Mechanisms Determining Course and Outcome of Diabetic Patients Who Have Had Acute Myocardial Infarction

  1. Doron Aronson, MD;
  2. Elliot J. Rayfield, MD; and
  3. James H. Chesebro, MD
  1. From Joslin Diabetes Center, Boston, Massachusetts; and Mount Sinai Medical Center, New York, New York. Requests for Reprints: Doron Aronson, MD, Joslin Diabetes Center, Research Division, Metabolism Section, One Joslin Place, Boston, MA 02215. Current Author Addresses: Dr. Aronson: Joslin Diabetes Center, Research Division, Metabolism Section, One Joslin Place, Boston, MA 02215.
     
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    Abstract

    Purpose: To review the pathogenic mechanisms that lead to the poor prognosis of diabetic patients after myocardial infarction and to determine the efficacy of current interventions for myocardial infarction in these patients.

    Data Sources: Search of the MEDLINE database from 1985 to 1995, using the keywords diabetes, myocardial infarction, and cardiomyopathy, and a search of the reference citations of relevant articles.

    Study Selection: Experimental and clinical studies on myocardial infarction in diabetic patients and basic research studies relevant to this topic.

    Data Synthesis: The excess in-hospital mortality of diabetic patients results primarily from an increased incidence of congestive heart failure. Several combined mechanisms reduce the compensatory ability of the noninfarcted myocardium; such mechanisms include preexisting congestive heart failure caused by diabetic cardiomyopathy, severe coronary artery disease, decreased vasodilatory reserve of epicardial and resistance arteries, and possibly abnormal metabolism of myocardial substrate.

    Late mortality results from increased reinfarction rates caused by the diffuse nature of the atherosclerotic disease and hypercoagulable state.Platelet hyperactivity, reduced fibrinolytic capacity, increased concentrations of hemostatic proteins, and endothelial dysfunction promote thrombosis at the site of plaque rupture. Autonomic neuropathy predisposes patients to ventricular arrhythmias. Thrombolytic agents, aspirin, β-blockers, and angiotensin-converting enzyme inhibitors are effective in patients with diabetes.

    Conclusions: In the thrombolytic era, mortality rates of diabetic patients who have had acute myocardial infarction remain 1.5 to 2 times higher than those in nondiabetic patients. This increased mortality rate is caused by diverse mechanisms that affect myocardial function and blood supply and by the tendency toward thrombosis in diabetic patients. Current therapies for myocardial infarction are effective in these patients. Improved metabolic control may also decrease mortality rates.

    Cardiovascular disease is a leading cause of death in diabetic patients; it accounts for almost 80% of all deaths among diabetic patients in North America [1]. Three quarters of these deaths result from coronary artery disease. Acute myocardial infarction is the cause of death in a substantial proportion of these patients [2]. Diabetic patients who have had myocardial infarction have a higher mortality rate than do nondiabetic patients, both in the acute phase [3, 4] and on long-term follow-up [5, 6]. We examine the mechanisms that may contribute to adverse outcome in diabetic patients who have had myocardial infarction.

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    Course of Acute Myocardial Infarction in the Prethrombolytic Era

    Studies done before the introduction of fibrinolytic therapy have consistently shown that the in-hospital mortality rates of diabetic patients who have had myocardial infarction are 1.5 to 2 times higher than those of nondiabetic patients [3, 4, 7-15]. Diabetic women have a particularly poor prognosis; their mortality rates are nearly twofold higher than those of diabetic men [4, 7, 13]. The risk conferred by diabetes also affects young diabetic patients who have good cardiovascular status at baseline [9, 16]. Most studies have shown no relation between the duration of known diabetes and in-hospital mortality after myocardial infarction [4, 15, 17].

    The excess in-hospital mortality of diabetic patients is primarily caused by an increased incidence of congestive heart failure [3, 4, 7, 10, 11, 14, 15, 18, 19]. Other contributing causes include increased rates of reinfarction, infarction extension, and recurrent ischemia [4, 12, 14, 20]. Most studies have found no excess of ventricular arrhythmias among diabetic patients [4, 11, 12, 14, 15, 21, 22].

    It has been well established that survival after myocardial infarction is related to residual left ventricular function and thus to the amount of damaged myocardium [23, 24]. However, congestive heart failure and cardiogenic shock in diabetic patients are more common and more severe than would be predicted from infarction size [3, 7, 18, 19, 21, 25-27]. Studies have found no evidence that diabetic patients have more extensive infarctions than do nondiabetic patients, whether infarction size is assessed by serial determinations of total creatine kinase activity [3, 4, 14, 18, 19, 22], radionuclide ventriculography [7, 27], or echocardiography [11]. Additional pathogenic processes thus compromise myocardial function [4] (Figure 1).

    Figure 1. Preexisting diabetic cardiomyopathy, impaired blood flow, and abnormal fuel use reduce the capacity of the noninfarcted myocardium to compensate.
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    Figure 1. Preexisting diabetic cardiomyopathy, impaired blood flow, and abnormal fuel use reduce the capacity of the noninfarcted myocardium to compensate. Probable mechanisms promoting congestive heart failure and associated in-hospital mortality in diabetic patients who have had acute myocardial infarction.

    Diabetic Cardiomyopathy

    The higher incidence of pump failure among diabetic patients has generally been ascribed to a preexisting subclinical impairment of left ventricular function [4, 28]. During acute ischemia, patients show “compensatory” hyperkinesis of the noninfarcted myocardium; this hyperkinesis may normalize global ejection fraction and correlates with hemodynamic status and survival [29, 30]. Several studies have shown a reduction in left ventricular ejection fraction [11, 4, 27, 31] and regional ejection fraction of the noninfarcted myocardium [27, 31] after myocardial infarction in diabetic patients compared with nondiabetic patients. Results of early angiography in the TAMI (Thrombolysis and Angioplasty in Myocardial Infarction) trials [13] showed that ventricular function was worse in noninfarcted areas in diabetic patients.

    Nevertheless, a considerable increase in the clinical manifestations of heart failure occurs with a modest decrease in left ventricular ejection fraction, indicating that the diastolic component is a major culprit of congestive symptoms [4]. Indeed, the cardiomyopathic process associated with diabetes initially manifests as diminished left ventricular compliance in the presence of normal systolic function [32-38]. Diastolic abnormalities occur in 27% to 69% of asymptomatic diabetic patients in the absence of or with only mild microvascular complications [32, 33, 36, 37]. Coexistent hypertension, which occurs about twice as frequently in diabetic patients as in the general population [39], results in more severe cardiomyopathy [40]. Hypertension leads to left ventricular hypertrophy and contributes to decreased left ventricular compliance [40]. However, impaired diastolic relaxation has been shown in the absence of concomitant hypertension in diabetic patients [32, 35-37, 41]. A lower ejection fraction in response to exercise in the presence of normal resting ejection fraction has also been shown in several studies [37, 38, 42, 43], suggesting that the contractile reserve is decreased in asymptomatic patients. Frank systolic dysfunction usually appears in patients with longstanding disease who have advanced microvascular complications or coexistent hypertension [35, 38, 40].

    Subclinical diabetic cardiomyopathy that is unrelated to large-vessel atherosclerosis therefore reduces the compensatory ability of the noninfarcted myocardium. In a diabetic patient who has a given degree of myocardial necrosis, the clinical picture is likely to reflect the extent of the cardiomyopathic process. Patients with preexisting diastolic dysfunction may develop clinical heart failure with a relatively preserved ejection fraction. It should be emphasized, however, that indices of left ventricular diastolic function provide prognostic information independent of ejection fraction [30, 44]. Patients with more advanced cardiomyopathy manifest congestive heart failure with decreased ejection fraction and possibly cardiogenic shock.

    Reduced Blood Flow to the Noninfarcted Myocardium

    The global effect of acute coronary occlusion is partly determined by the extent of coronary disease and its effect on the contraction of the surviving myocardium. Stenosis of more than 50% in noninfarction vessels is related to lack of hyperkinesis of noninfarcted areas [29, 45]. Both the GUSTO (Global Utilization of Streptokinase and t-PA [tissue plasminogen activator] for Occluded Coronary Arteries) [45] and the TAMI [46] trials have shown that the presence of multivessel coronary artery disease predicts short-term mortality in patients who have had acute myocardial infarction.

