The lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) is a multiligand receptor, whose repertoire of ligands includes oxidized low-density lipoprotein, advanced glycation endproducts, platelets, neutrophils, apoptotic/aged cells and bacteria. Sustained expression of LOX-1 by critical target cells, including endothelial cells, smooth muscle cells and macrophages in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage suggesting the interaction of cellular LOX-1 with its ligands to contribute to the formation and development of atherosclerotic plaques. Studies with transgenic and knockout mouse models have elucidated in part the role of LOX-1 in the pathogenesis of atherosclerosis and cardiac remodeling. Recently, a circulating soluble form of LOX-1 (sLOX-1), corresponding solely to its extracellular domain, has been identified in human serum. Circulating levels of sLOX-1 are increased in inflammatory and atherosclerotic conditions and are associated with acute coronary syndrome, with the severity of coronary artery disease, and with serum biomarkers for oxidative stress and inflammation, suggesting that they could be a useful marker for vascular injury. However, many interesting questions have not yet been answered and in this review, we provide an updated overview of the literature on this receptor and on likely future directions.
Metabolic syndrome is associated with dysfunctional adipose tissue that is most likely a consequence of the enlargement of adipocytes and infiltration of macrophages into adipose tissue. Obesity and ectopic lipid deposition are major risk factors for diseases ranging from insulin resistance to type 2 diabetes and atherosclerosis. Enlargement of adipocytes, due to impaired adipocyte differentiation, leads to a chronic state of inflammation in the adipocytes and adipose tissue with a reduction in the secretion of adiponectin and increase in the secretion of proinflammatory cytokines such as interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1. The secretion of cytokines like tumour necrosis factor (TNF)- α, mainly from macrophages, enhances local inflammation. These proinflammatory cytokines might also substantially affect cardiovascular function and morphology. Furthermore, a proinflammatory state in adipose tissue can lead to local insulin resistance with an impaired inhibitory effect of insulin on the release of FFAs and endothelial dysfunction that clearly promotes cardiovascular diseases and type 2 diabetes. The underlying mechanisms of ectopic fat accumulation in various tissues and the impact on metabolic syndrome and its association with insulin resistance are discussed.
Aim: The aim of this study was to clarify the relationship between platelet-derived microparticles (PDMPs) and the Framingham 10-yr coronary heart disease (CHD) risk score. Methods: A cross-sectional study of healthy volunteers free of medication, and cardiovascular or cerebrovascular disease was conducted. The subjects were 190 Japanese men (median age 41). An ELISA kit and monoclonal antibodies against CD42b and CD42a (glycoprotein Ib and IX) were used. Results: PDMPs are correlated with platelet count, high sensitivity C-reactive protein (hsCRP), and diastolic blood pressure by multivariate analysis (R2=0.316, p <0.001). Quartile range of PDMPs is significantly associated with the 10-yr CHD risk score after adjusting for age, platelet count, hsCRP, and hypertension (p=0.033) and for age, platelet count, hsCRP, and presence of metabolic syndrome (MS) (p=0.020). In individuals with a predicted 10-yr risk for CHD ≥8% (corresponding with the highest quartile), compared to those with a predicted 10-yr risk <8%, the odds ratio (OR), adjusted for age, platelet count, hsCRP, and hypertension, was 3.3 (1.2-8.9) and adjusted for age, platelet count, hsCRP, and MS, was 4.5 (1.6-11.8). The age-, platelet count-, hsCRP- and hypertension-adjusted OR for a 10-yr CHD risk score ≥8% was 0.8 (0.5-1.3) for hsCRP and 3.9 (1.6-9.4) for hypertension. The age-, platelet count-, hsCRP- and MS -adjusted OR for a 10-yr CHD risk score ≥8% was 0.7 (0.4-1.2) for hsCRP and 7.9 (2.6-24.5) for MS. Conclusion: Elevated PDMPs are associated with the 10-yr CHD risk score in healthy men.
Aim: The long-term effect of statin therapy in diabetic patients after coronary revascularization is not well established. Accordingly, we sought to determine if whether statin therapy initiated at the time of complete revascularization including percutaneous coronary intervention (PCI) and/or bypass surgery reduces total and cardiac mortality among diabetic patients. Methods: We collected data from 1,138 consecutive patients who underwent complete revascularization (PCI and/or bypass surgery). We then compared all-cause and cardiac mortality rates in 499 patients with diabetes mellitus of whom 149 (29.9%) were treated with statin at the time of revascularization. To adjust the variables that would have been related to the decision regarding statin administration, a propensity score was computed and multivariate Cox regression was carried out. Results: During follow-up (8.8±2.6 years), 103 patients died (including 43 who died of cardiac causes). The Multivariate analysis showed statin therapy to be significantly associated with reduced cardiac mortality (HR 0.39, 0.16-0.95; p=0.039), but not with all-cause mortality. Conclusion: Statin therapy was associated with a significantly reduced risk of cardiac mortality in patients with diabetes mellitus and coronary artery disease after complete revascularization.
