Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
早期公開論文
早期公開論文の67件中1~50を表示しています
  • Tomohiko C. Umei, Yoshimi Kishimoto, Masayuki Aoyama, Emi Saita, Hanak ...
    原稿種別: Original Article
    論文ID: 52027
    発行日: 2019年
    [早期公開] 公開日: 2019/11/18
    ジャーナル フリー 早期公開

    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.

  • Teresa Infante, Luca Del Viscovo, Maria Luisa De Rimini, Sergio Padula ...
    原稿種別: Review
    論文ID: 52407
    発行日: 2019年
    [早期公開] 公開日: 2019/11/12
    ジャーナル フリー 早期公開

    Early identification of coronary atherosclerotic pathogenic mechanisms is useful for predicting the risk of coronary heart disease (CHD) and future cardiac events. Epigenome changes may clarify a significant fraction of this “missing hereditability”, thus offering novel potential biomarkers for prevention and care of CHD. The rapidly growing disciplines of systems biology and network science are now poised to meet the fields of precision medicine and personalized therapy. Network medicine integrates standard clinical recording and non-invasive, advanced cardiac imaging tools with epigenetics into deep learning for in-depth CHD molecular phenotyping. This approach could potentially explore developing novel drugs from natural compounds (i.e. polyphenols, folic acid) and repurposing current drugs, such as statins and metformin. Several clinical trials have exploited epigenetic tags and epigenetic sensitive drugs both in primary and secondary prevention. Due to their stability in plasma and easiness of detection, many ongoing clinical trials are focused on the evaluation of circulating miRNAs (e.g. miR-8059 and miR-320a) in blood, in association with imaging parameters such as coronary calcifications and stenosis degree detected by coronary computed tomography angiography (CCTA), or functional parameters provided by FFR/CT and PET/CT. Although epigenetic modifications have also been prioritized through network based approaches, the whole set of molecular interactions (interactome) in CHD is still under investigation for primary prevention strategies.

  • Toshiyuki Ko, Michiaki Higashitani, Yukari Uemura, Makoto Utsunomiya, ...
    原稿種別: Original Article
    論文ID: 52647
    発行日: 2019年
    [早期公開] 公開日: 2019/11/12
    ジャーナル フリー 早期公開

    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.

  • Mayu Higashioka, Satoko Sakata, Takanori Honda, Jun Hata, Daigo Yoshid ...
    原稿種別: Original Article
    論文ID: 51961
    発行日: 2019年
    [早期公開] 公開日: 2019/11/11
    ジャーナル フリー 早期公開

    Aims: This 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 a Japanese community.

    Methods: A total of 3,080 participants without prior cardiovascular disease, aged 40 years or older, were followed up for 8 years. The participants were divided into the quartiles of serum sdLDL cholesterol levels. The risk estimates were computed using a Cox proportional hazards model.

    Results: During the follow-up period, 79 subjects developed CHD. Subjects in the highest quartile had a 5.41- fold (95% confidence interval, 2.12–13.82) higher risk of CHD than those in the lowest quartile after controlling for confounders. In the analysis classifying the participants into four groups according to the levels of serum sdLDL cholesterol and serum low-density lipoprotein (LDL) cholesterol levels, the risk of CHD almost doubled in subjects with sdLDL cholesterol of ≥ 32.9 mg/dL (median), regardless of serum LDL cholesterol levels, as compared with subjects with serum sdLDL cholesterol of <32.9 mg/dL and serum LDL cholesterol of <120.1 mg/dL (median). When serum sdLDL cholesterol levels were incorporated into a model with known cardiovascular risk factors, c-statistics was significantly increased (from 0.77 to 0.79; p=0.02), and the net reclassification improvement was also significant (0.40; p<0.001).

    Conclusions: The present findings suggest that the serum sdLDL cholesterol level is a relevant biomarker for the future development of CHD that offers benefit beyond the serum LDL cholesterol level and a possible therapeutic target to reduce the burden of CHD in a Japanese community.

  • Nobuhiko Joki, Yuri Tanaka, Toshihide Hayashi
    原稿種別: Editorial
    論文ID: ED122
    発行日: 2019年
    [早期公開] 公開日: 2019/11/06
    ジャーナル フリー 早期公開
  • Masako Yamazaki
    原稿種別: Editorial
    論文ID: ED120
    発行日: 2019年
    [早期公開] 公開日: 2019/11/01
    ジャーナル フリー 早期公開
  • Yue Qi, Jing Liu, Wei Wang, Miao Wang, Fan Zhao, Jiayi Sun, Jun Liu, Q ...
    原稿種別: Original Article
    論文ID: 49841
    発行日: 2019年
    [早期公開] 公開日: 2019/10/30
    ジャーナル フリー 早期公開

    Aim: A high-risk strategy has been implemented for lipid-lowering therapy in the primary prevention of cardiovascular disease. However, atherosclerosis and cardiovascular events are common among individuals with low cardiovascular risk. This study aimed to determine whether the small dense low-density lipoprotein cholesterol (sdLDLC) level can predict carotid atherosclerosis progression and identify high-risk individuals.

    Methods: Baseline sdLDLC and low-density lipoprotein cholesterol (LDLC) were measured in 808 participants from the Chinese Multi-provincial Cohort Study, aged 45–74 years. Adjusted relative risk was calculated using a modified Poisson regression model to assess the relationship between sdLDLC and 5-year atherosclerosis progression, as indicated by the progression, incidence, and multi-territorial extent of carotid plaque.

    Results: The 5-year atherosclerosis progression increased significantly with increased sdLDLC. Baseline sdLDLC was significantly associated with the short-term risk of plaque progression after multivariable adjustment, even in participants with low LDLC or a 10-year estimated cardiovascular risk. sdLDLC predicted plaque progression (relative risk 2.05; 95% confidence interval 1.43–2.93) in participants with LDLC <130 mg/dL. Furthermore, participants with the highest sdLDLC but intermediate or low cardiovascular risk (accounting for 16% of the cohort) had double the risk of plaque progression, which was comparable to those with the same sdLDLC and high cardiovascular risk, relative to those with the lowest sdLDLC levels and low cardiovascular risk.

    Conclusions: sdLDLC is independently associated with the progression of carotid atherosclerosis, which may provide a basis for clinicians to reclassify individuals believed to be at low cardiovascular risk into the high-risk category, and those with high sdLDLC may benefit from more aggressive cholesterol-lowering treatment.

  • Michio Shimabukuro
    原稿種別: Editorial
    論文ID: ED119
    発行日: 2019年
    [早期公開] 公開日: 2019/10/30
    ジャーナル フリー 早期公開
  • Meiping Wang, Wenjuan Chen, Yu Geng, Chenghua Xu, Xiaoxiao Tao, Yi Zha ...
    原稿種別: Original Article
    論文ID: 50674
    発行日: 2019年
    [早期公開] 公開日: 2019/10/25
    ジャーナル フリー 早期公開

    Aim: This study focused on the expression pattern of long non-coding RNA maternally expressed gene 3 (MEG3) and its value in ischemic stroke (IS).

    Methods: The expression pattern and the roles of MEG3 in the development of IS were explored in mice IS model and human brain microvascular endothelial cells (hBMECs). A case-control study, including 215 IS patients and 153 controls, was also conducted to investigate its prognostic value.