    Autopsy studies have shown that diabetic patients have more extensive coronary atherosclerosis than do controls without diabetes [47, 48]. Large angiographic studies indicate that diabetic patients who have established coronary artery disease have significantly more severe proximal and distal coronary artery disease [13, 49-51] (Table 1). Concomitant hypertension [40], atherogenic lipoprotein profile [52], and abdominal obesity [53] contribute to the accelerated atherosclerosis.

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    Table 1. Angiographic Studies in Patients with Diabetes*

    Angiographic assessment of epicardial stenoses does not fully reflect the adequacy of myocardial perfusion. In the normal heart, a balance between increased oxygen demand and supply is obtained by the dilatation of epicardial coronary arteries and small (resistance) arterioles. In diabetes, the capacity of the vascular bed to meet myocardial demand may also be impaired by abnormal epicardial vessel tone and microvascular dysfunction.

    Dilatation of epicardial arteries in response to hypoxia mainly relies on the release of endothelium-dependent relaxing factor [54]. Impaired endothelium-dependent relaxation is consistently found in diabetic patients [55-57] and occurs in various vascular beds, including the coronary arteries [58]. Hyperglycemia is the primary mediator of diabetic endothelial dysfunction. Impaired endothelium-dependent relaxation can be induced by brief exposure (several hours) to high glucose concentrations [56, 57] and can be reversed by pancreatic islet transplantation [59], implying a metabolic defect rather than irreversible damage to endothelial cells [55]. Endothelial dysfunction is thought to result primarily from increased generation of free radicals [56, 57, 60, 61] and the presence of advanced glycosylation end products [62] that deactivate nitric oxide.

    The abnormal vasodilatory response associated with diabetes also extends to the microcirculation. Locally regulated microvascular dilatation permits efficient distribution of blood flow in the myocardium [54]. Coronary arterial microvessels dilate in response to graded reductions in coronary perfusion. This autoregulatory response is blunted in hyperglycemic animals [63, 64] and diabetic patients [65]. This functional abnormality may also be related to endothelial dysfunction [66] and can be worsened by structural abnormalities of the coronary microcirculation [28].

    Severe and diffuse atherosclerotic disease, endothelial dysfunction of coronary arteries, impaired autoregulatory response of microvessels to increased myocardial demand, and structural changes in the coronary microvasculature can all lead to myocardial ischemia in the surviving myocardium, rendering it unable to compensate efficiently.

    In view of the above discussion, why do diabetic patients not have larger infarctions? Recent animal studies suggest that the hearts of diabetic patients are more tolerant to ischemic insults, such as coronary occlusion [67, 68]. Although the mechanism of this protection is unknown, it may be related to ischemic preconditioning [69].

    Abnormal Myocardial Substrate Metabolism

    Energy-independent transport of glucose across cell membranes is catalyzed by members of the facilitative glucose transporter family. The most important glucose transporter in cardiac myocytes is GLUT4, the insulin-responsive glucose transporter. Most of GLUT4 resides in intracellular membrane compartments, where it is prevented from contributing to cellular glucose transport. Insulin stimulates translocation of GLUT4 from the intracellular pool to the plasma membrane, resulting in increased glucose uptake by myocardial cells. GLUT4 also translocates to the plasma membrane in response to increased metabolic demand, such as that resulting from increased workload, hypoxia, and myocardial ischemia [70-72].

    The ischemic myocardium relies largely on the anaerobic metabolism of glucose [73]. Increased glucose uptake and metabolism during acute myocardial ischemia are associated with preserved myocardial function [74, 75]. Hence, decreased GLUT4 translocation caused by insulin deficiency could limit glucose availability, thereby promoting myocardial damage and reducing the compensatory capacity of the noninfarcted myocardium. In addition, insulin deficiency reduces the use of myocardial glucose with a shift toward fatty-acid metabolism. This altered pattern of exogenous substrate use may result in increased consumption of oxygen by the myocardium [73, 76].

    If specific metabolic abnormalities that are induced by diabetes can adversely affect mechanical performance or increase myocardial vulnerability to ischemic insult, then insulin administration and improved metabolic control may reduce myocardial damage, improve contractility, and decrease the mortality rate. Noninvasive quantification of myocardial glucose uptake using positron emission tomography with the glucose analogue 18F-fluorodeoxyglucose has shown that myocardial glucose uptake can be substantially improved or normalized if adequate insulin substitution is provided [77, 78].

    In one study [79], insulin-glucose infusion in the period immediately after infarction resulted in a substantial decrease in mortality rate. However, this approach has not been proven to be useful in the acute phase of myocardial infarction in other studies [80, 81].

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    Course of Acute Myocardial Infarction in the Thrombolytic Era

    Diabetic patients who have been treated with various fibrinolytic agents have the same reduction in mortality as nondiabetic patients do [13, 82-84] (Table 2). In an overview of fibrinolytic trials done in patients who had had myocardial infarction, the proportion of reduction in 35-day mortality was slightly, but not significantly, greater in patients who had diabetes (21.7%) than in those who did not (14.3%) [84]. In those trials, no increase in serious bleeding or stroke was seen in patients with diabetes [13, 84, 85].

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    Table 2. Effect of Thrombolytic Therapy in Patients with Diabetes*

    However, in the thrombolytic era, in-hospital mortality rates remain 1.5 to 2 times higher in diabetic than in nondiabetic patients (Table 2). In the TAMI trials [13], the in-hospital mortality rate was nearly twice as high for diabetic patients; these patients more frequently had congestive heart failure and had twice the rate of clinically recognized reinfarction. Similar results have been reported from other large studies [24, 26, 49, 85-88].

    The aforementioned mechanisms probably remain substantial contributors to in-hospital mortality in the thrombolytic era. In addition, reperfusion therapy has a more modest effect on left ventricular salvage, and many trials of thrombolytic therapy have failed to show improved left ventricular function [89]. However, because the response to thrombolytic therapy is a major prognostic factor in patients who have had acute myocardial infarction [90, 91], other mechanisms may come into play in relation to thrombolytic therapy in diabetic patients.

    Diabetes as a Possible Thrombolytic-Resistant State

    Thrombolytic therapy improves survival mainly by the achievement of early patency in the infarction-related artery [90, 91]. However, incomplete reperfusion is a frequent outcome of current thrombolytic regimens; it occurs in 20% to 40% of patients [92]. Thrombotic reocclusion of successfully reperfused arteries occurs in 10% to 15% of patients [45, 91-94]. Patients with reocclusion have a more complicated hospital course and higher in-hospital mortality rates [94, 95].

    Judged from these perspectives, factors that promote thrombus formation or that retard lysis may substantially affect the result of thrombolytic therapy and the clinical outcome. In several studies that used noninvasive indices, reperfusion was achieved less frequently in patients with diabetes then in those without [26, 96]. Reperfusion rates after catheter-directed thrombolysis for peripheral arterial occlusion are also substantially lower in diabetic patients [97].

    In contrast, results of early angiography in the TAMI investigations [13] showed similar rates of patency in the infarction-related artery (defined as Thrombolysis in Myocardial Infarction [TIMI] grade 2 or higher) in diabetic and nondiabetic patients. In that study, successful reperfusion was considered effective when TIMI grade 2 or 3 was achieved in the infarction-related artery. However, recent reports [91, 98] indicate that only patients who achieve complete reperfusion (TIMI grade 3) benefit from thrombolytic therapy. In the TAMI study [13], diabetic patients had the same angiographic reocclusion rates as nondiabetic patients, despite having twice the rate of clinically recognized reinfarction (that is, reocclusion).

    Possible Mechanisms of Resistance to Thrombolysis in Diabetes

    Failure of reperfusion may result from several factors, including thrombus composition, platelet activation by thrombolytic agents, or greater concentrations of inhibitors [92, 94, 99, 100].

