Hiroshi Mokuno

Concentrations of interleukins, interferon, and C-reactive protein in stable and unstable angina pectoris.

We analyzed the concentrations of interleukins (IL)-6, IL-10, IL-12, and IL-18, interferon (IFN)-gamma, and high-sensitivity C-reactive protein (hsCRP) in 40 patients with unstable angina (UAP), 39 patients with stable angina (SAP), and 52 age- and gender-matched controls. Compared with the control group, IL-12 concentrations were significantly higher in both the SAP and UAP groups, especially in the UAP group, and the IL-18 concentrations tended to be higher in the UAP group. Conversely, IL-10 concentrations were significantly lower in the SAP and UAP groups. Both IL-6 and hsCRP concentrations were significantly higher in the UAP group. The levels of hsCRP were positively correlated with inflammatory or proinflammatory cytokines (IL-6, IL-12, and IL-18), and negatively correlated with anti-inflammatory cytokine (IL-10). Moreover, the levels of IL-12 were positively correlated with IL-18, and negatively correlated with IL-10, and the results revealed the T-helper 1 dominant state. These results suggested that the inflammatory response was strongly associated with coronary atherosclerosis and angina pectoris, and that the T-helper 1 dominance may play an important role in these diseases.

Common polymorphism in the promoter of the CD14 monocyte receptor gene is associated with acute myocardial infarction in Japanese men

We investigated whether C(-260)-->T polymorphism in the promoter of the CD14 monocyte receptor gene predisposed to coronary atherosclerosis and acute myocardial infarction (AMI) in Japanese men. The frequencies of T allele and T/T homozygotes in patients with AMI were significantly higher than in controls and in patients with angina without prior AMI, suggesting that the CD14 promoter polymorphism is associated with AMI rather than with coronary atherosclerosis, and this polymorphism may be one of the genetic risk factors for AMI in Japanese men.

Lack of Increased Coronary Atherosclerotic Risk Due to Elevated Lipoprotein(a) in Women ≥55 Years of Age

BACKGROUND Numerous studies have indicated that there is an association between lipoprotein(a) [Lp(a)] and coronary artery disease (CAD) in middle-aged men; however, few studies have addressed this issue in women or the elderly. METHODS AND RESULTS Serum Lp(a) concentrations were determined in 354 women and 706 men with or without angiographically defined CAD (one or more coronary arteries with narrowing of > or = 75%). The age-specific impact of elevated Lp(a) (> or = 30 mg/dL) on CAD was examined in each sex. In the younger age group (< 55 years old), elevated Lp(a) was independently associated with CAD in both sexes (adjusted odds ratio [OR]: women, 6.90, P < .01; men, 2.63, P < .05). The age-specific ORs declined with age, and elevated Lp(a) no longer conferred an increased CAD risk in either elderly men or women > or = 65 years old. In the age group of 55 to 64 years, elevated Lp(a) was positively associated with CAD for men (adjusted OR: 2.45, P < .05) but not for women (adjusted OR: 0.56, P = NS). CONCLUSIONS For both sexes, elevated Lp(a) appears to be an independent risk factor for premature CAD and the importance of Lp(a) appears to decrease with age. However, for women, the risk estimate of Lp(a) began to decline at an age approximately 10 years younger than for men. These data suggest that not only age- but also sex-specific factors such as menstrual status may interact with the association between Lp(a) and CAD.

Effects of troglitazone on atherogenic lipoprotein phenotype in coronary patients with insulin resistance.

Insulin resistance is associated with atherogenic lipoprotein phenotype, including small dense LDL particle, hypertriglycemia and low HDL cholesterol levels. Troglitazone, a novel insulin sensitizing agent, may improve the associated lipid profile in patients with insulin resistance. We examined the effects of troglitazone (400 mg daily for 12 weeks) in 12 non-diabetic coronary patients (60+/-10 years), all of whom had hyperinsulinemic response to an oral glucose load. Troglitazone markedly reduced the insulin response. After the treatment, plasma triglycerides decreased by 32% (P<0.05), HDL cholesterol increased by 11%, (P<0.05) and LDL peak particle diameter increased from 24.7+/-0.3 to 25.5+/-0.5 nm (P<0.01). These lipidic improvements were associated with a significant rise in postheparin lipoprotein lipase levels (175+/-52 to 217+/-69 ng/ml, P<0.01). In patients with insulin resistance syndrome, troglitazone improved the atherogenic lipoprotein phenotype as well as hyperinsulinemia. Our data suggest that troglitazone therapy could reduce the atherosclerotic risk due to insulin resistance even in non-diabetic patients.

