Akira Yashiro

Comparison of serum lipid values in variant angina pectoris and fixed coronary artery disease with normal subjects

Lipid and apolipoprotein (apo) levels in patients with variant angina were examined and compared with patients with coronary artery disease (CAD) and normal subjects (control). Cholesterol and triglyceride levels in plasma, lipoprotein fractions and several apolipoproteins were measured in 108 men (90 of whom had undergone coronary angiography): 22 had variant angina, 56 had fixed CAD (effort angina and old myocardial infarction) and 30 were normal subjects. Patients with variant angina showed more severe atherosclerotic lesions than the control group, but less severe lesions than the patients with fixed CAD. In comparison with lipid and apolipoprotein, high density lipoprotein cholesterol, apo AI and apo AII decreased significantly in control, variant angina and fixed CAD groups, respectively. Additionally, stepwise discriminant analysis revealed that apo AI was the best discriminator among the 3 groups or between variant angina or fixed CAD and the control group. Variant angina and fixed CAD patients could be discriminated from the control subjects by an apo AI level of 135 and 126 mg/dl, with 71% (p less than 0.025) and 73% (p less than 0.005) accuracy, respectively. By these criteria 77% of the patients with variant angina and 73% of the patients with fixed CAD were precisely discriminated. Discrimination between variant angina and fixed CAD patients, however, was not practical, even if the best discriminator was used. Thus, the apo AI level is useful in discriminating patients with variant angina and fixed CAD from normal subjects. Therefore, symptomatic patients with low apo AI levels should be aggressively examined.

Increased susceptibility of angiographically smooth left anterior descending coronary artery to an impairment of vasoresponse to acetylcholine, and the relation between impaired vasoresponse and low-density lipoprotein cholesterol level

In the present study, we demonstrated that the angiographically smooth LAD is more susceptible than the LC to an impairment of vasoresponse to acetylcholine, suggesting the more severe endothelial dysfunction in the LAD. We also showed that levels of LDL play a partial but important role on endothelial dysfunction.

Simvastatin increases plasma NO2− and NO3− levels in patients with hypercholesterolemia

In this study, plasma NO2- and NO3- (NOx-) levels were studied after lowering cholesterol with simvastatin in 26 outpatients with hypercholesterolemia (male, 9; female, 17; mean age, 59 +/- 12 years; cholesterol level > 220 mg/dl). Simvastatin (5 mg) was orally administered once daily, and blood samples were collected before, and after 4 and 12 weeks of treatment. Total, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) cholesterol were lowered (total, 254 +/- 44 mg/dl to 209 +/- 34 mg/dl; VLDL, 48 mg/dl [5-126 mg/dl] to 34 mg/dl [10-67 mg/dl]; LDL, 171 +/- 41 mg/dl to 133 +/- 37 mg/dl), but high-density lipoprotein (HDL) cholesterol was elevated (33 +/- 9.5 mg/dl to 39 +/- 11 mg/dl) at 12 weeks after starting simvastatin. Although the effects of simvastatin on the lipid levels nearly reached their maximum levels at 4 weeks, NOx- was elevated in a linear fashion with simvastatin (before; 8 +/- 17 mumol/l, at 12 weeks; 57 +/- 32 mumol/l). The % changes in the NOx- correlated directly with those in HDL-cholesterol at 12 weeks (P < 0.002) but not with other lipoprotein cholesterol fractions. These results suggest that simvastatin lowers cholesterol levels and elevates HDL while increasing the plasma NOx- levels.

Sustained-release nifedipine (nifedipine-L) suppresses plasma thromboxane B2 and 6-keto prostaglandin F1α in both young male smokers and nonsmokers

Sustained-release nifedipine (nifedipine-L) (40 mg twice a day) was administered orally to healthy young adult male smokers and nonsmokers for 10 days, and its effects on platelet aggregation, beta-thromboglobulin and platelet factor 4 levels, and plasma thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-Keto-PGF1 alpha) concentrations were studied. The plasma nifedipine-L concentration in smokers (46.0 +/- 7.4 ng/ml) was significantly lower than that in nonsmokers (88.2 +/- 1.2 ng/ml). Nifedipine-L did not affect platelet aggregation induced by adenosine diphosphate, collagen, or epinephrine in either smokers or nonsmokers. The plasma beta-thromboglobulin level on the tenth day of nifedipine-L administration in nonsmokers was lower than that in smokers, but there were no significant differences either with or without nifedipine-L or between nonsmokers and smokers. Nifedipine-L had no effect on the concentration of platelet factor 4 in either smokers or nonsmokers. On the other hand, nifedipine-L significantly decreased the plasma TxB2 and 6-keto-PGF1 alpha concentrations in both smokers and nonsmokers. Thus we concluded that nifedipine-L suppressed the production of plasma TxB2 from platelets and also subsequently suppressed the production of 6-keto-PGF1 alpha and that this action was not affected by cigarette smoking.

