John Yarnell

European guidelines on cardiovascular disease prevention in clinical practice

Guidelines aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making. A great number of guidelines have been issued in recent years by different organisations--European Society of Cardiology (ESC), American Heart Association (AHA), American College of Cardiology (ACC), and other related societies. By means of links to web sites of National Societies several hundred guidelines are available. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing guidelines. In spite of the fact that standards for issuing good quality guidelines are well defined, recent surveys of guidelines published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied with in the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilisation of health resources. In addition, the legal implications of medical guidelines have been discussed and examined, resulting in position documents, which have been published by a specific task force. The ESC Committee for practice guidelines (CPG) supervises and coordinates the preparation of new guidelines and expert consensus documents produced by task forces, expert groups or consensus panels. The Committee is also responsible for the endorsement of these guidelines or statements.

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.

Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations

Elevation in plasma homocysteine concentration has been associated with vascular disease and neural tube defects. Methionine synthase is a vitamin B12‐dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. One relatively common polymorphism in the methionine synthase gene (D919G) is an A to G transition at bp 2,756, which converts an aspartic acid residue believed to be part of a helix involved in co‐factor binding to a glycine. We have investigated the effect of this polymorphism on plasma homocysteine levels in a working male population (n = 607) in which we previously described the relationship of the C677T “thermolabile” methylenetetrahydrofolate reductase (MTHFR) polymorphism with homocysteine levels. We found that the methionine synthase D919G polymorphism is significantly (P = 0.03) associated with homocysteine concentration, and the DD genotype contributes to a moderate increase in homocysteine levels across the homocysteine distribution (OR = 1.58, DD genotype in the upper half of the homocysteine distribution, P = 0.006). Unlike thermolabile MTHFR, the homocysteine‐elevating effects of the methionine synthase polymorphism are independent of folate and B12 levels; however, the DD genotype has a larger homocysteine‐elevating effect in individuals with low B6 levels. This polymorphism may, therefore, make a moderate, but significant, contribution to clinical conditions that are associated with elevated homocysteine. Genet. Epidemiol. 17:298–309, 1999.

The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations.

Epidemiological evidence has revealed that an elevated plasma homocysteine level (hyperhomocysteinemia) confers an increased risk of cardiovascular disease and neural tube defects. Hyperhomocysteinemia is caused by both nutritional (e.g. folate, vitamins B(6) and B(12)) and genetic factors, including functional polymorphisms of key enzymes involved in homocysteine metabolism. One such enzyme, methionine synthase reductase (MTRR), maintains adequate levels of methylcob(III)alamin, the activated cofactor for methionine synthase, which catalyzes the remethylation of homocysteine to methionine. A common MTRR polymorphism, i.e. a 66 A-->G substitution specifying an isoleucine to methionine substitution (I22M), was recently identified. To assess the influence of this polymorphism on total plasma homocysteine (tHcy), we undertook a genotype/phenotype analysis in a study population of 601 Northern-Irish men, aged 30--49, for which biochemical and genetic data relevant to folate/homocysteine metabolism had already been acquired. The 66AA genotype has a frequency of 29% in this population. We established that there was a significant influence of MTRR genotype on tHcy ranking (P=0.004) and that the 66AA genotype contributes to a moderate increase in tHcy levels across the distribution [OR 1.59 (95% CI: 1.10--2.25) for the 66AA genotype to be in the upper half of the tHcy distribution, P=0.03]. The homocysteine-elevating effect of the 66AA genotype is independent of serum folate, vitamin B(12) and vitamin B(6) levels. Based on published estimates of the enhanced cardiovascular disease risk conferred by defined increments of plasma tHcy, we estimate that 66AA homozygotes have, on average, an approximately 4% increase in cardiovascular disease risk compared to 66GG homozygotes. This study provides the first evidence that the MTRR A66G polymorphism significantly influences the circulating tHcy concentration.

Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis.

ObjectiveWe investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk.MethodsWe examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women’s Heart and Health Study (4,286 women aged 60–80) and the Caerphilly Cohort (2,398 men aged 45–59) using Cox regression and pooled our findings with previous prospective studies’ in fixed and random effects meta-analyses.ResultsCRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk.ConclusionsOur findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role.

