J. R. O'Brien

Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell collaborative heart disease studies.

BackgroundRecent studies have suggested that hemostatic factors and white blood cell count are predictive of ischemic heart disease (IHD). The relations of fibrinogen, viscosity, and white blood cell count to the incidence of IHD in the Caerphilly and Speedwell prospective studies are described. Methods and ResultsThe two studies have a common core protocol and are based on a combined cohort of 4,860 middle-aged men from the general population. The first follow-up was at a nearly constant interval of 5.1 years in Caerphilly and 3.2 years in Speedwell; 251 major IHD events had occurred. Age-adjusted relative odds of IHD for men in the top 20% of the distribution compared with the bottom 20% were 4.1 (95% confidence interval, 2.6-6.5) for fibrinogen, 4.5 (95% confidence interval, 2.8-7.4) for viscosity, and 3.2 (95% confidence interval, 2.0-4.9) for white blood cell count. Associations with IHD were similar in men who had never smoked, exsmokers, and current smokers, and the results suggest that at least part of the effect of smoking on IHD is mediated through fibrinogen, viscosity, and white blood cell count. Multivariate analysis shows that white blood cell count is an independent risk factor for IHD as is either fibrinogen or viscosity, or possibly both. Jointly, these three variables significantly improve the fit of a logistic regression model containing all the main conventional risk factors. Further, a model including age, smoking habits, fibrinogen, viscosity, and white blood cell count predicts IHD as well as one in which the three hemostatic/rheological variables are replaced by total cholesterol, diastolic pressure, and body mass index. Conclusion. Jointly, fibrinogen, viscosity, and white blood cell count are important risk factors for IHD. (Circulation 1991;83:836–844)

Ischemic heart disease and platelet aggregation. The Caerphilly Collaborative Heart Disease Study.

The Caerphilly Collaborative Heart Disease Study is based on a large cohort of men (2,398) aged 49-66 years at the time of study. Platelet aggregation induced by collagen, thrombin, and ADP was measured in fasting blood samples and was related to prevalent angina, past myocardial infarction, and electrocardiographic evidence of ischemic heart disease. A number of subjects had taken aspirin, other nonsteroidal anti-inflammatory drugs, or other drugs affecting platelet aggregation 7 days before blood sample collection; after the exclusion of these subjects, data were available for 1,811 men. No relations were demonstrated with angina, but significant relations were shown between past myocardial infarctions and electrocardiographic evidence of ischemia and ADP-induced aggregation (both primary and secondary) and between electrocardiographic evidence of ischemia and thrombin-induced aggregation. The strongest relation indicated more than a twofold increase in the odds of a past myocardial infarction in subjects of the highest fifth of ADP-induced primary platelet aggregation compared with the lowest fifth. No significant relations were detected with collagen-induced aggregation. Accounting for a number of possible confounding factors had a relatively small impact on the relations between platelet aggregation and ischemic heart disease. Other evidence, including the well-established effect of aspirin on reducing the incidence of ischemic heart disease, indicates that the relations we describe are unlikely to be simply an effect of IHD on platelets.

Some long term effects of smoking on the haemostatic system: a report from the Caerphilly and Speedwell Collaborative Surveys

Data from two community studies on men from South Wales and the west of England suggest that the effects of smoking on the haemostatic system remain for many years after giving up. Long term correlations between several variables, including plasma fibrinogen and white cell count, and the length of time after giving up were seen in ex-smokers. Dose response relations were apparent in current smokers in terms of the white cell count and two haematological variables, the packed and mean cell volumes. These long term correlations probably reflect the toxicity of other agents in tobacco smoke besides nicotine and carbon monoxide, which act only in the short term. Identification of these agents may further our understanding of the mechanism by which cigarette smoking is associated with atherosclerotic disease.

Temperature and risk factors for ischaemic heart disease in the Caerphilly prospective study.

OBJECTIVE--To examine the associations between air temperature and risk factors for ischaemic heart disease. METHOD--Data on risk factors are available from up to 2036 men in the Caerphilly Prospective Heart Disease Study. Daily temperatures were obtained from the Meteorological Office. Relations between these were examined by regression. RESULTS--The coldest month of the year has a mean temperature that is 16 degrees C lower than that in the warmest month. A fall in temperature of this magnitude is associated with higher blood pressures (by 3-5 mm Hg) and a lower concentration of high density lipoprotein cholesterol (by 0.08 mmol/l). The most important effects however, seem to be on the haemostatic system. Fibrinogen is 0.34 g/l higher in the coldest month than in the warmest (p < 0.001) and alpha 2 macroglobulin, a protein that inhibits fibrinolysis, is also raised. Platelet count is increased by 30% of a standard deviation and the sensitivity of platelets in whole blood to adenosine diphosphate is increased by cold. CONCLUSIONS--These effects on haemostasis, together with the effect on blood pressure, could explain a large part of the increase in ischaemic heart disease in the winter but are unlikely to explain much of the difference in mortality within different areas of England and Wales.

Exercise, fibrinogen, and other risk factors for ischaemic heart disease. Caerphilly Prospective Heart Disease Study.