    Platelets play a key role in reducing the efficacy of thrombolytic therapy and facilitating reocclusion [99]. In the presence of diabetes, platelet aggregation may be accelerated at sites of arterial occlusion. Platelets from diabetic patients have enhanced adhesiveness and hyperaggregability in response to various agonists [101, 102]. In diabetic patients, elevated fractions of activated platelets circulate in the absence of clinically detectable vascular lesions [103, 104]. Enhanced activity of the platelet arachidonic acid pathway with increased synthesis of thromboxane A2 also occurs in diabetic patients [105]. The increased functional behavior of platelets is more evident in patients with vascular complications. However, it is also seen in newly diagnosed patients, suggesting that altered platelet function may be a consequence of metabolic changes that are secondary to the diabetic state [101-103].

    Recent evidence suggests that elevated plasminogen activator inhibitor 1, the principal physiologic inhibitor of tissue-type plasminogen activator, reduces the likelihood of a patent infarction-related artery after thrombolytic therapy with t-PA [106, 107]. Reduced plasma fibrinolytic activity caused by elevated concentrations of plasminogen activator inhibitor 1 is a characteristic feature of insulin resistance and hyperinsulinemia [108, 109]. Proinsulin and insulin augment plasminogen activator inhibitor 1 gene expression [110]. Thus, elevated plasminogen activator inhibitor 1 activity in plasma in diabetic patients who have hyperinsulinemia may partly account for the lower reperfusion rates in diabetic patients. In one study, increased levels of plasminogen activator inhibitor 1 in diabetic patients who presented with acute myocardial infarction were associated with enzymatic evidence of reperfusion failure and in-hospital reinfarction [96]. Novel plasminogen activators with improved fibrinolytic potency and increased resistance to inhibition by plasminogen activator inhibitor 1 are of special interest for diabetic patients [111].

    Because diabetic patients have an inherently greater incidence and rate of thrombus formation, the dynamic and simultaneous processes of thrombosis and thrombolysis are probably weighted toward thrombosis during and after thrombolysis [100].

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    Long-Term Prognosis

    Among patients who have survived myocardial infarction, diabetic patients have higher late mortality rates than do nondiabetic patients [4-620, 22, 112-115]. With regard to in-hospital mortality, prognosis is also substantially poorer in diabetic women [114, 116]. The late mortality rate is primarily related to recurrent myocardial infarction and the development of new congestive heart failure [20, 26, 115, 117]. This premise holds true in the thrombolytic era [13, 26, 118].

    Survival and cardiovascular events over a period of years in patients who survive myocardial infarction are closely related to the following categories of risk: extent of global pump dysfunction, extent of myocardium at risk for further ischemia, increased thrombogenicity and the surrounding hematologic milieu, and presence of autonomic imbalance [119, 120] (Figure 2).

    Figure 2. Late mortality is primarily related to recurrent myocardial infarction and preexisting left ventricular dysfunction. Multivessel coronary artery disease and the hypercoaguable state promote recurrent infarctions. Autonomic imbalance may promote arrhythmic events.
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    Figure 2. Late mortality is primarily related to recurrent myocardial infarction and preexisting left ventricular dysfunction. Multivessel coronary artery disease and the hypercoaguable state promote recurrent infarctions. Autonomic imbalance may promote arrhythmic events. Factors leading to poor long-term survival in diabetic patients after myocardial infarction.

    Residual Left Ventricular Function

    Left ventricular function is a crucial factor in determining prognosis after acute myocardial infarction [119, 120] and contributes to the diminished survival rates in diabetic patients. It has also been suggested that diabetic patients tend to develop ischemic cardiomyopathy more frequently than nondiabetic patients do because the residual myocardium associated with diabetes may adversely influence the process of left ventricular remodeling after myocardial infarction [12, 121].

    Residual Myocardial Ischemia

    Multivessel coronary artery disease is associated with recurrent myocardial infarctions, an increased number of plaques that are vulnerable to disruption, and higher mortality rates [119, 120, 122]. However, no apparent relation exists between the severity of lesions and their propensity to cause future cardiac events. Lesions that are presumably responsible for plaque disruption and myocardial infarction have only mild-to-moderate stenosis in most patients [123, 124]. Accordingly, diabetic patients are likely to have recurrent events not only because of the presence of more substantial (>70%) lesions (Table 1) but also because of the diffuse nature of atherosclerotic disease. For example, diabetic patients in the TAMI trials [13] had more diffuse coronary artery disease as assessed by the mean number of coronary artery segments, with at least 1 stenosis of 25% or greater. In the Coronary Artery Surgery Study (CASS) [47], the risk for having more than 11 segments with a stenosis of 50% or greater was increased almost twofold. Furthermore, a significant increase in plaque ulceration and thrombosis is found at angioscopy in diabetic patients [125].

    Systemic Thrombogenic Risk Factors

    The severity and extent of coronary artery disease may not fully explain the higher rate of recurrent infarction in diabetic patients. The thrombotic-thrombolytic equilibrium at the time of plaque disruption plays a decisive role in the thrombotic response and therefore in clinical outcome [100, 123]. The risk for recurrent infarction is partly determined by certain prognostically significant hemostatic variables that may be related to the arterial wall, the blood, or both [126-131] (Table 3).

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    Table 3. Coagulation and Fibrinolytic Abnormalities of Prognostic Significance in Diabetes

    The clotting and fibrinolytic profile of diabetic patients bears a striking resemblance to that of patients at high risk for future cardiovascular events [101-104, 132-138] (Table 3). Furthermore, altered anticoagulant properties of the endothelium, including enhancement of tissue factor-mediated procoagulant activity [139], expression of plasminogen activator inhibitor 1 [140], and reduction in the effects of endogenous endothelial inhibitors of platelet aggregation (that is, nitric oxide [56, 57] and prostacyclin [141, 142]), promote intraluminal thrombus formation.

    Autonomic Imbalance

    Imbalance of the autonomic nervous system of the heart with decreased vagal activity or increased sympathetic activity, as determined by decreased variability of the heart rate, contributes to the genesis of ventricular arrhythmia and sudden cardiac death [119] and constitutes an independent risk factor for death among survivors of acute myocardial infarction [143, 144].

    Data from the Honolulu Heart Program indicate that diabetes is a predictor of sudden death and that this predisposition is related to an increased risk for death from arrhythmia [145]. Diabetic patients with clinical autonomic neuropathy are especially prone to sudden cardiac death [146-148]. Although clinical features of autonomic neuropathy generally occur in patients with long-term diabetes, cardiac autonomic neuropathy evolves early in the course of disease [149, 150]. Diminished heart rate variability is characteristic and particularly sensitive for early autonomic neuropathy in diabetic patients [150, 151].

    Diabetic patients also lose parasympathetic dominance during the night and have a higher sympathetic predominance during the day than do nondiabetic patients [152, 153]. The marked prevalence in sympathetic predominance during the day may facilitate onset of cardiovascular events [152, 153].

    Occult autonomic insufficiency may increase the tendency toward ventricular arrhythmia and cardiovascular events after infarction. In this context, it is noteworthy that that β-blockers, which reduce the incidence of sudden cardiac death and recurrent infarction partly by increasing cardiac vagal tone, are particularly efficacious in diabetic patients [154]. Few studies have reported increased rates of sudden cardiac death in diabetic patients who have survived myocardial infarction [4, 26, 113, 117]; in addition, few studies have correlated loss of heart rate variability with increased mortality rates [25]. In patients receiving placebo who participated in the Cardiac Arrhythmia Suppression Trial (CAST), diabetes was associated with an increased risk for death from arrhythmia [117]. The causative relation between cardiac diabetic autonomic neuropathy and both increased mortality rates and predictive value remain unclear.

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    Treatment of Diabetic Patients Who Have Had Acute Myocardial Infarction

    Through diverse mechanisms, diabetes exerts a deleterious effect on the short- and long-term course after myocardial infarction; some of these mechanisms (such as cardiomyopathy) cannot be modified at the time of presentation. Because diabetic patients are at greater risk, the application of effective preventive and therapeutic measures may result in a particularly large survival benefit.

