Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Advance online publication
Displaying 1-50 of 117 articles from this issue
  • Takashi Miida
    Article type: Editorial
    Article ID: ED204
    Published: 2022
    Advance online publication: May 27, 2022
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  • Masato Takase, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hat ...
    Article type: Original Article
    Article ID: 63523
    Published: 2022
    Advance online publication: May 26, 2022
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    Aim: Although many epidemiological studies have shown that obesity assessed by body mass index is associated with carotid intima-media thickness (cIMT), few studies have evaluated fat-free mass, which is a component of body composition. We investigated the associations between the combined fat mass index (FMI) and fat-free mass index (FFMI) with cIMT.

    Methods: We conducted a cross-sectional study of 3,873 men and 9,112 women aged 20 years or older who lived in Miyagi prefecture, Japan. The FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. The indices were classified into sex-specific quartiles and were combined into 16 groups. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between the combined FMI and FFMI with cIMT adjusted for age and smoking status. The linear trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1 (lowest) to 4 (highest), and entering the number as a continuous term in the regression model.

    Results: In multivariable models, a higher FMI was not related to higher cIMT in men and women in most FFMI subgroups. Conversely, a higher FFMI was related to higher cIMT in all FMI subgroups (p<0.001 for linear trend).

    Conclusions : FMI was not associated with cIMT in most FFMI subgroups. Conversely, FFMI was positively associated with cIMT independently of FMI.

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  • Tadahiro Matsumoto, Yuichi Saito, Takanori Sato, Daichi Yamashita, Sak ...
    Article type: Original Article
    Article ID: 63576
    Published: 2022
    Advance online publication: May 25, 2022
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    Aims: The Academic Research Consortium (ARC) has proposed international criteria to standardize the definition of high bleeding risk (HBR) in patients undergoing percutaneous coronary intervention (PCI). In this context, Japan has also established its own guidelines, that is, the Japanese version of HBR (J-HBR) criteria. However, the J-HBR criteria have not been fully validated, especially in patients with acute myocardial infarction (MI).

    Methods: This bi-center registry included 1079 patients with acute MI undergoing primary PCI in a contemporary setting. Patient bleeding risks were evaluated using the ARC-HBR and J-HBR criteria. The primary endpoint was rates of major bleeding events (Bleeding Academic Research Consortium type 3 or 5) at 1 year.

    Results: Of the 1079 patients, 505 (46.8%) and 563 (52.2%) met the ARC-HBR and J-HBR criteria, respectively. Patients who met the J-HBR criteria were found to have a higher rate of major bleeding events at 1 year than those who did not (12.8% vs. 3.3%, p<0.001). When patients were scored and stratified using the J-HBR major and minor criteria, risks of major bleedings were progressively increased with the increase in the number of J-HBR criteria. In the receiver operating characteristic curve analysis, the ARC-HBR and J-HBR significantly predicted subsequent major bleedings after PCI, with ARC-HBR having greater predictive ability than J-HBR.

    Conclusions: More than half of the patients with acute MI undergoing primary PCI in Japan met the J-HBR criteria. Although the J-HBR criteria successfully identified patients who were likely to develop major bleeding events after primary PCI, the superiority of J-HBR to ARC-HBR in predicting bleeding outcomes warrants further investigation.

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  • Takanari Kitazono, Masahiro Kamouchi, Yuji Matsumaru, Masato Nakamura, ...
    Article type: Original Article
    Article ID: 63473
    Published: 2022
    Advance online publication: May 21, 2022
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    Aim: To examine the efficacy and safety of prasugrel vs clopidogrel in thrombotic stroke patients at risk of ischemic stroke.

    Methods: This multicenter, active-controlled, randomized, double-blind, double-dummy, parallel group study enrolled thrombotic stroke patients aged ≥ 50 years at risk of ischemic stroke. Patients received prasugrel (3.75 mg/day) or clopidogrel (75 or 50 mg/day) for 24–48 weeks; other antiplatelet drugs were prohibited. The primary efficacy endpoint was the composite incidence of ischemic stroke, myocardial infarction (MI), and death from other vascular causes from the start to 1 day after treatment completion or discontinuation. Secondary efficacy endpoints included the incidences of ischemic stroke, MI, death from other vascular causes, ischemic stroke and transient ischemic attack, and stroke. Safety endpoints included bleeding events and adverse events (AEs).

    Results: In the prasugrel (N=118) and clopidogrel (N=112; all received 75 mg) groups, the primary efficacy endpoint composite incidence (95% confidence interval) was 6.8% (3.0%–12.9%) and 7.1% (3.1%–13.6%), respectively. The risk ratio (prasugrel/clopidogrel) was 0.949 (0.369–2.443). Secondary efficacy endpoints followed a similar trend. The combined incidences of life-threatening, major, and clinically relevant bleeding were 5.0% and 3.5% in the prasugrel and clopidogrel groups, respectively. The incidences of all bleeding events and AEs were 19.2% and 24.6% and 76.7% and 82.5% in the prasugrel and clopidogrel groups, respectively. No serious AEs were causally related to prasugrel.

    Conclusions: We observed a risk reduction of 5% with prasugrel vs clopidogrel, indicating comparable efficacy. There were no major safety issues for prasugrel.

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  • Hidekatsu Yanai
    Article type: Editorial
    Article ID: ED203
    Published: 2022
    Advance online publication: May 21, 2022
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  • Kazunori Otsui
    Article type: Editorial
    Article ID: ED201
    Published: 2022
    Advance online publication: May 20, 2022
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  • Naoyuki Takashima
    Article type: Editorial
    Article ID: ED202
    Published: 2022
    Advance online publication: May 20, 2022
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  • Kanako Ota, Kazumasa Yamagishi, Rie Kishida, Tomomi Kihara, Renzhe Cui ...
    Article type: Original Article
    Article ID: 63321
    Published: 2022
    Advance online publication: May 18, 2022
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    Aim: In this study, we aimed to evaluate the association between age at menarche and risk of cardiovascular disease mortality.

    Methods: In total, 54,937 women aged 40-79 years old between 1988 and 1990 without a history of cardiovascular disease were eligible for analysis and were followed through December 2009. We used the Cox proportional hazards models to examine the association between age at menarche and risk of cardiovascular disease.

    Results: Compared with women with age at menarche of 15 years, the hazard ratios (95% confidence intervals) of stroke were 1.22 (0.85-1.75) for women with age at menarche of 9-12 years, 1.08 (0.85-1.36) for those of 13 years, 1.23 (1.02-1.47) for those of 14 years, 1.27 (1.07-1.50) for those of 16 years, 1.16 (0.95-1.41) for those of 17 years, and 1.39(1.16-1.68) for those of 18-20 years (P for trend=0.045). A similar pattern was observed for hemorrhagic stroke, ischemic stroke, and total cardiovascular disease. No such association was found for coronary heart disease. When stratified by age, for women aged 40-59 at baseline, the similar U-shaped association was observed. In contrast, for women aged 60-79 years at baseline, a significantly high hazard ratio was noted in the group of late age at menarche, but not in the group of early age at menarche.

    Conclusions: Both women with early and late age at menarche were determined to have higher risk of death from stroke and cardiovascular disease.

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  • Hironori Imano, Kazumasa Yamagishi, Tetsuya Ohira, Akihiko Kitamura, T ...
    Article type: Original Article
    Article ID: 63378
    Published: 2022
    Advance online publication: May 15, 2022
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    Aims: Epidemiological evidence is extremely limited about high-sensitivity cardiac troponin T (hs-cTnT) and future coronary heart disease (CHD) events for the general population in countries with low mortality from CHD. Therefore, we investigated the association between hs-cTnT levels and the risk of incident CHD using a nested case–control study in a large Japanese cohort study.

