Heart and Metabolism

Metabolic imaging of myocardial stunning

Sharmila Dorbala, Marcelo F. Di Carli*
Division of Nuclear Medicine, Department of Radiology at Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass, USA
Correspondence: Dr Marcelo F. Di Carli, Brigham and Women’s Hospital, Division of Nuclear Medicine, 75 Francis Street, Boston, MA 02115, USA. Tel: +1 617 7326291, fax: +1 617 5826056, e-mail: mdicarli@partners.org

Abstract

Myocardial stunning refers to a reversible state of regional contractile dysfunction that can occur after restoration of coronary blood flow following a brief episode of ischemia despite the absence of necrosis. Stunned myocardium can also result from repeated ischemic episodes caused by increases in oxygen demand in the setting of chronic coronary artery disease. During acute myocardial ischemia, there is a sharp decline in free fatty acid oxidation that is followed by a markedly increased rate of glucose utilization. However, soon after reperfusion, glucose utilization in stunned myocardium is reduced compared with that in normal regions. This relative reduction in glucose uptake in stunned regions is usually restored to control levels within a week after reperfusion, depending on the severity and duration of the initial flow deficit. These abnormalities in glucose metabolism can be assessed noninvasively with the glucose analog 18F-deoxyglucose and SPECT or PET imaging. These metabolic alterations present in stunning appear different from those typically associated with hibernation. Thus, this different metabolic adaptation may prove useful for the noninvasive characterization of infarcted and viable (stunned and/or hibernating) myocardium in patients with severe left ventricular dysfunction who are being considered for potential myocardial revascularization. n Heart Metab. 2003;19:18–22.

Keywords: Myocardial stunning, metabolic imaging, glucose utilization, free fatty acid oxidation,
18 F-deoxyglucose, PET, myocardial hibernation.

Introduction
Myocardial stunning refers to a reversible state of regional contractile dysfunction that can occur after restoration of coronary blood flow following a brief episode of ischemia despite the absence of necrosis [1]. It is considered a form of reperfusion injury, whereby reintroduction of oxygen after a period of ischemia induces a transient calcium overload that damages the contractile apparatus. The postischemic contractile abnormality is fully reversible provided that recurrent ischemia (followed by stunning) does not occur and suf-
ficient time is allowed for the myocardium to recover. Stunned myocardium has been described in animals [2] and subsequently documented in humans [1], where it is considered to play a role in the prolonged contractile dysfunction seen in patients undergoing reperfusion therapy for acute myocardial infarction, following attacks of unstable angina, and in some patients with exercise-induced ischemia. Although commonly regarded as an acute phenomenon, stunned myocardium may also occur in patients with chronic coronary stenoses who experience recurrent episodes of ischemia (symptomatic or asymptomatic) in the same territory (so-called repetitive stunning) [3]. The latter mechanism is probably the most common form of stunning in patients with chronic left ventricular dysfunction due to coronary artery disease and will be the focus of this review.

Metabolic abnormalities during ischemia-reperfusion
Metabolic alterations during myocardial ischemia
A reduction in oxygen supply or an inadequate blood flow response to increased demand is associated with an almost instantaneous decline or loss of contractile function. The inadequate oxygen supply or supply-demand imbalance causes profound metabolic alterations. There is a sharp decline in free fatty acid oxidation, which is followed by an increased flux of glucose through the glycolytic pathway [4]. The increased glycolytic flux during ischemia appears to involve a specific stimulation of membrane transport of glucose through the rapid translocation of glucose transporters (GLUT4 and GLUT1 isoforms) and an increased activity of key glycolytic enzymes [5, 6]. Such increases in glucose uptake during acute ischemia have been demonstrated in experimental animals and in patients with chronic coronary artery disease [4, 7].

Metabolic changes post reperfusion
Several metabolic abnormalities have been described in stunned myocardium, including alterations in glucose as well as in fatty acid kinetics. In experimental models, myocardial stunning induced by a single or multiple brief episodes of low-flow ischemia has been consistently associated with a reduction in myocardial glucose utilization (approximately 30% compared with controls), at least early after reperfusion [8–12]. Although in some studies glucose utilization was shown to increase after 24 hours of reperfusion, such changes have not been universally observed. For example, Buxton et al [13] showed regional increases in fluorodeoxyglucose uptake in stunned myocardium 24 hours after reperfusion. In contrast, we have shown a prolonged reduction of glucose utilization in stunned myocardium subjected to multiple cycles of ischemia and reperfusion (Figure 1).

Figure 1. PET images of a dog heart in short-axis views obtained at corresponding midventricular
levels obtained post reperfusion after four, 5-minute LAD coronary occlusions, each followed by 5
minutes of reperfusion. The images are oriented with the anterior wall at the top, the inferior wall at the bottom, the interventricular septum to the left, and the lateral wall to the right. Each image is scaled to its own maximum. Images of blood flow (left column) were obtained with 13N-ammonia and images of glucose metabolism (middle column) with 18F-deoxyglucose. Images of oxidative metabolism (MVO2) (right column) were obtained with 11C-acetate; the early phase denotes delivery of the tracer to the myocardium while the late phase represents regional washout of the tracer through the tricarboxylic acid cycle (oxidation). (Top panel): Depicts corresponding midventricular short-axis sections of regional blood flow, glucose and MVO2 4 hours post reperfusion. The flow images (left) demonstrate near-normal perfusion in the stunned regions (ie, anterior and anteroseptum). However, stunned regions demonstrated reduced glucose utilization (arrow) and slow clearance of 11C-acetate (impaired oxidation) relative to normal myocardium (lateral wall). (Middle panel): One day post reperfusion. Myocardial perfusion in stunned myocardium is near-normal, glucose uptake (arrow) remains depressed and the MVO2 is still lower (arrow) than in normal myocardium. (Bottom panel): One week after reperfusion. Blood flow, glucose uptake, and MVO2 are largely homogenous. Wall motion and metabolism demonstrated a parallel recovery with time. (Reproduced from Di Carli et al [12] with permission from the Society of Nuclear Medicine.)

