Yukihiko Momiyama

Plasma osteopontin levels are associated with the presence and extent of coronary artery disease

Recently, osteopontin (OPN) mRNA was reported to be highly expressed in atherosclerotic plaques, most strikingly in calcified plaques. We examined if plasma OPN levels are associated with coronary stenosis and calcification in patients with coronary artery disease (CAD). We measured plasma OPN levels in 178 patients undergoing coronary angiography. Compared with 71 patients without CAD, 107 with CAD had higher OPN levels (616+/-308 ng/ml versus 443+/-237 ng/ml, P<0.001). A stepwise increase in OPN levels was found depending on the number of >50% stenotic coronary vessels: 540+/-293 ng/ml in 1-vessel, 615+/-230 ng/ml in 2-vessel, and 758+/-416 ng/ml in 3-vessel disease. OPN levels also correlated with the numbers of >50% and >25% stenotic segments (r=0.35 and 0.43, respectively, P<0.001). In multivariate analysis, OPN levels were significantly associated with CAD (odds ratio=1.21, 95% CI=1.05-1.39 for a 100 ng/ml increase) independent of traditional risk factors. Coronary calcification was found in 86 patients. OPN levels were higher in patients with calcification than in those without calcification (608+/-328 ng/ml versus 490+/-246 ng/ml, P<0.01) and correlated with the number of calcified segment (r=0.26, P<0.001). However, OPN levels were not independently associated with coronary calcification. Thus, plasma OPN levels were found to be associated with the presence and extent of CAD.

Effects of Interleukin-1 Gene Polymorphisms on the Development of Coronary Artery Disease Associated With Chlamydia Pneumoniae Infection

OBJECTIVES This study was done to elucidate the effects of interleukin (IL)-1 gene polymorphisms on coronary artery disease (CAD) associated with Chlamydia pneumoniae (CP) infection. BACKGROUND It was suggested that CP was associated with CAD. However, genetic factors involved in CAD associated with CP infection are unknown. METHODS We evaluated CP immunoglobulin G (IgG) seropositivity and IL-1 beta (a C/T transition at -511) and IL-1 receptor antagonist (IL-1Ra) (a variable-number repeat in intron 2) gene polymorphisms in 292 patients undergoing coronary angiography. RESULTS Seropositivity for CP was present in 61% of patients with CAD versus 51% without CAD (p = NS). The percentage of patients having IL-1 beta (-511) C/C genotype and/or IL-1Ra (intron 2) 2- or 3-repeat allele was higher in patients with CAD than without CAD (29 vs. 16%, p < 0.025). To clarify the effects of these CAD-associated variants (IL-1 beta C/C and/or IL-1Ra 2- or 3-repeat), patients were divided into four groups. A stepwise increase in CAD prevalence was observed depending on CP seropositivity and the variants. Odds ratios (ORs) for CAD were 1.4 in the group with seropositivity alone, 1.7 with the variants alone and 3.8 with seropositivity and the variants. Such variants were associated with CAD in both patients with and without seropositivity. Interestingly, high prevalence of myocardial infarction (MI) was confined to the group with seropositivity and the variants (OR, 2.8). The variants were associated with MI only in patients with CP seropositivity. CONCLUSIONS The IL-1 gene polymorphisms were found to play a role in the development of CAD, especially MI, in patients with CP infection.

Green Tea Consumption and Serum Malondialdehyde-Modified LDL Concentrations in Healthy Subjects

