Lipoprotein(a), Chlamydia pneumoniae, leptin and tissue plasminogen activator as risk markers for valvular aortic stenosis.

AIMS: The aim of the present study was to identify risk markers for the development of valvular aortic stenosis (AS). Lipoprotein(a) (Lp(a)) and Chlamydia pneumoniae IgG antibody titres in plasma and in circulating immune complexes as well as leptin and tissue plasminogen activator (t-PA) in plasma were studied. METHODS AND RESULTS: One hundred and one patients (41 women and 60 men, mean age 71+/-8 years) with significant AS and 101 age- and sex-matched controls were included in this study. All patients underwent aortic valve replacement at the University Hospital in Umeå, Sweden. The controls had no symptoms of cardiovascular disease and they were examined echocardiographically. An Lp(a) level >or=480 mg x l(-1), a C. pneumoniae-specific IgG titre >or=1/128, a high leptin level and a high t-PA mass concentration in plasma were identified as risk markers for AS. A strong synergism between Lp(a) and C. pneumoniae IgG antibodies in circulating immune complexes was found. CONCLUSION: Our data indicate that a chronic C. pneumoniae infection and a high plasma Lp(a) level might influence and aggravate aortic heart valve sclerosis via the formation of circulating immune complexes. The present study also strongly suggests an association between high plasma leptin, t-PA mass concentration and AS.

Is lipoprotein(a) a predictor for survival in patients with established coronary artery disease? Results from a prospective patient cohort study in northern Sweden.

OBJECTIVES: Lipoprotein(a) [Lp(a)] is a known risk factor for the development of atherosclerosis. The aim of the present study was to test the importance of Lp(a) as a predictor for the further prognosis in patients with established coronary artery disease. DESIGN: A prospective patient cohort study was carried out. SETTING AND SUBJECTS: The cohort consists of 1216 patients who were examined with coronary angiography at the University Hospital in Umeå, Sweden, because of stable effort angina. MAIN OUTCOME MEASURES: Lipids, Lp(a), fibrinogen, antithrombin III (AT III), sedimentation rate and clinical data were registered at angiography. After a mean follow-up time of 6.7 years information on survival was collected from the municipal census lists and death certificates were examined. Total mortality and mortality because of cardiovascular disease were both used as outcome variables in the survival analyses. RESULTS. The total mortality in the patient cohort was 16.4%. An Lp(a) level of 300 mg L-1 or more was found in 30% of the study population and was found to be an independent predictor for death. A high fibrinogen, a low AT III level, a depressed left ventricular function and a high coronary obstruction score were other significant independent predictors of death. Total cholesterol, HDL- and LDL-cholesterol were not related to survival in this study, but a substantial proportion of the population probably received lipid-lowering agents during the study period. CONCLUSIONS: An Lp(a) level exceeding 300 mg L-1 indicates a poor further prognosis and may help to identify patients who probably need powerful secondary prevention programmes to improve their prognosis.

The proatherogenic properties of lipoprotein(a) may be enhanced through the formation of circulating immune complexes containing Chlamydia pneumoniae-specific IgG antibodies.

AIMS: To investigate a possible relationship between the atherogenic properties of lipoprotein(a) (Lp(a)) and Chlamydia pneumoniae infections. METHODS AND RESULTS: The study population was nested within the Västerbotten Intervention Program or the WHO MONICA project. In this incident case-control study, 78 patients who had suffered acute myocardial infarction and 156 matched controls were included. The contents of circulating immune complexes were analysed for C. pneumoniae IgG antibodies and Lp(a). A significantly larger proportion of cases than controls had >/=13 mg. l(-1)Lp(a) and a C. pneumoniae specific IgG antibody titre >/=1/2 in circulating immune complexes (odds ratio=3.8). CONCLUSION: The proatherogenic effects of Lp(a) may be enhanced and/or partly mediated through the formation of circulating immune complexes containing C. pneumoniae -specific IgG antibodies. The connection between chronic C. pneumoniae infections and atherosclerosis may, at least in part, be explained by an interaction with Lp(a) through the formation of circulating immune complexes.

Chlamydia pneumoniae antibodies and high lipoprotein(a) levels do not predict ischemic cerebral infarctions. Results from a nested case-control study in Northern Sweden.

