Aim: Experimental studies of human atherogenesis require an appropriate animal model that mimics human physiology and pathology. Because swine physiology is similar to human physiology, we developed a hyperlipidemia-induced atherosclerosis model using the recently developed world’s smallest MicrominipigTM. Methods: These animals weigh only 5kg at 3months of age, much smaller than any other miniature pig. We found that the administration of a high-fat/high-cholesterol diet containing at least 0.2% cholesterol without cholic acid for as little as eight weeks induces hypercholesterolemia and subsequent atherosclerosis in these animals. Results: The serum levels of low-density lipoprotein cholesterol(LDL-C) and the percent distribution of cholesterol in the LDL fractions were markedly increased. The hepatic expression of LDL receptor and hydroxymethylglutaryl-CoA reductase was coordinately decreased. The cholesteryl ester transfer protein activity, which plays a role in reverse cholesterol transport, was detected in the serum of the Microminipigs. Niemann-Pick C1-like 1 protein was expressed in both the liver and small intestine; however, hepatic apoB mRNA editing enzyme was not expressed. As in humans, and in contrast to that observed in mice, most of the hepatic lipase activity was localized in the liver. These results suggest that the hyperlipidemia-induced gene expression profile linked to cholesterol homeostasis and atherogenesis is similar in Microminipigs and humans. Conclusion: We conclude that the characteristics of the Microminipig, including its easy handling size, make it an appropriate model for studies of atherosclerosis and related conditions.
Aim: As the major atheroprotective particle in plasma, high-density lipoprotein(HDL) is oxidized during atherosclerotic processes. Oxidized HDL(ox-HDL) may lose its cardioprotective properties and develop a proinflammatory and proatherogenic phenotype. The proliferation and migration of vascular smooth muscle cells(VSMCs) play a crucial role in atherogenesis. However, the influence of ox-HDL on VSMC proliferation and migration remains poorly understood.
Methods: VSMCs were treated with native HDL(N-HDL) or ox-HDL at varying concentrations for different time intervals and used in several analyses. The degree of cell proliferation was assayed using CCK-8 kits. The level of cell migration was determined using a Transwell chamber and scratch-wound assay. The presence of intracellular reactive oxygen species(ROS) was detected based on ROS-mediated 2’,7’-dichlorofluorescein fluorescence. The activation of NADPH oxidase was measured in terms of the Rac1 activity and NADP＋/NADPH ratio. Results: Compared to N-HDL, ox-HDL significantly promoted VSMC proliferation and migration in a dose-dependent manner. In addition, ox-HDL remarkably activated NADPH oxidase and enhanced ROS generation in the VSMCs. Diphenyleneiodonium chloride, an inhibitor of NADPH oxidase, and N-acetylcysteine, a ROS scavenger, efficiently inhibited the ROS production triggered by ox-HDL and subsequently blocked the proliferating and migrating effects of ox-HDL in the VSMCs. Conclusions: Ox-HDL significantly induces VSMC proliferation and migration by promoting NADPH oxidase activation and ROS production. Furthermore, the inhibition of NADPH oxidase and ROS generation blocks the proliferation and migration of VSMCs induced by ox-HDL. These proliferating and migrating effects of ox-HDL are closely related to its proinflammatory and proatherogenic roles.
Aim: To assess the long-term effects of intracoronary stem cell (SC) infusion following acute myocardial infarction (AMI) on the local atherosclerotic process at the site of infusion after four years of follow-up. Methods: We evaluated 18 post-AMI patients. Group 1 consisted of nine patients given an intracoronary injection of autologous mononuclear SC, and group 2 consisted of nine patients given a placebo injection. The plaque count, plaque burden (PB) and coronary calcium score (CCS) were assessed using multislice 64 CT angiography of the coronary tree four years after SC injection. Results: The total PB and CCS along the entire coronary segment distal to the site of infusion were significantly lower in the SC group (PB-702 mm3 vs. 1.465 mm3, p=0.0006; CCS-295 vs. 796, p＜ 0.0001).The mean PB per coronary artery was 112.12 mm3±16.82 mm3 for the treated arteries vs. 189.56 mm3±20.98 mm3 for the untreated arteries (p＜0.0001), while the mean CCS was 53.12±16.4 vs. 106.43±10.86 (p＜0.0001). In the SC group, there were significant differences in the mean PB (87.75 mm3 vs. 112.12 mm2, p= 0.005) and mean CCS (36.87 vs. 53.12, p=0.04) between the coronary segment infused with SC and the entire coronary artery. Conclusions: Multislice CT angiography of atheromatous plaques in the coronary tree four years after SC infusion in post-AMI patients indicates a significantly lower atheromatous plaque burden, as demonstrated by a lower plaque volume and lower CCS at the site of stem cell infusion compared with other coronary territories.
