Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.

BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

[Aortic calcification and calcium].

Vascular calcification occurred as the last step of arteriosclerosis makes a lot of disturbances on vascular function and should influence on the worsening of the vascular diseases. Calcium is the main component of the vascular calcification like bone, and one of causes of vascular calcification should be the hypoparathyroidism due to the lowering of serum calcium and the following calcium paradox seen in osteoporosis. Bone calcium must shift to the arterial wall from the bone. Medial calcification could be formed under the molecular regulatory control like in bone by differentiated osteoblast or chondroblast from pericyte like cell origin smooth muscle cell. Many substances such as osteopontine, osteocalcine, bone morphogenetic protein 2, matrix Gla protein and alkaliphosphatase were found in calcified area. In intimal calcification, degenerated elastin and macrophage originated calcification were found. In the process of degeneration of elastin polypentapeptide structure in elastin can be easily conbined to Ca(2+), elastin-Ca(2+) complex is neutralized by PO4(2-) and calcium phosphate is accumulated in degenerated elastin.

Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial.

BACKGROUND: The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. METHODS: Patients aged 20-79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1-5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1·33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. FINDINGS: Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2·76% (n=82) in the cilostazol group and 3·71% (n=119) in the aspirin group (hazard ratio 0·743, 95% CI 0·564-0·981; p=0·0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0·77%, n=23) than on aspirin (1·78%, n=57; 0·458, 0·296-0·711; p=0·0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. INTERPRETATION: Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. FUNDING: Otsuka Pharmaceutical.

Impact of statin treatment on the clinical fate of heterozygous familial hypercholesterolemia.

AIM: Familial hypercholesterolemia (FH) patients are at particular risk for premature coronary artery disease (CAD) caused by high levels of low density lipoprotein (LDL). Administration of statins enabled us to reduce LDL-C levels in heterozygous FH patients. To evaluate the impact of statins on the clinical fate of heterozygous FH, a retrospective study was performed. METHODS: We analyzed the clinical influence of statins on age at the first clinical onset of CAD in 329 consecutive FH patients referred to the lipid clinic of the National Cardiovascular Center. Among 329 heterozygous FH patients, the onset of CAD was identified in 101. RESULTS: The age at onset of CAD was 58.8+/-12.5 years in the 25 patients on statins at onset, significantly higher than that in the 76 patients not on statins (47.6+/-10.5 years) (p <0.001). The average age at CAD onset was significantly higher after widespread use of statins (54.2+/-13.2 years in 48 patients, Group 1) compared to before October 1989 when statins were approved in Japan (46.9+/-9.6 years in 53 patients; Group 2, p=0.002). A significant difference was seen between Groups 1 and 2 in the variables, including sex, prevalence of smoking habit, LDL-C, and the use of statins, aspirin and probucol. After adjusting for these variables, only statin use was independently associated with the difference in age at CAD onset by multivariable analysis. CONCLUSION: Statins have improved the clinical course of patients with heterozygous FH.

Prognostic value of plasma high-sensitivity C-reactive protein levels in Japanese patients with stable coronary artery disease: the Japan NCVC-Collaborative Inflammation Cohort (JNIC) Study.

High-sensitivity C-reactive protein (hsCRP) levels can predict cardiovascular events among apparently healthy individuals and patients with coronary artery disease (CAD). However, hsCRP levels vary among ethnic populations. We previously reported hsCRP levels in Japanese to be much lower than in Western populations. We investigated the prognostic value of hsCRP levels in Japanese patients with stable CAD. The hsCRP levels were measured in 373 Japanese patients who underwent elective coronary angiography and thereafter decided to receive only medical treatment. Patients were followed up for 2.9+/-1.5 years for major cardiovascular events (death, myocardial infarction, unstable angina, stroke, aortic disease, peripheral arterial disease, or heart failure). The median hsCRP level was 0.70 mg/l. During the follow-up, cardiovascular events occurred in 53 (14%) of the 373 patients. Compared with 320 patients without events, 53 with events had higher hsCRP levels (median 1.06 vs. 0.67 mg/l, P<0.05). To clarify the association between hsCRP levels and cardiovascular events, the 373 study patients were divided into tertiles according to hsCRP levels: lower (<0.4 mg/l), middle (0.4-1.2mg/l), and higher (>1.2mg/l). The Kaplan-Meier analysis demonstrated a significant difference in the event-free survival rate between higher vs. middle or lower tertiles (P<0.05). In multivariate Cox regression analysis, the hsCRP level of >1.0mg/l was an independent predictor for cardiovascular events (hazard ratio, 2.0; 95%CI, 1.1-3.4; P<0.05). Thus, in Japanese patients with stable CAD who received only medical treatment, higher hsCRP levels, even >1.0mg/l, were found to be associated with a significantly increased risk for further cardiovascular events.

