726
    Published: 2020
    [Advance publication] Released: May 20, 2020
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    Aim: Coronary plaque regression is weak in acute coronary syndrome (ACS) patients with diabetes mellitus (DM). We evaluated whether dual lipid-lowering therapy (DLLT) with ezetimibe and atorvastatin attenuates coronary plaques in ACS patients with DM.

    Methods: The prospective, randomized controlled, multicenter PRECISE-IVUS (Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial assigned 246 patients undergoing percutaneous coronary intervention to DLLT or atorvastatin monotherapy and evaluated IVUS-derived changes in percent atheroma volume (ΔPAV), at baseline and 9-12-month follow-up, in 126 ACS cases, including 25 DM patients. The atorvastatin dose was up-titrated to achieve low-density lipoprotein cholesterol (LDL-C) <70 mg/dL.

    Results: In DM patients, the monotherapy group (n=13) and the DLLT group (n=12) showed a similar prevalence of coronary risks and baseline lipid profiles. During the study, the change in LDL-C level was similar between DM and non-DM patients. Compared with non-DM patients, DM patients showed weaker regression of ΔPAV by DLLT than those who underwent monotherapy (DM: −2.77±3.47% vs. −0.77±2.51%, P=0.11; non-DM: −2.01±3.36% vs. −0.08±2.66%, P=0.008). The change in LDL-C level was not correlated with ΔPAV in non-DM patients, but there was significant correlation between the change in LDL-C level and ΔPAV in DM patients (r=0.52, P=0.008).

    Conclusions: ACS patients with DM showed weaker coronary plaque regression than their counterparts. A significant correlation between the change in LDL-C level and ΔPAV in DM patients suggested that more intensive lipid-lowering therapy is required in ACS patients with DM.

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  • Tomoaki Morioka
    Type: Editorial
    Article ID: ED129
    Published: 2020
    [Advance publication] Released: May 20, 2020
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  • Shin-Joe Yeh, Sung-Chun Tang, Li-Kai Tsai, Chih-Hung Chen, Shih-Pin Hs ...
    Type: Original Article
    Article ID: 55210
    Published: 2020
    [Advance publication] Released: May 15, 2020
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    Aim: Chronic kidney disease (CKD) is associated with unfavorable outcomes in patients with ischemic stroke. One major metabolic derangement of CKD is dyslipidemia, which can be managed by statins. This study aimed to investigate whether the association of statins with post-stroke outcomes would be affected by renal function.

    Methods: We evaluated the association of statin therapy at discharge with 3-month outcomes according to the estimated glomerular filtration rate (eGFR) of 50,092 patients with acute ischemic stroke from the Taiwan Stroke Registry from August 2006 to May 2016. The outcomes were mortality, functional outcome as modified Rankin Scale (mRS), and recurrent ischemic stroke at 3 months after index stroke.

    Results: Statin therapy at discharge was associated with lower risks of mortality (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.34 to 0.50) and unfavorable functional outcomes (mRS 3–5; aHR, 0.80; 95% CI, 0.76 to 0.84) in ischemic stroke patients. After stratification by eGFR, the lower risk of mortality associated with statins was limited to patients with an eGFR above 15 mL/min/1.73 m2. Using statins at discharge was correlated with a lower risk of unfavorable functional outcomes in patients with an eGFR of 60–89 mL/min/1.73 m2. Statin therapy in patients with an eGFR of 60–89 mL/min/1.73 m2 may be associated with a higher risk of recurrent ischemic stroke compared with nonusers (aHR, 1.29; 95% CI, 1.07 to 1.57).

    Conclusions: In patients with acute ischemic stroke, the associations of statins with mortality and functional outcomes was dependent on eGFR.

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  • Chika Okada, Yasuhiko Kubota, Ehab S Eshak, Cui Renche, Akiko Tamakosh ...
    Type: Original Article
    Article ID: 54114
    Published: 2020
    [Advance publication] Released: May 02, 2020
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    Aim: The aim of this study was to assess the association between weight change and mortality due to cardiovascular diseases (CVDs) in a Japanese population.

    Methods: We used the data of a population-based prospective cohort study that was conducted from 1988 to 1990 in 45 areas throughout Japan. Among a total of 69,681 men and women aged 40–79 with no history of CVD or cancer at baseline, the association between weight change from 20 years of age to baseline and CVD-related mortality was evaluated.

    Results: During a median follow-up period of 19.1 years, we observed 4,274 deaths from total CVD. After adjusting for age, sex, and other potential confounding factors, compared with participants with a weight change of <2.5 kg (stable weight), participants with a greater weight change (either loss or gain) had an increased risk of mortality from total CVD (U-shaped association). The hazard ratios for the total CVD risk in participants with a weight loss and a weight gain of ≥ 12.5 kg were 1.50 (95% confidence interval [CI], 1.30–1.72) and 1.21 (95% CI, 1.07–1.36), respectively. The associations between weight change and risk of mortality from ischemic heart disease or stroke showed similar trends. The risk of intracerebral hemorrhage was associated with weight loss only. Weight change was not associated with mortality from subarachnoid hemorrhage.

    Conclusions: Weight loss or gain could be a risk factor for mortality from total or ischemic CVD, while weight loss could be a risk factor for intracerebral hemorrhage.

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  • Shizuya Yamashita, Hidenori Arai, Hideaki Bujo, Daisaku Masuda, Tohru ...
    Type: Original Article
    Article ID: 55327
    Published: 2020
    [Advance publication] Released: April 24, 2020
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    Aims: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD).

    Methods: PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with an low-density lipoprotein (LDL)-cholesterol (HDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima–media thickness in a subset of patients.

    Results: The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport.

    Conclusion: Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).

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  • Hyun-Jae Kang, Moo Hyun Kim, Jidong Sung, Sang-Hyun Kim, Cheol-Ho Kim, ...
    Type: Original Article
    Article ID: 55616
    Published: 2020
    [Advance publication] Released: April 24, 2020
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    Aim: In a prospective randomized multinational open blinded endpoint study, the long-term effects of probucol or probucol and cilostazol with statin on carotid mean intima media thickness (IMT) were evaluated for the first time.

    Methods: Hypercholesterolemic patients with coronary artery disease were randomized to three groups and received study drugs for 3 years: the control with statin alone; the probucol group with statin and probucol; and the combo group with statin, probucol, and cilostazol. Primary efficacy endpoint was changes of mean carotid IMT at 3 years. Biomarkers, major adverse cerebro-cardiovascular events (MACCEs) and safety were secondary endpoints.

    Results: Two hundred eighty-one patients were randomized into three groups. All three groups showed significant regression of carotid IMT at 3 years compared with baseline. Decrease in mean carotid IMT was significantly greater in the combo group than in the control group at 1 year. However, there were no significant differences in changes of mean carotid IMT between groups at 3 years (control; −0.12±0.36 mm vs. probucol; −0.11 ±0.32 mm vs. combo; −0.16±0.38 mm). MACCEs were frequent in the control group, but the difference was not significant (control; 10.8% vs. probucol; 4.4% vs. combo; 6.9%, p=0.35). Probucol and cilostazol were well tolerated in long-term treatment without serious drug-related adverse reactions.

    Conclusion: Probucol or probucol and cilostazol with statin did not reduce carotid IMT in comparison with statin alone in this study. However, the clinical outcome of probucol-based treatment with current standard statin treatment may need further studies.

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  • Mayu Higashioka, Satoko Sakata, Takanori Honda, Jun Hata, Mao Shibata, ...
    Type: Original Article
    Article ID: 55350
    Published: 2020
    [Advance publication] Released: April 18, 2020
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    Aim: The present study aims to investigate the association between serum small dense low-density lipoprotein (sdLDL) cholesterol level and the development of coronary heart disease (CHD) in subjects at high cardiovascular risk.

    Methods: A total of 3,080 participants without prior cardiovascular disease (CVD), aged ≥ 40 years, were followed up for a median of 8.3 years, which were divided into two groups, those with serum sdLDL cholesterol levels of <35 mg/dL or ≥ 35 mg/dL. Then, subjects were stratified by the status of diabetes, CVD-related comorbidities (defined as the presence of diabetes, chronic kidney disease, or peripheral artery disease), and the CVD risk assessment according to the Japan Atherosclerosis Society Guidelines. The hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using a Cox proportional hazards model.

    Results: During the follow-up, 79 subjects developed CHD. The risk for incident CHD was higher in subjects with serum sdLDL cholesterol of ≥ 35 mg/dL than those with sdLDL cholesterol of <35 mg/dL (HR 2.09, 95%CI 1.26–3.45) after adjusting for traditional risk factors. In the subgroup analyses, the multivariable-adjusted HR for incident CHD increased significantly in those with serum sdLDL cholesterol of ≥ 35 mg/dL among subjects with diabetes (HR 2.76, 95%CI 1.09–7.01), subjects with CVD-related comorbidities (HR 2.60, 95%CI 1.21–5.58), and high-risk category defined as the presence of CVD-related comorbidities or a Suita score of ≥ 56 points (HR 1.93, 95%CI 1.02–3.65).

