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.
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 (ClinicalTrials.gov, 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.
Aim: Stroke is associated closely with vascular homeostasis, and several complex processes and interacting pathways, which involve various genetic and environmental factors, contribute to the risk of stroke. Although adrenomedullin (ADM) has a number of physiological and vasoprotective functions, there are few studies of the ADM receptor system in humans. The ADM receptor comprises a calcitonin-receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs). We analyzed single nucleotide polymorphisms (SNPs) in the RAMP2 and CLR genes to determine their association with stroke in the light of gene-environment interactions.
Methods: Using cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study in the baseline surveys, 14,087 participants from 12 research areas were genotyped. We conducted a hypothesis-based association between stroke prevalence and SNPs in the RAMP2 and CLR genes based on data abstracted from two SNPs in RAMP2 and 369 SNPs in CLR. We selected five SNPs from among the CLR variants (rs77035639, rs3815524, rs75380157, rs574603859, and rs147565266) and one RAMP2 SNP (rs753152), which were associated with stroke, for analysis.
Results: Five of the SNPs (rs77035639, rs3815524, rs75380157, rs147565266, and rs753152) showed no significant association with obesity, ischemic heart disease, hypertension, dyslipidemia, and diabetes. In the logistic regression analysis, rs574603859 had a lower odds ratio (0.238; 95% confidence interval, 0.076–0.745, adjusted for age, sex, and research area) and the other SNPs had higher odds ratios for association with stroke.
Conclusions: This was the first study to investigate the relationships between ADM receptor genes (RAMP2 and CLR) and stroke in the light of gene-environment interactions in human.
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.
White adipose tissue (WAT) stores energy as triacylglycerol in preparation for fasting state. In contrast, brown adipose tissue (BAT) consumes energy and produces heat in a cold environment. One of the major differences between these two adipose tissues is the morphology of the intracellular lipid droplet (LD), which is large and unilocular in WAT and small and multilocular in BAT. Although the fat-specific protein 27 alpha (FSP27α), belonging to the cell death-inducing DNA fragmentation factor A (DFFA)-like effector (Cide) family, was known to be indispensable for large unilocular LD formation in WAT, the mechanism that regulated small multilocular LD formation in BAT remained unknown. We recently uncovered that FSP27β, a novel isoform of FSP27 abundantly expressed in BAT, plays a crucial role in small multilocular LD formation by inhibiting the homodimerization of CideA in BAT. We speculate that unilocular LD formation is ideal for efficient lipid storage in WAT because lipolysis from the LD surface is restricted due to the minimum LD surface area. In addition, hydrolyzed free fatty acid (FFA) and glycerol can efficiently flow out into the circulation from the cell surface. In contrast, small multilocular LD formation is ideal for efficient intracellular lipolysis from the LD surface and the subsequent facilitation of FFA transport to mitochondria that are adjacent to LDs for β-oxidation in BAT. Thus, intracellular LD morphology is closely related to the functions and characteristics of adipose tissues. Given that the browning of adipose tissue leads to enhanced energy expenditure and the prevention of obesity, clarification of the mechanism with respect to intracellular LD formation is very meaningful.
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.
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.
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.
Aim: The aim of this study was to investigate whether information on arterial stiffness can improve the value of single-photon emission computed tomography (SPECT) in the detection of obstructive coronary artery disease (CAD).
Methods: A total of 233 patients (age: 62.2±10.8 years, 60.3% males) with detected ischemia on SPECT undergoing invasive coronary angiography (ICA) and brachial-ankle pulse wave velocity (baPWV) measurement within a month was retrospectively reviewed.
Results: Of the 233 patients, 190 (81.5%) had obstructive CAD (≥50% luminal stenosis). The difference in baPWV according to the presence of obstructive CAD was significant in patients in the mild ischemia group [summed stress score (SSS): 4–8] (1,770±364 cm versus 1,490±328 cm, p＜0.001) but not in the moderate (SSS: 9–13) or severe (SSS: ≥14) ischemia groups (p＞0.05 for each). Receiver operating characteristic curve analyses showed that the diagnostic value of baPWV for obstructive CAD was significant only in patients in the mild ischemia group (area under curve: 0.714; p=0.001) but not in the moderate or severe ischemia groups (p＞0.05 for each). Adding information on baPWV to SPECT results and clinical parameters significantly increased diagnostic accuracy in the detection of obstructive CAD in patients with mild ischemia (integrated discrimination improvement p=0.006) but not in those with moderate or severe ischemia on SPECT (p＞0.05 for each).
Conclusions: The results of this study suggest that baPWV may have additional value to SPECT for the detection of obstructive CAD, especially in patients with mild ischemia on SPECT.
Aim: To investigatethe association of plasma epoxyeicosatrienoic acids (EETs) with early neurologic deterioration (END), and whether EETs are mediated by EPHX2 variants in patients with minor ischemic stroke (MIS).
