Unique Characteristics Of Coronary Artery Disease In The Diabetic Population

Several features distinguish coronary artery disease in the diabetic population from the non-diabetic population. Factors such as premature presentation, greater extent of disease, coagulation abnormalities, and autonomic dysfunction may contribute to the higher morbidity and mortality of coronary heart disease in the diabetic patients (Table 1).

Premature Presentation

Diabetic patients often present with premature coronary artery disease. In type 1 diabetic patients, the duration of diabetes is the most important predictor of premature coronary artery disease, and coronary artery disease may present as early as the third or fourth decade of life.

TABLE 1 Unique Characteristics of Cardiovascular Disease in the Diabetic Patient

Premature presentation Extensive disease upon initial presentation Multiple coronary arteries diseased Distal coronary artery disease Small vessel disease Impaired autoregulation in vessels Increased risk of developing heart failure Acceleration of coronary thrombosis Endothelial dysfunction Platelet dysfunction Coagulation abnormalities Plaque composition Autonomic dysfunction Impaired vagal activity and increased sympathetic tone Increased risk for ischemic events Increased risk for sudden cardiac death Impaired pain response to ischemia Atypical symptoms of ischemia Absence of symptoms of ischemia

These patients often lack other traditional coronary artery disease risk factors such as hypercholesterolemia, hypertension, tobacco use, and family history of premature coronary artery disease. In contrast, type 2 diabetes patients typically have several cardiovascular risk factors and present in the fifth or sixth decade of life, or later (26).

Extent of Disease

Diabetic patients often have more extensive coronary artery disease at the time of diagnosis. Multi-vessel coronary artery disease is common. The thrombolysis and angioplasty in TAMI trial included 148 diabetic and 923 non-diabetic patients, in whom cardiac catheterizations were performed at 90 min and in seven to ten days after thrombolytic therapy. Diabetic patients had a significantly higher incidence of multi-vessel disease (66% vs. 46%) and a greater number of diseased vessels as compared to non-diabetic patients (12). Pathological and angiographic evidence indicate that the coronary arteries are more diffusely and distally diseased in diabetic patients (2,26-30). Recognition of the propensity for severe coronary artery disease in patients presenting with myocardial infarction is especially important because the presence of multi-vessel coronary disease predicts short-term mortality in patients with acute myocardial infarction (31,32). Multi-vessel disease also contributes significantly to the increased rates of recurrent ischemic episodes and infarction in diabetic patients. This is true for severe (<70% obstruction) and less severe lesions. Plaque disruption leading to infarction most often occurs in vessels with mild to moderate stenoses (33,34). Thus, recurrent ischemic events in diabetics are results of not only the more extensive disease, but also the increased number of vessels with mild to moderate disease (Fig. 1).

In addition to a greater extent of epicardial coronary artery disease, there may be generalized endothelial dysfunction and abnormalities of small vessels in the diabetic patient. Dilatation of the coronary arteries in response to hypoxia is mainly dependent upon endothelium relaxing factor (2,35). Impaired endothelium-dependent relaxation is present in the vascular beds of diabetic patients, including coronary arteries (36-38). The auto-regulatory responses in the microcirculation also appear to be impaired (2).

Increased Risk for the Development of Congestive Heart Failure

The Framingham Study established a strong association between diabetes and heart failure (39). Such association has been confirmed in subsequent studies (40-53). Diabetes alone predicted heart failure independent of coexisting hypertension or coronary artery disease, the relative risk was 3.8 in diabetic men and 5.5 in diabetic women. The frequency of

FIGURE 1 Coronary angiogram of a patient with type 2 diabetes mellitus and angina. (A) Left coronary angiogram with left anterior oblique and cranial angulation showed a mildly diseased left main (LM) artery that bifurcates to the diffusely diseased left anterior descending artery (LAD) and the left circumflex artery (LCx). The LAD tapers to a smaller vessel after the first major septal perforator (S). There are several moderate stenoses in the mid- to distal LAD (arrow). There is a high-grade stenosis at the proximal portion of a diagonal branch (D). The LCx is diffusely diseased, particularly in the more distal segment. (B) Right coronary angiogram with left anterior oblique angulation showed a moderate-sized right coronary artery (rCa) with a moderate stenosis in the mid- to distal portion, and a high-grade stenosis (arrow).

FIGURE 1 Coronary angiogram of a patient with type 2 diabetes mellitus and angina. (A) Left coronary angiogram with left anterior oblique and cranial angulation showed a mildly diseased left main (LM) artery that bifurcates to the diffusely diseased left anterior descending artery (LAD) and the left circumflex artery (LCx). The LAD tapers to a smaller vessel after the first major septal perforator (S). There are several moderate stenoses in the mid- to distal LAD (arrow). There is a high-grade stenosis at the proximal portion of a diagonal branch (D). The LCx is diffusely diseased, particularly in the more distal segment. (B) Right coronary angiogram with left anterior oblique angulation showed a moderate-sized right coronary artery (rCa) with a moderate stenosis in the mid- to distal portion, and a high-grade stenosis (arrow).

