Myocardial Blood Flow, Glucose Uptake, and Recruitment of Inotropic Reserve in Chronic Left Ventricular Ischemic Dysfunction
Implications for the Pathophysiology of Chronic Myocardial Hibernation
Background Previous work has documented that dysfunctional noninfarcted collateral-dependent myocardium, a condition typical of myocardial hibernation, exhibited almost normal resting perfusion. The present study was designed to test whether these observations could be extended to unselected patients with chronic dysfunction and a previous infarction.
Methods and Results Dynamic positron emission tomographic imaging with [13N]ammonia and [18F]fluorodeoxy-glucose (FDG) to assess myocardial perfusion and glucose uptake was performed in 39 patients with chronic anterior wall dysfunction undergoing coronary revascularization. Left ventricular function was evaluated by echocardiography before (at rest and during low-dose dobutamine infusion) and 5 months after revascularization. At follow-up, wall motion was improved in 24 patients and unchanged in 15 patients. Before revascularization, absolute myocardial blood flow was higher (84±27 versus 60±26 mL·min−1·100 g−1, P=.007) in reversibly compared with persistently dysfunctional segments. In segments with reversible dysfunction, values of myocardial blood flow were similar to those in the remote segments of the same patients or in anterior segments of normal volunteers. During glucose clamp, FDG uptake was higher (69±17% versus 49±18%, P<.01) but myocardial glucose uptake was not different (38±20 versus 29±19 μmol·min−1·100 g−1, P=NS) in reversibly compared with persistently dysfunctional segments. A flow-metabolism mismatch was present in 18 of 24 reversibly injured but absent in 10 of 15 persistently dysfunctional segments. With dobutamine, wall motion improved in 17 of 24 reversibly dysfunctional segments and did not change in 13 of 15 segments with persistent dysfunction.
Conclusions This study indicates that chronic but reversible ischemic dysfunction is associated with almost normal resting myocardial perfusion, with maintained FDG uptake, and with recruitable inotropic reserve. These data support the contention that chronic hibernation is not the consequence of a permanent reduction of transmural myocardial perfusion at rest.
Chronic reversible left ventricular ischemic dysfunction, a condition often referred to as “myocardial hibernation,” was postulated to represent an adaptive response of the myocardium to chronic underperfusion.1 2 Support for this hypothesis arises from the clinical observation that many reversibly dysfunctional segments display reduced uptake of radiolabeled flow tracers on perfusion imaging. Accordingly, in his original description of the condition, Rahimtoola2 postulated that myocardial hibernation resulted from a “relatively uncommon response to reduced myocardial blood flow at rest whereby the heart downgrades its myocardial function to the extent that blood flow and function are once again in equilibrium, and as a result, neither myocardial necrosis or ischemic symptoms are present.” This concept has recently been challenged by studies in patients with dysfunctional albeit noninfarcted collateral-dependent myocardium.3 In these patients, quantitative measurements of absolute levels of myocardial perfusion by PET failed to demonstrate any significant reduction of resting myocardial perfusion despite markedly reduced contraction. Interestingly, little myocardial perfusion reserve was preserved in the dysfunctional collateral-dependent segments, which led to the hypothesis that repetitive intermittent episodes of ischemia followed by stunning could have caused persistent dysfunction.3
Although existing data suggest that chronic underperfusion does not account for the regional dysfunction of patients with noninfarcted collateral-dependent myocardium, little is known about absolute levels of myocardial blood flow in unselected patients with chronic but reversible left ventricular ischemic dysfunction and a past history of myocardial infarction. Accordingly, the present study was aimed at delineating the flow and metabolic correlates of the reversibility of left ventricular ischemic dysfunction in patients with chronic coronary artery disease and at testing the hypothesis that, even in unselected patients with chronic but reversible dysfunction, regional contraction is disproportionately reduced compared with resting perfusion. An additional aim was to assess whether, like stunned4 and short-term hibernating5 myocardium, chronically but reversibly dysfunctional myocardium has recruitable inotropic reserve on stimulation with catecholamines.
Thirty-nine consecutive patients (34 men and 5 women; mean age, 60±9 years; range, 39 to 75 years) with chronic coronary artery disease and left ventricular dysfunction undergoing coronary revascularization served as subjects in the present study. Patients were considered eligible for inclusion in the study if they had (1) severe dysfunction in the anterior wall at contrast cineventriculography; (2) proximal LAD disease suitable for CABG or PTCA; (3) revascularization of all dysfunctional segments; (4) absence of perioperative or periprocedural myocardial infarction, defined as new-onset Q wave on the ECG and/or a postrevascularization increase in plasma cardiac enzyme activity; and (5) adequate transthoracic echocardiograms to assess wall motion in every segment of the left ventricle. Twenty-three patients had sustained a previous anterior Q-wave myocardial infarction, the most recent occurring 13 days before inclusion in the study. Seven patients had type II diabetes mellitus, among whom six were treated with sulfonylurea and one with insulin (70 IU/d SC). The study protocol was approved by the Ethical Committee of our institution, and no complications resulted from any part of the study. Six nonsmoking normal male volunteers (mean age, 24±3 years; range, 21 to 28 years) served as control subjects for the measurement of absolute myocardial blood flow and glucose uptake.