Food Omega-3 Fatty Acid Intake of Individuals (Total, Linolenic Acid, Long-Chain) and Their Blood Pressure. INTERMAP Study

Findings from short-term randomized trials indicate that dietary supplements of omega-3 polyunsaturated fatty acids (PFA) lower blood pressure of hypertensive persons, but effect size in nonhypertensive individuals is small and nonsignificant. Data are lacking on food omega-3 PFA and blood pressure in general populations. The International Study of Macro- and Micro-nutrients and Blood Pressure (INTERMAP) is an international cross-sectional epidemiologic study of 4680 men and women ages 40 to 59 from 17 population-based samples in China, Japan, United Kingdom, and United States. We report associations of food omega-3 PFA intake (total, linolenic acid, long-chain) of individuals with blood pressure. Systolic and diastolic blood pressure were measured 8 times at 4 visits. With several models to control for possible confounders (dietary, other), linear regression analyses showed inverse relationship of total omega-3 PFA from food (percent kilocalories, from four 24-hour dietary recalls) to systolic and diastolic blood pressures. With adjustment for 17 variables, estimated systolic blood pressure/diastolic blood pressure differences with 2 standard deviation higher (0.67% kcal) omega-3 PFA were −0.55/−0.57 mm Hg (Z-score −1.33, −2.00); for 2238 persons without medical or dietary intervention, −1.01/−0.98 mm Hg (Z −1.63, −2.25); for 2038 nonhypertensive persons from this sub-cohort, −0.91/−0.92 mm Hg (Z −1.80, −2.38). For linolenic acid (largely from vegetable foods), blood pressure differences were similar, eg, for the 2238 “nonintervened” individuals, −0.97/−0.87 mm Hg (Z −1.52, −1.95); blood pressure differences were −0.32/−0.45 mm Hg for long-chain omega-3 PFA (largely from fish). In summary, food omega-3 PFA intake related inversely to blood pressure, including in nonhypertensive persons, with small estimated effect size. Food omega-3 PFA may contribute to prevention and control of adverse blood pressure levels.

Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study.

The relationships of three measurements of the factor VIII/von Willebrand factor (VWF) complex (factor VIII activity, FVIIIc (one‐stage assay); VWF antigen, VWF Ag (ELISA); and VWF activity, VWF act, measured by a recently‐developed ELISA) to major ischaemic heart disease (IHD) events were studied in 1997 men aged 49–65 years, in the second phase of the Caerphilly Heart Study. These variables were related using logistic regression analysis to myocardial infarction or IHD death, which occurred in 129 men during an average follow‐up period of 61 months. All three measurements were highly correlated (ru2003=u20030.63–0.77), and each was significantly associated with incident major IHD on univariate analyses (relative odds in highest fifth compared to lowest fifth, 1.68–1.90; Pu2003=u20030.028–0.006) and on multivariate analyses adjusting for major IHD risk factors and for baseline IHD. Neither FVIIIc nor VWF act was significantly related to incident IHD following adjustment for VWF Ag. We therefore suggest that the associations between these three measurements of the factor VIII/VWF complex and incident IHD might have at least three explanations: VWF Ag is a marker of arterial endothelial disturbance; VWF act promotes platelet adhesion/aggregation and hence the platelet component of arterial thrombosis; and FVIIIc promotes fibrin formation and hence the fibrin component of arterial thrombosis.

Leisure time physical activity and regular walking or cycling to work are associated with adiposity and 5 y weight gain in middle aged men the PRIME study