Method: This was a prospective, multi-center observational study in patients with acute MIS in the Chinese population.Plasma EETs levels were measured on admission. Single nucleotide polymorphisms (SNPs) of EPHX2 rs751141 were genotyped using mass spectrometry. The primary outcome was END within 10 days after admission. END was defined as an increase in NIHSS of 2 or more points. The degree of disability was assessed using the modified Rankin Scale (mRS) at 3 months after admission.
Results: A total of 322 patients were enrolled, of which 85 patients (26.4%) experienced END. The mean EETs level was 64.1±7.5 nmol/L. EETs levels were significantly lower in patients with END compared to patients without END. Frequency of EPHX2 rs751141 GG was higher in patients with END than in patients without END, and EPHX2 rs751141 GG genotype was associated with lower EETs levels. Low level (＜64.4 nmol/L) of EETs was an independent predictor of END (first and second quartiles) in multivariate analyses. END was associated with a higher risk of poor outcome (mRS scores 3–6) at 3 months.
Conclusion: END is fairly common and associated with poor outcomes in acute MIS. EPHX2 variants may mediate EETs levels, and low levels of EETs may be a predictor for END in acute MIS.
The adoption of the Western-style diet, with decreased fish intake and lack of exercise, has increased the prevalence of cardiovascular disease (CVD) in Japan. Statin treatment has been established to reduce the risk of cardiovascular events; however, 60%–70% of these events occur despite its use. Thus, the residual risk for CVD should be identified and resolved to reduce further cardiovascular events. The serum levels of n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid and docosahexaenoic acid, are reportedly associated with an increased incidence of cardiovascular events and mortality, whereas the addition of n-3 PUFA treatment to the statin treatment decreases cardiovascular events. Similar to statins, n-3 PUFAs have pleiotropic effects in addition to lipid-modifying effects. Pre-clinical and clinical studies have shown that n-3 PUFAs prevent cardiovascular events by ameliorating endothelial function and attenuating lipid accumulation, vascular inflammation, and macrophage recruitment, thereby causing coronary plaque development and rupture. Taken together, n-3 PUFAs are comprehensively able to attenuate the atherogenic response. Therefore, n-3 PUFA intake is recommended to prevent cardiovascular events, particularly in patients with multiple cardiovascular risk factors.
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.
Chronic vascular diseases such as atherosclerosis, aneurysms, diabetic angiopathy/retinopathy as well as fibrotic and proliferative vascular diseases are generally complicated by the progression of degenerative insults, which are characterized by endothelial dysfunction, apoptotic/necrotic cell death in vascular/immune cells, remodeling of extracellular matrix or breakdown of elastic lamella. Increasing evidence suggests that dysfunctional calpain proteolytic systems and defective calpain protein metabolism in blood vessels contribute to degenerative disorders. In vascular endothelial cells, the overactivation of conventional calpains consisting of calpain-1 and -2 isozymes can lead to the disorganization of cell-cell junctions, dysfunction of nitric oxide synthase, sensitization of Janus kinase/signal transducer and activator of transcription cascades and depletion of prostaglandin I2, which contributes to degenerative disorders. In addition to endothelial cell dysfunctions, calpain overactivation results in inflammatory insults in macrophages and excessive fibrogenic/proliferative signaling in vascular smooth muscle cells. Moreover, calpain-6, a non-proteolytic unconventional calpain, is involved in the conversion of macrophages to a pro-atherogenic phenotype, leading to the pinocytotic deposition of low-density lipoprotein cholesterol in the cells. Here, we discuss the recent progress that has been made in our understanding of how calpain contributes to degenerative vascular disorders.
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.
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.
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 F2α (8-epi-PGF2α), 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.
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 (clinicaltrials.gov: 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.
Aim: Children exposed to parental smoking are at increased long-term risk of subclinical atherosclerosis in adulthood. However, it has not been quantified if exposure to parental smoking in childhood is associated with adult systemic inflammation. This study aimed to determine if childhood exposure to parental smoking was associated with high-sensitivity C-reactive protein (hsCRP) in adulthood.
Methods: This longitudinal analysis of 2,511 participants used data from the Cardiovascular Risk in Young Finns Study, a prospective cohort of Finnish children. In 1980 or 1983, parents self-reported their smoking status and serum hsCRP was collected up to 31 years later in adulthood.
Results: Compared with children with non-smoking parents, the relative risk of developing high hsCRP (＞3 mg/L) in adulthood increased among those with 1 or both parents who smoked [relative risk (RR), 1.3; 95%confidence interval (CI), 1.0-1.8] after adjustment for socioeconomic status, cardiovascular risk factors, and smoking status in childhood and adulthood. Moreover, children exposed to mother smoking [RR, 2.4; 95% CI, 1.3-4.2] had highest risk of developing high hsCRP in adulthood compared with those exposed to father smoking [RR, 1.6; 95% CI, 1.2-2.3] and both parents smoking [RR, 1.4; 95% CI, 0.9-2.0].
Conclusion: Our findings suggest that children exposed to parental smoking are at increased risk of having high hsCRP in adulthood. Limiting children's exposure to passive smoking may have long-term benefits on general low-grade inflammation.