Aim: Data regarding the prognostic value of peripheral endothelial function testing in patients with cardiovascular disease are conflicting. Peripheral arterial tonometry(PAT) is increasingly used to measure the peripheral endothelial function. The prognostic value of this method has not been investigated thus far in patients with cardiovascular disease and/or a high cardiovascular risk profile. Methods: In 96 patients with significant coronary artery disease(CAD) or＜70% stenosis and ≥ three cardiovascular risk factors, reactive hyperemia was induced following upper arm occlusion and the PAT-ratio between baseline and hyperemia was calculated. The patients were followed for cardiovascular events(revascularization, acute coronary syndrome, ischemic stroke, cardiovascular death, repeat coronary angiography due to chest pain) for 44±14 months. The first event was included in the combined end point. Results: The study cohort was divided according to the median PAT-ratio(1.91). The combined end point occurred in 14 patients with a PAT-ratio below the median(1.91) and in 12 patients with a PAT-ratio of ≥1.91 (p=0.65). In a subgroup of 76 patients, the PAT-ratio was reassessed after six months. No differences in the event rate were found between the patients who exhibited deterioration(n=50) and those who exhibited an improvement in the PAT-ratio of ＞0.1(n=26; 22 vs. 32%, p=0.32). The combined end point occurred earlier in the patients with a PAT-ratio within the 1st tertile than in those with a PAT-ratio within the 2nd/3rd tertile(11.3±11.0 vs. 27.5±18.6 months, p=0.03). Conclusions: In patients with established CAD or a high cardiovascular risk profile, the PAT-ratio cannot be used to predict the risk of future cardiovascular events. However, a lower PAT-ratio may be associated with the earlier occurrence of cardiovascular events.
Aim: Previous meta-analyses have demonstrated an increased risk of adverse events in aspirin-resistant patients. In this meta-analysis, we aimed to update clinical evidence regarding the relationship between aspirin resistance and major adverse cardiovascular events (MACEs) in patients with coronary heart disease (CHD) on confirmed aspirin adherence. Methods: An electronic literature search of PubMed, EMBASE, Web of Science and the Cochrane Library and a hand search of bibliographies through April 2013 were conducted. Studies were included if they prospectively investigated the association between aspirin resistance and the risk of adverse cardiovascular events during follow-up in CHD patients, mentioned confirmed compliance and provided adequate data for a statistical analysis. Results: Nine prospective studies with a total 1,889 CHD patients who were followed for one month to 2.5 years and study sample sizes ranging from 86 to 496 patients were identified. Overall, 622 of the 1,889 CHD patients (33.0%) were classified as being aspirin resistant with confirmed aspirin adherence. The aspirin-resistant patients exhibited a significantly higher risk of adverse events than the aspirin-sensitive patients (odds ratio 2.44, 95% confidence interval 1.81 to 3.30; p＜0.00001). Conclusions: Among CHD patients, approximately one in three individuals can be diagnosed as aspirin resistant on confirmed aspirin adherence. Patients identified as having laboratory aspirin resistance exhibit a 2.4-fold increased risk of MACE compared with aspirin-sensitive patients.
Aim: Previous epidemiological studies demonstrated that the ratio of n-6 to n-3 polyunsaturated fatty acids is associated with cardiovascular diseases. We herein investigated whether the beneficial effect of highly purified eicosapentaenoic acid(EPA) on arterial stiffness is associated with changes in the ratio of polyunsaturated fatty acids, such as EPA, docosahexaenoic acid(DHA) and dihomo-γ-linolenic acid(DGLA), relative to arachidonic acid(AA), in obese Japanese patients with dyslipidemia. Methods: The EPA/AA, DHA/AA and DGLA/AA ratios were compared between obese patients with(n=94) and without (n=31) dyslipidemia. Among the former group, 88 patients received either highly purified EPA treatment(1.8g daily, n=45) or treatment without EPA(control, n=43). Results: At baseline, the ratios of DHA/AA and DGLA/AA were significantly(P＜0.05) higher in obese patients with dyslipidemia than in those without, while the EPA/AA ratio was similar between patients with and without dyslipidemia. EPA significantly reduced the hemoglobin A1c, total cholesterol, triglycerides, CRP, cardio-ankle vascular index(CAVI)(an index of arterial stiffness) and the DGLA/AA ratio relative to the control at three months after the treatment. On the other hand, EPA significantly increased the adiponectin level and EPA/AA ratio(P＜0.05). A multivariate regression analysis revealed that only age, an increase in the EPA/AA ratio and a decrease in the CRP level were significant determinants of a reduction of the CAVI by EPA. Conclusion: These findings suggest that EPA improves the arterial stiffness in association with an increase in the EPA/AA ratio and a decrease in inflammation in obese patients with dyslipidemia.
