Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
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Showing 1-49 articles out of 49 articles from Advance online publication
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  • Tamio Teramoto, Takahito Kai, Asuka Ozaki, Bruce Crawford, Hidenori Ar ...
    Article ID: 41483
    [Advance publication] Released: January 19, 2018

    Aim: To evaluate the epidemiology and real-world treatment patterns associated with lipid-modifying therapies (LMTs) among groups of Japanese patients with familial hypercholesterolemia (FH).

    Methods: A retrospective observational study was conducted using an electronic hospital-based administrative claims database and electronic medical records. Patients with existing diagnosis of FH (FH-D) and patients with suspected FH (FH-S) defined by low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL were included, and medical records of hospitals across Japan were analyzed to assess the diagnostic status, management of LDL-C levels, and treatment patterns.

    Results: Among the 3,495 patients who met the inclusion criteria, 193 patients were FH-D and 3,339 patients were FH-S. Among them, 83.5% had not achieved the LDL-C of 100 mg/dL recommended for patients with FH at the index date. Mean LDL-C levels for all patients and for FH-D and FH-S patients were 145.8 mg/dL, 119.2 mg/dL, and 147.6 mg/dL, respectively. 44.5% of the patients were not currently treated with LMTs. High-intensity statins were used only in 19.2% and 2.3% of the FH-D and FH-S patients, respectively. Furthermore, among the FH-D and FH-S statin-treated patients, 61 (69.3%) and 1,059 (89.7%) remained on monotherapy even when their LDL-C was ≥100 mg/dL.

    Conclusions: Treatment and management of LDL-C in Japanese FH patients remain suboptimal. The results suggest that FH is underdiagnosed in real-world, routine clinical practice in Japan. There is an urgent need to improve the diagnostic rate of FH and to provide the appropriate therapy to achieve the recommended LDL-C levels of 100 mg/dL or a more than 50% reduction for patients with FH in Japan.

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  • Aryandhito Widhi Nugroho, Hisatomi Arima, Itsuko Miyazawa, Takako Fuji ...
    Article ID: 42812
    [Advance publication] Released: January 19, 2018

    Aim: Although renal dysfunction has been identified as a novel risk factor affecting stroke prognosis, few have analyzed the association within large-scale population-based setting, using wide-range estimated glomerular filtration rate (eGFR) category. We aimed to determine the association of admission eGFR with acute stroke outcomes using data from a registry established in Shiga Prefecture, Japan.

    Methods: Following exclusion of patients younger than 18 years, with missing serum creatinine data, and with onset more than 7 days prior to admission, 2,813 acute stroke patients registered in the Shiga Stroke Registry year 2011 were included in the final analysis. The Japanese Society of Nephrology equation was used to estimate GFR. Multivariable logistic regression was performed to analyze the association of eGFR with all-cause in-hospital death (modified Rankin Scale [mRS] 6), and at-discharge death/disability (mRS 2–6). Separate analyses were conducted within stroke subtypes.

    Results: Compared to eGFR 60–89 mL/min/1.73 m2, adjusted odds ratios (ORs) and 95% confidence interval [95% CI] for in-hospital death (in the order of eGFR <45, 45–59, and ≥90 mL/min/1.73 m2) were 1.54 [1.04–2.27], 1.07 [0.72–1.58], and 1.04 [0.67–1.59]. Likewise, adjusted ORs [95% CI] for at-discharge death/disability were 1.54 [1.02–2.32], 0.97 [0.73–1.31], and 1.48 [1.06–2.05]. Similar pattern was further evident in the eGFR <45 mL/min/1.73 m2 group for both outcomes within acute ischemic stroke patients.

    Conclusions: Our study has ascertained that in acute stroke, particularly ischemic stroke, low eGFR was significantly associated with in-hospital death and at-discharge death/disability. Additionally, high eGFR was found to be associated with at-discharge death/disability.

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  • Daiji Nagayama, Yasuhiro Watanabe, Atsuhito Saiki, Kohji Shirai, Ichir ...
    Article ID: 42291
    [Advance publication] Released: January 12, 2018

    Aim: To investigate the associations of conventional lipid parameters with arterial stiffness assessed by cardio–ankle vascular index (CAVI).

    Methods: A retrospective cross-sectional study was conducted in 23,257 healthy Japanese subjects (12,729 men and 10,528 women, aged 47.1±12.5 years, body mass index (BMI) 22.9±3.4 kg/m2) who underwent health screening between 2004 and 2006 in Japan.

    Results: Male subjects had significantly higher BMI, CAVI and triglycerides (TG), and lower high-density lipoprotein cholesterol (HDL-C) compared to female subjects. After adjusting for confounders, including gender, age, systolic blood pressure and BMI identified by multiple regression analysis, adjusted CAVI was lower in normolipidemic than in dyslipidemic subjects. Among dyslipidemic subjects, those with hypertriglyceridemia had higher adjusted CAVI. A trend test detected linear relations between adjusted CAVI and all the conventional lipid parameters throughout the entire range of serum levels. After adjusting for confounders, logistic regression models showed that all lipid parameters contributed independently to high CAVI (≥90th percentile). Receiver–operating–characteristic analysis determined reliable cut-off values of 93 mg/dl for TG (area under the curve, AUC= 0.735), 114 mg/dl for low-density lipoprotein cholesterol (AUC=0.614) and 63 mg/dl for HDL-C (AUC=0.728) in predicting high CAVI. These cut-off values were confirmed to independently predict high CAVI in a bivariate logistic regression model.

    Conclusion: The present study demonstrated independent contribution of conventional lipid parameters to CAVI, indicating a possible association of lipid parameters with early vascular damage.

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  • Naoko Fujiyoshi, Hisatomi Arima, Atsushi Satoh, Toshiyuki Ojima, Nobuo ...
    Article ID: 42531
    [Advance publication] Released: January 11, 2018

    Aim: To investigate associations between socioeconomic status (SES) and the prevalence and treatment status of hypercholesterolemia in a general Japanese population.

    Methods: In 2010, we established a cohort study of 2417 adults (age 20–91 yr) from 300 randomly selected areas across Japan who participated in the National Health and Nutrition Survey of Japan. We cross-sectionally examined an association between SES and (1) prevalence of hypercholesterolemia in 2417 participants (999 men and 1418 women) and (2) not receiving medication for hypercholesterolemia in 654 participants (215 men and 439 women). SES included employment status, marital status, length of education, and household expenditures. Hypercholesterolemia was defined as a total serum cholesterol level of ≥6.21 mmol/L (240 mg/dL) or the use of lipid-lowering medications.

    Results: The overall prevalence of hypercholesterolemia was 21.5% in men and 31.0% in women. In men, the lowest quintile of household expenditures was associated with a higher prevalence of hypercholesterolemia (28.3%) compared with the upper 4 quintiles (19.9%) (multivariable-adjusted odds ratio 1.66; 95% confidence interval [CI] 1.16–2.38). Among participants with hypercholesterolemia, 55.4% of men and 55.1% of women were not receiving medication. Unmarried men were more likely to be untreated (75.0%) than married men (50.9%) (multivariable-adjusted odds ratio 2.53;95%CI 1.05–6.08). SES had no significant effects in women.

    Conclusion: In a general population of Japanese men, low household expenditures were associated with a higher prevalence of hypercholesterolemia, and unmarried men with hypercholesterolemia were less likely to receive medication.

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  • Yusuke Takahara, Tomotake Tokunou, Toshihiro Ichiki
    Article ID: 42481
    [Advance publication] Released: January 10, 2018

    Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose levels through inhibition of incretin degradation, which stimulates insulin secretion. Recent studies reported that DPP-4 inhibitors suppressed atherogenesis in apolipoprotein E-knockout (ApoEKO) mice. In this study, we investigated whether teneligliptin, a DPP-4 inhibitor, affects the development of abdominal aortic aneurysms (AAA) in ApoEKO mice.

    Methods: ApoEKO mice were fed a high-fat diet (HFD) and infused with angiotensin (Ang) II by osmotic mini pumps for 4 weeks to induce AAA with (DPP-4i group) or without (control group) teneligliptin administered orally from 1 week before HFD and Ang II infusion to the end of the experiment. Confluent rat vascular smooth muscle cells (VSMCs) were serum-starved for 48 hours, then incubated with or without teneligliptin for another 24 hours and stimulated with Ang II.

    Results: Treatment with teneligliptin significantly reduced the AAA formation rate (30.7% vs. 71.4% vs. control, P<0.05), aortic dilatation (1.32±0.09 mm vs. 1.76±0.18 mm in the control, P<0.05) and severity score (0.75±0.28 vs. 1.91±0.4 in the control, P<0.05). Elastin degradation grade was also attenuated in DPP-4i group (2.83±0.17 vs. 3.45±0.16 in the control, P<0.05). The number of macrophages infiltrating into the abdominal aorta was decreased in the DPP-4i group (51.8± 29.8/section vs. 219.5±78.5/section in the control, P<0.05). Teneligliptin attenuated Ang II-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and mRNA expression of monocyte chemoattractant protein-1 in VSMCs.

    Conclusion: Treatment with teneligliptin suppressed AAA formation in ApoEKO mice with HFD and Ang II infusion. Suppression of macrophage infiltration by teneligliptin may be involved in the inhibition of AAA formation.