    Results: In vivo study showed that MEG3 increased significantly in the IS group (P=0.004), and its level remained stable within 3 to 48h after the onset of IS. Besides, the survival time of the mouse in the high MEG3 group was significantly lower than that in the low MEG3 group (P=0.042). In vitro study showed that oxygen-glucose deprivation (OGD) treatment significantly up-regulated expressions of MEG3, Bax, and cleaved caspase-3, and further promoted apoptosis of hBMECs, while si-MEG3 blocked these effects. A human study showed that MEG3 increased markedly within 48h of IS onset and was positively associated with the National Institutes of Health Stroke Scale (r=0.347, P<0.001), modified Rankin Scale (r=0.385, P<0.001), high-sensitivity C-reactive protein (r=0.221, P=0.002) level, and infarct volume (r=0.201, P=0.006). Overall survival analysis showed that patients with higher MEG3 expression within 48h had a relatively poor prognosis (P<0.001). Meanwhile, multivariate analysis revealed that MEG3 was an independent prognostic marker for unfavorable functional outcome and death in IS patients.

    Conclusions: This study suggested that MEG3 might be considered as an intervention point and potential prognostic indicator for IS.

  • Mariko Harada-Shiba
    原稿種別: Editorial
    論文ID: ED121
    発行日: 2019年
    [早期公開] 公開日: 2019/10/24
    ジャーナル フリー 早期公開
  • Takahiro Sawada, Kenzo Uzu, Naoko Hashimoto, Tetsuari Onishi, Tomofumi ...
    原稿種別: Original Article
    論文ID: 50807
    発行日: 2019年
    [早期公開] 公開日: 2019/10/18
    ジャーナル フリー 早期公開

    Aim: So far, the mechanisms behind the cardiovascular benefits of sodium/glucose cotransporter 2 (SGLT2) inhibitors have not been fully clarified.

    Methods: In order to evaluate the effects of SGLT2 inhibitors on systemic hemodynamics, glucose metabolism, lipid profile, and endothelial function, 50 diabetic patients with established coronary artery disease (CAD) were included in this analysis and were given empagliflozin 10 mg/d. Cookie meal testing (carbohydrates: 75 g, fats: 28.5 g), endothelial function testing using flow-mediated dilatation (FMD), and body composition evaluation were performed before and after six months of treatment. Changes in %FMD between the treatment periods and its association with metabolic biomarkers were evaluated.

    Results: After six months of treatment, the body weight and body fat percentage decreased significantly, while the body muscle percentage increased significantly. The hemoglobin A1c level and fasting and postprandial plasma glucose levels were significantly decreased with treatment. Postprandial insulin secretion was also significantly suppressed and the insulin resistance index was significantly decreased. Furthermore, the fasting and postprandial triglyceride (TG) levels decreased significantly, while total ketone bodies increased significantly after the six-month treatment. While the plasma brain natriuretic peptide level was not changed, the C-reactive protein level was decreased and FMD was significantly improved after the six-month treatment. Multiple regression analysis showed that the strongest predictive factor of FMD improvement is change in the plasma TG levels.

    Conclusion: SGLT2 inhibitors improve multiple metabolic parameters. Of these, a reduction in plasma TGs was strongly associated with endothelial function recovery in diabetic patients with CAD, and this reduction may be related to the cardiovascular benefits of SGLT2 inhibitors.

  • Jin Kirigaya, Noriaki Iwahashi, Hironori Tahakashi, Yugo Minamimoto, M ...
    原稿種別: Original Article
    論文ID: 51409
    発行日: 2019年
    [早期公開] 公開日: 2019/10/18
    ジャーナル フリー 早期公開

    Aim: The purpose of this study is to investigate the impact of arterial stiffness assessed using Cardio-ankle Vascular Index (CAVI) on long-term outcome after acute coronary syndrome (ACS).

    Methods: A total of 387 consecutive patients (324 males; age, 64±11 years) with ACS were enrolled. We examined CAVI and brachial-ankle pulse wave velocity (ba PWV) as the parameters of arterial stiffness. The patients were divided into two groups according to the cut-off value of CAVI determined using the receiver operating characteristic curve for the prediction of major adverse cardiovascular events (MACE): low-CAVI group, 177 patients with CAVI <8.35; high-CAVI group, 210 patients with CAVI ≥ 8.35. The primary endpoint was the incidence of MACE (cardiovascular death, recurrence of ACS, heart failure requiring hospitalization, or stroke).

    Results: A total of 62 patients had MACE. Kaplan–Meier analysis demonstrated a significantly higher probability of MACE in the high-CAVI group than in the low-CAVI group (median follow-up: 62 months; log-rank, p<0.001). Multivariate analysis suggested that CAVI was an independent predictor of MACE (hazard ratio [HR], 1.496; p=0.02) and cardiovascular death (HR, 2.204; p=0.025), but ba PWV was not. We investigated the incremental predictive value of adding CAVI to the GRACE score (GRS), a validated scoring system for risk assessment in ACS. Stratified by CAVI and GRS, a significantly higher rate of MACE was seen in patients with both higher CAVI and higher GRS than the other groups (p<0.001). Furthermore, the addition of CAVI to GRS enhanced net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI, 0.337, p=0.034; and IDI, 0.028, p=0.004).

    Conclusion: CAVI was an independent long-term predictor of MACE, especially cardiovascular death, adding incremental clinical significance for risk stratification in patients with ACS.

  • Bao Liao, Meng-xiao Zhou, Feng-kun Zhou, Xiu-mei Luo, Song-xin Zhong, ...
    原稿種別: Original Article
    論文ID: 51102
    発行日: 2019年
    [早期公開] 公開日: 2019/10/10
    ジャーナル フリー 早期公開

    Aim: Exosome-derived microRNAs (miRNAs) are potential diagnostic biomarkers. However, little is known about their effectiveness as diagnostic biomarkers of intracranial aneurysms (IAs). This study aimed to explore miRNA levels in plasma exosomes of patients with IA to identify potential biomarkers that predict the development and progress of IA.

    Methods: A total of 69 patients with IA and 30 healthy controls (HC) were recruited, among whom 30 had unruptured IA (UA), and 39 had ruptured IA (RA). The miRNA expression profiles of plasma exosomes in 12 IA patients (4 UA and 8 RA) and 4 HC were determined using next-generation sequencing. In addition, significantly differentially expressed miRNAs were further analyzed by Quantitative Real-Time PCR (qRT-PCR) in a validation cohort of 99 subjects.

    Results: From the sequencing analysis, 181 miRNAs were identified to be differently (p<0.05) expressed. Of these, 9 miRNAs were up-regulated, and 20 were down-regulated in patients with UA compared with HC. Also, 21 were up-regulated, and 10 were down-regulated in patients with RA compared with HC. In addition, compared with UA, 92 miRNAs were up-regulated in RA, whereas 29 were down-regulated. Furthermore, qRT-PCR analysis confirmed that miR-145-5p and miR-29a-3p were up-regulated in IA samples. To distinguish IA patients from controls, the area under the receiver operating characteristic curve was 0.791 for miR-29a-3p, while that of miRNA-145-5p was 0.773 in terms of discriminating whether the aneurysm was ruptured.

    Conclusions: Circulating exosomal miRNAs can serve as biomarkers of the development and progression of IA.

  • Bancha Satirapoj, Wutipong Triwatana, Ouppatham Supasyndh
    原稿種別: Original Article
    論文ID: 52084
    発行日: 2019年
    [早期公開] 公開日: 2019/10/10
    ジャーナル フリー 早期公開

    Aims: Arterial stiffness is known to be an important surrogate marker for atherosclerosis and predictor of peripheral vascular and cardiovascular (CV) disease. Whether high cardio-ankle vascular index (CAVI) is associated with the development of rapid glomerular filtration rate (GFR) decline remains uncertain. The study aimed to determine the relationship between CAVI and renal function progression among patients with high CV risk.

    Methods: This study employed a prospective cohort design with 1-year follow-up among patients with high CV risk. Arterial stiffness was measured using CAVI method. GFR was estimated using the chronic kidney disease (CKD) epidemiology collaboration equation, and rapid decline in GFR was defined with decrease in GFR ≥ 5 mL/min/1.73 m2 yearly.

