The cellular mechanisms by which LDL inhibits thrombin-induced endothelium-dependent relaxation in porcine coronary arteries were investigated using rabbit-washed platelets and cultured porcine endothelial cells. Thrombin-induced platelet aggregation was dose-dependently inhibited by sodium nitroprusside (10^-7-10^-3M), which activates guanylate cyclase. When platelets were coincubated, either with suspended endothelial cells or endothelial cells cultured on microcarrier beads, and then stimulated with thrombin, platelet aggregation was reduced and the lag time increased as the number of endothelial cells increased. However, the presence of LDL (1mg prot./ml) greatly reversed the inhibition by the endothelial cells, while the presence of hemoglobin (10^-6M) which is known to degrade the endothelium-derived relaxing factor (EDRF), completely blocked such inhibition. Likewise, thrombin-induced ¹⁴C-serotonin release from the platelets was inhibited by coincubation of the platelets and endothelial cells, but such inhibition was not observed when either LDL or hemoglobin were present. In addition, platelets aggregated as usual when they were exposed to an EC-thrombin mixture 5min after stimulation of the endothelial cells with thrombin. In contrast to native LDL, heat (60°C, 10min)-treated LDL and acid (pH 2, 30min)-treated LDL showed no such effects.
These results suggest that thrombin-induced plate-let aggregation and secretion were simultaneously inhibited by EDRF release from the thrombin-stimulated endothelial cells, and that by interacting with EC, LDL blocked EDRF release and thereby reversed the inhibitory effects of the endothelial cells on platelet aggregation.

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Metabolic syndrome X, a combination of hyper-insulinemia, hypertriglyceridemia, low HDL-cholesterol level, impaired glucose tolerance and hypertension, is associated with the risk of coronary heart disease. To investigate the relationship between visceral fat accumulation and metabolic syndrome X, we measured coronary artery stenosis, several metabolic variables, and the distribution of abdominal fat by CT scanner in 161 patients who underwent coronary angiography. Using a multiple regression analysis, visceral fat area was correlated with the sum of insulin during an oral glucose tolerance test (r=0.321, p=0.0004), HDL-cholesterol level (r=-0.319, p=0.0154), and the sum of glucose (r=0.181, p=0.0401). TG level, however, correlated not with regional fat distribution but with BMI (r=0.283, p=0.0126). Subcutaneous fat area and BMI were not significant predictors of any of the metabolic variables except insulin. Multivariate analysis indicated that the sum of glucose (r=0.364, p=0.0039) and plasma insulin concentration (r=0.233, p=0.048) were found to be independent of other risk factors for CAD in male Japanese. In normotensive patients, however, insulin concentration was not a significant predictor of CAD. In hypertensive patients, the combination of elevated plasma insulin level, visceral fat accumulation, triglyceride concentration and the exacerbation of glucose tolerance was important. We conclude that visceral fat accumulation is a generator of metabolic syndrome X, and that the combination of visceral fat accumulation and hypertension play an important role in CAD among male Japanese.

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We assessed serum lipoproteins and certain clinical factors and compared the results of those patients with ischemic heart disease (IHD) to those without in a group of non-insulin dependent diabetic (NIDD) patients complicated with hyperlipidemia (n=21 and 23, respectively), age (61±7 vs. 61±9 years, mean±SD), BMI (kg/m²: 23.1±3.0 vs. 23.8±2.3), and sex (% male: 67% vs. 52%) were equivalent in both groups. Clinical factors and serum lipids were comparable in both groups. The relative distribution of TG in the pre-β fraction (pre β-TG (%)) (64±12% vs. 53±16%, p<0.02) was significantly higher in patients with IHD, while the relative distribution of TG in the β fraction (β-TG (%)) (26±10% vs. 36±16%, p<0.02) was significantly lower. Apo E/pre β-TG ratio tended to be low in patients with IHD, though the difference was not statistically significant. We would suggest that IHD in NIDD patients is associated not only with hyperlipidemia but also with an abnormal distribution of lipids in the lipoprotein fraction.