These apparently contradictory results appear to be more related to differences in experimental design than to physiologic discrepancies. Indeed, when studies are performed under fasting conditions, which reduces glucose utilization by normal myocardium, stunned regions show a relative increase in glucose uptake. However, when such changes are evaluated during standardized substrate availability (as assessed by the hyperinsulinemic-euglycemic clamp) to reduce the normal physiologic inhomogeneity in glucose uptake in normal myocardium during fasting conditions [9, 13], relative glucose uptake appears reduced in stunned myocardium. The acute reduction in glucose utilization appears to improve gradually to control levels between 48 hours and 1 week after reperfusion. The relative reduction in glucose uptake in postischemic stunning appears to relate to the severity and duration of the preceding flow deficit. Thus, stunned myocardium can demonstrate normal or a relative reduction in glucose uptake.
Human studies also suggest that similar metabolic alterations can be seen in some patients with ischemic left ventricular dysfunction. Perrone-Filardi et al [14] observed decreased glucose utilization in dysfunctional myocardial regions with normal resting blood flow. Interestingly, they also reported that 63% of those regions had reversible perfusion defects on stress thallium imaging, suggesting that stunning (caused by transient but repetitive ischemic episodes) was the underlying mechanism. We have shown similar findings in 15 patients with coronary artery disease and severe left ventricular dysfunction, in whom we evaluated the clinical, functional, and arteriographic correlates of myocardial regions showing decreased glucose utilization and normal blood flow (so-called reversed mismatch) on PET imaging [15]. All these regions showed severe wall motion abnormalities despite relatively normal resting blood flow. Consistent with the results of Perrone-Filardi et al, these dysfunctional regions showed a consistent reduction in glucose uptake (~30% lower than normal) and oxidative metabolism (~15% lower than normal) (Figure 2). Coronary angiography demonstrated highly significant stenoses in the coronary arteries supplying these segments. Thus, this perfusion-contraction “uncoupling” with decreased metabolism agrees with our experimental observations post reperfusion and suggests that it probably reflects the metabolic correlate of “repetitive” stunning.

Figure 2. PET images of a human heart in short-axis views obtained in corresponding midventricular
levels before and after coronary artery bypass surgery (CABG). The images have the same orientation as those of Figure 1. Images of blood flow (left column) were obtained with 13N-ammonia and images of glucose metabolism (right column) with 18F-deoxyglucose. (Top panel): A patient with three-vessel coronary artery disease and a severe wall motion abnormality in the anterior and septal walls. The resting flow images (left) demonstrate a small perfusion defect in the anterior wall and near-normal perfusion in the interventricular septum. A 99mTc sestamibi perfusion scan (not shown) demonstrated exercise-induced ischemia in these regions. Glucose metabolism in the anterior and septal walls is markedly reduced compared with normal myocardium (lateral wall). (Bottom panel): Same patient 4 weeks after CABG. Blood flow and glucose metabolism are largely homogenous.
A 2-D echocardiogram post CABG demonstrated improvement in systolic wall motion in the anterior and septal regions.

Potential mechanisms of metabolic alterations
Oxidation of all major substrates, including glucose, is depressed post reperfusion, andnonglucose substrates are the preferred substrate for oxidative metabolism [16, 17]. Indeed, previous studies have demonstrated that reperfused myocardium has a strong preference for and aerobic use of fatty acids during reflow [16, 17]. Further, carbohydrate utilization for oxidative metabolism during reflow is significantly reduced [8, 18]. One possible mechanism for the reduced glucose uptake in reperfused tissue may be that shifting levels of metabolites following ischemia and reperfusion may have decreased the activity of key regulatory enzymes of the glycolytic pathway [19]. Another possibility may be that multiple cycling of ischemia and reperfusion or their metabolic byproducts could have decreased glucose uptake by decreasing the number of insulin receptors or their sensitivity to insulin [20], or by altering the process in which insulin signals GLUT4 translocation [21, 22], or both.

Clinical implications
The experimental and clinical data presented above suggest that the metabolic alterations present in stunning are different from those typically associated with hibernation. Hibernating myocardium appears to show increased glucose uptake in areas with reduced blood flow at rest, so-called perfusion-metabolism mismatch on PET imaging. In contrast, stunned myocardium caused by multiple cycles of ischemia-reperfusion (as it may occur in patients with chronic coronary artery disease) may show normal or reduced glucose uptake in areas with preserved blood flow at rest, so-called reverse mismatch on PET imaging.
This different metabolic adaptation may prove useful for the noninvasive characterization of infarcted and viable (stunned and/or hibernating) myocardium in patients with severe left ventricular dysfunction who are being considered for potential myocardial revascularization.

REFERENCES

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