    Results: Of 352 patients with mean age 67.8±10.1 years, 224 patients (63.6%) were suspected to have arteriosclerosis (CAVI ≥ 9), and 208 patients (59.1%) had CKD (GFR <60 mL/min/1.73 m2). Annual decline of GFR was −0.75 [interquartile range (IQR), −1.16 to 6.08] mL/min/1.73 m2/year, and 30.1% of patients experienced a rapid decline in GFR. Compared with normal CAVI (CAVI <8), high CAVI (CAVI ≥ 9) and borderline CAVI (CAVI 8-8.9) in all subjects and subgroup of baseline GFR >60 mL/min/1.73 m2 were associated with rapid GFR decline. Multivariable analysis showed that high CAVI and borderline CAVI were associated with 2.47-fold (95% CI, 0.89-6.84; P=0.082) and 4.04-fold (95% CI, 1.46-11.18; P=0.007) increased odds ratio of rapid GFR decline, respectively.

    Conclusion: Among patients with high risk of CV with or without CKD, high CAVI (cut point of ≥ 9) was independently associated with a rapid decline in GFR, suggesting that systemic vascular stiffness predicted a decrease in renal function in this population.

  • Osamu Iida, Mitsuyoshi Takahara, Yasutaka Yamauchi, Yoshiaki Shintani, ...
    原稿種別: Original Article
    論文ID: 51631
    発行日: 2019年
    [早期公開] 公開日: 2019/10/05
    ジャーナル フリー 早期公開

    Aim: To investigate the impact of institutional volume on clinical outcomes after aortoiliac (AI) stenting in patients with symptomatic peripheral artery disease (PAD).

    Methods: We analyzed the clinical database from the Observational prospective Multicenter registry study on the Outcomes of peripheral arTErial disease patieNts treated by AngioplaSty tHerapy in the aortoIliac artery (OMOTENASHI) registry. The volume of each institution was evaluated as the number of endovascular therapy (EVT) procedures performed in 2 years (2014–2015). High-volume centers were defined as being in the highest tertile of the procedural volume (≥ 611 EVT procedures in 2 years). Clinical outcomes, treatment strategies, and endovascular procedures were compared between high- and low-volume centers using a propensity score matching.

    Results: The propensity score matching extracted 236 pairs of patients (as many patients treated at high-volume centers and 519 patients treated at low-volume centers), with no remarkable intergroup differences in the baseline characteristics. Patients treated at high-volume hospitals had a significantly lower 12-month restenosis rate than that of patients treated at low-volume hospitals (6.5% vs. 15.8%, P=0.032), although comparable outcomes between the two groups included the technical success rate (99.6% vs. 99.8%, P=0.58) and the rate of 30-day major adverse events (0.4% vs. 0.8%, P=0.59).

    Conclusion: Institutional volume was associated with the 12-month restenosis rate after AI stenting for PAD, although comparable perioperative outcomes were also observed between high-volume and low-volume hospitals.

  • Ivo N. SahBandar, Lishomwa C. Ndhlovu, Katelyn Saiki, Lindsay B. Koho ...
    原稿種別: Original Article
    論文ID: 49791
    発行日: 2019年
    [早期公開] 公開日: 2019/10/04
    ジャーナル フリー 早期公開

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

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

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

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

  • Kouji Kajinami, Kazuhisa Tsukamoto, Shinji Koba, Ikuo Inoue, Masashi Y ...
    原稿種別: Correspondence
    論文ID: 50948
    発行日: 2019年
    [早期公開] 公開日: 2019/10/04
    ジャーナル フリー 早期公開
  • Yasuhiro Watanabe, Ichiro Tatsuno
    原稿種別: Review
    論文ID: 50658
    発行日: 2019年
    [早期公開] 公開日: 2019/10/03
    ジャーナル フリー 早期公開

    An epidemiological study of Greenlandic Inuit suggested that fish oil, or omega-3 polyunsaturated fatty acids (PUFA), was important in preventing atherosclerotic disease. After this landmark study, many large-scale epidemiological studies and meta-analyses have examined the health benefits of omega-3 PUFA as part of a fatty acid-rich diet to demonstrate its beneficial roles in the prevention of cardiovascular diseases. Recent research has also focused attention on the anti-inflammatory effects of omega-3 PUFA and on specialized pro-resolving mediators. Findings of these studies have led to the development of omega-3 PUFA preparations for the treatment of dyslipidemia, including a highly purified eicosapentaenoic acid (EPA)-ethyl ester product (Epadel®) in Japan and an EPA/docosahexaenoic acid (DHA) preparation (Lotriga®) in the United States and Europe. Although various large-scale clinical trials on the cardiovascular preventive effect of omega-3 PUFA were conducted and reported, the results were not always consistent. The issues of not targeting subjects with hypertriglyceridemia and using low dose of omega-3 PUFA have been suggested to contribute to the failure of demonstrating the preventive effect of omega-3 PUFA in these clinical trials. Taking into account the above issues, the REDUCE-IT trial evaluated a highly purified EPA preparation at a high dose of 4 g/day in patients with hypertriglyceridemia and high cardiovascular risk, and demonstrated an extraordinary outcome of 25% relative reduction in cardiovascular events. This article reviews studies on omega-3 fatty acids during the last 50 years, including the progress in elucidating molecular mechanisms and recent large-scale clinical studies.

  • Noriko Kameyama, Chizuko Maruyama, Yuri Shijo, Ariko Umezawa, Aisa Sat ...
    原稿種別: Original Article
    論文ID: 52316
    発行日: 2019年
    [早期公開] 公開日: 2019/10/03
    ジャーナル フリー 早期公開

    Aim: We aimed to clarify actual food and nutrient intakes in Japanese patients with dyslipidemia. We also compared food and nutrient intakes between patients with and without low-density lipoprotein cholesterol (LDL-C) lowering drug therapy.

    Methods: Food and nutrient intakes were assessed employing 3-day weighted dietary records in this cross-sectional study of 104 Japanese outpatients with dyslipidemia, age 30-65 years, not given dietary counseling. Anthropometric and biochemical parameters were measured after an overnight fast. Food and nutrient intakes were compared between patients with versus without LDL-C lowering drug prescriptions. Stepwise multiple regression analysis was performed to identify relationships between the serum LDL-C concentrations and food intakes.

    Results: Of the 104 patients, 43.3% were prescribed LDL-C lowering drugs, primarily statins. Of the total patients, 83% had lipid intakes over 25% of total energy consumption (%E), exceeding the recommendation for dyslipidemia by the Japan Atherosclerosis Society. Similarly, 77% had saturated fatty acid intakes over 7%E, and 88% had cholesterol intakes over 200 mg per day. Dietary fiber consumption was low (<25 g) in 97% of patients. Those taking LDL-C lowering drugs consumed less “meat, poultry and processed meat products” and “cereals”, and more “fish”, “fruits” and “nuts”, than patients not taking these drugs (p<0.05). Food intakes correlating with LDL-C concentrations independently of drug therapy differed between patients taking versus not taking these medications.

    Conclusion: Our results support the necessity of diet therapy for patients with dyslipidemia regardless of whether LDL-C lowering drugs are prescribed.

    The clinical trial registration number: UMIN000022955

  • Yasuhiro Tomita, Takatoshi Kasai, Sayaki Ishiwata, Hiroyuki Daida, Koj ...
    原稿種別: Original Article
    論文ID: 50286
    発行日: 2019年
    [早期公開] 公開日: 2019/09/28
    ジャーナル フリー 早期公開

    Aim: Patients with obstructive sleep apnea (OSA) are likely to show increased arterial stiffness and progressive systemic atherosclerosis. Chest radiography reveals atherosclerotic changes in the aorta via measurement of aortic knob width. However, to our knowledge, aortic knob width in patients with OSA has never been evaluated.