Association of serum lipocalin-type prostaglandin D synthase levels with subclinical atherosclerosis in untreated asymptomatic subjects.

Recent studies suggest that lipocalin-type prostaglandin (PG) D synthase (L-PGDS), which converts PGH2 to PGD2, is implicated in the pathogenesis of atherosclerosis. However, clinical evidence for the association between serum L-PGDS levels and atherosclerosis has not been reported. In this study, we measured the serum L-PGDS concentration using sandwich enzyme-linked immunosorbent assay (ELISA) and investigated the association with traditional cardiovascular risk factors and surrogate atherosclerotic indices, such as the maximum score of the intima-media complex thickness of the carotid artery (C-IMT(max)) and the brachial-ankle pulse wave velocity (ba-PWV), in 500 non-treated asymptomatic subjects. The serum concentration of L-PGDS was 0.56+/-0.01 (mean+/-SEM, range 0.25-1.27, median 0.54) mg/L. Serum L-PGDS levels increased with age and were higher in men than in women. Serum L-PGDS was higher in subjects with hypertension and increased with increasing numbers of the traditional atherosclerotic risk factors. When the subjects were divided into four groups according to the levels of serum L-PGDS, the age-adjusted values of C-IMT(max) and ba-PWV were significantly increased in subjects with higher serum L-PGDS levels (quartile 3 and quartile 4) compared to those in the lowest quartile (quartile 1), for both genders. Multiple regression analysis including risk factors revealed that serum L-PGDS was an independent determinant for ba-PWV (beta=0.130, p<0.001). Serum L-PGDS tended to associate with C-IMT(max) but was not statistically significant (beta=0.084, p=0.075). In conclusion, our results suggest that an increase in serum L-PGDS concentration is associated with the progression of atherosclerosis.

A low level of C-reactive protein in Japanese adults and its association with cardiovascular risk factors: the Japan NCVC-Collaborative Inflammation Cohort (JNIC) study.

High-sensitivity C-reactive protein (hs-CRP) levels vary remarkably by race and ethnic group. We examined hs-CRP levels and their association with cardiovascular risk factors in the Japanese general population. The Japan National Cardiovascular Center (NCVC)-collaborative Inflammation Cohort (JNIC) Study recruited 5213 men and 7071 women aged > or = 40 years from seven communities in Japan during 2002-2004. hs-CRP was measured using nephelometry calibrated with CRM 470, the international plasma protein reference material. Traditional cardiovascular risk factors and their aggregation were studied in multivariate logistic models, stratified by overweight status. Median hs-CRP levels in men and women were 0.60 and 0.45 mg/L, respectively. The percentage of subjects with hs-CRP levels < 1.0, 1.0-3.0, and > 3.0 mg/L was 67.4%, 22.0%, and 10.6% in men, respectively, and 76.3%, 16.7%, and 7.0% in women. hs-CRP levels showed significant linear associations with traditional risk factors. Overweight, hypertension, dyslipidemia (men only), smoking (men only), and diabetes (women only) contributed significantly to elevated hs-CRP levels. Overweight individuals with hypertension, dyslipidemia, and diabetes had a high prevalence of elevated hs-CRP levels in both sexes. Japanese adults have very low hs-CRP levels. An aggregation of metabolic risk factors is associated with elevated hs-CRP levels among overweight individuals, particularly in women.