Possible role of high susceptibility of high-density lipoprotein to lipid peroxidative modification and oxidized high-density lipoprotein in genesis of coronary artery spasm

Recent study demonstrated high susceptibility of plasma LDL to lipid peroxidative modification in patients with variant angina. Oxidized stress state, especially oxidized LDL, may induce coronary artery spasm by its impairing effect of endothelium-dependent arterial relaxation, but precise mechanisms remain unclear. Study subjects included 93 patients who underwent coronary angiographic examination: 12 patients with coronary artery spasm provoked by ergonovine without organic stenosis (group I), 11 patients who did not demonstrate coronary artery spasm or organic stenosis (group II) and 70 patients with organic coronary artery stenosis (group III). Levels of plasma HDL-cholesterol and apoA-I in group I were similar to those in III but were significantly lower than those in II, although the other plasma lipid parameters were not different among the three groups. The levels of TBARS in plasma and HDL were significantly higher in group I than in II or III (2.94+/-1.56 vs. 1.91+/-0.35 or 2.23+/-0.89 nmol MDA/ml and 1.23+/-1.00 vs. 0.54+/-0.37 or 0.70+/-0.63 nmol MDA/mg protein; P < 0.05), although the levels of TBARS in LDL were not significantly different. In the monitoring curve of diene production during copper-induced lipid peroxidation of HDL, its propagation slope was steeper and levels of maximum diene absorbance was higher in group I as compared with that in II or III, but not found in those of LDL. These results suggested that high susceptibility of HDL to lipid peroxidative modification in group I may contribute to the genesis of coronary artery spasm, and oxidized HDL rather than oxidized LDL is more likely to be related to coronary artery spasm.

Characterization of low-density lipoprotein subclasses in children☆☆☆

Low-density lipoprotein (LDL) particles are heterogeneous in density, size, and chemical composition, and this heterogeneity is thought to be genetically influenced. In the present study, plasma LDL subclasses in 248 children aged 7 to 13 years were analyzed by gradient gel electrophoresis. The prevalence of small dense LDL (SDLDL), a potent atherogenic LDL, was 9.3%, which is lower than that reported in adults. Furthermore, children with this LDL subclass showed increased body fatness and dyslipidemia, including elevated plasma triglyceride and apolipoprotein (apo) B concentrations and decreased plasma high-density lipoprotein (HDL) cholesterol and apo A-I concentrations, compared with children without this phenotype. These findings suggest that in addition to genetic factors, environmental factors that affect these cardiovascular risk factors may also influence expression of the SDLDL subclass.

Serum levels of remnant lipoprotein cholesterol and oxidized low-density lipoprotein in patients with coronary artery disease

BACKGROUND Oxidized low-density lipoprotein (OxLDL) and remnant lipoprotein play a crucial role in the development of atherosclerosis. Recently, a novel method for measuring remnant cholesterol levels (remnant lipoproteins cholesterol homogenous assay: RemL-C) has been established. However, the correlation between OxLDL and remnant lipoprotein, including RemL-C, has not been fully investigated. METHODS We enrolled 25 consecutive patients with documented coronary artery disease (CAD) and 20 controls. Remnant-like particle cholesterol (RLP-C) and RemL-C were used to determine the levels of remnant lipoprotein cholesterol. Serum levels of malondialdehyde-modified LDL (MDA-LDL) and OxLDL using a monoclonal antibody DLH3 (OxPC) were used to measure the concentration of circulating OxLDL. RESULTS The CAD group had high levels of fasting glucose and glycosylated hemoglobin (HbA1c), and low levels of high-density lipoprotein cholesterol compared with the control group. Serum levels of total cholesterol or LDL cholesterol were not significantly different between the two groups. The levels of RemL-C (p = 0.035), MDA-LDL (p = 0.018), and MDA-LDL/LDL-C (p = 0.036) in the CAD group were significantly higher than those in the control group. The levels of RLP-C tended to be higher in the CAD group than those in the control group (p = 0.096). Positive correlations were demonstrated between remnant lipoprotein cholesterol and OxLDL (RLP-C and MDA-LDL/LDL-C, r = 0.45, p = 0.0024, RLP-C and OxPC, r = 0.51, p = 0.0005, RemL-C and MDA-LDL/LDL-C, r = 0.42, p = 0.0044, RemL-C and OxPC, r = 0.43, p = 0.0043). Similar trends were observed in non-diabetic subjects and in subjects without metabolic syndrome. Positive correlations were also observed between RLP-C and RemL-C (r = 0.94, p < 0.0001) and between MDA-LDL/LDL-C and OxPC (r = 0.40, p = 0.0074). CONCLUSIONS These results suggest that the association between high levels of remnant lipoprotein cholesterol and high OxLDL levels might be linked to atherogenesis in patients with CAD.