Aim: Ezetimibe is known to target Niemann-Pick Type C1 Like1 (NPC1L1), a key protein in intestinal cholesterol absorption, and thus to decrease serum LDL-cholesterol (LDL-C) levels. The response of serum LDL-C levels to ezetimibe was reported to differe among NPC1L1 haplotypes. We analyzed NPC1L1 genotypes in Japanese and investigated differences in markers of cholesterol synthesis/absorption among the genotypes. Methods: Blood samples were collected from 42 adult volunteers to measure markers of cholesterol synthesis (lathosterol) and absorption (sitosterol and campesterol) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Based on a study by Hegele RA et al. in Canada, we selected three SNPs (1735 C>G, 25342 A>C and 27677 T>C (numbers relative to the transcription start site)) and analyzed them using PCR-RFLP. Results: The frequencies of genotypes were as follows: 1735 C/G (46%)>C/C (35%)>G/G (19%), 25342 A/A (97%)>A/C (3%)>C/C (0%) and 27677 T/T (97%)>T/C (3%)>C/C (0%). Serum campesterol levels were significantly higher in the 1735 G/G group than 1735 C/G+C/C group, but lathosterol levels showed no significant differences between the genotypes. Conclusion: Our results revealed differences in the frequency of the NPC1L1 polymorphism between Japanese and Canadians. In Japanese, the 1735 G/G group showed enhanced cholesterol absorption from the intestine, as compared to the 1735 C/G+C/C group.
Aim: The relationship between psychosocial characteristics and smoking cessation behavior was examined among Japanese male eversmokers with type 2 diabetes mellitus. Methods: The psychosocial characteristics and smoking cessation behavior of 441 male ever-smokers with type 2 diabetes mellitus were investigated. Personality was assessed using an egogram (five ego states: the Critical Parent, Nurturing Parent, Adult, Free Child, and Adapted Child) and each patient was classified into a high score or low score group based on the median. The current smokers were divided into 2 categories according to their readiness to quit smoking. Results: In multivariate analyses, the ever-smokers with a high Adult score had a lower risk of current smoking (OR=0.67, 95%CI=0.41-0.93), the ever-smokers with a high Free Child score were over 3 times more likely to currently smoke (OR=3.12, 95%CI=1.97-4.97), and the ever-smokers who had a low educational background had a higher risk of current smoking (OR=3.02, 95% CI=1.73-5.28). In addition, the current smokers with a high Adult score had a lower risk of being in the immotive and precontemplation stage (OR=0.55, 95%CI=0.24-0.96). The current smokers who had a low educational background had a higher risk of being in the immotive and precontemplation stage (OR=2.13, 95%CI=1.08-5.42). Conclusion: There is a need to develop a smoking cessation program for patients with high “Free Child” scores and a “low education level”.
Aim: We investigated whether nocturnal intermittent hypoxia, a surrogate marker for obstructive sleep apnea, is associated with metabolic syndrome and its components among Japanese. Methods: We examined 1,710 male and 2,896 female community-dwelling Japanese aged 40 to 69, who participated in annual cardiovascular examinations and investigations of sleep. Nocturnal intermittent hypoxia was estimated based on a 3% oxygen desaturation index measured with pulse-oximetry during sleep. No, mild and moderate-to-severe nocturnal intermittent hypoxia were defined by <5, 5 to <15 and ≥15 events/hour, respectively. Metabolic syndrome was defined by modified criteria of the Adult Treatment Panel III guidelines. Results: Compared with no nocturnal intermittent hypoxia, the multivariable odds ratio of metabolic syndrome was 1.9 (95% confidence interval: 1.6-2.4) for mild and 3.2 (2.2-4.7) for moderate-to-severe nocturnal intermittent hypoxia among men; 2.6 (2.1-3.4) and 5.8 (3.4-9.8) among women, respectively. When stratified by overweight status (body mass index ≥25 kg/m2), the multivariable odds ratio of two or more metabolic risk factors (other than overweight) associated with moderate-to-severe nocturnal intermittent hypoxia was 1.9 (1.2-3.1) among non-overweight subjects and 1.4 (0.9-2.1) among overweight subjects (p for interaction=0.002). Conclusions: Nocturnal intermittent hypoxia was associated with the accumulation of metabolic risk factors, especially among non-overweight individuals.
