Peter M. Sweetnam

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)

Birthweight, body-mass index in middle age, and incident coronary heart disease

BACKGROUNDnSeveral studies have shown a relation between fetal development, as shown by birthweight, and later coronary heart disease. This study investigated whether this relation is predominantly the consequence of early life exposures, or can best be explained in terms of an interaction between influences in early life and in adulthood.nnnMETHODSnThis prospective study in Caerphilly, South Wales, included 1258 men, aged 45-59 at initial screening, who were able to provide birthweight data. These men are from an initial cohort of 2512 men, from whom information has been obtained in a series of examinations since 1979 on health-related behaviours, incidence of coronary heart disease, and risk factors. The main outcome measure was fatal and non-fatal coronary heart disease during 10 years of follow-up.nnnFINDINGSnHigher birthweight was related to lower risk of coronary heart disease during the follow-up period: coronary heart disease occurred in 46 (11.6%) men in the lowest birthweight tertile, 44 (12.0%) of those in the middle tertile, and 38 (9.1%) of those in the highest tertile (p = 0.03). Stratification of the cohort by body-mass index (BMI) revealed a significant interaction such that the inverse association between birthweight and risk of coronary heart disease was restricted to men in the top tertile of BMI (interaction test p = 0.048 adjusted for age, and p = 0.012 fully adjusted). Within the top BMI tertile, coronary heart disease occurred in 19 (16.4%) of men in the lowest birthweight tertile, 13 (12.6%) of those in the middle tertile, and 13 (7.5%) of those in the highest tertile (p = 0.0005). These associations were not changed substantially by adjustment for age, fathers social class, own social class, marital status, fibrinogen and cholesterol concentrations, systolic blood pressure, and smoking history.nnnINTERPRETATIONnThe association between birthweight and risk of coronary heart disease cannot be explained by associations with childhood or adulthood socioeconomic status. Nor do conventional risk factors for coronary heart disease in adulthood account for the association. However, there is an important interaction between birthweight and BMI such that the increased risk of coronary heart disease associated with low birthweight is restricted to people who have high BMI in adulthood. Risk of coronary heart disease seems to be defined by the combined effect of early-life and later-life exposures.

Aspirin and secondary mortality after myocardial infarction.

Three randomized controlled trials of aspirin and secondary mortality have been conducted in patients who had had a myocardial infarction. One trial was based on 1239 men followed for 1-2 years; the second was based on 1468 men and 257 women followed for 1 year after infarction. Although the results are not statistically significant in either trial, they are consistent with a reduction in mortality during the year after infarction of about 24% and 17%. Detailed analyses, in which allowance is made for small imbalances between the groups on aspirin and on placebo, indicate that the estimate of benefit of 17% in one of the trials is almost certainly an underestimation. The third trial, in which we analyzed only very early mortality based on 2530 patients, did not show evidence of benefit from aspirin given during the acute phase of infarction.

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.

C-Reactive Protein, Fibrin D-Dimer, and Incident Ischemic Heart Disease in the Speedwell Study Are Inflammation and Fibrin Turnover Linked in Pathogenesis?

Abstract— Plasma levels of C-reactive protein (CRP, a marker of the reactant plasma protein component of the inflammatory response) and of fibrin D-dimer (a marker of cross-linked fibrin turnover) have each been associated in recent studies with the risk of future ischemic heart disease (IHD). Previous experimental studies have shown that fibrin degradation products, including D-dimer, have effects on inflammatory processes and acute-phase protein responses. In the Speedwell Prospective Study, we therefore measured CRP and D-dimer levels in stored plasma samples from 1690 men aged 49 to 67 years who were followed-up for incident IHD for an average of 75±4 months (mean±SD) and studied their associations with each other, with baseline and incident IHD, and with IHD risk factors. CRP and D-dimer levels were each associated with age, plasma fibrinogen, smoking habit, and baseline evidence of IHD. CRP was associated with D-dimer (r =0.21, P <0.00001). On univariate analyses, both CRP and D-dimer were associated with incident IHD. The incidence of IHD increased with CRP independently of the level of D-dimer (P =0.0002) and also increased with D-dimer independently of the level of CRP (P =0.048). In multivariate analyses, inclusion of D-dimer and conventional risk factors reduced the strength of the association between CRP and incident IHD; likewise, inclusion of CRP and conventional risk factors reduced the strength of the association between D-dimer and incident IHD. We conclude that although these respective markers of inflammation and fibrin turnover show modest association with each other in middle-aged men, they may have additive associations with risk of incident IHD. Further larger studies are required to test this hypothesis.