    Methods: The participants were residents of four Japanese communities in the Circulatory Risk in Communities Study (CIRCS). We obtained 120 cases (81 men and 39 women, aged 38–86 years at baseline) of first incident CHD and 240 controls matched by age, sex, communities, and blood sampling term. Serum hs-cTnT levels were measured using an electrochemiluminescence immunoassay with stored sera collected between 2001 and 2011. The median period between sampling at survey and CHD incidence was 2.0 (interquartile range, 0.9–3.7) years. After adjusting for conventional risk factors, the multivariable odds ratios (ORs) of CHD were calculated using conditional logistic regression analyses.

    Results: hs-cTnT ranged from ≤ 3 (assay detection limit) to 155 ng/L. Compared with the lowest quartile of hs-cTnT, multivariable ORs (95% confidence intervals) of CHD for the second, third, and highest quartiles were 1.30 (0.57–2.95), 2.48 (1.09–5.64), and 3.01 (1.27–7.12), respectively. Similar associations were observed after adjusting for estimated glomerular filtration, or after excluding matched groups, including people with chronic kidney disease.

    Conclusion: Serum hs-cTnT could predict CHD in the Japanese general population. These findings implicate a benefit from monitoring hs-cTnT to predict CHD even among populations in countries with low mortality from CHD.

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  • Wataru Umishio, Toshiharu Ikaga, Kazuomi Kario, Yoshihisa Fujino, Masa ...
    Article type: Original Article
    Article ID: 63494
    Published: 2022
    Advance online publication: May 13, 2022
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    Aim: Issuance of the WHO Housing and health guidelines has paralleled growing interest in the housing environment. Despite accumulating evidence of an association between outdoor temperature and serum cholesterol, indoor temperature has not been well investigated. This study examined the association between indoor temperature and serum cholesterol.

    Methods: We collected valid health checkup data of 2004 participants (1333 households), measured the indoor temperature for 2 weeks in winter, and divided participants according to whether they lived in a warm (average bedroom temperature ≥ 18℃), slightly cold (12–18℃) or cold house (<12˚C). The relationship between bedroom temperature and serum cholesterol was analyzed using multivariate logistic regression models, adjusting for demographics, lifestyle habits and the season in which the health checkup was conducted, with a random effect of climate areas in Japan.

    Results: The sample sizes for warm, slightly cold, and cold houses were 206, 940, and 858, respectively. Compared to those in warm houses, the odds ratio of total cholesterol exceeding 220 mg/dL was 1.83 (95%CI: 1.23–2.71, p=0.003) for participants in slightly cold houses and 1.87 (95%CI: 1.25–2.80, p=0.002) in cold houses. Similarly, the odds ratio of LDL/non-HDL cholesterol exceeding the standard range was 1.49 (p=0.056)/1.67 (p=0.035) for those in slightly cold houses and 1.64 (p=0.020)/1.77 (p=0.021) in cold houses. HDL cholesterol and triglycerides were not significantly associated with bedroom temperature.

    Conclusion: Besides lifestyle modification, improving indoor thermal environment through strategies such as installing high thermal insulation and appropriate use of heating devices may contribute to better serum cholesterol condition.

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  • Xiangming Tang, Huanjin Zhou, Haizhao Yan, Manabu Niimi, Jianglin Fan
    Article type: Letter to Editor
    Article ID: LE002
    Published: 2022
    Advance online publication: May 11, 2022
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  • Kazuki Shiina, Takamichi Takahashi, Hiroki Nakano, Masatsune Fujii, Yo ...
    Article type: Original Article
    Article ID: 63544
    Published: 2022
    Advance online publication: April 28, 2022
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    Aims: This prospective observational study, which utilized repeated annual measurements performed over a 9-year period, applied mixed model analyses to examine age-related differences in longitudinal associations between alcohol intake and arterial stiffness, pressure wave reflection, and inflammation.

    Methods: In 4016 middle-aged (43±9 years) healthy Japanese male employees, alcohol intake, brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), and serum C-reactive protein (CRP) levels were measured annually during a 9-year study period.

    Results: The estimated marginal mean baPWV (non-drinkers=1306 cm/s, mild–moderate drinkers=1311 cm/s, and heavy drinkers=1337 cm/s, P<0.01) and that of rAI showed significant stepped increases in an alcohol dose-dependent manner in the entire cohort, but an increase in rAI was not observed in subjects aged ≥ 50 years. The estimated slope of the annual increase in baPWV, but not rAI, was higher for heavy drinkers than for non-drinkers (slope difference, 1.84; P<0.05), especially for subjects aged <50 years (slope difference, 2.84; P<0.05).

    Conclusion: In middle-aged male Japanese employees, alcohol intake may attenuate inflammatory activity. While alcohol intake may exacerbate the progression of arterial stiffening in a dose-dependent manner without mediating inflammation, especially in subjects under 50 years of age, it may promote pressure wave reflection abnormalities with aging at earlier ages without further exacerbation at older ages.

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  • Archna Bajaj, Marina Cuchel
    Article type: Review
    Article ID: RV17065
    Published: 2022
    Advance online publication: April 24, 2022
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    Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extreme elevations of low-density lipoprotein cholesterol (LDL-C) leading to premature atherosclerotic cardiovascular disease (ASCVD) as early as in childhood. Management of HoFH centers around aggressive and adequate reduction of LDL-C levels to slow the trajectory of ASCVD development. Historically, lowering LDL-C levels in HoFH has been challenging because of both the markedly elevated LDL-C levels (often >400 mg/dL) and reduced response to treatment options, such as statins, for which the mechanism of action requires a functional LDL receptor. However, the treatment landscape for HoFH has rapidly progressed over the last decade. While statins and ezetimibe remain first-line treatment, patients often require addition of multiple therapies to achieve goal LDL-C levels. The PCSK9 inhibitors are an important recent addition to the available treatment options, along with lomitapide, bile acid sequestrants, and, possibly, bempedoic acid. Additionally, ANGPTL3 has emerged as an important therapeutic target, with evinacumab being the first available ANGPTL3 inhibitor on the market for the treatment of patients with HoFH. For patients who cannot achieve adequate LDL-C reduction, lipoprotein apheresis may be necessary, with the added benefit of reducing lipoprotein(a) levels that carries an added risk if also elevated in patients with HoFH. Finally, gene therapy and genome editing using CRISPR/Cas-9 are moving through clinical development and may dramatically alter the future landscape of treatment for HoFH.

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  • Makiko Egawa, Eiichiro Kanda, Hiroshi Ohtsu, Tomohiro Nakamura, Masayu ...
    Article type: Original Article
    Article ID: 63527
    Published: 2022
    Advance online publication: April 23, 2022
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    Aim: Cardiovascular disease (CVD) is the second largest cause of death in Japanese women. Pregnancy and childbirth are events that put a strain on the cardiovascular system. When postpartum weight retention is insufficient, weight gain due to fat deposition during pregnancy might lead to obesity. Thus, we examined the effects of body mass index (BMI) in middle and older ages and the number of children on CVD and metabolic disorders.

    Methods: From the Tohoku Medical Megabank database, we used data from 32,000 women aged ≥ 50 years. This database contains obstetrical history, medical history, and laboratory data obtained once from 2013 to 2015.

    Results: The mean age of participants was 64.2 years, and 47.7% of women had two children. Compared with nulliparous women, those who had a higher number of children had higher BMI and systolic blood pressure. The prevalence of CVD was highest in obese class I (30 kg/m2 ≤ BMI) women with three or more children and the prevalence of hypertension was high in pre-obese (25 kg/m2 ≤ BMI <30 kg/m 2 ) and obese class I women with children. Conversely, the prevalence of diabetes and proportion of women whose HbA1c values were >6.5% was highest in obese class I women with no children.

    Conclusion: In this study, we found that not only BMI but also the number of children influenced the health status of middle- and older-aged women, suggesting the importance of childbirth history in the health management of women.