Acute inhibition of lymphatic cholesterol transport in rat intestine by SCH 58053.

To clarify the pharmacological mechanism of ezetimibe, SCH 58053, an analog of ezetimibe, was intraduodenally administered to lymph-fistula rats, and its effect on lymphatic lipid transport in the intestine was monitored. SCH 58053, 5.0 mg/kg body weight, was administered one hour before a 5-hour infusion of a lipid emulsion containing 40 micromol/h of triolein and 2.74 micromol/h of cholesterol (Experiment 1) or co-administered at 5.0 mg/kg body weight/h with the lipid emulsion for 4 hours to rats that had been infused with the lipid emulsion alone for 3 hours (Experiment 2). SCH 58053 administration significantly inhibited lymphatic cholesterol transport, but not triglyceride transport, in both groups compared to control rats that did not receive SCH 58053. The ratio of free cholesterol to total cholesterol in the lymph of the treated rats was unchanged compared to the control rats. Thus, the results showed that SCH 58053 is a potent, rapid, and selective inhibitor of lymphatic cholesterol transport in the intestine.

Association of ceramides in human plasma with risk factors of atherosclerosis.

Atherosclerosis is a multifactorial disorder. Recent studies indicate that the plasma level of sphingomyelin, which yields ceramide, correlates with the risk of coronary heart disease. Therefore, ceramide, a well-known lipid causing apoptosis in various cell types, may contribute to atherogenesis. We examined the relationship between ceramide concentration and risk factors of atherosclerosis in normal human plasma using electrospray tandem mass spectrometry (LC-MS/MS). Major ceramides in human plasma were C24:0 and C24:1. The ceramide concentration showed a significant positive correlation with total cholesterol (TC) and triglycerides (TG). In addition, plasma ceramide level increased drastically at a high level of LDL cholesterol (more than 170 mg/dL). Our previous studies demonstrated that the sum of fragmented and conjugated apolipoprotein B-100 proteins (B-ox), which were products of a radical reaction of LDL as well as plasma, was a reliable index of atherosclerosis. B-ox showed a significant positive correlation with the plasma ceramide level. Based on these results, we propose that the ceramide level in human plasma is a risk factor at the early stages of atherosclerosis.

Serum apolipoprotein j in health, coronary heart disease and type 2 diabetes mellitus.

Apolipoprotein (apo) J, clusterin, is ubiquitously expressed in many tissues, and is a component of high-density lipoproteins (HDLs). There is experimental evidence that it may be anti-atherogenic through its effects on cholesterol transport, smooth muscle cell proliferation and lipid peroxidation. HDLs containing apo J and apo A-I carry paraoxonase (PON1), which protects low-density lipoproteins from oxidative modification; however, the extent to which apo J affects coronary heart disease (CHD) is not known. We have developed a sandwich ELISA that enables apo J to be assayed in the range of 13-200 microg/mL. Serum apo J was 52.8+/-0.8 microg/mL (mean+/-SEM; range, 36.0-84.3 microg/mL; n=92) in healthy Japanese men, and 49.3+/-0.5 microg/mL (34.5-72.8; n=241) in healthy Japanese women. Multiple regression of these data and results from 67 men with CHD showed that apo J concentration was unrelated to age, sex or body mass index, but was positively related to serum PON1 (p<0.001) and apo B (p<0.02) concentrations. In women, it was also positively related to blood glucose (p<0.02). After adjusting for its associations with covariates, serum apo J averaged 5.4 microg/mL, lower in CHD men than in controls (p<0.003). Type 2 diabetics had higher apo J concentrations (men, 83.1+/-3.4 microg/mL, n=64; women, 64.0+/-2.3 microg/mL, n=46) than healthy men and women (p<0.001). In these Type 2 diabetics, apo J concentration was unrelated to PON1 concentration, but was positively related to blood glucose (p<0.01). After adjustment for its relation to blood glucose, the mean apo J concentration was similar in diabetics and healthy subjects. These findings suggest that apo J may be anti-atherogenic in humans, and that its concentration is raised by Type 2 diabetes.

