Gösta H. Dahlén

PLASMINOGEN ACTIVATOR INHIBITOR IN PLASMA: RISK FACTOR FOR RECURRENT MYOCARDIAL INFARCTION

Measurements of haemostatic function and metabolic and angiographic indices of risk were included in a prospective cohort study of variables predictive of recurrences within 3 years in 109 unselected men with a first myocardial infarction (MI) before the age of 45. In the course of follow-up, 16 patients had at least one reinfarction (fatal recurrences in 9 and nonfatal in 7) and 1 died suddenly. High plasma concentrations of the fast-acting plasminogen activator inhibitor were independently related to reinfarction along with dyslipoproteinaemia involving VLDL and HDL, poor left ventricular performance, and multiple-vessel coronary artery disease. Besides being independently associated with reinfarction in the present population, high triglyceride levels were possibly connected with a predisposition to thrombosis through a coexisting high level of plasminogen activator inhibitor. The data indicate that reduced fibrinolytic capacity due to increased plasma levels of the plasminogen activator inhibitor predisposes to reinfarction in a complex interplay with atherogenic factors, multiple coronary lesions, and compromised left ventricular function.

Genetic and Environmental Influences on Serum Lipid Levels in Twins

BACKGROUND The extent to which serum lipid levels are affected by genetic and environmental factors remains a point of controversy. We examined both genetic and environmental influences on serum lipid levels in twins reared either together or apart who participated in the Swedish Adoption/Twin Study of Aging. METHODS We studied 302 pairs of twins (mean age, 65.6 years; range, 52 to 86); 146 pairs had been reared apart. We simultaneously compared the twins on the basis of both zygosity and rearing status, which allowed joint estimation of genetic and environmental influences on serum lipid levels. Genetic influence was expressed in terms of heritability, the proportion of the population variation attributable to genetic variation (a value of 1.0 indicates that all of the population variation is attributable to genetic variation). The serum lipids and apolipoproteins measured included total cholesterol, high-density lipoprotein cholesterol, apolipoproteins A-I and B, and triglycerides. RESULTS Structural-equation analyses revealed substantial heritability for the serum levels of each lipid measured, ranging from 0.28 to 0.78. Comparisons of the twins reared together with those reared apart suggested that the environment of rearing had a substantial impact on the level of total cholesterol (accounting for 0.15 to 0.36 of the total variance). Sharing the same environment appeared to affect the other lipid measures much less, however, than did genetic factors and unique environmental factors not shared by twins. Comparisons of younger with older twins suggested that heritability for apolipoprotein B and triglyceride levels decreased with age. CONCLUSIONS The effect of genetic factors on the serum levels of some but not all lipids appears to decrease with age. Early rearing environment appears to remain an important factor in relation to levels of total cholesterol later in life, but it has less effect on other serum lipids and apolipoproteins in the elderly.

Lp(a) lipoprotein and pre-β1-lipoprotein in patients with coronary heart disease

Certain properties of the atypical serum lipoprotein, referred to as pre‐β1‐lipoprotein, suggested that it might be identical to the lipoprotein carrying the Lp(a) antigen: Lp(a) lipoprotein. Both lipoprotein phenomena are under genetic control and occur in a certain proportion of healthy people. Pre‐β1‐lipoprotein occurs more frequently in patients with coronary heart disease (CHD) than in the healthy population.

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.

SERUM-HIGH-DENSITY-LIPOPROTEIN AND ATHEROSCLEROTIC HEART-DISEASE

Serum-high-density-lipoprotein (H.D.L.) concentrations were determined in 49 men who had had a myocardial infarction and in 102 healthy, middle-aged men, all from Northern Sweden. A quantitative immunological assay based on a monospecific antiserum to the main polypeptide (apoprotein A-I) of H.D.L. was used. The mean H.D.L. concentration was significantly lower in the men with coronary heart-disease than in the controls. The results accord with the hypothesis that high levels of H.D.L. to some extent protect against ischaemic heart-disease.

Relationship of angiographically defined coronary artery disease to serum lipoproteins and apolipoproteins in young survivors of myocardial infarction.