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  • Weili Li, Xueqin Sui, Cong Li, Wenbo Zhao, Shuhua Yuan, Shoutan Dou, G ...
    Article type: Original Article
    Article ID: 63381
    Published: 2022
    Advance online publication: April 22, 2022
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    Aim: Mechanical thrombectomy (MT) has become the gold standard for the treatment of large vessel occlusion (LVO) in acute ischemic stroke. However, it remains controversial whether emergency angioplasty or stenting in patients with intracranial atherosclerotic stenosis (ICAS) should be adopted. Thus, we performed a retrospective analysis of clinical data to determine whether emergency angioplasty or stenting is necessary.

    Methods: We retrospectively analyzed data from patients undergoing MT with ICAS-related LVO of the acute anterior circulation between 2017 and 2019. Eligible patients were divided into two treatment groups: those who received rescue angioplasty or stenting [Patients treated with rescue angioplasty or stenting (PTAS) group] and those who received thrombectomy alone (non-PTAS group). The primary outcomes were good prognosis at 90 days (mRS: 0-2). Mortality, symptomatic intracranial hemorrhage, and reocclusion rate were evaluated as secondary outcomes.

    Results: A total of 184 patients with severe stenosis after MT were enrolled, including 64 patients receiving rescue angioplasty or stenting and 120 patients without rescue angioplasty or stenting. Compared with the non-PTAS group, a better functional outcome (mRS0-2) (51.6% vs. 35.0%, adjusted odds ratio: 2.11, 95% confidence interval [CI]: 1.22-4.29; P=0.02), lower 7-day National Institutes of Health Stroke Scale [6 (3-12.75) vs. 10 (4-16); P=0.04], lower 24-h neurological deterioration rate (7.8% vs. 21.7%, P=0.02), and lower 24-h reocclusion rate were observed in the PTAS group (6.3% vs. 17.5%, P=0.03). There were no significant differences in mortality or incidence of symptomatic intracerebral hemorrhage.

    Conclusion: Emergency angioplasty or stenting could be a safe and feasible therapeutic option with better outcomes for stroke patients with ICAS-related LVO.

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  • Chien-An Yao, I-Ling Chen, Chung-Yen Chen, Pao-Ling Torng, Ta-Chen Su
    Article type: Original Article
    Article ID: 63254
    Published: 2022
    Advance online publication: April 20, 2022
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    Aim: This study aimed to determine whether sleep disturbance, defined as the wakeup frequency at night, is associated with atherogenic dyslipidemia and to explore possible sex differences.

    Methods: A total of 1,368 adults aged 19–70 years were included in the study of lifestyles and atherogenic dyslipidemia at the National Taiwan University Hospital in the period of 2008–2012. They completed a questionnaire regarding lifestyle information and sleep quality, including sleep hour duration, use of sleeping pills, and wakeup frequency during nighttime sleep. The measured lipid profiles included total cholesterol, triglycerides, low- and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), non-HDL-C, and small dense LDL-C (sdLDL-C). Multivariate logistic regression was performed to determine habitual interrupted sleep and the odds ratio of atherogenic dyslipidemia following adjustment for conventional risk factors and for sex-based subgroup analysis.

    Results: A wakeup frequency ≥ 3 times per night was independently associated with an increased risk [odds ratio (95% confidence interval)] of dyslipidemia was 1.96 (1.17–3.28), and non-HDL-C ≥ 160 mg/dL was 1.78 (1.09–2.89). A higher wakeup frequency was associated with increased atherogenic dyslipidemia in women than in men. The multivariate adjusted relative risks for non-HDL ≥ 160 mg/dL and cholesterol ≥ 200 mg/dL were 3.05 (1.27–7.34) and 4.01(1.29-12.45) for female individuals with insomnia and those with a wakeup frequency ≥ 2 times per night, respectively.

    Conclusion: A higher wakeup frequency was associated with atherogenic dyslipidemia in Taiwanese adults, particularly in women. This study also provided another evidence of increasing cardiovascular diseases in subjects with habitual interrupted sleep.

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  • Hironori Imano, Jiaqi Li, Mari Tanaka, Kazumasa Yamagishi, Isao Muraki ...
    Article type: Original Article
    Article ID: 63358
    Published: 2022
    Advance online publication: April 20, 2022
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    Aims: We investigated the optimal cut-off points of nonfasting and fasting triglycerides in Japanese individuals with lower average triglyceride levels than westerners.

    Methods: Residents aged 40–69 years without a history of ischemic heart disease or stroke were enrolled between 1980 and 1994 and followed. Serum triglyceride concentrations were measured from 10851 nonfasting (<8 h after meal) and 4057 fasting (≥ 8 h) samples. As a prerequisite, we confirmed the shape of a receiver operating characteristic (ROC) curves, the area under ROC curves (AUC), and the integrated time-dependent AUC. We identified optimal cut-off points for incident ischemic heart disease based on C-statistic, Youden index, and Harrell’s concordance statistic. We used dichotomized concentrations of triglycerides via the univariate logistic regression and Cox proportional hazards regression models. We also calculated multivariable hazard ratios and population attributable fractions to evaluate the optimal cut-off points.

    Results: Nonfasting and fasting optimal cut-off points were 145 mg/dL and 110 mg/dL, with C-statistic of 0.594 and 0.626, Youden index of 0.187 and 0.252, and Harrell’s concordance statistic of 0.590 and 0.630, respectively. The corresponding multivariable hazard ratios of ischemic heart disease were 1.43 (95%CI 1.09–1.88)and 1.69 (1.03–2.77), and the corresponding population attributable fractions were 16.1% (95%CI 3.3–27.2%) and 24.6 (−0.3–43.3).

    Conclusion: The optimal cut-off points of nonfasting and fasting triglycerides in the Japanese general population were 145 mg/dL and 110 mg/dL, respectively, lower than the current cut-off points recommended in the US and Europe.

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  • Miho Iida
    Article type: Editorial
    Article ID: ED200
    Published: 2022
    Advance online publication: April 16, 2022
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  • Masayuki Teramoto, Kazumasa Yamagishi, Renzhe Cui, Kokoro Shirai, Akik ...
    Article type: Original Article
    Article ID: 63452
    Published: 2022
    Advance online publication: April 13, 2022
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    Aim: We aimed to examine the impact of overweight and obesity on mortality from nonrheumatic aortic valve disease.

    Methods: In the Japan Collaborative Cohort Study, we analyzed data of 98,378 participants aged 40–79 years, with no history of coronary heart disease, stroke, or cancer at baseline (1988–1990) and who completed a lifestyle questionnaire including height and body weight; they were followed for mortality until the end of 2009. The Cox proportional hazards model was used to calculate the multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) of nonrheumatic aortic valve disease mortality according to body mass index (BMI) after adjusting for potential confounding factors.

    Results: During the median 19.2 years follow-up, 60 deaths from nonrheumatic aortic valve disease were reported. BMI was positively associated with the risk of mortality from nonrheumatic aortic valve disease; the multivariable HRs (95% CIs) were 0.90 (0.40–2.06) for persons with BMI <21 kg/m2 , 1.71 (0.81–3.58) for BMI 23–24.9 kg/m2 , 1.65 (0.69–3.94) for BMI 25–26.9 kg/m2 , and 2.83 (1.20–6.65) for BMI ≥ 27 kg/m2 (p for trend=0.006), compared with persons with BMI 21–22.9 kg/m2 . Similar associations were observed between men and women (p for interaction=0.56). Excluding those who died during the first ten years of follow-up or a competing risk analysis with other causes of death as competing risk events did not change the association materially.

    Conclusions: Overweight and obesity may be independent risk factors for nonrheumatic aortic valve disease mortality in Asian populations.