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  • Hirofumi Okada, Hayato Tada, Kenshi Hayashi, Hiroki Kawashima, Tadanor ...
    Article ID: 42705
    [Advance publication] Released: January 10, 2018

    Aim: The aims of this study were: 1) to determine whether the accumulation of aortic root calcification (ARC) assessed using coronary computed tomography angiography (CCTA) can predict future cardiovascular events, and 2) to estimate the onset and progression of ARC in patients with familial hypercholesterolemia (FH).

    Methods: One hundred thirteen consecutive Japanese patients with heterozygous FH (male=54, mean age=52.1±15.6 years, mean LDL-C=299.0±94.6 mg/dL), without known coronary artery disease, who underwent 64-detector row CCTA were retrospectively evaluated. ARC was defined as the presence of calcium at the aortic root. The extent of ARC was expressed in Agatston units as the ARC-score. Major adverse cardiac events (MACE) were defined as either cardiac death, ST elevated myocardial infarction (STEMI), non-ST elevated myocardial infarction (NSTEMI), unstable angina pectoris (UAP), planned percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), or stroke. The periods to MACE were estimated using multivariate logistic regression analysis.

    Results: During the follow-up period (median 1635 days), 19 instances of MACE occurred. Multivariate logistic regression analysis revealed that ARC was a significant independent predictor of MACE (OR=1.48; 95% CI 1.11–1.87, p<0.001, respectively). The regression equations were Y=0.09X– 1.59 (R2=0.34, p<0.001) in males and Y=0.08X–1.60 (R2=0.13, p<0. 05) in females.

    Conclusions: ARC was significantly associated with future MACE in Japanese patients with heterozygous FH. ARC may start to develop, on average, at 17.4 and 19.7 years of age in males and females, respectively, with heterozygous FH.

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  • Momoko Muto, Osamu Ezaki
    Article ID: 41632
    [Advance publication] Released: December 20, 2017

    Aim: The associations between dietary saturated fatty acids and the risks of stroke subtypes in cohort studies were examined by a meta-analysis of separate ethnic Japanese and non-Japanese cohorts, and causes of their difference were elucidated.

    Method: Log hazard ratio (HR) with 95% confidence interval (CI) of the highest versus the lowest saturated fat intake from cohort studies were weighed by an inverse variance method to combine HRs.

    Results: Five studies of intracerebral hemorrhage and 11 studies/comparisons of ischemic stroke were selected. A meta-analysis of intracerebral hemorrhage excluding subarachnoid hemorrhage showed a strong inverse association in Japanese (n=3, HR=0.55, 95% CI 0.32–0.94) but not in non-Japanese (n=2, HR=0.98, 95% CI 0.62–1.53). A meta-analysis of ischemic stroke showed a mild inverse association in Japanese (n=4, HR=0.82, 95% CI 0.71–0.93) but not in non-Japanese (n=7, HR= 0.93, 95% CI 0.84–1.03). The effect size of saturated fat in reducing the risk of stroke in Japanese was stronger for intracerebral hemorrhage (45% reduction) than for ischemic stroke (18% reduction).

    Conclusions: In Japanese but not in non-Japanese, a diet high in saturated fat is associated with a low risk of intracerebral hemorrhage and ischemic stroke. This may be due to differences in the range of intake of saturated fat, genetic susceptibility, incidence of lacunar infarction, and/or confounding factors such as dietary proteins. An intervention study targeting Japanese will be required to verify the causality.

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  • Kazuyo Tsushita, Akiko S Hosler, Katsuyuki Miura, Yukiko Ito, Takashi ...
    Article ID: 42010
    [Advance publication] Released: December 12, 2017

    Aim: All health insurers in Japan are mandated to provide Specific Health Checkups and Specific Health Guidance (SHG) focusing on metabolic syndrome (MetS) in middle-aged adults, beginning in 2008; intensive HG for individuals who have abdominal obesity and two or more additional MetS risk factors, and motivational HG for individuals with one risk factor. The aim of this study is to describe medium-term changes in health indexes for intensive and motivational HG groups using the National Database.

    Methods: We compared changes of risk factors and initiation of pharmacological therapy over 3 yr between participants (n=31,790) and nonparticipants (n=189,726) who were eligible for SHG in 2008.

    Results: Body weight reduction in intensive HG was 1.98 kg (participants) vs 0.42 kg (nonparticipants) in men (p<0.01) and 2.25 vs 0.68 kg in women (p<0.01) after 1 yr. In motivational HG, the respective reduction was 1.40 vs 0.30 kg in men (p<0.01) and 1.53 vs 0.42 kg in women (p<0.01). Waist circumference reduction was also greatest among participants in intensive HG (2.34 cm in men and 2.98 cm in women). These reductions were fairly unchanged over 3 yr and accompanied greater improvements in MetS risk factors in participants. We also detected significantly smaller percentages of SHG participants who initiated pharmacological therapy compared with nonparticipants.

    Conclusion: Participants in SHG showed greater improvements in MetS profiles with proportionally smaller pharmacological treatment initiations than did nonparticipants for 3 yr. Although selection bias may be present, this study suggests SHG would be a feasible strategy to prevent MetS and its sequelae.

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  • Atsushi Shioi, Yuji Ikari
    Article ID: RV17020
    [Advance publication] Released: December 12, 2017

    Plaque calcification develops by the inflammation-dependent mechanisms involved in progression and regression of atherosclerosis. Macrophages can undergo two distinct polarization states, that is, pro-inflammatory M1 phenotype in progression and anti-inflammatory M2 phenotype in regression. In plaque progression, predominant M1 macrophages promote the initial calcium deposition within the necrotic core of the lesions, called as microcalcification, through not only vesicle-mediated mineralization as the result of apoptosis of macrophages and vascular smooth muscle cells (VSMCs), but also VSMC differentiation into early phase osteoblasts. On the other hand, in plaque regression M2 macrophages are engaged in the healing response to plaque inflammation. In association with the resolution of chronic inflammation, M2 macrophages may facilitate macroscopic calcium deposition, called as macrocalcification, through induction of osteoblastic differentiation and maturation of VSMCs. Oncostatin M, which has been shown to promote osteoblast differentiation in bone, may play a pivotal role in the development of plaque calcification. Clinically, two types of plaque calcification have distinct implications. Macrocalcification leads to plaque stability, while microcalcification is more likely to be associated with plaque rupture. Statin therapy, which reduces cardiovascular mortality, has been shown to exert its dual actions on plaque morphology, that is, regression of atheroma and increment of macroscopic calcium deposits. Statins may facilitate the healing process against plaque inflammation by enhancing M2 polarization of macrophages. Vascular calcification has pleiotropic properties as pro-inflammatory “microcalcification” and anti-inflammatory “macrocalcification”. The molecular mechanisms of this process in relation with plaque progression as well as plaque regression should be intensively elucidated.

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  • Tomohisa Nezu, Naohisa Hosomi, Shiro Aoki, Noriyuki Suzuki, Tsukasa Te ...
    Article ID: 42101
    [Advance publication] Released: December 09, 2017

    Aims: Although several antihypertensive agents reduced the carotid intima–media thickness (IMT), it remains unclear whether those agents affect the interadventitial diameter (IAD). We aimed to examine whether cilnidipine, an L/N-type calcium channel blocker, reduced the common carotid IMT or IAD in post-stroke hypertensive patients.

    Methods: The common carotid IMT and IAD were measured at the start of cilnidipine treatment and 12 months from that. The changes in the mean max-IMT or IAD between baseline and the 12-month follow-up were evaluated and compared between the thick group (max-IMT ≥1.1 mm) and the normal group (max-IMT <1.1 mm).

    Results: A total of 603 post-stroke hypertensive subjects (mean age=69.3 yr, 378 males) were included in the analysis. At baseline, IAD was increased stepwise according to the value of max-IMT (p for trend <0.001). Among them, 326 subjects were followed up for 12 months. The mean max-IMT from baseline to 12 months did not change in the normal group (-0.01 mm, 95% confidence interval [CI] -0.03 to 0.01, n=170), whereas a significant reduction was observed in the thick group (-0.09 mm, 95% CI -0.13 to -0.05, n=156). The mean IAD was significantly reduced during the study period in the normal group (-0.14 mm, 95% CI -0.22 to -0.05) as well as in the thick group (-0.12 mm, 95% CI -0.21 to -0.03).

    Conclusions: Cilnidipine promoted the regression of common carotid IMT in post-stroke hypertensive patients, especially in the thick group. Cilnidipine also reduced the IAD in both normal and thick groups.

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  • Tian Xu, Peng Zuo, Lin Cao, Zhiwei Gao, Kaifu Ke
    Article ID: 42135
    [Advance publication] Released: December 09, 2017

    Aims: Omentin-1 was proved to be associated with ischemic stroke clinical functional outcome. It also predicted carotid atherosclerosis among metabolic syndrome subjects and type 2 diabetes patients. Our aim was to examine the association of omentin-1 levels with carotid plaque instability and stenosis degree among ischemic stroke patients.

    Methods: A total of 173 acute ischemic stroke patients were included in this study. Serum omentin-1 levels were assayed. Carotid ultrasound examinations were performed to evaluate the carotid plaque instability and stenosis degree. Multivariable logistic analyses were used to examine the association of serum omentin-1 levels with carotid plaque instability and stenosis degree.