A novel enzyme-linked immunosorbent assay specific for high-molecular-weight adiponectin.

Human plasma contains at least three forms of adiponectin: a trimer, a hexamer, and a high-molecular-weight (HMW) multimer. We purified HMW adiponectin from human plasma using its affinity to gelatin and obtained monoclonal antibodies against it. On Western blot analysis, the reactivity of these monoclonal antibodies was shown to be restricted to a non-heat-denatured form of adiponectin molecules. On heating, the collagen-like domain of adiponectin molecules became denatured, and thus the trimer form could not be maintained. From these, monoclonal antibodies against HMW adiponectin were suggested to react with the intact trimer of adiponectin. With these monoclonal antibodies, we developed a sandwich ELISA system for quantifying adiponectin in human serum. Its specificity was verified by analysis of serum fractions separated by gel-filtration chromatography, and our ELISA system was found to be HMW adiponectin-specific. With this novel ELISA, the HMW adiponectin concentrations were 8.4 +/- 5.5 microg/ml (mean +/- SD) in healthy women and 6.2 +/- 3.6 microg/ml in healthy men. Also, serum with a lower HMW adiponectin concentration was shown to have a lower HMW ratio (i.e., HMW adiponectin/total adiponectin).

Relationships of nutrient intake and lifestyle-related factors to serum folate and plasma homocysteine concentrations in 30-69 year-old Japanese.

We studied non-hospitalized 30-69 y-old Japanese subjects to ascertain the influences of a 677C-T methylene-tetrahydrofolate reductase (MTHFR) genotype, nutritional intake and lifestyle-related factors on plasma homocysteine (Hcys) and serum folate concentrations. Hcys was higher and serum folate was lower in males than in females (p < .01). The Hcys concentration was higher in the VV group than in the AA and AV groups for both males and females. However, a relatively low serum folate concentration of 18 +/- 7 nmol/L was found in the entire male group as compared with 22 +/- 10 nmol/L in all females. In the female subjects, serum folate concentrations differed among MTHFR genotypes, being lowest in the VV group. In all male subjects, log folate intake per 1,000 kcal was a significant positive predictor of log serum folate concentration (p < 0.01), while in females the log vitamin C intake per standard body weight was a significant positive variable (p < 0.001) predicting the log serum folate concentration. Smokers had significantly lower serum folate concentrations, regardless of dietary folate intake. High folate and vitamin C consumptions, appears to be beneficial to normal and heterozygous MTHFR genotype subjects for maintaining serum folate concentrations. Even a 400 microg daily intake of folate might be less than what is needed, especially for homozygous MTHFR subjects and smokers, to maintain an adequate serum folate concentration.

Pulse pressure is an independent predictor for the progression of aortic wall calcification in patients with controlled hyperlipidemia.

Recent epidemiological studies suggested that calcifications of the aorta and the coronary arteries are important predictors for cardiovascular morbidity and mortality. However, the relation between blood pressure components and the progression of vascular wall calcification has remained unclear. We quantified calcium deposits in the abdominal aorta as the percentage of aortic calcification volume (%ACV) using computed tomography in patients with hyperlipidemia. Those who had aortic calcification were treated with lipid-lowering agents and followed-up for >2 years (6.3+/-3.2 years). The relationship between the components of blood pressure and the increase in %ACV per year (Delta%ACV/year) was assessed in subjects in whom serum lipid levels were well controlled during the follow-up periods. An age- and sex-adjusted correlation analysis showed that Delta%ACV/year was significantly correlated to body mass index (r=0.229, P=0.015), systolic blood pressure (r=0.244, P=0.009), and pulse pressure (r=0.359, P<0.001). A multivariate regression analysis revealed that pulse pressure is an independent and the most sensitive predictor for Delta%ACV/year (beta=0.389, P<0.001) among the blood pressure components. These results suggested that increase in pulse pressure promotes the progression of vascular calcification.