    Thrombolytic therapy is of substantial benefit in diabetic patients. As a high-risk group, diabetic patients who have evolving infarction may benefit equally from immediate angioplasty if it is available. In a small study, immediate angioplasty was more effective than thrombolytic therapy for restoration of patency in the infarction-related artery, for preventing reocclusion, and for preventing recurrent ischemia during hospitalization [155]. However, infarction size was similar in three of four studies [155-158] and, in a large community setting, mortality rates of primary angioplasty and thrombolysis were similar during hospitalization and after 3 years of follow-up [159]. The issue is complicated by the high frequency of restenosis after successful angioplasty in diabetic patients [160], which is seen in conventional therapy and with potent antiplatelet therapy with an antibody directed to the glycoprotein IIb/IIIa receptor [161]. It is complicated further by the recent report of increased mortality rates in diabetic patients who had had angioplasty compared with those who had had bypass surgery [162].

    Aspirin is an effective secondary prevention therapy in diabetic patients [163], but the ISIS-2 (Second International Study of Infarct Survival) study showed no reduction in mortality rates in diabetic patients who received 160 mg of aspirin daily [82]. Data suggest that diabetic patients may require larger doses of aspirin to suppress the synthesis of thromboxane A2[82, 105, 164].

    β-blockers effectively reduce reinfarction and sudden death in diabetic patients, perhaps to a greater extent than in nondiabetic patients [154, 165-167]. Early treatment of myocardial infarction with β-blockers reduced the mortality rate by 13% for all patients and by 37% for diabetic patients, whereas the long-term mortality reduction was 33% in all patients and 48% in diabetic patients [154]. Deterioration in glycemic control or blunted counterregulatory response to hypoglycemia are seldom serious clinical problems, especially when cardioselective β1-blockers are used [154, 168].

    Inhibition of angiotensin-converting enzymes is now unequivocally associated with a substantial reduction in the mortality rates of patients who have survived myocardial infarction. Data from GISSI-3 (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico) [169] show a marked reduction in the 6-week mortality rates of diabetic patients who received lisinopril therapy.

    Although strict peri-infarction glycemic control is feasible [79-81], it remains uncertain whether such therapy alters clinical outcome. In a recent study, insulin-glucose infusions followed by an intensive insulin regimen reduced 1-year mortality rates [81]. More studies are needed to better delineate the importance of metabolic derangements in diabetic patients during myocardial ischemia.

    The Scandinavian Simvastatin Survival Study (4S) showed the effectiveness of cholesterol-lowering therapy for the secondary prevention of mortality and morbidity in patients with angina or previous infarction [170]. When the diabetes group was compared with the placebo group, the 6-year relative mortality rate was 57% with treatment, the cardiovascular mortality rate was 64%, and the risk for a major cardiovascular event was 45% [171]. It has been proposed that the preservation of normal endothelial vasomotor and anticoagulant function may partly account for the decrease in ischemic events seen with cholesterol-lowering and antioxidant therapies [172]. The salutary effects of improved glycemic control [59] and antioxidants [61, 173] on endothelial function in diabetes may prove beneficial in reducing the rate of cardiovascular events.

    Current data indicate that routine management of diabetic patients who have had acute myocardial infarction should include thrombolytic therapy if no specific contraindications exist. Early therapy should also include aspirin, β-adrenergic blockers, and angiotensin-converting enzyme inhibitors. This therapy should be continued for the long term, together with aggressive cholesterol reduction and improved glycemic control.

    Dr. Rayfield: Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai Medical Center, New York, NY 10029-6575.

    Dr. Chesebro: Division of Cardiology, Department of Medicine, Mount Sinai Medical Center, New York, NY 10029-6575.