Selective coronary arteriography was performed from the femoral approach in every patient at an average of 4 days before the PET study. The severity of coronary stenoses was graded visually by two observers (W.W., J.-L.J.V.) blinded to the results of the PET studies and to the functional outcome of the patients. Significant coronary artery disease was defined as a >75% luminal diameter stenosis. Eighteen patients showed complete occlusion of the proximal LAD. The remaining 21 patients had a severe proximal stenosis of this vessel. Six patients had isolated LAD disease; 11 patients had two-vessel disease, of whom 6 had right and 5 circumflex coronary artery disease; and 22 patients had three-vessel disease.
Postoperative angiographic follow-up to assess the adequacy of revascularization was prospectively requested in every patient but could be obtained in only 22 of them. The reasons why the other 17 patients did not have follow-up angiograms were always refusal by the patient or by the referring cardiologist. As judged from the results of this follow-up angiographic study, adequate revascularization of the initially dysfunctional segments was achieved in all 17 patients undergoing CABG and in 3 of 5 patients undergoing PTCA (2 patients had moderate restenosis [50% to 75% luminal diameter stenosis] at the site of an initially successful PTCA, 1 of whom did not improve function at follow-up). It is noteworthy that all 3 PTCA patients who refused to undergo recatheterization improved function at follow-up.
Two-dimensional echocardiograms were obtained at rest, before and 5.0±1.9 months after revascularization, and during the infusion of dobutamine. Images from the parasternal long-axis and short-axis and apical four- and two-chamber views were digitized on line (Image Vue, Nova Microsonics) in a quad-screen, cineloop format and stored on 512-byte-per-sector rewritable optical disks. Regional function was interpreted in 16 myocardial segments (basal, midventricular, and apical levels of the septum and lateral, anterior, and inferior walls; and basal and midventricular levels of the anteroseptal and posterior walls) and was defined as normal (1), hypokinetic (2), or akinetic (3), as previously described.6 Normal wall motion was defined as ≥5 mm of endocardial excursion and obvious systolic wall thickening. Hypokinesis was defined as <5 mm of endocardial excursion and reduced wall thickening. Akinesis was defined as near absence of endocardial excursion or thickening. A wall motion score for the segments supplied by the LAD was calculated by summing up the scores of the midanterior, lateroapical, and anteroapical segments. End-systolic and end-diastolic volumes and LVEFs were calculated by use of a modified Simpson's method.
All patients underwent dobutamine echocardiography during the same hospital admission as for cardiac catheterization. They were allowed to take their prescribed medications with the exception of β-blockers, which were withdrawn for at least 24 hours before the test. Before the infusion was started, a clinical history was recorded, a rest ECG and an echocardiogram were obtained, and a venous line was secured. Dobutamine was then infused in 3-minute dose increments from 5 to 10 μg·kg−1·min−1. Digitized echocardiographic recordings were obtained at the end of each step. During dobutamine infusion, the ECG was monitored continuously by use of the orthogonal Frank lead system.
A normal segmental response to dobutamine was defined as a progressive enhancement in regional contraction during stress. Ischemia was identified by a stress-induced wall motion abnormality. Dysfunctional myocardium at baseline was considered to be responsive to dobutamine if wall motion improved by at least one full grade in any of the three segments assigned to the LAD or to be nonresponsive if wall motion did not improve with dobutamine. Similarly, dysfunctional myocardium at baseline was considered to have improved functionally after revascularization if wall motion decreased by one full grade in any of the three segments assigned to the LAD after revascularization or to remain persistently dysfunctional if no change was noted.
Positron Emission Tomography
Tomographic acquisitions were obtained with the ECAT III tomograph (CTI Inc) in 24 patients and with the ECAT EXACT HR tomograph (CTI) in the remaining 15 patients and in the normal volunteers. All patients and volunteers were studied during hyperinsulinemic euglycemic glucose clamp, as described previously by De Fronzo et al7 and by Knuuti et al.8 Briefly, insulin was infused at an initial rate of 16 mU·min−1·m−2 for 4 minutes, then lowered to 8 mU·min−1·m−2 for another 3 minutes, and maintained thereafter at a constant rate of 4 mU·min−1·m−2. Glucose was coadministered, starting 4 minutes after the beginning of the insulin infusion. Glucose infusion rates were adapted to maintain glucose plasma levels between 75 and 95 mg/dL throughout the study. Arterial blood samples were regularly withdrawn from the radial artery and analyzed on a Beckman glucose analyzer type II. Samples for insulin and free fatty acids were obtained at baseline and at the end of the glucose clamp.