BACKGROUND AND PURPOSE: An association between high lipoprotein(a) [Lp(a)] levels and positive Chlamydia pneumoniae IgG titers in coronary artery disease has been described. The possibility of predicting ischemic stroke by measurements of plasma Lp(a) and C pneumoniae antibodies was investigated. METHODS: This incident case-control study included 101 case subjects (cases) who had suffered ischemic cerebral infarctions and 201 matched control subjects (controls). The study population was nested within the Västerbotten Intervention Program or the WHO MONICA project. Plasma samples were measured for C pneumoniae-specific IgG and IgA antibodies and Lp(a). RESULTS: A significantly higher mean Lp(a) level was found in female cases than in female controls. However, plasma Lp(a) was unable to predict ischemic cerebral infarctions in either women or men. The proportion of individuals with positive C pneumoniae-specific IgG or IgA titers did not differ between cases and controls. Antibody titers were unable to predict a future stroke. The proportion of individuals with a positive C pneumoniae IgG titer in combination with a high Lp(a) level did not differ significantly between cases and controls. CONCLUSIONS: These data suggest that there is no association between baseline plasma Lp(a) levels, presence of C pneumoniae antibodies, and future ischemic cerebral infarctions. Furthermore, no evidence of an interactive effect between high Lp(a) levels and C pneumoniae IgG titers was found. However, selection bias and a recent C pneumoniae epidemic may have influenced the results.

The relation between bone mineral density, insulin-like growth factor I, lipoprotein (a), body composition, and muscle strength in adolescent males.

Osteoporosis is the most common metabolic bone disease. A low peak bone mass is regarded a risk factor for osteoporosis. Heredity, physical activity, and nutrition are regarded important measures for the observed variance in peak bone mass. Lp(a) lipoprotein is a well-known risk factor for atherosclerosis. Serum insulin-like growth factor I (IGF-I) has been found to be increased in males with early cardiovascular disease. In this study, we evaluated the association between bone mass, body constitution, muscle strength, Lp(a), and IGF-I in 47 Caucasian male adolescents (mean age, 16.9 yr). Bone mineral density (BMD) and body composition were measured by dual x-ray absorptiometry, muscle strength of thigh using an isokinetic dynamometer, IGF-I by RIA, and Lp(a) by enzyme-linked immunosorbent assay. IGF-I was only associated with Lp(a) (r = 0.38, P < 0.01). Lp(a) was related to total body (r = 0.40, P < 0.01), skull (r = 0.45, P < 0.01), and femoral neck BMD (r = 0.44, P < 0.01). Lp(a) was also related to fat mass (r = 0.34, P < 0.05) and muscle strength (r = 0.30-0.42, P < 0.05). After multiple regression and principal component (PC) analysis, the so-called PC body size (weight, fat mass, lean body mass, and muscle strength) was the most significant predictor of BMD (beta = 0.28-0.51, P < 0.05-0.01), followed by the so-called PC physical activity (beta = 0.28-0.38, P < 0.05-0.01, weight-bearing locations). However, the PC analysis confirmed that Lp(a) was an independent predictor of total body, skull, and femoral neck BMD (beta = 0.33-0.36, P < 0.01). The present investigation confirms that BMD, body size, and muscle strength are closely related and that the level of physical activity is a major determinant of BMD. However, the positive relation of Lp(a), a major risk factor for cardiovascular disease, to BMD has not previously been described. The importance of this observation has to be further investigated.

The importance of serum lipoprotein (a) as an independent risk factor for premature coronary artery disease in middle-aged black and white women from the United States.