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  • Yangchen Li, Fengxin Chen, Bo Yang, Sheng Xie, Ce Wang, Runcai Guo, Xu ...
    Article type: Original Article
    Article ID: 63520
    Published: 2022
    Advance online publication: April 13, 2022
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    Aims: The basilar artery (BA) geometry and plaque characteristics may play an important role in the development of atherosclerosis. This study was performed to explore the relationship between the mid-BA angle and plaque characteristics and its effect on pontine infarction using high-resolution magnetic resonance imaging and three-dimensional time-of-flight magnetic resonance angiography.

    Methods: In total, 77 patients with BA plaques were included in this study. According to the presence of acute pontine infarction on diffusion-weighted imaging, the patients were divided into a pontine infarction group and pontine non-infarction group. The mid-BA angle, plaque burden, stenosis ratio, positive remodeling, and intraplaque hemorrhage were evaluated to investigate their effects on stroke.

    Results: The pontine infarction group had a greater plaque burden, stenosis ratio, positive remodeling, and mid-BA angle than the pontine non-infarction group. The correlation between the plaque burden and mid-BA angle was the highest (r=0.441, P<0.001). Multivariate logistic regression analysis showed that the plaque burden (odds ratio, 1.164; 95% confidence interval, 1.093-1.241; P<0.001) was an independent risk factor for pontine infarction.

    Conclusion: The mid-BA angle may increase the incidence of pontine infarction by increasing the plaque burden.

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  • Michio Shimabukuro
    Article type: Editorial
    Article ID: ED197
    Published: 2022
    Advance online publication: April 13, 2022
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  • Yohko Yoshida, Ippei Shimizu, Tohru Minamino
    Article type: Review
    Article ID: RV17064
    Published: 2022
    Advance online publication: April 01, 2022
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    Prognosis of heart failure remains poor, and it is urgent to find new therapies for this critical condition. Oxygen and metabolites are delivered through capillaries; therefore, they have critical roles in the maintenance of cardiac function. With aging or age-related disorders, capillary density is reduced in the heart, and the mechanisms involved in these processes were reported to suppress capillarization in this organ. Studies with rodents showed capillary rarefaction has causal roles for promoting pathologies in failing hearts. Drugs used as first-line therapies for heart failure were also shown to enhance the capillary network in the heart. Recently, the approach with senolysis is attracting enthusiasm in aging research. Genetic or pharmacological approaches concluded that the specific depletion of senescent cells, senolysis, led to reverse aging phenotype. Reagents mediating senolysis are described to be senolytics, and these compounds were shown to ameliorate cardiac dysfunction together with enhancement of capillarization in heart failure models. Studies indicate maintenance of the capillary network as critical for inhibition of pathologies in heart failure.

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  • Sunmie Kim, Su-Yeon Choi, Heesun Lee, Jin Ju Kim, Hyo Eun Park
    Subject Area: Original Article
    Article ID: 63371
    Published: 2022
    Advance online publication: March 31, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aim: We investigated the effects of metabolic syndrome (MetS) and its components, including a body shape index (ABSI), on increased arterial stiffness measured using the cardio-ankle vascular index (CAVI) according to sex and age strata.

    Methods: A total of 7127 asymptomatic Korean participants aged 21–90 years (men, 69.4%) were included. Age–sex-specific increased CAVI was defined as having the highest quartile of CAVI in each age group.

    Results: The CAVI increased with age and was higher in men. MetS was associated with an increased risk of high CAVI by 1.30 times in men and 1.45 times in women. The risk of high CAVI with an increasing MetS risk score was greater in women. MetS was significantly associated with increased CAVI in men only aged 51–70 years and in women aged ≥ 51 years, and the size of association increased with age (odds ratio (OR) of 1.41 in 51–70 years vs. OR of 2.96 in ≥ 71 years of women). Among MetS components, triglyceride (men, all ages), hypertension (men, 51–70 years; women, ≤ 70 years), glucose intolerance (men, 51–70 years; women, ≥ 51 years), and HDL-cholesterol (women, ≥ 71 years) were associated with increased CAVI.

    Unlike increased waist circumference (WC), increased ABSI revealed an association with high CAVI. MetS diagnosed with ABSI instead of WC was more significantly associated with increased CAVI in all age–sex groups.

    Conclusion: The association of MetS and its components with increased CAVI differed with age and sex, which might provide a new insight for the management of MetS risk factors to promote vascular health.

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  • Mitsuaki Sawano
    Article type: Editorial
    Article ID: ED198
    Published: 2022
    Advance online publication: March 23, 2022
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  • Mika Hori, Yukiko Hasegawa, Yoshitaka Hayashi, Tomoko Nakagami, Mariko ...
    Article type: Original Article
    Article ID: 60921
    Published: 2022
    Advance online publication: March 19, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: We previously reported that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduced serum low-density lipoprotein cholesterol (LDL-C) levels in patients with type 2 diabetes mellitus receiving statins, which increased LDL receptor (LDLR) expression. Nevertheless, it remains unclear how much LDLR expression contributes to the LDL-C-lowering effect of GLP-1RAs. We examined the effect of a GLP-1RA, namely, exendin-4, on serum LDL-C levels and its mechanism in Ldlr−/− and C57BL/6J mice.

    Methods: Ten-week-old Ldlr−/− and C57BL/6J mice received exendin-4 or saline for 5 days, and serum lipid profiles and hepatic lipid levels were examined. Cholesterol metabolism-related gene expression and protein levels in the liver and ileum and the fecal bile acid (BA) composition were also examined.

    Results: Exendin-4 treatment significantly decreased serum very-low-density lipoprotein cholesterol (VLDL-C) and LDL-C levels and mature hepatic SREBP2 levels and increased hepatic Insig1/2 mRNA expression in both mouse strains. In Ldlr−/− mice, exendin-4 treatment also significantly decreased hepatic cholesterol levels and fecal BA excretion, decreased hepatic Cyp7a1 mRNA expression, and increased small intestinal Fgf15 mRNA expression. In C57BL/6J mice, exendin-4 treatment significantly decreased small intestinal NPC1L1 levels.

    Conclusions: Our findings demonstrate that exendin-4 treatment decreased serum VLDL-C and LDL-C levels in a manner that was independent of LDLR. Exendin-4 treatment might decrease serum cholesterol levels by lowering hepatic SREBP2 levels and cholesterol absorption in Ldlr−/− and C57BL/6J mice. Exendin-4 treatment might decrease cholesterol absorption by different mechanisms in Ldlr−/− and C57BL/6J mice.

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  • Li-wei Guo, Yi-kai Wang, Shi-jie Li, Guo-tian Yin, Duan Li
    Article type: Original Article
    Article ID: 63460
    Published: 2022
    Advance online publication: March 19, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aim: Roles of fibroblast growth factor 23 (FGF23) in endothelial dysfunction remain controversial, and evidence from population-based studies is lacking. The present study aimed to explore the effects of FGF23 on endothelial dysfunction on the basis of both clinical data of patients with coronary artery disease (CAD) and the in vitro research in human umbilical vein endothelial cells (HUVECs).

    Methods: A total of 321 CAD patients were enrolled after coronary angiography, brachial artery flow-mediated dilation (FMD) was assessed using ultrasound equipment. Serum FGF23, nitric oxide (NO), and endothelin-1 (ET-1) were detected via enzyme-linked immunosorbent assay. Apoptosis was determined using the annexin V-fluorescein isothiocyanate/propidium lodide apoptosis detection kit. Cell migration was evaluated by wound healing and transwell migration assays. Reactive oxide species levels were determined using fluorescent probes, and NF-κB p65 nuclear translocation was assessed via immunofluorescence.