What level of physical activity protects against premature cardiovascular death? The Caerphilly study

Objective: To examine the optimal intensity of leisure time physical activity (LTPA) to decrease the risk of all cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in a population sample of middle aged British men. Design: Prospective study of middle aged men with an 11 year follow up. Setting: A whole population sample of men from Caerphilly, South Wales, UK. Subjects: 1975 men aged 49–64 years without historical or clinical evidence of CHD at baseline examination. Main outcome measures: All cause, CVD, and CHD mortality. Results: Total (cumulative) LTPA had a graded, significant relation with all cause, CVD, and CHD mortality but no trend with cancer deaths. When different intensities of activity were considered, light and moderate intensity LTPA had inconsistent and non-significant relations with all cause, CVD, or CHD mortality whether adjusted only for age or for other cardiovascular risk factors. In contrast a significant dose–response relation was found for heavy intensity LTPA for all cause, CVD, and CHD mortality fully adjusted for other risk factors. Conclusions: These data suggest that, in a population of men without evidence of CHD at baseline, only leisure exercise classified as heavy or vigorous was independently associated with reduced risk of premature death from CVD.

Lifestyle and hemostatic risk factors for ischemic heart disease : the Caerphilly Study.

We have recently shown that fibrin D-dimer, tissue plasminogen activator (tPA) antigen, von Willebrand factor antigen, fibrinogen, plasma viscosity, and white cell count are associated with subsequent ischemic heart disease (IHD) in men aged 49 to 65 years in the Caerphilly Study from South Wales. We now report the contribution of major lifestyle factors to plasma levels of these new risk predictors for IHD. Results were available for up to 2188 men. The contribution of factors associated with lifestyle (smoking, alcohol, body mass index, leisure and work activity, social class, and use of prescribed medicines) to variation in plasma levels of 8 hemostatic variables was examined. All results were adjusted for other lifestyle variables, age, and time of day. Most hemostatic variables increased with age and smoking habit. Increasing levels of alcohol consumption were associated with increases in tPA and plasminogen activator inhibitor (PAI-1) activity and with decreases in fibrinogen and white cell count. tPA, PAI-1, fibrinogen (nephelometric), and viscosity were positively associated with body mass index. Increasing levels of leisure activity were inversely associated with D-dimer, von Willebrand factor, nephelometric fibrinogen, and viscosity. Use of prescribed medicines (a marker for chronic illness) was associated with adverse levels of D-dimer, fibrinogen, plasma viscosity, and white cell count. tPA, PAI-1, and plasma viscosity were associated with blood pressure, cholesterol, and triglycerides but not with lipoprotein(a) or homocysteine. We conclude that several lifestyle factors are associated with hemostatic risk predictors for IHD. Lifestyle modifications may reduce IHD risk partly by altering hemostatic function; large intervention studies are required to test this hypothesis.

Comparison of weight in middle age, weight at 18 years, and weight change between, in predicting subsequent 14 year mortality and coronary events: Caerphilly Prospective Study