    Methods: We measured the aortic knob width in chest radiographs of 549 patients (age: 52.5±13.2 years; 69 women) who underwent overnight polysomnography. Moreover, we evaluated the association between aortic knob width and other clinical characteristics, including cardio–ankle vascular index (CAVI) and apnea–hypopnea index (AHI). Multivariate linear regression analysis was conducted to identify factors associated with aortic knob width.

    Results: A significant direct correlation between aortic knob width and CAVI and between aortic knob width and AHI was observed. In multivariate linear regression analysis, either CAVI or AHI was independently associated with aortic knob width (p=0.004 and p<0.001, respectively) in addition to age, male gender, body mass index, and systolic blood pressure.

    Conclusion: A significant independent correlation between aortic knob width and OSA severity was observed. Our findings suggest that an increase in the aortic knob width suggests atherosclerotic changes in the aorta and may be associated with OSA and increased arterial stiffness.

  • Sung Keun Park, Min-Ho Kim, Eunhee Ha, Ju Young Jung, Chang-Mo Oh, Joo ...
    原稿種別: Original Article
    論文ID: 50757
    発行日: 2019年
    [早期公開] 公開日: 2019/09/27
    ジャーナル フリー 早期公開

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

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

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

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

  • Brian Tomlinson, Paul Chan, Zhong-Min Liu
    原稿種別: Correspondence
    論文ID: 50435
    発行日: 2019年
    [早期公開] 公開日: 2019/09/25
    ジャーナル フリー 早期公開
  • Naoki Iwakawa, Akihito Tanaka, Hideki Ishii, Takashi Kataoka, Kiyoshi ...
    原稿種別: Original Article
    論文ID: 50930
    発行日: 2019年
    [早期公開] 公開日: 2019/09/25
    ジャーナル フリー 早期公開

    Aim: An inverse association between diabetes mellitus (DM) and aortic dilatation has recently been reported. However, little is known about the association between DM and the progression of aortic dilatation/calcification as atherosclerosis progresses.

    Methods: We identified 216 patients who had undergone percutaneous coronary intervention (PCI) and abdominal computed tomography (CT) during the PCI and follow-up phases. The patients were classified into two groups: those with DM (DM+ group; n=107) and those without DM (DM− group; n=109). The infrarenal aortic diameter and aortic calcification index (ACI) were measured, and annual changes were calculated using measurement results obtained during the PCI and follow-up phases.

    Results: Infrarenal aortic diameters were significantly shorter in the DM+ group than in the DM- group during the PCI phase, and no significant ACI differences were observed between the DM+ and DM− groups. The median duration between the PCI and follow-up phase CT was 3.0 years. The growth rate of the infrarenal aortic dilatation from the PCI phase in the DM+ group was similar to that in the DM− group. Annual ACI changes were significantly larger in the DM+ group than in the DM− group. Multivariate logistic regression analysis indicated that the prevalence of DM was an independent predictor of rapid aortic calcification progression (odds ratio: 2.51; 95% confidence interval: 1.23-5.14; p=0.01).

    Conclusion: Our findings suggest that DM negatively affects aortic dilatation during an earlier phase of atherosclerosis progression and positively affects the progression of aortic calcification in a later phase.

  • Tomohisa Nezu, Naohisa Hosomi, Kazuo Kitagawa, Yoji Nagai, Yoko Nakaga ...
    原稿種別: Original Article
    論文ID: 51391
    発行日: 2019年
    [早期公開] 公開日: 2019/09/25
    ジャーナル フリー 早期公開

    Aim: Posterior circulation stroke (PCS) has different clinical features and prognosis compared with anterior circulation stroke (ACS), and whether the effect of statin therapy on stroke prevention differs according to infarction location remains unclear. This post hoc analysis of the J-STARS study aimed to compare the usefulness of statin at different infarction locations (i.e., ACS and PCS).

    Methods: In the J-STARS study, 1578 patients were randomly assigned to the pravastatin or control group. The subjects were divided into two subgroups (ACS and PCS groups) based on the arteries responsible for the infarction. Cox proportional hazards models were used to investigate whether the all stroke recurrence rate was different between the ACS and PCS groups.

    Results: The PCS group (n=499) had a significantly higher prevalence of diabetes than the ACS group (n=1022) (30.7% vs. 19.8%, P<0.001). During the follow-up (4.9±1.4 years), the incidence of all stroke was significantly lower in the pravastatin group than in the control group among patients with PCS (adjusted hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.25–0.83, P=0.009); however, the stroke recurrence rates were not significantly different between both groups among patients with ACS (adjusted HR 1.32, 95% CI 0.93–1.88,P=0.123). A significant interaction between the ACS and PCS groups in terms of pravastatin effects was noted (P=0.003 for interaction).

    Conclusions: Pravastatin significantly reduced the recurrence rate of all stroke among patients with PCS. Thus, the effect of statin on the recurrence of stroke may differ according to infarction location.

  • Yuji Hirowatari, Hiroshi Yoshida
    原稿種別: Review
    論文ID: RV17037
    発行日: 2019年
    [早期公開] 公開日: 2019/09/20
    ジャーナル フリー 早期公開

    Separation analysis of lipoprotein classes have various methods, including ultracentrifugation, electrophoresis, and gel permeation chromatography (GPC). All major lipoprotein classes can be separated via ultracentrifugation, but performing the analysis takes a long time. Low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), and very low-density lipoprotein (VLDL) in patient samples cannot be sufficiently separated via electrophoresis or GPC. Thus, we established a new method [anion-exchange high-performance liquid chromatography (AEX-HPLC)] by using HPLC with an AEX column containing nonporous gel and an eluent containing chaotropic ions. AEX-HPLC can separate five lipoprotein fractions of high-density lipoprotein (HDL), LDL, IDL, VLDL, and others in human serum, which can be used in substitution for ultracentrifugation method. The method was also approved for clinical use in the public health-care insurance in Japan in 2014. Furthermore, we developed an additional method to measure cholesterol levels of the four leading lipoprotein fractions and two subsequent fractions (i.e., chylomicron and lipoprotein(a)). We evaluated the clinical usefulness of AEX-HPLC in patients with coronary heart disease (CHD), diabetes, and kidney disease and in healthy volunteers. Results indicate that the cholesterol levels in IDL and VLDL measured by AEX-HPLC may be useful risk markers of CHD or diabetes. Furthermore, we developed another new method for the determination of alpha-tocopherol (AT) in lipoprotein classes, and this method is composed of AEX-HPLC for the separation of lipoprotein classes and reverse-phase chromatography to separate AT in each lipoprotein class. The AT levels in LDL were significantly correlated with the lag time to copper ion-induced LDL oxidation, which is an index of oxidation resistance. The application of AEX-HPLC to measure various substances in lipoproteins will be clinically expected in the future.

  • Isao Saito, Kazumasa Yamagishi, Yoshihiro Kokubo, Hiroshi Yatsuya, Hir ...
    原稿種別: Original Article
    論文ID: 50385
    発行日: 2019年
    [早期公開] 公開日: 2019/09/19
    ジャーナル フリー 早期公開

    Aim: A positive association between non-high-density lipoprotein cholesterol (non-HDL-C) and coronary heart disease (CHD) has been established; however, associations between non-HDL-C and stroke subtypes have not been determined.

    Methods: We conducted a prospective study of 30,554 individuals aged 40–69 yrs with no history of cardiovascular disease (CVD) in Japan. Sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the incidence of stroke subtypes and CHD were estimated according to quintiles of non-HDL-C, using Cox proportional hazard models adjusted for other established risk factors.