    Results: Serum FGF23 was significantly increased in CAD patients combined with severe endothelial dysfunction (FMD <2%) compared to those with FMD ≥ 2% (P<0.001). Furthermore, the levels of FGF23 were negatively correlated with NO, whereas positively correlated with ET-1 both in unadjusted analysis and multivariate-adjusted analysis. In HUVECs, FGF23 interfered with the bioavailability of NO via increased oxidative stress. Moreover, FGF23 directly impaired the endothelium by promoting HUVECs apoptosis and attenuating the migration of HUVECs. Additional experiments showed that FGF23 induced endothelial injury through activation of the NF-κB signaling pathway.

    Conclusions: Elevated FGF23 is clinically associated with endothelial dysfunction in CAD patients, and FGF23 impairs endothelial function through activation of the NF-κB signaling pathway.

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  • Naoko Miyagawa
    Article type: Editorial
    Article ID: ED196
    Published: 2022
    Advance online publication: March 13, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
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  • Kosuke Matsuzono, Shigeru Fujimoto, Junya Aoki, Tadashi Ozawa, Kazumi ...
    Article type: Original Article
    Article ID: 63409
    Published: 2022
    Advance online publication: March 12, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aim: A previous randomized study showed that dual antiplatelet therapy (DAPT) with aspirin and cilostazol is not superior to aspirin monotherapy for patients with acute non-cardioembolic stroke; however, the reason for this remains uncertain. We focused on the unusual side effects of cilostazol, namely, tachycardia changes, and validated their influence on patients with acute non-cardioembolic stroke.

    Methods: This post-hoc study extracted data from the acute aspirin plus cilostazol dual therapy study (ADS) registry, a multicenter, prospective, randomized, open-label trial. Patients were randomly allocated to the dual group (aspirin plus cilostazol) and the aspirin monotherapy group (aspirin alone). Tachycardia changes were defined as ≥ 5% heart rate increase at 48 h after admission compared with that at admission. Baseline data and outcomes were validated with four divided groups: aspirin-non-tachycardia changes (AN), aspirin-tachycardia changes (AT), dual-non-tachycardia changes (DN), and dual-tachycardia changes (DT).

    Results: Finally, 1,188 patients were analyzed in this ADS post-hoc analysis (aspirin monotherapy group, 594; dual group, 594). The proportion of change in tachycardia was 19.2% in the aspirin monotherapy group and 38.2% in the dual group (p<0.001***). Although the recurrences of symptomatic stroke and transient ischemic attack were not significantly different, the neurological deterioration was significantly different among the AN, AT, DN, and DT groups (p<0.05).

    Conclusions: Tachycardia changes increase neurological deterioration even in patients with non-cardioembolic acute stroke. DAPT consisting of aspirin and cilostazol increases the proportion of tachycardia changes and is not superior to aspirin monotherapy.

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  • Naoyuki Takashima, Yasuyuki Nakamura, Naoko Miyagawa, Aya Kadota, Yosh ...
    Article type: Original Article
    Article ID: 63323
    Published: 2022
    Advance online publication: March 10, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: High-sensitivity C-reactive protein (hsCRP) associates with atherosclerotic diseases such as stroke. However, previous results on the association between hsCRP levels and functional disability were controversial.

    Methods: We analyzed 2,610 men and women who did not exhibit functional disability or death within the first 3 years of the baseline survey and those aged 65 years or older at the end of follow-up. The levels of hsCRP were assessed using latex agglutination assay at baseline survey from 2006 to 2014. Functional disability was followed up using the long-term care insurance (LTCI) program until November 1, 2019. Functional disability was defined as a new LTCI program certification. Cox proportional hazards model with competing risk analysis for death was used to evaluate the association between hsCRP levels and future functional disability.

    Results: During a 9-year follow-up period, we observed 328 cases of functional disability and 67 deaths without prior functional disability incidence. The multivariable-adjusted hazard ratio (HR, 95% confidence interval [CI]) of functional disability in log-transferred hsCRP levels was 1.43 (1.22–1.67) in men and 0.97 (0.81–1.15) in women. When hsCRP level was analyzed as a categorical variable, low hsCRP levels (<1.0 mg/l) as the reference, the multivariable-adjusted HR (95% CI) of functional disability in high hsCRP levels (≥ 3.0 mg/l) was 2.37 (1.56–3.62). Similar results were observed when stratified by sex, but it was not significant in women.

    Conclusions: This study demonstrates that low-grade systemic inflammation to assess hsCRP might predict the future incidence of functional disability, especially in men.

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  • Tetsuo Shoji, Yusuke Akiyama, Hisako Fujii, Mariko Harada-Shiba, Yutak ...
    Article type: Original Article
    Article ID: 63311
    Published: 2022
    Advance online publication: March 05, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aim: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Individuals with reduced kidney function or chronic kidney disease (CKD) are at an increased risk for cardiovascular disease. Hence, we examined the relationship between estimated glomerular filtration rate (eGFR) and serum markers of cholesterol absorption and synthesis.

    Methods: The CACHE (Cholesterol Absorption and Cholesterol synthesis in High-risk patiEnts) Consortium, comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured via gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were utilized for five analyses including this CKD analysis.

    Results: This study analyzed data from 2200 individuals including 522 hemodialysis patients; 42.3% were female, the median age was 58 years, and the median eGFR was 68.9 mL/min/1.73 m2. Latho, Campe, and Campe/Latho ratio were significantly different when compared across CKD stages. When the associations of eGFR with these markers were assessed with multivariable nonlinear regression models, Latho, Campe, and Campe/Latho ratio showed positive, inverse, and inverse associations with eGFR. These associations were significantly modified by sex, the presence/absence of diabetes mellitus, and the presence/absence of statin use.

    Conclusion: We showed that individuals with lower eGFR have lower cholesterol synthesis marker levels and higher cholesterol absorption marker levels in this large sample.

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  • Kazuki Fukuma, Hiroshi Yamagami, Masafumi Ihara, Tomotaka Tanaka, Tosh ...
    Article type: Original Article
    Article ID: 63369
    Published: 2022
    Advance online publication: March 05, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: We aimed to determine the association between acute platelet reactivity and clinical outcome in acute ischemic stroke (AIS) or transient ischemic attack (TIA) with large-artery atherosclerosis (LAA).

    Methods: In this prospective, 16-multicenter study, we enrolled AIS/TIA patients with LAA receiving clopidogrel. We assessed the association of P2Y12 reaction units (PRU) 24 hours after initiation of antiplatelets with the CYP2C19 genotype and recurrent ischemic stroke within 90 days, and the difference between acute (≤ 7 days) and subacute (8–90 days) phases.

    Results: Among the 230 AIS/TIA patients enrolled, 225 with complete outcome data and 194 with genetic results were analyzed. A higher PRU was significantly associated with recurrent ischemic stroke within 90 days (frequency, 16%), and within 7 days (10%). Twenty-nine patients (15%) belonged to a CYP2C19 poor metabolizer group (CYP2C19 2/2, 2/3, or 3/3). Multivariable receiver-operating characteristic analysis showed a greater area-under-the-curve (AUC) in predicting recurrence within 7 days, compared to 8–90 days (AUC, 0.79 versus 0.64; p=0.07), with a cut-off PRU of 254. Multivariable analysis showed high PRU (≥ 254), which had a comparable predictive performance for recurrent ischemic stroke within 7 days (odds ratio, 6.82; 95% CI, 2.23–20.9; p<0.001) to the CYP2C19 poor metabolizer genotype. The net reclassification improvement, calculated by adding high PRU (≥ 254) to a model including the CYP2C19 poor metabolizer genotype in the prediction of recurrence within 7 days, was 0.83 (p<0.001).

    Conclusions: Acute PRU evaluation possesses predictive value for recurrent ischemic stroke, especially within 7 days in AIS/TIA with LAA.