OBJECTIVE: To determine the association of serum levels of lipoprotein (a) (Lp(a)) with coronary artery disease (CAD) in relation to other risk factor variables in black and white women. DESIGN: Retrospective case-control study. SETTING: Community of Bogalusa, Louisiana and Cardiac Catheterization Laboratory at the Medical Center of Louisiana, New Orleans, USA. SUBJECTS: The study included 47 female cases (52% black; mean +/- SD age: 50.8 +/- 6.3 years) with confirmed myocardial infarction (MI) or at least 75% blockage of one or more major epicardial coronary arteries determined by angiography, and 55 controls (60% black; mean +/- SD age: 49.6 +/- 7.9 years) with no high grade obstructive lesion (< 50% blockage) and no history of CAD. MAIN OUTCOME MEASURES: Lipoprotein variables, homocysteine, body mass index and cigarette smoking. RESULTS: In the whole group, mean values of Lp(a), total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and very-low-density lipoprotein cholesterol (VLDL-C) were higher (P < 0.05-0.001) and apoA-I was lower (P < 0.05) in cases than in controls. The multivariate logistic regression analysis showed elevated levels of Lp(a) (> 500 mg L-1) and LDL-C (> 3.36 mmol L-1) as strong independent risk factors, with odds ratios (with 95% confidence intervals) of 13.6 (4.00-46.30) and 4.64 (1.31-16.49), respectively. ApoA-I, with an odds ratio of 0.11 (0.02-0.64), was a protective factor only at high levels (> 53.6 mumol L-1). Between races, significant odds ratios were noted in the black women for Lp(a) (OR = 15.98; P < 0.01) and LDL-C (OR = 7.69; P < 0.05) and in the white women for only Lp(a) (OR = 15.23; P < 0.01). CONCLUSIONS: Lp(a) is an important risk factor for CAD both in black and in white women.

Lipoprotein(a) and cholesterol levels act synergistically and apolipoprotein A-I is protective for the incidence of primary acute myocardial infarction in middle-aged males. An incident case-control study from Sweden.

OBJECTIVE: To further establish the importance of total plasma apolipoprotein A-I and lipoprotein(a) in the prediction of primary acute myocardial infarction (AMI) in men. DESIGN: An incident case-control study. SETTING: The study was nested within the Västerbotten Intervention Program (VIP) and the Northern Sweden MONICA cohorts. SUBJECTS: A total of 62 male AMI cases and 124 matched controls, randomly selected from the study cohorts. RESULTS: In multivariate logistic regression, significant odds ratios (OR) were found for Lp(a) above 200 mg L-1, apo A-I below the mean value (1136 mg L-1) and total cholesterol (TC) above 7.8 mmol L-1. TC interacted significantly with Lp(a); for Lp(a) above 200 mg L-1 and TC below 6.5 mmol L-1, OR = 5.6; for Lp(a) above 200 mg L-1 and TC above 6.5 mmol L-1, OR = 12.6. To evaluate the potential effect of reducing high levels of Lp(a) or TC on the incidence of AMI in males, the attributable risk percentage (ARP) was calculated when interaction between the two variables was present. ARP is 31% for Lp(a) and 21% for TC, implying that 31% of the cases are due to high Lp(a) and 21% of the cases are due to high TC levels. CONCLUSIONS: In the Swedish male population, total apo A-I in plasma is a protective factor and a plasma Lp(a) level above 200 mg L-1 is a risk factor for AMI in males. A TC level above 6.5 mmol L-1 increased the risk of AMI if the Lp(a) level was above 200 mg L-1, suggesting Lp(a) to be useful in identifying high risk individuals needed to be treated.

Perceived health modifies the effect of biomedical risk factors in the prediction of acute myocardial infarction. An incident case-control study from northern Sweden.

OBJECTIVES: To assess the importance of biomedical risk factors, social factors and self-reported health in the prediction of the first event of acute myocardial infarction (AMI) in an apparently healthy middle-aged population. DESIGN: An incident case-control study. SETTING: The study was nested within the Västerbotten Intervention Program and the Northern Sweden MONICA cohorts. SUBJECTS: The study consists of 78 AMI cases with two randomly selected controls per case from the same study cohorts. RESULTS: Significant odds ratios were found for history of diabetes, daily smoking, cholesterol, body-mass index, hypertension, lower education and perceived ill health. In multivariate logistic regression smoking, hypertension and cholesterol of > or =7.8 mmol L(-1) remained significant. An interaction was observed between number of biomedical risk factors and perceived health. CONCLUSIONS: Smoking, hypertension and hypercholesterolaemia explain a major share of incident AMI events in a Swedish middle-aged population. The study further illustrates that perceived ill health negatively modifies the impact of these risk factors.

Lp(a) lipoprotein is a major risk factor for cardiovascular disease: pathogenic mechanisms and clinical significance.

