Hemostatic factors play a crucial role in generating thrombotic plugs at sites of vascular damage (atherothrombosis). However, whether hemostatic factors contribute directly or indirectly to the pathogenesis of atherosclerosis remains uncertain. Autopsy studies have revealed that intimal thickening represents the first stage of atherosclerosis and that lipid-rich plaque arises from such lesions. Several factors contribute to the start of intimal thickening. Platelets release several growth factors and bioactive agents that play a central role in development of not only thrombus but also of intimal thickening. We have been investigating which coagulation factors simultaneously, or subsequently with platelet aggregation, participate in thrombus formation. Tissue factor (TF) is an essential initiator of blood coagulation that is expressed in various stages of atherosclerotic lesions in humans and other animals. Factors including thrombin and fibrin, which are downstream of the coagulation cascade activated by TF, also contribute to atherosclerosis. TF is involved in cell migration, embryogenesis and angiogenesis. Thus TF, in addition to factors downstream of the coagulation cascade and the protease-activated receptor 2 activation system, would be a multifactorial regulator of atherogenesis.
Background: Although insulin resistance (IR) is present in non-diabetic subjects, it is unknown whether IR affects statin treatment. We assessed the relationship between IR and the changes of lipid profile in patients with hyperlipidemia treated by atorvastatin. Methods: Forty-four non-diabetic patients were included. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. We used the value of 2.5 as the threshold for IR. Results: High-density lipoprotein (HDL) cholesterol at baseline was lower and triglyceride (TG) at baseline was higher in the IR group than in the nonIR group (p < 0.05). Changes in all lipid measurements did not differ between the two groups. HOMA-IR was correlated with HDL cholesterol at baseline and at follow-up and correlated with TG at baseline and at follow-up (r = −0.40, r = −0.53, r = 0.38, r = 0.35, p < 0.01, respectively). However, HOMA-IR did not associate with changes in total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, and TG. Conclusion: The IR did not affect the degree of reduction in cholesterol by atorvastatin in non-diabetic subjects. The IR may influence hypertriglyceridemia greater than the effect of atorvastatin in non-diabetic subjects.
Total plasma homocysteine (tHcy) was measured by high pressure liquid chromatography (HPLC) method in 28 patients (12 females and 16 males) at the onset of type 1 diabetes mellitus (T1DM), 4 females during diabetes ketoacidosis (DKA) and 154 (68 females and 86 males) during follow-up. Serum folate, pyridoxal 5’ phosphate (PLP) and Vitamin B12 (Vit B12) were also measured. Plasma tHcy levels were not found significantly different in T1DM patients known to have diabetes (males 9.2 ± 7.7 and females 7.0 ± 2.8 μmol/l) and in those who were newly diagnosed (males 9.7 ± 4.8 and females 7.16 ± 2.8 μmol/l) than in healthy controls (males 8.7 ± 3.5 and females 7.8 ± 2.55 μmol/l). Only a significant difference for sex was observed in known diabetes (p = 0.0281). Serum folate, PLP and Vit B12 were normal (12.6 ± 3.6 ng/ml, 20.11 ± 0.8 ng/ml and 416.7 ± 41.9 pg/ml) in all T1DM patients. Age significantly correlated with plasma tHcy. Only in 4 patients, studied during DKA, plasma tHcy was significantly lower (2.76 ± 1.33 μmol/l, p < 0.001) than the healthy controls.
We investigated the suppressive effect of cocoa powder (cacao polyphenol content: 7.8%) on atherosclerosis in a spontaneous familial hypercholesterolemic model, Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbits. Six-month dietary administration of cocoa powder had no effects on body weight, hematology or blood chemistry parameters or a lipid profile in KHC rabbits. Antioxidative activity of low-density lipoprotein (LDL) was observed in the 2nd month and 3rd month of administration. Thiobarbituric acid reactive substances (TBARS), the marker of lipid peroxidation, in plasma were decreased in the cocoa powder treated group from the 2nd month of administration during the study period compared to that in the control group. The area of atherosclerotic lesions in th aorta was significantly smaller in the cocoa powder group (30.87%) than in the control (52.39%). Tissue cholesterol content also tended to decrease. Distensibility of the aortic wall was improved significantly in the cocoa powder treated group due to decreases in fatty streaks and intimal thickening compared to that in the control group. These results suggest that cocoa powder has suppressive effect on development of atherosclerotic lesions. We consider that antioxidative activity of polyphenols rich in cocoa powder may be a key factor for the anti-atherosclerotic effect.
This study describes the clustering patterns of several lifestyle-related factors in urban Japanese subjects. The effect of aging on these patterns was also investigated. Data of 8 factors that included body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLc), gamma-glutamyl-transferase (GGT), and cigarette smoking were analyzed for 12,525 individuals (4,591 men and 7,934 women) aged either 40, 50, or 60 years. Factor analysis showed eight factors clustered into 3 unrelated groups. BMI and BP were excluded in subjects aged 60 years. Our data showed that the effect of obesity on the prevalence of type 2 diabetes mellitus was age dependent. In spite of the established inverse relationship between TG and HDLc, we found that TG had an association with GGT. These results indicated that aging may have a major influence on the expression of multiple risk factors. The influence of BMI on the lifestyle-related factors appeared to be mostly expressed in younger people, while these factors appeared to be independent of BMI at age 60.
