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Background/objectives: Body mass index (BMI) is the most commonly used surrogate marker for evaluating the risk of cardiovascular disease (CVD) mortality in relation to general obesity, while abdominal obesity indicators have been proposed to be more informative in risk prediction., Subject/methods: A prospective cohort study consisting of 46 651 Europeans aged 24-99 years was conducted to investigate the relationship between CVD mortality and different obesity indicators including BMI, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), A Body Shape Index (ABSI) and waist-to-hip-to-height ratio (WHHR). Hazard ratio (HR) was estimated by the Cox proportional hazards model using age as timescale, and compared using paired homogeneity test., Results: During a median follow-up of 7.9 years, 3435 participants died, 1409 from CVD. All obesity indicators were positively associated with increased risk of CVD mortality, with HRs (95% confidence intervals) per standard deviation increase of 1.19 (1.12-1.27) for BMI, 1.29 (1.21-1.37) for WC, 1.28 (1.20-1.36) for WHR, 1.35 (1.27-1.44) for WSR, 1.34 (1.26-1.44) for ABSI and 1.34 (1.25-1.42) for WHHR in men and 1.37 (1.24-1.51), 1.49 (1.34-1.65), 1.45 (1.31-1.60), 1.52 (1.37-1.69), 1.32 (1.18-1.48) and 1.45 (1.31-1.61) in women, respectively. The prediction was stronger with abdominal obesity indicators than with BMI or ABSI (P<0.05 for all paired homogeneity tests). WSR appeared to be the strongest predictor among all the indicators, with a linear relationship with CVD mortality in both men and women., Conclusions: Abdominal obesity indicators such as WC, WHR, WSR and WHHR, are stronger predictors for CVD mortality than general obesity indicator of BMI.

Objective: The purpose of this study was to investigate the effects of plasminogen activator inhibitor-1 (PAI-1) gene (SERPINE1) single nucleotide polymorphisms (SNPs) on the risk of myocardial infarction (MI), on PAI-1 levels, and factors related to the metabolic syndrome., Methods and Results: Eleven SNPs capturing the common genetic variation of the SERPINE1 gene were genotyped in the HIFMECH study. In the 510 male cases and their 543 age-matched controls, a significant gene-smoking interaction was observed. In nonsmokers, the rs7242-G allele was more frequent in cases than in controls (0.486 versus 0.382, P=0.013) whereas the haplotype derived from the rs2227631 (-844A>G)-G and rs2227683-A alleles was approximately 3-fold lower in cases than in controls (0.042 versus 0.115, P=0.006). SERPINE1 haplotypes explained 3.5% (P=0.007) of the variability of PAI-1 levels, which was attributable to the combined effects of 3 SNPs, -844A>G, rs2227666, and rs2227694. The rs6092 (Ala15Thr) and rs7242 SNPs acted additively to explain 4.4% of the variability of plasma insulin levels and 1.6% of the variability of BMI (P<10(-3) and P=0.023, respectively)., Conclusions: SERPINE1 haplotypes are mildly associated with plasma levels of PAI-1 and with the risk of MI in nonsmokers. They are also associated with insulin levels and BMI.

Elevated plasma IL-6 levels have been implicated in the pathogenesis of coronary heart disease. We have investigated the association of two polymorphisms in the promoter of IL-6 (-572G>C and -174G>C) with levels of inflammatory markers and risk of myocardial infarction (MI) in a European study of MI survivors and age-matched controls from two high-risk centres in the North of Europe, and two low risk centres in the South. IL-6 and CRP levels were similar in controls in both regions, but were higher in cases. For the -174G>C polymorphism the rare -174C allele showed a regional difference in allele frequency, being more common in the North European group (0.43 vs 0.28; p < 0.0005), where -174C allele carriers showed an apparent reduced risk of MI compared to -174GG homozygotes (OR 0.53, 95%CI 0.32, 0.86). No such effect was observed in the South or with the -572G>C in either group. Neither genotype was associated with a significant effect on plasma IL-6 levels in either cases or controls. Furthermore, no regional difference was observed in the frequency of the -572G>C SNP, suggesting that these polymorphisms are unlikely to be contributing to the observed increased risk of cardiovascular disease in Northern Europe.