    Results: We identified 1,705 stroke and 296 CHD events over a median 15 yrs of follow-up. The fractional polynomials analysis revealed a U-shaped association between non-HDL-C and stroke risk in men. When analyzed for stroke subtypes, the data revealed an inverse relationship between non-HDL-C and intracerebral hemorrhage (ICH), primarily with lobar ICH, and a positive association between non-HDL-C and large-artery occlusive infarction in men [adjusted HR 0.55 (95% CI, 0.35–0.87) and 2.05 (95% CI, 1.07–3.93) for the highest and lowest quintile of non-HDL-C, respectively]. The lowest risk of ICH in women was observed in the fourth quintile, and the lowest risk of embolic infarction was observed in the third quintile. In contrast, non-HDL-C was positively associated with CHD in both sexes.

    Conclusions: In Japanese men, lower non-HDL-C levels were associated with a decreased risk of large-artery occlusive infarction and an increased risk of ICH, particularly lobar ICH.

  • Naohisa Hosomi, Kazuo Kitagawa, Yoji Nagai, Yoko Nakagawa, Shiro Aoki, ...
    原稿種別: Original Article
    論文ID: 50518
    発行日: 2019年
    [早期公開] 公開日: 2019/09/18
    ジャーナル フリー 早期公開

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

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

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

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

  • Zhibin Li, Chunmei He, Yongwen Liu, Dongmei Wang, Mingzhu Lin, Changqi ...
    原稿種別: Original Article
    論文ID: 49619
    発行日: 2019年
    [早期公開] 公開日: 2019/09/13
    ジャーナル フリー 早期公開

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

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

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

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

  • Yongin Cho, Hyangkyu Lee, Hyun Ki Park, Eun Yeong Choe, Hye Jin Wang, ...
    原稿種別: Original Article
    論文ID: 50039
    発行日: 2019年
    [早期公開] 公開日: 2019/09/13
    ジャーナル フリー 早期公開

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

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

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

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

  • Hiroshi Yoshida, Hayato Tada, Kumie Ito, Yoshimi Kishimoto, Hidekatsu ...
    原稿種別: Original Article
    論文ID: 50187
    発行日: 2019年
    [早期公開] 公開日: 2019/09/05
    ジャーナル フリー 早期公開

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

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

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

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

  • Satoko Sakurai, Hideki Kato, Yoko Yoshida, Yuka Sugawara, Madoka Fujis ...
    原稿種別: Original Article
    論文ID: 49494
    発行日: 2019年
    [早期公開] 公開日: 2019/09/04
    ジャーナル フリー 早期公開

    Aim: Atypical hemolytic uremic syndrome (aHUS), characterized by thrombotic microangiopathy (TMA), is a genetic, life-threatening disease which needs many differential diagnoses. This study aimed to reveal coagulation and fibrinolysis profiles in aHUS and secondary TMA patients. Furthermore, we investigated whether aHUS patients progress to, and meet, disseminated intravascular coagulation (DIC) criteria.

    Methods: The acute phase samples were available in 15 aHUS and 20 secondary TMA patients. We measured PT-ratio, activated partial thromboplastin time (APTT), fibrinogen, fibrin degradation product (FDP), fibrin monomer complex (FMC), antithrombin (AT), plasmin-α2 plasmin inhibitor complex (PIC), and von Willebrand factor antigen (VWF:Ag). We examined and compared these tests among aHUS, secondary TMA patients, and healthy volunteer (HV), and evaluated whether patients with aHUS and secondary TMA met DIC criteria.

    Results: PT-ratio, APTT, FDP, FMC and PIC in patients with aHUS and secondary TMA were higher than those in HV. Fibrinogen and AT showed no significant difference among three groups. VWF:Ag was higher in only aHUS patients. No tests showed significant difference between aHUS and secondary TMA patients. Three aHUS patients out of 15 met DIC criteria.

    Conclusion: We revealed the profiles and distributions of coagulation and fibrinolysis tests of aHUS and secondary TMA patients. All tests were enhanced compared to HV; however, our results showed the no specificities in distinguishing aHUS from secondary TMA patients. We also clarified that some aHUS patients fulfilled DIC diagnostic criteria, indicating that DIC itself cannot be an exclusion criterion of aHUS.

  • Tomohiro Komatsu, Yoshinari Uehara
    原稿種別: Editorial
    論文ID: ED115
    発行日: 2019年
    [早期公開] 公開日: 2019/09/04
    ジャーナル フリー 早期公開
  • Michihiro Satoh
    分野: Editorial
    論文ID: ED117
    発行日: 2019年
    [早期公開] 公開日: 2019/09/04
    ジャーナル フリー 早期公開
  • Toshihide Izumida, Yosikazu Nakamura, Yumika Hino, Shizukiyo Ishikawa
    原稿種別: Original Article
    論文ID: 49528
    発行日: 2019年
    [早期公開] 公開日: 2019/08/29
    ジャーナル フリー 早期公開

    Aims: Small dense low-density lipoprotein cholesterol (sdLDL-C) and remnant-like particle cholesterol (RLP-C) are the novel atherosclerotic risk factors and might be strongly associated with inflammation. The basic evidence supports that sdLDL and RLP have some different mechanisms inducing an inflammatory response. Many studies have focused on the mechanism of inflammation of sdLDL-C or RLP-C per se, with limited data on the association between sdLDL-C and RLP-C in the real-world, population-based setting. Thus, the aim of this study was to investigate the association between sdLDL-C and RLP-C with inflammation.

    Methods: We examined the baseline cross-sectional data of participants from the Jichi Medical School-II Cohort Study. In total, 5,305 participants (2,439 men and 2,866 women) were included in this study.

    Results: Of all quartiles of sdLDL-C, the fourth had the highest high-sensitivity C-reactive protein (hs-CRP) level. Once adjusted for age, sex, smoking status, homeostasis model assessment of insulin resistance, antidyslipidemic and antihyperglycemic medication use, and RLP-C, sdLDL-C was significantly and positively associated with hs-CRP (geometric mean, 95% confidence interval (CI), 0.36 mg/L (0.34–0.38 mg/L), 0.37 mg/L (0.35–0.39 mg/L), 0.40 mg/L (0.37–0.42 mg/L) versus 0.44 mg/L (0.42–0.47 mg/L), P<0.001 for trend). After stratifying the participants into four sdLDL-C×four RLP-C categories, the group in the fourth sdLDL-C quartile and the forth RLP-C quartile had the highest hs-CRP level (geometric mean, 95% CI, 0.52 mg/L, 0.48–0.57 mg/L, interaction P=0.75).

    Conclusions: SdLDL-C and RLP-C had different associations with inflammation. Our results support sdLDL-C as the potential novel factor of cardiovascular disease, independently of RLP-C.

  • Masato Nakamura
    原稿種別: Editorial
    論文ID: ED118
    発行日: 2019年
    [早期公開] 公開日: 2019/08/29
    ジャーナル フリー 早期公開
  • Jiancong Ren, Yanshuo Han, Tongming Ren, Hong Fang, Xiaohan Xu, Yu Lun ...
    原稿種別: Original Article
    論文ID: 49106
    発行日: 2019年
    [早期公開] 公開日: 2019/08/28
    ジャーナル フリー 早期公開

    Aim: Inflammation plays a significant role in the pathogenesis of human abdominal aortic aneurysm (AAA). AEBP1 can promote activation of the NF-κB pathway, subsequently affecting the expression of NF-κB target genes, including inflammatory cytokines and matrix metalloproteinases (MMPs). Our objective was to examine the role of AEBP1 in the development of AAA and characterize the underlying mechanism.

