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15 February 1997 | Volume 126 Issue 4 | Pages 296-306
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, ß-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.
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). REVIEW
Mechanisms Determining Course and Outcome of Diabetic Patients Who Have Had Acute Myocardial Infarction
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.
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].
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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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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].
Course of Acute Myocardial Infarction in the Thrombolytic Era
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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].
Long-Term Prognosis
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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).
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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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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 ß-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.
Treatment of Diabetic Patients Who Have Had Acute Myocardial Infarction
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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].
ß-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 ß-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 ß1-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, ß-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.
Author and Article Information
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