OBJECTIVE--To examine the associations between physical activity and a wide range of risk factors for ischaemic heart disease including fibrinogen concentration and viscosity. DESIGN--Cross sectional evidence from the 2398 men aged 50-64 years in the Caerphilly Prospective Heart Disease Study. METHODS--Validated questionnaires were used to quantify energy expenditure on leisure activities and to grade activities related to occupation. Risk factors for heart disease examined included blood pressure, lipids, fibrinogen, and plasma viscosity. Possible confounding variables included smoking, employment, and prevalent heart disease (angina, previous myocardial infarction, and electrocardiographic evidence of ischaemia). RESULTS--Fibrinogen concentration was lower by 0.24 g/l and viscosity by 0.026 cP in the third of men who were most active in leisure activities (about 0.25 x 1 SD). A weak positive relation was found with high density lipoprotein cholesterol, but none with total cholesterol or fasting glucose concentrations or blood pressure. Triglyceride concentrations seem to be substantially lower in the most active men, although the evidence for this is not consistent. Work related activity showed relation with the lipid concentration but not with the haemostatic tests. CONCLUSIONS--Leisure activities of all levels seem to affect haemostatic and lipid factors beneficially. These effects correspond to a difference in the risk of heart disease for an active man and a sedentary man of at least 7% or 8%. Fasting triglyceride concentrations have already been shown to be strongly predictive of heart disease in this cohort of men, and the effect of exercise on this factor is also likely to confer benefit.

Haemostatic factors and ischaemic heart disease. The Caerphilly study.

In a preliminary report from the Caerphilly study four haemostatic factors showed univariate associations with prevalent ischaemic heart disease after adjusting for age. These factors were fibrinogen concentration, plasma viscosity, white cell count, and the heparin-thrombin clotting time. Age and these haemostatic variables were entered into a stepwise multiple logistic regression analysis; after age the white cell count and heparin-thrombin clotting time remained significantly associated with ischaemic heart disease. Further regression analyses indicated that diastolic blood pressure contributed additionally to this association with ischaemic heart disease but that smoking habit did not.

Platelet aggregation and incident ischaemic heart disease in the Caerphilly cohort

Background Platelets are involved in myocardial infarction but evidence of prediction of infarction by measures of platelet function are sparce. Methods Platelet aggregation to thrombin and to ADP in platelet rich plasma was recorded for 2176 men aged 49–65 years in the Caerphilly cohort study. Results Results from 364 men were excluded, 80 of whom had not fasted before venepuncture; most of the others were excluded because antiplatelet medication had been taken shortly before the platelet tests. During the five years following the platelet tests 113 ischaemic heart disease (IHD) events which fulfilled the World Health Organisation criteria were identified—42 fatal and 71 non-fatal. No measure of platelet aggregation was found to be significantly predictive of incident IHD. The possibility that platelet function is predictive for only a limited time after it is characterised, and that prediction falls off with time, was tested. When IHD events are grouped by their time of occurrence after aggregation had been measured, the test results show a gradient suggestive of prediction of early IHD events. Thus, 24% of the men who had an event within 500 days of the test had had a high secondary response to ADP while only 12% of those whose IHD event had been 1000 or more days after the test had shown a high platelet response at baseline. The trend in these proportions is not significant. Conclusions Platelet aggregation to thrombin and ADP in platelet rich plasma was recorded in the Caerphilly cohort study. No measure of aggregation was found to be predictive of IHD.

A Genome Wide Association Study of Plasmodium falciparum Susceptibility to 22 Antimalarial Drugs in Kenya

Background Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. Methods and Principal Findings Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. Conclusions/Significance Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

Inter-relationships between haemostatic tests and the effects of some dietary determinants in the Caerphilly cohort of older men

Inter-relationships between fibrinogen, platelets and other haemostatic factors were examined in 1030 men aged 55–99 years. Fasting blood was taken and used for cell counts, platelet counts and platelet parameters, aggregation of platelets to ADP by a whole blood method and a filter test of platelet activation. Plasma fibrinogen, von Willebrand factor, factor VII and plasma viscosity were measured by standard methods. A stressed bleeding time was conducted on the forearm of the arm not used for venepuncture. Variability within the laboratory and short-term intra-subject variation were examined and found to be acceptably small. The effect of age on the tests was modest, except for von Willebrand factor which increased by about 50% of a SD for every 10 years of age. Cholesterol and triglyceride levels had small effects on the platelet tests and a large effect on factor VII. A number of dietary and life-style determinants were examined: smokers had increased levels of fibrinogen, viscosity and white cell count and reduced bleeding times. Alcohol drinkers showed reduced platelet activity and have lower levels of fibrinogen, von Willebrand factor and white cell count. Men who took fish oil capsules had substantially increased bleeding times and lower levels of von Willebrand factor and men who took capsules containing an extract of garlic showed reduced platelet retention in the filter test.

Platelets, aspirin, and cardiovascular disease.

Aspirin was first synthesised 100 years ago and its preparation and marketing is generally reckoned to have been the foundation of the pharmaceutical industry. For most of the time since then it has been used for the relief of pain and fever. The modern phase of aspirin use commenced with the reporting in 1974 of a randomised controlled trial in the secondary prevention of death by low-dose aspirin given to patients who had suffered a myocardial infarct. Reports of other trials followed and an overview of the first six trials was presented to the inaugural meeting of the Society for Clinical Trials in Philadelphia in 1980. There have been two further major overviews and the most recent, based on 145 trials, established that low-dose aspirin reduces vascular events by around one third. It has been estimated that, used appropriately, aspirin could prevent 100,000 premature deaths each year worldwide, at a cost of about 250 Pounds (