Sphingosine 1-phosphate (S1P) is a potent lipid mediator that works on five kinds of S1P receptors located on the cell membrane. In the circulation, S1P is distributed to HDL, followed by albumin. Since S1P and HDL share several bioactivities, S1P is believed to be responsible for the pleiotropic effects of HDL. Plasma S1P levels are reportedly lower in subjects with coronary artery disease, suggesting that S1P might be deeply involved in the pathogenesis of atherosclerosis. In basic experiments, however, S1P appears to possess both pro-atherosclerotic and anti-atherosclerotic properties; for example, S1P possesses anti-apoptosis, anti-inflammation, and vaso-relaxation properties and maintains the barrier function of endothelial cells, while S1P also promotes the egress and activation of lymphocytes and exhibits pro-thrombotic properties. Recently, the mechanism for the biased distribution of S1P on HDL has been elucidated; apolipoprotein M (apoM) carries S1P on HDL. ApoM is also a modulator of S1P, and the metabolism of apoM-containing lipoproteins largely affects the plasma S1P level. Moreover, apoM modulates the biological properties of S1P. S1P bound to albumin exerts both beneficial and harmful effects in the pathogenesis of atherosclerosis, while S1P bound to apoM strengthens anti-atherosclerotic properties and might weaken the pro-atherosclerotic properties of S1P. Although the detailed mechanisms remain to be elucidated, apoM and S1P might be novel targets for the alleviation of atherosclerotic diseases in the future.
Aim: Sarcopenic obesity (SO) is closely associated with cardiovascular disease (CVD) in elderly women. Increases in body fat and decreases in muscle mass are closely associated with increased carotid intima-media thickness (CIMT). The aim of this study was to examine the influence of a 24-week aerobic and resistance training program on carotid parameters in SO.
Methods: Fifty elderly women (74.1±6.1 years) with SO were randomly divided into an exercise group and a control group. The exercise group performed combined exercise over 24 weeks, consisting of resistance and aerobic training for 50-80 min, 5 times a week. Carotid variables were measured using B-mode ultrasound. The differences in the carotid variables and the relative changes between baseline and after 24 weeks were evaluated.
Results: In the analysis of variance (ANOVA) results, CIMT (p=0.013), systolic flow velocity (p=0.007), diastolic flow velocity (p=0.006), and wall shear rate (p=0.010) showed significant interactions. In paired t-test results of the exercise group, CIMT significantly decreased (p＜0.01) and systolic flow velocity (p＜0.01), diastolic flow velocity (p＜0.001), and wall shear rate (p＜0.05) significantly increased after 24 weeks.
Conclusion: The 24-week combined exercise effectively decreased CIMT and increased carotid flow velocity and wall shear ratio. Therefore, combined exercise is thought to contribute to the improvement of the risk of CVD in elderly women with SO.
Aim: Coronary computed tomography angiography (CCTA) findings of positive remodeling (index ＞1.1) and low-attenuation plaque (＜30 Hounsfield units) are recognized as CT-verified high-risk plaque (CT-HRP). Therefore, we investigated the incremental prognostic value of evaluation of plaque characteristics using CCTA in asymptomatic patients.
Methods: Overall, 495 consecutive patients without any known coronary artery disease who underwent CCTA were included in this study. Patients who underwent revascularization within 30 days of CCTA or had scans with poor image quality were excluded. Clinical follow-up data (716.5±262.6 days) were available for 339 patients, who were analyzed for the current study. Framingham risk score (FRS), coronary artery calcium score (CACS), and CT-HRP were investigated as predictors of cardiac events by multivariable analysis using Cox proportional hazard model. Improvement of predictive accuracy by including CT findings was evaluated from reclassification [net reclassification indices (NRI) and integrated discrimination improvement (IDI)] standpoints.
Results: During the follow-up period, 9 cardiac events (cardiac death: 0, nonfatal myocardial infarction: 2, hospitalization for unstable or progressive angina: 7) occurred. Multivariate Cox proportional hazard analysis demonstrated that CACS (HR, 13.23; 95% CI, 1.62–107.78, p＜0.0164) and CT-HRP (HR, 11.27; 95% CI, 1.24–102.12, p＜0.0321) were the independent predictors of cardiac events. NRI was 0.9556 (p＜0.0007) and IDI was 0.2582 (p＜0.0203), and the diagnostic performance improved by CT-HRP added to the combination of CACS and FRS.
Conclusion: Although the cardiac event rate was low, the evaluation of CCTA plaque characteristics may provide incremental prognostic value to CACS in asymptomatic patients.
Aim: Cigarette smoking is one of the major risk factors for cardiovascular diseases and induces deleterious vascular damage. Oxidative stress is involved in vascular inflammation, the process of atherosclerosis. The purpose of the present study was to investigate whether the effects of oxidative stress on the arterial wall differ between smokers and non-smokers.
Methods: Male smokers and non-smokers without physical deconditioning who visited Enshu hospital for an annual physical check-up were enrolled in the study. To assess oxidative stress, serum levels of derivative reactive oxygen metabolites (d-ROM) were measured. The radial augmentation index (RAI) was measured using an automated device and was used as an index for arterial stiffness.
