An elevated plasma level of lipoprotein(a) (Lp(a)) is known to be an independent risk factor for coronary artery disease (CAD). Lp(a) is an unique lipoprotein containing apo(a), which has a high degree of structual homology to plasminogen. Recent in vitro studies have demonstrated linkage between Lp(a) and the fibrinolytic system. In the present study, plasma concentrations of Lp(a), thrombinantithrombin III complex (TAT), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), tPA-PAI complex and α2-plasmin inhibitorplasmin complex (PIC) were determined in healthy subjects (n=21). Lp(a) concentrations showed a significant positive correlation with PIC values in the healthy group (r=0.629, p<0.01). On the contrary, the coefficient value in patients with angiographically defined CAD (n =73) had no significance, and even showed a tendency toward negative correlation (r=-0.030).
Furthermore, the relationship between Lp(a)phenotypes and PIC values were also investigated in both groups. PIC values in the healthy subjects with double-band phenotypes were significantly higher than those with single-band phenotypes (p<0.05), while those of patients with a double-band were significantly lower than those with a single-band (p<0.05). These results have confirmed our previous findings on the relationships between Lp(a) phenotypes and Lp(a) concentrations, and on the frequency of double-band phenotypes in the healthy subjects and CAD patients.
These results suggest that Lp(a) has the potential to regulate the coagulation-fibrinolytic system and that it may interfere with the fibrinolytic system at least in patients with CAD.

抄録全体を表示

We examined serum lipids, lipoproteins including lipoprotein(a) (Lp(a)), apolipoproteins, and C_4b binding protein (C₄bp) in 262 patients (130 males and 132 females) with cerebrovascular diseases (CVD), consisting of cerebral infarction of cortical artery (16 males/13 females, age; 68.4±11.3 years), cerebral infarction of the perforated artery (12/11, 70.2±8.2), multiple infarctions (39/38, 75.5±8.1), vascular dementia (16/13, 72.9±4.7), cerebral embolism (5/10, 70.1±13.6), cerebral bleeding (35/34, 66.3±11.0), and subarachnoideal bleeding (7/13, 64.9±12.1).
Total serum cholesterol and/or LDL-cholesterol levels increased in cerebral infarction, multiple infarction, cerebral embolism and cerebral bleeding, compared with the control subjects. Serum triglycerides levels increased in cerebral infarction, multiple infarction and cerebral bleeding, and subarachnoideal bleeding. Serum HDL-cholesterol levels were low in cerebral infarction, multiple infarction, vascular dementia, cerebral bleeding, and subarachnoideal bleeding.
Serum Lp(a) levels were significantly higher in all types of CVD, especially in multiple infarctions and vascular dementia, except cerebral infarction of the perforated artery.
C₄bp, a regulatory protein in the complement system, has an important role in both the blood coagulation and the fibrinolysis system. Recently, it has been reported that C₄bp is identical to prolinerich protein, which has an affinity with several serum lipids. In this study, there was no significant difference in the serum C₄bp levels of the control subjects and of the patients with CVD.
Serum Lp(a) levels are genetically regulated, and serum Lp(a) is accepted as an independent risk factor of atherosclerotic disease. However, our study showed a positive correlation between serum Lp(a) and C₄bp levels. Both proteins were involved in the change in serum lipids, blood coagulation, fibrinolysis, and inflammation. Serum Lp(a) and C₄bp levels were probably correlated with each other according to these similarities.

抄録全体を表示

To clarify the sex difference in coronary risk factors, we studied the joint effect of glucose intolerance, hypertension, and hyperinsulinemia on the severity of CAD in patients with catheterization-proved CAD.
In postmenopausal women, the less glucose intolerance, the greater the frequency of hypertension, and the more exacerbated the severity of CAD. The combination of hypertension and glucose intolerance increased the severity of CAD. Glucose intolerance and hypertensive groups were shown to have higher levels of insulinemia and cholesterolemia than glucose intolerant normotensive groups.
By contrast, in men, we could not find an independent relationship between CAD severity and coronary risk factors, such as glucose intolerance, hypertension and hyperinsulinemia. However, the combination of hyperinsulinemia and hypertension increased the severity of CAD.