The results of two previous and two recent studies of middle-aged males and females are presented to exemplify the clinical importance of lipoprotein(a) (Lp(a)) as a risk factor for atherosclerosis and coronary heart disease. In these studies various conventional and recently suggested risk factors were included and different methods for Lp(a) quantification were used. Lp(a) was a significant risk factor in all four studies. In the recent prospective case-control study, Lp(a) and cholesterol were found to act synergistically and predict primary acute myocardial infarction in Swedish males. A cholesterol level above 6.5 mmol/l increased the risk of acute myocardial infarction if the Lp(a) level was above 200 mg/l. The plasma apo A-I level was a protective factor. In the other recent case-control study, an Lp(a) level above 500 mg/l was a highly significant risk factor in Black and White US women with myocardial infarction or advanced coronary artery disease in addition to low density lipoprotein cholesterol levels above 130 mg/dl. A high apo A-I level was a protective factor. In these studies no other factors tested reached significance in multivariate logistic regression analysis. A hypothetical association between high Lp(a) levels and intracellular infection with Chlamydia pneumoniae is discussed. The results suggest that the Lp(a) level is useful in identifying high-risk individuals. Lowering low density lipoprotein cholesterol below 100 mg/dl (<2.6 mmol/l) seems to be most important in both males and females with high-risk Lp(a) levels.

Potential environmental effects on adult lipoprotein(a) levels: results from Swedish twins.

Two hundred and ninety four pairs of Swedish twins reared apart and twins reared together were used to evaluate the importance of genetic and environmental influences on lipoprotein(a) (Lp(a)) levels. Lp(a) levels ranged from <10 mg/l to 926 mg/l with 7.9% of the sample having undetectable Lp(a) levels (i.e. <10 mg/l). A substantial genetic component in Lp(a) variation was indicated by a heritability estimate of approximately 90%. No difference in heritability was found across age groups. Quantitative genetic analyses also suggest correlated environmental effects most likely composed of maternal, neonatal and postnatal environmental influences. However, these effects did not reach statistical significance, partly due to a lack of power. Results from analyses of co-twin differences in Lp(a) levels for monozygotic twins indicate that sex hormone use may be of importance for Lp(a) variation in women. There was no evidence of potential influences of alcohol consumption, beta-blocker and diuretic administration on Lp(a) levels in either men or women.

Influence of oral contraceptive use on lipoprotein (a) and other coronary heart disease risk factors.

We have studied the influence of oral contraceptive use on lipoprotein (a) levels in a cohort of women aged 18, 21 and 24 years (n = 559). Data was available on oral contraceptive formulation and dosage, anthropometric variables, exercise, serum lipoprotein (a), insulin, lipid and apolipoprotein levels. Lipoprotein (a) was determined by radioimmunoassay. Differences were assessed with non-parametric statistical methods. Forty per cent of the study women used oral contraceptives. The use of desogestrel-containing monophasic preparations was associated with lower levels of lipoprotein (a) compared to triphasic/levonorgestrel formulations or to non-users (P = 0.005). This effect was seen only in non-smoking women. Oral contraceptive users had higher levels of serum apolipoprotein B, HDL3-cholesterol, apolipoprotein A-I, triglycerides and systolic blood pressure, and lower serum lecithin:cholesterol acyltransferase activity. Lifestyle factors (smoking, exercise) showed no significant influence on lipoprotein levels. In conclusion, the use of desogestrel-containing oral contraceptives has a marked lowering effect on lipoprotein levels. Prospective studies will be needed to assess the net influence of oral contraceptive use on cardiovascular health.

Lp(a) lipoprotein, IgG, IgA and IgM antibodies to Chlamydia pneumoniae and HLA class II genotype in early coronary artery disease.