Unlabelled: Although the potential role of plasminogen activator inhibitor-1 (PAI-1) in the development of coronary artery disease is strongly supported by its biological characteristics, results of clinical studies remain controversial., Objectives: To investigate whether plasma PAI-1 concentrations and the -675 4G/5G polymorphism located in the PAI-1 gene could constitute risk markers for myocardial infarction (MI)., Patients and Methods: We used a European case-control study, the HIFMECH study, comparing 598 men with MI and 653 age-matched controls., Results: Insulin resistance explained a major part of the variation in PAI-1 (24%) whereas inflammation had only a minor contribution (0.01%). For both cases and controls plasma PAI-1 concentrations were significantly higher in the North than the South, and in both regions were higher in individuals with MI compared with control subjects [overall odds ratio (OR) for a 1 SD increase=1.54, 95% confidence interval (CI) 1.34, 1.77]. This difference was observed in all the centers studied. Overall, the difference between cases and control subjects remained significant after controlling for inflammation variables (OR=1.30, 95% CI 1.08, 1.57), but lost significance after controlling for insulin resistance variables (OR=1.17, 95% CI 0.98, 1.40). The 4G allele was associated with significantly higher PAI-1 levels in cases but not controls and, taken independently, did not modify the risk of MI (P=0.9). However, a significant interaction was observed with both insulin or proinsulin and the risk of MI (P=0.05 and 0.02, respectively), but not with triglycerides or body mass index (BMI). The insulin or proinsulin effect on risk was observed only in the carriers of the 4G/4G genotype. This interaction appeared not to be mediated by plasma PAI-1 antigen concentrations (P=0.01 and 0.02 after adjustment for PAI-1 plasma levels). The interaction with proinsulin but not insulin remained statistically significant after further adjustment for other factors associated with insulin resistance (triglycerides and BMI) and C-reactive protein (P=0.01)., Conclusion: This study suggests that PAI-1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the -675 4G/5G polymorphism was observed in risk for MI. The mechanisms for these interactions remain to be determined.

Aims: To provide estimates of the 10-year risk of coronary heart disease events for diabetic and nondiabetic men and women with different levels of risk factors and, for diabetic subjects, with and without microalbuminuria., Methods: Use of risk coefficients derived from the Framingham Study and a meta-analysis of the influence of microalbuminuria on cardiovascular disease. The risk of a coronary heart disease event has been calculated for men and women with and without diabetes mellitus, and among diabetic subjects, with and without microalbuminuria, according to age, systolic blood pressure and the ratio of total to high density lipoprotein cholesterol., Results: These risk estimates have been developed as a series of colour charts. The use of Framingham estimates of risk have been validated by comparing them with estimates derived from the Dundee Risk Disk and from the PROCAM Study, these estimates providing reasonable agreement despite the geographical and temporal differences in their development., Conclusions: These charts permit the overall level of risk to be derived, which can inform decision making about thresholds for therapeutic interventions, as well as assisting in patient education.

Objective: To define the potential role of proinsulin-like molecules as risk factors for cardiovascular disease., Research Design and Methods: Fasting concentrations of proinsulin, des-31,32-proinsulin, and insulin, and of insulin 2 h after a 75-g glucose load, were measured in 1,034 nondiabetic europid subjects and 257 south Asian subjects and related to prevalent coronary heart disease (Minnesota-coded electrocardiographic criteria or ischemic chest pain). In 137 south Asian subjects, the fasting concentrations were related to incident coronary heart disease over a 6.5-year follow-up., Results: The standardized odds ratios for prevalent coronary heart disease were as follows: fasting insulin, 1.29 (1.11-1.49), P = 0.0006; 2-h insulin, 1.25 (1.08-1.45), P = 0.003; proinsulin, 1.23 (0.99-1.53), P = 0.058; and des-31,32-proinsulin, 1.32 (1.03-1.69), P = 0.026. The odds ratios were similar in the two ethnic groups. These relationships became insignificant when controlling for age, sex, and BMI. The standardized odds ratios for incident coronary heart disease were as follows: fasting insulin, 0.99 (0.63-1.55), P = 0.97; proinsulin, 1.13 (0.72-1.78), P = 0.59; and des-31,32-proinsulin, 1.00 (0.61-1.63), P = 1.00., Conclusions: We have found similar relationships between concentrations of proinsulin-like molecules and prevalent coronary heart disease, as are observed for insulin in these nondiabetic subjects, although these molecules comprise only approximately 10% of all insulin-like molecules. It appears biologically implausible that these relationships represent cause and effect.

Platelets take up and store noradrenaline and adrenaline in proportion to plasma concentrations and may, therefore, provide an integrated index of sympathoadrenomedullary arousal. Plasma and platelet catecholamine concentrations were measured in 290 European and 155 Asian subjects, and were related to blood pressure, insulin levels, and social class. Plasma noradrenaline concentrations correlated with systolic and diastolic blood pressure in both ethnic groups (r = 0.20-0.30), and these levels were significantly elevated in hypertensive subjects (P < 0.003). In Europeans, but not in Asians, these relationships remained significant after adjusting for age and gender, and were independent of the relationship between insulin and blood pressure. There were much weaker relationships between platelet catecholamine concentrations and blood pressure, which were dependent on age and gender as covariates. In neither ethnic group was there any relationship of either plasma or platelet catecholamine concentrations with insulin concentrations, body mass index, or glucose intolerance. European subjects in manual occupations had significantly higher concentrations of plasma noradrenaline than those with nonmanual occupations. The findings suggest a significant role for the sympathetic nervous system in the determination of blood pressure, but do not provide evidence for a connection between hyperinsulinemia and sympathetic nervous system activity. The role of platelet catecholamines as an epidemiological marker of stress has not been supported.