Atherosclerosis is a leading cause of mortality and long-term morbidity worldwide. It is a lipoprotein-driven disease that leads to plaque formation at focal areas in the arterial blood vessels through intimal inflammation, necrosis, fibrosis, and calcification. Adventitial and intimal angiogenesis contributes to the progression of intimal hyperplasia and the development of a necrotic core. The volatile nature of an atheromatous plaque is responsible for approximately 60% of symptomatic carotid artery diseases and about 75% of acute coronary events. In this review the pathogenesis of atherosclerosis is discussed from the initial step of lipid retention to advanced stages of immune-mediate inflammation and associated angiogenesis. Mechanisms of plaque rupture are also discussed.

View full abstract

Aim: Selective PPARα modulators (SPPARMα) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARMα K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out.
Methods: Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARMα on the liver gene expression.
Results: Consequently, a cell-based transactivation assay showed that K-877 activates PPARα with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid β-oxidative genes in human hepatocytes and the mouse liver. Almost all genes up- or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly induced in the K-877-treated mouse liver, but not human hepatocytes, thus suggesting that the clinical dose of K-877 may not induce peroxisome proliferation or liver toxicity in humans. Notably, K-877 significantly induces the expression of clinically beneficial target genes (VLDLR, FGF21, ABCA1, MBL2, ENPEP) in human hepatocytes.
Conclusion: These results indicate that changes in the gene expression induced by K-877 treatment are mainly mediated through PPARα activation. K-877 regulates the hepatic gene expression as a SPPARMα and thus may improve dyslipidemia as well as metabolic disorders, such as metabolic syndrome and type 2 diabetes, without untoward side effects.

View full abstract

Aim: The role of platelet-derived microparticles (PDMPs) in the crosstalk between coagulopathy and inflammation in critically ill patients remains unclear. The aim of this cohort observational study was to investigate the associations between the PDMP levels and hospital mortality or disseminated intravascular coagulopathy (DIC).
Methods: This study included 119 patients who were admitted to the ICU. The PDMP levels were measured using an enzyme-linked immunosorbent assay three times a week, for a total of 372 samples. We calculated the maximum (max) PDMP value, max PDMP/platelet (PDMP/Plts) ratio (converted to the PDMP levels per 10⁴ platelets) and nadir platelet count during the ICU stay. Baseline patient data and scores, including the Japanese Association for Acute Medicine (JAAM) DIC score, were collected, and potential predictors were analyzed for possible associations with hospital mortality.
Results: The max PDMP/Plts ratio was significantly different comparing the survivors (n=98: median, 2.54) and non-survivors (n=21: median 17.59; p＜0.001). There was a weak but statistically significant negative correlation between the max PDMP level and nadir platelet count (r=-0.332, p＜0.001). The max PDMP level and max PDMP/Plts ratio were higher in the DIC group (81.48 and 9.27, respectively) than in the non-DIC group (34.88 and 2.35, p=0.001 and p＜0.001, respectively). The max PDMP/Plts ratio was the only variable found to be independently associated with hospital mortality according to a multivariate logistic regression analysis.
Conclusions: PDMPs are involved in the development of DIC but are not related to hospital mortality. There is a good association between the PDMP/Plts ratio and hospital mortality and/or DIC in critically ill patients.

View full abstract

Aim: Intravascular ultrasound (IVUS) is a useful modality for visualizing atherosclerotic lesions in coronary arteries, not only for the degree of arterial luminal stenosis but also for the plaque composition within the vessel walls. We aimed to determine the relationship between the clinical parameters and coronary plaque characteristics evaluated by IVUS in patients with stable angina under medical treatment.
Methods: Plaque measurements within the coronary arteries were collected by coronary angiography and iMAP-IVUS in 40 men with stable angina. The serum remnant-like cholesterol (RemL-C) was measured using homogeneous assays and serum adiponectin and omentin-1 levels were measured by enzyme-linked immunosorbent assays.
Results: The iMAP-IVUS analysis of the coronary arteries demonstrated that the plaque cross-sectional area (CSA) was 11.0±3.5 mm². Plaque CSA positively correlated with body mass index and negatively correlated with the serum adiponectin levels. Both areal and volumetric analyses of the plaque characteristics demonstrated that the serum RemL-C level was a positive determinant for %Necrosis and the negative determinant for %Fibrosis of the plaques. Neither serum high-density lipoprotein cholesterol nor low-density lipoprotein cholesterol levels correlated with the proportion of any plaque components. Additionally, the RemL-C/triglyceride ratio positively correlated with %Lipid significantly in the areal analysis.
Conclusion: Elevation of the serum RemL-C levels in the patients with stable angina may link to coronary plaque vulnerability, which is characterized by high necrotic and low fibrotic components.