Aim: Based on evidence that ionizing radiation can ameliorate chronic and autoimmune diseases in patients and experimental animals, we investigated the effects of radiation on the induction and development of experimental atherogenesis. Methods: Male New Zealand rabbits were divided into 5 groups and given an atherogenic diet for 90 days. Peritoneal and thoracic areas (9 Gy) were irradiated on the 1st and 45th days for groups 1 and 2, the 45th day for groups 3 and 4, and not at all for group 5. Prior to irradiation, the peritoneal cavity of animals from groups 1 and 3 was washed with buffered saline. Cells collected by peritoneal washing were reinfused into the peritoneal cavity of the same animal after irradiation. Animals from groups 2 and 4 were intraperitoneally injected with saline as a control. Results: Despite similar lipid profiles among the experimental groups, the percentage of aortas covered by plaques was remarkably reduced (p<0.001) among animals submitted to irradiation (groups 2 and 4). These differences were completely abolished in irradiated animals reconstituted with their own peritoneal cells. Conclusions: These findings point to an important role of resident inflammatory peritoneal cells in experimental atherogenesis.
Aim: Pioglitazone, an agonist of peroxisome proliferator-activated receptor γ, showed various anti-atherosclerotic effects on type 2 diabetic patients. This retrospective study was done to ascertain which risk factor(s) associate with anti-atherosclerotic effects of pioglitazone. Methods: We enrolled 160 diabetic patients treated through diet only and 62 treated with pioglitazone and annually evaluated carotid maximum (MaxIMT) and averaged intima-media thickness (AveIMT) for 2 years. We analyzed the relation of 99 single-nucleotide polymorphisms (SNP) as well as conventional risk factors with the progression or regression of carotid atherosclerosis. Results: The D allele of the angiotensin-converting enzyme (ACE) gene and 677 allele of the methyllene-tetrahydrofolate reductase (MTHFR) gene showed a significant association with increases in MaxIMT among the diabetic subjects treated through diet only. The pioglitazone-treated carriers of the D allele showed an attenuation of MaxIMT as compared with the diet-treated carriers. The pioglitazone-treated carriers of the 677T allele carriers showed a significant attenuation of MaxIMT compared with the diet-treated carriers. Conclusions: Pioglitazone may exert anti-atherosclerotic effects on type 2 diabetics carrying the ACE gene's D allele and/or MTHFR gene's 677T allele, who showed a progression of carotid atheroscle-rosis without the drug.
Aim: This study was conducted to investigate the role of chronic kidney disease (CKD) in 1-year allcause mortality and cardiovascular mortality among Chinese patients who were at least 50 years old and had a history of coronary artery disease (CAD), stroke, or peripheral vascular disease (PAD), or with two or more cardiovascular risks. Methods: Of 3,732 hospitalized patients enrolled, 3,423 patients (91.7%) with complete data were eligible for 1-year follow-up. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2. Results: 1,166 (34.1%) were diagnosed with CKD. Most cases were unrecognized. Patients having an eGFR of <30 mL/min/1.73 m2 were less likely to be prescribed beta-blockers, statins, or aspirin (all p<0.001). A powerful relationship was observed between the severity of renal dysfunction and all causes of death or cardiovascular death. Adjusted for other covariates, the hazard ratio (HR) for all causes of death and for cardiovascular death among patients with an eGFR of 30-45 mL/min/1.73 m2 was 1.70 (95% CI, 1.18-2.45) and 1.85 (95% CI, 1.12-3.01) as compared with 2.93 (95% CI, 1.96-4.38) and 3.47 (95% CI, 1.91-6.31) for patients with an eGFR of <30 mL/min/1.73 m2. Conclusions: One third of Chinese patients at high risk for atherosclerotic events were diagnosed with CKD. Most of these cases were unrecognized and undertreated. An eGFR of <45 mL/min/1.73 m2 was an independent predictor of all causes of death and of cardiovascular death.
Aim: To examine whether plasma levels of coagulation factors II, V, IX, X, XI, and XII, plasminogen, and α-2 antiplasmin are associated with coronary heart disease (CHD) in a prospective case-cohort study. Methods: This case-cohort sample consisted of 368 African-Americans or whites with incident CHD that occurred between 1990-92 and 1998, from the Atherosclerosis Risk in Communities (ARIC) study, and a cohort random sample of n=412. Hemostatic factors were measured in the case-cohort sample using plasma stored at -70°C since 1990-92. Results: After adjustments for age, sex and race, coagulation factors IX and XI, and α-2 antiplasmin were associated positively with risk of CHD: The hazard ratio [95% confidence interval] for the highest vs lowest quartiles was 1.52 [1.01-2.27] for factor IX; 2.26 [1.47-3.48] for factor XI; and 1.64 [1.05-2.57] for α-2 antiplasmin. However, as these hemostatic factors were correlated with classical risk factors, their association with CHD was attenuated and no longer statistically significant after multivariable adjustments. No association was observed between CHD and factor II, V, X, or XII, or plasminogen. Conclusions: Positive associations of factors IX and XI, and α-2 antiplasmin with incident CHD were not strong and accounted for by classical coronary risk factors.