    Conclusions: Elevated serum sdLDL cholesterol was associated with the development of CHD even in subjects at high cardiovascular risk.

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  • Hiroaki Ikezaki, Norihiro Furusyo, Yuya Yokota, Masumi Ai, Bela F Aszt ...
    Type: Original Article
    Article ID: 54130
    Published: 2020
    [Advance publication] Released: April 10, 2020
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    Aim: The association between small dense low-density lipoprotein cholesterol (sdLDL-C) levels and carotid intimal medial thickness (cIMT) progression has not been evaluated fully. We assessed specialized lipoproteins, including sdLDL-C, with regard to cIMT progression in a prospective observational study in Japan.

    Methods: Plasma total cholesterol, direct LDL-C, sdLDL-C, LDL-triglycerides (LDL-TG), high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL3-C, triglycerides, Lp(a), and adiponectin were measured in 2,030 men and women (median age 59 years, free of cardiovascular disease (CVD) and off cholesterol lowering medication). At both baseline and after a five-year follow-up, cIMT was assessed. Univariate, multivariate regression, and least square analyses were performed to examine the relationships between direct LDL-C, sdLDL-C, and other lipoproteins with cIMT progression.

    Results: The median cIMT at baseline was 0.63 mm and five-year progression was 0.18 mm. After adjustment for standard CVD risk factors, including age, gender, systolic blood pressure, total cholesterol, HDL-C, smoking, diabetes, and hypertension treatment, only direct LDL-C, sdLDL-C, and the sdLDL-C/LDL-C ratio were associated with cIMT progression. Even in subjects with direct LDL-C <100 mg/dL, who were considered at low CVD risk, elevated sdLDL-C were associated with cIMT progression (P for trend=0.009) in a model with established CVD risk factors, although the sdLDL-C/LDL-C ratio did not. Those correlations did not change by including triglycerides as a controlling factor or excluding premenopausal women from the analyzed population.

    Conclusions: Small dense LDL-C has a stronger relationship with cIMT progression than LDL-C does; therefore, measuring sdLDL-C may allow for the formulation of optimal therapy for CVD prevention.

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  • Masanori Munakata
    Type: Editorial
    Article ID: ED128
    Published: 2020
    [Advance publication] Released: April 10, 2020
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  • Michihiro Satoh, Takayoshi Ohkubo, Kei Asayama, Yoshitaka Murakami, Da ...
    Type: Original Article
    Article ID: 52613
    Published: 2020
    [Advance publication] Released: April 08, 2020
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    Aim: Lifetime risk (LTR) indicates the absolute risk of disease during the remainder of an individual's lifetime. We aimed to assess the LTRs for coronary heart disease (CHD) mortality associated with blood pressure (BP) and total cholesterol levels in an Asian population using a meta-analysis of individual participant data because no previous studies have assessed this risk.

    Methods: We analyzed data from 105,432 Japanese participants in 13 cohorts. Apart from grade 1 and 2–3 hypertension groups, we defined “normal BP” as systolic/diastolic BP <130/<80 mmHg and “high BP” as 130–139/80–89 mmHg. The sex-specific LTR was estimated while considering the competing risk of death.

    Results: During the mean follow-up period of 15 years (1,553,735 person-years), 889 CHD deaths were recorded. The 10-year risk of CHD mortality at index age 35 years was ≤ 0.11%, but the corresponding LTR was ≥ 1.84%. The LTR of CHD at index age 35 years steeply increased with an increase in BP of participants with high total cholesterol levels [≥ 5.7 mmol/L (220 mg/dL)]. This risk was 7.73%/5.77% (95% confidence interval: 3.53%–10.28%/3.83%–7.25%) in men/women with grade 2–3 hypertension and high total cholesterol levels. In normal and high BP groups, the absolute differences in LTRs between the low and high total cholesterol groups were ≤ 0.25% in men and ≤ 0.40% in women.

    Conclusions: High total cholesterol levels contributed to an elevated LTR of CHD mortality in hypertensive individuals. These findings could help guide high-risk young individuals toward initiating lifestyle changes or treatments.

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  • Teruhide Koyama, Nagato Kuriyama, Etsuko Ozaki, Satomi Tomida, Ritei U ...
    Type: Original Article
    Article ID: 54320
    Published: 2020
    [Advance publication] Released: April 08, 2020
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    Aim: Accumulating evidence reveals that sedentary behavior is associated with mortality and cardiometabolic disease; however, there are potential age and sex differences in sedentary behavior and health outcomes that have not been adequately addressed. This study aimed to determine the association of sedentary behavior with cardiometabolic diseases such as hypertension, dyslipidemia, diabetes mellitus, and its risk factors in a large Japanese population according to age and sex.

    Methods: Using data from the Japan Multi-Institutional Collaborative Cohort Study obtained from baseline surveys, data of 62,754 participants (27,930 males, 34,824 females) were analyzed. This study uses a cross-sectional design and self-administered questionnaires to evaluate sedentary time and anamnesis. For the logistic regression analysis, sedentary time <5 h/day was used as the reference and then adjusted for age, research areas, leisure-time metabolic equivalents, and alcohol and smoking status. From the analysis of anthropometric and blood examinations, 35,973 participants (17,109 males, 18,864 females) were analyzed.

    Results: For hypertension and diabetes, sedentary time was associated with a significantly higher proportion of male participants. Both sexes were associated with a significantly higher proportion of participants with dyslipidemia. Participants who had longer sedentary time tended to have increased levels of blood pressure, triglycerides, and non-high-density lipoprotein cholesterol (HDL-C), and decreased levels of HDL-C, especially in the 60–69 years group.

    Conclusions: Independent of leisure-time physical activity, sedentary time was associated with cardiometabolic diseases in a large Japanese population classified by age and sex. Our findings indicate that regularly interrupting and replacing sedentary time may contribute to better physical health-related quality of life.

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  • Osamu Iida, Mitsuyoshi Takahara, Yoshimitsu Soga, Akio Kodama, Hiroto ...
    Type: Original Article
    Article ID: 54866
    Published: 2020
    [Advance publication] Released: March 28, 2020
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    Aim: To investigate the associations between preoperative characteristics and the risk of reintervention in patients undergoing revascularization for chronic limb-threatening ischemia (CLTI) in a contemporary real-world setting.

    Methods: We retrospectively analyzed data from a clinical database formed by the Surgical Reconstruction Versus Peripheral Intervention in Patients With Critical Limb Ischemia (SPINACH) study, which was a multicenter, prospective, observational study. The study population was composed of 520 CLTI patients with the wound, ischemia, and foot infection (WIfI) classes I-3 with resting pain or classes I-2/3 with ulcers/gangrene. Of the 520 patients, 192 had surgical reconstruction planned, whereas 328 had endovascular therapy (EVT) alone planned at the time of registration. The current analysis was conducted to explore the associations between preoperative characteristics and the risk of reintervention.

    Results: A total of 452 participants (87%) completed the 3-year follow-up regarding reintervention. The competing risk analysis estimated that the three-year cumulative incidence rates for reintervention and reintervention-free deaths were 44.0% and 28.7%, respectively. No preoperative characteristics had a significant interaction effect with EVT versus surgical reconstruction. The risk analysis identified the following independent risk factors for reintervention: 1) EVT instead of bypass reconstruction, 2) renal dysfunction, 3) history of revascularization after CLTI onset (i.e., requirement of redo revascularization for CLTI), and 4) bilateral CLTI. Patients with more than one of these risk factors had an increased risk of reintervention.

    Conclusions: The current study identified preoperative characteristics associated with an increased risk of reintervention. No preoperative characteristics had any significant interactions with EVT or surgical reconstruction.

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  • Hirofumi Tomita
    Type: Editorial
    Article ID: ED127
    Published: 2020
    [Advance publication] Released: March 28, 2020
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  • Satoshi Shoji, Shun Kohsaka, Mitsuaki Sawano, Tomonori Okamura, Aya Hi ...
    Type: Original Article
    Article ID: 54171
    Published: 2020
    [Advance publication] Released: March 19, 2020
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    Aims: P-wave terminal force in lead V1 (PTFV1) is an electrocardiogram marker of increased left atrial pressure and may be a noninvasive and early detectable marker for future cardiovascular events in the general population compared to serum B-type natriuretic peptide (BNP) concentration. The clinical significance of PTFV1 in the contemporary general population is an area of unmet need. We aimed to demonstrate the correlation between PTFV1 and BNP concentrations in a contemporary representative Japanese population.

    Methods: Among 2,898 adult men and women from 300 randomly selected districts throughout Japan (NIPPON DATA2010), we analyzed 2,556 participants without cardiovascular disease (stroke, myocardial infarction, and atrial fibrillation). Elevated BNP was defined as a value of ≥ 20 pg/mL based on the definition from the Japanese Circulation Society guidelines.

    Results: In total, 125 (4.9%) participants had PTFV1. Participants with PTFV1 were older with a higher prevalence of hypertension, major electrocardiographic findings, and elevated BNP concentrations (13.5 [6.9, 22.8] versus 7.8 [4.4, 14.5] pg/mL; P<0.001). After adjustment for confounders, PTFV1 was correlated with elevated BNP (odds ratio, 1.66; 95% confidence interval, 1.05–2.62; P=0.030). This correlation was consistent among various subgroups and was particularly evident in those aged <65 years or those without a history of hypertension.