抄録全体を表示

When a 63-year-old female recovered from diabetic ketoacidosis after the 14th day at the hospital, the value of HDL-cholesterol increased from 71 to 101mg/dl. The activity of her hepatic triglyceride lipase (HTGL) and the activity of her lipoprotein lipase (LPL) decreased. The activity of her HTGL decreased (HTGL: 2.8-2.9μmol·FFA/ml/hr) during her clinical course, while the activity of her LPL and cholesteryl ester transfer protein (CETPA) had been within the normal range (LPL: 11.1-11.2μmol·FFA/ml/hr, CETPA: 30.3%), with good control of blood glucose. Analysis of apolipoprotein A-I or B-100-containing particles was performed by selective affinity columns prepared from the monoclonal antibodies of our patient. The ratio of cholesterol ester (CE) to free cholesterol (FC) in apolipoprotein A-I or B-100 particles increased with poor control of blood glucose, while the ratio decreased with good control of blood glucose. The activity of lecithin-cholesterol acyltransferase decreased from 106 to 66nmol/ml/hr with good control of blood glucose. The mean size of Apolipoprotein A-I particles, which was detected by electron microscopy, was significantly larger in this case (21.2±1.8nm, mean±SEM) than in the control case (13.6±0.2nm).

抄録全体を表示

The aim of this study was to investigate the relationship of glucose concentration to coronary heart disease (CHD) in nondiabetic elderly subjects. Those who had a diabetic history or FPG≥140mg/dl were excluded. We analyzed a total of 482 cases. All of the subjects were inmates of the Yokufukai Home for the Aged who had undergone a 50-g OGTT before expiring, and were then subjected to autopsy. The subjects were divided into quintiles by 2h glucose concentration. In subjects aged<75 at the time of OGTT, the incidence of myocardial infarction was significantly lower in quintile 1 than in quintile 2 or 4. The severity of the coronary artery stenosis was significantly lower in quintile 1 than in the other quintiles. Of those subjects aged≥75 at the time of OGTT, the five quintile groups showed no significant differences in the incidence of myocardial infarction or in severity of coronary artery stenosis. Our results demonstrate an apparent, nonlinear relationship between glucose concentration and CHD, with an increase of CHD occurring in subjects above the 20th percentile of post-challenge glucose, compared with those in the lowest quintile. Our results also suggest that mild glucose intolerance in subjects in their mid-seventies and above does not significantly affect the development of CHD.

抄録全体を表示

Having recently been able to measure particle remnant, we measured the lipoproteins (particle remnant, RLP, Lipo-Z) that do not bind to an immunoaffinity gel mixture of anti-human apo B-100 and apo A-I monoclonal antibodies. RLP are known to be rich in apo E and consist of remnants of chylomicrons and VLDL. RLP have been suggested to be atherogenic. We measured the cholesterol (RLP (CHO)) and triglycerides (RLP (TG)) in RLP. RLP (CHO) has been associated with some atherosclerotic diseases. We regarded RLP (CHO) levels higher than 5mg/dl as RLP (CHO) positive. The subjects were 22 patients with chronic cerebral infarction (12 male, 10 female, mean age: 74.5±9.15 years), and 11 patients with no history of cerebral infarction as age-matched controls. In the patients with chronic cerebral infarction (CI group), RLP (CHO) levels were significantly higher than those of the control group (p<0.05). There were no significant differences between the CI group and the control group in other plasma lipid levels.
Eight patients (36%) were RLP (CHO) positive in the CI group, whereas RLP (CHO) levels were negative in the entire control group. In the CI group, 7 patients (32%) had hyperlipidemia (T-CHO>220mg/dl or TG>150mg/dl). Of the 7 patients, 6 patients (86%) were highly RLP (CHO) positive. Four patients (36.4%) had hyperlipidemia in the control group. In the 8 patients with chronic cerebral infarction which were RLP (CHO) positive, the levels of total cholesterol (p<0.01), Lipo-Z (p<0.01), apo A-I (p<0.05), apo A-II (p<0.05) and apo E (p<0.01) were significantly higher than the levels in the 14 patients with chronic cerebral infarction which were RLP (CHO) negative. These results suggest that further study of the relation between RLP, cerebral infarction and hyperlipidemia may contribute to the understanding of cerebral infarction due to lipid abnormalities.