Myocardial perfusion was assessed with [13N]ammonia and glucose metabolism with FDG. The tracers were injected intravenously over 30 seconds by means of an infusion pump (model 351, Sage Instruments). One dynamic midventricular transaxial study per patient was analyzed for dynamic imaging. For acquisitions performed with the ECAT EXACT HR, this slice was obtained by summing four smaller slices of 3.2 mm to obtain a slice width comparable to that from the ECAT III (15 mm). Three large irregular volumes of interest were assigned to each image of the left ventricular myocardium, and a circular volume of interest was assigned to the center of the left ventricular blood pool. One of the volumes of interest encompassed the interventricular septum, another the anterior wall, and the remaining the lateral free wall of the left ventricle. The lateral free wall was considered to be the remote normal segment if no dysfunction was present on two-dimensional echocardiograms. Counts were corrected for partial-volume and spillover effects by use of a specially developed Monte Carlo simulation,9 as well as for dead-time losses. The volumes of interest drawn on the FDG study were copied onto the [13N]ammonia study. Identical placement of the volumes of interest on all dynamic studies was ascertained, and manual correction for patient movement was done if necessary.
[13N]Ammonia and [18F]FDG cross-sectional images were analyzed with an operator-interactive computer program using circumferential profiles.9 The program normalizes 18F and 13N counts within a given myocardial cross section to maximal activity in the same ventricular slice. Each cross section of the left ventricle was divided into serial 10° segments. Activity within each segment was expressed in relative terms (reported as 18F and 13N uptake) as percentage of maximal activity. A pattern of flow-metabolism “mismatch” was considered to be present when the relative ammonia uptake was lower than the minimal range of the normal volunteers (70%) and when the ratio of FDG to ammonia exceeded 1.2.9 For this analysis, both FDG and ammonia activity were normalized to peak [13N]ammonia activity.
Quantification of Tomographic Data
Tomographic data were quantified as previously described.9 10 Regional myocardial perfusion was quantified by use of a previously validated three-compartment model.10 No correction for circulating metabolites was applied. Patlak graphic analysis was used to estimate myocardial glucose uptake.9 Glucose extraction was calculated as the ratio of regional glucose uptake and myocardial blood flow.11 12 Table 1⇓ provides definitions and calculation methods for the various parameters of glucose metabolism.
Continuous variables were expressed as mean±SD. Groups were compared for categorical data by Fisher's exact test or the χ2 test, when the minimum expected cell size was >5. A Mann-Whitney rank-sum test was used to assess differences in continuous variables between patients with and without improved wall motion. One-way ANOVA was used to compare anterior segments that improved wall motion with those that did not, with remote segments, and with segments from normal volunteers. Post hoc comparisons were made by Scheffe´'s test. All tests were two-sided, and a probability value of <.05 was considered statistically significant.
Similar values for absolute regional myocardial blood flow or glucose uptake were found in the septal, anterior, and lateral regions of the normal volunteers. Absolute myocardial blood flow averaged 88±22 mL·min−1·100 g−1 in anterior and lateral segments (range, 60 to 125 mL·min−1·100 g−1). During hyperinsulinemic euglycemic glucose clamp, blood insulin levels increased significantly (from 12±4 μU/mL at baseline to 85±14 μU/mL at the end of the procedure, P<.001), plasma glucose levels remained unchanged (from 92±5 to 87±10 mg/dL, P=NS), and the arterial concentration of fatty acid decreased (from 532±205 to 132±91 μmol/L, P<.001). During clamp, myocardial glucose uptake averaged 53±11 μmol·min−1·100 g−1, ranging from 40 to 76 μmol·min−1·100 g−1, and was similar among the different myocardial regions. Glucose extraction was 0.54±0.11 μmol/mL, ranging from 0.38 to 0.69 μmol/mL.
The baseline clinical and angiographic characteristics of the study population are summarized in Table 2⇓. Subsequent to the echocardiographic and PET studies, but independent of their results, all patients underwent successful coronary revascularization. The interval from these studies to coronary revascularization averaged 53 days (range, 1 to 132 days). CABG was performed in 31 patients, using the left internal mammary artery to graft the LAD, and PTCA was performed in the remaining 8 patients. No patient had evidence of perioperative or periprocedural myocardial infarction, defined as new-onset Q waves on the ECG or an increase in plasma cardiac enzyme activity.