Objective: Green tea was shown to inhibit LDL oxidation, platelet aggregation, and matrix metalloproteinases (MMPs) activities in vitro. We tried to elucidate whether or not green tea consumption may have these effects in vivo, which may be protective against atherosclerotic disease. Methods: We measured serum malondialdehyde-modified LDL (MDA-LDL) concentrations and urine 8-epi-prostaglandin (PG) F2α in 22 healthy male nonsmokers. They drank 7 cups/day of water for 2 weeks and drank 7 cups/day of green tea for the next 2 weeks. Regarding platelet aggregation, plasma thromboxane B2 (TXB2) and 6-keto-PGF1α concentrations and ex vivo platelet aggregation were evaluated. Plasma MMP-2 and -9 concentrations were also measured. Results: Of the 22 subjects, 20 had been in the habit of drinking green tea before the study. Plasma catechins concentrations significantly decreased at the end of the water period and then increased at the end of the green tea period. Although no change in plasma LDL-cholesterol concentrations (110 ± 33 vs. 113 ± 28 mg/dL, p = NS) was found, MDA-LDL concentrations (84 ± 45 vs. 76 ± 40 IU/L, p < 0.05) and the ratio of MDA-LDL/LDL-cholesterol (0.74 ± 0.21 vs. 0.65 ± 0.20, p < 0.02) significantly decreased at the end of the green tea period. However, no significant changes were observed in urine 8-epi-PGF2α concentrations, in platelet aggregation, nor in plasma TXB2, 6-keto-PGF1α or MMP concentrations. Conclusion: Daily consumption of green tea decreased serum MDA-LDL concentrations, but it had no significant effects on platelet aggregation, platelet TX production or plasma MMPs concentrations. Our results suggest that green tea consumption may inhibit LDL oxidation in vivo.

Comparison of green tea intake in Japanese patients with and without angiographic coronary artery disease

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High plasma levels of matrix metalloproteinase-8 in patients with unstable angina

Matrix metalloproteinases (MMPs) play a role in collagen breakdown, leading to plaque instability. High levels of MMPs mRNA and proteins, especially MMP-1, MMP-2, MMP-8, MMP-9, and MMP-13, were shown in human atherosclerotic plaques. However, among various MMPs, only MMP-1, MMP-8 and MMP-13, so-called interstitial collagenases, can initiate collagen breakdown. To elucidate whether MMP-1, MMP-8 and MMP-13 levels in blood were high in patients with unstable angina (UAP), we measured serum MMP-1 and plasma MMP-8 and MMP-13 levels in 45 patients with UAP, 175 with stable coronary artery disease (CAD), and 45 controls. Plasma C-reactive protein levels tended to be higher in patients with UAP than in those with stable CAD and controls (median 0.94 vs. 0.69 and 0.51mg/l). Regarding blood levels of MMPs, MMP-13 levels were above the lower detection limit in only one patient with UAP (2%), one with stable CAD (1%), and none in controls. MMP-1 levels did not differ among patients with UAP, stable CAD, and controls (median 4.8, 5.3, and 5.4ng/ml). Notably, MMP-8 levels were higher in patients with stable CAD than in controls (median 3.5ng/ml vs. 2.8ng/ml, P<0.005), however, MMP-8 levels in patients with UAP were much higher than those in stable CAD (3.9ng/ml vs. 3.5ng/ml, P<0.05). In multivariate analysis, MMP-8 level was an independent factor for UAP. Thus, plasma MMP-8 levels were found to be high in patients with UAP, suggesting that MMP-8 levels in UAP may reflect coronary plaque instability and that MMP-8 is a promising biomarker for UAP.

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.

Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques: a 2-year follow-up by noninvasive MRI

Background Using MRI, we reported plaque regression in thoracic aorta and retardation of plaque progression in abdominal aorta by 1-year atorvastatin. However, association between serial plaque changes and LDL-cholesterol levels was not fully elucidated. Design A prospective, randomized, open-label trial. Methods We investigated the long-term effect of 20 versus 5-mg atorvastatin on thoracic and abdominal plaques and the association between plaque progression and on-treatment LDL-cholesterol levels in 36 hypercholesterolemia patients. MRI was performed at baseline and 1 and 2 years of treatment. Vessel wall area change was evaluated. Results The 20-mg dose markedly reduced LDL-cholesterol levels (−47%) versus 5-mg (−35%) dose. After 2 years of treatment, regression of thoracic plaques was found in the 20-mg group (−15% vessel wall area reduction), but not in the 5-mg group (+7%). Although the 20-mg dose induced plaque regression (−14%) from baseline to 1 year, no further regression was seen from 1 to 2 years of treatment (−1%). Regarding abdominal plaques, progression was found in the 5-mg group (+10%), but not in the 20-mg group (+2%). Plaque progression in the 5-mg group was found from baseline to 1 year (+8%), but not from 1 to 2 years (+2%). The degree of thoracic plaque regression correlated with LDL-cholesterol reduction (r = 0.61), whereas thoracic plaque change from 1 to 2 years correlated with on-treatment LDL-cholesterol levels (r = 0.64). Conclusion Twenty milligrams of atorvastatin regressed thoracic plaques. However, maintaining low LDL-cholesterol levels was needed to prevent plaque progression. In abdominal aorta, only retardation of plaque progression was found after 2 years of 20-mg treatment. Eur J Cardiovasc Prev Rehabil 16:222-228