heart failure in elderly diabetics was even higher. The prevalence of heart failure among Medicare beneficiaries with diabetes was 22.3% in 1994, with a subsequent incidence of newly diagnosed heart failure of 12.6% per year until 1999 (40). The incidence of heart failure after revascularization with angioplasty or bypass surgery is also greater in diabetics (54). This increase in heart failure causes much of the excess in in-hospital mortality of diabetic patients with acute myocardial infarction (2,12,21,45-53). The higher incidence of heart failure after myocardial infarction in the diabetic patient is related to a higher degree of diffuse atherosclerotic disease. Inadequate tissue perfusion to the non-infarcted myocardium leads to not only greater underlying global systolic dysfunction, but also the inability of the non-infarcted myocardium to adequately compensate for the dysfunction of the acutely infarcted region (2,26). In the TAMI trials, ventricular function assessed in the catheterization laboratory by left ventriculography was worse in non-infarcted areas in diabetic patients, as compared with non-diabetic patients (12). Factors associated with heart failure in diabetics include: age, duration of diabetes, insulin use, ischemic heart disease, peripheral arterial disease, elevated serum creatinine, poor glycemic control and microalbuminemia (40,42,44,55,56).

Diastolic dysfunction in diabetic patients can also occur in the absence of significant coronary artery disease, and it is likely an important contributor to worse patient outcomes (21,26,57,58). In fact, on initial presentation with congestive failure symptoms, diabetic patients more often have diminished left ventricular compliance and normal systolic function when compared with non-diabetic patients (2,59-65). The higher incidence of coexistent hypertension in diabetic patients may account for a large part of the diastolic dysfunction observed, although patients without hypertension have manifested diastolic impairment (2). Left ventricular hypertrophy is present in 28% of non-hypertensive type 2 diabetic patients, as compared with >10% of matched patients without diabetes (66).

Mechanisms of Increased Atherosclerosis in Diabetes

A number of mechanisms may contribute to the increased atherosclerosis in diabetics in addition to conventional risk factors such as hypertension and hypercholesterolemia. These mechanisms include endothelial dysfunction, increased platelet activation and aggregation, coagulation abnormalities and abnormal plaque composition.

Endothelial Dysfunction

Hyperglycemia can induce endothelial damage by a variety of molecular mechanisms, (67,68) thereby decrease the bioavalability of nitric oxide and prostacyclin, increase the synthesis of vasoconstrictor prostanoids and endothelin and promote atherosclerotic plaque formation (69). Insulin resistance alone may be associated with coronary endothelial dysfunction (70,71). Although endothelial function can be improved by thiazolidinedion (71) metformin (72) and atorvastatin treatment, (73) whether these improvements result in better outcome remains unknown.

Platelet Dysfunction

Diabetics have altered platelet function, including increased platelet aggregation and activation, (74-77) and enhanced binding of fibrinogen to the glycoprotein Ilb/IIIa complex. The platelet abnormalities may be in part mediated by elevated blood glucose, but not plasma insulin level (78). In recent trials of acute coronary syndrome and percutaneous coronary interventions, diabetic patients have benefited from aggressive platelet inhibition from platelet glycoprotein IIb/IIIa antagonists (79,80).

Coagulation Abnormalities

Coagulation abnormalities associated with diabetes include an increase in plasma fibrinogen, (81-83) a reduction in fibrinolytic activity,(84,85) elevations in plasminogen activator inhibitor (PAI-1), (86) and increase in tissue factors and blood thrombogenicity (87). These coagulation disturbances may also decrease the efficacy of thrombolytic therapy in the treatment of ST segment elevation myocardial infarction. The TAMI trials failed to show a difference in angiographic patency rates in diabetic as compared with non-diabetic patients (12). However, non-invasive measures of reperfusion have suggested that reperfusion is achieved less frequently in diabetic patients.

Plaque Composition

Plaque composition may be different in diabetics. Both macrophage infiltration and lipid-rich atheroma are greatly increased in coronary plaques in atherectomy specimens from diabetic patients (88). Both features are associated with a greater risk for plaque rupture and a higher incidence of thrombosis (88). This observation was confirmed by a recent autopsy study (89). Aggressive lipid lowering can reduce cardiovascular events by 22% independent of baseline lipid levels, therefore, it has become a cornerstone of diabetic treatment (90).

Autonomic Dysfunction

The autonomic innervations of the heart may be affected in diabetic patients. Diminished heart rate variability and elevated resting heart rate are often present in early autonomic neuropathy in diabetic patients (2,66). Increased sympathetic activity or decreased vagal activity may contribute to sudden cardiac death. In addition, increased sympathetic activity may facilitate ischemic events.

Autonomic neuropathy may also impair the pain response to ischemia in diabetic patients. This can complicate the detection of coronary artery disease, since the diabetic patient may be asymptomatic or manifest atypical symptoms, such as dyspnea, increased fatigue, or indigestion (26). Langer et al., observed that the uptake of metaiodobensyl- guanidine (MIBG), a norepinephrine analog, is reduced in diabetic patients with silent ischemia (91). This finding supports the notion that silent ischemia in diabetics may be caused by autonomic denervation of the heart. Similar findings have been demonstrated with positron emission tomography (92,93).

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