The increase in risk is higher in women than in men [236,241,242]. Thrombotic complications of macroangiopathy are the leading cause of death in diabetes [29,243–245].
Coronary artery disease is 3.3 times more frequent in diabetic than in nondiabetic people [246]. Myocardial infarction is 3.7 times more frequent in diabetic men and 5.9 times more frequent in diabetic women [242]. In another study [247] the increase was 6.7 times in type 2 and 12.2 times in type 1 diabetic women. The higher risk of women goes along with more atherogenic lipid profiles (see below). The standardized mortality rate (corrected for age and gender) for any heart disease is 9.1 times higher if diabetes mellitus is diagnosed before the age of 30 and 2.3 times higher if it is diagnosed later [248]. As a rough estimate, in western societies about half of diabetic people die of premature cardiac death. Stroke is about twice as frequent as in the general population, and two out of three amputations are performed in diabetic people.
Pathology
The histology of lesions in the arterial wall of diabetic subjects is similar to what is seen in the general population. However, lesions tend to be located in more distal regions of the vasculature. In diabetic subjects, the established sequence of early events in atherogenesis seems to be the same as in nondiabetic subjects:-adhesion of monocytes to endothelial cells, mediated by VCAM-1-penetration of monocytes into the vessel wall, mediated by MCP-1-activation of monocytes to form macrophages/foam cells/fatty streaks, mediated by MCSF (macrophage colony stimulating factor). The classical risk factors of atherosclerosis are also effective in diabetes mellitus [135,154,249–251], and diabetes enhances the impact of these risk factors. Hyperglycemia contributes to the pathogenesis of macroangiopathy. However, the correlation with the duration of diabetes and HbA1c is weak. There must be additional specific risk factors in diabetic people, which are absent or only weakly expressed in non-diabetic people (Table 1.13).
Activated hemostasis seems to play an important role. It results from increased plasma coagulation and decreased fibrinolysis together with a loss of physiological endothelial platelet resistance, increased thrombogenicity of the subendothelial matrix, and platelet activation [138,140,252–255]. The plasma factors involved in hypercoagulation have been summarized by Ceriello [256,257]: increase of plasma fibrinogen, factor VII and VIII, α2-macroglobulin, and PAI-1, decrease of protein C. protein S, and prostacycline, and increase in the activity of factor X, antithrombin III, heparin cofactor II. and von Willebrand factor. Only some of the mechanisms underlying these disorders are known, e.g., the regulation of PAI-1 by TNF-α, insulin. VLDL, AGE, and endothelial injury [258].
Table 1.13 Risk factors of atherosclerosis and diabetic macroangiopathy
| Classical risk factors of atherosclerosis | Additional specific risk factors of diabetic macroangiopathy |
|---|---|
| Hypertension, systolic and diastolic | Hyperglycemia |
| Dyslipidemia | Abnormal lipoproteins |
| Obesity | Platelet activation |
| Smoking | Endothelial dysfunction |
| Stress | Hypercoagulation (increased fibrinogen and PAI-1) |
| Physical inactivity | Albuminuria |
| Family history of atherosclerosis | Hyperhomocystinemia |
| Age | Insulin? |
| Previous myocardial infarction | Duration of diabetes? |
Platelet activation, which is well documented [259–261], is in part constitutional and results from the priming of megakaryocytes [262,263]. However, it may also be induced reactively by LDL [264] and by endothelial injury through thromboxane A2 which is increased in diabetes [265]. Platelet activation goes along with increased expression of adhesion molecules. It favors thrombogenesis and the formation of circulating aggregates of platelets and platelets with leukocytes that are large enough to occlude small vessels [266]. This process is promoted by dyslipoproteinemia [267]. The expression of adhesion molecules contributes to the unfavorable rheological properties of the blood.
After interaction of activated platelets with injured endothelial cells, various growth factors are released which are known to be involved in atherogenesis, such as platelet-derived growth factor (PDGF), TGF-β, endothelium-derived relaxing factor (EDRF), endothelial, and others [268]. Thus, platelet activation may favor thrombogenesis, atherogenesis, capillary occlusion, and microvascular proliferation.
Endothelial dysfunction is another key factor in the pathogenesis of diabetic angiopathies [140,269]. The balanced interaction between blood and vessel wall, which regulates blood flow, hemostasis and vessel wall metabolism, is disturbed in diabetes. Loss of normal endothelial function and activation of abnormal reactions [270] may initially be caused by endothelial injury, and this may finally result in loss of cellular integrity and in cell death.
Endothelial dysfunction is a ubiquitous defect which is not limited to the regions of clinical angiopathy. Its early clinical marker seems to be microalbuminuria.
Blood flow is mainly regulated by vasodilatory EDRF (EDRF = nitric oxide) and the prostaglandin derivative prostacyclin, while endothelin-1, angiotensin II and the platelet factors thromboxane and serotonin are vasoconstrictive. In diabetes the balance of this system is disturbed. The main cause seems to be nitric oxide quenching by AGE [150] and other oxidative stress [271,272].
Lipids and lipoproteins are predictors of coronary artery disease [