Results: Univariate and multivariate linear regression analysis showed that RAI was independently associated with d-ROM levels only in smokers. Moreover, RAI was significantly higher in smokers than in non-smokers. Logistic regression analysis with the endpoint of a higher RAI than the mean revealed that older age (＞65 years), hypertension, and smoking were independently associated with higher RAI. Similarly, logistic regression analysis with the endpoint of higher d-ROM levels than the mean showed that older age and smoking were independently associated with higher d-ROM levels.
Conclusions: Increased RAI is significantly associated with smoking and, in smokers, with increased d-ROM levels. These results suggest that the effects of oxidative stress on arterial properties differ between smokers and non-smokers and that oxidative stress is closely associated with arterial stiffness, especially in smokers.
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.
Aims: Excessive consumption of sugar-sweetened beverages (SSBs) may increase the prevalence of obesity and other metabolic risk factors. However, data regarding the relationship between SSB consumption and metabolic risk factors are insufficient in Chinese children. Hence, we aimed to explore the association between SSB consumption and cardio-metabolic risk factors in children aged 7–18 years living in South China.
Methods: A cross-sectional study was conducted in a total of 2,032 children aged 7–18 years were enrolled, including 1,013 boys and 1,019 girls. Based on a multistage cluster sampling, five elementary and four secondary schools in Guangzhou, China were included. Fasting blood glucose levels, lipid profiles, and anthropometric characteristics were evaluated. Information on demography, dietary, and physical activities were self-reported.
Results: Overall, 34.7% participants were non-drinkers and 21.6% consumed more than 120 mL/day SSB. The body mass index (19.43±0.18 kg/m2) and triglyceride concentration (0.96±0.03 mmol/L) were higher and high-density lipoprotein concentration (1.32±0.31 mmol/L) was lower in consumers than in non-consumers (all P＜0.001). Furthermore, in contrast to non-consumers, the adjusted odds ratio of SSB consumption more than 120 mL/day was 2.08 (95% CI: 1.21–3.54) for obesity, 1.83 (95% CI: 1.25–2.69) for abdominal obesity, and 1.70 (95% CI: 1.02–3.06) for hypertriglyceridemia in consumers.
Conclusion: A positive association between SSB consumption and the risks of obesity and hypertriglyceridemia was observed in children living in South China, which suggests that high SSB consumption enhances the risk of cardio-metabolic risk factors and the consequent cardio-metabolic diseases.
Aim: Smoking cessation is particularly important for maintaining health; however, the subsequent risk of an increased body weight is of major concern. The present study investigated the influence of smoking cessation on the incidence of metabolic syndrome and its components in the Japanese general population.
Methods: This study enrolled individuals without metabolic syndrome or a history of smoking via our annual health checkup program (n=5,702, 55.2±11.5 years). Participants were divided into three groups mentioned below and followed up with the endpoint being the development of metabolic syndrome: (1) subjects who had never smoked and did not smoke during the observation period (non-smoker); (2) those who continued smoking during the observation period (continuous smoker); and (3) those who ceased smoking during the observation period (smoking cessation).
Results: During the observation period (median 1,089 days), 520 subjects developed metabolic syndrome, and Kaplan–Meier analysis showed a higher incidence of metabolic syndrome in the smoking cessation group than in the other groups. Smoking cessation was confirmed as an independent predictor of the new onset of metabolic syndrome by multivariate Cox proportional hazard analysis after adjustment. Subjects only from the smoking cessation group showed a significant deterioration in metabolic factors during the study in correlation with an increased waist circumference after smoking cessation.
Conclusions: Smoking cessation without instruction could be followed by the development of metabolic syndrome, and the incidence of metabolic syndrome might reduce the benefit obtained from smoking cessation. Therefore, further educational outreach is needed to prevent the progression of metabolic syndrome during the course of smoking cessation.
Aim: Statins have a protective impact against cardiovascular diseases through not only lipid-lowering effects but also pleiotropic effects, including activation of the endothelial nitric oxide synthase (eNOS) system. We aimed to clarify the protective effects of a statin against atherogenesis and ischemia in eNOS－/－ mice.
Methods: Study 1. eNOS－/－Apolipoprotein E (ApoE)－/－ mice were treated with a vehicle or pitavastatin (0.3 mg/kg/day) for 4 weeks. Study 2. eNOS－/－ mice were also treated with a vehicle or the same dose of pitavastatin for 2 weeks prior to hind-limb ischemia.