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    References

    1. 1.↵
      Consensus statement: role of cardiovascular risk factors in prevention and treatment of macrovascular disease in diabetes. American Diabetes Association. Diabetes Care. 1993; 16(Suppl 2):72-8.
    2. 2.↵
      Morrish NJ, Stevens LK, Head J, Fuller JH, Jarrett RJ, Keen H. A prospective study of mortality among middle-aged diabetic patients (the London cohort of the WHO Multinational Study of Vascular Disease in Diabetics) I: causes and death rates. Diabetologia. 1990; 33:538-41.
    3. 3.↵
      Jaffe AS, Spadaro JJ, Schechtman K, Roberts R, Geltman EM, Sobel BE. Increased congestive heart failure after myocardial infarction of modest extent in diabetic patients mellitus. Am Heart J. 1984; 108:31-7.
    4. 4.↵
      Stone PH, Muller JE, Hartwell T, York BJ, Rutherford JD, Parker CB, et al. The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and left ventricular dysfunction to the adverse prognosis. The MILIS Study Group. J Am Coll Cardiol. 1989; 14:49-57.
    5. 5.↵
      Smith JW, Marcus FI, Serokman R. Prognosis of patients with diabetes mellitus after acute myocardial infarction. Am J Cardiol. 1984; 54:718-21.
    6. 6.↵
      Herlitz J, Malmberg K, Karlson BW, Ryden L, Hjalmarson A. Mortality and morbidity during a five-year follow-up of diabetics with myocardial infarction. Acta Med Scand. 1988; 244:31-8.
    7. 7.↵
      Savage MP, Krolewski AS, Kenien GG, Lebeis MP, Christlieb AR, Lewis SM. Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor. Am J Cardiol. 1988; 62(10 Pt 1):665-9.
    8. 8.↵
      Rytter L, Troelsen S, Beck-Nielsen H. Prevalence and mortality of acute myocardial infarction in diabetic patients. Diabetes Care. 1985; 8:230-4.
    9. 9.↵
      Czyzk A, Krolewski AS, Szablowska S, Alot A, Kopczynski J. Clinical course of myocardial infarction among diabetic patients. Diabetes Care. 1980; 3:526-9.
    10. 10.↵
      Tansey MJ, Opie LH, Kennelly BM. High mortality in obese women diabetics with acute myocardial infarction. Br Med J. 1977; 1:1624-6.
    11. 11.↵
      Kouvaras G, Cokkinos D, Spyropoulou M. Increased mortality of diabetics after acute myocardial infarction attributed to diffusely impaired left ventricular performance as assessed by echocardiography. Jpn Heart J. 1988; 29:1-9.
    12. 12.↵
      Malmberg K, Ryden L. Myocardial infarction in patients with diabetes mellitus. Eur Heart J. 1988; 9:259-64.
    13. 13.↵
      Granger CB, Califf RM, Young S, Candela R, Samaha J, Worley S, et al. Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. J Am Coll Cardiol. 1993; 21:920-5.
    14. 14.↵
      Lomuscio A, Castagnone M, Vergani D, Verzoni A, Beltrami A, Ravaglia R, et al. Clinical correlation between diabetic and non diabetic patients with myocardial infarction. Acta Cardiol. 1991; 46:543-54.
    15. 15.↵
      Yudkin JS, Oswald GA. Determinants of hospital admission and case fatality in diabetic patients with myocardial infarction. Diabetes Care. 1988; 11:351-8.
    16. 16.↵
      Abbud ZA, Shindler DM, Wilson AC, Kostis JB. Effect of diabetes mellitus on short- and long-term mortality rates of patients with acute myocardial infarction: a statewide study. Myocardial Infarction Data Acquisition System Study Group. Am Heart J. 1995; 130:51-8.
    17. 17.↵
      Oswald GA, Corcoran S, Yudkin JS. Prevalence and risks of hyperglycemia and undiagnosed diabetes in patients with acute myocardial infarction. Lancet. 1984; 1:1264-7.
    18. 18.↵
      Lehto S, Pyorala K, Miettinen H, Ronnemaa T, Palomaki P, Tuomilehto J, et al. Myocardial infarct size and mortality in patients with noninsulin-dependent diabetes mellitus. J Intern Med. 1994; 236:291-7.
    19. 19.↵
      Orlander PR, Goff DC, Morrissey M, Ramsey DJ, Wear ML, Labarthe DR, et al. The relation of diabetes to the severity of acute myocardial infarction and post-myocardial infarction survival in Mexican-Americans and non-Hispanic whites. Diabetes. 1994; 43:897-902.
    20. 20.↵
      Ulvenstam G, Aberg A, Bergstrand R, Johansson S, Pennert K, Vedin A, et al. Long term prognosis after myocardial infarction in men with diabetes. Diabetes. 1985; 34:787-92.
    21. 21.↵
      Gwilt DJ, Petri M, Lewis PW, Nattrass M, Pentecost BL. Myocardial infarct size and mortality in diabetic patients. Br Heart J. 1985; 54:466-72.
    22. 22.↵
      Karlson BW, Herlitz J, Hjalmarson A. Prognosis of acute myocardial infarction in diabetic and nondiabetic patients. Diabet Med. 1993; 10:449-54.
    23. 23.↵
      Risk stratification and survival after myocardial infarction. N Engl J Med. 1983; 309:331-6.
    24. 24.↵
      Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators. Circulation. 1995; 91:1659-68.
    25. 25.↵
      Fava S, Azzopardi J, Muscat HA, Fenech FF. Factors that influence outcome in diabetic subjects with myocardial infarction. Diabetes Care. 1993; 16:1615-8.
    26. 26.↵
      Zuanetti G, Latini R, Maggioni AP, Santoro L, Franzosi MG. Influence of diabetes on mortality in acute myocardial infarction: data from the GISSI-2 study. J Am Coll Cardiol. 1993; 22:1788-94.
    27. 27.↵
      Iwasaka T, Takahashi N, Nakamura S, Sugiura T, Tarumi N, Kimura Y, et al. Residual left ventricular pump function after acute myocardial infarction in NIDDM patients. Diabetes Care. 1992; 15:1522-6.
    28. 28.↵
      Zarich SW, Nesto RW. Diabetic cardiomyopathy. Am Heart J. 1989; 118(5 Pt 1):1000-12.
    29. 29.↵
      Grines CL, Topol EJ, Califf RM, Stack RS, George BS, Kereiakes D, et al. Prognostic implications and predictors of enhanced regional wall motion of the noninfarct zone after thrombolysis and angioplasty therapy of acute myocardial infarction. The TAMI Study Groups. Circulation. 1989; 80:245-53.
    30. 30.↵
      Jaarsma W, Visser CA, Eenige van MJ, Res JC, Funke Kupper AJ, Verheugt FW, et al. Prognostic implications of regional hyperkinesia and remote asynergy of noninfarcted myocardium. Am J Cardiol. 1986; 58:394-8.
    31. 31.↵
      Takahashi N, Iwasaka T, Sugiura T, Hasegawa T, Tarumi N, Kimura Y, et al. Left ventricular regional function after acute anterior myocardial infarction in diabetic patients. Diabetes Care. 1989; 12:630-5.
    32. 32.↵
      Zarich SW, Arbuckle BE, Cohen LR, Roberts M, Nesto RW. Diastolic abnormalities in young asymptomatic diabetic patients assessed by pulsed Doppler echocardiography. J Am Coll Cardiol. 1988; 12:114-20.
    33. 33.↵
      Uusitupa M, Mustonen J, Laakso M, Vainio P, Lansimies E, Talwar S, et al. Impairment of diastolic function in middle-aged type 1 (insulin-dependent) and type 2 (non–insulin-dependent) diabetic patients free of cardiovascular disease. Diabetologia. 1988; 31:783-91.
    34. 34.↵
      Riggs TW, Transue D. Doppler echocardiographic evaluation of left ventricular diastolic dysfunction in adolescents with diabetes mellitus. Am J Cardiol. 1990; 65:899-902.
    35. 35.↵
      Raev DC. Which left ventricular function is impaired earlier in the evolution of diabetic cardiomyopathy? An echocardiographic study of young type I diabetic patients. Diabetes Care. 1994; 17:633-9.
    36. 36.↵
      Paillole C, Dahan M, Paycha F, Solal AC, Passa P, Gourgon P. Prevalence and significance of left ventricular filling abnormalities determined by Doppler echocardiography in young type I (insulin-dependent) diabetic patients. Am J Cardiol. 1989; 64:1010-6.
    37. 37.↵
      Mildenberger RR, Bar-Shlomo B, Druck MN, Jablonsky G, Morch JE, Hilton JD, et al. Clinically unrecognized ventricular dysfunction in young diabetic patients. J Am Coll Cardiol. 1984; 4:234-8.
    38. 38.↵
      Shapiro LM, Leatherdale BA, Mackinnon J, Fletcher RF. Left ventricular function in diabetes mellitus. II: Relation between clinical features and left ventricular function. Br Heart J. 1981; 45:129-32.
    39. 39.↵
      Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension. 1992; 19:403-18.
    40. 40.↵
      Grossman E, Messerli FH. Diabetic and hypertensive heart disease. Ann Intern Med. 1996; 125:304-10.
    41. 41.↵
      van Hoeven KH, Factor SM. A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation. 1990; 82:848-55.
    42. 42.↵