    Results: Ischemic stroke patients with unstable carotid plaque had significantly lower levels of serum omentin-1 than patients with stable plaque (53 [40.2–64.1] vs 61.8 [52.4–77.2] ng/ml, P<0.01). Subjects in the highest tertile of serum omentin-1 levels had a 0.31-fold risk of having unstable plaque compared with those in the lowest tertile (P<0.05), and its trend test was significant (P for trend=0.03). The integrated discrimination improvement was significantly improved in predicting carotid plaque instability when omentin-1 data was added to the multivariable logistic regression model. No significant association was detected between omentin-1 and moderate–severe carotid stenosis or occlusion.

    Conclusions: Among ischemic stroke patients, higher omentin-1 levels were inversely associated with carotid plaque instability, but not associated with moderate–severe carotid stenosis or occlusion. Omentin-1 may represent a biomarker for predicting carotid plaque instability of acute ischemic stroke patients.

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  • Teruo Noguchi, Kazuhiro Nakao, Yasuhide Asaumi, Yoshiaki Morita, Fumiy ...
    Article ID: RV17019
    [Advance publication] Released: December 09, 2017

    Early identification of high-risk or vulnerable atherosclerotic plaques prone to rupture and performing preemptive therapy prior to catastrophic cardiovascular events are optimal goals of plaque imaging. Despite the advances in imaging modalities to identify vulnerable characteristics, the predictive value of the imaging techniques in the clinical setting is still developing. In this regard, reliable and high-sensitive imaging modalities identifying vulnerable plaque characters that may lead to future cardiovascular events will be useful. In this review article, we describe a current non-invasive plaque imaging technique to identify high-risk coronary plaque features.

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  • Seigo Sugiyama, Hideaki Jinnouchi, Noboru Kurinami, Kunio Hieshima, Ak ...
    Article ID: 40873
    [Advance publication] Released: December 08, 2017

    Aim: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy has been demonstrated to improve glycemic control and reduce body weight and fat mass in type 2 diabetes mellitus (T2DM). Here, our aim was to investigate the effects of SGLT2i dapagliflozin-treatment on body muscle mass and muscle fat content in patients with T2DM.

    Methods: We prospectively recruited uncontrolled (hemoglobin A1c [HbA1c] >7%) Japanese T2DM patients who had a body mass index (BMI) <35 kg/m2. Patients were treated with dapagliflozin (5 mg/day) or non-SGLT2i medicines for six months to improve HbA1c. We investigated changes in body composition using bioelectrical impedance analysis and changes in psoas muscle mass using abdominal computed tomography (CT).

    Results: Subjects were 50 T2DM patients (72% male) with a mean age of 56.1 years, mean BMI of 27.1 kg/m2 and mean HbA1c of 7.9%. HbA1c, body weight, and BMI were significantly decreased in both treatment groups, and the HbA1c decrease was not significantly different between groups. Dapagliflozin treatment significantly decreased body weight and total fat mass without affecting skeletal muscle mass. The absolute change in soft lean mass and skeletal muscle mass was not significantly different between groups. Dapagliflozin treatment did not significantly decrease psoas muscle index, and the absolute change in this index was not significantly different between groups. Dapagliflozin therapy also produced a significant increase in CT radiation attenuation in the third lumbar paraspinal muscles compared with non-SGLT2i therapy.

    Conclusions: Treatment with dapagliflozin for six months significantly improved glycemic control and reduced body weight without reducing muscle mass in T2DM patients.

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  • Yi Yao, Xiao-fang Tang, Chen He, Ying Song, Jing-jing Xu, Xian-min Men ...
    Article ID: 39982
    [Advance publication] Released: December 05, 2017

    Aims: Platelet endothelial aggregation receptor-1 (PEAR1) is a platelet transmembrane protein that plays an important role on platelet aggregation. The aim of this study was to investigate whether PEAR1 genetic variations are associated with 1-year outcomes in Chinese patients with acute myocardial infarction after percutaneous coronary intervention.

    Methods: A total of 647 consecutive Chinese patients with acute myocardial infarction that underwent percutaneous coronary intervention and that were exposed to standard dual antiplatelet therapy with aspirin and clopidogrel were enrolled in this study. Six single nucleotide polymorphisms of PEAR1 were detected using the ligase detection reaction method. The follow-up period was 12 months.

    Results: Overall, 66 (10.2%) adverse ischemic events occurred. Multivariate Cox regression analysis showed that carriage of the PEAR1 rs56260937 minor allele was an independent predictor of revascularization events (OR=2.15, 95% CI 1.12 4.15, p=0.022) after adjusting for confounding factors.

    Conclusions: Genetic testing for PEAR1 variants can be helpful in predicting adverse ischemic events in Chinese patients with acute myocardial infarction after percutaneous coronary intervention.

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  • Tai Pham, Akira Fujiyoshi, Hisatomi Arima, Sachiko Tanaka-Mizuno, Taka ...
    Article ID: 42416
    [Advance publication] Released: December 05, 2017

    Aim: The clinical significance of coronary artery calcification (CAC) is not fully determined in general East Asian populations where background coronary heart disease (CHD) is less common than in USA/Western countries. We cross-sectionally assessed the association between CAC and estimated CHD risk as well as each major risk factor in general Japanese men.

    Methods: Participants were 996 randomly selected Japanese men aged 40–79 y, free of stroke, myocardial infarction, or revascularization. We examined an independent relationship between each risk factor used in prediction models and CAC score ≥100 by logistic regression. We then divided the participants into quintiles of estimated CHD risk per prediction model to calculate odds ratio of having CAC score ≥100. Receiver operating characteristic curve and c-index were used to examine discriminative ability of prevalent CAC for each prediction model.

    Results: Age, smoking status, and systolic blood pressure were significantly associated with CAC score ≥100 in the multivariable analysis. The odds of having CAC score ≥100 were higher for those in higher quintiles in all prediction models (p-values for trend across quintiles <0.0001 for all models). All prediction models showed fair and similar discriminative abilities to detect CAC score ≥100, with similar c-statistics (around 0.70).

    Conclusions: In a community-based sample of Japanese men free of CHD and stroke, CAC score ≥100 was significantly associated with higher estimated CHD risk by prediction models. This finding supports the potential utility of CAC as a biomarker for CHD in a general Japanese male population.

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  • Yuji Ueno, Ryota Tanaka, Kazuo Yamashiro, Nobukazu Miyamoto, Kenichiro ...
    Article ID: 40691
    [Advance publication] Released: December 02, 2017

    Aim: We focused on the ratios of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to arachidonic acid (AA) and explored the significance of these ratios relative to clinical characteristics by age in ischemic stroke patients.

    Methods: We enrolled patients with acute ischemic stroke who underwent radiological investigations and laboratory examinations, including measurement of serum EPA, DHA, and AA levels, and controls. Patients were classified according to age (<65, 65–74, and ≥ 75 years) and the tertile of EPA/AA and DHA/AA ratios, and clinical aspects were compared with these factors.

    Results: We analyzed 373 patients (age 70.2±13.4 years; 245 males) and 105 controls. Among stroke patients, patients aged <65 years had the lowest EPA/AA (0.35±0.23, p=0.006) and DHA/AA (0.73±0.27, p<0.001) ratios. Compared with controls, patients aged <65 years showed lower EPA/AA (vs. 0.49±0.25, p<0.001) and DHA/AA (vs. 0.82±0.26, p=0.009) ratios. From logistic regression analysis, the EPA/AA (odds ratio 0.18, 95% confidence interval 0.04–0.81, p=0.026) and DHA/AA (odds ratio 0.09, 95% confidence interval 0.02–0.33, p<0.001) ratios were inversely related to patients aged <65 years. According to age-stratified analyses, we found an association of aortic arch calcification with a lower EPA/AA ratio for patients aged ≥ 75 years and an association of multiple infarctions and cerebral white matter lesions with a lower EPA/AA ratio for patients aged 65–74 years (p<0.05).

    Conclusions: The ratios of EPA/AA and DHA/AA could be specific markers for younger stroke patients. The EPA/AA ratio may be related to aortic arch calcification for elderly stroke patients and to multiple infarctions and cerebral white matter disease for middle-aged stroke patients.

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  • Daisaku Masuda, Takuya Kobayashi, Masami Sairyou, Hiroyuki Hanada, Toh ...
    Article ID: 41343
    [Advance publication] Released: December 02, 2017

    Aim: The morbidity of cardiovascular disease in patients with type 2 diabetes mellitus (DM) deteriorates in combination with dyslipidemia. The accumulation of remnant lipoproteins in patients with fasting and postprandial hypertriglyceridemia is highly atherogenic. The current study investigated whether the dipeptidyl peptidase-4 inhibitor sitagliptin ameliorates dyslipidemia and hyperglycemia.

    Methods: We enrolled 38 patients with type 2 DM (20 males and 18 females, 65.7±9.9 years old, HbA1c levels <8.4%), and all patients gave written informed consent. Sitagliptin (50 mg/day) was added to current antidiabetic treatments and increased to 100 mg/day to achieve low HbA1c levels (<7.4%). Glucose and lipoprotein metabolism profiles were analyzed at 0, 4, and 12 weeks after sitagliptin administration.