    Conclusions: In the contemporary general population cohort, PTFV1 was independently related to high BNP concentration. PTFV1 may be an alternative marker to BNP in identifying individuals at a higher risk of future cardiovascular events in the East Asian population.

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  • Mitsuyoshi Takahara, Osamu Iida, Yoshimitsu Soga, Akio Kodama, Hiroto ...
    Type: Original Article
    Article ID: 55145
    Published: 2020
    [Advance publication] Released: March 19, 2020
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    Aim: Recent studies suggested that past history of obesity or maximum body mass index (BMI) in the past was a strong prognostic predictor in a general population. The current study aimed to survey the distribution of current and maximum BMIs and to investigate their prognostic impact in patients with critical limb ischemia (CLI), whose prognosis was poor even after revascularization.

    Methods: We analyzed a database of a prospective, multicenter registry in Japan, including 499 CLI patients undergoing revascularization. Their current and maximum BMIs were surveyed at registration. The distribution and the impact on the prognosis were explored.

    Results: The estimated means (95% confidence intervals) of current and maximum BMIs were respectively 22.0 (21.7 to 22.3) and 25.3 (24.8 to 25.8) kg/m2; the difference was 3.3 (2.9 to 3.7) kg/m2. The prevalence of current obesity (BMI ≥ 25 kg/m2) was 18% (15% to 22%), whereas 48% (43% to 53%) had ever been obese (maximum BMI ≥ 25 kg/m2). Past obesity was not rare even in currently lean subjects (BMI <18.5 kg/m2), with the prevalence of 18% (7% to 29%). Current BMI, but not maximum BMI, was associated with the mortality risk; the adjusted hazard ratios per 5 kg/m2 increase were 0.61 [0.46, 0.81] (P=0.001) and 1.07 [0.87, 1.31] (P=0.55), respectively.

    Conclusion: The prevalence of current obesity was as low as 18% (15% to 22%) in Japanese CLI patients undergoing revascularization, whereas about a half were formerly obese. Maximum BMI was not independently associated with the mortality risk in the population.

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  • Pasquale Esposito, Daniela Verzola, Edoardo La Porta, Samantha Milanes ...
    Type: Original Article
    Article ID: 51144
    Published: 2020
    [Advance publication] Released: March 14, 2020
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    Aim: Myostatin (Mstn) has been described as a trigger for the progression of atherosclerosis. In this study, we evaluated the role of Mstn in arterial remodeling in patients with end-stage renal disease (ESRD).

    Methods: Vascular specimens were collected from 16 ESRD patients (56.4±7.9 years) undergoing renal transplant (recipients) and 15 deceased kidney non-uremic donors (55.4±12.1 years). We studied gene and protein expression of Mstn, ubiquitin ligases, Atrogin-1, and muscle ring finger protein-1 (MuRF-1), inflammatory marker CCL2, cytoskeleton components, and Klotho by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Moreover, we assessed vascular calcification and collagen deposition. Finally, we studied the effects of recombinant Mstn on rat vascular smooth muscle cells (VSMCs, A7r5) and evaluated the effects of uremic serum (US) on primary human VSMCs.

    Results: Myostatin mRNA was upregulated in the arterial vascular wall of recipients compared with donors (~15- folds, p<0.05). This response was accompanied by the upregulation of gene expression of Atrogin-1 and MuRF-1 (+2.5- and +10-fold) and CCL2 (+3-fold). Conversely, we found downregulation of protein expression of Smoothelin, α-smooth muscle actin (α-SMA), vimentin, and Klotho (-85%, -50%, -70%, and -80%, respectively; p<0.05) and gene expression of vimentin and Klotho. Exposition of A7r5 to Mstn induced a time-dependent SMAD 2/SMAD 3 phosphorylation and expression of collagen-1 and transforming growth factor β (TGFβ) mRNA, while US induced overexpression of Mstn and Atrogin-1 and downregulation of Smoothelin and Klotho.

    Conclusions: Our data suggest that uremia might induce vascular Mstn gene expression together with a complex pathway of molecular and structural changes in the vascular wall. Myostatin, in turn, can translate the metabolic alterations of uremia into profibrotic and stiffness inducing signals.

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  • Masanori Nagao, Gen Kobashi, Mitsumasa Umesawa, Renzhe Cui, Kazumasa Y ...
    Type: Original Article
    Article ID: 51664
    Published: 2020
    [Advance publication] Released: March 11, 2020
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    Aim: The association between urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress marker, and the incidence of cardiovascular disease (CVD) has not been confirmed because no previous studies evaluated 24-hour 8-OHdG excretion levels in the general population. We aimed to confirm the association between 24-hour urinary 8-OHdG levels and CVD risk among Japanese men and women.

    Methods: A nested case-control study was performed based on a 24-hour urine collection in a community-based cohort study performed from 1996 to 2005. Seventy-six cases (55 men and 21 women) who experienced their first CVD incidence during the follow-up period (median: 5.9 years) were recruited. The controls were frequency-matched 1:2, with each case for sex, age, area of residence, and baseline year. The 8-OHdG level was measured by enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression models adjusted for body mass index, ethanol intake, smoking status, and estimated glomerular filtration rate.

    Results: The geometric mean and geometric standard deviation (SD) of 8-OHdG levels (nmol/day) for cases and controls were 35.5 (1.55) and 35.5 (1.54) for men and 32.1 (1.35) and 25.0 (1.39) for women, respectively. The multivariable OR (95% CI) of CVD incidence according to the 1-SD increment of the log-transformed 8-OHdG level was 2.08 (0.99–4.37) for women. The multivariable ORs (95% CIs) for the 1st (lowest) and 4th versus 2nd quartile according to 8-OHdG for men were 3.29 (1.02-10.61) and 2.77 (0.96–7.96), respectively.

    Conclusion: A high 8-OHdG level tended to be associated with CVD incidence among women.

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  • Min Peng, Xiang Li, Yujing Liu, Min Zou, Yaqian Xia, Gelin Xu
    Type: Original Article
    Article ID: 53843
    Published: 2020
    [Advance publication] Released: March 07, 2020
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    Aim: Glycemic index (GI) and glycemic load (GL) influence postprandi al glucose concentrations and insulin responses. This study aims to ascertain the connection between GI, GL, and carotid atherosclerotic stenosis and cardiovascular disease (CVD) risk factors.

    Methods: A total of 669 patients with ischemic stroke within 7 days were enrolled. GI and GL were assessed with a validated food frequency questionnaire from patients. Computed tomography angiography (CTA) was used for the evaluation of carotid atherosclerotic stenosis. Traditional risk factors such as total cholesterol, triglycerides, LDL-C, HDL-C, C-reactive protein, homocysteine, neutrophil to lymphocyte ratio (NLR), fasting plasma glucose, and hemoglobin A1c were measured. GI/GL and its association with CVD risk factors and carotid stenosis were explored with Spearman analysis and multivariable logistic regression, respectively.

    Results: The prevalence of carotid stenosis was 63.2% of all 669 participants. The mean value of GI/GL was 49.3/137. Spearman test did not detect significant relationships between GI/GL and CVD risk factors. In multivariable regression models, GI (4th vs. 1st quartile, OR=2.11; 95% CI, 1.30–3.42) and GL (4th vs. 1st quartile, OR=1.82; 95% CI, 1.12–2.96) were observed a significant association with carotid stenosis after adjustment for major confounding factors. The association between GL and carotid stenosis became more pronounced among yo ungers (4th vs. 1st quartile, OR=2.42; 95% CI, 1.13–4.76) and women (4th vs. 1st quartile, OR=3.81; 95% CI, 1.45–5.05).

    Conclusion: Higher GI and GL were positively associated with a higher degree of carotid stenosis in these Chinese cerebral infarction patients, especially in younger patients and women.

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  • Ryosuke Sato, Eiichi Akiyama, Masaaki Konishi, Yasushi Matsuzawa, Hiro ...
    Type: Original Article
    Article ID: 52282
    Published: 2020
    [Advance publication] Released: March 05, 2020
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    Aim: The importance of sarcopenia in cardiovascular diseases has been recently demonstrated. This study aims to examine whether skeletal muscle mass (SMM), an important component of sarcopenia, is associated with an increased risk of poor outcome in patients after ST-segment elevation myocardial infarction (STEMI).

    Methods: We measured SMM in 387 patients with STEMI using dual-energy X-ray absorptiometry. Patients were divided into low- and high-appendicular skeletal mass index (ASMI: appendicular SMM divided by height squared (kg/m2)) groups using the first quartile of ASMI (≤ 6.64 kg/m2 for men and ≤ 5.06 kg/m2 for women). All patients were followed up for the primary composite outcome of all-cause death, nonfatal myocardial infarction, nonfatal ischemic stroke, hospitalization for congestive heart failure, and unplanned revascularization.