ENHANCED MACROPHAGE UPTAKE OF LIPOPROTEIN(A) AFTER CA2+-INDUCED AGGREGATE-FORMATION

We tested the hypothesis that aggregated lipoprotein(a) [Lp(a)] is avidly taken up by macrophages. Lp(a) was isolated by sequential centrifugations and gel chromatography from a patient with high plasma levels of Lp(a) who was being treated with low density lipoprotein (LDL)-apheresis. Aggregated Lp(a) was prepared by mixing native Lp(a) with 2.5 mmol/L CaCl2, and 54% of the 125I-Lp(a) aggregated after interacting with CaCl2. The binding and degradation of aggregated Lp(a) in macrophages were 4.6- and 4.7-fold higher than those of native Lp(a), respectively. An excess amount of LDL did not inhibit either increase. Cholesterol esterification in macrophages was markedly stimulated by aggregated Lp(a), and macrophages were transformed into foam cells. Cytochalasin B, a phagocytosis inhibitor, strongly inhibited the degradation and cholesterol esterification (78 and 83%, respectively). These findings suggested that aggregation may be partially involved in Lp(a) accumulation, thereby contributing to the acceleration of atherosclerosis.

Atherogenic lipoproteins inhibit catecholamine secretion in cultured bovine adrenal medullary cells.

The effects of lipoproteins on ion channel-mediated catecholamine secretion were investigated in cultured bovine adrenal medullary cells. Low density lipoprotein (LDL; 20–80 mg/dl) and lipoprotein(a) [Lp(a); 10–80 mg/dl] inhibited catecholamine secretion induced by carbachol, an activator of nicotinic acetylcholine receptor-ion channels. LDL and Lp(a) suppressed carbachol-induced 22Na+ influx as well as 45Ca2+ influx in a concentration-dependent manner similar to that of catecholamine secretion. The inhibition of catecholamine secretion by Lp(a) was not overcome by increasing the concentration of carbachol. On the other hand, high density lipoprotein (HDL; <150 mg/dl) had no effect on 22Na+ influx, 45Ca2+ influx, and catecholamine secretion. Like LDL and Lp(a), a synthetic peptide homologous to human plasma apolipoprotein B (apoB), apoB fragment3358–3372-amide (3–60 µM), attenuated 22Na+ influx, 45Ca2+ influx, and catecholamine secretion caused by carbachol. The apoB fragment also suppressed 22Na+ influx induced by veratridine (an activator of voltage-dependent Na+ channels) and 45Ca2+ influx induced by 56 mM K+ (an indirect activator of voltage-dependent Ca2+ channels). These findings suggest that atherogenic lipoproteins such as LDL and Lp(a) suppress catecholamine secretion by interfering with Na+ influx through nicotinic acetylcholine receptor-ion channels, in which apoB, a structural component common to both LDL and Lp(a), plays an important role. The inhibition by atherogenic lipoproteins of catecholamine secretion may influence the progression of atherosclerosis induced by these lipoproteins.

Long Term Effect of LDL Apheresis in Japan

LDL-apheresis is introduced in many cases all over Japan. Among them, evaluation of long-term effect on ischemic heart disease (IHD) has made on 10 cases with homozygous familial hypercholesterolemia (FH) and 49 cases with heterozygous FH.As to homozygous FH, 3 patients had angina pectoris. Mean duration of treatment was 26 months (52 treatments). The changes in total cholesterol (TC) in each treatment was from 426 mg/dl to 151 mg/dl. Improvement in IHD was observed in 5 out of 10 cases.As to heterozygous FH, 17 cases had history of myocardial infarction and 12 had angina pectoris. Mean duration of treatment was 13 months (19 treatments). Mean TC was decreased from 271 mg/dl to 126 mg/dl by each treatment. Regression in Achilles tendon thickenting or skin and palpebral xanthomas was observed. Frequency of anginal attacks decreased in 8 out of 17 cases. Ischemic change in ECG were improved in 3 out of 26 cases. Coronary angiography performed with 2 to 3 years of interval in some cases revealed regression o...