    Results: Sitagliptin significantly decreased fasting levels of triglyceride (TG) (161±90 vs. 130±66 mg/dl, p<0.01) and non-HDL-C (129±29 vs. 116±20 mg/dl, p<0.01) in combination with glucose (150±47 vs. 129±27 mg/dl, p<0.01) and HbA1c (7.1±0.6 vs. 6.6±0.7 mg/dl, p<0.001). Sitagliptin also significantly decreased the fasting levels of apolipoprotein (apo) B-48 (7.8±6.7 vs. 5.6±4.0 µg/ml, p<0.01), remnant lipoprotein cholesterol (15.3±9.5 vs. 12.0±7.9 mg/dl, p<0.05) and other apolipoproteins, such as apoB, apoC-II, apoC-III, and apoE. Analyses of the lipoprotein profiles of fasting sera revealed that sitagliptin significantly decreased cholesterol and TG levels of lipoprotein fractions in the size of very low density lipoprotein and low density lipoprotein.

    Conclusions: These findings indicated that sitagliptin administration ameliorated the lipid and lipoprotein profiles in patients with diabetes, which may be due to the decrease in atherogenic remnant lipoproteins (UMIN#000013218).

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  • Koshi Nakamura, Makoto Watanabe, Nagako Okuda, Katsushi Yoshita, Mai K ...
    Article ID: 42051
    [Advance publication] Released: December 02, 2017

    Aim: We investigated whether 2 types of personalized health guidance (repeated and single counseling) in the Japanese nationwide cardiovascular prevention system promoted smoking cessation among smokers.

    Methods: The study included 47,745 Japanese smokers aged 40 to 74 years classified into 2 personalized health guidance schemes. After a 1-year follow-up, we compared the rates of smoking cessation between individuals who had received counseling (“supported”) and those who had not received counseling (“unsupported”). Using propensity score matching analysis, we estimated the average treatment effect (ATE) of each approach on smoking cessation after balancing out the characteristics between the supported and unsupported groups. The propensity score regression model included age, medical insurance type, weight gain since the age of 20 years, exercise, eating habits, alcohol intake, quality of sleep, readiness to modify lifestyle, willingness to receive support, and body mass index.

    Results: In the repeated counseling scheme, the age-adjusted rates of smoking cessation in the supported and unsupported groups were 8.8% and 6.3% for males, and 9.8% and 9.1% for females respectively. In the single counseling scheme, the corresponding rates were 8.4% and 7.3% for supported and unsupported males, and 11.0% and 11.7% for supported and unsupported females respectively. The ATE of repeated counseling was +2.64% (95% confidence interval: +1.51% to +3.77%) for males and +3.11% (-1.85% to +8.07%) for females. The ATE of single counseling was +0.61% (-1.17% to +2.38%) for males and -1.06% (-5.96% to +3.85%) for females.

    Conclusions: In the Japanese cardiovascular prevention system, repeated counseling may promote smoking cessation among male smokers.

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  • Mariko Harada-Shiba, John J.P. Kastelein, G. Kees Hovingh, Kausik K. R ...
    Article ID: 42242
    [Advance publication] Released: November 29, 2017

    Aim: Children with Familial Hypercholesterolemia (FH) are widely prescribed statins, and it has been suggested that the effects of statins differ among ethnicities. We compared the efficacy and safety of pitavastatin in children and adolescents with FH in clinical trials conducted in Japan and Europe.

    Methods: Low-density lipoprotein cholesterol (LDL-C) reductions, adjusted for confounding factors, and safety were compared between the studies in Japan and Europe. In the Japanese study, 14 males with heterozygous FH, aged 11.8±1.6 years, were randomized to 52-week double-blind treatment with 1 or 2 mg/day pitavastatin. In the European study, 106 children and adolescents with high risk hyperlipidemia (103 heterozygous FH), aged 10.6±2.9 years, were randomized to 12-week double-blind treatment with 1, 2 or 4 mg/day pitavastatin or placebo; 84 of these patients and 29 new patients participated in a 52-week open-label extension study.

    Results: Age, body weight and baseline LDL-C were identified as factors influencing LDL-C reduction. There were no significant differences in the adjusted mean percentage reduction in LDL-C in Japanese and European children by pitavastatin (24.5% and 23.6%, respectively at 1 mg/day and 33.5% and 30.8%, respectively at 2 mg/day). Pitavastatin was well tolerated without any difference in the frequency or nature of adverse events between the treatment groups, or between the studies.

    Conclusion: There were no significant differences between the efficacy or safety of pitavastatin in Japanese and European children and adolescents with FH, suggesting no relevant ethnic differences in the safety or efficacy of pitavastatin.

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  • Sidi Ai, Zhiqing He, Ru Ding, Feng Wu, Zhigang Huang, Jiamei Wang, Shu ...
    Article ID: 40808
    [Advance publication] Released: November 24, 2017

    Aim: Endothelial progenitor cells (EPCs) are shown to participate in the pathological processes of atherosclerosis. While Vitamin D and its receptor axis might exert some effects on EPCs' function. But their exact relationship with clinical patients is still elusive, which inspired us to explore the potential association of vitamin D receptor (VDR) expression on circulating EPCs and serum vitamin D levels among patients with coronary artery disease (CAD).

    Methods: Two hundred patients with CAD after their admission to hospital and one hundred healthy controls were enrolled. Medical history data were retrieved and fresh blood samples were collected for flow cytometry analysis. VDR expressions on EPCs were evaluated according to the standardized protocol. Logistic regression analysis was used to investigate the potential risk factor of CAD.

    Results: CAD patients were found to have lower log10VDR-MFIs than those of control group, especially for patients with diabetes (p<0.001). Log10VDR-MFIs were inversely correlated with glycated hemoglobin (R=-0.472, p<0.001), and while EPCs challenged with high glucose had lower VDR expression. Multivariate logistic regression analysis revealed that lower log10VDR-MFIs were independently associated with the risk of CAD (OR=0.055, p=0.008).

    Conclusion: A significant decrease of VDR expression on circulating EPCs was observed among CAD patients, particularly among those also with diabetes. VDR expression on EPCs was independently negatively correlated with HbA1c and high glucose decreased EPCs' VDR expression. Low levels of VDR expression on circulating EPCs might serve as a potential risk factor of CAD.

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  • Shogo Watanabe, Shota Kumazaki, Katsuhiro Kusunoki, Terumi Inoue, Yui ...
    Article ID: 40956
    [Advance publication] Released: November 22, 2017

    Aim: Non-alcoholic steatohepatitis (NASH) increases cardiovascular risk regardless of risk factors in metabolic syndrome. However, the intermediary factors between NASH and vascular disease are still unknown because a suitable animal model has never been established. The stroke-prone (SP) spontaneously hypertensive rat, SHRSP5/Dmcr, simultaneously develops hypertension, acute arterial lipid deposits in mesenteric arteries, and NASH when feed with a high-fat and high-cholesterol (HFC) diet. We investigated whether SHRSP5/Dmcr affected with NASH aggravates the cardiac or vascular dysfunction.

    Method: Wister Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 rats each, and fed with a SP or HFC diet. After 8 weeks of HFC or SP diet feeding, glucose and insulin resistance, echocardiography, blood biochemistry, histopathological staining, and endothelial function in aorta were evaluated.

    Results: We demonstrate that SHRSP5/Dmcr rats fed with a HFC diet presented with cardiac and vascular dysfunction caused by cardiac fibrosis, endothelial dysfunction, and left ventricular diastolic dysfunction, in association with NASH and hypertension. These cardiac and vascular dysfunctions were aggravated and not associated with the presence of hypertension, glucose metabolism disorder, and/or obesity.

    Conclusions: SHRSP5/Dmcr rats may be a suitable animal model for elucidating the organ interaction between NASH and cardiac or vascular dysfunction.

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  • Nagako Okuda, Kazuyoshi Itai, Akira Okayama
    Article ID: 42226
    [Advance publication] Released: November 15, 2017

    Aim: There is a growing need for nutritional education for prevention and non-pharmacological treatment of risk factors for cardiovascular diseases (CVD). We compared the results of a short dietary propensity questionnaire (SDPQ) with those from the food frequency and quantity survey (FF Quantity), which had been previously quantitatively assessed by comparison with the 24-hr dietary recall (24hr-DR), to examine the usefulness of the SDPQ. The SDPQ was designed to assess dietary propensities of 12 food/nutrients relevant to CVD risk factors.

    Methods: We conducted a dietary survey using the SDPQ on Japanese men and women. After 2–3 weeks, we conducted the FF Quantity survey with the same participants. For each of the 12 food/nutrient categories, the relationships between quintiles of results from the SDPQ and FF Quantity were examined. Results from 79 participants who completed both surveys were used.

    Results: Spearman's correlation coefficients (r) were significant for all food/nutrient categories. Good correlations were found with alcohol (r=0.792), starchy foods (r=0.566), and milk and dairy products (r=0.687), for which good correlations between the FF Quantity and 24hr-DR had been observed previously. Moderate correlations were found for vegetables (r=0.386) and high-salt foods (r=0.505), although the FF Quantity survey poorly correlated with the 24hr-DR.

