Impact of apolipoprotein E polymorphism on lipoproteins and risk of myocardial infarction. The ECTIM Study

Human apolipoprotein (apo) E, a polymorphic protein with three common alleles, epsilon 2, epsilon 3, and epsilon 4, plays an important role in lipoprotein metabolism. This article describes the association of this polymorphism with lipids, apolipoproteins, and lipoproteins with a particular regard to lipoprotein particles, as defined by their apolipoprotein content, as well as the risk of myocardial infarction in a multicenter population-based case-control study (ECTIM study). In the ECTIM study, 574 male patients aged 25 to 64 were examined 3 to 9 months after myocardial infarction in four regions participating in the World Health Organization MONICA project: Belfast (Northern Ireland) and Lille, Strasbourg, and Toulouse (France). Control subjects (n = 722) were randomly selected from the regional populations. The distribution of apoE phenotypes was significantly different across the four control samples (P = .04), with a higher frequency of the epsilon 4 allele in Belfast (14.3%) than in Toulouse (8.2%). The association of apoE polymorphism with biological measurements was studied in the control groups (n = 640) after men with coronary heart disease or those taking hypolipidemic drugs were omitted, with the apoE3/3 phenotype as a reference after adjustment for concomitant factors. Individuals carrying the epsilon 2 allele had lower levels of plasma cholesterol, low-density lipoprotein cholesterol (LDL-C), and apoB and higher levels of triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), apoC-III, apoE, lipoprotein (Lp) C-III:B, and Lp E:B. However, the effect of the epsilon 2 allele on triglyceride, VLDL-C, apoE, and Lp E:B parameters was heterogeneous across the populations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Genetic variation at the apoA-IV gene locus and response to diet in familial hypercholesterolemia

Plasma lipid response to dietary fat and cholesterol is, in part, genetically controlled. The apolipoprotein A-IV (apoA-IV protein; APOA4, gene) has been shown to influence the response to dietary changes in normolipidemic individuals. The response to diet in subjects with familial hypercholesterolemia (FH) is also variable, and no studies are available on the influence of APOA4 mutations on dietary response in these subjects. We studied the effect of 2 common apoA-IV genetic variants (Gln360-->His and Thr347-->Ser) on the lipid response to the National Cholesterol Education Program type I (NCEP-I) diet in 67 FH heterozygotes (43 women and 24 men). Subjects were studied at baseline (after consuming for 1 month a diet with 35% fat [10% saturated] and 300 mg/d cholesterol) and after 3 months of consuming a low-fat diet. No sex-related differences were found, and results were combined for men and women. The APOA4-360 mutation was assessed in 67 subjects, 51 with genotype 1/1 and 16 with genotype 1/2. The APOA4-2 allele was associated with marginally significantly lower (P=0.049) low density lipoprotein (LDL) cholesterol levels and significantly lower (P=0.027) apoB levels independent of diet effects. After consuming an NCEP-I diet, carriers of the APOA4-2 allele showed a significantly lower reduction in apoB concentration (6.2%) than 1/1 subjects (14.1%; P=0.036); however, no significant differences in response were noted for LDL cholesterol. The APOA4-347 mutation was assessed in 63 individuals, 44 with the A/A allele and 19 with the A/T and T/T alleles. No significant differences were observed in baseline or post-NCEP-I diet values for these 2 groups in total, LDL, and high density lipoprotein cholesterol and plasma apoB levels. After dietary intervention, A/A individuals showed significant reductions in plasma triglyceride and very low density lipoprotein cholesterol levels; no changes were found in carriers of the T allele. Haplotype analysis suggested that in these FH subjects, the APOA4-360-2 allele was associated with lower plasma lipid levels during the NCEP-I diet period, whereas no significant effects were observed for the APOA4-347-T allele.     

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.     