The associations previously found between lipoprotein(a) (Lp(a)) levels and atherosclerotic disorders, diabetes, rheumatoid arthritis and renal diseases suggest that Lp(a) may be involved in autoimmune reactions. The relation found between Lp(a) levels and the HLA class II genotype in males with early coronary artery disease (CAD) further support that assumption. It was suggested that an autoimmune process, perhaps triggered by a concomitant intracellular infection may occur especially in patients with inherited high Lp(a) levels in combination with certain inherited HLA class II genotypes. In this study a Chlamydia pneumoniae IgG titer > or = 32 was significantly more common (P = 0.036) in CAD patients than in matched controls. This is in agreement with previous reports by other investigators. In addition, an IgG titer > or = 256 in combination with an Lp(a) level > or = 120 mg/l was found to occur significantly more often (P = 0.011) in male patients than in male controls. Certain HLA class II DR genotypes in combination with high Lp(a) levels and C. pneumoniae titers occurred more frequently in both male and female patients than in controls. Some combinations were very common in male patients, and the difference in comparison with male controls was highly significant.

Lipoprotein (a) levels in children and young adults: the influence of physical activity. The Cardiovascular Risk in Young Finns Study.

A high lipoprotein(a) (Lp(a)) level is an independent and predominantly genetically determined risk factor for coronary heart disease and other vascular diseases. We studied the levels of Lp(a) and the influence of physical activity on Lp(a) in the young Finnish population. The study cohort comprised children and young adults aged 9, 12, 15, 18, 21 and 24 years (n = 2464) participating in a large multicenter follow-up study of cardiovascular risk factors in children and young adults. Data were available on physical activity, anthropometric variables, serum Lp(a), insulin and lipid levels. A physical activity index was calculated based on several physical activity variables. Lp(a) was determined by radioimmunoassay with a detection threshold of 3 mg/dl. Differences were assessed with non-parametric statistical analyses. The observed range of Lp(a) was from < 3 to 90.8 mg/dl. The distribution of Lp(a) was highly skewed as 88% of the population (89% males and 87% females) had Lp(a) concentrations less than 25 mg/dl. A total of 35% of the subjects had Lp(a) levels less than 3 mg/dl. There were no significant differences in Lp(a) levels with respect to age or gender. The serum concentration of Lp(a) was statistically significantly correlated with the level of physical activity. Other behavioral variables studied did not have a significant contribution to the variability of Lp(a) levels. These results demonstrate that levels of Lp(a) are not related to age, gender or many of the known coronary heart disease risk factors. However, physical activity is associated with favorable Lp(a) levels, as high levels of Lp(a) (> 25 mg/dl) were less frequent in the physically most active subjects.

Indications of an autoimmune component in LP(a) associated disorders.

The exceptionally strong independent association found between Lp(a) lipoprotein [Lp(a)] levels and atherosclerotic disorders indicate that Lp(a) is a factor of considerable importance in the pathogenesis of atherosclerosis. The association between Lp(a) and diabetes, rheumatoid arthritis and renal diseases suggest that Lp(a) may be involved in immunological mechanisms. Lp(a) has a great tendency to aggregate and bind to glucosaminoglycans, fibrin and fibronectin and is preferentially retained in the extracellular matrix during development of atherosclerosis and is in vitro phagocytosed by macrophages, probably as small aggregates. It was previously found that the Lp(a) level is significantly related to the HLA class II genotype in male patients with early coronary artery disease. In this paper additional results of interleukin determinantions in relation to HLA type and Lp(a) levels are presented and discussed. It is suggested that an autoimmune process, perhaps triggered by a concomitant intracellular infection may occur, especially in patients with inherited high Lp(a) levels in combination with certain inherited HLA class II genotypes.

Lp(a) lipoprotein in cardiovascular disease.

The article summarizes the increased knowledge about the enigmatic Lp(a) lipoprotein and its clinical importance over the past 20 years. The mode of inheritance, the unique features of Lp(a) composition and structure and the unusual distribution of the mainly genetically determined plasma Lp(a) levels are discussed. The main factors that can significantly change the inherited plasma Lp(a) levels are endocrine disorders and hormone treatment. It seems possible that sex hormones protect females to a large extent from the potentially deleterious effects of inherited high Lp(a) levels until menopause. The exceptionally strong independent association found in most studies between Lp(a) lipoprotein levels and atherosclerotic disorders indicates that Lp(a) is a factor of outstanding importance in the pathogenesis of atherosclerosis. Probable pathogenetic mechanisms are reviewed. The associations found between LP(a) and insulin release, rheumatoid arthritis and renal diseases suggest that Lp(a) may be involved in immunological mechanisms. In a new hypothesis it is suggested that an autoimmune process might especially occur in individuals with inherited high Lp(a) levels and certain HLA class II genotypes, triggered by a concurrent infection.