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We compared clinical factors and serum lipoproteins between subjects with and without ischemic heart disease (IHD) in a group of normolipidemic non-insulin dependent diabetic (NIDD) patients (n=27 and 58, respectively). The patients with IHD were older (years of age: 65±10 vs. 59±9, mean±SD, p<0.01), had a longer history of diabetes mellitus (years: 14±9 vs. 11±8, p <0.05), and were more obese (Body Mass Index (BMI): kg/m²: 23.2±2.6 vs. 21.7±2.8, p<0.05) than those without IHD. The percentage of subjects over 60 years of age or with an BMI above 23.5kg/m² was significantly higher (p<0.05 in both cases) in the IHD group. Serum lipids, lipoproteins and apoproteins in both groups were comparable. Furthermore, the relative distribution of lipids in each lipoprotein fraction was also comparable in both groups. Results were the same for the age-, sex-, and BMI-matched subgroups. We would suggest that clinical factors such as age, duration of diabetes mellitus, obesity, and other, currently unknown factors play an important role in the development of atherogenesis in normolipidemic NIDD patients with IHD.

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The study was conducted to investigate the relationship between glucose concentration and cerebrovascular lesions in nondiabetic elderly subjects. Subjects who had a diabetic history or an FPG≥140mg/dl were excluded. We analyzed a total of 482 cases. All of the subjects were residents of the Yokufukai Home for the aged, had undergone a 50-g OGTT prior to death and had been autopsied. The subjects were divided into quintiles based on 2h glucose concentration. Among subjects who had been under 75 years of age at the time of the OGTT, the incidence of cerebral infarction with neurologic disability was significantly lower in the first quintile than in the other four. There were no significant differences among the five quintile groups in incidence of minor infarctions or in severity of cerebral athero-sclerosis. Among subjects 75 or over at the time of OGTT, there were no significant differences among the five quintile groups either in incidence of cerebral infarction or in severity of cerebral atherosclerosis. Our results demonstrate an apparent nonlinear relationship between glucose concentration and cerebral infarction, with an increase of cerebral infarction with neurologic disability occurring in subjects above the 80th percentile for post-challenge glucose. Our results also suggest that mild glucose intolerance in nondiabetic elderly subjects in their mid-seventies and above does not significantly affect the development of cerebrovascular lesions.

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Lipoprotein(a) [Lp(a)] is known to provoke atherosclerosis and has been confirmed as a major independent risk factor for cardiovascular and cerebrovascular diseases. At the same time, patients with hypertension (HT) are prone to develop atherosclerosis. Calcium antagonists have been shown to have antiatherosclerotic properties in addition to their vasodilatory and antihypertensive effects. We therefore investigated the effect of nisoldipine (Ni), a calcium antagonist, on plasma Lp(a) levels in HT patients.
(1) Plasma Lp(a) concentration was determined by ELISA for 59 (19 males and 40 females) untreated HT patients (group A; age: 32-74, mean 54 years) and found to be 19.1±2.2mg/dl (Mean±S. E.: range from 1.1 to 101.0). This was higher than the value of 11.8±0.8 (range from 0.2 to 46.1) determined for 106 (34 males and 72 females) healthy subjects in the same age range (group B; age: 30-75, mean 50 years, p<0.002). In addition, there was a higher incidence of Lp(a) levels above 25mg/dl in group A than in group B (28.8% and 6.6%, respectively; p<0.001).
(2) The mean plasma Lp(a) level of 113 patients (53 males and 60 females) treated for HT with calcium antagonists and/or ACE inhibitors (group C; age: 33-74, mean 58 years) was 14.1±1.2mg/dl (range from 0.4 to 76.0). This value was lower than that of group A and was not significantly different from that of group B. 14.2% of group C had high (i. e.>25mg/dl) Lp(a) levels, which was significantly lower than that of group A (p<0.025), but not significantly different from group B.
(3) Following Ni administration to the 32 patients in group A, Lp(a) value for the group declined to 15.8±2.0mg/dl (range from 3.2 to 45.9). The percentage of cases with high levels also decreased to 15.6%, close to that for group C.
In conclusion, while high plasma Lp(a) levels were observed in group A, group C tended to have levels lower than A and not different from B. Lp(a) levels in the A+Ni group followed a similar pattern in group C.