      Vered A, Battler A, Segal P, Liberman D, Yerushalmi Y, Berezin M, et al. Exercise-induced left ventricular dysfunction in young men with asymptomatic diabetes mellitus (diabetic cardiomyopathy). Am J Cardiol. 1984; 54:633-7.
    43. 43.↵
      Mustonen JN, Uusitupa MI, Laakso M, Vanninen E, Lansimies E, Kuikka JT, et al. Left ventricular systolic function in middle-aged diabetic patients mellitus. Am J Cardiol. 1994; 73:1202-8.
    44. 44.↵
      Clements IP, Brown ML, Zinsmeister AR, Gibbons RJ. Influence of left ventricular diastolic filling on symptoms and survival in patients with decreased left ventricular systolic function. Am J Cardiol. 1991; 67:1245-50.
    45. 45.↵
      The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. The GUSTO Angiographic Investigators. N Engl J Med. 1993; 329:1615-22.
    46. 46.↵
      Muller DW, Topol EJ, Ellis SG, Sigmon KN, Lee K, Califf RM. Multivessel coronary artery disease: a key predictor of short-term prognosis after reperfusion therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. Am Heart J. 1991; 121(4 Pt 1):1042-9.
    47. 47.↵
      Barzilay JI, Kronmal RA, Bittner V, Eaker E, Evans C, Foster ED. Coronary artery disease and coronary artery bypass grafting in diabetic patients aged >65 years (report from the coronary artery surgery study [CASS] registry). Am J Cardiol. 1994;74:334-9.
    48. 48.↵
      Waller BF, Palumbo PJ, Lie JT, Roberts WC. Status of the coronary arteries at necropsy in diabetes mellitus with onset after age 30 years. Analysis of 229 diabetic patients with and without evidence of coronary heart disease and comparison to 183 control subjects. Am J Med. 1980; 69:498-506.
    49. 49.↵
      Mueller HS, Cohen LS, Braunwald E, Forman S, Feit F, Ross A, et al. Predictors of early mortality and morbidity after thrombolytic therapy of acute myocardial infarction. Analyses of patient subgroups in the Thrombolysis in Myocardial Infarction (TIMI) trial, phase II. Circulation. 1992; 85:1254-64.
    50. 50.↵
      Stein B, Weintraub WS, Gebhart SP, Cohen-Bernstein CL, Grosswald R, Liberman HA, et al. Influence of diabetes mellitus on early and late outcome after percutaneous transluminal coronary angioplasty. Circulation. 1995; 91:979-89.
    51. 51.↵
      Vigorito C, Betocchi S, Bonzani G, Giudice P, Miceli D, Piscione F, et al. Severity of coronary artery disease in diabetic patients mellitus. Angiographic study of 34 diabetic and 120 nondiabetic patients. Am Heart J. 1980; 100(6 Pt 1):782-7.
    52. 52.↵
      Ginsberg NH. Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis. Diabetes Care. 1991; 14:839-55.
    53. 53.↵
      Bjorntorp P. “Portal” adipose tissue as a generator of risk factors for cardiovascular disease and diabetes. Arteriosclerosis. 1990; 10:493-6.
    54. 54.↵
      Umans JG, Levi R. Nitric oxide in the regulation of blood flow and arterial pressure. Annu Rev Physiol. 1995; 57:771-90.
    55. 55.↵
      Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 1993; 88:2510-6.
    56. 56.↵
      Cohen RA. Dysfunction of vascular endothelium in diabetes mellitus. Circulation. 1993; 87(Suppl 5):67-76.
    57. 57.↵
      Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med. 1994; 16:383-91.
    58. 58.↵
      Nitenberg A, Valensi P, Sachs R, Dali M, Aptecar E, Attali JR. Impairment of coronary vascular reserve and ACh-induced coronary vasodilation in diabetic patients with aniographically normal coronary arteries and normal left ventricular systolic function. Diabetes. 1993; 42:1017-25.
    59. 59.↵
      Pieper GM, Jordan M, Adams MB, Roza AM. Syngeneic pancreatic islet transplantation reverses endothelial dysfunction in experimental diabetes. Diabetes. 1995; 44:1106-13.
    60. 60.↵
      Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol. 1992; 263(2 Pt 2):H321-6.
    61. 61.↵
      Keegan A, Walbank H, Cotter MA, Cameron NE. Chronic vitamin E treatment prevents defective endothelium-dependent relaxation in diabetic rat aorta. Diabetologia. 1995; 38:1475-8.
    62. 62.↵
      Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes. J Clin Invest. 1991; 87:432-8.
    63. 63.↵
      Kersten JR, Brooks LA, Dellsperger KC. Impaired microvascular response to graded coronary occlusion in diabetic and hyperglycemic dogs. Am J Physiol. 1995; 268(4 Pt 2):H1667-74.
    64. 64.↵
      Sebbag L, Forrat R, Canet E, Wiernsperger N, Delaye J, Renaud S, et al. Effect of experimental non-insulin requiring diabetes on myocardial microcirculation during ischemia in dogs. Eur J Clin Invest. 1994; 24:686-90.
    65. 65.↵
      Nasher PJ Jr, Brown RE, Oskarsson H, Winniford MD, Rossen JD. Maximal coronary flow reserve and metabolic coronary vasodilation in patients with diabetes mellitus. Circulation. 1995; 91:635-40.
    66. 66.↵
      Griffith TM, Edwards DH, Davies RL, Harrison TJ, Evans KT. EDRF coordinates the behavior of vascular resistance vessels. Nature. 1987; 329:442-5.
    67. 67.↵
      Liu Y, Thornton JD, Cohen MV, Downey JM, Schaffer SW. Streptozotocin-induced non–insulin-dependent diabetes protects the heart from infarction. Circulation. 1993; 88:1273-8.
    68. 68.↵
      Tani M, Neely JR. Hearts from diabetic rats are more resistant to in vitro ischemia: possible role of altered Ca2+ metabolism. Circ Res. 1988; 62:931-40.
    69. 69.↵
      Braunwald E. Acute myocardial infarction-the value of being prepared [Editorial]. N Engl J Med. 1996; 334:51-2.
    70. 70.↵
      Zaninetti D, Greco-Perotto R, Jaenrenaud B. Heart glucose transport and transporters in rat heart: regulation by insulin, workload and glucose. Diabetologia. 1988; 31:108-13.
    71. 71.↵
      Wheeler TJ. Translocation of glucose transporters in response to anoxia in heart. J Biol Chem. 1988; 263:19447-54.
    72. 72.↵
      Sun D, Nguyen N, DeGrado TR, Schwaiger M, Brosius FC 3d. Ischemia induces translocation of the insulin-responsive glucose transporter GLUT4 of the plasma membrane of cardiac monocytes. Circulation. 1994; 89:793-8.
    73. 73.↵
      Liedtke AJ. Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Prog Cardiovasc Dis. 1981; 23:321-36.
    74. 74.↵
      Eberli FR, Weinberg EO, Grice WN, Horowitz GL, Apstein CS. Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global underperfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions. Circ Res. 1991; 68:466-81.
    75. 75.↵
      Runnman EM, Lamp ST, Weiss JN. Enhanced utilization of exogenous glucose improves cardiac function in hypoxic rabbit ventricle without increasing total glycolytic flux. J Clin Invest. 1990; 86:1222-33.
    76. 76.↵
      Rodrigues B, Cam MC, McNeill JH. Myocardial substrate metabolism: implications for diabetic cardiomyopathy. J Mol Cell Cardiol. 1995; 27:169-79.
    77. 77.↵
      vom Dahl J, Herman WH, Hicks RJ, Ortiz-Alonso FJ, Lee KS, Allman KC, et al. Myocardial glucose uptake in patients with insulin-dependent diabetes mellitus assessed quantitatively by dynamic positron emission tomography. Circulation. 1993; 88:395-404.
    78. 78.↵
      Ohtake T, Yokoyama I, Watanabe T, Momose T, Serezawa T, Nishikawa J, et al. Myocardial glucose metabolism in noninsulin-dependent diabetes mellitus patients evaluated by FDG-PET. J Nucl Med. 1995; 36:456-63.
    79. 79.↵
      Clark RS, English M, McNeill GP, Newton RW. Effect of intravenous infusion of insulin in diabetics with acute myocardial infarction. Br Med J (Clin Res Ed). 1985; 291:303-5.
    80. 80.↵
      Gwilt DJ, Petri M, Lamb P, Nattrass M, Pentecost BL. Effect of intravenous insulin infusion on mortality among diabetic patients after myocardial infarction. Br Heart J. 1984; 51:626-30.
    81. 81.↵
      Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995; 26:57-65.
    82. 82.↵
      Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988; 2:349-60.
    83. 83.↵
      Lynch M, Gammage MD, Lamb P, Nattrass M, Pentecost BL. Acute myocardial infarction in diabetic patients in the thrombolytic era. Diabet Med. 1994; 11:162-5.
    84. 84.↵
      Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more then 1000 patients. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Lancet. 1994; 343:311-22.
    85. 85.↵
