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Dysglycemia and Acute Myocardial Infarction

The Role of Echocardiography^_*

Cleveland Clinic, Cleveland, Ohio

Key Words: myocardial infarction • glucose • echocardiography • heart failure • prognosis • diabetes

The reduced life span in diabetic patients is largely caused by the consequences of atherosclerosis (1). Not only do these patients have a risk for future myocardial infarction (MI) or cardiovascular death that is at least similar to nondiabetic patients with established coronary artery disease (2–4), diabetes itself also confers a significant adverse prognosis after acute coronary syndromes (5). In addition, elevated glucose and glycated hemoglobin levels on admission—regardless of diabetic status—have repeatedly been shown to be independent prognostic determinants of both in-hospital and long-term outcome in patients with MI (6–8), as for every 18 mg/dl increase in glucose level there appears to be a 4% increase in mortality in nondiabetic patients (9).

Even though up to 50% of patients hospitalized with acute MI may develop a hyperglycemic response, cardiologists are cautioned not to disregard a disturbed glucometabolic state as simply an epiphenomenon of acute illness, as shown again in this issue of iJACC in a study by Høfsten et al. (10). The investigators evaluated the impact of abnormal glucose metabolism assessed by an oral glucose tolerance test on outcome in 203 consecutive patients with acute MI. They then correlated glucose metabolism with echocardiographic markers of systolic and diastolic function obtained shortly after admission (a median of 2 days after the diagnosis of acute MI). The investigators were able to demonstrate a linear relationship between progressive degrees of glucose intolerance and echocardiographic indexes of both systolic (ejection fraction) and diastolic (E/e', E-wave deceleration time and left atrial size) function. The indexes used have previously been shown to carry important prognostic information in post-infarct patients. The same linear relationship was seen between dysglycemia and serum N-terminal pro-B-type natriuretic peptide levels taken on the same day or shortly after the oral glucose tolerance test. Subsequently, a clear association was found between the degree of dysglycemia and outcome in terms of survival and readmission for congestive heart failure at a follow-up ranging from 12 to 44 months. Interestingly, a glucometabolic state during hospitalization was still predictive of adverse events after adjusting for left ventricular (LV) systolic and diastolic function, leading the investigators to conclude that prognosis after MI in hyperglycemic patients is not solely attributable to LV dysfunction.

This is another study highlighting the link between diabetes and post-MI heart failure. Importantly, the investigators demonstrate a linear increase in ventricular dysfunction and plasma N-terminal pro-B-type natriuretic peptide levels with increasing degrees of dysglycemia. How can this correlation be explained?

Many conditions specific to the heart in diabetes can affect post-infarct ventricular function (11,12). Although the heart uses free fatty acids as its major energy source under aerobic conditions, glucose oxidation is more efficient, as it requires less oxygen per molecule of adenosine triphosphate generated. MI will therefore normally result in enhanced glycogenolysis and increased glucose uptake by translocation of GLUT-4 receptors to the sarcolemma (13). Despite their hyperglycemia, glucose is relatively unavailable for diabetics under anaerobic conditions because of depressed levels of the GLUT-4 transporter protein (14), which may lead to more extensive ischemic damage. Insulinopenia is also associated with increased lipolysis, elevated levels of plasma free fatty acids, and increased fatty acid oxidation as glycolysis and glucose oxidation are suppressed. Free fatty acid metabolism in this setting may further lead to higher production of lactate and hydrogen ions that have an adverse effect on cardiac contractility and diastolic function and reduce the heart's threshold for arrhythmias (15). Increased production of oxygen-derived free radicals and activation of pro-inflammatory transcription factors may contribute to the impaired microcirculatory function and platelet hyper-reactivity that have been shown to have deleterious effects during ischemia and reperfusion in patients with hyperglycemia (12).

Some deficiencies of the current study should be noted. First, there were some important differences between the enrolled normal and dysglycemic patients. Not only were patients with abnormal glucose metabolism older with more frequent hypertension and atrial fibrillation (factors known to have a profound effect on the diastolic variables that were measured) but they also less frequently underwent revascularization, which undoubtedly influenced remodeling in this early phase. In addition, we do not know whether there were differences in infarct size (peak creatine kinase levels), location of the infarct (left anterior descending territory?), transmural extent of necrosis (or the proportion of ST-segment elevation MIs vs. non–ST-segment elevation MIs) and the symptom-to-balloon times. Even though the investigators adjusted for some of these factors, it is uncertain whether differences in glucose metabolism alone account for the differences in LV function seen by echocardiography in their study.