    Conclusion: The SDPQ may be useful for assessment of dietary propensities for alcohol, starchy foods, and milk and dairy products in Japan.

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  • Seimi Satomi-Kobayashi, Tatsuro Ishida
    Article ID: ED089
    [Advance publication] Released: November 14, 2017
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  • Shuichiro Kaji
    Article ID: RV17017
    [Advance publication] Released: November 10, 2017

    Stanford type B aortic dissection (TBAD) is a life-threatening disease. Current therapeutic guidelines recommend medical therapy with aggressive blood pressure lowering for patients with acute TBAD unless they have fatal complications. Although patients with uncomplicated TBAD have relatively low early mortality, aorta-related adverse events during the chronic phase worsen the long-term clinical outcome. Recent advances in thoracic endovascular aortic repair (TEVAR) can improve clinical outcomes in patients with both complicated and uncomplicated TBAD. According to present guidelines, complicated TBAD patients are recommended for TEVAR. However, the indication in uncomplicated TBAD remains controversial. Recent results of randomized trials, which compared the clinical outcome in patients treated with optimal medical therapy and those treated with TEVAR, suggest that preemptive TEVAR should be considered in uncomplicated TBAD with suitable aortic anatomy. However, these trials failed to show improvement in early mortality in patients treated with TEVAR compared with patients treated with optimal medical therapy, which suggest the importance of patient selection for TEVAR. Several clinical and imaging-related risk factors have been shown to be associated with early disease progression. Preemptive TEVAR might be beneficial and should be considered for high-risk patients with uncomplicated TBAD. However, an interdisciplinary consensus has not been established for the definition of patients at high-risk of TBAD, and it should be confirmed by experts including physicians, radiologists, interventionalists, and vascular surgeons. This review summarizes the current understanding of the therapeutic strategy in patients with TBAD based on evidence and expert consensus.

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  • Razuin Rahimi, Mansharan Kaur Chainchel Singh, Norizal Mohd Noor, Effa ...
    Article ID: 39107
    [Advance publication] Released: November 08, 2017

    Aims: The present study aimed to determine the epidemiological aspects of medico-legal autopsies and manifestation of coronary atherosclerosis.

    Methods: This was a cross sectional study involving 222 cases recruited from National Institute of Forensic Medicine (NIFM) Hospital Kuala Lumpur (HKL) and Department of Forensic Medicine Hospital Sungai Buloh (HSgB) for a period of 15 months, from December 2012 to April 2014. Sociodemographic and autopsy findings, including the cause and manner of death were documented.

    Results: Male and female subjects aged 18–70 years were recruited. Males contributed to 86% of the total subjects and comprised 61% of young adults. Road traffic accidents were the primary cause of death, contributing almost 50% of the subjects. One third of the cases comprised of death due to natural causes, wherein almost 75% of the subjects within this category succumbed to sudden cardiac death. Coronary artery disease (CAD) contributed to 60% of the sudden cardiac death (SCD). Single and double-vessel diseases were the most common pattern of atherosclerosis. In almost 80% of CAD cases, atherosclerosis affected the left anterior descending artery (LAD).

    Conclusion: Cardiovascular diseases were the most significant natural cause of sudden death with a staggering figure of 75%. CAD was the single most commonly encountered pathology within the SCD. Most cases presented with single and double-vessel diseases, observed in all subjects, as well as the young adult population.

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  • Shinichi Wada, Masatoshi Koga, Kazunori Toyoda, Kazuo Minematsu, Masah ...
    Article ID: 41533
    [Advance publication] Released: November 08, 2017

    Aims: There may be ethnic differences in carotid atherosclerosis and its contributing factors between Asian and other populations. The purpose of this study was to examine intima-media complex thickness (IMT) of the carotid artery and associated clinical factors in Japanese stroke patients with hyperlipidemia from a cohort of the Japan Statin Treatment Against Recurrent Stroke Echo Study.

    Methods: Patients with hyperlipidemia, not on statins, who developed noncardioembolic ischemic stroke were included in this study. Mean IMT and maximum IMT of the distal wall of the common carotid artery were centrally measured using carotid ultrasonography. Significant factors related to mean IMT and maximum IMT were examined using multivariable analysis.

    Results: In 793 studied patients, mean IMT was 0.89±0.15 mm and maximum IMT was 1.19±0.32 mm.Age (per 10 years, parameter estimate=0.044, p<0.001), smoking (0.022, p=0.004), category of blood pressure (0.022, p=0.006), HDL cholesterol (per 10 mg/dl, -0.009, p=0.008), and diabetes mellitus (0.033, p=0.010) were independently associated with mean IMT. Age (per 10 years, 0.076, p<0.001), smoking (0.053, p=0.001), HDL cholesterol (-0.016, p=0.036), and diabetes mellitus (0.084, p=0.002) were independently associated with maximum IMT.

    Conclusion: Baseline mean and maximum values of carotid IMT in Japanese noncardioembolic stroke patients with hyperlipidemia were 0.89±0.15 mm and 1.19±0.32 mm, respectively, which were similar to those previously reported from Western countries. Age, smoking, hypertension, HDL cholesterol, and diabetes mellitus were associated with mean IMT, and those, except for hypertension, were associated with maximum IMT.

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  • Ryo Shimomura, Tomohisa Nezu, Naohisa Hosomi, Shiro Aoki, Takamichi Su ...
    Article ID: 41335
    [Advance publication] Released: November 01, 2017

    Aims: Alpha-2-macroglobulin (α2MG) is thought to be associated with inflammatory reactions and procoagulant properties that might cause ischemic stroke. Endothelial dysfunction plays an important role in atherosclerosis development and in the occurrence of cardiovascular events. In this study, we investigated whether serum α2MG levels, endothelial function, and endothelial progenitor cell (EPC) number were associated in patients with chronic stroke or cardiovascular risk factors.

    Methods: Patients with a history of stroke or any established cardiovascular risk factors were enrolled in this study (n=102; 69 men, 70.1±9.2 years). Endothelial function was assessed by flow-mediated dilation (FMD). EPC numbers (CD34+/CD133+) were measured using flow cytometry (n=91). Serum α2MG levels were measured by nephelometry.

    Results: Patients in the highest tertile of serum α2MG levels were older (P=0.019) and more frequently exhibited dyslipidemia (P=0.021). Univariate-regression analysis revealed that increased α2MG levels were negatively associated with FMD values (r=−0.25; P=0.010), whereas increased EPC numbers were positively associated (r=0.21; P=0.044). Multivariate-regression analysis adjusted for male gender, hypertension, and severe white-matter lesions showed that serum α2MG levels were independently associated with FMD values (standardized partial regression coefficient [β] −0.185; P=0.033), although not significantly associated with EPC numbers.

    Conclusion: Serum α2MG levels might reflect endothelial dysfunction evaluated by FMD in patients with chronic stroke or cardiovascular risk factors.

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  • Ryosuke Nagasaka, Tomonari Koike, Norie Tsukada, Shohei Tamura, Masash ...
    Article ID: 41749
    [Advance publication] Released: November 01, 2017

    Aims: The relationship between the coronary artery running pattern and development of coronary lesions was re-examined herein using WHHLMI rabbits, an animal model of spontaneous coronary atherosclerosis.

    Methods: The coronary artery running pattern was analyzed using an X-ray computed tomography (CT) apparatus after perfusion. Pathological sections were prepared (Victoria blue-HE staining) at 100 µm intervals from the origin of the left circumflex artery (LCX). The severity of coronary lesions was evaluated based on cross-sectional narrowing (lesion area/inner area of the internal elastic lamina).

    Results: In the CT analysis, the angle of the main curvature of the LCX negatively correlated with the percentage of sections with lesions and cross-sectional narrowing. The percentage of sections with lesions was significantly higher in acute angle-type LCX than in obtuse angle-type LCX. Cross-sectional narrowing was also significantly greater in acute angle-type LCX than in obtuse angle-type LCX. The percentage of fibrous lesions was high at the proximal region of LCX, whereas that of lipid-rich lesions was high at the curvature. In 24 months age group, the percentage of sections with calcification in acute angle-type LCX was about twice that in obtuse angle-type LCX.

    Conclusions: Individual differences were observed in the angle of the main curvature of the LCX, which affected the occurrence and extension of atherosclerotic lesions.

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  • Nobuo Nishi
    Article ID: ED087
    [Advance publication] Released: October 20, 2017
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  • Jianglin Fan, Yajie Chen, Haizhao Yan, Manabu Niimi, Yanli Wang, Jingy ...
    Article ID: RV17018
    [Advance publication] Released: October 19, 2017

    Rabbits are one of the most used experimental animals for biomedical research, particularly as a bioreactor for the production of antibodies. However, many unique features of the rabbit have also made it as an excellent species for examining a number of aspects of human diseases such as atherosclerosis. Rabbits are phylogenetically closer to humans than rodents, in addition to their relatively proper size, tame disposition, and ease of use and maintenance in the laboratory facility. Due to their short life spans, short gestation periods, high numbers of progeny, low cost (compared with other large animals) and availability of genomics and proteomics, rabbits usually serve to bridge the gap between smaller rodents (mice and rats) and larger animals, such as dogs, pigs and monkeys, and play an important role in many translational research activities such as pre-clinical testing of drugs and diagnostic methods for patients. The principle of using rabbits rather than other animals as an experimental model is very simple: rabbits should be used for research, such as translational research, that is difficult to accomplish with other species. Recently, rabbit genome sequencing and transcriptomic profiling of atherosclerosis have been successfully completed, which has paved a new way for researchers to use this model in the future. In this review, we provide an overview of the recent progress using rabbits with specific reference to their usefulness for studying human atherosclerosis.