Timing of anti-platelet effect after oral aspirin administration in patients with sympathetic excitement.

Aspirin is used in percutaneous coronary interventions (PCI) for acute myocardial infarction (AMI) to prevent thrombosis. It is reported that the aspirin concentration in blood reaches its peak approximately 20 min after oral administration in healthy volunteers, but the absorption and bioavailability of aspirin in AMI may be quite different. In the present study patients undergoing coronary angiogram for the first time were enrolled as a model of sympathetic excitement and the timing of the antiplatelet effect after oral aspirin administration was investigated. Aspirin (162 mg) was administered to the patients in a catheter laboratory. Platelet count, aspirin concentration, and platelet aggregation were measured at scheduled timepoints before and up to 120 min. Ticlopidine was administered in the same procedure, and platelet count and platelet aggregation were evaluated at 0 and 120 min. There was no significant change in the platelet count. Aspirin concentration in blood had not reached its peak by 120 min. Platelet aggregation induced by collagen or ADP began to be inhibited 45 min after aspirin administration. No significant inhibition of platelet aggregation was observed up to 120 min following ticlopidine administration. During sympathetic excitement, aspirin absorption and its antiplatelet effect were significantly delayed in these patients. Ticlopidine did not show any antiplatelet effect by 120 min. For PCI performed in a patient with a high level of sympathetic excitement, aspirin should be administered at least 45 min before the first balloon dilatation.

Clinical features and genetic analysis of autosomal recessive hypercholesterolemia.

Previously we have reported on siblings with severe hypercholesterolemia, xanthomas, and premature atherosclerosis without any impairment of low-density lipoprotein receptor in their fibroblasts as a first characterization of autosomal recessive hypercholesterolemia (ARH). Recently, mutations were identified for this disease in a gene encoding a putative adaptor protein. The purpose of this study was to examine the molecular pathogenesis of ARH in Japanese siblings. A novel insertion mutation was discovered in the ARH gene of the siblings. An insertion of an extra cytosine residue was identified in a locus comprising eight consecutive cytosines at positions 599 through 606 in exon 6, resulting in a sequence of nine cytosines and generating an early stop codon at 657-659. The mother was heterozygous for this mutation. Neither transcription product nor protein of ARH was detected in the fibroblasts of the homozygous patients. A single nucleotide polymorphism was discovered among the normal control subjects at position 604 (cytosine to thymine: ARH-604C to ARH-604T), which changes the proline residue at 202 to serine. Interestingly, ARH is caused by a mutation of cytosine to adenine at this same position. Both siblings exhibited fatty liver, which may also be related to this mutation.

The ratio of serum paraoxonase/arylesterase activity using an improved assay for arylesterase activity to discriminate PON1(R192) from PON1(Q192).

Human serum paraoxonase (PON1) exists in 2 major polymorphic forms: Q (glutamine) or R (arginine) at codon 192. The PON1(192) activity polymorphism is substrate dependent. The PON1(Q192) isoform has a higher rate of in vitro hydrolysis of diazoxon, sarin, and soman, whereas the PON1(R192) isoform has higher activity for the hydrolysis of paraoxon and chlorpyrifos oxon. Both isoforms hydrolyze phenyl acetate at approximately the same rate. The present study described and evaluated a kinetic method of arylesterase activity determination with a modified fixed incubation method that used the oxidative coupling of phenol with 4-aminoantipyrine of phenyl acetate as the substrate. Our improved method shows that arylesterase activity is lower with the PON1(R192) isoform than with the PON1(Q192) isoform. The average activities of serum of individuals of a specific PON1(Q192) genotype showed higher arylesterase and lower paraoxonase activity than the PON1(R192) genotype. The ratio of paraoxonase/arylesterase activity showed a clear separation of all three PON1(192) genotypes with no overlap between the groups (QQ: < 5.0, QR: 5.0-11.0, RR: > 11.0). PCR has suggested that the PON1(192) phenotypes correspond to the PON1(192) genotypes. Therefore, when conducting epidemiological or mechanistic studies that examine the role of PON1 in organophosphorus or lipid metabolism, this ratio is more useful and informative than a PCR-based genotype alone.