View full abstract

Aim: Previous studies on the association between the SLCO1B1 521 T＞C and 388 A＞G polymorphisms and statin effectiveness have been inconsistent. We performed this meta-analysis to provide a more comprehensive estimation of this issue.
Methods: Multiple electronic literatues databases were searched on March 5th 2014. A quality assessment was performed using the Methodological Index for Non-Randomized Studies (MINORS) criteria. A meta-analysis, sub-group analysis, sensitivity analysis (RevMan 5.2), publication bias measuring and meta-regression analysis were conducted utilizing the Stata software program (version 12.0).
Results: A total of 13 studies were included in the final meta-analysis, which included 7,079 participants. Overall, there was no statistically significant association in the four genetic models of hypolipidemic effect. For the 521 T＞C polymorphism, significant associations were found for the long-term effectiveness of lowering the low-density lipoprotein cholesterol (LDL-C) and in non-Asian populations in the dominant model [(CC＋TC vs. TT: mean difference (MD)=1.44, 95% CI: 0.25-2.64,p=0.02) and (CC＋TC vs. TT: MD=1.38, 95% CI: 0.28-2.49, p=0.01)], the recessive model [(CC vs. TT＋TC: MD=3.31, 95% CI: 0.09-6.54, p=0.04) and (CC vs. TT＋TC: MD=2.83, 95% CI: 0.26-5.41, p=0.03)], and the homozygote comparison [(CC vs. TT: MD=3.68, 95% CI: 0.42-6.94,p=0.03) and (CC vs. TT: MD=3.33, 95% CI: 0.67-5.99, p=0.01)], respectively. There were no significant differences for the other analyses of the 521 T＞C polymorphism or all the analyses of the 388 A＞G polymorphism.
Conclusions: The overall results suggest that the SLCO1B1 521 T＞C and 388 A＞G polymorphisms do not affect the lipid-lowering effectiveness of statins. However, allele C of the SLCO1B1 521 T＞C polymorphism leads to an attenuated effect on lowering the LDL-C in non-Asian populations and the long-term effectiveness of statin treatment.

View full abstract

Aim: The immune system may play an important role in the pathogenesis of cardiovascular disease. T cell-driven inflammation in human hypertension and atherosclerosis has recently been revealed. In the present study, we evaluated the association between serum levels of the C-X-C chemokine receptor type 3 chemokines and the carotid intima media thickness (IMT) in humans.
Methods: One hundred sixty-four consecutive patients undergoing baseline and 2-year follow-up carotid IMT (110 men, 62.4±10.0 years) were enrolled. The maximum carotid IMT (max-IMT) and the mean carotid IMT (mean-IMT) were measured at baseline and after 24 months. Clinical and laboratory variables, including serum levels of the monokine induced by gamma interferon (MIG) and interferon gamma-induced protein 10 (IP-10), were analyzed at the time of initial enrollment.
Results: The baseline max- and mean-IMT were 0.992±0.235 and 0.793±0.191 mm, respectively. The serum levels of MIG and IP-10 significantly correlated with the carotid IMT. However, there was no significant correlation between the serum levels of MIG or IP-10 and IMT changes. A multivariate regression analysis revealed the serum MIG to be independently associated with the carotid IMT (max-IMT: β=0.194, p=0.010; mean-IMT: β=0.184, p=0.016) when controlled for age, sex, diabetes mellitus history, smoking history, body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, and aspirin and statin medication.
Conclusions: Circulating MIG levels are independently associated with the carotid IMT, after adjusting for confounding factors and medications. These findings indicate the potential clinical implication of MIG with respect to early atherosclerosis in humans.

View full abstract

Aim: The carotid intima-media thickness (CIMT) is now validated as a sensitive marker of atherosclerosis and is directly associated with an increased risk of cardiovascular disease. Considering that the independent association between the serum uric acid level and CIMT remains controversial due to the complex interrelationship with other known cardiovascular risk factors, further studies are needed. The aim of the present study is to explore the association between the serum uric acid level and CIMT in a general Chinese population and determine whether the association differs according to varied metabolic status.
Methods: The present study was cross-sectional in design. A total of 10,281 community-based participants 40 years of age or older from Shanghai, China were included in the current analysis. All participants underwent a detailed questionnaire interview, anthropometric measurements and ultrasonography to assess the CIMT. Blood and urine samples were collected for the biochemical measurements.
Results: The serum uric acid levels were positively associated with obesity- and diabetes-related parameters and the CIMT. In a logistic regression model controlling for potential confounders, compared with the participants in the first quartile of the uric acid level, those in the fourth quartile had a higher odds of an elevated CIMT in both men (odds ratio [OR]=1.37; 95% confidence interval [CI]=1.07-1.75) and women (OR=1.48; 95% CI=1.12-1.94). The subgroup analyses revealed that an association between an elevated CIMT and the serum uric acid level persisted regardless of diuretic use and the hypertension, diabetes mellitus and chronic kidney disease status. However, the association disappeared in the patients who consumed alcohol and in premenopausal women.
Conclusions: The serum uric acid level is positively associated with an elevated CIMT in middle-aged and elderly Chinese subjects, independent of known risk determinants of cardiovascular disease.