Heterogeneity at the CETP gene locus. Influence on plasma CETP concentrations and HDL cholesterol levels

This study was designed to investigate the association(s) between heterogeneity at the cholesteryl ester transfer protein (CETP) gene locus, CETP plasma concentrations, and HDL cholesterol levels. Healthy men with the lowest, median, and highest deciles of HDL cholesterol were selected from a large population database. We accounted for factors that are known to influence HDL cholesterol levels, such as smoking, exercise, body mass index, alcohol consumption, and blood pressure. Plasma CETP concentrations were measured, and we determined the allele frequency distribution of six CETP DNA polymorphisms. The group with low HDL cholesterol exhibited a significant increase in CETP concentration compared with both the median and high HDL cholesterol groups, whereas CETP concentrations did not differ among the groups with median and high HDL cholesterol. The allele frequency distributions of the TaqIB (intron 1), Msp I (intron 8), and Rsa I (exon 14) polymorphisms differed significantly between the groups with low and high HDL cholesterol. Further analysis revealed that the Msp I polymorphism had a 1.5-fold larger impact on CETP concentration than the TaqIB polymorphism and a fivefold larger impact than the Rsa I polymorphism. In conclusion, we demonstrated that heterogeneity at the CETP gene locus is correlated with CETP plasma concentrations and HDL cholesterol levels. More specifically, our data indicate the presence of a strong association between common variants of the CETP gene, high plasma CETP concentrations, and consequently hypoalphalipoproteinemia in healthy white men.     

Social support and prognosis in patients at increased psychosocial risk recovering from myocardial infarction.

Objective: To compare the impact of network support and different types of perceived functional support on all-cause mortality or nonfatal reinfarction for patients with a recent acute myocardial infarction (AMI). Design: Participants were recruited from the Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial; 2,481 AMI patients with depression or low social support were randomized to a cognitive-behavioral intervention or to a usual care control group. Data collection for certain measures of social support was limited: 2,466 participants completed the ENRICHD Social Support Inventory; 2,457 completed the Perceived Social Support Scale; 1,296 completed the Social Network Questionnaire; and 707 completed the Interpersonal Support and Evaluation List, Tangible Support subscale. Patients also completed the Beck Depression Inventory and were followed for up to 4.5 years. Main Outcome Measure: Time to death or nonfatal reinfarction. Results: Over the follow-up period, 599 patients (24%) died or had a nonfatal AMI. Survival models controlling age, sex, race, socioeconomic status, smoking, antidepressant use, and a composite measure of increased risk revealed that higher levels of perceived social support were associated with improved outcome for patients without elevated depression but not for patients with high levels of depression. Neither perceived tangible support nor network support were associated with more frequent adverse events. Conclusion: AMI patients should be assessed for multiple dimensions of perceived functional support and depression to identify those at increased psychosocial risk who may benefit from treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Plasma concentrations of fibrinogen and factor VII in adult life and their relation to intra-uterine growth

To examine the relation between fetal development and plasma concentrations of fibrinogen and factor VII in adult life we followed up 202 men and women, now aged around 50 years, who had been measured in detail at birth. Plasma concentrations of fibrinogen were related to weight and abdominal circumference at birth. In men, after adjustment for cigarette smoking and current obesity, plasma concentrations of fibrinogen fell by 0.12 g/l (95% CI 0.05-0.19) for each pound increase in birthweight and by 0.10 g/l (95% CI 0.03-0.17) for each inch increase in abdominal circumference. In contrast, analysis of the data for women showed no statistically significant relation between plasma fibrinogen concentration and weight or abdominal circumference at birth. No relation was seen between concentrations of factor VII and measurements made at birth in either sex. These findings suggest that, in men, reduced growth of the liver in fetal life has a long-term influence on fibrinogen metabolism.     