    Results: Low-ASMI group was older and had a more complex coronary lesion, a lower left ventricular ejection fraction, and a higher prevalence of Killip classification ≥ 2 than high-ASMI group. During a median follow-up of 33 months, the event rate was significantly higher in low-ASMI group than in high-ASMI group (24.7% vs 13.4%, log-rank p=0.001). Even after adjustment for patients' background, low ASMI was independently associated with the high risk of primary composite events (adjusted hazard ratio 2.06, 95% confidence interval 1.01– 4.19, p=0.04). In the subgroup analyses of male patients (n=315), the optimal cutoff point of ASMI for predicting primary composite outcome was 6.75 kg/m2, which was close to its first quartile value.

    Conclusions: Low ASMI is independently associated with poor outcome in patients with STEMI.

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  • Rie Kishida, Kazumasa Yamagishi, Isao Muraki, Mizuki Sata, Akiko Tamak ...
    Type: Original Article
    Article ID: 53447
    Published: 2020
    [Advance publication] Released: March 05, 2020
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    Aim: Seaweed is a popular traditional foodstuff in Asian countries. To our knowledge, few studies have examined the association of seaweed intake with mortality from cardiovascular disease. We examined the association of frequency of seaweed intake with total and specific cardiovascular disease mortality.

    Methods: We examined the association of seaweed intake with mortality from cardiovascular disease among 40,234 men and 55,981 women who participated in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk. Sex-specific hazard ratios for mortality from cardiovascular disease (stroke, stroke subtypes, and coronary heart disease) according to the frequency of seaweed intake were calculated stratified by study area and adjusted for potential cardiovascular risk factors and dietary factors.

    Results: During the 1,580,996 person-year follow-up, 6,525 cardiovascular deaths occurred, of which 2,820 were due to stroke, and 1,378, to coronary heart disease. Among men, the multivariable analysis showed that participants who ate seaweed almost every day compared with those who never ate seaweed had hazard ratios (95% confidence interval; P for trend) of 0.79 (0.62–1.01; 0.72) for total cardiovascular disease, 0.70 (0.49–0.99; 0.47) for total stroke, 0.69 (0.41–1.16; 0.11) for cerebral infarction. Among women, the multivariable-adjusted hazard ratios were 0.72 (0.55–0.95; 0.001) for total cardiovascular disease, 0.70 (0.46–1.06; 0.01) for total stroke, and 0.49 (0.27–0.90; 0.22) for cerebral infarction. No associations were observed between seaweed intake and risk of intraparenchymal hemorrhage and coronary heart disease among either men or women.

    Conclusions: We found an inverse association between seaweed intake and cardiovascular mortality among Japanese men and women, especially that from cerebral infarction.

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  • Akira Matsunaga, Mariko Nagashima, Hideko Yamagishi, Keijiro Saku
    Type: Original Article
    Article ID: 51540
    Published: 2020
    [Advance publication] Released: February 29, 2020
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    Aim: Hypertriglyceridemia is a type of dyslipidemia that contributes to atherosclerosis and coronary heart disease. Variants 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 glucokinase regulator (GCKR) are responsible for hypertriglyceridemia. We investigated the molecular basis of severe hypertriglyceridemia in adult patients referred to the Clinical Laboratory at Fukuoka University Hospital.

    Methods: Twenty-three adult patients with severe hypertriglyceridemia (>1,000 mg/dL, 11.29 mmol/L) were selected. The coding regions of candidate genes were sequenced by next-generation sequencing. Forty-nine genes reportedly associated with hypertriglyceridemia were analyzed.

    Results: In the 23 patients, we detected 70 variants: 28 rare and 42 common ones. Among the 28 rare variants with <1% allele frequency, p.I4533L in APOB, p.M490I in MLXIPL, p.L152M in NCAN, and p.S264T in TIMD4 were novel. We did not observe single gene homozygous or compound heterozygous disease-causing rare variants in any of the 23 hypertriglyceridemia cases. However, in silico algorithms and previous reports indicated that five rare variants, APOA5 (p.T184S), GCKR (c.354+1G>A), LMF1 (p.G410R), and LRP1 (p.G813R; p.R2173Q), and seven common variants, APOA5 (pG185C), APOE (p.C130R; p.E262K/p.E263K), GCKR (p.V103M), GPIHBP1 (p.C14F), LRP1 (p.Y4054F), and MLXIPL (p.Q241H), can cause hypertriglyceridemia. However, all five disease-causing rare variants detected in this study were heterozygous.

    Conclusions: The prevalence of disease-causing rare variants in candidate genes in severe hypertriglyceridemia patients was low. The major causes of severe hypertriglyceridemia were not single gene abnormalities, but involved multiple gene variations and environmental factors.

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  • Takao Sato, Yoshifusa Aizawa, Sho Yuasa, Satoshi Fujita, Yoshio Ikeda, ...
    Type: Original Article
    Article ID: 48009
    Published: 2020
    [Advance publication] Released: February 28, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Epicardial adipose tissue (EAT) may be associated with arrhythmogenesis. P-wave indices such as P-wave dispersion and P-wave variation indicated a slowed conduction velocity within the atria. This study investigated the effect of dapagliflozin on EAT volume and P-wave indices.

    Methods: In the present ad hoc analysis, 35 patients with type 2 diabetes mellitus and coronary artery disease were classified into dapagliflozin group (n=18) and conventional treatment group (n=17). At baseline, EAT volume, HbA1c and plasma level of tumor necrotic factor-α (TNF-α) levels, echocardiography, and 12-lead electrocardiogram (ECG) were performed. EAT volume was measured using computed tomography. Using 12-lead ECG, P-wave indices were measured.

    Results: At baseline, EAT volumes in the dapagliflozin and conventional treatment groups were 113±20 and 110±27 cm3, respectively. Not only HbA1c and plasma level of TNF-α but also echocardiography findings including left atrial dimension and P-wave indices were comparable between the two groups. After 6 months, plasma level of TNF-α as well as EAT volume significantly decreased in the dapagliflozin group only. P-wave dispersion and P-wave variation significantly decreased in the dapagliflozin group only (-9.2±8.7 vs. 5.9±19.9 ms, p=0.01; -3.5±3.5 vs. 1.7±5.9 ms, p=0.01). The change in P-wave dispersion correlated with changes in EAT volume and plasma level of TNF-α. In multivariate analysis, the change in EAT volume was an independent determinant of the change in P-wave dispersion.

    Conclusion: Dapagliflozin reduced plasma level of TNF-α, EAT volume, and P-wave indices, such as P-wave dispersion. The changes in P-wave indices were especially associated with changes in EAT volume.

    The number and date of registration: UMIN000035660, 24/Jan/2019

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  • Xianda Lin, Yungang Cao, Jueyue Yan, Zheng Zhang, Zusen Ye, Xiaoyan Hu ...
    Type: Original Article
    Article ID: 49783
    Published: 2020
    [Advance publication] Released: February 28, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Intracerebral hemorrhage (ICH) is one of the most severe complications of thrombolysis. Symptomatic ICHs are associated with adverse outcomes. It has been reported that symptomatic ICHs most commonly occur within the first few hours after the initiation of intravenous thrombolysis. Our aim here was to determine the risk factors for early ICH (within 12 h) after thrombolysis.

    Methods: We analyzed patients with acute ischemic stroke who received intravenous alteplase at two hospitals affiliated to Wenzhou Medical University between March 2008 and November 2017. The ICH diagnosis time was defined as the time from the intravenous administration of alteplase to the first detection of hemorrhage on computed tomography. Demographic data, medical history, clinical features, and laboratory examination results were collected. Univariate analysis followed by multivariable logistic regression analysis was performed to determine the predictors of early ICH (within 12 h) after thrombolysis.

    Results: Among 197 patients, early ICH (within 12 h) after thrombolysis occurred in 13 patients (6.6%). In the univariate analysis, patients with early ICHs were significantly correlated with prior stroke (P=0.04). After adjusting for potential confounders in the multivariate analysis, prior stroke (odds ratio [OR]: 5.752, 95% confidence interval [CI]: 1.487–22.248; P=0.011) and atrial fibrillation (OR: 5.428, 95% CI: 1.427–20.640; P=0.013) were associated with early ICH.

    Conclusions: Prior stroke and atrial fibrillation are independent risk factors for early ICHs (within 12 h) after intravenous thrombolysis with alteplase.

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  • Kohji Shirai
    Type: Editorial
    Article ID: ED125
    Published: 2020
    [Advance publication] Released: February 28, 2020
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  • Arief Rahadian, Daiju Fukuda, Hotimah Masdan Salim, Shusuke Yagi, Keny ...
    Type: Original Article
    Article ID: 52100
    Published: 2020
    [Advance publication] Released: February 26, 2020
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    Aim: Recent studies have demonstrated that selective sodium–glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular events, although their mechanism remains obscure. We examined the effect of canagliflozin, an SGLT2i, on atherogenesis and investigated its underlying mechanism.

    Method: Canagliflozin (30 mg/kg/day) was administered by gavage to streptozotocin-induced diabetic apolipoprotein E-deficient (ApoE-/-) mice. Sudan IV staining was performed at the aortic arch. Immunostaining, quantitative RT-PCR, and vascular reactivity assay were performed using the aorta. In vitro experiments using human umbilical vein endothelial cells (HUVECs) were also performed.

