Role of family history in patients with myocardial infarction. An Italian case-control study. GISSI-EFRIM Investigators.

BACKGROUND. A family history of heart disease has been reported to increase the risk of coronary heart disease. We examined the relation between family history of myocardial infarction (MI) and risk of acute MI to establish the independency of this association, the degree of risk in relation to the number and age of relatives affected, and the possible interaction between family history and other major risk factors for MI. METHODS AND RESULTS. In a case-control study conducted in Italy within the framework of the GISSI-2 Trial, 916 cases of newly diagnosed MI and 1,106 hospital controls were identified. Using a structured questionnaire, data were collected on the history of MI in first-degree relatives and the age at which the event occurred. Compared with subjects without family history of MI in first-degree relatives, the relative risk (RR) of MI was 2.0 (95% confidence interval, CI, 1.6-2.5) in those with one and 3.0 (95% CI, 2.0-4.4) in those with two or more relatives affected (chi 2(1) test for trend, 54.1; p less than 0.001). Such an increase was not substantially affected by allowance for recognized risk factors. The risk related to family history involving at least two relatives was higher for early MI (less than 55 years) (RR, 20.0; 95% CI, 3.3-121.2) compared with later MI (less than or equal to 65 years) (RR, 3.5; 95% CI, 1.8-6.6). When known risk factors were considered for their interaction with family history, the effect on RR was approximately multiplicative for several variables, including smoking, serum cholesterol, hypertension, and hyperlipidemia but not for diabetes and body mass index. Thus, the presence of both family history and smoking and cholesterol levels greater than or equal to 226 mg/dl led to an RR of 14 (95% CI, 3.7-50.0) and 8.3 (95% CI, 1.8-38.7), respectively. CONCLUSIONS. This study indicates that a family history of MI is an independent risk factor for MI, and that the number of relatives and the age at which they were affected is related to the strength of the association. There is a multiplicative effect on RR between family history and several major risk factors for MI.     

The fixed-dose combination drug for secondary cardiovascular prevention project: improving equitable access and adherence to secondary cardiovascular prevention with a fixed-dose combination drug. Study design and objectives

In spite of advances in prevention and treatment, the burden of cardiovascular diseases is increasing. A fixed-dose combination (FDC) pill, or "polypill," composed of evidence-based drugs has been proposed as a means of improving cardiovascular prevention by reducing cost and increasing patient adherence to treatment. The aim of the FOCUS project, funded by the 7th Framework Programme of the European Commission, is to characterize the factors that underlie inadequate secondary prevention and to test a new FDC. To achieve these goals, a 9-member consortium has been constituted, including institutions from Argentina, France, Italy, Spain, and Switzerland. FOCUS Phase-1 will examine factors potentially related to lack of adequate secondary prevention in 4,000 post-myocardial infarction (MI) patients and analyze the relationship between these factors and patient treatment adherence. Primary end points will be (1) the percentage of patients receiving aspirin, angiotensin-converting enzyme inhibitors, and statins and (2) adherence to treatment measured by the Morisky-Green test. FOCUS Phase-2 is a randomized trial that will compare adherence to treatment in 1,340 post-myocardial infarction patients either receiving an FDC comprising aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and simvastatin (40 mg) or receiving the same 3 drugs separately.     

Comparison and Possible Use of In Silico Tools for Carcinogenicity Within REACH Legislation

Seven in silico models have been used to assess the prediction accuracy of chemical compound carcinogenicity. More than 1500 compounds with experimental values have been used to evaluate the models. Here we review the application of these models for toxicity prediction and their advantages and disadvantages, discussing the different approaches underlying the models and their main critical points. Some models have fewer false negatives while others are better at avoiding false positives. Since carcinogenicity is typically evaluated using a series of studies, identification of a strategy using one, or preferably a battery of in silico models, could reduce the number of animal studies needed.     

New clues on carcinogenicity-related substructures derived from mining two large datasets of chemical compounds

In this study, new molecular fragments associated with genotoxic and nongenotoxic carcinogens are introduced to estimate the carcinogenic potential of compounds. Two rule-based carcinogenesis models were developed with the aid of SARpy: model R (from rodents' experimental data) and model E (from human carcinogenicity data). Structural alert extraction method of SARpy uses a completely automated and unbiased manner with statistical significance. The carcinogenicity models developed in this study are collections of carcinogenic potential fragments that were extracted from two carcinogenicity databases: the ANTARES carcinogenicity dataset with information from bioassay on rats and the combination of ISSCAN and CGX datasets, which take into accounts human-based assessment. The performance of these two models was evaluated in terms of cross-validation and external validation using a 258 compound case study dataset. Combining R and H predictions and scoring a positive or negative result when both models are concordant on a prediction, increased accuracy to 72% and specificity to 79% on the external test set. The carcinogenic fragments present in the two models were compared and analyzed from the point of view of chemical class. The results of this study show that the developed rule sets will be a useful tool to identify some new structural alerts of carcinogenicity and provide effective information on the molecular structures of carcinogenic chemicals.     

