Although the Japan Atherosclerosis Society guideline for the diagnosis and prevention of atherosclerosis cardiovascular diseases for the Japanese population provides targets for low-density lipoprotein (LDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol to prevent cardiovascular disease in patients with dyslipidemia, there is no guideline specifically targeting the treatment of type IIb dyslipidemia, which is one of the most common types of dyslipidemia, along with type IIa and type IV dyslipidemia. Type IIb dyslipidemia is important because it sometimes accompanies atherogenic lipid profiles, such as small, dense LDL, remnants, low HDL cholesterolemia. It is also associated with type 2 diabetes mellitus, metabolic syndrome, and chronic kidney disease (CKD), and most patients with familial combined hyperlipidemia (FCHL) show this phenotype; therefore, it is assumed that patients with type IIb dyslipidemia have a high risk for cardiovascular disease. Thus, the management of type IIb dyslipidemia is very important for the prevention of cardiovascular disease, so we have attempted to provide a guideline for the management of type IIb dyslipidemia.
Aim: Transforming growth factor-beta (TGF-β) plays important role in atherogenesis via TGF-β receptors and Smad proteins, which determine its signaling activity. In this study, we hypothesized, whether non-lipid related effects of atorvastatin, affect both endoglin/ALK-5/Smad2/eNOS and/or endoglin/ALK-1/Smad1/VEGF previously proposed pathways in ApoE/LDLR double knockout mice. Methods: ApoE/LDLR double knockout mice were divided into two groups. The chow group (CHOW) (n =8) was fed with chow diet, while in the atorvastatin group (ATV) (n =8) atorvastatin was added to the chow diet at dose 50 mg/kg/day. Biochemical analyses of lipid profile, lesion area measurement, immunohistochemistry and Western blot analysis of endoglin, ALK-1, 5, phosphorylated and non-phosphorylated forms Smad-1, 2, VEGF and eNOS proteins in mice aorta were performed. Results: Biochemical analysis of blood serum and morphometric analysis of aortic lesion size showed that atorvastatin treatment resulted in a significant increase of cholesterol levels and simultaneously in reduced lesion size in aortic sinus when compared to CHOW mice. Western blot analysis revealed that atorvastatin treatment significantly increase the expressions of endoglin by 102%, ALK-1 by 113%, ALK-5 by 296%, pSmad-1 by 202%, pSmad-2 by 34%, VEGF by 68% and eNOS by 687% as compared with CHOW mice. Immunofluorescence staining revealed endoglin coexpression with all studied markers that were increased by atorvastatin treatment mainly in endothelial cells covering atherosclerotic plaques. Conclusion: This study shows that atorvastatin treatment increases the expression of endoglin, ALK-1, ALK-5, phosphorylated forms of Smad1 and Smad2, VEGF and eNOS and reduces atherosclerotic lesion size beyond its lipid lowering effects. Therefore, we propose that endoglin related receptors and signal transducers might play protective role in atherogenesis.
Aim: Formula diet (FD), which is used as a tool for calorie restriction, has beneficial effects on metabolic disorders in obese patients; however, the molecular mechanism is not fully understood. Methods: Sixteen-week-old male Zucker Diabetic Fatty (ZDF) rats were divided into 3 groups (n= 10 each): calorie-controlled low-fat diet [Control; 75 kcal/day, protein : fat : carbohydrate (P:F:C)=25:15: 60], calorie-restricted low-fat diet (CR-LFD; 56 kcal/day, P:F:C=25:15:60), and calorie-restricted FD (CR-FD; 56 kcal/day, P:F:C=50:14:36) group, and fed each diet for 4 weeks. Before the study, baseline data were obtained in 10 rats. After 4 weeks, body weight and epididymal fat weight were measured, and blood samples, mesenteric and subcutaneous adipose tissues were collected for analyses. Messenger RNA expression was evaluated by real-time PCR, and protein expression by Western blotting. Results: The decrease in epididymal fat weight was significantly greater in the CR-FD group than in control and CR-LFD groups, although changes in body weight were not different among groups. The decrease in fasting plasma glucose and increase in plasma adiponectin were greater in the CR-FD group than in the control group, but not in the CR-LFD group. The decrease in triglyceride and increase in HDL-cholesterol were greatest in the CR-FD group. Both mRNA and protein of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, adiponectin, lipoprotein lipase and PPARγ were overexpressed in the CR-FD group, especially in mesenteric adipose tissue. Conclusions: FD may have beneficial effects on abdominal obesity and metabolic disorders by reducing visceral fat and improving glucose and lipid profiles, possibly through modulating adipose tissue function.Key words; Formula diet, High protein diet, Low carbohydrate diet, Obesity, Zucker diabetic fatty rat
Aim: Atherosclerotic lesions contain DNA signatures from a wide variety of bacteria, although little is known of how exposure to these organisms may modulate the accumulation of lipids in macrophages. Methods: To address this, a panel of nine bacteria representing those most frequently reported to be present in human atheroma were examined for their potential to promote lipid accumulation in human primary monocytes and murine J774 macrophages. Results: All bacteria examined, and defined stimulants of Toll-like receptors (TLRs) 2, 3, 4, 5 and 9, induced lipid body formation and cholesterol ester accumulation in a dose-dependent manner. The mechanisms of bacteria-mediated foam cell formation were found to be dependent on TLR2 and/or TLR4 signalling, but independent of lipoprotein oxidation pathways, since lipid accumulation was significantly inhibited by the TLR4 inhibitors polymyxin-B and TAK-242, or the TLR2 and TLR4 inhibitor oxidised palmitoyl-arachidonyl-phosphatidyl-choline, but not by the scavenger receptor blocker polyinosinic acid or the antioxidant butylated hydroxytoluene. A number of genes involved in lipid body biosynthesis, including perilipin-A, stearoyl-coenzyme-A desaturase 1, fatty acid synthase and HMG-CoA reductase were upregulated in response to TLR4 stimulation. Conclusions: The bacterial debris observed in human atheroma, which is currently considered to be harmless, may have potential to contribute to disease progression via TLR-dependent lipid body formation in macrophages.
