The clinical efficacy of fish oil and high-purity eicosapentaenoic acid ethyl ester (hp-EPA-E) for treating cardiovascular disease (CVD) has been reported. Fish oil contains saturated and monounsaturated fatty acids that have pharmacological effects opposite to those of ω3 fatty acids (ω3). Moreover, ω3, such as EPA and docosahexaenoic acid (DHA), do not necessarily have the same metabolic and biological actions. This has obscured the clinical efficacy of ω3. Recently, the Japan EPA Lipid Intervention Study (JELIS) of hp-EPA-E established the clinical efficacy of EPA for CVD, and higher levels of blood EPA, not DHA, were found to be associated with a lower incidence of major coronary events. A significant reduction in the risk of coronary events was observed when the ratio of EPA to arachidonic acid (AA) (EPA/AA) was ＞0.75. Furthermore, the ratio of prostaglandin (PG) I3 and PGI2 to thromboxane A2 (TXA2) ([PGI2＋PGI3]/TXA2) was determined to have a linear relationship with the EPA/AA ratio as follows: (PGI2＋PGI3)/TXA2 =λ＋π＊ (EPA/AA). Like PGI2, PGI3 not only inhibits platelet aggregation and vasoconstriction, but also is assumed to reduce cardiac ischemic injury and arteriosclerosis and promote angiogenesis. Thus, the effects of EPA in reducing the risk of CVD could be mediated by biological action of PGI3 in addition to hypotriglyceridemic action of EPA. Compared with DHA, EPA administration increases the EPA/AA ratio and the (PGI2＋PGI3)/TXA2 balance to a state that inhibits the onset and/or progression of CVD.
Aim: Both oxidized LDL and carbamylated LDL are considered important for initiating atherosclerosis in patients with end-stage kidney disease through vascular endothelial cell dysfunction or injury. However their effects on each other and their relationship related to pro-atherosclerotic effects on endothelial cells and macrophages have not been investigated. In this study, we analyzed the competition between LDL carbamylation and oxidation, tested biological effects of carbamylated-oxidized LDL (coxLDL) toward the endothelial cells, assessed its ability to cause foam cell development, and determined the roles of scavenger receptors in this process. Methods: Cross-competition between carbamylation and oxidation of LDL particles was tested using cell-free fluorescent ligand-receptor assay. Pro-atherogenic properties (cell proliferation, cytotoxicity, and foam cell formation) of all LDL isoforms were tested in vitro and ex vivo using endothelial cells and peritoneal macrophages. In addition, coxLDL was assessed in human sera and in vivo atherosclerotic plaques which were developed in mouse model of uremia-induced atherosclerosis. Results: Our data suggest that there is potential competition between carbamylation and oxidation of LDL, and that oxidation is a much stronger inhibitor of carbamylation than vice versa. coxLDL is highly cytotoxic to endothelial cells and strongly induce their proliferation measured by DNA synthesis. All three tested LDL isoforms demonstrated strong ability for transformation of primary mouse peritoneal macrophages to foam cells using predominantly CD36 scavenger receptor. coxLDL was the most potent inducer of foam cell development and macrophages/foam cell injury assessed by cell count and TUNEL, respectively. Finally, LDL particles modified by oxidation and carbamylation were detected in blood and shown to co-localize in atherosclerotic plaques in mice. Conclusion: Our study demonstrated that LDL particles can be simultaneously carbamylated and oxidized and modifications are likely coexisting in the same LDL particle. We also demonstrated proatherosclerotic properties of coxLDL and proposed its role in atherosclerosis.
Aim: Alogliptin, an efficacious inhibitor of DPP-4 that improves glycemic control, as well as the pancreatic beta-cell function, is now increasingly used to accomplish glycemic targets in type 2 diabetic patients. Interestingly, recent experimental studies have shown that alogliptin exerts anti-atherosclerotic effects in GLP-1-dependent and -independent manners. The aim of the present ongoing study is to investigate the preventive effects of alogliptin on the progression of atherosclerosis in type 2 diabetic subjects using the carotid intima-media thickness (IMT), an established marker of cardiovascular disease. Methods and Results: The Study of Preventive Effects of Alogliptin on Diabetic Atherosclerosis (SPEAD-A) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between March 2011 and March 2012, 341 participants were recruited at 11 clinical sites, and were randomly allocated either to an alogliptin treatment group (172 patients) or a conventional treatment group (169 patients). The primary outcomes are the changes in the maximum and mean IMT of the common carotid artery during a 24-month treatment period, as measured by carotid arterial echography. The secondary outcomes include the changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, the occurrence of cardiovascular events and adverse events and biochemical measurements reflecting vascular function. Conclusions: This is the first study to address the effects of DPP-4 inhibitors on the progression of changes in the carotid IMT, with the patients without DPP-4 inhibitor treatment serving as a control group. The results will be available soon, and these findings are expected to provide clinical data that will be helpful in the prevention of diabetic atherosclerosis and subsequent cardiovascular disease.