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  • Yuki Tanaka, Norihiro Furusyo, Yoshifumi Kato, Takatsugu Ueyama, Sho Y ...
    Article ID: 41251
    [Advance publication] Released: October 18, 2017

    Aim: The present large-scale Japanese population study was performed to evaluate the relation between the serum thyroid stimulating hormone (TSH) level and renal function.

    Methods: Out of 1,374 residents who participated in a free public physical examination between 2010 and 2011, we evaluated the data of 888 participants for whom the serum TSH level and estimated glomerular filtration rate (eGFR) were successfully measured. The participants were categorized into three groups based on TSH levels (normal TSH, ≤2.4; high-normal TSH, 2.5–4.4; and subclinical hypothyroid, ≥4.5 μIU/mL). Multiple linear regression analysis adjusted for cardiovascular risk factors was performed to determine the relationship between serum TSH level and renal function.

    Results: The mean±SD TSH level was 2.0±1.4 μIU/mL, and 75.9% (n=674) of the participants had normal, 17.9% (n=159) had high-normal, and 6.2% (n=55) had subclinical hypothyroid TSH levels. The mean eGFR significantly decreased with increased TSH levels (normal TSH, 79.3±14.1; high-normal TSH, 77.4±13.0; and subclinical hypothyroid, 72.3±12.2 mL/min/1.73 m2: P for trend 0.01). Multiple linear regression analysis extracted log-transformed TSH level as an independent factor correlated with eGFR in the high-normal TSH group (beta=−0.18, P=0.02).

    Conclusions: Our findings demonstrated a significant correlation between serum TSH levels and eGFR in high-normal TSH participants. In healthy individuals, high-normal TSH levels indicate increased the risk of chronic kidney disease.

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  • Yoshio Fujioka
    Article ID: ED088
    [Advance publication] Released: October 18, 2017
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  • Takuya Tsujimura, Osamu Iida, Masashi Fujita, Masaharu Masuda, Shin Ok ...
    Article ID: 41152
    [Advance publication] Released: October 05, 2017

    Aim: We investigated 2-year clinical outcomes after implantaton of EpicTM self-expanding nitinol stents for patients with peripheral artery disease (PAD) due to the aortoiliac occlusive disease (AIOD).

    Methods: This study was a multicenter and retrospective study. From February 2013 through October 2014, 292 lesions (chronic total occlusion, 21%; TASC Ⅱ C/D, 35%) in 217 consecutive patients (74±8 years; male, 81%; diabetes mellitus, 47%; dialysis, 21%; critical limb ischemia, 29%) who had undergone endovascular therapy (EVT) with EpicTM self-expanding nitinol stents for PAD with AIOD were analyzed. The primary endpoints were 2-year primary patency and target lesion revascularization (TLR)-free rate. The primary patency and freedom from TLR were determined by Kaplan-Meier analysis. Additionally, predictors for loss of patency were estimated by Cox proportional hazard model.

    Results: The mean follow-up duration was 19.1±8.5 months. Primary patency was 87.3% at 2 years. Freedom from TLR rate was 94.1% at 2 years. Multivariate analysis revealed that the presence of diabetes mellitus was associated with a loss of patency.

    Conclusion: The EpicTM self-expanding nitinol stent was demonstrated to be safe and effectivene for AIOD when tested for two years in patients with PAD.

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  • Hongxian Wu, Qiuna Du, Qiuyan Dai, Junbo Ge, Xianwn Cheng
    Article ID: RV17016
    [Advance publication] Released: October 05, 2017

    Atherosclerotic cardiovascular disease (ASCVD) is an inflammatory disease characterized by extensive arterial wall matrix protein degradation. Cysteine protease cathepsins play a pivotal role in extracellular matrix (ECM) remodeling and have been implicated in the development and progression of atherosclerosis-based cardiovascular diseases. An imbalance in expression between cathepsins (such as cathepsins S, K, L, C) and their inhibitor cystatin C may favor proteolysis of ECM in the pathogenesis of cardiovascular disease such as atherosclerosis, aneurysm formation, restenosis, and neovascularization. New insights into cathepsin functions have been made possible by the generation of knockout mice and by the application of specific inhibitors. Inflammatory cytokines regulate the expression and activities of cathepsins in cultured vascular cells and macrophages. In addition, evaluations of the possibility of cathepsins as a diagnostic tool revealed that the circulating levels of cathepsin S, K, and L, and their endogenous inhibitor cystatin C could be promising biomarkers in the diagnosis of coronary artery disease, aneurysm, adiposity, peripheral arterial disease, and coronary artery calcification. In this review, we summarize the available information regarding the mechanistic contributions of cathepsins to ASCVD.

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  • Yoshito Yamashiro, Hiromi Yanagisawa
    Article ID: RV17015
    [Advance publication] Released: September 22, 2017

    Thoracic aortic aneurysms (TAAs) are common, life-threatening diseases and are a major cause of mortality and morbidity. Over the past decade, genetic approaches have revealed that 1) activation of the transforming growth factor beta (TGF-β) signaling, 2) alterations in the contractile apparatus of vascular smooth muscle cells (SMCs), and 3) defects in the extracellular matrix (ECM) were responsible for development of TAAs. Most recently, a fourth mechanism has been proposed in that dysfunction of mechanosensing in the aortic wall in response to hemodynamic stress may be a key driver of TAAs. Interestingly, the elastin-contractile unit, which is an anatomical and functional unit connecting extracellular elastic laminae to the intracellular SMC contractile filaments, via cell surface receptors, has been shown to play a critical role in the mechanosensing of SMCs, and many genes identified in TAAs encode for proteins along this continuum. However, it is still debated whether these four pathways converge into a common pathway. Currently, an effective therapeutic strategy based on the underlying mechanism of each type of TAAs has not been established. In this review, we will update the present knowledge on the molecular mechanism of TAAs with a focus on the signaling pathways potentially involved in the initiation of TAAs. Finally, we will evaluate current therapeutic strategies for TAAs and propose new directions for future treatment of TAAs.

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  • Toshiro Kitagawa, Hideya Yamamoto, Takuya Hattori, Kazuhiro Sentani, S ...
    Article ID: 41178
    [Advance publication] Released: September 20, 2017

    Aims: Tumor necrosis factor (TNF)-α reportedly has key pro-inflammatory properties in both atherosclerosis and adipocytes. To further investigate the biologic impact of epicardial adipose tissue (EAT) on coronary atherosclerosis, we evaluated the relationship between TNF-α gene expression in EAT and clinically-assessed coronary atherosclerosis on computed tomography (CT).

    Methods: We studied 47 patients before cardiac surgery (coronary artery bypass grafting [CABG], n=26; non-CABG, n=21), assessing visceral adipose tissue (VAT) area, EAT volume, coronary calcium score (CCS), and the presence of non- and/or partially-calcified coronary plaque (NCP) on CT angiography. EAT and subcutaneous adipose tissue (SAT) samples were obtained during cardiac surgery. TNF-α mRNA in EAT was measured using quantitative real-time PCR, and normalized to that of SAT as control adipose tissue.

    Results: There was no difference in the TNF-α expression level between patients scheduled for CABG and non-CABG surgery (p=0.23), or among the subgroups based on CCS (p=0.68), while patients with NCP had the higher TNF-α expression level than those without NCP (median [interquartile range], 2.50 [1.01–5.53] versus. 1.03 [0.64–2.16], p=0.022). On multivariate analysis adjusted for age, sex, coronary risk factors, statin therapy, CABG versus non-CABG, VAT area, and EAT volume, the presence of NCP had close correlation with the elevated TNF-α expression level (β=0.79, p=0.003).

    Conclusions: TNF-α expressed regionally in EAT may exert potent effects on the progression of coronary atherosclerosis, suggesting a contribution of EAT to coronary artery disease through behavior of molecule.

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  • Atsushi Tanaka, Koichi Node
    Article ID: ED086
    [Advance publication] Released: September 20, 2017
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  • Naohisa Hosomi, Yoji Nagai, Kazuo Kitagawa, Yoko Nakagawa, Shiro Aoki, ...
    Article ID: 40196
    [Advance publication] Released: September 16, 2017

    Aims: The J-STARS study examined whether pravastatin (10 mg/day) reduces recurrence of stroke in non-cardioembolic ischemic stroke patients who were enrolled within 1 month to 3 years after initial stroke events (, NCT00221104). The main results showed that the frequency of atherothrombotic stroke was low in pravastatin-treated patients, although no effect of pravastatin was found for the other stroke subtypes. We evaluated differences of early (within 6 months) or late (after 6 months) pravastatin treatment benefits on the incidence of stroke or transient ischemic attack (TIA), as well as atherothrombotic stroke and the other subtypes.