Familial hypercholesterolemia (FH) results from low-density lipoprotein (LDL) receptor gene mutations. Heterozygotes have twice normal LDL-cholesterol concentrations in early childhood, and experience early myocardial infarction. We demonstrated bimodal cholesterol frequency distributions, independently confirming existence of an identifiable hypercholesterolemic subpopulation. We assayed blood lipids in 181 FH patients genetically diagnosed and 100 unaffected relatives. Receiver operating characteristics curves were constructed. Total cholesterol and LDL-cholesterol concentrations showed bimodality. A total cholesterol cutoff of 225 mg/dl produced results agreeing with DNA testing (specificity, 98.5%; sensitivity, 99.4%). An LDL-cholesterol cutoff of 161−163 mg/dl produced 98.5% specificity and 98.3% sensitivity. Areas under curves were 0.9826 ± 0.0058 for total cholesterol, and 0.9852 ± 0.0043 for LDL-cholesterol. In conclusion, we define total cholesterol and LDL-cholesterol levels of 225 and 160 mg/dl, respectively, as cutoff points of normal subjects and FH patients.
This study compared the effects of fluvastatin and pravastatin on the in vivo oxidation of LDL in a crossover design to evaluate whether or not it is justified to switch between the two statins with regard to serum levels of lipids, lipoproteins, and apolipoproteins (apo), and circulating autoantibodies to oxidized LDL (OxLDL-Ab). Patients with hypercholesterolemia (n = 46) were randomly assigned into groups who received fluvastatin (20 mg/d) or pravastatin (10 mg/d). After 3 months, they were crossed to receive the other statin for another 3 months. Circulating levels of OxLDL-Ab were measured by an OxLDL IgG ELISA test. Fluvastatin and pravastatin similarly decreased serum levels of total cholesterol (TC), LDL-C, and apo B, and increased HDL2-C levels. After crossover to the other statin, these lipid parameters were not further changed by either statin. Before crossover, circulating levels of OxLDL-Ab were decreased in patients with fluvastatin treatment, but not in those with pravastatin treatment. After switching from the other statin, both fluvastatin and pravastatin further decreased OxLDL-Ab levels. In conclusion, fluvastatin at 20 mg/d and pravastatin at 10 mg/d are similar with regard to their efficacy in decreasing TC, LDL-C, and apo B levels and increasing HDL2-C levels. Fluvastatin lowered circulating levels of OxLDL-Ab, and these effects continued after switching to pravastatin.
Our purpose in this study was to evaluate the new JAS guidelines as a risk assessment tool in Japanese patients with hypercholesterolemia, using the cohort of the Holicos-PAT study. The Holicos-PAT study was designed as a prospective observational study. 2039 patients were followed with or without pravastatin for 5 years. We assessed coronary heart disease (CHD) and cerebrovascular disease (CVD) risks by the patient categories described in the JAS guidelines. In the Holicos-PAT study, the primary endpoints were CHD, and the secondary endpoints were CVD and total mortality. CHD event includes onset and worsening of angina pectoris, performing CABG or PTCA, non-fatal and fatal myocardial infarction, and death from CHD including heart death and sudden death. CVD events are onset or recurrence of cerebral infarction, onset of cerebral hemorrhage, and death from cerebral infarction or hemorrhage. The event rates were calculated by the person-years method, and the differences in event rates between category groups were analyzed by chi-square test. The event rates of CHD in Category A, B1, B2, B3, B4 and C, were 1.1, 4.0, 2.8, 5.7, 18.2 and 38.8 per 1,000 person-years. The rates of CHD events in the higher risk category groups, Category B4 group (p = 0.004 in whole patients) and C group (p < 0.001 in whole patients), were significantly higher than that in the combined category groups A + B1 + B2. The event rates of CVD in Category A, B1, B2, B3, B4 and C, were 2.1, 1.8, 1.8, 0.6, 10.8 and 6.4 per 1,000 person-years. The event rates of CHD in men were significantly higher than those in women, in categories B4 (p < 0.001) and C (p < 0.001). From these results, each category classified by accumulation of risk factors, showed increasing event rates of CHD and CVD. The categories in the JAS guidelines are useful to assess CHD and CVD risk in Japanese patients with hypercholesterolemia. However, the risk evaluation by the JAS guideline categories may underestimate the risk in men and overestimate it in women.
TLRs are receptors involved in the recognition of pathogens by the innate immune system, and TLR2 and TLR4 play important roles in the activation of monocytes. A total of 105 consecutive patients who underwent coronary angiography comprised of 46 with stable effort angina (SA), 41 with unstable angina (UA), and 18 with no significant CAD (CNT) were enrolled. The baseline expression levels of TLR2 and TLR4 on monocytes in peripheral blood mononuclear cells (PBMCs) were determined by flow-cytometric analysis. Since TLR2 expression has been reported to be regulated by TLR4 signaling, we cultured PBMCs with or without lipopolysaccharide (LPS, 1 μg/ml). At baseline, TLR4 levels (mean of fluorescence intensity ) in SA (145 ± 58, p < 0.05) and UA (164 ± 65, p < 0.01) were higher than those in CNT (107 ± 37). As for TLR2, levels were higher in UA (108 ± 36, p < 0.05) than in SA (94 ± 18) and CNT (87 ± 22). After stimulation with LPS, TLR2 levels increased in SA but decreased in UA. In conclusions, TLR4 levels increased in both SA and UA. Monocytes in UA were characterized by elevated TLR2 levels and unresponsiveness of the TLR2 levels to TLR4 stimulation.