    Result: Canagliflozin decreased blood glucose (P<0.001) and total cholesterol (P<0.05) levels. Sudan IV staining showed that 12-week canagliflozin treatment decreased atherosclerotic lesions (P<0.05). Further, 8-week canagliflozin treatment ameliorated endothelial dysfunction, as determined by acetylcholine-induced vasodilation (P<0.05), and significantly reduced the expressions of inflammatory molecules such as ICAM-1 and VCAM-1 in the aorta at the RNA and protein levels. Canagliflozin also reduced the expressions of NADPH oxidase subunits such as NOX2 and p22phox in the aorta and reduced urinary excretion of 8-OHdG, suggesting a reduction in oxidative stress. Methylglyoxal, a precursor of advanced glycation end products, increased the expressions of ICAM-1 and p22phox in HUVECs (P<0.05, both). Methylglyoxal also decreased the phosphorylation of eNOSSer1177 and Akt but increased the phosphorylation of eNOSThr495 and p38 MAPK in HUVECs.

    Conclusion: Canagliflozin prevents endothelial dysfunction and atherogenesis in diabetic ApoE-/- mice. Anti-inflammatory and antioxidative potential due to reduced glucose toxicity to endothelial cells might be its underlying mechanisms.

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  • Kimie Tanaka, Daiju Fukuda, Yasutomi Higashikuni, Yoichiro Hirata, Iss ...
    Type: Original Article
    Article ID: 52720
    Published: 2020
    [Advance publication] Released: February 26, 2020
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    Aim: Synthetic vascular grafts are widely used in surgical revascularization, mainly for medium- to large-sized vessels. However, synthetic grafts smaller than 6 mm in diameter are associated with a high incidence of thrombosis. In this study, we evaluated silk fibroin, a major protein of silk, with high biocompatibility and biodegradability, as a useful material for extremely-small-diameter vascular grafts.

    Methods: A small-sized (0.9 mm inner diameter) graft was braided from a silk fibroin thread. The right carotid arteries of 8- to 14-week-old male C57BL/6 mice were cut at the midpoint, and fibroin grafts (5- to 7-mm in length) were transplanted using a cuff technique with polyimide cuffs. The grafts were harvested at different time points and analyzed histologically.

    Results: CD31+ endothelial cells had already started to proliferate at 2 weeks after implantation. At 4 weeks, neointima had formed with α-smooth muscle actin+ cells, and the luminal surface was covered with CD31+endothelial cells. Mac3+ macrophages were accumulated in the grafts. Graft patency was confirmed at up to 6 months after implantation.

    Conclusion: This mouse model of arterial graft implantation enables us to analyze the remodeling process and biocompatibility of extremely-small-diameter vascular grafts. Biodegradable silk fibroin might be applicable for further researches using genetically modified mice.

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  • Fengzhi Wang, Jiaoqi Wang, Qiu He, Liyu Wang, Yumeng Cao, Hemin Zhang, ...
    Type: Original Article
    Article ID: 54221
    Published: 2020
    [Advance publication] Released: February 16, 2020
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    Aim: There is no randomized controlled trial to compare the effectiveness and safety of mechanical thrombectomy (MT) to intravenous thrombolysis in patients with posterior circulation occlusion (PCO). Hence, we firstly performed a meta-analysis to investigate the outcomes of MT in PCO and then compared these outcomes to anterior circulation occlusion (ACO) to provide fundamental data to further studies.

    Methods: We searched the PubMed, EMBASE, and Cochrane Library from dates of inception to June 2019 for relevant studies. Outcomes including functional independence at 90 days, successful recanalization, mortality, symptomatic intracranial hemorrhage (sICH), and futile recanalization were extracted.

    Results: Seven studies involving 474 patients with PCO thrombectomy were analyzed. There was a lower rate of functional independence at 90 days and a higher rate of mortality after thrombectomy in PCO versus ACO (odds ratios (OR) 0.72; 95% confidence interval (CI) 0.57–0.90; OR 2.03; 95% CI 1.30–3.18). Recanalization rates were comparable (OR 1.01; 95% CI 0.62–1.65), but a higher futile recanalization rate was found in basilar artery occlusion (BAO) (OR 1.75; 95% CI 1.30–2.37). There was a lower rate of sICH in MT for patients with PCO versus ACO (OR 0.54; 95% CI 0.29–0.99).

    Conclusions: We found that the outcomes of MT for patients with PCO were poorer than with ACO. On the other hand, MT appears to have lower rates of sICH and to increase successful recanalization. Given the high recanalization rate, MT may serve as an adjunct to standard treatment. The key point to improve outcomes is recognizing reliable factors associated with futile recanalization and optimizing the results of MT. But in view of the different characteristics of posterior circulation stroke and anterior circulation stroke, the results are far from robust.

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  • Congying Xia, Marleen Vonder, Grigory Sidorenkov, Matthijs Oudkerk, Ja ...
    Type: Original Article
    Article ID: 52928
    Published: 2020
    [Advance publication] Released: February 15, 2020
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    Aim: Coronary artery disease (CAD) and cognitive impairment are common in the elderly, with evidence for shared risk factors and pathophysiological processes. The coronary artery calcium (CAC) score is a marker of subclinical CAD, which may allow early detection of individuals prone to cognitive decline. Prior studies on associations of CAC and clinical CAD with cognitive impairment had discrepant results. This systematic review aims to evaluate the association of (sub)clinical CAD with cognitive function, cognitive decline, and diagnosis of mild cognitive impairment (MCI) or dementia.

    Methods: A systematic search was conducted in MEDLINE, Embase, and Web of Science until February 2019, supplemented with citations tracking. Two reviewers independently screened studies and extracted information including odds ratios (ORs) and hazard ratios (HRs).

    Results: Forty-six studies, 10 on CAC and 36 on clinical CAD, comprising 1,248,908 participants were included in the systematic review. Studies about associations of (sub)clinical CAD with cognitive function and cognitive decline had heterogeneous methodology and inconsistent findings. Two population-based studies investigated the association between CAC and risk of dementia over 6–12.2 years using different CAC scoring methods. Both found a tendency toward higher risk of dementia as CAC severity increased. Meta-analysis in 15 studies (663,250 individuals) showed an association between CAD and MCI/dementia (pooled OR 1.32, 95%CI 1.17–1.48) with substantial heterogeneity (I2=87.0%, p<0.001). Pooled HR of CAD for incident MCI/dementia over 3.2–25.5 years in six longitudinal studies (70,060 individuals) was 1.51 (95%CI 1.24–1.85), with low heterogeneity (I2=14.1%, p=0.32). Sensitivity analysis did not detect any study that was of particular influence on the pooled OR or HR.

    Conclusions: Limited evidence suggests the CAC score is associated with risk of dementia. In clinical CAD, risk of MCI and dementia is increased by 50%, as supported by stronger evidence.

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  • Peiyang Zhou, Jincheng Liu, Lingyun Wang, Wenmin Feng, Zhihua Cao, Pu ...
    Type: Original Article
    Article ID: 53132
    Published: 2020
    [Advance publication] Released: February 15, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: To investigate the association of small dense low-density lipoprotein cholesterol (sdLDL-C) and acute ischemic stroke (AIS) in terms of risk, severity, and outcomes. Prediction models were established to screen high-risk patients and predict prognosis of AIS patients.

    Methods: We enrolled in this study 355 AIS patients and 171 non-AIS controls. AIS was subtyped according to TOAST criteria, and the severity and outcomes of AIS were measured. Blood glucose and lipid profiles including total cholesterol, triglyceride, and lipoproteins were measured in all patients using automatic measure. Lipoprotein subfractions were detected by the Lipoprint LDL system.

    Results: As compared with the non-AIS control group, the AIS group had higher sdLDL-C levels. Pearson correlation analysis revealed that the sdLDL-C level and risk of AIS, especially non-cardioembolic stroke, were positively correlated. The area under the curve of sdLDL-C for AIS risk was 0.665, better than that of other lipids. Additionally, the sdLDL-C level was significantly correlated with AIS severity and bad outcomes. A logistic regression model for assessing the probability of AIS occurrence and a prognostic prediction model were established based on sdLDL-C and other variables.

    Conclusions: Elevated levels of sdLDL-C were associated with a higher prevalence of AIS, especially in non-cardioembolic stroke subtypes. After adjustment for other risk factors, sdLDL-C was found to be an independent risk factor for AIS. Also, sdLDL-C level was strongly associated with AIS severity and poor functional outcomes. Logistic regression models for AIS risk and prognosis prediction were established to help clinicians provide better prevention for high-risk subjects and monitor their prognosis.

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  • Kexun Zhang, Yanfeng Jiang, Yingzhe Wang, Chen Suo, Kelin Xu, Zhen Zhu ...
    Type: Original Article
    Article ID: 52530
    Published: 2020
    [Advance publication] Released: February 08, 2020
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    Aims: We aimed to examine the associations of four extracranial artery indicators with cerebral small vessel disease (CSVD) and its total burden.