Genetic variation in the promoter region of the beta-fibrinogen gene is associated with ischemic stroke in a Japanese population

Seventy-three consecutive unicompartmental knee arthroplasties (UKAs) using a Marmor-style non-metal-backed cemented tibial component were performed from 1975 to 1990. Sixty-seven knees (58 patients) were evaluated with minimum 5-year follow-up (mean, 9.7 years; range, 5-20 years). Knee rating and patient function were assessed using the updated Knee Society scoring system. Survivorship was 91% at 5 years, 84% at 10 years, and 79% at 15 years. The mean knee rating for surviving implants was 91 (range, 48-100), and mean functional score was 77 (range, 5-100). Survivorship and functional outcome were not affected by body habitus, age, gender, or tibial component thickness. UKA offers long-term relief of symptoms and excellent knee function in a high percentage of carefully selected patients with single compartment gonarthrosis.     

Lifestyle factors fail to explain the variation in plasma leptin concentrations in women

The underlying causes of 35 children with primary congenital hypothyroidism at the Children's Hospital were studied. There were 21 girls and 14 boys. Serum T4 and TSH level, 24 hours 131I uptake, and technetium-99m thyroid scintigraphy were performed after discontinuation of synthetic thyroid hormone for 4-6 weeks. Athyrosis was the most common cause and accounted for forty-three per cent of the patients. Twenty per cent of the patients had thyroid hypoplasia. Ectopic thyroid was found in thirty-three per cent of the patients. Only a patient whose diagnosis was organification defect had slightly enlarged thyroid gland, high retention of 131I and positive perchlorate discharge test. Onset of symptoms before 9 months of age may be helpful for distinguishing between lingual thyroid and the others. Serum T4 level less than 2 micrograms/dL was observed to be more common in athyrosis and lingual thyroid groups than thyroid hypoplasia group.     

Prognostic value of plasma fibrinogen concentration in patients with unstable angina and non-Q-wave myocardial infarction (TIMI IIIB Trial)

The records of 60 patients with gallbladder carcinoma (GBC) operatively treated between 1966 and 1993 at Belen Hospital, Trujillo, Perú, were retrospectively reviewed. The ratio of men to women was 1:7.5 and the average of age was 61 years. The accuracy of ultrasonography and oral cholecystograms for the specific diagnosis was 21% and 0% respectively. The surgical procedures employed were simple cholecystectomy (n = 56), right hepatectomy (n = 2). Whipple operation (n = 1) and extended cholecystectomy (n = 1), and our resectability rate for GBC is currently 50%. Simple cholecystectomy was a potentially curative surgical procedure in patients with in situ cancer (stage O) and early GBC (stage 1). In hospital mortality was 11.6% and 5-year survival rate for the total series was 15%. Gallstones were present in 95% of patients and most tumors (58%) had grown by diffuse infiltration or were associated with empyema (38%). Tumor stage, depth of invasion, tumor grade histologic type were all predictive of patient outcome. This report reinforces the difficulty in diagnosis and the poor prognosis for patients with GBC. We hold the view that more radical approaches for invasive cancers will enhance the operative results.     

Free nor-adrenaline and adrenaline excretion in relation to complications in acute myocardial infarction

The authors report on the clinical data, operating technique, postoperative complications, and late results in a series of 31 epidermoid and 21 dermoid cysts of the central nervous system.     

Subjective side effects of mianserin in relation to plasma concentrations of mianserin and desmethylmianserin

The main purpose of the present study was to examine the possibility that plasma concentrations of mianserin and its metabolite, desmethylmianserin, might be predicted by recording subjective side effects. In 44 depressed patients, subjective side effects during 3 weeks of treatment with 30 mg of mianserin were evaluated by the UKU Side Effect Rating Scale, and their relationships to plasma concentrations of mianserin and desmethylmianserin were analyzed. There was no significant relationship between plasma concentrations of these compounds and the occurrence of mianserin-induced side effects, except for dryness of mouth during week one. Our study, therefore, suggests that it is difficult to predict plasma concentrations of mianserin and desmethylmianserin based on the occurrence of subjective side effects.     

