J. W. G. Yarnell

Low Paraoxonase Activity Predicts Coronary Events in the Caerphilly Prospective Study

Background—The hypothesis that paraoxonase (PON1) has a role in preventing atherosclerosis is based on experimental, transgenic, and case-control studies but has not previously been tested prospectively. Methods and Results—The Caerphilly Prospective Study is a cohort study of men aged 49 to 65 years observed for coronary heart disease (CHD) events (fatal and nonfatal myocardial infarction) over a mean period of 15 years. Serum PON1 activity toward paraoxon was measured in 1353 participants. PON1 activity was 20% lower in the 163 men who had a coronary event (P =0.039). Men in the highest quintile of PON1 activity had a decreased risk compared with those in the lowest quintile (OR 0.57 [95% CI, 0.33 to 0.96]). The inverse relationship between quintiles of serum PON1 activity and CHD risk was graded, the median change in OR across each quintile being 0.87 (0.77 to 0.98). After adjustment for all other CHD risk factors, including HDL cholesterol, this median value became 0.90 (0.78 to 1.02). PON1 was most predictive of a new CHD event in patients at highest risk by virtue of preexisting CHD (adjusted median OR for each quintile, 0.74 [0.59 to 0.93]; n=313) or the presence of other risk factors. For the highest tertile of CHD risk (n=390) calculated by the Framingham equation, adjusted median OR for each quintile was 0.84 (0.66 to 1.05); n=390. Conclusions—Low serum PON1 activity toward paraoxon is an independent risk factor for coronary events in men at high risk because of preexisting disease or other CHD risk factors.

Leg length, insulin resistance, and coronary heart disease risk: The Caerphilly Study

BACKGROUND Adult height has been inversely associated with coronary heart disease risk in several studies. The mechanism for this association is not well understood, however, and this was investigated by examining components of stature, cardiovascular disease risk factors and subsequent coronary heart disease in a prospective study. METHODS All men aged 45–59 years living in the town of Caerphilly, South Wales were approached, and 2512 (89%) responded and underwent a detailed examination, which included measurement of height and sitting height (from which an estimate of leg length was derived). Participants were followed up through repeat examinations and the cumulative incidence of coronary heart disease—both fatal and non-fatal—over a 15 year follow up period is the end point in this report. RESULTS Cross sectional associations between cardiovascular risk factors and components of stature (total height, leg length and trunk length) demonstrated that factors related to the insulin resistance syndrome—the homeostasis model assessment of insulin resistance, fasting triglyceride levels and total to HDL cholesterol ratio—were less favourable in men with shorter legs, while showing reverse or no associations with trunk length. Fibrinogen levels were inversely associated with leg length and showed a weaker association with trunk length. Forced expiratory volume in one second was unrelated to leg length but strongly positively associated to trunk length. Other risk factors showed little association with components of stature. The risk of coronary heart disease was inversely related to leg length but showed little association with trunk length. CONCLUSION Leg length is the component of stature related to insulin resistance and coronary heart disease risk. As leg length is unrelated to lung function measures it is unlikely that these can explain the association in this cohort. Factors that influence leg length in adulthood—including nutrition, other influences on growth in early life, genetic and epigenetic influences—merit further investigation in this regard. The reported associations suggest that pre-adult influences are important in the aetiology of coronary heart disease and insulin resistance.

Helicobacter pylori infection rates in relation to age and social class in a population of Welsh men.

The seroprevalence of IgG antibodies to Helicobacter pylori was determined using a standard enzyme linked immunosorbent assay in a population of 749 randomly selected men, aged 30-75 years, from Caerphilly, South Wales. The overall prevalence of H pylori was 56.9%, increasing sharply in middle age from 29.8% in those aged 30-34 to over 59% in those aged 45 or older (p less than 0.0001). Age standardised seroprevalence rates were lowest in combined social class categories I and II (49.2%), intermediate in categories IIIN and M (57.5%), and highest in categories IV and V (62.2%) (p = 0.01). In those aged 30-34 years, the prevalence rate for those in combined social class categories IV and V was 57.9% - double the rate for social class categories IIIM and N (28.3%) and five times the prevalence rate in those in social class categories I and II (11.1%). These differences in the infection patterns of H pylori by social class are consistent with patterns of peptic ulcer disease and gastric cancer.

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.

Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study.

Numerous case-control studies have suggested that elevated levels of endogenous estrogen and low levels of testosterone are associated with ischemic heart disease (IHD) in men. These findings were tested in the Caerphilly study of 2,512 men from the general population who were aged 45-59 years at baseline and were followed for 5 years. Some 153 men experienced a new episode of IHD (fatal and nonfatal) during the period of follow-up. Baseline values of estradiol were marginally higher in subjects who developed IHD than in those who did not, but the difference was not statistically significant. Plasma values of testosterone were similar in the two groups. Among quintiles of the distribution of the hormone values, the incidence of IHD was similar in the case of estradiol; there was also no clear trend in the case of testosterone. These findings provide no support for the suggestion that plasma estradiol or testosterone are primary risk factors for IHD, although the associations between plasma testosterone and other probable risk markers (triglycerides, insulin, body mass index, and high density lipoprotein cholesterol) indicate the possibility that testosterone may play an indirect role in the pathogenesis of IHD.