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Serum lipoprotein(a) {Lp(a)} is accepted as a potent risk factor for atherosclerotic disease. C_4b binding protein (C₄bp), a regulatory protein in complement system, plays important roles in blood coagulation and fibrinolysis, and is identical with proline-rich protein. Our previous study showed a positive correlation between serum Lp(a) and C₄bp levels (Nagata et al., J. Jpn. Atheroscler. Soc., 20: 651-655, 1992). Both the serum amyloid A (SAA) and serum amyloid P (SAP) components are precursors of the amyloid A and P proteins, which are the main amyloid components deposited in the tissue of secondary amyloidosis. In human blood, SAP binds with C₄bp, and SAA binds with HDL lipoprotein.
We examined effects of oral administration of niceritrol (750mg/day, for 16 weeks) on serum lipids, apolipoproteins, Lp(a), C₄bp, SAP, and SAA in 26 patients (12 males and 14 females) who had high serum Lp(a) levels (>30mg/dl) and the following cerebrovascular diseases: cerebral infarction (16 patients), cerebral bleeding (8 patients), and subarachinoidal hemorrhage (2 patients).
Niceritrol therapy decreased total cholesterol and triglyceride levels, confirming previous reports. HDL-cholesterol levels had increased 4 weeks after administration, but the increases after 16 weeks were not significant. Apolipoproteins B and C-III levels had decreased after 16 weeks, but other apolipoproteins showed no significant change.
Niceritrol obviously lowered serum Lp(a) levels; the percentage decrease from the pre-treatment level was 22±8% (12±4mg/dl) after administration for 16 weeks. Lp(a) levels rebounded to pre-treatment levels 4 weeks after niceritrol therapy was discontinued. C₄bp levels had also decreased after 4 weeks, but the decreases after 16 weeks were not significant. However, the percentage decreased in Lp(a) and C₄bp levels showed a positive correlation. In addition, both SAA and SAP levels decreased after 16 weeks, and the decreases, in percentage terms, percentage were positively correlated. Niceritorol therapy lowered the serum levels of C₄bp, SAA, and SAP as well as Lp(a). We speculate that niceritrol suppressed the production of these proteins in the liver.

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Daisaikoto is a traditional Chinese drug which has been recently been receiving attention in Japan. In order to evaluate the effects of Daisaikoto on the lipid and lipoprotein metabolism, either probucol (500mg/day), Daisaikoto (7.5g/day), or the two in combination were administered for to 96 hyperlipoproteinemic patients 16 weeks. In patients with type ha hyperlipoproteinemia, Daisaikoto suppressed the decrease of HDL cholesterol caused by probucol. In patients with type IIb or IV hyperlipoproteinemia, Daisaikoto lowered lipid levels (T-CHO: -8.5%, TG: -26.4%) equally as much as probucol (T-CHO: -13.4%, TG: -19.8%). Combination therapy lowered triglyceride levels (-29.7%) considerably more than probucol alone.

