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Symposium Clinical 6
Prevention and Treatment of Diabetic Cardiovascular Diseases: Progress at the Turn of the Century
Thomas K. Nordt
University of Freiburg, Freiburg, Germany
Satoshi Fujii
Hokkaido University Graduate School of Medicine, Sapporo, Japan
Shunichi Miyazaki
National Cardiovascular Center, Suita, Japan
Ikuyoshi Watanabe
Nihon University Surugadai Hospital, Tokyo, Japan
 
  • Proven and Promising Aspects of Prevention and Treatment
  • Diminished Left Ventricular Function, Coronary Perivascular Fibrosis and Increased Plasminogen Activator Inhibitor-1 Expression Associated with Insulin-Resistant Mice
  • Abnormal Glucose Tolerance and Long-Term Prognosis After Coronary Angioplasty
  • Treating Insulin Resistance in Non-Diabetic Patients



  • Proven and Promising Aspects of Prevention and Treatment


    In patients with diabetes mellitus, coronary artery disease (CAD) is not only more common than in non-diabetic persons (40% versus 2-4%) but is also more deadly. Its presence not only increases the risk for cardiovascular events, but worsens the prognosis in patients after a myocardial infarction (MI) or revascularization procedures. Mortality is increased two-fold in males and four-fold in females when diabetes and CAD co-exist, said Thomas K. Nordt, MD, of the University of Freiburg, Germany, in his keynote lecture during this symposium.

    Pathophysiologically, CAD in the setting of diabetes is characterized by endothelial dysfunction, increased platelet activity, increased coagulant activity, and reduced fibrinolytic activity. This enhanced hemostatic activity increases the frequency and severity of atherosclerotic lesions and leads to the development of more microthrombi that support the atherosclerotic lesion. Angiographically, diabetic patients with CAD exhibit more diffuse and more distally located lesions than their non-diabetic counterparts and are more likely to have multivessel and left main disease. This makes revascularization procedures more challenging.

    Diabetes is now considered a "CAD risk-equivalent," meaning that it contributes as much to the coronary event risk profile as does a previous history of a coronary event. The management of risk factors, therefore, becomes the most important means of preventing CAD in the setting of diabetes. The control of the underlying diabetes is quite protective in this regard. The United Kingdom Prospective Diabetes Study (UKPDS) of 3,867 type 2 diabetic patients demonstrated the value of glucose control. Intensive glucose control with insulin or sulfonylureas reduced the incidence of MI over 15 years as compared with conventional therapy. Every 1% increase in hemoglobin A1c (uncontrolled glucose) was accompanied by a 40% increase in MI, but reductions in hemoglobin A1c protected against fatal and non-fatal MI as well as the microvascular endpoints of retinopathy, nephropathy, and neuropathy. A similar association is seen in type 1 diabetes. A clear correlation between intensive insulin therapy or better glucose control and delay of the onset of cardiovascular or microvascular disease was shown in the Diabetes Control and Complications Trial of 1,441 patients.

    As for any person at risk for CAD, another important risk factor is hypercholesterolemia. Target LDL levels for diabetic patients are as strict as for patients with existing CAD, and statins are an essential part of the treatment plan. Statins have been shown to not only reduce hypercholesterolemia but, in some studies, to also protect against the development of diabetes.

    Platelet inhibition, beyond that achieved with aspirin, is also important in the prevention of coronary events in diabetics. In the CURE study [Clopidogrel in Unstable Angina to Prevent Recurrent Events], patients with acute coronary syndromes without ST segment elevations (including diabetics) had a reduction in cardiovascular deaths, MI, and stroke when they received clopidogrel in addition to aspirin, versus aspirin alone. Other studies have substantiated the benefit of the glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. In diabetics, pooled analysis of the major trials showed 30-day mortality to be 4.6% with these agents versus 6.2% without (Circulation 2001;104:2767-71). Their obvious benefit in diabetics may be based on the fact that diabetics have highly activated platelets as well as GPIIb/IIIa receptors. The meta-analysis, however, did not include GUSTO V, which found no benefit of adding the GPIIb/IIIa inhibitor abciximab to reteplase, a tissue plasminogen activator (Lancet 2001;357:1905-14), either in the whole population or in diabetics.