    Methods: ITRAQ, RT-PCR, western blot, immunohistochemistry, and ELISA were used to compare different experimental groups with the controls and to determine the differentially expressed genes. We generated an AAA model using porcine pancreatic elastase in Sprague–Dawley rats and silenced their AEBP1 in vivo by adenoviruses injected intra-adventitially. We also silenced or overexpressed AEBP1 in human vascular smooth muscle cells in vitro in the presence and in the absence of NF-κB inhibitor BAY 11-7082.

    Results: Proteome iTRAQ revealed a high expression of AEBP1 in AAA patients, which was verified by qRT-PCR, western blot, immunohistochemistry, and ELISA. The mean expression level of AEBP1 in AAA patients was higher than that in controls. Along with AEBP1 upregulation, we also verified mis-activation of NF-κB in human AAA samples. The in vivo studies indicated that AEBP1 knockdown suppressed AAA progression. Finally, the in vitro studies illustrated that AEBP1 promotes activation of the NF-κB pathway, subsequently upregulating pro-inflammatory factors and MMPs.

    Conclusions: Our results indicate a role of AEBP1 in the pathogenesis of AAA and provide a novel insight into how AEBP1 causes the development of AAA by activating the NF-κB pathway.

  • Xiaowei Song, Jun Li, Yang Hua, Chunxiu Wang, Beibei Liu, Chunxiao Liu ...
    原稿種別: Original Article
    論文ID: 49569
    発行日: 2019年
    [早期公開] 公開日: 2019/08/28
    ジャーナル フリー 早期公開

    Aims: To investigate the association of chronic kidney disease (CKD) and intracranial artery stenosis (ICAS), as well as its effects on ICAS distribution in the middle-aged and elderly population.

    Methods: Data from the China Hypertension Survey in Beijing was analyzed. Estimated glomerular filtration rate (eGFR) was used to evaluate CKD, and ICAS was assessed by transcranial doppler. Clinical and biochemical variables were compared between the ICAS group and the non-ICAS group, as well as in different vascular distribution groups. Univariable and multivariable logistic regression analyses were introduced to demonstrate the association between CKD and ICAS.

    Results: A total of 3678 subjects were included in this study, with a mean age of 62 years old. Of which, 19.2% presented with decreased eGFR (eGFR <60 ml/min/1.73 m2) and 17.4% for ICAS. The percentage of anterior circulation ICAS was 3.5 times than that of posterior circulation (10.9% vs. 3.1%). In multivariable regression analysis, eGFR <45 ml/min/1.73 m2 was independently associated with ICAS after correction for covariates, odds ratio (OR)=1.69, 95% confidence interval (CI) (1.08, 2.65); in particular, this association had a preference for posterior circulation but not anterior circulation ICAS with OR=2.29, 95% CI (1.28, 4.07) and OR=1.44, 95%CI (0.89, 2.33), respectively.

    Conclusion: Severe eGFR decline is associated with ICAS in the middle-aged and elderly population, and this correlation is more related to posterior circulation ICAS.

  • Tomonori Sugiura, Yasuaki Dohi, Yasuyuki Takagi, Naofumi Yoshikane, Mi ...
    原稿種別: Original Article
    論文ID: 50633
    発行日: 2019年
    [早期公開] 公開日: 2019/08/28
    ジャーナル フリー 早期公開

    Aim: Obesity is a social problem due to the prevalence of the Western lifestyle. In particular, visceral fat accumulation, which is a main component of metabolic syndrome, is closely associated with the progression of atherosclerosis. This study aimed to investigate the relationships of obesity-related indices and metabolic syndrome with subclinical atherosclerosis in middle-aged untreated workers.

    Methods: Employees undergoing their periodic health check-up but without previous cardiovascular events or cardiovascular medications were enrolled in this study (n=7,750). Body mass index (BMI), percent body fat, waist circumference, and visceral fat area were evaluated as obesity-related indices. Assessment of visceral fat area was performed by computed tomography (CT). Subclinical atherosclerosis was assessed by measuring arterial stiffness using cardio-ankle vascular index (CAVI) and by ultrasound examination of carotid intima-media thickness (IMT).

    Results: Obesity-related indices were significantly correlated with each other and were positively associated with carotid IMT but negatively associated with CAVI in multivariate regression analysis. In a logistic regression analysis including CAVI and carotid IMT simultaneously, CAVI was negatively associated, but carotid IMT was positively associated, with obesity defined by each obesity-related index. In contrast, both CAVI and carotid IMT were positively associated with the presence of metabolic syndrome based on visceral fat accumulation.

    Conclusions: Obesity-related indices were negatively associated with CAVI and positively associated with carotid IMT in middle-aged untreated workers, while both CAVI and carotid IMT were worsened in the presence of metabolic syndrome.

  • Hiroto Hiyamuta, Shigeru Tanaka, Masatomo Taniguchi, Masanori Tokumoto ...
    原稿種別: Original Article
    論文ID: 49833
    発行日: 2019年
    [早期公開] 公開日: 2019/08/22
    ジャーナル フリー 早期公開

    Aim: The incidence of sudden death and its risk factors in patients on hemodialysis remain unclear. This study aimed to clarify the incidence of sudden death and its risk factors in Japanese patients on hemodialysis.

    Methods: A total of 3505 patients on hemodialysis aged ≥ 18 years were followed for 10 years. Multivariate-adjusted hazard ratio (HR) with 95% confidence interval (95% CI) of each risk factor of sudden death were calculated using a Cox proportional hazards model.

    Results: During the 10-year follow-up, 1735 patients died, including 227 (13%) sudden deaths. The incidence rate of sudden death was 9.13 per 1000 person-years. In multivariable-adjusted Cox analysis, male sex (HR 1.67; 95% CI 1.20–2.33), age (HR 1.44; 95% CI 1.26–1.65 per 10-year higher), the presence of diabetes (HR 2.45; 95% CI 1.82–3.29), history of cardiovascular disease (HR 1.85; 95% CI 1.38–2.46), cardiothoracic ratio (HR 1.21; 95% CI 1.07–1.39 per 5% higher), serum C-reactive protein (HR 1.11; 95% CI 1.03–1.20 per 1-mg/dL higher), and serum phosphate (HR 1.15; 95% CI 1.03–1.30 per 1-mg/dL higher) were independent predictors of sudden death. A subgroup analysis stratified by sex or age showed that lower serum corrected calcium levels, not using vitamin D receptor activators in women, and a shorter dialysis session length in men or older people (≥ 65 years) increased the risk for sudden death.

    Conclusions: This study clarified the incidence of sudden death and its specific predictors in Japanese patients on hemodialysis.

  • Qiaowei Li, Fan Lin, Douli Ke, Qiong Cheng, Yongzhi Gui, Yuyan Zhou, Y ...
    原稿種別: Original Article
    論文ID: 50898
    発行日: 2019年
    [早期公開] 公開日: 2019/08/09
    ジャーナル フリー 早期公開

    Aim: Our study investigated the association between soluble endoglin and carotid subclinical atherosclerosis.

    Methods: We used endoglin as an adjunct to atherosclerotic cardiovascular disease (ASCVD) risk, in recognition of carotid clinical atherosclerosis, in order to explore a new model to refine risk assessment. Out of 3,452 participants, 978 subjects with detected soluble endoglin were enrolled in a cross-sectional investigation in Fujian Province were enrolled. Soluble endoglin concentration in serum samples was evaluated using an enzyme-linked immunosorbent assay method. Carotid ultrasonography was used to detect intima-media thickness and carotid plaque.

