Tommi A. Koivu

Serum matrix metalloproteinase-9 concentration in angiographically assessed coronary artery disease.

Expression of several matrix metalloproteinases (MMPs) in atherosclerotic plaques has been well documented, and there are findings to indicate that arterial inflammation is reflected in increased serum concentration of matrix metalloproteinase-9 (MMP-9). In coronary atherosclerosis, there is enhanced expression of this MMP, which may be predictive of the severity of the disease. We determined the concentrations of serum MMP-9 in 61 patients (47 males, 14 females) who had >50% obstruction in one or more coronary arteries as assessed by coronary angiography before bypass surgery. In a control group of 19 patients (9 males, 10 females) there were no pathological findings in coronary angiography. ANOVA showed that serum MMP-9 concentrations were highest in patients with 3-vessel coronary artery disease (CAD) (57.3 - 39.1 µg/L, p= 0.011). The difference remained statistically significant after adjustment for age, diabetes and sex (p= 0.025, ANCOVA). When the groups were compared with each other, serum MMP-9 concentration was higher in the patients with 3-vessel CAD than in those with 1- or 2-vessel CAD (40.4 - 25.1 µg/L, p= 0.044) or in the controls (32.2 - 16.1 µg/L, p= 0.007). These results show that serum MMP-9 is elevated in patients with severe coronary stenosis compared with controls. Since MMP-9 has been suggested to reflect inflammation in atherosclerotic plaques, it may be useful in the evaluation of the severity of cardiovascular disease.

Effect of pravastatin in mildly hypercholesterolemic young men on serum matrix metalloproteinases

Pravastatin decreases serum MMP-9 concentration in clinically healthy men. This may reflect reduction of nonsymptomatic chronic arterial inflammation.

The effect of hormone replacement therapy on atherosclerotic severity in relation to ESR1 genotype in postmenopausal women

OBJECTIVE The atheroprotective action of estrogen is mediated by estrogen receptors (ESR) 1 and 2, expressed in atherosclerotic lesions. The effects of hormone replacement therapy (HRT) and ESR1 PvuII genotypes on atherosclerosis have not previously been studied prospectively in postmenopausal women. METHODS We investigated the effect of HRT on the progression of atherosclerosis in a 5-year follow-up study of 88 postmenopausal women aged 45-71 years at baseline allocated into three groups based on the use of HRT. The HRT-EVP group (n=26) used sequential estradiol valerate (EV) plus progestin (P), the HRT-EV group EV alone (n=32), and a control group (n=30) was without HRT. The atherosclerosis severity score (AS) of the abdominal aorta and carotid arteries were determined by sonography and the ESR1 PvuII genotypes (P/P, P/p and p/p) by PCR. RESULTS HRT, time and ESR1 PvuII genotype had a statistically significant or borderline significant main effect on AS during 5-year follow-up (P=0.004, P<0.001 and P=0.090, respectively), when analyzed by repeated measures analysis of variance. There was a significant genotype-by-treatment (HRT-EVP and control groups) interaction for AS (P=0.034). In response to HRT-EVP, subjects with P/P, compared with those with P/p and p/p genotypes, had a less increase in AS (1.61+/-1.14 vs. 1.71+/-1.27 vs. 2.43+/-1.27). Baseline AS as covariate in similar model does not change the significant interaction effect between HRT-EVP and control groups (P=0.036). But this effect was not found between HRT-EV and control groups. CONCLUSIONS Our results suggest that the effect of HRT-EVP in postmenopausal women on progression of AS may be determined in part by the genotype of ESR1 PvuII.