    Methods: A total of 904 individuals aged 55–65 years old were included from the Taizhou Imaging Study. CSVD markers, including lacunes (LAC), white matter hyperintensities (WMH), cerebral microbleeds (CMB), and perivascular spaces (PVS), were rated based on brain magnetic resonance imaging. We also measured extracranial artery indices, including the brachial-ankle pulse wave velocity (baPWV), the ankle-brachial index, the carotid intima-media thickness (IMT), and carotid plaque. Linear and binary logistic regressions were adopted to test the associations among these four artery indicators and each CSVD marker when appropriate. Additionally, ordinal and multinomial logistic regressions were performed to assess the relationships between artery indicators and total CSVD score (range from 0–4 points).

    Results: A total of 443 (49.0%) participants were found to have at least one of the CSVD markers, including 172 (19.0%) with WMH, 184 (20.4%) with LAC, 147 (16.3%) with CMB, and 226 (25.0%) with PVS. Increased baPWV was significantly associated with each CSVD marker, increasing carotid IMT was associated with LAC and PVS, and the presence of carotid plaque was associated with WMH volume and PVS. Moreover, per SD increment of baPWV (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.11–1.50) and the presence of carotid plaque (OR: 1.42, 95% CI: 1.05–1.92) were significantly associated with greater total CSVD scores.

    Conclusion: Increased baPWV and the presence of carotid plaque appear to be associated with total CSVD burden in rural regions in China.

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  • Yandong Liu, Wei Huan, Jianjin Wu, Sili Zou, Lefeng Qu
    Type: Original Article
    Article ID: 52993
    Published: 2020
    [Advance publication] Released: February 08, 2020
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    Aims: To investigate the differentially expressed genes (DEGs) and molecular interaction in unstable atherosclerotic carotid plaques.

    Methods: Gene expression datasets GSE41571, GSE118481, and E-MTAB-2055 were analyzed. Co-regulated DEGs in at least two datasets were analyzed with the enrichment of Gene Ontology Biological Process (GO-BP), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein–protein interaction (PPI) networks, interrelationships between miRNAs/transcriptional factors, and their target genes and drug–gene interactions. The expression of notable DEGs in human carotid artery plaques and plasma was further identified.

    Results: The GO-BP enrichment analysis revealed that genes associated with inflammatory response, and extracellular matrix organization were altered. The KEGG enrichment analysis revealed that upregulated DEGs were enriched in the tuberculous, lysosomal, and chemokine signaling pathways, whereas downregulated genes were enriched in the focal adhesion and PI3K/Akt signaling pathway. Collagen type I alpha 2 chain (COL1A2), adenylate cyclase 3 (ADCY3), C-X-C motif chemokine receptor 4 (CXCR4), and TYRO protein tyrosine kinase binding protein (TYROBP) might play crucial roles in the PPI networks. In drug–gene interactions, colonystimulating factor-1 receptor had the most drug interactions. Insulin-like growth factor binding protein 6 (IGFBP6) was markedly downregulated in unstable human carotid plaques and plasma. Under a receiver operating characteristic curve analysis, plasma IGFBP6 had a significant discriminatory power (AUC, 0.894; 95% CI, 0.810–0.977), with a cutoff value of 142.08 ng/mL.

    Conclusions: The genes COL1A2, ADCY3, CXCR4, and TYROBP are promising targets for the prevention of unstable carotid plaque formation. IGFBP6 may be an important biomarker for predicting vulnerable plaques.

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  • Michikazu Nakai, Makoto Watanabe, Yoshihiro Kokubo, Kunihiro Nishimura ...
    Type: Original Article
    Article ID: 48843
    Published: 2020
    [Advance publication] Released: February 06, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: To construct a risk prediction model for cardiovascular disease (CVD) based on the Suita study, an urban Japanese cohort study, and compare its accuracy against the Framingham CVD risk score (FRS) model.

    Methods: After excluding participants with missing data or those who lost to follow-up, this study consisted of 3,080 men and 3,470 women participants aged 30–79 years without CVD at baseline in 1989–1999. The main outcome of this study was incidence of CVD, defined as the incidence of stroke or coronary heart disease. Multivariable Cox proportional hazards models with stepwise selection were used to develop the prediction model. To assess model performance, concordance statistics (C-statistics) and their 95% confidence intervals (CIs) were calculated using a bootstrap procedure. A calibration test was also conducted.

    Results: During a median follow-up period of 16.9 years, 351 men and 241 women developed CVD. We formulated risk models with and without electrocardiogram (ECG) data that included age, sex, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, diabetes mellitus, smoking, and urinary protein as risk factors. The C-statistics of the Suita CVD risk models with ECG data (0.782; 95% CI, 0.766–0.799) and without ECG data (0.781; 95% CI, 0.765–0.797) were significantly higher than that of the FRS model (0.768; 95% CI, 0.750–0.785).

    Conclusions: The Suita CVD risk model is feasible to use and improves predictability of the incidence of CVD relative to the FRS model in Japan.

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  • Atsushi Takahashi, Tetsuya Ohira, Kanako Okazaki, Seiji Yasumura, Akir ...
    Type: Original Article
    Article ID: 52225
    Published: 2020
    [Advance publication] Released: January 31, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The Fukushima Daiichi Nuclear Power Plant accident dramatically changed the lifestyle of residents who lived near the plant. We evaluated the association of metabolic syndrome (MetS) with specific lifestyle- and disaster-related factors in residents following the accident.

    Methods: This cross-sectional study included 20,920 residents who underwent both the Comprehensive Health Check and the Mental Health and Lifestyle Survey from June 2011 to March 2012. Associations between MetS and lifestyle- and disaster-related factors, including psychological distress (post-traumatic stress disorder [PTSD]), were estimated using logistic regression analysis, adjusted for demographic and lifestyle factors, in 2019.

    Results: MetS was present in 30.4% of men and 11.5% of women. There were significant differences in smoking, drinking status, and PTSD prevalence between subjects with and without MetS. Multivariable logistic regression analysis showed that age, quitting smoking, light to moderate drinking, and low physical activity were significantly associated with MetS. Moreover, PTSD was also significantly associated with MetS in women.

    Conclusions: Lifestyle- and disaster-related factors, including PTSD, were associated with MetS among subjects who lived near the Fukushima Daiichi Nuclear Power Plant accident.

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  • Daisaku Masuda, Shizuya Yamashita
    Type: Editorial
    Article ID: ED124
    Published: 2020
    [Advance publication] Released: January 31, 2020
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  • Kazuo Omori, Naoto Katakami, Shoya Arakawa, Yuichi Yamamoto, Hiroyo Ni ...
    Type: Original Article
    Article ID: 52506
    Published: 2020
    [Advance publication] Released: January 25, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: An identification of the high-risk group of atherosclerotic cardiovascular disease (CVD) is important in the management of patients with diabetes. Metabolomics is a potential tool for the discovery of new biomarkers. With this background, we aimed to identify metabolites associated with atherosclerosis in patients with type 2 diabetes mellitus (T2DM).

    Methods: A total of 176 patients with T2DM who have never had a CVD event and 40 who were survivors of coronary artery disease (CAD) events were enrolled. Non-targeted metabolome analysis of fasting plasma samples was performed using gas chromatography coupled with mass spectrometry (GC/MS) highly optimized for multiple measurement of blood samples. First, metabolites were screened by analyzing the association with the established markers of subclinical atherosclerosis (i.e., carotid maximal intima-media thickness (max-IMT) and flow-mediated vasodilation (FMD)) in the non-CVD subjects. Then, the associations between the metabolites detected and the history of CAD were investigated.

    Result: A total of 65 annotated metabolites were detected. Non-parametric univariate analysis identified inositol and indoxyl sulfate as significantly (p<0.05) associated with both max-IMT and FMD. These metabolites were also significantly associated with CAD. Moreover, inositol remained to be associated with CAD even after adjustments for traditional coronary risk factors.

    Conclusions: We identified novel biomarker candidates for atherosclerosis in Japanese patients with T2DM using GC/MS-based non-targeted metabolomics.

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  • Yuri Shojima, Yuji Ueno, Ryota Tanaka, Kazuo Yamashiro, Nobukazu Miyam ...
    Type: Original Article
    Article ID: 52373
    Published: 2020
    [Advance publication] Released: January 23, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aims: The ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) is related to major adverse events and death in cardiovascular diseases. The association between long-term prognosis of ischemic stroke and EPA/AA ratio has not been clarified.

    Methods: Acute ischemic stroke patients who had undergone blood examinations for polyunsaturated fatty acids were enrolled. Major cardiovascular events, including recurrence of ischemic stroke, occurrence of cardiovascular and peripheral artery diseases and hemorrhagic stroke, and death, were analyzed, retrospectively. Cox proportional hazards regression analysis was used to explore factors, including clinical characteristics, laboratory data including EPA/AA ratio, and treatments associated with major cardiovascular events and death.

    Results: A total of 269 patients (mean age, 70±13 years; 179 men) were enrolled. During follow-up (mean, 2.3 ±1.0 years), 64 patients exhibited major cardiovascular events and death (annualized rate, 10.5% per person-year). Multivariate Cox analysis revealed that EPA/AA ratio (hazard ratio, 0.26; 95% confidence interval, 0.07– 0.99; p=0.048) and statin therapy (hazard ratio, 0.43; 95% confidence interval, 0.25–0.73; p=0.002) correlated inversely with major cardiovascular events and death. In the Kaplan–Meier analysis, cumulative event-free rates were significantly lower among patients with EPA/AA ratio <0.33 and patients without statin therapy (p=0.006).