    Finally, with regard to interventional therapies, it appears that angioplasty may produce a worse outcome than coronary artery bypass grafting. This was suggested by the results of the Bypass Angioplasty Revascularization Investigation (BARI) of 22 patients with multivessel disease. In nondiabetic patients, all-cause and cardiac mortality was similar between the arms, but diabetic patients had a worse outcome after angioplasty. This was also shown in the Arterial Revascularization Therapy Study among diabetic patients who received angioplasty with stenting, versus bypass grafting.

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    Diminished Left Ventricular Function, Coronary Perivascular Fibrosis and Increased Plasminogen Activator Inhibitor-1 Expression Associated with Insulin-Resistant Mice


    Plasminogen-activator inhibitor-1 (PAI-1) may be a novel therapeutic target for cardiovascular diseases, according to research presented by Satoshi Fujii, of the Hokkaido University Graduate School of Medicine, Sapporo. These investigators previously showed that coronary perimicrovascular fibrosis is augmented by increased cardiac expression of PAI-1, an inhibitor of proteolysis (fibrinolysis) in genetically obese mice with insulin resistance. The present study was performed to explore the potential role of insulin receptor substrate-1 (IRS-1)-mediated signaling in heart PAI-1 expression in wild type (C57BL/6J) and IRS-1 knock-out (KO) mice.

    PAI-1 is the primary physiological inhibitor of fibrinolysis. Hypofibrinolysis can induce intravascular thrombosis by decreasing fibrin degradation, migration of vascular smooth muscle cells and accumulation of extracellular matrix. In subjects with insulin resistance, increased PAI-1 levels may reflect insulin-dependent and pro-insulin-dependent augmentation of the synthesis of PAI-1 by hepatic, vascular and adipose cells, but in heart tissues, PAI-1 expression and its influences and mechanisms are not fully understood.


    Figure 1. Myofiber diameters were reduced in the knock-out mice on quantitative image analysis of PAI-1 in tissue samples.
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    Figure 2. Perivascular fibrosis-to-lumen ratio and wall-to-lumen ratio was significantly increased in the IRS-1 KO mice compared to controls.
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    Figure 3. Diastolic and systolic LV diameters were significantly increased and fractional shortening was decreased in IRS-1 KO mice compared to controls.
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    In the experimental animals, at 20 weeks of age, the ratio of left ventricular (LV) weight to body weight was increased in the KO mice compared to controls, suggesting the presence of LV hypertrophy. Quantitative image analysis of PAI-1 in tissue samples showed myofiber diameters to be reduced in the KO mice (by lower pixel intensity), suggesting that IRS-1-mediated signaling may be important for normal cardiac growth and development (Figure 1); in addition, along with myocyte atrophy, the IRS-1 KO mice exhibited significantly increased perivascular fibrosis-to-lumen ratio and wall-to-lumen ratio versus controls,(Figure 2) suggesting the coronary arteries may undergo substantial remodeling in spite of the lack of IRS-1 signaling. Interestingly, the perivascular fibrosis was accompanied by high PAI-1 mRNA expression in the heart, suggesting that IRS-1-mediated signaling may not be so important in PAI-1 expression in cardiac tissues.

    Cardiac function was evaluated by 15 MHz high-resolution echocardiography. In these studies, diastolic and systolic LV diameters were found to be significantly increased in IRS-1 KO mice and fractional shortening was decreased, indicating dilatation and dysfunction in the KO animals (Figure 3). Without IRS-1-mediated signaling, cardiac function may be diminished, the results suggested.

    In sum, perimicrovascular fibrosis was augmented in genetically obese mice characterized by insulin resistance, hyperglycemia, hyperinsulinemia, and non-insulin-dependent diabetes. LV dysfunction, coronary perimicrovascular fibrosis, and increased cardiac PAI-1 expression associated with insulin resistance still occurred, despite the lack of IRS-1. It seems, therefore, that in the setting of insulin resistance, PAI-1 expression is not fully controlled by IRS-1-mediated signaling. PAI-1 may be an attractive therapeutic target for the prevention and treatment of diabetic vascular diseases, Dr. Fujii stated.

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    Abnormal Glucose Tolerance and Long-Term Prognosis After Coronary Angioplasty


    In diabetic patients undergoing coronary angioplasty, good glycemic control may improve long-term survival, according to a study from the National Cardiovascular Center, Suita, Japan, which showed that abnormal glucose tolerance was a greater predictor of prognosis than small vessel diameter. The interventional outcomes of patients with diabetes are known to be poorer than for non-diabetic persons, and the question has been whether this is due to diffuse disease that results in a small final lumen or to the diabetes itself.