Aims: Circulating endothelial progenitor cells (EPCs) were mobilized in cardiac ischemia, heart failure and vascular injuries associated with endothelial damage. Despite the occurrence of endothelial dysfunction in peripheral artery disease (PAD), few data are available on EPC mobilization in this setting. Methods: We investigated the correlations between EPC and disease severity and also other biomarkers in PAD. EPCs assessed as CD34+ cells co-expressing CD45dim, CD133 and vascular endothelial growth factor receptor-2 were studied in PAD (n =48) and non-PAD (n =22) patients. Membrane type-1 matrix metalloproteinase (MT1-MMP) on peripheral blood mononuclear cells, serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) and plasma pentraxin-3 were also measured. Results: The EPC level changed in the Fontaine and Trans-Atlantic Inter-Society Consensus (TASC) II classification. EPC was increased in Fontaine class IIa as compared with class IV and non-PAD patients (p < 0.05). EPCs and pentraxin-3 were increased in TASC II type A/B as compared with type C/D and non-PAD patients (p < 0.05), whereas the expression of MT1-MMP on peripheral blood mononuclear cells was significantly decreased in TASC II type A/B (both p < 0.05 versus type C/D and non-PAD patients). The EPC level showed a positive association with pentraxin-3 (r = 0.31; p < 0.05). There was an inverse association between the EPC level and MT1-MMP (r = −0.54; p < 0.01). The cardiovascular events was associated with reduced EPC and increased MDA-LDL (p < 0.05). Conclusion: EPC changed according to the Fontaine and TASC II classification and decreased in the advanced phases, and was associated with novel biomarkers and related to the severity of PAD.
Aim: The present study aimed to determine the up-to-date prevalence, awareness, treatment, and control of dyslipidemia, and their distribution and related influencing factors in adults in Beijing, China. Method: A cross-sectional study was conducted in 2008, using a four-stratified cluster sampling. Data from a questionnaire, physical examination, and blood sampling were obtained from 5761 adults aged 18-79 years. Results: The prevalence of high TC, high LDL-C, low HDL-C and TG was 12.2%, 17.9%, 12.0% and 15.1%, respectively. The prevalence of dyslipidemia was 35.4% (42.9% in men and 30.1% in women), and was similar in rural (35.3%) and urban (35.8%) areas. Dyslipidemia was associated with male gender, age, a family history of dyslipidemia, education at college or above, current smoker, overweight and obesity, intermediate and high waist circumference, hypertension and diabetes. Among all participants with dyslipidemia, 22.2% were aware of the diagnosis, 10.2% were receiving treatment, and 3.8% had dyslipidemia controlled. The proportion of those aware of their condition and those who were treated increased with age in both sexes. Of those aware of their dyslipidemia, 46.1% were on treatment, 51.0% had modified their lifestyle, and 24.5% were not receiving treatment or modifying their lifestyle. Conclusions: The major type of dyslipidemia in Beijing is high LDL-C rather than high TG. The prevalence of dyslipidemia is similarly high in rural and urban areas, with low awareness, treatment and control. A comprehensive strategy toward the prevention, screening, treatment, and control of dyslipidemia is needed to slow the epidemic of cardiovascular disease.
Aim: There are currently no data on ethnic differences in aortic atherosclerosis in Arab and Jewish patients from northern Israel with acute ischemic stroke. Methods: Data on demographic and risk factors alongside transesophageal echocardiography (TEE) data and treatment details for 509 patients with acute ischemic stroke were included in the study. Results: The patients with aortic atheromas were older and had significantly more frequent vascular risk factors (hypertension, hyperlipidemia, and smoking), as well as vascular disease (ischemic heart disease, peripheral vascular disease, and carotid plaques). They were also treated with statins more often than those without aortic atheroma. Logistic regression analysis showed that age, smoking, ethnicity, and the presence of carotid plaques were independent predictors for aortic atheromas. Aortic plaques were found more frequently in Jewish patients than Arab patients (160 (41.9%) vs. 35 (27.3%); p= 0.003). This finding did not change after adjustment for age, sex, all vascular risk factors, and type of antithrombotic treatment. We did not find any difference between Arab and Jewish patients in the distribution of plaques by location or complexity before and after adjustment for age, sex, all vascular risk factors, or type of antithrombotic or lipid-lowering treatment. Conclusions: Our findings emphasize the influence of ethnicity on the prevalence of aortic atheromas in acute ischemic stroke patients in northern Israel. The search for genetic, cultural, socioeconomic, and other factors explaining these ethnic differences should be the topic of future studies.