Aim: The appropriate selection of hospitalized patients for venous thromboembolism(VTE) prophylaxis is an important unresolved issue. We sought to validate the Caprini model, a famous individual VTE risk assessment model(RAM), in hospitalized Chinese patients. Methods: We performed a retrospective case-control study among unselected hospitalized patients admitted to a comprehensive hospital in China. A total of 347 patients were confirmed to have VTE during hospitalization, and 651 controls were randomly selected to match the patients according to medical service. Both the patients and controls were retrospectively assessed for the risk of VTE using the Caprini RAM. Results: The average Caprini cumulative risk score in the patients was significantly higher than that observed in the controls(4.69±2.58 vs 3.16±1.82, p＜0.0001). Compared with that observed in the low-risk group, a classification of high-risk according to the Caprini model was associated with a 1.65-fold increased risk of VTE(95%CI 1.05-2.61), while that of highest-risk was associated with a 4.84-fold increased risk of VTE(95%CI 3.06-7.64). After further stratifying the highest risk level with a cumulative risk score of ≥5 into scores of 5-6, 7-8 and ≥9, the patients with a score of 5-6 were found to exhibit a 3.33-fold increased risk of VTE(95%CI 2.06-5.40), those with a score 7-8 exhibited a 9.41-fold increased risk of VTE(95%CI 4.90-18.08) and those with a score of ≥9 exhibited a 24.69-fold(95%CI 7.98-76.40) increased risk of VTE compared with their low-risk counterparts. Conclusions: Our study suggests that the Caprini RAM can be used to effectively stratify hospitalized Chinese patients into VTE risk categories based on individual risk factors. The classification of the highest risk level with a cumulative risk score of ≥5 provided significantly more clinical information, and further stratification of this group of patients is needed.
Aims: To explore the association between resistin expression and the incidence of ischemic heart disease in the general population. Methods: A follow-up study of 6636 adults recruited randomly from the general population. Results: The serum resistin concentration was higher in women (6.1 ng/mL; CI95%=6.0-6.2) than in men (5.6 ng/mL; CI95%=5.5-5.7). Individuals in the 5th quintile or higher of resistin (RQ5) were younger (P＜0.001) and had a lower prevalence of arterial hypertension (P＜0.001), abdominal obesity (P＜0.001), diabetes (P＜0.001) and dyslipidemia (P＜0.001). The cardiovascular risk estimated by the Framingham function was also lower in the RQ5 subgroup (P＜0.001); however, the prevalence of smoking was higher (P＜0.001), as was the prevalence of low HDL cholesterol (P＜0.001). After 3.5 years of follow-up, the RQ5 subgroup had a higher incidence of acute myocardial infarction (AMI, RR=1.9; CI95%=1.01-3.54). In the population without diabetes, the RQ5 subgroup had a higher risk of AMI (RR=2.4; CI95%=1.10-5.17), and the risk of AMI was highest in women in this group (4.97; CI95%=1.33-18.57). The risk levels were significant in the Cox models adjusted for age, sex and smoking; and the hazard ratio was 2.5 for AMI (CI95%=1.29-4.70) in the sample of patients matched by sex and smoking status. Conclusions: Resistin may be a risk marker for ischemic heart disease in the general population. The serum resistin concentration is higher in women, and the associated increase in the risk of AMI based on the resistin level is also higher in women than in men.
Aim: Lipid accumulation product (LAP) is a new continuous marker of lipid overaccumulation that predicts cardiovascular risk. The aim of this study was to determine the cutoff value for LAP and evaluate its usefulness. Methods: Using a database of results of health checkup examinations for 10,170 Japanese workers (35-40 years of age) conducted at their workplaces, the cutoff value for a high LAP was calculated by analyzing receiver-operating characteristic (ROC) curves for the relationships of LAP with hyperglycemia and diabetes. Results: The cutoff value for LAP was 21.1 for women and 37.2 for men. The values were similar when calculated by analyzing the ROC curves for the relationships with hyperglycemia and diabetes. Using these cutoff values, the prevalence of a high LAP was calculated to be 23.7% in women and 28.8% in men. The odds ratio for diabetes in the subjects with vs. those without a high LAP, calculated after adjusting for age, smoking, alcohol consumption and regular exercise, was 19.09 (95% CI: 6.57-55.50) in women and 7.40 (95% CI: 5.10-10.75) in men. High odds ratios for hypertension (10.66 [95% CI: 7.77-14.63] in women and 7.31 [95% CI: 6.20-8.62] in men) were also obtained in the subjects with vs. those without a high LAP. Conclusions: Cutoff values for a high LAP in women and men were determined, and high odds ratios for diabetes and hypertension were obtained using the cutoff values for LAP. Further studies are needed to elucidate whether the proposed cutoff values are applicable to people of other ages, races and ethnicities.