    Conclusions: Low EPA/AA ratio at baseline and treatment without statins could predict mortality, recurrent ischemic stroke, cardiovascular and peripheral artery diseases, and hemorrhagic stroke among patients with acute ischemic stroke. The combination of baseline EPA/AA ratio and statin therapy could be critical in predicting the long-term prognosis of ischemic stroke patients.

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  • Md Maruf Haque Khan, Akira Fujiyoshi, Akihiko Shiino, Takashi Hisamats ...
    Type: Original Article
    Article ID: 51284
    Published: 2020
    [Advance publication] Released: January 22, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Coronary artery calcification (CAC) is an independent predictor of stroke and dementia, in which subclinical cerebrovascular diseases (SCVDs) play a vital pathogenetic role. However, few studies have described the association between CAC and SCVDs. Therefore, the aim of this study was to assess the clinical relationship between CAC and SCVDs in a healthy Japanese male population.

    Methods: In this observational study, 709 men, free of stroke, were sampled from a city in Japan from 2010 to 2014. CAC was scored using the Agatston method. The following SCVDs were assessed using magnetic resonance imaging: intracranial arterial stenosis (ICAS), lacunar infarction, deep and subcortical white matter hyperintensity (DSWMH), periventricular hyperintensity (PVH), and microbleeds. The participants were categorized according to CAC scores as follows: no CAC (0), mild CAC (1–100), and moderate-to-severe CAC (>100). The adjusted odds ratios of prevalent SCVDs were computed in reference to the no-CAC group using logistic regression.

    Results: The mean (standard deviation) age of the participants was 68 (8.4) years. Participants in the moderate-to-severe-CAC category showed significantly higher odds of prevalent lacunar infarction, DSWMH, and ICAS in age-adjusted and risk-factor-adjusted models. Microbleeds and PVH, in contrast, did not show any significant associations. The trends for CAC with lacunar infarction, DSWMH, and ICAS were also significant (all P-values for trend ≤ 0.02).

    Conclusions: Higher CAC scores were associated with higher odds of lacunar infarction, DSWMH, and ICAS. The presence and degree of CAC may be a useful indicator for SCVDs involving small and large vessels.

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  • Xingyang Yi, Ling Zhu, Guo Sui, Jie Li, Hua Luo, Ming Yu, Chun Wang, X ...
    Type: Original Article
    Article ID: 53074
    Published: 2020
    [Advance publication] Released: January 17, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: To examine the association between carotid plaque and variants in genes involved in inflammation and endothelial function.

    Methods: This was a multicenter, cross-sectional survey in southwestern China. The residents aged ≥ 40 years volunteered to participate in the face-to-face survey in eight communities. A total of 2,377 subjects with high stroke risk were enrolled. Carotid plaque and plaque phenotype were assessed by carotid ultrasound. Genotypes of 19 variants in 10 genes related to inflammation and endothelial function were examined. Gene–gene interaction was analyzed by generalized multifactor dimensionality reduction (GMDR).

    Results: Carotid plaques were found in 852 (35.8%) subjects, and 454 (53.3%) had stable plaques, whereas 398 (46.7%) had vulnerable plaques. PPARA rs4253655, HABP2 rs7923349, and IL1A rs1609682 were associated with the presence of carotid plaque, and NOS2A rs2297518 and PPARA rs4253655 were associated with vulnerable plaque in univariate analysis. The GMDR analysis revealed that there was a significant gene–gene interaction among HABP2 rs7923349, ITGA2 rs1991013, IL1A rs1609682, and NOS2A rs8081248, and the high-risk interactive genotype among the four variants was independently associated with a higher risk of carotid vulnerable plaque after adjusting the covariates (OR, 2.86, 95% CI: 1.32–7.13, P=0.003).

    Conclusion: The prevalence of carotid plaque was very high in the high-risk stroke population in southwestern China. Variants in genes involved in the endothelial function and inflammation were associated with the carotid plaque. The high-risk interactive genotype among rs7923349, rs1991013, rs1609682, and rs8081248 was independently associated with a higher risk of vulnerable plaque.

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  • Hongbing Liu, Kai Liu, Lulu Pei, Yuan Gao, Lu Zhao, Shilei Sun, Jun Wu ...
    Type: Original Article
    Article ID: 51151
    Published: 2020
    [Advance publication] Released: January 16, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Monocyte-to-high-density lipoprotein ratio (MHR) recently emerged as an inflammatory marker and has been reported to be a novel prognostic indicator of cardiovascular diseases. However, the relationship between MHR and prognosis of acute ischemic stroke (AIS) remains unclear.

    Methods: Consecutive AIS patients were prospectively identified from January 2015 to December 2017. Functional outcome was evaluated by the modified Rankin Scale (mRS). Poor outcome was defined as of mRS 3-6. Multivariate logistic regression analysis was conducted to evaluate the relationship between MHR and poor outcome.

    Results: A total of 1090 AIS patients within 24 hours of the onset of symptoms were recruited. MHR was higher in poor outcome group compared to that in good outcome group [0.53 (0.37-0.69) vs. 0.48 (0.33-0.60), P=0.007]. Multivariate logistic regression analysis indicated that higher MHR level was independently associated with the poor outcome at 3 months (OR 2.58, 95% CI, 1.21-5.51, P=0.015), especially the stroke subtype of large artery atherosclerosis (OR 2.52, 95% CI, 1.03-6.19, P=0.034). Receiver operating curve (ROC) analysis showed that the area under the ROC curves for MHR was 0.67 and the best predictive cutoff value of MHR was 0.51,with a sensitivity of 62.3% and a specificity of 66.5%.

    Conclusions: MHR may be a significant and independent predictor of poor functional outcome in patients with AIS.

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  • Kenji Ebihara, Kazumasa Yamagishi, Mitsumasa Umesawa, Isao Muraki, Ren ...
    Type: Original Article
    Article ID: 52241
    Published: 2020
    [Advance publication] Released: January 11, 2020
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP), frequently used as a biochemical marker for detecting and monitoring heart failure, is also a risk marker for development of coronary heart disease and total stroke. However, studies that explore subtypes of ischemic stroke with regard to NT-proBNP are scarce. Here, we examined NT-proBNP and its impact upon subtypes of ischemic stroke (lacunar stroke, large-artery occlusive stroke and embolic stroke) among Japanese.

    Methods: We measured NT-proBNP and categorized 4,393 participants of the Circulatory Risk in Communities Study into four groups (<55, 55-124, 125-399, and ≥ 400 pg/ml). We used a multivariable Cox proportional hazards model to examine association with risks of stroke and subtypes.

    Results: During 4.7 years of follow-up, we identified 50 strokes, including 35 ischemic (15 lacunar, 6 largeartery occlusive, 10 embolic strokes) and 14 hemorrhagic strokes. NT-proBNP was associated with stroke risk: the multivariable hazard ratio of total strokes was 7.29 (2.82-18.9) for the highest and 2.78 (1.25-6.16) for the second highest NT-proBNP groups compared with the lowest group. The respective hazard ratios for the highest NT-proBNP group were 9.37 (3.14–28.0) for ischemic stroke and 6.81 (1.11–41.7) for lacunar stroke. Further adjustment for atrial fibrillation did not attenuate these associations. The associations were similarly observed for large-artery occlusive and embolic strokes.

    Conclusion: We found that even moderate serum levels of NT-proBNP were associated with the risk of total and ischemic strokes among Japanese whose NT-proBNP levels were relatively low compared with Westerners.

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  • Wei-Ting Wang, Pai-Feng Hsu, Chung-Chi Lin, Yuan-Jen Wang, Yaw-Zon Din ...
    Type: Original Article
    Article ID: 51425
    Published: 2019
    [Advance publication] Released: December 27, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Coronary atherosclerotic plaques can be detected in asymptomatic subjects and are related to low-density lipoprotein cholesterol (LDL) levels in patients with coronary artery disease. However, researchers have not yet determined the associations between various plaque characteristics and other lipid parameters, such as HDL-C and TG levels, in low-risk populations.

    Methods: One thousand sixty-four non-diabetic subjects (age, 57.86±9.73 years; 752 males) who underwent coronary computed tomography angiography (CCTA) were enrolled and the severity and patterns of atherosclerotic plaques were analyzed.