Insulin in ischaemic heart disease: are associations explained by triglyceride concentrations? The Caerphilly prospective study.

OBJECTIVE--To investigate the predictive value of fasting insulin concentrations for subsequent fatal or non-fatal ischaemic heart disease at five year follow up and to examine the associations between insulin and other indicators of risk. DESIGN--A prospective population study among 2512 men aged 45 to 59 at recruitment. SETTING--A whole population sample of men resident in Caerphilly, South Wales. MEASUREMENTS--At recruitment fasting blood samples were taken for measurement of plasma lipids and serum insulin. Men were re-examined at a five year follow up and ischaemic heart disease events during this period were assessed from hospital notes, death certificates, and electrocardiograms. MAIN RESULTS--Diabetic men and those men with a fasting blood glucose of > or = 8 mmol/l were excluded from all analyses. In a univariate analysis the incidence of ischaemic heart disease increased with increasing concentration of fasting insulin, such that for men in the top 20% of the insulin distribution the odds of developing ischaemic heart disease were 1.87 relative to men in the bottom 20%. On multivariate analysis this relation disappeared on adjusting for plasma triglycerides, body mass index, and evidence of ischaemic heart disease at recruitment. CONCLUSION--In this population in South Wales there was no evidence that the fasting insulin concentration is an independent risk factor for ischaemic heart disease. The univariate association between insulin and incident disease was almost entirely explained by the association of both with triglycerides and body mass index.

Concentrations of proinsulin like molecules predict coronary heart disease risk independently of insulin: prospective data from the Caerphilly Study.

Abstract.Aims/hypothesis: Higher concentrations of insulin correlate with several coronary heart disease (CHD) risk factors and have been shown to predict incident CHD in several studies, leading to hypotheses concerning the proatherogenic properties of insulin. However, in cross-sectional studies, relationships of concentrations of the insulin precursor molecules, proinsulin and des 31, 32 proinsulin, relate as strongly, or more strongly, to levels of risk factors and to (prevalent) CHD. Methods: We investigated the relationship between concentrations of insulin, measured with a specific assay, and of proinsulin-like molecules, and risk factors in 1181 non-diabetic men 50–64 years old during Phase II of the Caerphilly Study. We also related concentrations of these molecules to incident CHD during the 10–14 years follow-up. Results: The relationship between concentrations of insulin, of proinsulin and of des 31, 32 proinsulin and BMI (r = 0.36–0.45), triglyceride (r = 0.25–0.31), high density lipoprotein- (HDL-) cholesterol (r = –0.17 to –0.21), systolic (r = 0.05–0.11) and diastolic blood pressure (r = 0.11–0.15) were similarly close, those with risk factors being somewhat and similarly reduced after adjustment for BMI. The correlation between insulin and of proinsulin-like molecules and those plasminogen activator inhibitor-1 (PAI-1) antigen was also similar (r = 0.28–0.29). There was a negative correlation between concentrations of proinsulin-like molecules – but not insulin – and birth weight. Insulin concentrations correlated positively with height (r = 0.12). In logistic regression models, concentrations of proinsulin-like molecules, but not insulin, predicted incident of CHD over a follow-up of 10–14 years (insulin – standardised odds ratio (SOR) 1.30 (95 %-CI) 0.91, 1.85), p = 0.15; des 31, 32 proinsulin – SOR 1.38 (95 %-CI 1.02, 1.85), p = 0.034; sum of proinsulin-like molecules – SOR 1.54 (95 %-CI 1.07, 2.20), p = 0.019 after adjusting for age and BMI. The predictive ability of these molecules was reduced by around one third after adjustment for standard risk factors and concentrations of tryglyceride and HDL-cholesterol, and by about half after further adjustment for PAI-1 concentrations. Conclusion/interpretation: We conclude that concentrations of proinsulin-like molecules provide a better way to predict the incidence of CHD than those of insulin. However, the lack of biological evidence for a causative relationship suggests an association through a common antecedent, and this antecedent is not likely to be intrauterine growth retardation. [Diabetologia (2002) 45: 327–336]

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.

C-Reactive Protein, Fibrin D-Dimer, and Risk of Ischemic Heart Disease The Caerphilly and Speedwell Studies

Background—There is increasing interest in the predictive value of C-reactive protein (CRP) and fibrin D-dimer in the prediction of ischemic heart disease (IHD). We assessed their joint and independent associations with IHD in a large combined analysis of 2 population cohorts. Methods and Results—Men aged 49 to 66 years from the general populations of Caerphilly and Speedwell were studied between 1982 and 1988 and re-examined for new IHD events at fixed intervals of ≈105 months (Caerphilly) and 75 months (Speedwell). 3213 men had CRP and D-dimer measured at baseline and 351 (11%) had a new IHD event. Mean levels of CRP and D-dimer were significantly higher among men in whom IHD developed. The relative odds of IHD in men in the top 20% of the distribution of CRP was 2.97 (95% CI, 2.04, 4.32) and for D-dimer was 2.40 (95% CI, 1.69, 3.40); CRP and D-dimer had additive effects on risk of IHD. Multivariate analysis reduced the size of the relative odds, which remained significant for D-dimer. Conclusions—Both inflammatory and thrombogenic markers are important (and potentially additive) predictors of coronary risk.