A Possible Association Between Coronary Plaque Instability and Complex Plaques in Abdominal Aorta

Objective—Coronary plaque instability causes myocardial infarction (MI). Angiographic lesions with such instability are complex lesions. Complex carotid plaques were reported to be prevalent in unstable angina. We investigated associations between coronary plaque instability, such as MI and angiographic complex coronary lesions, and aortic plaques. Methods and Results—Aortic MRI was performed in 146 patients undergoing coronary angiography, of whom 108 had coronary artery disease (CAD) and 44 also had MI. Prevalence of plaques in thoracic and abdominal aortas was higher in patients with than without CAD (73% and 94% versus 32% and 79%), but it was similar in CAD patients with and without MI. Notably, complex plaques in abdominal aorta were more prevalent in CAD patients with than without MI (36% versus 14%; P<0.025). In multivariate analysis, abdominal complex plaques were associated with MI (odds ratio [OR], 4.5; 95% CI, 1.5 to 13.8). Among patients without MI, thoracic and abdominal complex plaques were more prevalent in patients with than without complex coronary lesions (22% and 33% versus 2% and 7%; P<0.05). Abdominal complex plaques were also associated with complex coronary lesions (OR, 9.8; 95% CI, 1.1 to 85.9). Conclusion—Complex plaques in abdominal aorta were associated with MI and complex coronary lesions, suggesting a link between coronary and aortic plaque instability.

Insulin edema in diabetes mellitus associated with the 3243 mitochondrial tRNALeU(UUR) mutation; Case reports

We encountered a patient with diabetes mellitus due to the 3243 mitochondrial tRNA mutation(DM-Mt3243), who developed insulin edema and hepatic dysfunction after starting insulin. Such a rare phenomenon was unlikely to be a fortuitous coincidence in mitochondrial diabetes, as none in 197 non-mutant NIDDM patients had same episode. Moreover, similar leg edema was noticed in another DM-Mt3243 patient, and other two DM-Mt3243 patients had leg edema which responded to coenzyme Q10. These observations suggest further a role of mitochondrial function on leg edema. The mechanism of his insulin edema may involve vasomotor changes induced by the rapidly glycemic control, because our case of insulin edema had a prominent increase of strong succinate dehydrogenase reactive vessels. Alternatively, myocardial dysfunction might have produced leg edema and hepatic dysfunction, because he had subclinical myocardial dysfunction, judged by imaging with beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid. The third explanation is that a rapid improvement of glycemic control might have induced hepatic reoxygenation and the production of reactive oxygen species in the liver that contributed to cell damage. Thus, although we cannot draw definite conclusion, our experiences here suggest that mitochondrial dysfunction is important in the etiology of insulin edema.

Associations between serum lipoprotein(a) levels and the severity of coronary and aortic atherosclerosis

To elucidate the associations between Lp(a) levels and coronary and aortic atherosclerosis, we performed aortic MRI in 143 patients undergoing coronary angiography. Severity of aortic atherosclerosis was represented as plaque scores. Of the 143 patients, 104 had coronary artery disease (CAD). Thoracic and abdominal aortic plaques were found in 89 and 131 patients. Lp(a) levels increased stepwise with the number of stenotic coronary vessels: 15.7 (CAD(-)), 21.2 (1-vessel), 21.4 (2-vessel), and 22.9 mg/dl (3-vessel) (P<0.05). For aortic atherosclerosis, 143 patients were divided into quartiles by plaque scores. Lp(a) did not differ among quartiles of thoracic plaques: 17.1, 19.0, 23.5, and 21.2 mg/dl (P=NS), whereas Lp(a) increased stepwise with quartiles of abdominal plaques: 17.1, 19.2, 19.1, and 24.0 mg/dl (P<0.05). Lp(a) was an independent factor for CAD and abdominal aortic plaques, but not thoracic plaques. Thus, Lp(a) levels were associated with aortic atherosclerosis, especially in abdominal aorta, as well as coronary atherosclerosis.