    Methods: Subjects in the J-STARS study were classified into two cohorts, depending on whether they enrolled early (1 to 6 months) or late (6 months to 3 years) following initial stroke events.

    Results: A total of 1578 patients (491 female, 66.2±8.5 years) were randomly assigned to either the pravastatin group (n=793; n=426 in the early cohort, n=367 in the late cohort) or the control group (n=785; n=417 in the early cohort, n=368 in the late cohort). During the follow-up of 4.9± 1.4 years, the rate of atherothrombotic stroke was lower in the pravastatin group compared to controls in the early cohort (0.24 vs. 0.88%/year, p=0.01) but not in the late cohort (0.17 vs. 0.39%/year, p=0.29). However, this difference of pravastatin effect on atherothrombotic stroke was not significantly interacted by the early or late cohort (p=0.59). The incidence rates of other stroke subtype were not different in between pravastatin and control groups despite the timing of entry.

    Conclusions: Pravastatin is likely to reduce atherothrombotic stroke in patients enrolled within 6 months after stroke onset. However, the clinical efficacy for prevention of recurrent stroke was not conclusive with earlier statin treatment.

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  • Huan Liu, Jinbo Liu, Hongwei Zhao, Yingyan Zhou, Lihong Li, Hongyu Wan ...
    Article ID: 39685
    [Advance publication] Released: September 12, 2017

    Aim: The study was done to establish the relationship between serum uric acid (UA) and vascular function and structure parameters including carotid femoral pulse wave velocity (CF-PWV), carotid radial pulse wave velocity (CR-PWV), cardio ankle vascular index (CAVI), ankle brachial index (ABI), and carotid intima-media thickness (CIMT), and the gender difference in a real-world population from China.

    Methods: A total of 979 subjects were enrolled (aged 60.86±11.03 years, male 416 and female 563). Value of UA was divided by 100 (UA/100) for analysis.

    Results: Body mass index (BMI), diastolic blood pressure (DBP), fasting plasma glucose (FPG), UA, and UA/100 were significantly higher in males compared with females (all p<0.05); pulse pressure (PP), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were lower in males than females (all p<0.05). All vascular parameters including CF-PWV, CR-PWV, CAVI, ABI, and CIMT were higher in males than females (all p<0.05). Multiple linear regression analysis showed that UA/100 was independently positively linearly correlated with CAVI (B=0.143, p=0.001) and negatively correlated with ABI in the male population (B=-0.012, p=0.020). In people with higher UA, the risk of higher CF-PWV was 1.593 (p<0.05).

    Conclusions: 1. All vascular parameters were higher in males than females. There was no gender difference in the relationship between UA and vascular markers except in ABI. 2. UA was independently linearly correlated with CAVI. 3. In people with higher UA level, the risk of higher CF-PWV increased. Therefore, higher UA may influence the vascular function mainly instead of vascular structure.

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  • Qiong Ye, Guo-Ping Tian, Hai-Peng Cheng, Xin Zhang, Xiang Ou, Xiao-Hua ...
    Article ID: 40212
    [Advance publication] Released: September 01, 2017

    Aims: Atherosclerosis is the most common cause of cardiovascular disease, such as myocardial infarction and stroke. Previous study revealed that microRNA (miR)-134 promotes lipid accumulation and proinflammatory cytokine secretion through angiopoietin-like 4 (ANGPTL4)/lipid lipoprotein (LPL) signaling in THP-1 macrophages.

    Methods: ApoE KO male mice on a C57BL/6 background were fed a high-fat/high-cholesterol Western diet, from 8 to 16 weeks of age. Mice were divided into four groups, and received a tail vein injection of miR-134 agomir, miR-134 antagomir, or one of the corresponding controls, respectively, once every 2 weeks after starting the Western diet. After 8 weeks we measured aortic atherosclerosis, LPL Activity, mRNA and protein levels of ANGPTL4 and LPL, LPL/ low-density lipoprotein receptor related protein 1 Complex Formation, proinflammatory cytokine secretion and lipid levels.

    Results: Despite this finding, the influence of miR-134 on atherosclerosis in vivo remains to be determined. Using the well-characterized mouse atherosclerosis model of apolipoprotein E knockout, we found that systemic delivery of miR-134 agomir markedly enhanced the atherosclerotic lesion size, together with a significant increase in proinflammatory cytokine secretion and peritoneal macrophages lipid contents. Moreover, overexpression of miR-134 decreased ANGPTL4 expression but increased LPL expression and activity in both aortic tissues and peritoneal macrophages, which was accompanied by increased formation of LPL/low-density lipoprotein receptor-related protein 1 complexes in peritoneal macrophages. However, an opposite effect was observed in response to miR-134 antagomir.

    Conclusions: These findings suggest that miR-134 accelerates atherogenesis by promoting lipid accumulation and proinflammatory cytokine secretion via the ANGPTL4/LPL pathway. Therefore, targeting miR-134 may offer a promising strategy for the prevention and treatment of atherosclerotic cardiovascular disease.

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  • Akihiro Tokushige, Masaaki Miyata, Takeshi Sonoda, Ippei Kosedo, Daisu ...
    Article ID: 41012
    [Advance publication] Released: August 30, 2017

    Aim: Previous studies have reported a 10.2%–22% rate of silent cerebral infarction and a 0.1%–1% rate of symptomatic cerebral infarction after coronary angiography (CAG). However, the risk factors of cerebral infarction after CAG have not been fully elucidated. For this reason, we investigated the incidence and risk factors of CVD complications within 48 h after CAG using magnetic resonance imaging (MRI) (Diffusion-weighted MRI) at Kagoshima University Hospital.

    Methods: From September 2013 to April 2015, we examined the incidence and risk factors, including procedural data and patients characteristics, of cerebrovascular disease after CAG in consecutive 61 patients who underwent CAG and MRI in our hospital.

    Results: Silent cerebral infarction after CAG was observed in 6 cases (9.8%), and they should not show any neurological symptoms of cerebral infarction. Only prior coronary artery bypass grafting (CABG) was more frequently found in the stroke group (n=6) than that in the non-stroke group (n=55); however, no significant difference was observed (P=0.07). After adjusting for confounders, prior CABG was a significant independent risk factor for the incidence of stroke after CAG (odds ratio: 11.7, 95% confidence interval: 1.14–129.8, P=0.04).

    Conclusions: We suggested that the incidence of cerebral infarction after CAG was not related to the catheterization procedure per se but may be caused by atherosclerosis with CABG.

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  • Fumiaki Furuyama, Shinji Koba, Yuya Yokota, Fumiyoshi Tsunoda, Makoto ...
    Article ID: 41095
    [Advance publication] Released: August 30, 2017

    Aims: We evaluated whether exercised-based cardiac rehabilitation (CR) can ameliorate the HDL function, i.e., cholesterol efflux capacity (CEC) and paraoxonase-1 activity in patients with acute coronary syndrome (ACS).

    Methods: This study is a retrospective analysis of stored serum from patients with ACS following successful percutaneous coronary intervention. The CEC, measured by a cell-based ex vivo assay using apolipoprotein B-depleted serum and 3H-cholesterol labeled macrophages and arylesterase activity (AREA) at the onset or early phase of ACS, and the follow-up periods were compared between 69 patients who completed the five-month outpatient CR program (CR group) and 15 patients who did not participate and/or dropped out from CR program (non-CR group).

    Results: Apolipoprotein A-I (apoA-I) and CEC significantly increased by 4.0% and 9.4%, respectively, in the CR group, whereas HDL-cholesterol and AREA were not changed during the follow-up periods in both groups. Among CR patients, the CEC significantly increased, irrespective of the different statin treatment, while HDL-cholesterol and apoA-I significantly increased in patients treated with rosuvastatin or pitavastatin. Although CEC and AREA were significantly correlated each other, there is a discordance between CEC and AREA for their correlations with other biomarkers. Both CEC and AREA were significantly correlated with apoA-I rather than HDL-cholesterol. Changes in CEC and those in AREA were significantly correlated with those in apoA-I (rho=0.328, p=0.002, and rho=0.428, p<0.0001, respectively) greater than those in HDL-cholesterol (rho=0.312, p= 0.0042,and rho=0.343, p=0.003, respectively).

    Conclusions: CR can improve HDL function, and it is beneficial for secondary prevention.

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  • Takehiro Hashikata, Taiki Tojo, Yusuke Muramatsu, Toshimitsu Sato, Ryo ...
    Article ID: 39560
    [Advance publication] Released: August 19, 2017

    Aim: Fractional flow reserve (FFR) reflects on the diffuse atherosclerosis per coronary artery. It is unknown whether the statin therapy affects long term FFR after stenting. The aim of this study was to evaluate the long term FFR after stent implantation in patients who are intaking fixed-dose rosuvastatin.

    Methods: A total of 22 patients with stable angina pectoris were enrolled. The values of FFR were measured before, immediately after, and 18 months after (follow-up day) the implantation of everolimus eluting stent (EES; Promus ElementTM or Promus Element PlusTM). A fixed dose of rosuvastatin at 5 mg/day was administrated to all patients.