Results: In Study 1, pitavastatin attenuated plaque formation and medial fibrosis of the aortic root with decreased macrophage infiltration in eNOS－/－ApoE－/－ mice. PCR array analysis showed reductions in aortic gene expression of proatherogenic factors, including Ccl2 and Ccr2 in pitavastatin-treated double mutant mice. In addition, pitavastatin activated not only atherogenic p38MAPK and JNK but also anti-atherogenic ERK1/2 and ERK5 in the aorta of the double mutant mice. In Study 2, pitavastatin prolonged hind-limb survival after the surgery with increased BCL2-to-BAX protein ratio and inactivated JNK. Enhanced expression of anti-apoptotic genes, including Vegf, Api5, Atf5, Prdx2, and Dad1, was observed in the ischemic limb of pitavastatin-treated eNOS－/－ mice. Furthermore, pitavastatin activated both aortic and skeletal muscle AMPK in the eNOS-deficient vascular injury models.
Conclusion: Pitavastatin exerts eNOS-independent protective effects against atherogenesis and hind-limb ischemia in mice, which may occur via modifications on key molecules such as AMPK and diverse molecules.
Aim: A successful antegrade wire crossing for femoro-popliteal chronic total occlusion (FP-CTO) is still a technical challenge. We attempted to demonstrate the safety and feasibility of the OUTBACK® Elite reentry catheter and the bi-directional approach for failed FP-CTO cases with the antegrade approach.
Methods: Endovascular therapy for FP-CTO was performed in 219 lesions from May 2013 to December 2016 at Morinomiya Hospital. We retrospectively analyzed the data of 43 consecutive lesions which underwent endovascular therapy using the bi-directional approach with distal access and the mono-directional approach with the OUTBACK® Elite reentry catheter for FP-CTO lesions. The antegrade success using a combination of traditional and Intravascular Ultrasound (IVUS) -guided techniques was achieved in 170 lesions out of a total of 219 lesions. From May 2013 to June 2016 (phase 1), the bi-directional approach with distal access was applied to 22 lesions after failed antegrade approaches. From July 2016 to December 2016 (phase 2), the mono-directional approach with the OUTBACK® Elite reentry catheter was applied to 21 lesions.
Results: Clinical and lesion characteristics in phase 1 were not significantly different from those in phase 2. The overall initial technical success rate was 100% in both phases. The total wire number and amount of contrast media were significantly less, and the total procedure time and the total fluoroscopic time were significantly shorter in phase 2 than in phase 1 (p＜0.01).
Conclusions: Endovascular therapy for FP-CTO using the OUTBACK® Elite reentry catheter is feasible and safe after a failed antegrade approach.
Aim: Accelerated thrombin action is associated with insulin resistance. It is known that upon activation by binding to dermatan sulfate proteoglycans, heparin cofactor Ⅱ(HCⅡ) inactivates thrombin in tissues. Because HCⅡ may be involved in glucose metabolism, we investigated the relationship between plasma HCⅡ activity and insulin resistance.
Methods and Results: In a clinical study, statistical analysis was performed to examine the relationships between plasma HCⅡ activity, glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and homeostasis model assessment-insulin resistance (HOMA-IR) in elderly Japanese individuals with lifestyle-related diseases. Multiple regression analysis showed significant inverse relationships between plasma HCⅡ activity and HbA1c (p=0.014), FPG (p=0.007), and HOMA-IR (p= 0.041) in elderly Japanese subjects. In an animal study, HCⅡ＋/＋ mice and HCⅡ＋/− mice were fed with a normal diet or high-fat diet (HFD) until 25 weeks of age. HFD-fed HCⅡ＋/− mice exhibited larger adipocyte size, higher FPG level, hyperinsulinemia, compared to HFD-fed HCⅡ＋/＋ mice. In addition, HFD-fed HCⅡ＋/− mice exhibited augmented expression of monocyte chemoattractant protein-1 and tumor necrosis factor, and impaired phosphorylation of the serine/threonine kinase Akt and AMP-activated protein kinase in adipose tissue compared to HFD-fed HCⅡ＋/＋ mice. The expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase was also enhanced in the hepatic tissues of HFD-fed HCⅡ＋/− mice.
Conclusions: The present studies provide evidence to support the idea that HCⅡ plays an important role in the maintenance of glucose homeostasis by regulating insulin sensitivity in both humans and mice. Stimulators of HCⅡ production may serve as novel therapeutic tools for the treatment of type 2 diabetes.
Aim: Both the ankle brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are surrogates for atherosclerosis. In this study, we aimed to evaluate the ability of ABI and baPWV to predict stroke outcome in patients with first-ever non-cardioembolic stroke.
Methods: This study included consecutive patients with first-ever non-cardioembolic stroke admitted within 1 week after onset to Ota Memorial Hospital between January 2011 and December 2013. Baseline characteristics and National Institutes of Health stroke scale scores at admission were noted. ABI and baPWV were evaluated within 5 days of admission. The patients were categorized according to ABI (cut-off 0.9) and baPWV (cut-off 1870 cm/s) determined using the receiver operation curve for poor outcome. Clinical outcomes were defined based on the modified Rankin scale (mRS) scores 3 months after stroke onset as good (0 and 1) or poor (2–6).
