J.G. van der Bom

Tissue plasminogen activator and risk of myocardial infarction : The Rotterdam study

BACKGROUND Impaired fibrinolytic capacity, as assessed by euglobulin clot lysis time or plasma concentration of fibrinolytic parameters, has been associated with an increased risk of myocardial infarction (MI). We studied the association of a polymorphism in the gene for TPA and of plasma concentrations of TPA (antigen and activity) with the prevalence of MI. METHODS AND RESULTS A case-control study was performed. Subjects with a history of MI (n = 121) and controls (n = 250) were drawn from the Rotterdam Study, a population-based cohort study of 7983 subjects > or = 55 years old. We determined TPA antigen and activity in plasma and genotyped all subjects for the Alu repeat insertion/deletion polymorphism in intron h in the TPA gene. Homozygosity for the insertion was associated with twice as many cases of MI as was homozygosity for the deletion (odds ratio, 2.24; 95% CI, 1.11-4.50). TPA antigen was positively associated with the risk of MI; compared with that in the lowest quartile, the relative risks (odds ratio) in the second, third, and upper quartiles were 1.7 (CI, 0.9-3.3), 2.3 (1.2-4.4), and 2.0 (1.0-3.8), respectively. When adjusted for body mass index, HDL and total cholesterol, systolic and diastolic blood pressures, and current smoking, the risk associated with TPA antigen concentration was attenuated. Increased concentrations of TPA activity tended to be associated with an increased risk of MI. CONCLUSIONS This study provides evidence for an independent association of the insertion allele of the insertion/deletion polymorphism in the TPA gene with nonfatal MI. Increased TPA antigen is associated with an increased risk of MI; however, this association was not independent of cardiovascular disease risk factors.

Antithrombin and Atherosclerosis in the Rotterdam Study

Antithrombin is a potent inhibitor of thrombotic tendency. Whether atherosclerotic disease is associated with high or low antithrombin is unclear. Studies of the relation between antithrombin and presence of arterial disease have shown contrasting results. In the Rotterdam Study, a single-center, population-based cohort study of 7983 subjects aged 55 years and older, the association between atherosclerosis and antithrombin was evaluated. The ratio of ankle to arm blood pressure is a graded marker for atherosclerosis and provides the opportunity to investigate nonlinear associations. In the first 1427 participants of the Rotterdam Study who did not use anticoagulants, both antithrombin and the ratio of ankle to arm blood pressure were measured. In men the association between the two was quadratic: antithrombin activity was increased in men with moderate peripheral arterial atherosclerosis compared with those without, and in men with more severe atherosclerosis it was decreased. In women the association was linear: a decreased ratio of ankle to arm pressure was associated with increased antithrombin activity. These associations were independent of smoking, body mass index, serum lipids, fibrinogen, and factor VIIc. We propose that antithrombin activity rises in response to increased risk of cardiovascular disease and also in response to the presence of atherosclerosis, whereas antithrombin may decrease with increasing severity of the atherosclerotic process in men. This may explain the contrasting results found in previous studies. Changes in antithrombin over time might be useful in predicting the risk of cardiovascular disease and progression.

Measurement of β-thromboglobulin in the elderly. Findings from the Rotterdam study

Abstract Objective: The platelet specific protein, β-thromboglobulin has been suggested to be a sensitive marker of in vivo platelet activation. The aim of the present study was to evaluate β-thromboglobulin levels in an elderly population and to determine to which extent β-thromboglobulin levels are associated with blood sampling procedures. Methods: This report presents baseline findings on β-thromboglobulin of the first 2,831 participants of the Rotterdam Study, a population based prospective cohort study among persons aged 55 years and over. Nonfasting blood samples were taken at varying times during the day. β-Thromboglobulin was assayed by an ELISA method. Applied stasis and quality of blood flow during sampling were registered on three grade scales. Results: The overall mean level of β-thromboglobulin was 69.2 (SD 75.5) IU/ml (range 6–612 IU/ml). In women and to a lesser extent in men, β-thromboglobulin was positively associated with age. According to increasing stasis applied during sampling mean β-thromboglobulin levels were 65.3 (SE 2.31), 74.1 (3.18), 77.6 (8.66) IU/ml. Mean β-thromboglobulin in three grades of decreasing quality of blood flow were 69.0 (1.73), 104.0 (11.5), 86.0 (23.7) IU/ml. Mean levels of β-thromboglobulin differed slightly, but significantly between the 14 laboratory technicians who collected the blood. Conclusion: In elderly women and to a lesser extent in elderly men, β-thromboglobulin is positively associated with age. A wide range in β-thromboglobulin is found in elderly subjects which is determined to a limited extent by quality of blood sampling.