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  • Erika Matsumoto, Kentaro Oniki, Ami Ota-Kontani, Yuri Seguchi, Yuki Sa ...
    Article type: Original Article
    Article ID: 63277
    Published: 2022
    Advance online publication: March 04, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: High levels of high-density lipoprotein cholesterol (HDL-C) are not necessarily effective in preventing atherosclerotic cardiovascular disease, and cholesterol efflux capacity (CEC) has attracted attention regarding HDL functionality. We aimed to elucidate whether drinking habits are associated with CEC levels, while also paying careful attention to confounding factors including serum HDL-C levels, other life style factors, and rs671 (2), a genetic polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene determining alcohol consumption habit.

    Methods: A cross-sectional study was performed in 505 Japanese male subjects who were recruited from a health screening program. Associations of HDL-C and CEC levels with drinking habits and ALDH2 genotypes were examined.

    Results: The genotype frequencies of ALDH2 1/1 (homozygous wild-type genotype), 1/2 and 2/2 (homozygous mutant genotype) were 55%, 37% and 8%, respectively. Both HDL-C and CEC levels were higher in ALDH2 1/1 genotype carriers than in 2 allele carriers. Although HDL-C levels were higher in subjects who had a drinking habit than in non-drinkers, CEC levels tended to be lower in subjects with ≥ 46 g/day of alcohol consumption than in non-drinkers. Furthermore, CEC levels tended to be lower in ALDH2 1/1 genotype carriers with a drinking habit of ≥ 46 g/day than non-drinkers, while for 2 allele carriers, CEC levels tended to be lower with a drinking habit of 23-45.9 g/day compared to no drinking habit.

    Conclusions: Our results suggest that heavy drinking habits may tend to decrease CEC levels, and in the ALDH2 2 allele carriers, even moderate drinking habits may tend to decrease CEC levels.

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  • Toshiyuki Hayashi, Masumi Ai, Satoshi Goto, Marie Nakamura, Hiroe Naga ...
    Article type: Original Article
    Article ID: 63383
    Published: 2022
    Advance online publication: March 04, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: We established automated assay kits for quantifying small dense low-density lipoprotein (sdLDL)-cholesterol (C), LDL-triglyceride (TG), and high-density lipoprotein (HDL)3-C, and apolipoprotein (apo)E-rich HDL-C, and these have been recognized as sensitive biomarkers for predicting coronary artery disease. We investigated the circadian rhythms of these novel lipids to determine if fasting is required to determine basal levels.

    Methods: Forty-eight inpatients with type 2 diabetes and 19 healthy volunteers were studied. Blood samples were collected at seven time points, which were obtained after an overnight fast, before and 2 h after each meal, and before the next breakfast. sdLDL-C, LDL-TG, remnant-like particle (RLP)-C, TG-rich lipoprotein (TRL-C), HDL3-C, and apoE-rich HDL-C were measured by the homogeneous methods. NonHDL-C, large buoyant (lb) LDL-C and HDL2-C were calculated by subtracting sdLDL-C from LDL-C or HDL3-C from HDL-C, respectively.

    Results: Serum TG levels were significantly increased after meals in both healthy participants and patients with diabetes. RLP-C and TRL-C were also increased postprandially. LDL-TG, LDL-C, nonHDL-C, HDL2,3-C, and apoE-rich HDL-C did not exhibit significant fluctuation during the day in healthy participants and patients with diabetes. sdLDL-C was slightly increased postprandially in subjects with diabetes (1-2 mg/dl, 3%-9%), though its increase was not significant compared to the baseline (fasting) level. Significant postprandial reduction was observed with LDL-C and lbLDL-C. There was no influence of statin therapy or oral anti-diabetes drugs on the circadian rhythm of LDL-C subspecies.

    Conclusions: Subtle postprandial increase in sdLDL-C is considered a negligible level in general clinical practice. Fasting is not mandatory to measure basal concentrations of LDL and HDL subspecies.

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  • Naruhiko Ito
    Article type: Editorial
    Article ID: ED194
    Published: 2022
    Advance online publication: March 03, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
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  • Tomoyuki Kabutoya
    Article type: Editorial
    Article ID: ED195
    Published: 2022
    Advance online publication: March 03, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
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  • Ryo Kawasaki
    Article type: Editorial
    Article ID: ED190
    Published: 2022
    Advance online publication: March 02, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
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  • Masahito Iioka, Shiro Fukuda, Norikazu Maeda, Tomoaki Natsukawa, Shunb ...
    Article type: Original Article
    Article ID: 63305
    Published: 2022
    Advance online publication: February 26, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: T-cadherin (T-cad) is a specific binding partner of adiponectin (APN), adipocyte-specific secretory protein. APN exhibits organ protection via the T-cad-dependent accumulation onto several tissues such as the aorta, heart, and muscle. Recently, for the first time, we showed that three forms (130, 100, and 30 kDa) of soluble T-cad existed in human serum and correlated with several clinical parameters in patients with type 2 diabetes. Nevertheless, the significance of soluble T-cad has not been elucidated in the acute stage of cardiovascular diseases. We herein examined soluble T-cad concentrations and investigated their clinical significance in patients with emergency hospital admission due to ST-segment elevation myocardial infarction (STEMI).

    Methods: This observational study enrolled 47 patients with STEMI who were treated via primary percutaneous coronary intervention (PCI). Soluble T-cad and APN concentrations were measured by using an enzyme-linked immunosorbent assay. This study is registered with the University Hospital Medical Information Network (Number: UMIN 000014418).

    Results: Serum concentrations of soluble 130 and 100 kDa T-cad rapidly and significantly decreased after hospitalization and reached the bottom at 72 h after admission (p<0.001 and p<0.001, respectively). The patients with high soluble T-cad and low APN concentrations on admission showed a significantly higher area under the curve of serum creatine kinase-MB (p<0.01).

    Conclusion: Serum soluble T-cad concentration changed dramatically in patients with STEMI, and the high T-cad and low APN concentrations on admission were associated with the myocardial infarction size. Further study is needed to investigate the usefulness of categorizing patients with STEMI by serum T-cad and APN for the prediction of severe prognoses.

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  • Masatoshi Koga, Manabu Inoue, Kaori Miwa, Sohei Yoshimura, Mayumi Fuku ...
    Article type: Original Article
    Article ID: 63337
    Published: 2022
    Advance online publication: February 24, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aim: This study aimed to assess the potential effect of prior antithrombotic medication for thrombolysis in an unknown onset stroke.

    Methods: This was a predefined sub-analysis of the THAWS trial. Stroke patients with a time last known well >4.5 h who had a DWI-fluid-attenuated inversion recovery mismatch were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg (alteplase group) or standard medical treatment (control group). Patients were dichotomized by prior antithrombotic medication.

    Results: Of 126 patients (intention-to-treat population), 40 took antithrombotic medication (24 with antiplatelets alone, 13 with anticoagulants alone, and 3 with both), and the remaining 86 did not before stroke onset. Of these, 17 and 52 patients, respectively, received alteplase, and 23 and 34, respectively, had standard medical treatment. Antithrombotic therapy was initiated within 24 h after randomization less frequently in the alteplase group (12% vs. 86%, p<0.01). Both any intracranial hemorrhage within 22-36 h (26% vs. 14%) and a modified Rankin Scale score of 0-1 at 90 days (good outcome) (47% vs. 48%) were comparable between the two groups. A good outcome was more common in the alteplase group than in the control group in patients with prior antithrombotic medication [relative risk (RR) 2.25, 95% confidence interval (CI) 1.02-4.99], but it tended to be less common in the alteplase group in those without (RR 0.69, 95% CI 0.46-1.03) (p<0.01 for interaction). The frequency of any intracranial hemorrhage did not significantly differ between the two groups in any patients dichotomized by prior antithrombotic medication.

    Conclusion: Alteplase appears more beneficial in patients with prior antithrombotic medication.