Effectiveness of LDL-apheresis in preventing restenosis after percutaneous transluminal coronary angioplasty (PTCA): LDL-apheresis angioplasty restenosis trial (L-ART)

To investigate the efficacy of reducing plasma lipoprotein(a) (Lp(a)) as well as low density lipoprotein cholesterol (LDL-C) levels on the prevention of restenosis after PTCA, LDL-apheresis was attempted on a total of 54 patients at six institutions. LDL-apheresis using a dextran sulfate cellulose column has been proven to be an effective method for reducing both plasma Lp(a) and LDL-C levels. As a subgroup (apheresis-drug combined group), 29 of the 54 patients were given Pravastatin (HMG CoA reductase inhibitor) and Niceritrol (Nicotinic Acid) in addition to LDL-apheresis to maintain low plasma levels of both Lp(a) and LDL-C through the follow-up period of 5 months after PTCA. Patients whose plasma Lp(a) levels were reduced by more than 50% showed a lower restenosis rate than those whose plasma Lp(a) levels were reduced by less than 50% (21.2% vs. 52.4%, P = 0.0179), especially in patients with high plasma Lp(a) levels above 30 mg/dl where a much lower restenosis rate (15.0%) was observed. Furthermore, in the apheresis-drug combined group, the restenosis rate was 11.8% regardless of baseline plasma Lp(a) levels, including even those below 30 mg/dl. In conclusion, in patients with high plasma Lp(a) levels, a greater than 50% reduction in Lp(a) levels by LDL-apheresis is effective in preventing restenosis after PTCA. If the plasma Lp(a) reduction rate is greater than 50%, LDL-apheresis combined with lipid-lowering drugs such as niceritrol and pravastatin seems to be more effective, even in patients with low plasma Lp(a) levels.

Involvement of cholesterol-enriched microdomains in class A scavenger receptor-mediated responses in human macrophages

OBJECTIVE Lipid rafts are cholesterol-enriched microdomains on cell membranes. We hypothesized that these microdomains could involve modified low-density lipoprotein (LDL) uptake. METHODS AND RESULTS Co-localizations of cholesterol-enriched microdomains and CD204 during the uptake of acetyl LDL (AcLDL) and oxidized LDL were observed using Alexa488-labeled polyethylene glycol cholesteryl ester, which is a sensitive probe used to analyze the dynamics of cholesterol-rich lipid microdomains in living cells. The lipid raft disruptors, methyl-β cyclodextrin and filipin, inhibited the uptake of AcLDL. CD204 siRNA treatments significantly reduced AcLDL uptake by 80%. We also demonstrated the presence of CD204 in the detergent-resistant membrane fraction (DRM) by immunoblotting analysis. The ratio of CD204/flotillin-1 in DRM was increased 11.5-fold by modified LDL administration. The PI3 kinase inhibitor LY294002, but not the Src kinase inhibitor PP1 or the Gαi/o inhibitor pertussis toxin, inhibited modified LDL uptake. The production of interleukin (IL)-8, but not CCL2, CXCL2, CXCL3, IL-6 or tumor necrosis factor-α was increased by AcLDL administration. The AcLDL-induced IL-8 production was inhibited by LY294002 and filipin. CONCLUSIONS These data firstly demonstrated that PI3 kinase-associated cholesterol-enriched microdomains are involved in CD204-mediated modified LDL uptake in human macrophages. Cholesterol-enriched microdomains may play a critical role in inflammatory processes.

High prevalence of seropositivity for antibodies to Chlamydia-specific lipopolysaccharide in patients with acute coronary syndrome.

Background Results of recent studies have demonstrated that there is an association between infection with Chlamydia pneumoniae and coronary artery disease (CAD). Inflammatory response caused by chlamydial infection has been considered to contribute to the development of atherosclerosis in coronary arteries. Objective The aim of this study was to investigate the specific relations between chlamydial infection and coronary events in patients with CAD. Methods We measured serum levels of immunoglobulin A and G antibodies against Chlamydia spp.-specific lipopolysaccharide in 155 patients with CAD and 60 age-matched and sex-matched healthy controls by enzyme-linked immunosorbent assay. CAD patients were divided into groups of the patients with acute coronary syndrome [(ACS), n = 35], old myocardial infarction [(OMI), n = 60] and chronic coronary heart disease [(CCHD), n = 60]. Results Prevalence of both seropositive antibodies in the control group and CCHD group were not different. In contrast, in ACS group there were significantly higher prevalences of seropositive immunoglobulin A (46 versus 12%, P = 0.0001) and G (74 versus 45%, P = 0.005) antibodies and in OMI group there was a significantly higher prevalence of seropositive immunoglobulin A antibodies (28 versus 12%, P = 0.02). Furthermore, compared with CCHD group, in ACS group there were significantly higher prevalences of seropositive immunoglobulin A (P = 0.00006) and G (P = 0.002) antibodies and in OMI group there was a higher prevalence of seropositive immunoglobulin A (P = 0.01). Adjustment for confounding factors did not change these findings. Conclusions Infection with Chlamydia is significantly associated with ACS and OMI, but not with CCHD. These findings suggest that chronic and reactive infection with Chlamydia can lead to disruption of vulnerable plaque in patients with ACS.