    Results: Of the 22 patients, 2 were excluded because of adverse effect of rosuvastatin and in-stent total occlusion after EES implantation. Overall, the values of FFR immediately after and 18 months after EES implantation did not show significant change (from 0.90±0.05 to 0.88±0.06, p=0.16). However, there was a significant negative correlation between low density lipoprotein (LDL) cholesterol level at follow-up day and changes in the value of FFR (p=0.01, r =-0.74). There was an increase in the FFR value after stenting in 8 out of 9 patients with LDL cholesterol level below 75 mg/dl (area under the curve 0.92, p=0.0005).

    Conclusions: LDL cholesterol level was associated with the change in the FFR value in patients following stent implantation. Lower LDL cholesterol tended to improve in the long-term FFR, underscoring the importance of lowering LDL cholesterol to prevent the progression of coronary atherosclerosis.

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  • Masami Sairyo, Takuya Kobayashi, Daisaku Masuda, Koutaro Kanno, Yingho ...
    Article ID: 39693
    [Advance publication] Released: August 05, 2017

    Aims: Fasting and postprandial hypertriglyceridemia (PHTG) are caused by the accumulation of triglyceride (TG)-rich lipoproteins and their remnants, which have atherogenic effects. Fibrates can improve fasting and PHTG; however, reduction of remnants is clinically needed to improve health outcomes. In the current study, we investigated the effects of a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), K-877 (Pemafibrate), on PHTG and remnant metabolism.

    Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) only, or an HFD containing 0.0005% K-877 or 0.05% fenofibrate, from 8 to 12 weeks of age. After 4 weeks of feeding, we measured plasma levels of TG, free fatty acids (FFA), total cholesterol (TC), HDL-C, and apolipoprotein (apo) B-48/B-100 during fasting and after oral fat loading (OFL). Plasma lipoprotein profiles after OFL, which were assessed by high performance liquid chromatography (HPLC), and fasting lipoprotein lipase (LPL) activity were compared among the groups.

    Results: Both K-877 and fenofibrate suppressed body weight gain and fasting and postprandial TG levels and enhanced LPL activity in mice fed an HFD. As determined by HPLC, K-877 and fenofibrate significantly decreased the abundance of TG-rich lipoproteins, including remnants, in postprandial plasma. Both K-877 and fenofibrate decreased intestinal mRNA expression of ApoB and Npc1l1; however, hepatic expression of Srebp1c and Mttp was increased by fenofibrate but not by K-877.Hepatic mRNA expression of apoC-3 was decreased by K-877 but not by fenofibrate.

    Conclusion: K-877 may attenuate PHTG by suppressing the postprandial increase of chylomicrons and the accumulation of chylomicron remnants more effectively than fenofibrate.

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  • Sentaro Suzuki, Hisatomi Arima, Soichiro Miyazaki, Akira Fujiyoshi, Ay ...
    Article ID: 40527
    [Advance publication] Released: July 26, 2017

    Aim: There are few data regarding associations between sleep duration and subclinical atherosclerosis in Japan. The aim of this study was to evaluate associations of self-reported sleep duration with calcification in the coronary arteries (CAC) and carotid intima media thickness (IMT) in Japanese men.

    Methods: This was a cross-sectional survey of 1093 randomly selected men from Kusatsu City, Japan. Average sleep duration on weekdays was estimated through questionnaire; CAC by computed tomography; and carotid IMT by ultrasonography.

    Results: The prevalence of CAC was 50.0% for participants with sleep duration <5.5 h, 43.9% with 5.5–6.4 h, 50.0% with 6.5–7.4 h, 49.3% with 7.5–8.4 h, and 62.5% with ≥8.5 h. In univariate analysis, participants with sleep duration ≥8.5 h had significantly higher prevalence of CAC than those with 6.5–7.4 h (p=0.043). After adjustment for age and other risk factors, however, the association was not significant (p=0.776). The average IMT was 0.85 mm for participants with sleep duration <5.5 h, 0.83 mm with 5.5–6.4 h, 0.85 mm with 6.5–7.4 h, 0.88 mm with 7.5–8.4 h, and 0.90 mm with ≥8.5 h. None of the differences in IMT observed in crude or multivariable-adjusted analyses was significant (all p>0.1).

    Conclusion: Self-reported sleep duration was not associated with increased CAC or carotid IMT in a general population of Japanese men.

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  • Minkyung Kim, Minjoo Kim, Hye Jin Yoo, Seung Yeon Lee, Sang-Hyun Lee, ...
    Article ID: 39388
    [Advance publication] Released: July 22, 2017

    Aim: Pulse wave velocity (PWV) is thought to have different relationships with metabolic syndrome (MS) components, inflammatory markers, and oxidative stress, according to age. However, age-specific determinants of PWV have not yet been studied. We investigated age-dependent relationships among PWV and MS components, inflammatory markers, and oxidative stress.

    Methods: A total of 4,318 subjects were divided into 4 groups: 19–34 y (n=687), 35–44 y (n=1,413), 45–54 y (n=1,384), and 55–79 y (n=834). MS components, brachial-ankle PWV (baPWV), high-sensitivity C-reactive protein (hs-CRP), and oxidative stress markers were measured.

    Results: There were age-related increases in MS, body mass index (BMI), waist circumference, systolic blood pressure (SBP), diastolic BP (DBP), triglycerides, glucose, hs-CRP, oxidized low-density lipoprotein (LDL), 8-epi-prostaglandin F (8-epi-PGF), and baPWV. BaPWV was significantly associated with sex and elevated BP in the 19–34 y group; with age, sex, BMI, elevated BP and triglycerides in the 35–44 y group; with age, sex, elevated BP, fasting glucose, hs-CRP and oxidized LDL in the 45–54 y group; and with age, BMI, elevated BP, fasting glucose and oxidized LDL in the 55–79 y group.

    Conclusions: Our results show that age-related increases in baPWV are associated with age-related changes in MS components, inflammatory markers, and oxidative stress. However, each of these factors has an age-specific, different impact on arterial stiffness. In particular, oxidative stress may be independently associated with arterial stiffness in individuals older than 45 y.

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  • Brian Tomlinson, Paul Chan, Zhong-Min Liu
    Article ID: 40204
    [Advance publication] Released: July 21, 2017
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  • Won-tak Joo, Chan Joo Lee, Jaewon Oh, In-Cheol Kim, Sang-Hak Lee, Seok ...
    Article ID: 40469
    [Advance publication] Released: July 21, 2017

    Aim: The association of social networks with cardiovascular disease (CVD) has been demonstrated through various studies. This study aimed to examine the association between social network betweenness –a network position of mediating between diverse social groups–and coronary artery calcium.

    Methods: The data of 1,384 participants from the Cardiovascular and Metabolic Disease Etiology Research Center–High Risk Cohort, a prospective cohort study enrolling patients with a high risk of developing CVD ( NCT02003781), were analyzed. The deficiency in social network betweenness was measured in two ways: only-family networks, in which a respondent had networks with only family members, and no-cutpoint networks, in which the respondent does not function as a point of bridging between two or more social groups that are not directly connected.

    Results: Participants who had higher coronary artery calcium scores (CACSs) were likely to have a smaller network size (p<0.001), only-family networks (p<0.001), and no-cutpoint networks (p<0.001). Multiple logistic regression analyses revealed no significant association between network size and CACS. Only no-cutpoint networks had a significant relationship with CACS >400 (odds ratio, 1.72; 95% confidence interval, 1.07–2.77; p=0.026). The association was stronger among older (age >60 years) and female respondents.

    Conclusion: Deficiency in social network betweenness is closely related to coronary calcium in participants with a high risk of CVD. To generalize these results to a general population, further study should be performed.

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  • Kentaro Watanabe, Hideki Fujii, Shunsuke Goto, Kentaro Nakai, Keiji Ko ...
    Article ID: 40170
    [Advance publication] Released: July 01, 2017

    Aim: Chronic kidney disease–mineral bone disorder (CKD–MBD) is associated with all-cause and cardiovascular morbidity and mortality in patients with CKD. Thus, elucidating its pathophysiological mechanisms is essential for improving the prognosis. We evaluated characteristics of CKD–MBD in a newly developed CKD rat model.

    Methods: We used male Sprague–Dawley (SD) rats and spontaneously diabetic Torii (SDT) rats, which are used as models for nonobese type 2 diabetes. CKD was induced by 5/6 nephrectomy (Nx). At 10 weeks, the rats were classified into six groups and administered with a vehicle or a low- or high-dose paricalcitol thrice a week. At 20 weeks, the rats were sacrificed; blood and urinary biochemical analyses and histological analysis of the aorta were performed.

    Results: At 20 weeks, hemoglobin A1c (HbA1c) levels, blood pressure, and renal function were not significantly different among the six groups. Serum calcium and phosphate levels tended to be higher in SDT-Nx rats than in SD-Nx rats. The urinary excretion of calcium and phosphate was significantly greater in SDT-Nx rats than in SD-Nx rats. After administering paricalcitol, serum parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels were significantly higher in SDT-Nx rats than in SD-Nx rats. The degree of aortic calcification was significantly more severe and the aortic calcium content was significantly greater in SDT-Nx rats than in SD-Nx rats.

    Conclusions: We suggest that our new CKD rat model using SDT rats represents a useful CKD-MBD model, and this model was greatly influenced by paricalcitol administration. Further studies are needed to clarify the detailed mechanisms underlying this model.

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