[Assessment of coronary calcification by computed tomography inclusive of 3DCT].

Coronary artheroclerosis in diabetes patients can be divided into 2 phases, one is seen in the early phase of diabetes or insulin resistance syndrome as unstable plaque with lipid-rich core, thinner fibrous caps and small dose or a lack of calcification and the other in the late or advanced stage of diabetes is hard and stable plaque with much fibrous protein and calcification which extends from truncal to peripheral areas. In diabetic patients in the late stage, coronary accidents occur as the chronic multiple vessel diseases with a lot of calcification, while in the early stage of diabetes vasospastic angina and acute coronary syndrome with less calcification tends to occur. We can find out the coronary calcification by EBCT or 3DCT easily which is characteristic in patients of diabetes complicated with coronary artery disease and in the early stage the stenosis of left truncal artery or large vessels of LAD can be detectable by 3DCT.

Evaluation of apolipoprotein B-100 fragmentation and cross-linkage in serum as an index of atherosclerosis.

It is well established that radical reaction of low density lipoprotein (LDL) causes fragmentation and cross-linkage of apolipoprotein B-100 (apoB). Our previous studies demonstrated that fragmented and cross-linked apoB proteins are present in normal human serum and tended to increase with age based on immunoblot analysis. These observations suggest that the fragmentation and cross-linkage pattern of apoB reflects the oxidative stress in an individual and that this pattern is a good atherosclerotic index. In this study, a method was developed to evaluate the fragmentation and conjugation pattern of apoB. A parameter named B-ox was introduced for each serum sample to quantitate the staining bands of the immunoblotting analysis. B-ox represents the relative abundance of radical reaction products (a sum of fragmented and conjugated apoB proteins) based on one control subject. If this value increases, it indicates that radical reaction products have increased, i.e., the oxidative stress has increased in the subject. Based on measurements of subjects in a rural area of Japan, B-ox showed significant positive correlation with intima-media thickness (IMT) of the carotid artery, LDL cholesterol, and age, while it showed significant negative correlation with high density lipoprotein (HDL) cholesterol and vitamin C. These results suggest that B-ox is a reliable indicator of atherosclerosis.

Report of the Japan Atherosclerosis Society (JAS) Guideline for Diagnosis and Treatment of Hyperlipidemia in Japanese adults.

This paper described the Guideline for Diagnosis and Management of Hyperlipidemias for Prevention of Atherosclerosis proposed by The Japan Atherosclerosis Society (JAS) Guideline Investigating Committee (1,995-2,000) under the auspices of the JAS Board of Directors. 1) The guideline defines the diagnostic criteria for serum total cholesterol (Table 1), LDL-cholesterol (Table 1), triglycerides (Table 4) and HDL-cholesterol (Table 7). It also indicates the desirable range (Table 1), the initiation levels of management (Table 2) and the target levels of treatment (Table 2) for total and LDL-cholesterol. 2) Though both total and LDL-cholesterol are shown as atherogenic parameter in the guideline, the use of LDL-cholesterol, rather than total cholesterol, is encouraged in daily medical practice and lipid-related studies, because LDL-cholesterol is more closely related to atherosclerosis. 3) Elevated triglycerides and low HDL-cholesterol are included in the risk factors, since no sufficient data have been accumulated to formulate the guideline for these two lipid disorders. 4) Emphasis is laid on evaluation of risk factors of each subject before starting any kind of treatment (Table 2). 5) This guideline is applied solely for adults (age 20-64). Lipid abnormalities in children or the youth under age 19, and the elderly with an age over 65 have to be evaluated by their own standard. 6) This part of the guideline gives only the diagnostic aspects of hyperlipidemias. The part of management and treatment will follow in the second section of the guideline that will be published in future.