OBJECTIVE The prevalence of obesity is increasing in many European countries and in the United States. This report examines the mortality and morbidity associated with being overweight and obese in the Caerphilly Prospective Study and the relative effects of weight in middle age and self reported weight at 18 years. DESIGN All men aged 45 to 59 years from the town of Caerphilly, South Wales and outlying villages were identified and 2512 men were examined for the first time between 1979 and 1983. Men were asked to recall their weight at 18 years of age (when the majority had been examined for National Service) so that weight then, weight at screening, and the difference could be related to their 14 year follow up from screening. A total of 2335 men could recall their weight at 18 years. By 14 years of follow up from screening 465 men had died and 382 had had coronary events. RESULTS Mean body mass index in men who reported their weight at 18 years was 22.3 (SD 2.8) kg/m2 and only 41 of these men (1.8%) were classified as obese (index ⩾ 30 kg/m2). The index did not predict all cause mortality when examined by quintile. For major ischaemic heart disease (non-fatal or fatal ischaemic heart disease) the relative odds was 1.73 (95% CI 1.21, 2.48) in the top fifth of the distribution (body mass index ⩾ 24.2 kg/m2) compared with the bottom fifth (body mass index <20.1 kg/m2). In men with an index ⩾ 30 kg/m2 however, the relative odds were 2.03 (95% CI, 1.03, 4.01) for all cause mortality and 2.17 (95% CI, 1.08, 4.34) for major ischaemic heart disease, adjusted for age, smoking habit and social class. When men were recruited to the study, from 1979 to 1983; the mean body mass index had increased to 26.2 (SD 3.6), a mean increase of 3.9 kg/m2 or 11.2 kg; 299 men (12.1%) were classified as obese and showed significantly increased relative odds of both all cause mortality (1.53 (95% CI 1.14, 2.06) and major ischaemic heart disease (1.55 (95% CI 1.13, 2.11)), adjusted for age, smoking habit and social class relative to the non-obese men. The effect of gain in weight from 18 years to recruitment was also examined; all cause mortality showed highest mortality in the fifth of the distribution who experienced weight loss or minimal weight gain. For major ischaemic heart disease an inconsistent, weak trend was shown, the relative odds rising to a maximum of 1.26 (0.89, 1.80) in the top fifth of weight gain compared with the bottom fifth. Weight gain showed strong associations with potential cardiovascular risk factors measured at recruitment; insulin, triglyceride, glucose, diastolic and systolic blood pressure and high density lipoprotein-cholesterol. CONCLUSIONS Body mass at 18 years of age of 30 kg/m2 or more conferred increased risk for all cause mortality and major ischaemic heart disease during 14 years of follow up of men aged 45 to 59 years. By the baseline examination the prevalence of obesity (body mass index ⩾30) had increased from 1.8% to 12.1%; obese men also showed an excess risk of major ischaemic heart disease and overall mortality, but these risks were lower than those predicted from 18 years of age. Weight gain was strongly associated with smoking habit, the greatest weight gain being among ex-smokers and the least among light smokers. Weight gain from 18 years of age to baseline examination showed little relation with subsequent mortality and risk of major ischaemic heart disease when adjusted for age, smoking habit and social class. The lowest mortality rate occurred in the “fifth” of men who gained a mean weight of 16.1 kg. Weight gain is closely associated with some adverse cardiovascular risk factors; in particular with insulin, triglyceride, glucose and diastolic blood pressure.

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.

Anger and incident heart disease in the Caerphilly study

OBJECTIVEnThe idea that anger may predict ischemic heart disease (IHD) is more than 30 years old. Some, but not all, prospective studies have supported this suggestion. Attention has focused on hostility as the critical component of anger for IHD risk. This idea is explored using prospective data from the Caerphilly study.nnnMETHODSnA sample of 2890 men aged 49 to 65 years living in and around Caerphilly, South Wales, was identified. Anger was assessed using the Framingham scales comprising anger symptoms, anger in, anger out, and anger discuss. A new suppressed anger scale was also constructed. Cardiovascular risk factors assessed included baseline blood pressure, total and high-density lipoprotein cholesterol, fibrinogen, white cell count, psychiatric caseness as assessed by the General Health Questionnaire, social support, smoking habit, alcohol consumption, leisure exercise, body mass index, and calorie intake. Prediction of IHD, measured as the occurrence of a major event over a follow-up period of 9 years, was assessed using multiple logistic regression analysis.nnnRESULTSnA low anger out score predicted increased risk of a major IHD event (relative odds (RO) = 1.70; 95% confidence interval = 1.26-2.29 for all RO). This association was unchanged on controlling for physiological risk factors (RO = 1.74), psychosocial risk factors (RO = 1.72), and behavioral risk factors (RO = 1.69). Suppressed anger showed associations with incident IHD similar to those of anger out but identified the population at risk more closely.nnnCONCLUSIONSnAnger out and suppressed anger were predictive of incident IHD. Neither of these constructs are overtly similar to hostility. These findings suggest there may be mechanisms other than hostility by which anger predicts IHD risk and that a conceptually varied approach to anger is currently appropriate.