Aim: Low-density lipoprotein cholesterol (LDL-C), the ratio of LDL-C to high-density lipoprotein cholesterol (HDL-C; LDL-C/HDL-C), and non-HDL-C were evaluated to determine their ability to predict cardiovascular disease (CVD) risk with pravastatin treatment. Methods: We conducted a large-scale randomized primary prevention trial in Japan (MEGA Study), in which we randomly allocated 7832 mild hypercholesterolemic patients to diet alone (n= 3966) and diet plus pravastatin groups (n= 3866) and followed them for an average of 5 years. We compared baseline levels and the CVD incidence in the diet alone group, and time-dependent receiver operating characteristic curves in the overall population. To determine the best parameter for predicting the efficacy of pravastatin, the diet plus pravastatin group was divided into tertiles to compare lipid parameters and CVD incidence versus the diet alone group. Results: Significantly graded correlations were found between CVD and LDL-C/HDL-C and non-HDL-C. Significantly more CVD events were associated with LDL-C/HDL-C > 186 mg/dL and LDL-C/HDL-C > 2.9. Furthermore, LDL-C/HDL-C or non-HDL-C was more predictive than LDL-C. By measuring LDL-C/HDL-C or non-HDL-C, we allocated 32% of the diet plus pravastatin group into a different risk category. The lowest significant incidence of CVD was found in patients with LDL-C 119.8-133.4 mg/dL, LDL-C/HDL-C < 1.9, and non-HDL-C 145.2-160.8 mg/dL. Conclusion: Non-HDL-C and LDL-C/HDL-C have a greater ability to predict CVD risk in mild-to-moderate hypercholesterolemic Japanese individuals than LDL-C, and are more useful to evaluate the effect of pravastatin; however, these parameters should be interpreted independently when assessing CVD risk.
Aim: Clopidogrel, an essential drug for the prevention of stent thrombosis, is a prodrug activated by CYP enzyme family including CYP2C19. It is known that activity-defective polymorphisms of CYP2C19 (CYP2C19*2 and*3) are associated with reduced clopidogrel efficacy and poor prognosis. Recently, the 13C-pantoprazole breath test is developed to evaluate the CYP2C19 activity. The aim of this study is to evaluated the efficiency of the CYP2C19 activity test as a predictor of antiplatelet effect of clopidogrel Methods: The CYP2C19 activity and the antiplatelet effect of clopidogrel were evaluated in 27 healthy volunteers. Change of the carbon isotope ratios (13CO2/12CO2) in expiration gas between before and after 13C-pantoprazole intake was evaluated as delta over baseline (DOB) ratio (‰). Results: DOB at 30 min was significantly lower in poor metabolizers (PMs) than extensive metabolizers (EMs) and intermediate metabolizers (IMs) (EM vs. PM, p=0.0108; IM vs. PM, p=0.016). The antiplatelet effect of clopidogrel was significantly different in three groups (inhibition of platelet aggregation: p=0.0148, P2Y12 reaction unit: p=0.0241). DOB at 30 min was correlated with the antiplatelet effect of clopidogrel. A cut-off value of DOB at 30 min below 1.0‰ predicted PMs with 96% specificity and 100% sensitivity. Conclusions: The 13C-pantoprazole breath test can detect CYP2C19 PMs and predict low responders to clopidogrel rapidly.
Aim: The present study examined the importance of reducing non-high-density lipoprotein cholesterol (non-HDL-C) for the primary prevention of the occurrence of coronary artery disease (CAD) in the JELIS, and the effects of EPA. Methods: The patients were distributed into 4 subgroups using the lipid management goal for LDL-C recommended by the Japan Atherosclerosis Society guideline (2007) and the goal for non-HDL-C defined as 30 mg/dL higher than LDL-C: A) achieved both goals; B) achieved the LDL-C but not non-HDL-C goal; C) achieved the non-HDL-C but not LDL-C goal; and D) did not attain either goal. The incidences of CAD in the 4 subgroups were compared, and the effects of eicosapentaenoic acid (EPA) on the risk of CAD in these subgroups were examined. Results: In the non-EPA group, the incidence of CAD in patients who did not achieve the goals for LDL-C or non-HDL-C was higher than in patients who achieved those goals. Patients in subgroups B, C, and D were at higher risk for CAD than those in subgroup A (B, HR 2.31; C, HR 1.90; D, HR 2.47). EPA reduced the risk of CAD by 38% in subgroups B, C, and D (p= 0.007). Conclusion: We reconfirmed non-HDL-C as a predictor of the risk for CAD and a residual risk marker of CAD after LDL-C-lowering therapy. EPA was useful to reduce the occurrence of CAD in patients who did not achieve the goals for LDL-C and/or non-HDL-C.