      Barbash GI, White HD, Modan M, Van de Werf F. Significance of diabetes mellitus in patients with acute myocardial infarction receiving thrombolytic therapy. Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial. J Am Coll Cardiol. 1993; 22:707-13.
    86. 86.↵
      Hillis LD, Forman S, Braunwald E. Risk stratification before thrombolytic therapy in patients with acute myocardial infarction. The Thrombolysis in Myocardial Infarction (TIMI) Phase II Co-Investigators. J Am Coll Cardiol. 1990; 16:313-5.
    87. 87.↵
      Murphy JF, Kahn MG, Krone RJ. Prethrombolytic versus thrombolytic era risk stratification of patients with acute myocardial infarction. Am J Cardiol. 1995; 76:827-9.
    88. 88.↵
      Klein HH, Hengstenberg C, Peuckert M, Jurgensen R. Comparison of death rates from acute myocardial infarction in a single hospital in two different periods (1977-1978 versus 1988-1989). Am J Cardiol. 1993; 71:518-23.
    89. 89.↵
      Harrison JK, Califf RM, Woodlief LH, Kereiakes D, George BS, Stack RS, et al. Systolic left ventricular function after reperfusion therapy for acute myocardial infarction. Analysis of determinants of improvement. The TAMI Study Group. Circulation. 1993; 87:1531-41.
    90. 90.↵
      Braunwald E. The open-artery theory is alive and well-again [Editorial]. N Engl J Med. 1993; 329:1650-2.
    91. 91.↵
      Simes RJ, Topol EJ, Holmes DR Jr, White HD, Rutsch WR, Vahanian A, et al. Link between the angiographic substudy and mortality outcomes in a large randomized trial of myocardial reperfusion. Importance of early and complete infarct artery reperfusion. GUSTO-I Investigators. Circulation. 1995; 91:1923-8.
    92. 92.↵
      Anderson HV, Willerson JT. Thrombolysis in acute myocardial infarction. N Engl J Med. 1993; 329:703-9.
    93. 93.↵
      Reiner JS, Lundergan CF, van den Brand M, Boland J, Thompson MA, Machecourt J, et al. Early angiography cannot predict postthrombolytic coronary reocclusion: observations from the GUSTO angiographic study. Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries. J Am Coll Cardiol. 1994; 24:1439-44.
    94. 94.↵
      Lincoff MA, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation. 1993; 88:1361-74.
    95. 95.↵
      Ohman EM, Califf RM, Topol EJ, Candela R, Abbottsmith C, Ellis S, et al. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. The TAMI Study Group. Circulation. 1990; 82:781-91.
    96. 96.↵
      Gray RP, Yudkin JS, Patterson DL. Enzymatic evidence of impaired reperfusion in diabetic patients after thrombolytic therapy for acute myocardial infarction: a role for plasminogen activator inhibitor? Br Heart J. 1993; 70:530-6.
    97. 97.↵
      Ouriel K, Shortell CK, Azodo MV, Guiterrez OH, Marder VJ. Acute peripheral arterial occlusion: predictors of success in catheter-directed thrombolytic therapy. Radiology. 1994; 193:561-6.
    98. 98.↵
      Anderson JL, Karagounis LA, Becker LC, Sorensen SG, Menlove RL. TIMI perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarction. Ventriculographic, enzymatic, and electrocardiographic evidence from the TEAM-3 Study. Circulation. 1993; 87:1829-39.
    99. 99.↵
      Coller BS. Platelet and thrombolytic therapy. N Engl J Med. 1990; 322:33-42.
    100. 100.↵
      Chesebro JH, Fuster V. Dynamic thrombosis and thrombolysis. Role of antithrombins [Editorial]. Circulation. 1991; 83:1815-7.
    101. 101.↵
      Winocour PD. Platelet abnormalities in diabetes mellitus. Diabetes. 1992; 41(Suppl 2):26-31.
    102. 102.↵
      Tschoepe D, Roesen P, Schwippert B, Gries FA. Platelets in diabetes: the role of the hemostatic regulation in atherosclerosis. Semin Thromb Hemost. 1993; 19:122-8.
    103. 103.↵
      Tschoepe D, Driesch E, Schwippert B, Nieuwenhuis HK, Gries FA. Exposure of adhesion molecules on activated platelets in patients with newly diagnosed IDDM is not normalized by near-normoglycemia. Diabetes. 1995; 44:890-4.
    104. 104.↵
      Tschoepe D, Roesen P, Esser J, Schwippert B, Nieuwenhuis HK, Kehrel B, et al. Large platelets circulate in an activated state in diabetes mellitus. Semin Thromb Hemost. 1991; 17:433-8.
    105. 105.↵
      Davi G, Catalano I, Averna M, Notarbartolo A, Strano A, Ciabattoni G, et al. Thromboxane biosynthesis and platelets function in type II diabetes mellitus. N Engl J Med. 1990; 322:1769-74.
    106. 106.↵
      Sane DC, Stump DC, Topol EJ, Sigmon KN, Kereiakes DJ, George BS, et al. Correlation between baseline plasminogen activator inhibitor levels and clinical outcome during therapy with issue plasminogen activator for acute myocardial infarction. Thromb Haemost. 1991; 65:275-9.
    107. 107.↵
      Barbash GI, Hod H, Roth A, Miller HI, Rath S, Zahav YH, et al. Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct artery after thrombolytic therapy in acute myocardial infarction. Am J Cardiol. 1989; 64:1231-5.
    108. 108.↵
      McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes. 1994; 43:104-9.
    109. 109.↵
      Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia. 1991; 34:457-62.
    110. 110.↵
      Nordt TK, Sawa H, Fujii S, Sobel BE. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation. 1995; 91:764-70.
    111. 111.↵
      Keyt BA, Nicholas PF, Refino CJ, Berleau L, Nguyen H, Chow A, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci U S A. 1994; 91:3670-4.
    112. 112.↵
      Gilpin E, Ricou F, Dittrich H, Nicod P, Henning H, Ross J Jr. Factors associated with recurrent myocardial infarction within one year after acute myocardial infarction. Am Heart J. 1991; 121(2 Pt 1):457-65.
    113. 113.↵
      Herlitz J, Karlson BW, Edvardsson N, Emanuelsson H, Hjalmarson A. Prognosis in diabetics with chest pain or other symptoms suggestive of acute myocardial infarction. Cardiology. 1992; 80:237-45.
    114. 114.↵
      Abbott RD, Donahue RP, Kannel WB, Wilson PW. The impact of diabetes on survival following myocardial infarction in men vs women. The Framingham study. JAMA. 1988; 260:3456-60.
    115. 115.↵
      Jacoby RM, Nesto RW. Acute myocardial infarction in the diabetic patient: pathophysiology, clinical course and prognosis. J Am Coll Cardiol. 1992; 20:736-44.
    116. 116.↵
      Milo C, Reicher-Reiss H, Goldbourt U, Boyko V, Behar S. Comparison of prognosis of acute myocardial infarction in insulin-treated diabetic women versus men. The SPRINT Study Group. Am J Cardiol. 1994; 74:1275-6.
    117. 117.↵
      Capone RJ, Pawitan Y, el-Sherif N, Geraci TS, Handshaw K, Morganroth J, et al. Events in the cardiac arrhythmia suppression trial: baseline predictors of mortality in placebo-treated patients. J Am Coll Cardiol. 1991; 18:1434-8.
    118. 118.↵
      Taylor GJ, Moses HW, Katholi RE, Korsmeyer C, Kolm P, Dove JT, et al. Six-year survival after coronary thrombolysis and early revascularization for acute myocardial infarction. Am J Cardiol. 1992; 70:26-30.
    119. 119.↵
      Woo KS, White HD. Factors affecting outcome after recovery from myocardial infarction. Annu Rev Med. 1994; 45:325-39.
    120. 120.↵
      Pitt B. Evaluation of the postinfarct patient. Circulation. 1995; 91:1855-60.
    121. 121.↵
      Iwasaka T, Sugiura T, Abe Y, Karakawa M, Matsui Y, Wakayama Y, et al. Residual left ventricular pump function following acute myocardial infarction in postmenopausal diabetic women. Coron Artery Dis. 1994; 5:237-42.
    122. 122.↵
      Schulman SP, Achuff SC, Griffith LS, Humphries JO, Taylor GJ, Mellits ED, et al. Prognostic cardiac catheterization variables in survivors of acute myocardial infarction: a five year prospective study. J Am Coll Cardiol. 1988; 11:1164-72.
    123. 123.↵
      Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992; 326:242-50, 310-8.
    124. 124.↵
      Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995; 91:2844-50.
    125. 125.↵
      Silva JA, Escobar A, Collins TJ, Ramee SR, White CJ. Unstable angina. A comparison of angioscopic findings between diabetic and nondiabetic patients. Circulation. 1995; 92:1731-6.
    126. 126.↵
      Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med. 1995; 332:635-41.
    127. 127.↵
      Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperactivity and prognosis in survivors of myocardial infarction. N Engl J Med. 1990; 322:1549-54.
    128. 128.↵
