Insulin resistance syndrome and hemostasis, fibinolysis and inflammation—their role in coronary heart disease
The insulin resistance syndrome (metabolic syndrome) is a clustering of central obesity, dyslipidemia, hyperglycemia and hypertension, with or without measurement of serum insulin concentration or resistance. It is a common early abnormality in the development of Type 2 diabetes, and is associated with increased risk of cardiovascular disease, including coronary heart disease (CHD), in prospective epidemiological studies. The current global epidemic of increasing obesity, insulin resistance and Type 2 diabetes predicts increase in the global epidemic of cardiovascular disease. The increased risk of CHD in persons with insulin resistance or diabetes is not fully explained by the major conventional risk factors (tobacco smoke exposure, blood pressure and serum cholesterol), hence there is increasing interest in the role of hemostatic, fibrinolytic and inflammatory variables  which have been associated with increased risk of CHD in meta-analyses of prospective epidemiological studies of generally healthy populations [2,3]. We summarize data from epidemiological studies (which are least prone to bias) on the associations between hemostatic and fibrinolytic and inflammatory variables and (i) CHD risk in general populations; (ii) prevalent insulin resistance syndrome and its components; and (iii) prevalent Type 2 diabetes, with or without CHD. Platelet-related variables are not considered here, because they are unrelated to CHD risk in epidemiological studies .
CHD risk in general populations
Meta-analyses of prospective studies [2,3] have established that fibrinogen , C-reactive protein (CRP) , viscosity and hematocrit, von Willebrand factor (VWF) antigen , tissue plasminogen activator (t-PA) antigen , and fibrin D-dimer are associated with increased risk of CHD in general population cohorts, as well as in cohorts with baseline evidence of cardiovascular disease or diabetes. Further data are required for other hemostatic, fibrinolytic or inflammatory variables, including coagulation factor (F)VII, factor (F)VIII and factor (F)IX; plasminogen activator inhibitor type 1 (PAI-1) ; other markers of activated coagulation and fibrinolysis; proinflammatory cytokines such as interleukins (IL-6 and IL-18), leptin, and tumor necrosis factor (TNF)-α; and the anti-inflammatory cytokine, adiponectin [2,3]. These cytokines are associated with abdominal obesity and insulin resistance, and are produced (in part) by adipose tissue (adipocytokines) [7–9]; IL-6 in particular has been associated with increased fibrinogen, CRP, viscosity, VWF and t-PA . It should be noted that none of these hemostatic, fibrinolytic or inflammatory variables has been established as a causal risk factor for CHD by randomized controlled trials of selective, long-term reduction.
Prevalent insulin resistance syndrome and its components
Several epidemiological studies have reported positive associations between measures of insulin resistance and hemostatic, fibrinolytic and inflammatory variables [7–18]. The strongest associations are with PAI-1 and t-PA antigen (which correlates closely with PAI-1, probably reflecting measurement of circulating t-PA–PAI-1 complexes), and have been studied in detail by Juhan-Vague and colleagues . Consistent associations have also been observed with fibrinogen (especially in women), CRP, viscosity, hematocrit, vitamin K-dependent coagulation factors (FVII, FIX, factor X), and VWF; but not with coagulation activation markers such as D-dimer. Clustering of these variables with specific components of the insulin resistance syndrome has been reported in some studies [13,14,17]. In the British Regional Heart Study of 2722 non-diabetic men without baseline evidence of CHD or stroke , we observed specific associations of fasting insulin with CRP, viscosity, hematocrit, FVII, FVIII and FIX, VWF antigen and t-PA antigen (but not with fibrinogen), suggesting that insulin itself may increase levels of these variables (e.g. by inducing endothelial dysfunction with increased synthesis/release of VWF and t-PA–PAI-1). However, specific influences of triglyceride (viscosity, FVII and FIX, t-PA), obesity (CRP, viscosity, FIX, t-PA) and glucose (viscosity, FVIII, t-PA) were also observed; while low HDL and hypertension showed the least specific associations with hemostatic, fibrinolytic and inflammatory variables. Reduction in insulin resistance by weight loss (diet and exercise) [9,18], metformin , or glitazones lowers levels of CRP, PAI-1 and t-PA antigen, possibly due to an altered balance between pro- and anti-inflammatory adipocytokines . We have reported in the British Regional Heart Study that increasing leisure-time physical activity is associated with reductions in not only CRP and t-PA antigen, but also fibrinogen, viscosity, FVII, FVIII and FIX, and VWF .
Prevalent Type 2 diabetes, with or without CHD
While many studies have reported abnormalities of hemostasis, fibrinolysis and inflammation in prevalent Type 2 diabetes, there is a lack of studies of these variables in persons with diabetes only and CHD only. In the British Regional Heart Study, we compared men with Type 2 diabetes not on insulin therapy (325 without CHD, 101 with CHD) and men without diabetes (2899 with CHD, 741 with CHD) . Among men without CHD, those with diabetes had higher levels of all components of insulin resistance, and of all measured hemostatic, fibrinolytic and inflammatory variables (except hematocrit and D-dimer). Among men with CHD, those with diabetes had higher levels of FVIII, VWF, FIX and t-PA antigen. In men with diabetes, increased insulin resistance (homeostasis model assessment, HOMA) was associated with increased levels of hemostatic, fibrinolytic and inflammatory markers; as well as with increased prevalence of CHD. These data suggest that reducing insulin resistance in men with diabetes may reduce their tendency to thrombosis, and hence reduce risk of CHD . This hypothesis requires to be tested in randomized controlled trials.