gamma-Glutamyl carboxylase activity in experimental tumor tissues: a biochemical basis for vitamin K dependence of cancer procoagulant

Rabbit V2 carcinoma tissues have been described to possess a procoagulant activity with specific characteristics; this material has been purified and identified as a cysteine proteinase able to directly activate coagulation factor X. We have shown here that the procoagulant activity of V2 carcinoma extracts is depressed in warfarin-treated animals, thus suggesting that cancer procoagulant could represent a new vitamin K-dependent protein. The biochemical basis for this effect is offered by the identification of gamma-glutamyl carboxylase in the microsomal fraction of tumor tissues. The V2 carcinoma has a carboxylase activity which is increased in warfarin-treated animals. An endogenous substrate of tumor carboxylase, the nature of which has not been identified, has been found 5-fold increased in warfarin-treated animals. The presence of gamma-glutamyl carboxylase was also described in several murine tumors including both carcinomas and fibrosarcomas. It is worth mentioning that all the tumors tested produce a procoagulant with the peculiar characteristics of that described in V2 carcinoma. It is conceivable that cancer procoagulant could represent at least one of the substrates for gamma-glutamyl carboxylase in these experimental tumor tissues.     

Increased susceptibility to the anticoagulant effect of warfarin in mice bearing the Lewis lung carcinoma. Role of vitamin K deficiency

This study reports an increased susceptibility to warfarin anticoagulation in mice bearing an experimental tumour, the Lewis lung carcinoma. In these animals, following a single i.v. injection of warfarin, the prothrombin complex activity decreased normally but recovered far slower than in controls, while the rate of degradation of the clotting factors was not modified. At the level of the vitamin K-dependent liver carboxylase, it was possible to demonstrate an increase in the endogenous substrate (reflecting an impairment of the carboxylase vitamin K dependent system). This abnormality was reversed by vitamin K administration and can be reasonably ascribed to a vitamin K deficiency in association with tumour growth.     

Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials

Context  Aspirin therapy reduces the risk of cardiovascular disease in adults who are at increased risk. However, it is unclear if women derive the same benefit as men. Objective  To determine if the benefits and risks of aspirin treatment in the primary prevention of cardiovascular disease vary by sex. Data Sources and Study Selection  MEDLINE and the Cochrane Central Register of Controlled Trials databases (1966 to March 2005), bibliographies of retrieved trials, and reports presented at major scientific meetings. Eligible studies were prospective, randomized controlled trials of aspirin therapy in participants without cardiovascular disease that reported data on myocardial infarction (MI), stroke, and cardiovascular mortality. Six trials with a total of 95 456 individuals were identified; 3 trials included only men, 1 included only women, and 2 included both sexes. Data Extraction  Studies were reviewed to determine the number of patients randomized, mean duration of follow-up, and end points (a composite of cardiovascular events [nonfatal MI, nonfatal stroke, and cardiovascular mortality], each of these individual components separately, and major bleeding). Data Synthesis  Among 51 342 women, there were 1285 major cardiovascular events: 625 strokes, 469 MIs, and 364 cardiovascular deaths. Aspirin therapy was associated with a significant 12% reduction in cardiovascular events (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.79-0.99; P = .03) and a 17% reduction in stroke (OR, 0.83; 95% CI, 0.70-0.97; P = .02), which was a reflection of reduced rates of ischemic stroke (OR, 0.76; 95% CI, 0.63-0.93; P = .008). There was no significant effect on MI or cardiovascular mortality. Among 44 114 men, there were 2047 major cardiovascular events: 597 strokes, 1023 MIs, and 776 cardiovascular deaths. Aspirin therapy was associated with a significant 14% reduction in cardiovascular events (OR, 0.86; 95% CI, 0.78-0.94; P = .01) and a 32% reduction in MI (OR, 0.68; 95% CI, 0.54-0.86; P = .001). There was no significant effect on stroke or cardiovascular mortality. Aspirin treatment increased the risk of bleeding in women (OR, 1.68; 95% CI, 1.13-2.52; P = .01) and in men (OR, 1.72; 95% CI, 1.35-2.20; P<.001). Conclusions  For women and men, aspirin therapy reduced the risk of a composite of cardiovascular events due to its effect on reducing the risk of ischemic stroke in women and MI in men. Aspirin significantly increased the risk of bleeding to a similar degree among women and men.