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Death from cardiac rather than pulmonary causes is common in patients with sarcoidosis in Japan. At the same time, asymptomatic myocardial infarction is more common in diabetics than non-diabetics. In addition to diabetes mellitus, high serum concentration of lipoprotein(a) has been shown to be an independent risk factor for coronary artery disease. Our report discusses the case of a 60-year-old diabetic man with skin sarcoid lesions and elevated lipoprotein(a) levels who developed asymptomatic myocardial infarction. He had skin eruptions in the lower part of the left ear over a 20 year period. A skin biopsy revealed multiple noncaseating granulomas in September 1987, when he was also found to have diabetes mellitus. However, his ECG was normal. Treatment with glibenclamide (5mg daily) resulted in good glycemic control. An ECG taken in February 1989 showed changes in the anterolateral wall typical of myocardial infarction.
During this period, he displayed no signs or symptoms suggestive of acute myocardial infarction. His glycemic control was excellent, with a mean (±SE) HbA_1C of 6.9±0.1% over 11 measurements. Serum levels of total and HDL cholesterol averaged 210±4mg/dl and 47.8±1.4mg/dl, respectively. Serum lipoprotein(a) concentrations, however, were extremely high (59.4±1.5mg/dl, n=4) when compared to a control group (15.7±1.7mg/dl, n=76). Coronary arteriograms revealed a complete obstruction of the left anterior descending artery. However, right ventricular endomyocardial biopsy demonstrated no lesions suggestive of sarcoidosis, and systemic gallium scintigrams showed abnormal accumulation in the left ear but not the mediastinum.

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The serum cholesterol levels of 97, 062 (32, 101 males, 64, 961 females) subjects were measured between 1987 and 1991 in Fujieda City, population 121, 799. Average serum cholesterol levels from 1987 to 1991 were 196.8, 200.0, 199.0, 200.5, and 200.5mg/dl, respectively.
Among males, the highest serum cholesterol levels were noted among 45-49 year olds; levels slowly decreased with subsequent age. Average serum cholesterol level was 185.6mg/dl in 1987 and 191.4mg/dl in 1991. Net increase between 1987 and 1991 was highest among 40-45 year olds, at 8.8mg/dl, and lowest among 65-69 year olds at 3.7mg/dl.
Among females, average serum cholesterol levels from 1987 to 1991 were 202.6, 205.5, 204.1, 205.4, and 204.9mg/dl, respectively.
The highest serum cholesterol levels were noted among 55-64 year olds while the lowest were among 40-44 year olds.
The greatest increase in serum cholesterol levels among women 4.8mg/dl over the 5 years was seen in the 40-44 age group, at 4.8mg/dl, the minimum increase noted was among 55-59 year olds at -0.1mg/dl. The average increase in cholesterol between 1987 and 1991 was 2.3mg/dl. Annual mortality from myocardial infarction between 1987 and 1991 was 23, 21, 22, 32, 45 subjects yearly. Myocardial infarction gradually increased, accounting for 4.5 and 6.6% of deaths in 1990 and 1991, as compared
to 3.9% in 1987.
Among males, mortality from myocardial infarction was present in those 50 years old and up, and accounted for 60-70% of deaths among those aged 70 and up.
Among females, 90% had died at the age of over 70 years old. These data suggest that mortality is closely related to changes in lipid phenotypes with age.

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Probucol (250-500mg/day) was administered for five years to treat hypercholesterolemia in non-insulin dependent diabetes mellitus (NIDDM). Changes in total cholesterol, LDL-cholesterol and HDL-cholesterol levels were investigated in 120 diabetic patients (29 males and 91 females, aged between 30 and 83 years). The following results were obtained:
(1) The total-cholesterol level decreased by 45mg/dl (17%) after one year of probucol treatment and the decreased level was maintained subsequently for five years.
(2) The LDL-cholesterol level decreased by 32mg/dl (17%) after one year of probucol treatment and this decreased level was maintained subsequently for five years.
(3) Among the groups receiving only a dietary, sulfonylureas, or insulin treatment, there were no significant differences in the effects of the treatment with probucol on the serum TC, LDL-C, and HDL-C levels over a five-year period.
(4) In patients with an HDL-cholesterol level ≤40mg/dl, there was no significant decrease in the HDL-cholesterol level, although the total- and LDL-cholesterol levels were significantly decreased.
(5) No episodes of arteriosclerotic disease were newly reported during the study period. There were also no reports of adverse reactions requiring the discontinuation of probucol treatment.
These findings suggest that probucol is useful for the long-term treatment of hypercholesterolemia in NIDDM.

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