Some methodological issues should also be acknowledged. The major predictor of post-MI heart failure in the general population is LV remodeling, a process involving expansion of the infarct-related segments with subsequent ventricular dilation and hypokinesis of the noninfarcted regions. Although ejection fraction is a universally recognized parameter for systolic function, analysis of end-systolic volume would have been useful as the issue of remodeling is clearly of interest in their study. Given the clear trend in their study for patients with dysglycemia to more frequently have had prior MIs (potentially underestimated due to the frequent silent infarctions in this population), it would have been interesting to know whether there was a difference in end-systolic volumes between* normoglycemic and dysglycemic subjects in the early phase after MI, as this parameter has been shown to be closely connected with early management (16). Larger samples of patients hospitalized with acute MI have previously shown that admission glucose levels are independently associated with a much greater increase in the risk of death, particularly in patients without an antecedent history of diabetes (8,9). Høfsten et al. (10) equally suggest that differences in ventricular function alone do not account for the increased rates of heart failure and mortality commonly observed in diabetics with MI. Can we make that conclusion based on the data provided by these investigators? Again, it would have been interesting to know why a significant proportion of patients with diabetes did not have coronary angiography or revascularization. Besides more extensive distal vessel disease, these patients may have had more advanced renal insufficiency, peripheral vascular disease, cerebrovascular disease, or other types of comorbidities. All these variables are typically related to the glucometabolic state and have important prognostic power but were apparently not entered in the multivariable analysis. Unfortunately, the investigators did not collect follow-up echocardiographic data, which would have enabled them to make more definite conclusions about the differential impact of remodeling, diastolic indexes, and the presence of a (pre-)diabetic state on outcome in post-infarct patients. In that respect, it is interesting to compare this study with the data of Carrabba et al. (17), who addressed the very same question in a series of 325 consecutive patients (including 45 diabetics) with acute MI, all successfully treated with primary angioplasty. Despite some animal studies suggesting insulin resistance and diabetes cause a greater degree of LV dysfunction and accelerated LV remodeling after coronary artery ligation (18), these investigators did not observe a greater propensity for LV remodeling in patients with diabetes. At 6-month follow-up, similar patterns of changes in global and regional systolic function were found by 2-dimensional echocardiography in diabetic versus nondiabetic patients. Carrabba et al. (17) did not perform oral glucose tolerance testing nor did they use the World Health Organization criteria for whole blood glucose levels to account for differences in the degree of glucometabolic dysregulation. Contrary to the findings of Høfsten et al., however, these investigators found a similar pattern of diastolic dysfunction at baseline between diabetic and nondiabetic patients. Although the presence of heart failure was primarily related to the development of LV remodeling in the nondiabetics, diabetes itself (and not remodeling!) was independently associated with the development of late-onset heart failure in the diabetic population. It is noteworthy that in the subgroup of patients who developed heart failure at 6 months, diabetic subjects demonstrated more advanced diastolic dysfunction than nondiabetic subjects, suggesting that the persistence or development of diastolic dysfunction after the acute phase of acute MI may significantly contribute to the development of heart failure in patients with diabetes.

The mechanisms by which diabetes may trigger a series of maladaptive stimuli leading to myocardial fibrosis and collagen deposition (even in the absence of coronary artery disease) are incompletely understood and largely reviewed elsewhere (18,19), but the findings by both Høfsten et al. (10) and Carrabba et al. (17) suggest that further prospective studies evaluating serial changes of diastolic variables in a larger sample of patients with different degrees of dysglycemia are needed to better understand the impact of the "diabetic factor" on post-infarct heart failure.

Once again, the association between in-hospital hyperglycemia and prognosis has been demonstrated. The available literature seems to suggest that elevated blood glucose with acute MI may in fact be a mediator of adverse outcomes rather than simply an innocent marker of acute illness, released by a series of counter-regulatory hormones in response to cardiovascular stress (12). However, there is still much uncertainty with respect to the optimal management of hyperglycemia immediately after acute MI (20). The concept of a cardioprotective cocktail (glucose-insulin-potassium [GIK]) to promote glycolysis, reduce free fatty acid concentrations, and stabilize membranes by restoring potassium influx in ischemic cardiomyocytes has been the focus of numerous clinical trials (15). The results of these studies have been variable, and therefore GIK is at present not recommended as a standard adjunctive treatment with reperfusion. Likely explanations for the negative results in some of these trials are the fixed-dose cocktails without adjustments in the amount of intravenous volume or glucose administered. In those studies, the potential benefit of GIK may have been offset by the development of fluid overload or exacerbation of hyperglycemia early in the course of myocardial injury.

Apart from the GIK strategy, there are definitely a number of arguments favoring tight glycemic control in the coronary care unit (12). Although a target blood glucose level as close as possible to 110 mg/dl is sometimes advocated, one should be cautious in extrapolating the results of other trials showing beneficial effects of aggressive insulin therapy in the intensive care unit (21), as patients with acute MI likely represent a completely different study population. Of concern are 2 observational studies that showed an association between the development of hypoglycemia during hospitalization for acute MI and an increased risk of death (22,23). The optimal glycemic control in these patients after admission is another issue that remains highly uncertain. Two recent large randomized trials investigating the effect of intensive glucose lowering in type 2 diabetes patients with established cardiovascular disease or additional cardiovascular risk factors failed to demonstrate a significant effect on the risk of major macrovascular events and even identified an increase in mortality with such an approach (24,25). Ongoing trials will hopefully provide additional clarification (26–29).

In the meantime, what is the role of cardiac imaging? Høfsten et al. (10) have shown that the link between abnormalities in glucose metabolism and cardiac function provides a fruitful area for future research. To date, the main echocardiographic findings in patients with diabetes or diabetic cardiomyopathy seemed aspecific and rather insensitive: evidence of cardiac hypertrophy along with some degree of diastolic dysfunction. Some studies showed that a decrease in longitudinal function detected by tissue Doppler or strain imaging may be a more sensitive sign of early or subclinical myocardial dysfunction due to diabetes (30,31). The concept of a linear relationship between the degree of dysglycemia and the degree of cardiac dysfunction definitely deserves further attention. Are the current diagnostic capabilities of echocardiography really accurate enough to detect small differences in systolic and diastolic function between patients with different degrees of dysglycemia (also outside the context of acute MI)? How do the diastolic characteristics change over time in post-infarct patients with different degrees of glucose intolerance? To what extent can we detect the effects of optimized glucose control in diabetic patients with and without coronary artery disease? These and other questions remain to be answered.

	Footnotes

 
^_* Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.

^_* Reprint requests and correspondence: Dr. James D. Thomas, Cardiovascular Medicine, Section of Imaging, Cleveland Clinic, Cleveland, Ohio 44195 (Email: THOMASJ{at}ccf.org).

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