The Leu33/Pro polymorphism (PlA1/PlA2) of the glycoprotein IIIa (GPIIIa) receptor is not related to myocardial infarction in the ECTIM Study. Etude Cas-Temoins de l''Infarctus du Myocarde

The GPIIb/IIIa receptor complex may contribute to acute coronary syndromes by mediating platelet aggregation. The Leu33/Pro polymorphism (PlA1/PlA2) of the GPIIIa has recently been shown to be associated with CHD in a small case-control study. We have investigated this polymorphism in a large multicenter study of patients with myocardial infarction and controls and found no difference in the distribution of allele and genotype frequencies between cases and controls.     

Antibodies to prothrombin imply a risk of myocardial infarction in middle-aged men

Antiphospholipid antibodies in patients with "antiphospholipid syndrome" may be directed at least in part against plasma phospholipid-binding proteins, such as beta 2-glycoprotein I or prothrombin, which are involved in the control of thrombosis and haemostasis. IgG-class antibodies against prothrombin and beta 2-glycoprotein I were measured by enzyme-linked immunoassay in initially healthy middle-aged dyslipidaemic men (non-high-density lipoprotein > 5.2 mml/l). Serum samples had been drawn at entry to a 5-year coronary primary-prevention trial with gemfibrozil from 106 subjects who experienced either a non-fatal myocardial infarction or cardiac death during the follow-up and from 106 subjects without coronary episodes, matched for treatment group (gemfibrozil/placebo) and geographical area. The antiprothrombin antibody level, as expressed in optical density units, was significantly higher in patients than in controls (0.26 +/- 0.17 versus 0.22 +/- 0.09; p < 0.02). A high level of antiprothrombin antibodies (highest tertile of distribution) predicted a 2.5-fold increase in the risk (95% confidence interval 1.2-5.3) of myocardial infarction or cardiac death. The distribution of IgG-class antibodies against beta 2-glycoprotein I did not differ significantly between cases and controls. The joint effect of antiprothrombin antibodies and other factors associated with hypercoagulative state: triglyceride level, lipoprotein(a) and smoking, was multiplicative for the risk. Antiprothrombin antibodies are a new immunological predictor of myocardial infarction and the effect of these antibodies may be mediated by hypercoagulative mechanisms.     

Educational attainment, anger, and the risk of triggering myocardial infarction onset. The Determinants of Myocardial Infarction Onset Study Investigators

BACKGROUND: While it has recently been shown that anger may trigger the onset of acute myocardial infarction, there has been no study of the role of socioeconomic factors in such triggering. Socioeconomic factors, such as educational attainment, may modulate the risk of triggering because of their influence on individual reactivity to external stressors and on the prevalence of traditional cardiac risk factors. OBJECTIVE: To evaluate the influence of educational attainment on the relative risk of myocardial infarction onset following episodes of anger. METHODS: We interviewed 1623 patients (501 women) an average of 4 days following a myocardial infarction. Data were collected on standard demographic variables as well as risk factors for coronary artery disease. Educational attainment was categorized into 3 levels: less than high school, completed high school, and at least some college. Anger was assessed by the Onset Anger Scale, a single-item, 7-level, self-report scale. Occurrence of anger in the 2 hours preceding the onset of myocardial infarction was compared with its expected frequency using self-matched control data based on the case-crossover study design. RESULTS: The risk of having a myocardial infarction triggered by isolated episodes of anger declined consistently and significantly with increasing levels of educational attainment (P = .03). The relative risk was twice as high among those with less than high school education (relative risk, 3.3; 95% confidence interval, 2.0-5.4) compared with patients with at least some college education (relative risk, 1.6; 95% confidence interval, 0.9-2.9). CONCLUSIONS: These findings indicate that socioeconomic factors are potent modulators of the risk of triggering acute cardiovascular disease onset. A better understanding of the physiological mechanisms underlying this association may lead to novel approaches to prevent acute cardiovascular events.     