Aim: To clarify the clinical significance of small,dense LDL (sLDL) in the metabolic syndrome associated with type 2 diabetes. Methods: One hundred and ten healthy non-diabetic and non-metabolic syndrome subjects (58 male/52 female), 77 non-metabolic diabetic subjects (62/15), 58 non-diabetic metabolic subjects (25/33), and 46 metabolic diabetic subjects (29/17) were enrolled in this study. Results: The subjects with metabolic syndrome (both with and without type 2 diabetes) had significantly higher fasting blood glucose, total-cholesterol (C), LDL-C, triglyceride, sLDL-C and hs-CRP levels than non-metabolic and non-diabetic subjects. HDL-C levels were significantly decreased in the former compared to the latter. Among the metabolic syndrome subjects, those with type 2 diabetes had significantly higher fasting blood glucose, systolic blood pressure and hs-CRP values than those without diabetes. sLDL-C, LDL-C and hs-CRP were the highest and HDL-C was lowest in the metabolic syndrome with diabetes group. A multiple regression analysis revealed the most significant determinant of sLDL-C to be LDL-C, followed by HDL-C, total-C, metabolic syndrome, type 2 diabetes mellitus, and triglyceride. Conclusion: Metabolic syndrome is a significant determinant of the plasma sLDL-C level. Hs-CRP was the highest in the metabolic syndrome patients with type 2 diabetes. Therefore, type 2 diabetes may further increase the risk of coronary artery disease in the metabolic syndrome subjects through cardiovascular inflammation.
Aim: In Japan, heart disease and cerebral ischemic disease are major causes of death. A decrease in the level of low-density lipoprotein cholesterol (LDL-C) through intensive treatment with statins positively correlates with a reduction in the volume of plaques in patients with cardiovascular disease. The METEOR trial, evaluating the effect of rosuvastatin on carotid intima-media thickness (IMT), was conducted only in Europe and the US. Here we planned another trial, the Justification for Atherosclerosis Regression Treatment (JART) study, to clarify the efficacy of intensive lipid-lowering therapy with rosuvastatin in Japanese with atherosclerosis. Methods and Results: Four hundred patients with hypercholesterolemia (LDL-C ≥140 mg/dL) and a maximum IMT of ≥1.1 mm will be treated for 24 months either with intensive lipid-lowering therapy with rosuvastatin (target LDL-C levels: 80 mg/dL for primary prevention, and 70 mg/dL for secondary prevention) or conventional lipid-lowering therapy with pravastatin (target LDL-C level: complying with JASGL2007). The primary endpoint will be the percent change of mean-IMT and the objectives of the study are to compare the two protocols. Conclusion: The JART trial is a prospective, randomized, open-label, blinded end-point evaluation, multi-center, parallel-group, comparative study to examine the regressive effect of intensive lipidlowering therapy with statins on atherosclerosis by evaluating IMT in the Japanese population.
Aim: Serum high molecular weight (HMW) adiponectin improves insulin sensitivity, and a decreased level has been reported as a risk factor for the development of diabetes and coronary heart disease. This association may be further confounded by smoking, which is involved in the development of insulin resistance. The aim of this study was to determine whether smoking status is associated with serum HMW adiponectin levels in community-dwelling males. Methods: The cross-sectional study was carried out in 2002. Study participants without a clinical history of diabetes (724 men aged 60±14 (mean±standard deviation) (range, 20-89) years) were randomly recruited from a single community at an annual physical examination. They were classified into never-smokers, ex-smokers, light-smokers (<30 pack·year), and heavy-smokers (≥30 pack·year). Results: Mean serum HMW adiponectin levels were significantly lower in the current smokers than in the never- and ex-smokers but showed no significant difference between the light and heavy-smokers. Multiple linear regression analyses revealed that smoking status was significantly associated with HMW adiponectin levels, as were age, BMI, alcohol consumption, triglycerides, and high-density lipoprotein cholesterol. Multivariate-adjusted mean serum HMW adiponectin levels were lowest in the heavy-smokers, and significantly decreased in heavy-smokers compared with never-smokers and ex-smokers of an age ≥60 years, BMI≥22kg/m2, alcohol consumption ≥22.9g of ethanol/day, and HOMA-IR ≥1.6. Conclusion: Smoking status is associated with serum HMW adiponectin levels in community-dwelling Japanese men.