    Results: The mean 10-year ASCVD risk by the new Pooled Cohort Equations accounted for 10.04% (±12.35). The mean soluble endoglin level was 15.35 ng/ml (±6.64). Multivariable regression demonstrated that age, systolic blood pressure, diastolic blood pressure, total cholesterol, high density lipoprotein cholesterol, and serum uric acid were independent determinants of soluble endoglin. Adding tests of ASCVD and endoglin together, in parallel, will increase the sensitivity and decrease specificity in recognizing carotid subclinical atherosclerosis. Evaluating the added value of endoglin to the ASCVD risk model showed significantly improved discrimination with analysis of C-statistics, continuous net reclassification index and integrated discrimination index. Both ASCVD risk and soluble endoglin showed positively linear correlation with carotid intima-media thickness (cIMT) (β=0.006, P<0.001; β=0.485, P<0.001). Even with adjustment for other factors, the relationship between log-transformed soluble endoglin with cIMT was still significant (β=0.369, P<0.001).

    Conclusions: The combination of ASCVD risk and endoglin levels increases carotid atherosclerosis recognition.

  • Tatsuro Mitsuse, Koichi Kaikita, Masanobu Ishii, Yu Oimatsu, Nobuhiro ...
    原稿種別: Original Article
    論文ID: 49700
    発行日: 2019年
    [早期公開] 公開日: 2019/08/08
    ジャーナル フリー 早期公開

    Aims: The assessment of bleeding risk in patients with coronary artery disease (CAD) is clinically important. We recently developed the Total Thrombus-Formation Analysis System (T-TAS) for the quantitative analysis of thrombus formation using microchips with thrombogenic surfaces. Here, we assessed the utility of T-TAS parameters in predicting 1-year bleeding events in patients with CAD.

    Methods: The study subjects were 561 consecutive patients who underwent coronary angiography (CAG) between August 2013 and September 2016 for suspected CAD. Blood samples collected at the time of CAG were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip. Patients were divided into three groups according to AR10-AUC30 (low: ≤ 1603, intermediate, and high: >1765, n=187 each). One-year bleeding events were defined by the Platelet Inhibition and Patient Outcomes criteria.

    Results: Bleeding occurred in 21 (3.7%) patients and was classified as major (8 [1.4%]) and minor (13 [2.3%]). The AR10-AUC30 levels were significantly lower in the bleeding group than the non-bleeding group (median [interquartile range] 1590 [1442–1734] vs. 1687 [1546–1797], p=0.04). Univariate Cox regression analysis demonstrated that low AR10-AUC30 , high prothrombin time-international normalized ratio levels, and diabetes correlated with bleeding events. Multivariate Cox regression analysis identified low AR10-AUC30 levels as a significant determinant of bleeding events. Kaplan-Meier survival curves showed a higher rate of bleeding events in the low than the high AR10-AUC30 group (p=0.007).

    Conclusions: The results highlight the potential usefulness of the AR10-AUC30 levels in the prediction of 1-year bleeding events in patients with CAD treated with various antithrombotic therapies.

  • Takehiro Michikawa
    原稿種別: Editorial
    論文ID: ED116
    発行日: 2019年
    [早期公開] 公開日: 2019/08/07
    ジャーナル フリー 早期公開
  • Satoshi Tsuchiya, Yasuharu Matsumoto, Tsuyoshi Doman, Taku Fujiya, Jun ...
    原稿種別: Case Report
    論文ID: 49239
    発行日: 2019年
    [早期公開] 公開日: 2019/08/03
    ジャーナル フリー 早期公開

    An 83-year-old woman with severe aortic stenosis was admitted to our hospital due to heart failure with refractory anemia requiring blood transfusions. She had repetitive bleeding episodes from endoscopically proven angiodysplasia in the stomach. Moreover, she repeatedly underwent endoscopic argon plasma coagulation for hemostasis. Importantly, she had a deficiency of the high-molecular-weight (HMW) multimers of von Willebrand factor (VWF), and she was diagnosed with Heyde's syndrome.

    After she underwent transcatheter aortic valve implantation (TAVI), aortic valve area and mean left ventricular aorta pressure gradient improved. Notably, endoscopy showed cessation of bleeding at 10 days after TAVI and the disappearance of angiodysplasia at 4 months after TAVI. Even at 2 years after TAVI, follow-up endoscopy showed remaining free of angiodysplasia in the stomach. She experienced no episodes of anemia since TAVI procedure. Additionally, analysis of HMW multimers demonstrated immediate and lasting recovery after TAVI.

    Recovery of HMW multimers of VWF with cessation of gastrointestinal bleeding following aortic valve replacement has been previously reported in a patient diagnosed with Heyde's syndrome. To the best our knowledge, this is the first case to demonstrate that angiodysplasia disappears after TAVI for a long term with endoscopic images in a patient with Heyde's syndrome. Here, we summarized case reports of patients with Heyde's syndrome that required aortic valve intervention. Cessation of gastrointestinal bleeding and anemia after aortic valve intervention for severe aortic stenosis may be attributed not only to recovery of HMW multimers of VWF but also to the disappearance of angiodysplasia.

  • Shinji Katsuragi, Tomonori Okamura, Yoshihiro Kokubo, Makoto Watanabe, ...
    原稿種別: Original Article
    論文ID: 49577
    発行日: 2019年
    [早期公開] 公開日: 2019/07/25
    ジャーナル フリー 早期公開

    Aim: To investigate the relationship between perinatal condition around birth and cardiovascular risk in later life.

    Methods: Retrospective data were examined from 1241 city dwellers (521 men, 720 women; age 41–69 years) who had undergone medical examination at a single institution including blood tests and physical measurements from 2007 to 2008. The questionnaire was conducted to determine how perinatal factors affect their lives later. We also selected and studied a total of 28 individuals (12 men and 16 women) specifically about the conformity rate of the breastfeeding method between participants' memories and what was written in the maternal and child health handbooks.

    Results: The conformity rate of the breastfeeding method between a self-questionnaire and his/her maternal and child health handbook was well correlated (r=0.73; p<0.025). Among the data in women who were born at home, HbA1C levels (5.36±0.03 vs. 5.25±0.05 mg/dL, p=0.03) and low-density lipoprotein cholesterol (136.0±1.4 vs. 129.3±2.5 mg/dL, p=0.04) were higher than women who were born at the hospital. Women raised by formula showed higher low-density lipoprotein cholesterol levels than women fed breast milk or a mixture of breast milk and formula (150.2±4.8 vs. 138.7±3.7, 142.5±2.6 mg/dL, p=0.04). Fasting blood glucose levels at an adult time in men and women born through breech presentation were higher than those by the cephalic presentation (123.2±7.8 vs. 106.8±1.2 mg/dL, p=0.03).

    Conclusion: The study proposed that some perinatal conditions around birth such as delivery place, presenting part, and lactation affected especially Japanese women's cardiovascular risks between ages 41 and 69 years.

  • Song Yang, Yanping Zhao, Xiaotian Chen, Xiangfeng Lu, Yanchun Chen, Xi ...
    原稿種別: Original Article
    論文ID: 49536
    発行日: 2019年
    [早期公開] 公開日: 2019/07/19
    ジャーナル フリー 早期公開

    Aim: β-actin (ACTB) participates in the vascular remodeling and contributes to the cardiovascular diseases. Herein, we investigated the associations of ACTB with hypertension and stroke.

    Methods: Three single-nucleotide polymorphisms in ACTB were selected for genotyping in 2,012 hypertension cases and 2,210 controls. The associations of ACTB with hypertension and stroke were examined in another follow-up study. Logistic and Cox regression were performed in a case-control study and a follow-up study, respectively. Additive scale interaction was examined by calculating the relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (SI). The multiplicative interaction hazard ratio was calculated by fitting the Cox regression model. ACTB mRNA in peripheral blood mononuclear cells was measured in ischemic stroke (IS) cases and in controls.