    Figure 4. Baseline characteristics of the study population.
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    Figure 5. Five-year event-free survival in the study population.
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    Figure 6. Variables studied in relation to cardiac events and mortality.
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    The study, reported by Shunichi Miyazaki, included 559 patients who underwent their first successful elective balloon angioplasty (without stenting) between 1985 and 1990. Of these, 69 had diabetes and 120 had impaired glucose tolerance, comprising the "abnormal glucose tolerance" (AGT) subset. All patients were divided into four groups according to the presence of AGT and their final vessel diameter. Patients without AGT and < 2.5 mm diameter were considered the "small-normal" group; those without AGT and > 2.5 mm were the "large-normal" group; those with AGT and < 2.5 mm were the small-DM (diabetes mellitus) group; and those with AGT and > 2.5 mm were the "large- DM" group. The endpoints were death, cardiac death, and cardiac events, including non-fatal MI, repeat revascularization, or death. The baseline characteristics of the study population are shown in Figure 4.

    Survival analysis at 5 years showed a worse event-free survival for patients with AGT, especially the small-DM group (Figure 5). The small-normal patients (who had normal glucose tolerance and small vessel diameter) had a similar event-free survival curve as the large- DM and large-normal groups.

    In a multivariate analysis, the cardiac events were associated with the presence or absence of AGT (Figure 6). Among the four groups, event-free survival was poorest for the small-DM patients; event-free survival in the small-normal was similar to the large-DM and large-normal patients up to 5 years, though for the large-DM patients survival declined suddenly and inexplicably 5 years after intervention. Importantly, final vessel diameter was not predictive of long-term survival, while on the contrary the presence of AGT was an important determinant, Dr. Miyazaki reported.

    The patients were further evaluated for their level of glycemic control, with hemoglobin A1c levels < 6.0 considered poor control and those > 6.0 representing good control. Poorly controlled AGT patients had the worse event-free survival, while AGT patients who were well controlled had survival similar to non-diabetic patients. The investigators concluded, therefore, that good control of blood sugar levels is an important means of improving outcomes in diabetic patients undergoing angioplasty.

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    Treating Insulin Resistance in Non-Diabetic Patients


    Non-diabetic patients with insulin resistance should be treated to prevent the development of coronary artery disease (CAD), according to the results of a study from Nihon University Surugadai Hospital, Tokyo.

    Ikuyoshi Watanabe, who presented the study, pointed out that the relationship between insulin resistance and CAD receives attention, but insulin resistance is also associated with arteriosclerotic diseases such as ischemic heart disease. The study investigated the relationship between insulin resistance and endothelial vasomotor function of the coronary artery of non-diabetic patients with chest pain, to elucidate the significance of insulin resistance in CAD.


    Figure 7. Clinical characteristics of the study patients.
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    Figure 8. No significant difference was seen in the percent change in average peak flow velocities in the insulin resistant (IR) and non-insulin resistant (NIR) groups after administration of papaverin and isosorbide dinitrate.
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    Figure 9. Papaverin and isosorbide dinitrate administration caused little difference in the percent changes in diameter in the IR and NIR groups.
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    The study included 25 non-diabetic patients with chest symptoms, who were divided into an insulin resistant (IR) group (plasma glucose level >/= 135 mg/dL) and a non-insulin resistant group (NIR) (< 135 mg/dL). The patient characteristics are shown in Figure 7. The effect of acetylcholine, papaverin, and isosorbide dinitrate on the vasomotor response of the coronary endothelium was studied and compared between the groups.

    The percent change in diameter of the coronary artery after injection of acetylcholine (20 microgram/ml/min) was 84 +/- 17% in the IR group and 109 +/- 18% in the NIR group (p < 0.01). The percent change in coronary flow velocity after injection of acetylcholine (20 microgram/ml/min) was 120 +/- 67% in the IR group compared to 256 +/- 58% in the NIR group (p < 0.01). The increase in coronary artery flow velocity in the IR group was significantly smaller than that of the NIR group (p < 0.01).

    Papaverin and isosorbide dinitrate were injected to confirm coronary flow results without the influence of the endothelial function. After the administration of these control substances, the percent change in average peak flow velocities in the IR and NIR groups did not significantly differ between each other, nor did the percent changes in diameter (Figures 8 and 9). The conclusion of the study was that non-diabetic patients with insulin resistance have endothelial vasomotor dysfunction, thus suggesting the possibility that such patients may benefit from treatment to prevent coronary heart disease.

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