Results: A total of 861 patients were available for evaluation. ABI ＜0.9 and baPWV ＞1870 cm/s were associated with poor outcome in the univariate analysis (p＜0.001 and p＜0.001, respectively). After adjusting for factors that showed differences between groups, ABI ＜0.9 was associated with poor outcome. Among patients with ABI ≥ 0.9, higher baPWV showed a slight association with poor outcome after adjustment [odds ratio 1.46 (95% CI 0.95–2.27)].
Conclusion: Our study suggests that the stroke outcome can be predicted using ABI and to an extent using baPWV when ABI ≥ 0.9 in patients with non-cardioembolic stroke.
Aim: We have recently established a novel swine model for studies of atherosclerosis using MicrominipigsTM (µMPs) fed a high-fat/high-cholesterol diet (HcD). Using this swine model, we re-evaluated the effects of dietary cholic acid (CA) on serum lipid profile, atherosclerosis and hepatic injuries.
Methods: The µMPs were fed HcD supplemented with 0.7% CA (HcD＋CA) for eight weeks, and the effect of CA on serum lipoprotein levels, expression of oxidative stress markers, adiposity and lesion formation in the aorta, liver, and other organs was investigated.
Results: The HcD＋CA-fed group exhibited more visceral adiposity, progression of atherosclerosis and higher serum levels of oxidative stress markers than the HcD-fed group, even though they showed similar serum lipid levels. The liver demonstrated increased lipid accumulation, higher expression of oxidative stress markers, accelerated activation of foamy Kupffer cells and stellate cells, and increased hepatocyte apoptosis, indicating non-alcoholic fatty liver disease (NAFLD). Intriguingly, foamy macrophage mobilization was observed in various organs, including the reticuloendothelial system, pulmonary capillary vessels and skin very often in HcD＋CA-fed µMPs.
Conclusion: To our knowledge, this is the first large animal model, in which visceral obesity, NAFLD and atherosclerosis are concomitantly induced by dietary manipulation. These data suggest the detrimental effects of CA, potentially through local and systemic activation of oxidative stress-induced signaling to macrophage mobilization, on the acceleration of visceral adiposity, atherosclerosis and NAFLD.
Aim: Many cohort studies have shown that increased trans fatty acid (TFA) intake increases the risk of developing coronary heart disease. However, whether TFA intake is directly associated with the development of diabetes mellitus (DM) remains unknown.
Methods: We performed the 75-g oral glucose tolerance test in two Japanese cohorts: a cohort of 454 native Japanese living in Hiroshima, Japan, and a cohort of 426 Japanese-Americans living in Los Angeles, USA, who shared identical genetic predispositions but had different lifestyles. Serum elaidic acid concentration was measured and compared, and its association with insulin resistance was assessed.
Results: Serum elaidic acid concentrations were significantly higher in the Japanese-Americans (median, 18.2 µmol/L) than in the native Japanese (median, 11.0 µmol/L). The serum elaidic acid concentrations in the native Japanese DM group (16.0 µmol/L) were significantly higher compared with those in the normal glucose tolerance (10.8 µmol/L) and impaired glucose tolerance (11.7 µmol/L) groups. Multiple linear regression analyses showed that serum elaidic acid concentrations were significantly positively associated with homeostasis model assessment for insulin resistance (HOMA-IR) values after adjusting for various factors.
Conclusions: These results suggest that excessive TFA intake worsens insulin resistance and increases the risk of developing DM even in the native Japanese, whose intakes of animal fat and simple carbohydrates were presumed to be lower than those of the Japanese-Americans.
Aims: Recent studies suggested that subclasses of high-density lipoprotein (HDL) may be a better biomarker to predict the risk of atherosclerotic disorders. We aimed to examine the association of HDL2- and HDL3-cholesterol (HDL2-C and HDL3-C) with carotid intima-media thickness (IMT) using a new method to quantify the HDL-C subclasses.
Methods: Participants were 657 Japanese subjects (434 women) who received a health examination (mean age: 73 years). Serum samples were analyzed by the homogenous assay for HDL-C and HDL3-C. HDL2-C was calculated indirectly by subtracting HDL3-C from HDL-C. HDL3-C measured by this assay was well correlated with that measured by ultracentrifugation (r=0.898, p＜0.001). The maximum IMT (max-IMT) and plaque score (PS) were evaluated by ultrasonography following the standard protocol.
Results: HDL3-C was associated with age both in men (r=－0.322, p＜0.0001) and women (r=－0.315, p＜0.0001). In a simple regression analysis, max-IMT showed an inverse association with HDL3-C, whereas no significant association was observed with HDL2-C. A multiple linear regression analysis indicated, however, that the association between HDL3-C and max-IMT was not significant in both aged and younger populations when age was included in the analysis. Further, not only HDL2-C but also HDL3-C was not a significant predictor of ‘atherosclerotic arteries' defined as the max-IMT ≥1.5 mm. Similar results were observed in the analysis on PS.
Conclusions: Neither HDL3-C nor HDL2-C was significantly associated with carotid atherosclerosis in the Japanese population in this study.