      Jansson JH, Nilsson TK, Johnson O. von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J. 1991; 66:351-5.
    129. 129.↵
      Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987; 2:3-9.
    130. 130.↵
      Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986; 2:533-7.
    131. 131.↵
      Cooper J, Douglas AS. Fibrinogen level as a predictor of mortality in survivors of myocardial infarction. Fibrinolysis. 1991; 5:105-8.
    132. 132.↵
      Stehouwer CD, Nauta JJ, Zeldenrust GC, Hackeng WH, Donker AJ, den Ottolander GJ. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non–insulin-dependent diabetes mellitus. Lancet. 1992; 340:319-23.
    133. 133.↵
      Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Marcucci G, et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Thromb Haemost. 1993; 70:380-5.
    134. 134.↵
      Kannel WB, D'Agostino RB, Wilson PW, Belanger AJ, Gagnon DR. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J. 1990; 120:672-6.
    135. 135.↵
      De Feo P, Gaisano GM, Haymond MW. Differential effects of insulin deficiency on albumin and fibrinogen synthesis in humans. J Clin Invest. 1991; 88:833-40.
    136. 136.↵
      Ganda OP, Arkin CF. Hyperfibrinogenemia. An important risk factor for vascular complications in diabetes. Diabetes Care. 1992; 15:1245-50.
    137. 137.↵
      Ceriello A, Giugliano D, Quatraro A, Dello Russo P, Torella R. Blood glucose may condition factor VII levels in diabetic and normal subjects. Diabetologia. 1988; 31:889-91.
    138. 138.↵
      Gruden G, Cavallo-Perin P, Bazzan M, Stella S, Vuolo A, Pagano G. PAI-1 and factor VII activity are higher in IDDM patients with microalbuminuria. Diabetes. 1994; 43:426-9.
    139. 139.↵
      Esposito C, Gerlach H, Brett J, Stern D, Vlassara H. Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface procoagulant properties. J Exp Med. 1989; 170:1387-407.
    140. 140.↵
      Nordt TK, Klassen KJ, Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis. Arterioscler Thromb. 1993; 13:1822-8.
    141. 141.↵
      Johnson M, Harrison HE, Raftery AT, Elder JB. Vascular prostacyclin may be reduced in diabetes in man [Letter]. Lancet. 1979; 1:325-6.
    142. 142.↵
      Umeda F, Inoguchi T, Nawata H. Reduced stimulatory activity on prostacyclin production by cultured endothelium cells in serum from aged diabetic patients. Atherosclerosis. 1989; 75:61-6.
    143. 143.↵
      Van Ravenswaaij-Arts CM, Kollee LA, Hopman JC, Stoelinga GB, van Geijn HP. Heart rate variability. Ann Intern Med. 1993; 118:436-47.
    144. 144.↵
      Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987; 59:256-62.
    145. 145.↵
      Curb JD, Rodriguez BL, Burchfiel CM, Abbott RD, Chiu D, Yano K. Sudden death, impaired glucose tolerance, and diabetes in Japanese American men. Circulation. 1995; 91:2591-5.
    146. 146.↵
      O'Brien IA, McFadden JP, Corrall RJ. The influence of autonomic neuropathy on mortality in insulin-dependent diabetes. Q J Med. 1991; 79:495-502.
    147. 147.↵
      Sampson MJ, Wilson S, Karagiannis P, Edmonds M, Watkins PJ. Progression of diabetic autonomic neuropathy over a decade in insulin dependent diabetics. Q J Med. 1990; 75:635-46.
    148. 148.↵
      Ewing DJ, Campbell IW, Clarke BF. Mortality in diabetic autonomic neuropathy. Lancet. 1976; 1:601-3.
    149. 149.↵
      Rollins MD, Jenkins JG, Carson DJ, McClure BG, Mitchell RH, Iman SZ. Power spectral analysis of the electrocardiogram in diabetic children. Diabetologia. 1992; 35:452-5.
    150. 150.↵
      Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halter JB, Ensinck JW. et al. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care. 1984; 7:447-53.
    151. 151.↵
      Malpas SC, Maling TJ. Heart-rate variability and cardiac autonomic function in diabetes. Diabetes. 1990; 39:1177-81.
    152. 152.↵
      Bernardi L, Ricordi L, Lazzari P, Solda P, Calciati A, Ferrari MR, et al. Impaired circadian modulation of sympatovagal activity in diabetes. A possible explanation for altered temporal onset of cardiovascular disease. Circulation. 1992; 86:1443-52.
    153. 153.↵
      Zarich S, Waxman S, Freeman RT, Mittleman M, Hegarty P, Nesto RW. Effect of the autonomic nervous system dysfunction on the circadian pattern of myocardial ischemia in diabetes mellitus. J Am Coll Cardiol. 1994; 24:956-62.
    154. 154.↵
      Kendall MJ, Lynch KP, Hjalmarson A, Kjekshus J. β-blockers and sudden cardiac death. Ann Intern Med. 1995; 123:358-67.
    155. 155.↵
      Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O'Keefe J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty In Myocardial Infarction Study Group. N Engl J Med. 1993; 328:673-9.
    156. 156.↵
      Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, Suryapranata H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med. 1993; 328:680-4.
    157. 157.↵
      Gibbons RJ, Holmes DR, Reeder GS, Bailey KR, Hopfenspirger MR, Gersh BJ. Immediate angioplasty compared with administration of a thrombolytic agent following by conservative treatment for myocardial infarction. The Mayo Coronary Care Unit and Catheterization Laboratory Groups. N Engl J Med. 1993; 328:685-91.
    158. 158.↵
      Ribeiro EE, Silva LA, Carneiro R, D'Oliveira LG, Gasquez A, Amino JG, et al. Randomized trial of direct coronary angioplasty versus intravenous streptokinase in acute myocardial infarction. J Am Coll Cardiol. 1993; 22:376-80.
    159. 159.↵
      Every NR, Parsons LS, Hlatky M, Martin JS, Weaver WD. A comparison of thrombolytic therapy with primary coronary angioplasty for acute myocardial infarction. N Engl J Med. 1996; 335:1253-60.
    160. 160.↵
      Aronson D, Bloomgarden Z, Rayfield EJ. Potential mechanisms promoting restenosis in diabetic patients. J Am Coll Cardiol. 1996; 27:528-35.
    161. 161.↵
      Moliterno DJ, Califf RM, Anderson K, Weisman HF, Topol EJ. Special considerations in diabetics receiving platelet IIb/IIIa antagonists during coronary interventions. Results from the EPIC Trial [Abstract]. J Am Coll Cardiol. 1995; 25:155A.
    162. 162.↵
      Comparison of bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. N Engl J Med. 1996; 335:217-25.
    163. 163.↵
      Collaborative overview of randomised trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ. 1994; 308:81-106.
    164. 164.↵
      DiMinno G, Silver MJ, Cerbone AM, Murphy S. Trial of repeated lowdose aspirin in diabetic angiopathy. Blood. 1986; 68:886-91.
    165. 165.↵
      Gundersen T, Kjekshus J. Timolol treatment after myocardial infarction in diabetic patients. Diabetes Care. 1983; 6:285-90.
    166. 166.↵
      Malmberg K, Herlltz J, Hjalmarson A, Ryden L. Effects of metoprolol on mortality and late infarction in diabetics with suspected acute myocardial infarction. Retrospective data from two large studies. Eur Heart J. 1989; 10:423-8.
    167. 167.↵
      Kjekshus J, Gilpin E, Cali G, Blackey AR, Henning H, Ross J Jr. Diabetic patients and β-blockers after acute myocardial infarction. Eur Heart J. 1990; 11:43-50.
    168. 168.↵
      Tse WY, Kendall M. Is there a role for β-blockers in hypertensive diabetic patients? Diabet Med. 1994; 11:137-44.
    169. 169.↵
      Zuanetti G, Latini R, Maggioni AP, Santoro L, Franzosi M, Tognoni G. Prognosis of diabetic patients after myocardial infarction: effect of early treatment with ACE-inhibitors. The GISSI-3 Investigators [Abstract]. J Am Coll Cardiol. 1996; 27:319A.
    170. 170.↵
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344:1383-9.
    171. 171.↵
      Bloomgarden ZT. Cardiovascular disease and diabetes: issues raised at the European Association for the Study of Diabetes annual meeting. Diabetes Care. 1996; 19:187-90.
    172. 172.↵
      Levine GN, Keaney JF Jr, Vita JA. Cholesterol reduction in cardiovascular disease. Clinical benefits and possible mechanisms. N Engl J Med. 1995; 332:512-21.
    173. 173.↵
      Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non–insulin-dependent diabetes mellitus. J Clin Invest. 1996; 97:22-8.
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    1. Ann Intern Med February 15, 1997 vol. 126 no. 4 296-306
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