Association of serum MMP-9 with autoantibodies against oxidized LDL

Monocyte-derived macrophages in atherosclerotic plaques secrete matrix metalloproteinases (MMPs), which may contribute to plaque rupture. There has been much speculation as to which factors precipitate in the arterial inflammation. Oxidized low density lipoprotein (oxLDL) has been suggested to have proinflammatory properties, and it has been shown to increase matrix metalloproteinase-9 (MMP-9) secretion by macrophages in vitro. We determined serum MMP-9 concentration and autoantibodies against oxLDL by ELISA in men with angina pectoris (n=243) and age-matched controls (n=238). The association between serum MMP-9 concentration and autoantibodies against oxLDL was evaluated. Autoantibody level against oxLDL, expressed in optical density units, was significantly higher in subjects with angina pectoris compared to controls (0.100+/-0.064 versus 0.088+/-0.051, respectively, P=0.030), but serum levels of MMP-9 did not differ significantly between these groups (54.2+/-29.9 versus 50.6+/-23.1 microg/l). However, autoantibodies against oxLDL correlated positively with serum MMP-9 (r=0.21, P<0.001). In a multiple regression model (including age, diastolic blood pressure, cholesterol, HDL cholesterol, triglycerides, BMI, smoking and MMP-9) serum MMP-9 (beta=0.200, P<0.001) and smoking (beta=0.179, P<0.001) were significantly associated with autoantibodies against oxLDL. In conclusion, autoantibodies against oxLDL were positively associated with angina pectoris and serum MMP-9. Since autoantibody level against oxLDL could be expected to reflect the degree of oxLDL in the vessel wall, our results suggest that oxLDL is associated with MMP-9 in vivo.

Association of carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) with serum lipid profile in the Finnish population.

BACKGROUND Moderate consumption of alcohol may reduce mortality from vascular diseases. The beneficial effects of alcohol may partly be mediated by its effects on lipoprotein metabolism. We studied the connection between alcohol consumption and the serum lipid profile from a well-documented national health program study. METHODS AND RESULTS Carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) were used as biochemical markers for alcohol consumption. The laboratory analyses were carried out on 5675 subjects (3097 males and 2578 females). The subjects were divided into quartiles on the basis of CDT or GGT value. The highest CDT quartile and the lowest GGT quartile seemed to be associated with a favorable lipid profile and the lowest CDT quartile and the highest GGT quartile were associated with an unfavorable lipid profile. Serum high density lipoprotein (HDL) cholesterol values were significantly higher and triglycerides lower with increasing serum CDT concentrations for both men and women. Increasing serum GGT was associated with higher serum total cholesterol and higher triglycerides in both men and women and lower HDL cholesterol in men. CONCLUSIONS CDT and GGT seem to detect different populations of subjects in regard to lipid metabolism. These observations may lead to a better understanding of the effects of alcohol consumption on lipids as well as mechanisms behind favorable and detrimental effects of alcohol on vascular diseases. CONDENSED ABSTRACT Carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) were used as biochemical markers for alcohol consumption. A total of 3097 males and 2578 females were divided into quartiles on the basis of their CDT or GGT values. The highest CDT quartiles had higher HDL and lower triglycerides, whereas the highest GGT quartiles appeared to be associated with higher total cholesterol and triglycerides in both genders and lower HDL in men. CDT and GGT seem to detect different populations of subjects in regard to lipid metabolism. These observations may have important clinical and public health implications.

Hepatic lipase C-480T polymorphism modifies the effect of HDL cholesterol on the risk of acute myocardial infarction in men: a prospective population based study

Previous studies have revealed an inverse association between high density lipoprotein cholesterol (HDL-C) levels and the risk of acute myocardial infarction (AMI).1,2 HDL-C level is modulated by genetic factors as well as environmental factors such as obesity, smoking, and physical exercise. Hepatic lipase (HL) is a lipolytic enzyme in lipoprotein metabolism, functioning as a phospholipase, an acylglycerol hydrolase, and a ligand of cell surface glycosaminoglycans, hydrolysing triglyceride-rich lipoprotein particles.3 Recently, it has been reported that HL is synthesised by macrophages.4 The HL gene variation has a significant effect on the variability of HDL-C in the population.5,6 The functional HL promoter C-480T transition, also referred to as (-514C/T), leads to three common genotypes: CC, CT, and TT. The C and T alleles are associated with high and low HL activity, respectively.7–9 However, the common polymorphisms of HL (-480T), cholesterol ester transfer protein (CETP) (TaqIB), lipoprotein lipase (S447X), and lecithin cholesterol acyl transferase (S208T) contribute only about 2.5% to the variance of HDL-C in the population.10 This suggests that the HL C-480T polymorphism and HDL-C levels are different factors, and studying their interaction is justified. One previous study has shown that there might be an interaction between CETP gene polymorphism and HDL-C on the risk of myocardial infarction.11 This result raises the possibility that other polymorphisms associated with HDL-C—for example, HL gene polymorphism—might interact with HDL-C and thus modify the risk of AMI. In fact, an effect of the C-480T polymorphism on coronary artery disease (CAD) has been sought in several studies with both negative7,12 and positive findings.13–15 One possible reason for the mixed results may be the interaction between HL C-480T genotype and HDL levels on CAD, a hypothesis not studied previously. To address this question, and …