Aim: We have conducted medical surveys on two Japanese populations (Japanese Americans living in the US and native Japanese living in Japan) to investigate the impact of westernization of lifestyles on diseases in Japanese people. A 1998 survey revealed that the progression of carotid intima-media wall thickness (IMT) was faster by approximately 20 years in Japanese Americans than in native Japanese. In this study, we compared the progression of atherosclerosis in native Japanese versus that in Japanese Americans using carotid IMT data from medical examinations conducted in the 2010s.
Methods: This study included 115 native Japanese living in Hiroshima who underwent a medical examination in 2014 and 112 Japanese Americans living in Hawaii who underwent a medical examination in 2012, excluding those receiving medication for diabetes mellitus (DM) or dyslipidemia. Carotid IMT was compared between the two Japanese populations.
Results: Serum total and low-density lipoprotein cholesterol levels were significantly higher in native Japanese than in Japanese Americans. The median carotid IMT was significantly greater in Japanese Americans than in native Japanese [median (25th-75th percentile): 1.27 (0.86-2.02) mm vs. 1.00 (0.80-1.30) mm, P =0.001]. Regression curves showed that the age at which IMT exceeded 1.1 mm was estimated at ＞50 years in Japanese Americans and at approximately 60 years in native Japanese.
Conclusions: According to surveys conducted in 2012 and 2014, carotid IMT was still greater in Japanese Americans than in native Japanese. However, a comparison with data from the 1998 survey showed that current native Japanese had higher serum lipid levels and more advanced atherosclerosis.
Aim: To examine the association between the serum endostatin levels and subclinical atherosclerosis independent of traditional risk factors in a healthy Japanese population.
Methods: Among 1,057 residents who attended free public physical examinations between 2010 and 2011, we evaluated the data of 648 healthy residents for whom the serum endostatin level and common carotid intima-media thickness (IMT) were successfully measured.
Results: The median endostatin level was 63.7 ng/mL (interquartile ranges: 49.7–93.2 ng/mL), and the mean carotid IMT was 0.68±0.12 mm. Residents with above median endostatin had significantly higher carotid IMT than did those with below median endostatin (0.71±0.14 vs. 0.65±0.09 mm, P＜0.001). Multiple linear regression analysis demonstrated that increased serum endostatin is significantly associated with carotid IMT (above vs. below median endostatin level; beta=0.11, P=0.03), independent of the known covariates of age, sex, body mass index, drinking and smoking status, systolic blood pressure, diastolic blood pressure, hemoglobin A1c, low density lipoprotein cholesterol, estimated glomerular filtration rate, and log-transformed high sensitive C-reactive protein.
Conclusions: A higher serum endostatin level reflected subclinical atherosclerosis in this Japanese population.
Aim: To study atherosclerosis risk in diabetes, we investigated ATP-binding cassette transporter A1 (ABCA1) expression and high-density lipoprotein (HDL) biogenesis in the liver and hepatocytes under hyperglycemic conditions.
Methods and Results: In streptozotocin-induced diabetic mice, plasma HDL decreased while ABCA1 protein increased without changing its mRNA in the liver, only in the animals that responded to the treatment to show hypoinsulinemia and fasting hyperglycemia but not in the poor responders not showing those. To study the mechanism for this finding, hepatocytes were isolated from the control and diabetic mice, and they showed no difference in expression of ABCA1 protein, its mRNA, and HDL biogenesis in 1 g/l d-glucose but showed decreased HDL biogenesis in 4.5 g/l d-glucose although ABCA1 protein increased without change in its mRNA. Similar findings were confirmed in HepG2 cells with d-glucose but not with l-glucose. Thus, these cell models reproduced the in vivo findings in hyperglycemia. Labeling of cell surface protein revealed that surface ABCA1 decreased in high concentration of d-glucose in HepG2 cells despite the increase of cellular ABCA1 while not with l-glucose. Immunostaining of ABCA1 in HepG2 cells demonstrated the decrease of surface ABCA1 but increase of intracellular ABCA1 with high d-glucose. Clearance of ABCA1 was retarded both in primary hepatocytes and HepG2 cells exposed to high d-glucose but not to l-glucose, being consistent with the decrease of surface ABCA1.
Conclusions: It is suggested that localization of ABCA1 to the cell surface is decreased in hepatocytes in hyperglycemic condition to cause decrease of HDL biogenesis.
Aims: Tartrate-resistant acid phosphatase (TRACP)-5b and osteoprotegerin (OPG) are specific and sensitive markers of bone resorption in patients with rheumatoid arthritis (RA) and chronic kidney disease (CKD). The TRACP-5b level is associated with the severity of RA and CKD, while the OPG level is associated with the severity of coronary atherosclerosis and calcification, and can predict a poor outcome in patients with coronary artery disease (CAD). However, the impact of TRACP-5b on coronary atherosclerosis in CAD patients remains unclear.
Methods: A total of 71 CAD patients (57 men, 14 women; mean age: 69.0±9.7 years) and 28 age- and gender- matched healthy subjects were investigated. The number of diseased vessels (a marker of the severity of coronary atherosclerosis) and the Gensini score (a marker of the extent of coronary atherosclerosis), as well as the OPG and TRACP-5b levels were measured in CAD patients. The TRACP-5b levels were classified into quartiles.