Factor VII coagulant activity is related to blood lipids in the elderly. The Rotterdam study

Abstract Objective: To study the distribution of factor VII coagulant activity and its association to serum lipids in the elderly. Methods: The Rotterdam study is a single centre population based prospective cohort study among 7,983 subjects aged 55 years and over. Baseline measurements include assessment of factor VII activity, serum total and high density lipoprotein (HDL) cholesterol. Results: The results are based on the first 1,805 consecutive participants in which factor VIIc, and serum lipids were measured. We excluded 89 persons that were using anticoagulant drugs, leaving 604 men (mean age 70.5 years (SD 8.3) and 1,112 women (mean age 71.9 years (9.2)). Mean levels of cholesterol were 6.3 mmol/l (SD 1.2) and 6.8 mmol/l (1.2) and of HDL cholesterol were 1.2 mmol/l (0.3) and 1.4 mmol/l (0.3) in men and women, respectively. Factor VIIc was normally distributed with a mean of 101 % (20) in men and 111 % (20) in women. Factor VIIc was not associated with age. Linear regression analysis demonstrated that factor VIIc was positively and significantly associated with serum total cholesterol. An increase in total cholesterol of 1 mmol/1 was associated with an increase in factor VIII of 5% (SE 0.5). This association did not materially change after adjustment for age, smoking habit, and body mass index. A comparison of the relatively older age groups with the younger ones revealed similar associations. The magnitude of the association was the same in men and women. HDL cholesterol was not independently associated with factor VIII. Conclusion: Factor VIIc increases with increasing cholesterol with the same strength in the elderly.

89. Polymorphism of the blood clot lysis enzyme tissue-type plasminogen activator is associated with myocardial infarction

Objective: Impaired fibrinolysis has been suggested to be associated with increased risk of myocardial infarction. An insertion/deletion (I/D) polymorphism of the tissue-type plasminogen activator (t-PA) gene has been described which may be associated with impaired fibrinolysis. We studied the association between this polymorphism and the prevalence of myocardial infarction. Design: A population based case control study. Setting: A district of Rotterdam, the Netherlands. Participants: From the cohort that consisted of 7983 men and women aged 55 years and over, we selected 162 subjects with a documented history of myocardial infarction and 258 age matched control subjects without arterial disease. Measurements: All subjects were typed for the Alu sequence insertion/deletion polymorphism located in intron h of the t-PA gene. Results: Allele frequencies were 0.54 for the insertion allele and 0.46 for the deletion allele, and were in Hardy Weinberg equilibrium. Homozygosity for the insertion (n=138) was associated with an increased risk of myocardial infarction compared to homozygosity (n=75) for the deletion: relative risk 2.0(95% CI 1.1, 3.6). Conclusion: These findings suggest an association of the insertion allele of the t-PA gene with the occurrence of myocardial infarction. The I/D polymorphism seems to be a linkage marker for an unknown mutation at, or near, the tPA gene. The insertion allele may reflect an impaired capacity of the fibrinolytic system to respond adequately to acute coronary thrombosis.

Activated protein C response and cardiovascular risk factors in the elderly. The Rotterdam Study

Background and objective. A low activated protein C (APC) response increases the risk of venous thrombosis, and possibly arterial disease. Apart from the factor V Leiden mutation, other factors may determine the level of APC response. In most studies on the association with arterial disease, cardiovascular risk factors were not appropriately controlled for as possible confounders. We studied the association of APC response to cardiovascular risk factors in a sample of the general population. Methods. The Rotterdam Study is a cohort study among 7983 subjects aged 55 years or over, living in the Ommoord suburb in Rotterdam, The Netherlands. APC response was measured in 928 subjects as part of two case-control studies (subjects with and without symptomatic cardiovascular disease (CVD) and with and without dementia). APC response was determined in double centrifuged platelet poor plasma. Those on anticoagulants were excluded. Linear regression analyses were done in age strata (55-64, 65-74, 75-84, ≤ 85), with adjustment for age, sex, CVD, and dementia. Results. APC response was lower in women than in men (difference 0.56 (p < 0.01)). In men, APC response decreased with age (0.15 per decade (p = 0.02)). In women, a non-significant rise was seen (0.05 per decade (p = 0.27)). Associations with cardiovascular risk factors differed by age, not gender. In those aged 55-64 years inverse associations were found with total cholesterol (0.14 decrease per 1 mmol/l increase, p = 0.08) and diastolic pressure (0.12 decrease per 10 mmHg increase, p = 0.06). In those aged ≤ 85 years a positive association was seen with smoking (0.76 increase, p = 0.01). No associations were found with systolic pressure and body mass index. Conclusion. These findings suggest that in the elderly age, gender, serum lipids, diastolic pressure and smoking may influence APC response, the extent of which may differ by age. These factors should be allowed for in studies on the association between APC response and arterial disease.