The relation of oxidized LDL autoantibodies and long-term hormone replacement therapy to ultrasonographically assessed atherosclerotic plaque quantity and severity in postmenopausal women.

BACKGROUND In epidemiologic studies, the incidence of atherosclerosis rises soon after menopause in women, and hormone replacement therapy (HRT) has proved to be useful in preventing onset of clinical manifestations of the disease. However, it is not known how HRT affects sonographically determined atherosclerotic severity (AS) and number of atherosclerotic plaques (NAP) in large arteries. Furthermore, it is not clear how HRT affects oxidation of low density lipoproteins (LDL), which obviously has an important role in the pathogenesis of atherosclerosis. OBJECTIVES The purpose of the study was to determine whether HRT has a beneficial effect on sonographically determined AS and NAP in large arteries of 101 postmenopausal women compared to 40 controls without HRT. We also studied the interaction of HRT and antibodies against oxidized LDL on AS and NAP progression. RESULTS Estradiol valerate alone, combined estradiol valerate-levonorgestrel and combined estradiol valerate-medroxyprogesterone acetate therapy are each associated with lower NAP and AS as compared to controls without HRT. In a multiple regression model explaining NAP in the whole study population, the strongest predictors were HRT (P=0.0006) and copper-oxidized LDL cholesterol autoantibodies (P=0.0491). DISCUSSION Our findings indicate that postmenopausal HRT is associated with a lower total number of atherosclerotic plaques and less severe atherosclerotic lesions, as compared to controls without HRT, and that this outcome may be associated with the effect of HRT on LDL cholesterol oxidation.

Serum homocysteine does not associate with uncomplicated coronary heart disease.

Background Elevated serum homocysteine concentrations have been related to coronary heart disease. However, the association has not indisputably been proven, and the mechanisms by which homocysteine may be atherogenic have only partially been elucidated. The objective of the present study was to investigate whether serum homocysteine is associated with angina pectoris and myocardial infarction.

Apolipoprotein E and A-IV Polymorphisms in Ethnic Russians Living in Estonia

To determine the distribution of genetic variations in apolipoprotein E (apoE) and apolipoprotein A-IV (apoA-IV) genes, 137 Russians living in Estonia was screened by isoelectric focusing and immunoblotting procedures. The apoA-IV-2 allele and apoEε4 allele frequency of the Russians tended to be lower than in most other European populations.

Trends in serum cholesterol and lifestyle indicators in Members of the Finnish Parliament

OBJECTIVE To examine the extent that public health promotion activity is reflected in life styles of national decision makers, by analysing trends in coronary heart disease risk factors in Members of the Finnish Parliament (MPs). METHODS The MPs were studied at the beginning of two subsequent 4-year parliamentary periods between 1991 and 1999. The studies included analyses of serum total cholesterol and high-density lipoprotein (HDL) cholesterol, and a questionnaire about alcohol, smoking and physical activity. RESULTS Serum total cholesterol was above the national recommendation of 5.0 mmol/l in 85% of the male MPs and 62% of the female MPs. The mean level of serum total cholesterol increased in female MPs during the 4-year follow-up period (P < 0.05), and male MPs showed an increase in mean HDL cholesterol (P < 0.001). The mean body mass index increased in both male (P < 0.01) and female (P < 0.01) MPs during the same period. Alcohol consumption, smoking and physical activity were unchanged during follow-up. CONCLUSIONS From the public health perspective, serum cholesterol is too high in most MPs, and the level in males is above the national average. Both males and females put on weight during the parliamentary period, and male MPs also showed an increase in HDL cholesterol, which may be explained by other lifestyle factors.