Results: The TRACP-5b levels were significantly higher in CAD patients than in healthy subjects. Patients with higher TRACP-5b levels had higher OPG levels and Gensini scores than those with lower TRACP-5b levels. Higher TRACP-5b levels were associated with an increased number of diseased vessels. A multivariate linear regression analysis showed that the OPG level and the number of diseased vessels or the Gensini score were significantly and independently associated with the TRACP-5b level.
Conclusions: These data indicate that the TRACP-5b level is significantly associated with the OPG level and with the severity and extent of coronary atherosclerosis in CAD patients.
Aim: Myriad biological effects of leptin may lead to broad therapeutic applications for various metabolic diseases, including diabetes and its complications; however, in contrast to its anorexic effect, the molecular mechanisms underlying adipopenic and glucose-lowering effects of leptin have not been fully understood. Here we aim to clarify the role of hormone-sensitive lipase (HSL) in leptin's action.
Methods: Wild-type (WT) and HSL-deficient (HSLKO) mice were made hyperleptinemic by two commonly-used methods: adenovirus-mediated overexpression of leptin and continuous subcutaneous infusion of leptin by osmotic pumps. The amount of food intake, body weights, organ weights, and parameters of glucose and lipid metabolism were measured.
Results: Hyperleptinemia equally suppressed the food intake in WT and HSLKO mice. On the other hand, leptin-mediated fat loss and glucose-lowering were significantly blunted in the absence of HSL when leptin was overexpressed by recombinant adenovirus carrying leptin. By osmotic pumps, the fat-losing and glucose-lowering effects of leptin were milder due to lower levels of hyperleptinemia; although the difference between WT and HSLKO mice did not reach statistical significance, HSLKO mice had a tendency to retain more fat than WT mice in the face of hyperleptinemia.
Conclusions: We clarify for the first time the role of HSL in leptin's effect using a genetic model: leptin-promoted fat loss and glucose-lowering are at least in part mediated via HSL-mediated lipolysis. Further studies to define the pathophysiological role of adipocyte lipases in leptin action may lead to a new therapeutic approach to circumvent leptin resistance.
Aim: Fast-progressing vascular calcification (VC) is accompanied by renal atrophy and functional deterioration along with atherosclerosis in patients with chronic kidney disease (CKD). However, the relationship between VC progression and renal functional and/or morphological changes remains unclear.
Methods: We included 70 asymptomatic patients with CKD without hemodialysis in our study. To identify temporal variations, the coronary artery calcification score (CACS), abdominal aortic calcification index (ACI), and renal parenchymal volume index (RPVI) were determined via spiral computed tomography scans taken during the study. We investigated significant factors related to annualized variations of CACS (ΔCACS/y) and ACI (ΔACI/y).
Results: During the follow-up period (4.6 years), median values of CACS [in Agatston units (AU)] and ACI increased from 40.2 to 113.3 AU (p=0.053) and from 13.2 to 21.7% (p=0.036), respectively. Multivariate analysis revealed that CACS at baseline (p＜0.001) and diabetes mellitus (DM) status (p=0.037) for ΔCACS/y and ACI at baseline (p=0.017) and hypertension (HT) status (p= 0.046) for ΔACI/y were significant independent predictors. Furthermore, annualized RPVI variation was significantly related to both ΔCACS/y and ΔACI/y (R=−0.565, p＜0.001, and R=−0.289, p=0.015, respectively). On the other hand, independent contributions of the estimated glomerular filtration rate (eGFR) and annualized eGFR variation to VC progression were not confirmed.
Conclusion: The degree of VC at baseline, DM, HT, and changes in renal volume, but not eGFR, had a strong impact on VC progression in patients with CKD.
Aim: Polyunsaturated fatty acids (PUFAs) take part in various biological events linked to the pathogenesis of venous thromboembolism (VTE), including inflammation, endothelial dysfunction, and hypercoagulability. Several studies have demonstrated the association between PUFAs and the occurrence of VTE. However, the role of PUFAs in the pathogenesis of VTE remains unclear.
Methods: We enrolled 45 patients with acute VTE and 37 age-, gender-, and body mass index-matched healthy volunteers to examine their PUFA levels. Serum omega 3 (eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) and omega 6 (dihomogammalinolenic acid: DGLA and arachidonic acid: AA) fatty acids levels were measured within 24 h of admission.
Results: Patients with VTE showed significantly higher AA and lower EPA levels, and lower EPA/AA ratios than the controls. Multivariate analysis revealed that AA was an independent marker for VTE. In addition, we divided the patients based on their median age (58 years old). The younger patients with VTE showed significantly lower EPA/AA levels than their age-matched controls, whereas older patients with VTE showed a significantly higher AA/DGLA levels than the older controls.
Conclusions: High serum AA levels and low EPA levels are associated with the development of acute VTE, suggesting that the imbalance of PUFAs may be a potential therapeutic target for preventing acute VTE.
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