The correlation of insulin and its precursors with macroangiopathy has received much attention [300]. It has been shown that insulin stimulates the migration, proliferation, LDL binding, and cholesterol synthesis of vascular smooth muscle cells. It may also raise blood pressure by enhancing sodium reabsorption and the sympathetic tone of vessel walls. Insulin is a prerequisite of increased VLDL synthesis, which is an important early step in the development of dyslipoproteinemia. Insulin, proinsulin, and hypertriglyceridemia stimulate PAI-1 synthesis in endothelial cells and liver and inhibit fibrinolysis [301]. However, the possible role of insulin in the pathogenesis of macroangiopathy remains a matter of debate. It may make a difference whether insulin is being used to restore insulin deficiency or whether it occurs as hyperinsulinemia in insulin-resistant states.
Clinical Picture and Management of Coronary Heart Disease
Considering the high mortality associated with myocardial infarction and the high risk of reinfarction, primary and secondary prevention of coronary heart disease (CHD) is of utmost importance.
In both types of diabetes mellitus, myocardial infarction and macroangiopathy are related to metabolic control, but a significant lowering of risk by lowering HbA1c alone could not be shown [127,130]. Treatment of obese type 2 diabetic subjects with metformin significantly lowered the incidence of myocardial infarction [133], indicating that this drug has not only anti-diabetic effects, but also others. In type 2 diabetes myocardial infarction is also associated with hypertension [159]. However, as shown in the UKPDS [158], which used calcium channel and β-receptor blockers, lowering of blood pressure by itself was not able to reduce significantly the risk of myocardial infarction. In contrast, studies with ACE inhibitor ramipril significantly lowered the risk of myocardial infarction, stroke, and cardiovascular death [222,302], indicating that other than blood pressure lowering effects must be important.
Primary and secondary prevention with aspirin has been recommended [138,303,304], and dyslipidemia should also be treated. In secondary prevention, clinical data showed that β-blockers [305] and ACE inhibitors [306,307] were beneficial.
From the list of known risk factors (Table 1.13) it is evident that primary prevention of macroangiopathy should pay attention to more than just the risk factors considered in the Diabetes Control and Complications Study (DCCT) and UKPDS. The need for a holistic view [308] is underlined by intervention studies in diabetic populations [309,310].
In myocardial infarction in diabetic subjects, most frequently the left coronary artery is occluded, and often two or three arteries are involved. The lesions tend to be localized distally; unstable plaques are frequent.
The most frequent complications of myocardial infarction in diabetes mellitus are left ventricular dysfunction, congestive heart failure, cardiogenic shock, arrhythmias, and sudden death [311–313]. Silent infarction is frequent and seems to be more closely related to the severity of the coronary artery disease than to cardiac autonomic neuropathy [314–316].
The prognosis depends on age, acute metabolic control, and duration of diabetes [317–319]. Early and late mortality is increased 1.5- to 2.5-fold in men and four-fold in women [29,320]. Recently one-year mortality was reduced by infusion of glucose with insulin and potassium [321]. The benefit of thrombolytic therapy is debated [322,323]. A considerable reduction of late mortality has been achieved by surgical therapy [324]. The indication for interventional therapy of myocardial infarction in diabetes is the same as in the general population. In most studies the early mortality associated with percutaneous transluminal coronary angioplasty, stent implantation, and coronary bypass surgery was no higher than in nondiabetic subjects, but long-term survival is still lower [325–330].
In addition to coronary artery disease, diabetic subjects may have cardiac problems even when the coronary arteries are intact. They have been attributed to diabetic cardiomyopathy and microvascular dysfunction characterized by reduced coronary flow reserve [331,332].
Prevention
Since diabetes mellitus has taken on epidemic dimensions, with an incidence that continues to rise, prevention is indispensable if we are to gain control of this disease. In the etiology of both types of diabetes, genes and environmental factors complement one another. Genes will most likely not become the target of preventive measures in the foreseeable future. However, environmental factors could offer the chance for successful intervention.
At present we do not know the environmental factors involved in the pathogenesis of type 1 diabetes mellitus. Ongoing prevention studies are aiming at the elimination of potential triggers of the autoimmune process and intervention studies at the level of the insulitis, or the basic mechanisms of autoimmunity [43,333,334].