Aim: To clarify whether the cardio-ankle vascular index (CAVI) independently contributes to the development of exudative age-related macular degeneration (AMD) compared with carotid arteriosclerosis parameters and other risk factors. Methods: Eighty-eight consecutive patients with exudative AMD were enrolled. A control group (40 age-matched men, 65 years of age or older) was also evaluated, and the parameters were compared between the two groups. A logistic regression analysis was used to determine independent factors for the diagnosis of AMD. In addition, simple linear and multiple regression analyses were used to determine the relationships between the CAVI and other parameters. Results: The carotid intima-media thickness and plaque scores in the AMD group did not differ significantly from those observed in the control group. The CAVI in the AMD group was significantly (p=0.01) higher than that observed in the control group. A logistic regression analysis showed that the CAVI (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.26-7.20; p=0.007) and the use of lipid-lowering drugs (OR, 0.29; 95% CI, 0.10-0.86; p=0.03) independently contributed to the diagnosis of AMD. Age, the high-sensitivity C-reactive protein level and the incidence of exudative AMD each independently contributed to the CAVI. Conclusions: The CAVI is more significantly associated with exudative AMD than carotid atherosclerosis parameters. The overall arterial stiffness is correlated with the pathogenesis of exudative AMD. The CAVI is a useful marker of exudative AMD in elderly patients with arteriosclerosis risk factors.
Aim: The cardio-ankle vascular index (CAVI) reflects arterial stiffness from the aorta to the ankle, independent of blood pressure (BP). We investigated the age-stratified CAVI in healthy, normotensive individuals to evaluate the effects of age on arterial stiffness. Methods: The CAVI and peripheral BP were determined in healthy, normotensive Koreans 20 to 79 years of age. The subjects had no history of cardiovascular disease and did not take any medications for hypertension, diabetes mellitus or dyslipidemia (N=1,380; 44.1% in men). Results: The mean systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were 117, 75 and 42 mmHg, respectively. The CAVI increased linearly with age and was determined using the following equation: CAVI=5.0＋0.048×age (year) in men (r2=0.395, p＜0.001), CAVI=4.8＋0.045×age (year) in women (r2=0.450, p＜0.001). However, SBP, DBP and PP did not change progressively with age. Age emerged as the major determinant of the CAVI in a stepwise multiple regression analysis (r2 change=43.1%). Conclusions: The CAVI scores increased with age in the healthy, normotensive individuals, whereas SBP, DBP and PP did not. Age was the dominant risk factor for the progression of arterial stiffness. These data suggest that the CAVI is a sensitive marker of the arterial aging process, above and beyond conventional upper arm BP.
Aim: Several factors contribute to the development of atherogenesis in patients with obesity. The aim of our study was to evaluate the different roles of insulin resistance, strictly correlated to visceral adiposity, and the body mass index (BMI), an estimate of overall adiposity, on early vascular impairment in patients with morbid obesity. Methods: We enrolled 65 morbidly obese subjects (BMI 44.6±7 kg/m2) who were free of previous cardiovascular events and 28 nonobese subjects (control group) in a cross-sectional study. The presence of glycemia and insulinemia, the levels of lipids and liver parameter and the ultrasonographic assessment of the flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) and visceral fat area (VFA) were evaluated in all subjects. Results: In the obese patients with a median HOMA value of ≥3.5, the FMD was significantly lower (p＜.05) and the left carotid maximum-IMT was significantly higher (p＜.05) than those observed in the group with lower HOMA values. No vascular differences were found between the two groups that were subdivided according to the BMI median value.
Both the left max-IMT and FMD exhibited a significant correlation with HOMA-IR (“ρ”.292, p=0.02 , “ρ”－.292, p=0.02 respectively) but not with BMI. According to a multivariate analysis, the VFA was an independent predictor of a reduced FMD (β－.541, p.002; p of the model .002), while age (β .611 p＜.0001) and HOMA-IR (β .399 p＜.001) were independent predictors of the left max-IMT (p of the model .002). Conclusions: The HOMA-IR, which is strictly related to visceral fat and is an index of metabolic impairment, and not BMI, which reflects of global adiposity, can be used to identify early vascular impairment in patients with morbid obesity.