View full abstract

Aim: Angiotensin Ⅱ(Ang Ⅱ) produces reactive oxygen species (ROS), thus contributing to the development of cardiac hypertrophy and subsequent heart failure, and stimulates the expression of monocyte chemoattractant protein-1 (MCP-1). In addition, Toll-like receptor 4 (TLR4) is involved in the upregulation of MCP-1. In order to clarify whether TLR4 is involved in the onset of cardiac dysfunction caused by Ang Ⅱ stimulation, we investigated the effects of TLR4 on oxidative stress, the MCP-1 expression and cardiac dysfunction in mice with Ang Ⅱ-induced hypertension.
Methods: TLR4-deficient (Tlr4^lps-d) and wild-type (WT) mice were randomized into groups treated with Ang Ⅱ, norepinephrine (NE) or a subdepressor dose of the Ang Ⅱreceptor blocker irbesartan (IRB) and Ang Ⅱ for two weeks.
Results: Ang Ⅱ and NE similarly increased systolic blood pressure in all drug-treated groups compared to that observed in the control group among both WT and Tlr4^lps-d mice (p＜0.05). In the WT mice, Ang Ⅱ induced cardiac hypertrophy as well as vascular remodeling and perivascular fibrosis of the intramyocardial arteries and monocyte/macrophage infiltration in the heart (p＜0.05). Furthermore, Ang Ⅱ treatment decreased the left ventricular diastolic function and resulted in a greater left ventricular end-systolic dimension (p＜0.05) in addition to producing a five-fold increase in the NADPH oxidase activity, ROS content and MCP-1 expression (p＜0.05). In contrast, the Tlr4^lps-d mice showed little effects of Ang Ⅱ on these indices. In the WT mice, IRB treatment reversed these changes compared to that seen in the mice treated with Ang Ⅱ alone. NE produced little effect on any of the indices in either the WT or Tlr4^lps-d mice.
Conclusions: TLR4 may be involved in the processes underlying the increased oxidative stress, selectively activated MCP-1 expression and cardiac hypertrophy and dysfunction seen in cases of Ang Ⅱ- induced hypertension.

View full abstract

Aim: Chronic kidney disease (CKD) is known to frequently cause cardiovascular events. However, it is unclear how renal dysfunction affects the vascular response. We herein studied the effects of renal dysfunction on the aortic behavior in adenine-fed mice, investigating mechanisms underlying the occurrence of cardiovascular events in CKD patients.
Methods: Biochemical analyses of the plasma creatinine, blood urea nitrogen (BUN) and glucose levels and measurements of the blood pressure were performed using C57BL/6 mice fed with and without an adenine-containing diet. The relaxing effects of acetylcholine (ACh) or sodium nitropurusside (SNP) and effects of NO synthase (NOS) inhibitors on the contractions induced by phenylephrine (PE) were measured in endothelium-intact aortas obtained from both mice.
Results: The mice fed 0.25% adenine for four weeks showed greater plasma creatinine and BUN concentrations than the control mice, suggesting that adenine-fed mice are a useful CKD model. Furthermore, ACh relaxed the PE-stimulated, endothelium-intact aortas, the effect of which was less potent in the adenine-fed mice than in the control mice. In contrast, the degree of SNP-induced relaxation of the aortas was the same in the adenine-fed mice and control mice. The α₁-adrenergic agonist, PE, induced more potent absolute tension of the endothelium-intact aortas in the CKD model mice than in the control mice, while the NOS inhibitors, N-nitro-L-arginine (LNA) and asymmetric dimethylarginine (ADMA) enhanced the contraction effects of PE in both mice.
Conclusions: The findings of this study indicate that spontaneous and stimulated NO release from the endothelium is decreased in the CKD model mouse aorta. The NO-mediated correlation between renal and elastic arterial endothelial dysfunction is suggested to be a cause of cardiovascular events in patients with CKD.

View full abstract

Aim: The prevalence of overweight and a change in atherosclerotic lipid profiles may be linked to region-specific differences in atherosclerotic diseases. We evaluated whether the lipid phenotype could be linked to region- and sex-specific differences in the degree of atherosclerosis.
Methods: Non-diabetic subjects included Okinawa (n=1674) and Nagano (n=1392) residents aged 30–75 years who underwent carotid ultrasonography for the measurement of maximum intima-media thickness (max IMT).
Results: Average max IMT was higher in Okinawa men and women, and the increase in max IMT with age was enhanced in men. Multiple regression analysis showed that in addition to age and systolic blood pressure, low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol were IMT determinants only in men for both Okinawa and Nagano. Meanwhile, HDL-cholesterol was a determinant for Okinawa men and women, but not for Nagano men and women.
Conclusions: This is the first report to show region- and sex-specific differences in the determinants for max IMT in a Japanese population. The evaluation of the relationship between lipid profile patterns and region- and sex-specific differences in carotid atherosclerosis burden may be required.

View full abstract