Importance of Lp(a) lipoprotein and HLA genotypes in atherosclerosis and diabetes.

Lp(a) lipoprotein [Lp(a)] was found in previous studies to be independently associated with early atherosclerosis and its sequelae. Lp(a) in vitro bound to glucosaminoglycans and was easily aggregated at physiological Ca2+ concentration, and small Lp(a) aggregates were phagocytosed by macrophages. Lp(a) was also found to be related to carbohydrate metabolism, and increased Lp(a) levels have been described in diabetic patients with clinical complications and were recently found in rheumatoid arthritis patients. In this study of nondiabetic male patients with documented CAD before 50 years of age and controls, a significant correlation was found between Lp(a) and IGF-1 levels. HLA class II DR13 (DR6) was more frequent and DR15 (DR2) was less frequent in patients than in controls. The calculated relative risk for CAD was 4.0 for DR17 (DR3), but the difference was not significant. These differences seem to be related to high Lp(a) levels. It is suggested that phagocytosis of preferably Lp(a) aggregates can induce an immunological tissue response that may contribute in the pathogenesis of Lp(a)-associated diseases and may be more prominent in combination with some inherited HLA class II haplotypes. Probably due to sex hormone effects, the association may be most pronounced in young males and in older females.

Tissue plasminogen activator, plasminogen activator inhibitor-1 and von Willebrand factor in rheumatoid arthritis.

Tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF), all of endothelial origin and active in the haemostasis, were analysed in 74 patients with rheumatoid arthritis. The concentrations were related to extra-articular disease and to the incidence of thromboembolic events (TE) registered in a 2-year follow-up period. Patients with extra-articular disease had a significant increase in PAI-1 activity and reduced tPA release in the venous occlusion test. von Willebrand factor, PAI-1 and also haptoglobin and triglycerides were significantly increased in the group of patients who later suffered from TE. In a multiple regression model, in which cholesterol, triglycerides and lipoprotein (a) showed significant association with TE, vWF had the strongest additive explanatory value. No distinct acute phase pattern of PAI-1 was found in any patient subgroup.

Lipoprotein (a) in a randomly selected 25-64 year old population: the Northern Sweden Monica Study.

Lipoprotein (a) (Lp (a)) was determined in 1527 individuals participating in the Northern Sweden WHO MONICA project for monitoring of cardiovascular risk factors in the general population. Subjects were randomly selected and stratified according to sex and age. A weak but significant relation between Lp (a) and increasing age was found in both sexes (p < 0.01). Menopausal status was the strongest independent predictor of Lp (a) level in women (p = 0.010). Fibrinogen was independently related to Lp (a) in both men and women (p < 0.05). An inverse relation between waist-to-hip ratio and Lp (a) was found in men (p < 0.01). Hypertensive subjects treated with diuretics had significantly higher Lp (a) than hypertensives on other agents (p < 0.05). Only a minor proportion of Lp (a) variance could be explained by lifestyle factors, which supports the contention that genetic factors primarily control Lp(a) level.

Lp(a) lipoprotein and HLA-DR genotype in early coronary artery disease.

The interest in Lp(a) lipoprotein [Lp(a)] has increased dramatically during the last few years due to the documented strong association between high Lp(a) levels and early atherosclerosis and its sequelae and the probable additional thrombogenic effect of inherited high Lp(a) levels. However, some paradoxes still remain to be solved in Lp(a) research. This pilot study was performed to test whether some criteria could be found for an association between Lp(a) levels, HLA genotype, and early coronary heart disease. If so, it could help to explain why some individuals with high Lp(a) levels get atherosclerosis while others with comparable lipid levels do not. It would also indicate that immunological processes could be involved in Lp(a) associated atherosclerosis. In this case-control study the HLA-DR genotypes 13 or 17 were significantly more frequently encountered in 30 male patients with early coronary heart disease than in 30 sex and age matched healthy controls (P = 0.012). These HLA-DR specificities were especially frequent in male patients with high Lp(a) levels. The same HLA-DR genotype pattern was not seen in 30 female patients, although there was a trend towards more frequent 13a genotype.