OBJECTIVE: To examine the influence of physical activity on body mass index (BMI), waist circumference (W) and body mass changes (ΔBMI) in middle-aged men, with special regard to moderate-intensity activities.DESIGN: Longitudinal study of adults who participated in the PRIME Study.SUBJECTS: A cohort of 8865 men aged 50–59u2005y, free of coronary heart disease.MEASUREMENTS: BMI and W at baseline, body mass changes over a 5u2005y period. Detailed baseline assessment of net energy expenditure due to physical activity (PAE) in the preceding year, according to category of activity, by means of the MOSPA Questionnaire. PAE was expressed in weekly metabolic equivalent scores (MET h/week).RESULTS: After adjustment for confounders, the multiple regression analyses indicated that BMI, W and ΔBMI were inversely associated with PAE spent in getting to work (P<10−5, <10−5 and 0.04, respectively) and practice of high-intensity (≥6 MET) recreational activities (<0.01, <10−5 and <0.01). Men who regularly spent more than 10 MET h/week in walking or cycling to work had a mean BMI, W and ΔBMI respectively 0.3u2005kg/m2, 1u2005cm and 0.06u2005kg/m2 lower than those who did not expend energy in getting to work. In the subgroup of subjects who did not perform high-intensity activities, the level of recreational PAE was inversely associated with BMI and W but not with subsequent weight-gain.CONCLUSION: These findings indicate that, in middle-aged men, physical activities of moderate-intensity, which are probably easier to promote than more vigorous activities and, in particular, a more current daily activity, walking or cycling to work, may have a favourable effect on body fat markers and body mass gain.

Birthweight, adult risk factors and incident coronary heart disease: the Caerphilly study

OBJECTIVEnTo determine the relationships between birthweight, the incidence of coronary heart disease, and a range of coronary heart disease risk factors that operate during adult life.nnnDESIGNnCohort study with a 10-year follow-up period.nnnSETTINGnThe town of Caerphilly, South Wales, and five adjacent villages.nnnSUBJECTSn1,258 men aged 45-59 at time of recruitment between 1979 and 1983.nnnMAIN OUTCOME MEASURESnAll deaths, coronary heart disease deaths, non-fatal CHD events.nnnRESULTSnThe validity of the birthweight data was supported by the strong graded associations between birthweight and anthropometric measures in adulthood, particularly height, body mass index, triceps, skinfold thickness and percentage body fat. An inverse relationship was found between birthweight and incident fatal and non-fatal CHD, (P = 0.01), though no relationship was found between birthweight and all-cause mortality. Amongst the major CHD risk factors, only fibrinogen shows a statistically significant relationship with birthweight (P = 0.008), fibrinogen levels being lower among the men with lower birthweights. When social and biological variables are included in models relating incident CHD and birthweight, the relationship between birthweight and incident fatal and non-fatal CHD remains essentially unchanged.nnnCONCLUSIONnA graded association between low birthweight and later CHD has been demonstrated in this cohort. This inverse association cannot be explained by the measured social or behavioural variables, or by other risk factors operating in adult life.

Frequency of fruit and vegetable consumption and coronary heart disease in France and Northern Ireland: the PRIME study

Fruit and vegetable consumption is associated with low CHD risk in the USA and Northern Europe. There is, in contrast, little information about these associations in other regions of Europe. The goal of the present study was to assess the relationship between frequency of fruit and vegetable intake and CHD risk in two European populations with contrasting cardiovascular incidence rates; France and Northern Ireland. The present prospective study was in men aged 50-59 years, free of CHD, who were recruited in France (n 5982) and Northern Ireland (n 2105). Fruit and vegetable intake was assessed by a food-frequency questionnaire. Incident cases of acute coronary events and angina were recorded over a 5-year follow-up. During follow-up there was a total of 249 ischaemic events. After adjustment on education level, smoking, physical activity, alcohol consumption, employment status, BMI, blood pressure, serum total and HDL-cholesterol, the relative risks (RR) of acute coronary events were 0.67 (95% CI 0.44, 1.03) and 0.64 (95% CI 0.41, 0.99) in the 2nd and 3rd tertiles of citrus fruit consumption, respectively (P for trend <0.03). Similar results were observed in France and Northern Ireland. In contrast, the RR of acute coronary events for other fruit consumption were 0.70 (95% CI 0.31, 1.56) and 0.52 (95% CI 0.24, 1.14) respectively in Northern Ireland (trend P<0.05) and 1.29 (95% CI 0.69, 2.4) and 1.15 (95% CI 0.68, 1.94) in France (trend P=0.5; interaction P<0.04). There was no evidence for any association between vegetable intake and total CHD events. In conclusion, frequency of citrus fruit, but not other fruits, intake is associated with lower rates of acute coronary events in both France and Northern Ireland, suggesting that geographical or related factors might affect the relationship between fruit consumption and CHD risk.