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  • QiaoYu Shao, ZhiQiang Yang, YuFei Wang, QiuXuan Li, KangNing Han, Jing ...
    Article type: Original Article
    Article ID: 63397
    Published: 2022
    Advance online publication: February 24, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: This study aimed to investigate the association of elevated RC levels with adverse cardiovascular outcomes in acute coronary syndrome (ACS) patients with and without diabetes.

    Methods: We analyzed data from 1716 patients with ACS undergoing percutaneous coronary intervention. RC was calculated as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol. RC >75th percentile of the cohort (>0.79 mmol/L) was defined as abnormally elevated RC. Cox-regression models and Kaplan-Meier analyses were used to assess the relationship between RC >0.79 mmol/L and major adverse cardiovascular events (MACE).

    Results: During a median follow-up of 927 days, a total of 354 patients had at least one event. In the overall population, compared with those with RC ≤ 0.79 mmol/L, patients with RC >0.79 mmol/L had a significantly higher risk of MACE after adjustment for potential confounders (hazard ratio: 1.572, 95% confidence interval: 1.251-1.975, P<0.001). In addition, RC >0.79 mmol/L was associated with an increased risk of MACE of 66.7% (P=0.001) and 50.1% (P=0.022) in the diabetic and non-diabetic subgroups (P for interaction=0.073), respectively. The addition of RC significantly improved the predictive ability of baseline models for MACE in diabetic patients (all P<0.05), but not in non-diabetic patients (all P>0.05).

    Conclusion: Abnormally elevated RC was significantly associated with worse prognosis in both diabetic and non-diabetic patients with ACS; however, the prognostic value of RC might be superior among diabetic patients.

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  • Hiroshi Hayashi
    Article type: Editorial
    Article ID: ED192
    Published: 2022
    Advance online publication: February 23, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
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  • Yasuyuki Nakanishi, Yoshihiko Furuta, Jun Hata, Tomohiro Yubi, Emi Ois ...
    Article type: Original Article
    Article ID: 63344
    Published: 2022
    Advance online publication: February 19, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aim: Secular trends in the risk of recurrent stroke have been reported in several epidemiological studies worldwide, but this issue has not been investigated in general Japanese populations. We examined the trends in the 5-year risk of recurrent stroke over a half century using community-based prospective data in Japan.

    Methods: We established 4 cohort studies in 1961, 1974, 1988, and 2002. To examine the risk of recurrent stroke, participants who developed stroke during a 10-year follow-up period in each cohort were followed-up for 5 years from the date of first onset. A total of 154 (first sub-cohort: 1961-1971), 144 (second sub-cohort: 1974-1984), 172 (third sub-cohort: 1988-1998), and 146 (fourth sub-cohort: 2002-2012) participants from each cohort were enrolled in the present study. The 5-year cumulative risk of recurrent stroke was compared among the sub-cohorts using the Kaplan-Meier method and the age- and sex-adjusted Cox proportional hazards model.

    Results: The risks of recurrent stroke after any stroke and ischemic stroke decreased significantly from the first to the third sub-cohort, but they did not clearly change from the third to the fourth sub-cohort. The risk of recurrent stroke after hemorrhagic stroke decreased mainly from the first to the second sub-cohort and there was no apparent decrease from the second to the fourth sub-cohort. These trends were substantially unchanged after adjusting for age and sex.

    Conclusions: In the Japanese community, the risk of recurrent stroke decreased mainly from the 1960s to 1990s, but there was no apparent decrease in recent years.

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  • Katsunao Tanaka, Masahiro Koseki, Hisashi Kato, Kazuya Miyashita, Take ...
    Article type: Case Report
    Article ID: 63348
    Published: 2022
    Advance online publication: February 18, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Primary hyperchylomicronemia is characterized by marked hypertriglyceridemia exceeding 1,000 mg/dL. It is caused by dysfunctional mutations in specific genes, namely those for lipoprotein lipase (LPL), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), apolipoprotein C2 (ApoC-II), lipase maturation factor 1 (LMF1), or apolipoprotein A5 (ApoA-V). Importantly, antibodies against LPL or GPIHBP1 have also been reported to induce autoimmune hyperchylomicronemia.

    The patient was a 46-year-old man diagnosed with immune thrombocytopenia (ITP) at 41 years. At the time, he was administered prednisolone (PSL) and eltrombopag, a thrombopoietin receptor agonist. At 44 years, he suffered from acute myocardial infarction, and PSL was discontinued to avoid enhancing atherogenic risks. He was maintained on eltrombopag monotherapy. After discontinuing PSL, marked hypertriglyceridemia (>3,000 mg/dL) was observed, which did not improve even after a few years of pemafibrate therapy. Upon referral to our clinic, the triglyceride (TG) level was 2,251 mg/dL, ApoC-II was 19.8 mg/dL, LPL was 11.1 ng/mL (0.02-1.5 ng/mL), GPIHBP1 was 47.7 pg/mL (740.0-1,014.0 pg/mL), and anti-GPIHBP1 antibody was detected. The patient was diagnosed to have anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia. He was administered PSL 15 mg/day, and TG levels were controlled at approximately 200 mg/dL.

    Recent studies have reported that patients with anti-GPIHBP1 antibody-induced autoimmune hyperchylomicronemia had concomitant rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's disease, and Graves' disease. We report a rare case of anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia with concomitant ITP, which became apparent when PSL was discontinued due to the onset of steroid-induced acute myocardial infarction.

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  • Tatsuo Shimosawa
    Article type: Editorial
    Article ID: ED191
    Published: 2022
    Advance online publication: February 09, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
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  • Tomonori Sugiura, Yasuaki Dohi, Yasuyuki Takagi, Takashi Yokochi, Naof ...
    Article type: Original Article
    Article ID: 63368
    Published: 2022
    Advance online publication: February 03, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: Serum uric acid increases with metabolic disorders; however, whether the effects of uric acid on atherosclerosis are different in females and males has not been sufficiently evaluated. Therefore, this study compared the impact of uric acid on arterial stiffness and atherosclerosis between females and males.

    Methods: We enrolled 10196 untreated middle-aged subjects (46±8 years, 3021 females and 7175 males) who underwent periodic health check-ups. Serum uric acid levels were measured and arterial stiffness and atherosclerosis were assessed by the cardio-ankle vascular index (CAVI), carotid intima-media thickness (IMT), and plaque, using ultrasound imaging.

    Results: Females with increased arterial stiffness (CAVI ≥ 8.0) or carotid plaques had higher uric acid than those without (P<0.0001), but males did not. In multivariable regression analyses including overall participants, uric acid was significantly associated with the CAVI, where sex interacted with uric acid. In sex-specific analyses, uric acid was significantly associated with the CAVI, but not with carotid IMT, in both sexes. However, logistic regression analyses revealed that serum uric acid was independently associated with the presence of carotid plaques in females. The exclusion of subjects with abdominal obesity or metabolic syndrome from the analysis did not alter the results in females.

    Conclusions: Serum uric acid was significantly associated with the CAVI in both sexes, but the interaction of sex was confirmed and associated with a carotid plaque only in females. These findings support the increased impact of serum uric acid on arterial stiffness and atherosclerosis in females.

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  • Miwako Maeda, Tomoki Maeda, Kenji Ihara
    Article type: Original Article
    Article ID: 63056
    Published: 2022
    Advance online publication: January 29, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: We assessed 27-year trends in obesity and blood lipid levels of 10-year-old children to estimate the risk of metabolic syndrome in adulthood.