    Results: The associations of rs852426 with hypertension and stroke had statistical significance in drinkers but not after Bonferroni correction. An additive interaction of rs852426 and drinking was observed for stroke incidence, the adjusted RERI was −0.907 (p=4.108×10-4), and the multiplicative interaction was still sound (HR=0.541, p=0.048). Furthermore, the significant interaction was further replicated in a nested case-control study. In the drinking population, the relative expression of ACTB mRNA in IS was lower (0.99±0.26) than that in controls (1.13±0.20), with a p value of 0.026.

    Conclusions: ACTB rs852426 was significantly associated with alcohol consumption on stroke risk, and the expression of ACTB mRNA in IS who had a drinking habit was significantly down-regulated. This finding will provide a novel insight into the prevention of stroke.

  • Zhiguang Wang, Aimin Dang, Naqiang Lv
    原稿種別: Original Article
    論文ID: 48447
    発行日: 2019年
    [早期公開] 公開日: 2019/07/04
    ジャーナル フリー 早期公開

    Aim: Takayasu arteritis (TAK) is a rare inflammatory large-vessel vasculitis with increased cardiovascular morbidity and mortality. Brachial-ankle pulse wave velocity (ba-PWV) is a widely used measure of arterial stiffness and serves as an indicator of either cardiovascular risk or severity of vascular damage. However, the studies about the relationship between TAK and ba-PWV are limited. This study aimed to investigate the use of ba-PWV in the patients with TAK.

    Methods: Sixty-seven patients with TAK and 67 age and sex matched healthy controls were recruited. Patients with TAK were grouped according to disease activity. The routine hematological parameters and ba-PWV were summarized.

    Results: Ba-PWV was significantly higher in the patients with TAK than in the healthy controls (P<0.001). Ba-PWV was significantly higher in the patients with active TAK than in the patients with inactive TAK (P= 0.04). Multiple liner regression analysis indicated that TAK (β=363.97, P=0.013), and mean arterial pressure (MAP) (β=8.52, P=0.012) were independently related to ba-PWV. Ba-PWV did not correlate with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in overall patients with TAK (both P>0.05). In patients with TAK without immunosuppressive therapy, ba-PWV significantly correlated with CRP (r=0.419, P=0.008) but not ESR (P>0.05). Multiple logistic regression analysis indicated that ba-PWV was an independent predictor of active TAK in overall patients with TAK (OR=1.003, 95% CI=1.000–1.007; P=0.040) and patients with TAK without immunosuppressive therapy (OR=1.006, 95% CI=1.001–1.012; P=0.031).

    Conclusions: Being significantly increased in patients with TAK, ba-PWV is significantly associated with TAK disease activity, and it probably correlates with systematic inflammation.

  • Yoshimitsu Soga, Masahiko Fujihara, Yusuke Tomoi, Osamu Iida, Takayuki ...
    原稿種別: Original Article
    論文ID: 50369
    発行日: 2019年
    [早期公開] 公開日: 2019/06/29
    ジャーナル フリー 早期公開

    Aim: Paclitaxel-eluting stents' (Eluvia and Zilver PTX) effectiveness has been recently reported for femoropopliteeal (FP) lesions. However, there is no evaluation of one-year late lumen loss (LLL). Therefore, we evaluated one-year LLL after implantation with Eluvia or Zilver PTX.

    Methods: This was a multicenter, prospective study. Patients who had symptomatic de novo lesions in the native FP artery were enrolled. The primary endpoint was one-year angiographic LLL, and the secondary endpoints were binary restenosis and target lesion revascularization (TLR) at one year.

    Results: From December 2015 to December 2016, 48 patients (Eluvia, 36 patients; Zilver PTX, 12 patients) were enrolled. No significant difference was found in baseline and lesion characteristics between both groups. One-year, LLL was significantly lower in the Eluvia group (0.60 {plus minus}0.80 mm) than in the Zilver PTX group (1.74 {plus minus}0.89 mm) (P=0.0003). Negative LLL was observed only in the Eluvia group (0% vs. 23%, p=0.096). The binary restenosis rate was significantly lower than in the Zilver PTX group (0% vs. 16.7%, P=0.012). The one-year TLR in the Eluvia group tended to be lower (0% vs. 8.3%, P=0.08). Stent thrombosis was not observed in either group.

    Conclusion: One-year LLL in the Eluvia group was significantly lower than that in the Zilver PTX group for FP lesions.

  • Hidetaka Itoh, Hidehiro Kaneko, Hiroyuki Kiriyama, Yuriko Yoshida, Kok ...
    原稿種別: Original Article
    論文ID: 48728
    発行日: 2019年
    [早期公開] 公開日: 2019/06/22
    ジャーナル フリー 早期公開

    Aim: Obesity and metabolic syndrome (MetS) frequently coexist and are both important risk factors for cardiovascular disease. However, the pathophysiological role of obesity without MetS, also referred to as metabolically healthy obesity (MHO), remains unclear. In this study, we aim to clarify the effect of MHO on the development of carotid plaque using a community-based cohort.

    Methods: We examined 1,241 subjects who underwent health checkups at our institute. Obesity was defined by a body mass index of ≥ 25.0 kg/m2. Subjects were divided into three groups: non-obese, MHO, and metabolically unhealthy obesity (MUO).

    Results: The prevalence of carotid plaque, defined as intima-media thickness (IMT) ≥ 1.1 mm, was higher in subjects with MUO and MHO than in non-obese subjects. Multivariable analysis demonstrated that MHO (odds ratio 1.6, p=0.012) and MUO (odds ratio 1.9, p=0.003) as well as age of ≥ 65 years, male sex, hypertension, and diabetes mellitus were independently associated with carotid plaque formation. A similar trend was observed in each subgroup according to age and sex.

    Conclusions: MHO increased the prevalence of carotid plaque when compared with non-obese subjects, suggesting the potential significance of MHO in the development of subsequent cardiovascular diseases.

  • Hirofumi Tomiyama
    分野: Editorial
    論文ID: ED113
    発行日: 2019年
    [早期公開] 公開日: 2019/06/22
    ジャーナル フリー 早期公開
  • Yae Matsuo, Hisao Kumakura, Hiroyoshi Kanai, Toshiya Iwasaki, Shuichi ...
    分野: Original Article
    論文ID: 49767
    発行日: 2019年
    [早期公開] 公開日: 2019/06/19
    ジャーナル フリー 早期公開

    Aim: The Geriatric Nutritional Risk Index (GNRI) was developed to assess the nutritional risk and is associated with mortality. However, there are limited reports on the relationship between the GNRI and overall survival (OS) in peripheral artery disease (PAD). Therefore, the purpose of this study was to examine the relationship between GNRI and OS and cardiovascular or limb events in patients with PAD.

    Methods: A prospective cohort study was performed on 1,219 patients with PAD. The baseline GNRI was calculated from the serum albumin level and body mass index obtained at the first visit. The patients were divided into four groups according to the GNRI: G0 (>98), G1 (92–98), G2 (82–91), and G3 (<82). The endpoints were OS and freedom from major adverse cardiovascular events (MACE) and MACE plus limb events (MACLE).

    Results: The median follow-up period was 73 months. There were 626 deaths (51.4%) during the follow-up. The rate of cardiovascular death was 51.3%. OS clearly depended on the GNRI (p<0.01), with five-year OS rates of 80.8% for G0, 62.0% for G1, 40.0% for G2, and 23.3% for G3. In multivariate analyses, the GNRI, age, ankle–brachial pressure index (ABPI), critical limb ischemia, estimated glomerular filtration rate (eGFR), and C-reactive protein (CRP) were independent factors associated with OS, and GNRI, age, ABPI, coronary artery disease, diabetes mellitus, eGFR, and CRP were associated with MACE and MACLE (all p<0.05). Statins were found to improve OS, MACE, and MACLE (p<0.01).

    Conclusions: GNRI is an independent predictor for OS, MACE, and MACLE in patients with PAD.

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