抄録全体を表示

Selective alpha 1-adrenoceptor blockers (e. g., prazosin, doxazosin, terazosin) have been reported to have beneficial effects on serum lipid and lipoprotein levels. Those drugs tend to reduce the total and LDL cholesterol levels in hypertensive patients in clinical use. However, the mechanism of these beneficial effects is not clear. In this paper, we investigated the effect of selective alpha 1-adrenoceptor blockers on lipid metabolism, especially on HMG CoA reductase activity. In clinical study, doxazosin reduced serum total cholesterol levels. Serum apo B levels also decreased. In our in-vitro study using cultured human skin fibroblasts, prazosin inhibited the HMG CoA reductase activity in a dosedependent manner up to 40ng/ml (95nM). Maximum suppression of the activity was -42.6%, compared to the control group, which was not treated with any drugs. Doxazosin suppressed activity significantly at concentrations of 10nM and 30nM, and terazosin did the same at 2nM. Moreover, ketanserin (5HT2-serotonergic receptor antagonist), which also possesses an alpha adrenoceptor blocking effect, suppressed HMG CoA reductase activity in a dosedependent manner up to 300ng/ml. These concentrations were selected on the basis of those achieved in plasma during clinical use of these drugs. At the same concentration, prazosin, doxazosin and ketanserin induced increased regulation of LDL receptor activity. In our in-vivo study using hyperlipidemic hamsters, as well doxazosin reduced serum total cholesterol and triglyceride levels. Both free and esterified cholesterol content in the liver decreased from doxazosin. And doxazosin suppressed microsomal HMG CoA reductase activity (5-34%). From these data, we concluded that selective alpha 1-adrenoceptor blockers suppressed HMG CoA reductase activity and induced increased regulation of LDL receptor activity, and that this was one of the mechanisms of total and LDL cholesterol reduction in patients treated with alpha 1-adrenoceptor blockers.

抄録全体を表示

Lipids metabolism was investigated in a total of 85 patients (70 males and 15 females) with symptomatic arteriosclerotic obstruction (ASO) in the lower extremities. Dyslipidemia had been already pointed out as one of the risk factors for obstructive coronary lesions. 36 patients had a serum total cholesterol (TC) level higher than 220mg/dl (or 42.4%), while patient with a serum low density lipoprotein cholesterol (LDL-C) level higher than 140mg/dl. In a total of 42 patients (49.4%), dyslipidemia with high levels of both types of cholesterol were confirmed.
Twenty-eight of the patients have been treated with a series of LDL apheresis in which LDL is selectively removed in the manner of extracorporeal circulation. Dyslipidemia has been rapidly corrected after an initial couple of the apheresis, while clinical signs of ASO have produced parallel improvements in such conditions as coldness of the legs in 17 of 19 patients (89.5%), intermittent claudication in 14 of 17 patients (82.4%), foot pain at rest in 15 of 18 patients (83.3%), arterial pulsation in 12 of 16 patients (75.0%) and diminution in the size of ulcers or necrosis in 3 of 5 patients (60.0%).
Improvements in plethysmographic and thermographic findings have been concurrently observed in 10 out of 10 patients (100.0%) and 13 out of 14 patients (92.9%), respectively.
One tentative conclusion is that dyslipidemia may be a risk factor for symptomatic ASO in the lower extremities, and that attempts to actively correct it may be worth while.

抄録全体を表示

Intimal thickening of the coronary artery begins late in the fetal period. Migration of smooth muscle cells (SMCs) of the media into the intima, and their proliferation, are thought to be key events in the genesis of atherosclerosis. Therefore, we examined whether phenotypic modulation of SMCs occurs in the early development of the intimal thickenings of a human fetal coronary artery, obtained from autopsy cases, by using ultrastructural and stereological methods.
As a whole, there were no significant differences in the volume fractions of synthetic organelles (Vs) between intimal (Vs=21.9%, n=136) and medial SMCs (Vs=20.1%, n=216). Mean Vss of solitary intimal, migrating, and medial SMCs were 31.4, 23.9, and 20.1%, respectively. These findings suggest that phenotypic modulations of SMCs might be caused by separation of the medial layer from the environment, particularly release from extracellular matricies, or boosted by substances which promote separation.

抄録全体を表示

Cultured rat aortic smooth muscle cells (cultured rat aortic SMCs: 5×10⁵) suspended in the upper compartment of a Boyden chamber migrated through the pores of the filters separating the two compartments in response to rat platelet-derived attractant (rat PDA) in the lower compartment. We have previously demonstrated that this enhanced migration is inhibited when the filter is coated with elastin purified from normal human aorta. However, cultured rat aortic SMCs again migrate well toward the rat PDA when the elastin-coated filter is treated prior to the migration assay with 15% human plasma LDL. Pretreatment of elastin-coated filters with 15% human plasma HDL fails to remove the inhibitory effect of elastin. Pretreatment of elastin-coated filters with rabbit-anti human aortic elastin antibody at protein concentrations of from 36μg/ml to 36mg/ml also removed the inhibitory effect of elastin, although to the lesser extent than the effect of LDL.
These results suggest that the atherogenic effect of LDL might be due in part to an effect in vivo on the elastin, elastic fibers of the arterial wall.

抄録全体を表示