    Methods: Based on a screening program for lifestyle-related diseases in school children in Oita City, Japan, we evaluated secular trends in height, weight, percentage of overweight (POW), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) of fifth graders (median age: 10.8 years) in Oita City from 1991 to 2017. We focused on the secular trend in the percentage of children with inappropriate serum levels of each lipid. We also evaluated the long-term trends in the 95th, 50th, and 5th percentiles for each parameter, as dependent variables, with the calendar year as an independent variable. Percentages of children with mild obesity (POW-20), moderate obesity (POW-30), and severe obesity (POW-50) were set as dependent variables.

    Results: A total of 58,699 boys and 56,864 girls were evaluated during the study period. The percentage of children with severe obesity (POW-50) consistently increased during these years, and the 95th percentile of degree of obesity significantly increased in both boys and girls. The plot of percentages of children with inappropriate levels of TC, TG, and non-HDL-C showed a mild inverted U shape during the study period. The HDL-C level typically decreased in the study period, and the TC, TG, and non-HDL-C levels were markedly higher while the HDL level was lower in obese children than in non-obese children.

    Conclusion: The number of children with severe obesity increased, and obese children had higher percentages of inappropriate lipid levels than non-obese children. The rate of dyslipidemia with low HDL levels gradually increased in all children in Oita City, Japan, over the past 27 years.

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  • Makoto Kurano, Kazuhisa Tsukamoto, Eri Sakai, Yutaka Yatomi
    Article type: Original Article
    Article ID: 63249
    Published: 2022
    Advance online publication: January 27, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aim: In addition to the quantity and quality, the carriers, such as lipoproteins and albumin, can affect the physiological properties and clinical significance of lipids. This study aimed to elucidate the modulation of the levels of ceramides and sphingosine, which are considered as proatherosclerotic lipids, in lipoproteins and lipoprotein-depleted fractions in subjects with type 2 diabetes.

    Methods: We separated the serum samples collected from healthy subjects (n=22) and subjects with type 2 diabetes (n=39) into Triglyceride (TG)-rich lipoproteins (TRL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein-depleted fractions via ultracentrifugation. Then, we measured the levels of six species of ceramides, sphingosine, and dihydrosphingosine via LC-MS/MS and statistically analyzed them to identify the sphingolipids in each fraction, which are associated with diabetes as well as cardiovascular and renal complications.

    Results: In subjects with diabetes, the levels of sphingosine and dihydrosphingosine in the TRL, LDL, and lipoprotein-depleted fractions were higher, whereas those in the HDL were lower. In addition, the ceramide levels in HDL were lower, whereas those in lipoprotein-depleted fractions were higher. Furthermore, The levels of ceramides in lipoproteins, especially LDL, were negatively associated with the presence of cardiovascular diseases and stage 4 diabetic nephropathy.

    Conclusions: The contents of ceramides and sphingosine in lipoproteins and lipoprotein-depleted fractions were differently modulated in diabetes and associated with cardiovascular diseases and diabetic nephropathy. The carrier might be an important factor for the biological properties and clinical significance of these sphingolipids.

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  • Ouyang Meishuo, Ehab S. Eshak, Isao Muraki, Renzhe Cui, Kokoro Shirai, ...
    Article type: Original Article
    Article ID: 63195
    Published: 2022
    Advance online publication: January 26, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aim: Manganese (Mn) is an essential element in the human body, and it has a significant impact on cardiovascular risk factors such as diabetes, blood pressure, and cholesterol levels. However, no research has been conducted on the association between Mn and cardiovascular disease (CVD), to the best of our knowledge. This study thus examined the association between dietary Mn intake and CVD mortality in the general Japanese population.

    Methods: The CVD mortality among 58,782 participants from the Japan Collaborative Cohort Study (JACC) aged 40–79 years was determined during a median follow-up period of 16.5 years. The Mn intake was estimated using a food frequency questionnaire at the baseline (1989–1990), and multivariate-adjusted hazard ratios (HRs) for mortality were computed according to quintiles of energy-adjusted Mn intake.

    Results: During the follow-up period, a total of 3408 CVD deaths were recorded. Participants in the highest quintile of Mn intake had a lower risk of mortality from total stroke (HR:95% CI, 0.76: 0.64–0.90), ischemic stroke (HR: 0.77, 0.61–0.97), ischemic heart disease (HR: 0.76, 0.58–0.98), and total CVD (HR: 0.86, 0.76–0.96) compared with those in the lowest quintile. The reduced risk of mortality from intraparenchymal hemorrhage with high Mn intake was observed among women (HR: 0.60, 0.37–0.96) but not men (HR: 0.93, 0.59–1.47). The observed associations were more robust in postmenopausal than in premenopausal women.

    Conclusions: Our study is the first to show the prospective association between dietary Mn intake and reduced risk of mortality from CVD in the Japanese population.

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  • Jiaqi Li, Yoshihiro Kokubo, Ahmed Arafa, Haytham A. Sheerah, Makoto W ...
    Article type: Original Article
    Article ID: 63317
    Published: 2022
    Advance online publication: January 15, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Aims: This study aimed to investigate the association of mild hypertensive retinopathy with cardiovascular disease (CVD) risk.

    Methods: A total of 7,027 residents aged 30–79 years without a history of CVD participated in the annual health checkups and retinal photography assessments. Retinal microvascular abnormalities were graded using the standard protocols and classified according to the Keith–Wagener–Barker classification. Mild hypertensive retinopathy was defined as grades 1 and 2. Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for total CVD and its subtypes according to the presence and absence of mild hypertensive retinopathy.

    Results: During a median follow-up of 17 years, 351 incident stroke and 247 coronary heart disease (CHD) cases were diagnosed. After adjustment for traditional cardiovascular risk factors, mild hypertensive retinopathy was positively associated with risk of CVD (multivariable HR=1.24; 95% CI, 1.04–1.49) and stroke (1.28; 1.01–1.62) but not with risk of CHD (1.19; 0.89–1.58). Generalized arteriolar narrowing and enhanced arteriolar wall reflex were positively associated with CVD risk, the multivariable HR (95% CI) was 1.24 (1.00– 1.54)and 1.33 (1.02–1.74), respectively. Moreover, mild hypertensive retinopathy was positively associated with stroke risk in normotensive participants.

    Conclusion: Mild hypertensive retinopathy was positively associated with CVD and stroke risk in the urban Japanese population. Especially, generalized arteriolar narrowing and enhanced arteriolar wall reflex were positively associated with CVD risk. These findings suggested that retinal photography could be helpful for cardiovascular risk stratification in the primary cardiovascular prevention.

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  • Masa-aki Kawashiri
    Article type: Editorial
    Article ID: ED188
    Published: 2022
    Advance online publication: January 15, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION
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  • Yu Kataoka, Sayaka Funabashi, Takahito Doi, Mariko Harada-Shiba
    Article type: Review
    Article ID: RV17063
    Published: 2022
    Advance online publication: January 13, 2022
    JOURNAL OPEN ACCESS ADVANCE PUBLICATION

    Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder that elevates low-density lipoprotein cholesterol and increases the risk of premature atherosclerotic cardiovascular disease (ASCVD). However, despite their atherogenic lipid profiles, the cardiovascular risk of HeFH varies in each individual. Their variety of phenotypic features suggests the need for better risk stratification to optimize their therapeutic management. The current review summarizes three potential approaches, including (1) definition of familial hypercholesterolemia (FH)-related risk scores, (2) genetic analysis, and (3) biomarkers. The International Atherosclerosis Society has recently proposed a definition of severe FH to identify very high-risk HeFH subjects according to their clinical characteristics. Furthermore, published studies have shown the association of FH-related genetic phenotypes with ASCVD, which indicates the genetic analysis's potential to evaluate individual cardiovascular risks. Biomarkers reflecting disease activity have been considered to predict the formation of atherosclerosis and the occurrence of ASCVD in HeFH subjects. Incorporating these risk stratifications will be expected to allocate adequate intensity of lipid-lowering therapies in HeFH subjects, which ultimately improves cardiovascular outcomes.

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