The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Etude CasTemoins de I'nfarctus du Mycocarde

We have investigated the interrelationships of plasma PAI-1 activity, the PAI-1 4G/5G polymorphism and risk of myocardial infarction (MI) in the ECTIM study, a case-control study of MI based in Belfast, Lille, Strasbourg and Toulouse. Mean PAI-1 levels in cases were similar across all centres but in controls, levels in the French centres were significantly higher. Only in Belfast were PAIl1 levels higher in cases (11.7 AU/ml) than controls (10.5 AU/ml). The PAI-1 4G allele frequency was similar in cases and controls (0.55 and 0.54). In all groups, 4G homozygotes had the highest mean plasma PAI-1 level (4G4G vs 5G5G; cases overall: 14.2 vs 12.1AU/ml; controls overall: 15.0 vs 12.6AU/ml), with the heterozygotes generally intermediate. The data from Belfast are consistent with the literature implicating PAI-1 level as an MI risk factor. In ECTIM, the PAI-1 4G/5G polymorphism is not a genetic risk factor for MI but is associated with PAI-1 activity. Thus homozygosity for the 4G allele may predispose to elevated PAI-1 and impaired fibrinolysis, perhaps requiring interaction with other genetic or environmental factors to influence MI risk.     

Incidence and prevalence of recognised and unrecognised myocardial infarction in women. The Reykjavik Study

AIMS: The incidence and prevalence of recognised and unrecognised myocardial infarction were determined in the Icelandic cohort study of 13,000 women (the Reykjavik Study), followed for up to 29 years (mean 15 years). METHODS AND RESULTS: Women attending the Reykjavik Study, born between 1908 and 1935, were examined in five stages from 1968 to 1991. A health survey included history and ECG manifestations of coronary heart disease. Data retrieved from hospitals, autopsy records and death certificates identified 596 fatal and non-fatal myocardial infarctions to the end of 1992 (61 prior to examination, 320 non-fatal and 215 fatal). The incidence of recognised myocardial infarction ranged from 22 cases/100,000/year at 35-39 years to 1800 cases/100,000/year at 75-79 years. The incidence of unrecognised myocardial infarction ranged from 18 cases/100,000/year at 35 years to 219 cases/100,000/year at 75 years. Thirty-three percent of non-fatal myocardial infarctions were unrecognised. More occurred in the younger age groups (40%) than in the older (27%). The prevalence of recognised myocardial infarction was influenced by age and calendar year. In 1990, it was 1.3/1,000 at 35 years and 60/1000 at 75 years. Prevalence showed a time trend, tripling in all age groups from 1968-1992. Fore unrecognised myocardial infarction, prevalence rose from 0.9/1000 at 35 years to 19.2/1000 at 75 years, although there was no evident time trend. CONCLUSION: Myocardial infarction in women is very age-dependent with both incidence and prevalence increasing continuously and steeply with age. There was a significant trend for an increase in prevalence of recognised myocardial infarction from 1968 to 1992. The proportion of unrecognised non-fatal infarctions ranged from 27% in the oldest age group to 40% in the youngest. On average, this form of coronary heart disease is as common as in men.     

Hostility, aggression and the risk of nonfatal myocardial infarction in postmenopausal women

Integration of human papillomavirus type 16 DNA sequences into host DNA is a frequent event in cervical carcinogenesis. However, recent studies showing that HPV16 is present exclusively in an episomal form in many primary cervical cancers suggest that HPV16 can transform target cells by mechanisms that do not require viral integration. We have established a cervical carcinoma cell line that harbors episomal copies of HPV16 DNA of approximately 10 kb. Restriction enzyme and two-dimensional gel analysis confirmed that HPV16 DNA was extrachromosomal with both monomeric and multimeric forms present. HPV16 was maintained as episomes with passage both in culture and after subcutaneous growth in nude mice. The 10 kb viral genome, consisting of a full-length copy of HPV16 and a partial duplication of the long control region and the L1 open reading frame, exhibited transforming activity comparable to prototype HPV16. This cell line should provide a useful model system for studying the biological significance of the physical state of the HPV16 genome in cervical carcinoma cells.