The relationship of serum lipoprotein and apolipoprotein concentrations to angiographically determined coronary artery disease was investigated in 105 consecutive male survivors of myocardial infarction under the age of 45. Concentrations and composition of lipoproteins, lipid indexes, and nonlipid risk factors (tobacco consumption, hypertension, reduced glucose tolerance, and obesity) were related to a recently developed scoring system for semiquantitative estimation of diffuse coronary atheromatosis, as well as to the number and severity of significant coronary artery stenoses. The concentrations of cholesterol in very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), in combination with serum triglyceride or VLDL triglyceride level, comprised the best set of independent discriminatory lipid variables between patients and control subjects. In the patients, LDL cholesterol and apolipoprotein B levels showed strong relationships to the extent and severity of coronary atheromatosis but not to the number and severity of distinct coronary stenoses. HDL2 cholesterol concentration correlated inversely with the coronary atheromatosis score, whereas other variables reflecting HDL concentration and composition or VLDL lipids were not independently related to any of the coronary scores. The LDL triglyceride level, an index of intermediate-density lipoprotein (IDL) accumulation, was significantly correlated to the coronary atheromatosis score in univariate analysis. Nonlipid risk factors were correlated neither to coronary atheromatosis nor to severity of stenoses. Stepwise multiple regression analyses of data adjusted for age, cumulative tobacco consumption, and weight indicated that 18% of the variation in the coronary atheromatosis score could be accounted for by levels of apolipoprotein B. Addition of other lipoprotein variables or the nonlipid variables hypertension and glucose tolerance did not significantly increase the value of R2. When ratios of lipoprotein lipids and apolipoproteins were included in the regression model, the highest multiple correlation coefficient was obtained with the LDL/HDL cholesterol ratio alone (R2 = .22). The present data demonstrate the importance of elevated LDL cholesterol and apolipoprotein B concentrations for the development of coronary atheromatosis in young male survivors of myocardial infarction. The lack of correlations between the levels of lipoprotein lipids and serum apolipoproteins and the severity of coronary stenoses suggests that mechanisms other than disturbances of lipoprotein metabolism may be involved in the progression of more advanced coronary lesions.

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.

Interrelationships between plasma levels of plasminogen activator inhibitor, tissue plasminogen activator, lipoprotein (a), and established cardiovascular risk factors in a north Swedish population.

Serum lipids, lipoprotein (a), plasminogen activator inhibitor and tissue plasminogen activator levels were measured in 260 subjects, constituting a cross-section sample of 30-60-year-old men and women. For Lp(a), there were positive correlations with age and cholesterol, but not with any of other measured parameters. Triglyceride, cholesterol, and HDL-cholesterol (inversely) levels were associated with waist-to-hip girth circumference ratio: this variable remained significant in a multiple regression model. PAI-1 activity and tPA antigen levels were positively associated with triglycerides and inversely associated with HDL-cholesterol. Moreover, tPA antigen was positively related to total cholesterol level. In multiple regression analysis, however, only triglycerides were found to contribute significantly to the variance of tPA antigen and PAI-1 activity levels, when BMI (in men) and abdominal skinfold thickness (in women) were entered into the model. Insulin or glucose postload responses to an OGTT were not independently related to any lipid or fibrinolytic variable. These data demonstrate the importance of anthropometric variables both for fibrinolytic variables and traditional lipid risk factors. Only Lp(a) was found to be largely unrelated to the endocrine-metabolic and anthropometric variables.

Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study

The Scandinavian Simvastatin Survival Study (4S) was a double‐blind. randomized placebo‐controlled multi‐centre clinical trial of long‐term Simvastatin therapy in patients with coronary heart disease who had total cholesterol levels between 5.5 and 8.0 mmol/1, comprising 4444 patients, equally distributed to a Simvastatin and a placebo group. Patients achieved a significant 30% relative reduction in overall mortality with Simvastatin therapy through a 42% relative reduction in coronary heart disease mortality. Lp(a) lipoprotein levels in Scandinavian coronary heart disease patients were strikingly higher than in healthy controls. Numbers of deaths in the Simvastatin group differed significantly between quartiles of Lp(a) lipoprotein levels, the reduction in deaths being most pronounced in the second (next to lowest) quartile. Subjects with major coronary events had significantly higher Lp(a) lipoprotein levels than subjects without such events, in all groups. The relationship between Lp(a) lipoprotein level and total mortality as well as between Lp(a) lipoprotein level and major coronary events was significantly different from zero, in logistic regression analyses. The findings show that Lp(a) lipoprotein predicts major coronary events as well as death in secondary prevention with Simvastatin. This prospective study provides independent confirmation that a high Lp(a) lipoprotein level is a significant coronary heart disease risk factor.

Genetic and cultural inheritance of serum lipids, low and high density lipoprotein cholesterol and serum apolipoproteins A-I, A-II and B

The genetic and cultural heritability of serum cholesterol and triglyceride concentrations, as well as of the concentrations of low and high density lipoprotein cholesterol and serum apolipoproteins A-I, A-II and B, were estimated by path analysis in families selected through probands with premature myocardial infarction and in families randomly selected from the general population. Genetic heritability was high for serum cholesterol (0.64) and low density lipoprotein cholesterol (0.67) concentrations, whereas it was lower for high density lipoprotein cholesterol level (0.42). Cultural inheritance was of less importance than genetic inheritance for all cholesterol variables. For serum triglyceride concentration genetic (0.33) and cultural (0.23) heritability was of similar significance. The results for serum apolipoproteins A-I and A-II parallelled those for HDL cholesterol. A marked intergenerational difference was found in the genetic heritability for apolipoprotein B concentration. The parental genetic heritability was 0.14, whereas the genetic heritability was 0.51 among siblings.