    Results: Statin use was reported by 25% of the study population, and subjects with greater coronary plaque involvement (segment involvement score, SIS) were older and had a higher body mass index (BMI), blood pressure, unfavorable lipid profiles and comorbidities. After adjusting for comorbidities, only age (β=0.085, p<0.001), the male gender (β=1.384, p<0.001), BMI (β=0.055, p=0.019) and HbA1C levels (β=0.894, p<0.001) were independent factors predicting the greater coronary plaque involvement in non-diabetic subjects. In the analysis of significantly different (>50%) stenosis plaque patterns, age (OR: 1.082, 95% CI: 10.47-1.118) and a former smoking status (OR: 2.061, 95% CI: 1.013-4.193) were independently associated with calcified plaques. For partial calcified (mixed type) plaques, only age (OR: 1.085, 95% CI: 1.052-1.119), the male gender (OR: 7.082, 95% CI: 2.638-19.018), HbA1C levels (OR: 2.074, 95% CI: 1.036-4.151), and current smoking status (OR: 1.848, 95% CI: 1.089-3.138) were independently associated with the risk of the presence of significant stenosis in mixed plaques.

    Conclusions: A higher HbA1c levels is independently associated with the presence and severity of coronary artery atherosclerosis in non-diabetic subjects, even when LDL-C levels are tightly controlled.

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  • Haixin Bo, Yilin Li, Ge Liu, Yufen Ma, Zhen Li, Jing Cao, Ying Liu, Ji ...
    Type: Original Article
    Article ID: 51359
    Published: 2019
    [Advance publication] Released: December 17, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: We sought to validate the 2010 Caprini risk assessment model (RAM) in risk stratification for deep vein thrombosis (DVT) prophylaxis among Chinese bedridden patients.

    Methods: We performed a prospective study in 25 hospitals in China over 9 months. Patients were risk-stratified using the 2010 Caprini RAM.

    Results: We included a total 24,524 patients. Fresh DVT was found in 221 patients, with overall incidence of DVT 0.9%. We found a correlation of DVT incidence with Caprini score according to risk stratification (χ2 =196.308, P<0.001). Patients in the low-risk and moderate-risk groups had DVT incidence <0.5%. More than half of patients with DVT were in the highest risk group. Compared with the low-risk group, risk was 2.10-fold greater in the moderate-risk group, 3.34-fold greater in the high-risk group, and 16.12-fold greater in the highest-risk group with Caprini scores ≥ 9. The area under the receiver operating characteristic curve was 0.74 (95% confidence interval, 0.71–0.78; P<0.01) for all patients. A Caprini score of ≥ 5 points was considered the criterion of a reliably increased risk of DVT in surgical patients with standard thromboprophylaxis. Predicting DVT using a cumulative risk score ≥ 4 is recommended for nonsurgical patients.

    Conclusions: Our study suggested that the 2010 Caprini RAM can be effectively used to stratify hospitalized Chinese patients into DVT risk categories, based on individual risk factors. Classification of the highest risk levels using a cumulative risk score ≥ 4 and ≥ 5 provides significantly greater clinical information in nonsurgical and surgical patients, respectively.

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  • Masako Miyashima, Tetsuo Shoji, Yoshinori Kakutani, Yuko Yamazaki, Aki ...
    Type: Original Article
    Article ID: 52886
    Published: 2019
    [Advance publication] Released: December 06, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Inter-arm blood pressure difference (IAD) is known to be associated with a composite of cardiovascular disease (CVD) and with CVD risk factors. However, only limited information is available regarding the contribution of diabetes mellitus to IAD and the association of IAD with individual CVDs, such as coronary artery disease (CAD), stroke, and peripheral artery disease (PAD).

    Methods: We addressed these issues in this cross-sectional study of 2580 participants who had simultaneous blood pressure measurements in both arms using an automated device.

    Results: Compared with 1,264 nondiabetic subjects, 1316 patients with diabetes mellitus had a greater IAD (P=0.01) and a higher prevalence of IAD of ≥ 10 mmHg (8.4% vs. 5.4%, P=0.002). However, such difference was not significant after the adjustment for potential confounders. Among CAD, stroke, and PAD, only PAD was significantly associated with IAD in a model adjusted for the CVD risk factors. Age was found to modify the association between IAD and PAD, with the association being more prominent in the younger subgroup.

    Conclusion: Thus, diabetes mellitus itself was not an independent factor associated with IAD. A larger IAD was preferentially associated with the presence of PAD, and this association was modified by age.

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  • Mitsuyoshi Takahara, Osamu Iida, Shun Kohsaka, Yoshimitsu Soga, Masahi ...
    Type: Original Article
    Article ID: 53330
    Published: 2019
    [Advance publication] Released: November 21, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The aim of the current study is to describe the presentation pattern of symptomatic peripheral artery disease undergoing endovascular therapy (EVT) in comparison to symptomatic coronary artery disease undergoing percutaneous coronary intervention (PCI) based on data from nationwide databases.

    Methods: Data were extracted from the nationwide procedural databases of EVT and PCI in Japan (J-EVT and J-PCI) between 2012 and 2017. The presentation pattern was investigated using a Poisson regression model, including the month, seasonality, and weekend (versus weekday) as the explanatory variables. Seasonality was expressed as a cosine function of a 12-month period, and its significance was evaluated using the Fisher–Yates shuffle method.

    Results: A total of 41,906 and 62,585 cases underwent EVT for critical limb ischemia (CLI) and intermittent claudication (IC), respectively, whereas 518,858 and 504,139 cases underwent PCI for acute coronary syndrome (ACS) and stable angina (SA). The procedural volume increased by 21.6%, 12.3%, 4.5%, and 3.6% per year in CLI, IC, ACS, and SA. CLI and ACS, but not IC or SA, showed a significant volume seasonality. Compared with ACS, CLI demonstrated a larger peak-to-trough ratio of seasonality (1.75 versus 1.21; P<0.001), and a later peak appearance (February–March versus January–February by 1.37 months; P<0.001). The procedural volume on weekends relative to weekdays was smaller for SA, IC, and CLI than for ACS. These distinct features were observed in a diabetic population and a non-diabetic population.

    Conclusions: The current study analyzed nationwide procedural databases and demonstrated the presentation pattern of symptomatic PAD and CAD warranting revascularization.

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  • Tomohiko C. Umei, Yoshimi Kishimoto, Masayuki Aoyama, Emi Saita, Hanak ...
    Type: Original Article
    Article ID: 52027
    Published: 2019
    [Advance publication] Released: November 18, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: The degradation of the vascular extracellular matrix is important for atherosclerosis. The cysteine protease legumain was shown to be upregulated in atherosclerotic plaques, especially unstable plaques. However, no study has reported blood legumain levels in patients with coronary artery disease (CAD).

    Methods: We investigated plasma legumain and C-reactive protein (CRP) levels in 372 patients undergoing elective coronary angiography.

    Results: CAD was found in 225 patients. Compared with patients without CAD, those with CAD had higher CRP levels (median 0.60 [0.32, 1.53] vs. 0.46 [0.22, 0.89] mg/L, P<0.001), but no difference was found in legumain levels between patients with and without CAD (median 5.08 [3.87, 6.82] vs. 4.99 [3.84, 6.88] ng/mL). A stepwise increase in CRP was found depending on the number of >50% stenotic vessels: 0.55 mg/L in 1-vessel, 0.71 mg/L in 2-vessel, and 0.86 mg/L in 3-vessel diseases (P<0.001). However, legumain did not differ among 1-, 2-, and 3-vessel diseases (5.20, 4.93, and 5.01 ng/mL, respectively). Of 225 patients with CAD, 40 (18%) had complex lesions. No difference was found in CRP levels between patients with CAD with and without complex lesions (0.60 [0.34, 1.53] vs. 0.60 [0.32, 1.51] mg/L). Notably, legumain levels were higher in patients with CAD with complex lesions than without such lesions (6.05 [4.64, 8.64] vs. 4.93 [3.76, 6.52] ng/mL, P<0.01). In multivariate analysis, legumain levels were not a factor for CAD, but were a factor for complex lesions. The odds ratio for complex lesions was 2.45 (95% CI=1.26–4.79) for legumain >5.5 ng/mL.

    Conclusion: Plasma legumain levels were associated with the presence of complex coronary lesions.

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  • Toshiyuki Ko, Michiaki Higashitani, Yukari Uemura, Makoto Utsunomiya, ...
    Type: Original Article
    Article ID: 52647
    Published: 2019
    [Advance publication] Released: November 12, 2019
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aim: Previous studies on peripheral artery disease (PAD) only enrolled patients with atherosclerotic lesion limited to any one of isolated locations (aortoiliac [AI], femoropopliteal [FP], and below the knee [BTK]). However, the interventions for PAD in a real-world clinical setting are often simultaneously performed for several different locations.

    Methods: We conducted a prospective multicenter study that included 2,230 patients with PAD who received intervention for lower extremity lesions in each area and across different areas. Patients were divided into 7 groups according to the combination of treatment locations. Overall survival (OS), major adverse limb events (MALEs), and risk factors for OS and MALEs were statistically analyzed.

    Results: After adjustment for confounding factors, the attributable risk for OS was similar among isolated AI, FP, and BTK treatments. MALEs increased in correlation with the number of treatment locations. Dialysis, critical limb ischemia, and cardiac contractile dysfunction were the common risk factors for OS and MALEs. However, the contribution of other factors such as type of drug usage was different according to treatment locations.

    Conclusions: In patients with PAD, OS was largely defined by comorbidities but not by lesion location. The background risk factors, underlying comorbidities, and event rates were different according to PAD location, suggesting that stratified treatment should be established for different patient populations.

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