Effects of Coronary Revascularization on Segmental and Global Left Ventricular Function
Follow-up echocardiograms were obtained 5.0±1.9 months after the revascularization procedure. Anterior wall motion score improved after revascularization in 24 patients (from grade 8.0±1.0 to 5.7±1.6) and did not change in the other 15 patients (from grade 8.3±0.7 to 8.4±0.6). All but 2 patients with improved anterior wall motion after revascularization also had improved global left ventricular function (defined as a >5% increase in LVEF). In these 24 patients, LVEF increased from 36±11% to 48±11% (P<.002). By contrast, no significant changes were noted in the 15 patients with persistent regional dysfunction (from 29±7% to 28±9%, P=NS). Although baseline anterior wall motion score was similar among patients with and without improved wall motion after revascularization, LVEF was higher (36±11% versus 29±7%, P<.05) and both end-diastolic (191±53 versus 234±54 mL; P<.05) and end-systolic (126±54 versus 167±45 mL; P<.05) volumes were lower in patients with than in those without postrevascularization functional improvement.
Myocardial Blood Flow and Metabolism Before Revascularization
Before revascularization, reversibly dysfunctional myocardium exhibited significantly higher absolute myocardial blood flow (84±27 versus 60±26 mL·min−1·100 g−1, P<.007; Fig 1⇓, Table 3⇓) than persistently dysfunctional myocardium. In segments with reversible dysfunction, values of absolute myocardial blood flow were not significantly different from those measured in the remote normal segments of the same patients (82±22 mL·min−1·100 g−1) or in anterior and lateral segments of the normal volunteers (88±22 mL·min−1·100 g−1). Only 4 of 24 dysfunctional segments that improved after revascularization had baseline levels of absolute myocardial blood flow below the lowest value of the normal volunteers, ie, 60 mL·min−1·100 g−1.
During hyperinsulinemic euglycemic glucose clamp, insulin plasma levels increased from 25±15 to 96±68 μU/mL, while both glucose and fatty acid plasma levels initially decreased (from 114±54 to 86±35 mg/dL and from 1142±536 to 665±428 μmol/L, respectively). Glucose levels, which were regularly monitored throughout the clamp, remained stable thereafter (86±35 mg/dL before FDG versus 80±26 mg/dL at the end of the FDG acquisition, P=NS). During glucose clamp, estimates of myocardial glucose uptake in remote segments reached values similar to those found in normal volunteers (47±17 versus 53±11 μmol·min−1·100 g−1, P=NS). In dysfunctional anterior segments, myocardial glucose uptake was not significantly different among reversibly and persistently dysfunctional segments (38±20 versus 29±19 μmol·min−1·100 g−1, P=NS) (Fig 2⇓). There was a significant difference in both FDG uptake (derived from circumferential profiles) and normalized glucose uptake (expressed as percentage of remote) between the two types of segments (69±17% versus 49±18% and 79±27% versus 57±24%, respectively, both P<.01). A pattern of flow-metabolism mismatch was present in 18 of 24 dysfunctional regions (75%) that improved functionally after revascularization but was absent in 10 of 15 regions (66%) that remained dysfunctional despite revascularization.
Regional Myocardial Recovery Coefficients and Wall Thickness Before Revascularization
Computation of regional myocardial recovery coefficients and spillover factors by use of the Monte Carlo simulation allows for an individual correction of partial-volume and spillover effects for each individual segment analyzed and permits calculation of mean myocardial wall thickness. Estimates of mean wall thickness were larger in segments that improved functionally after revascularization (1.26±0.32 mm) compared with those that remained persistently dysfunctional (1.05±0.27 mm, P=.05).
Segmental Response to Dobutamine Before Revascularization
Infusion of 10 μg·kg−1·min−1 of dobutamine resulted in only minor changes in heart rate (from 73±12 to 76±13 bpm) and mean blood pressure (101±15 to 104±15 mm Hg). The rate-pressure product increased marginally by an average of 10%, from 9446±2390 to 10 362±2634 mm Hg·bpm. There was no significant difference in the hemodynamic response to dobutamine between patients with and without postoperative functional improvement. During dobutamine infusion, 17 of 24 patients with reversible dysfunction (71%) demonstrated an improvement in anterior wall motion, 2 others showed deterioration of wall motion, and the remaining 5 showed no change. On average, in patients with reversibly dysfunctional myocardium, anterior wall motion improved from 8.0±1.0 to 6.5±1.4 grades with dobutamine. There was no difference in baseline hemodynamics, left ventricular function, severity of LAD disease, regional myocardial blood flow, or glucose uptake among patients who did and those who did not respond to dobutamine. Two patients among the 15 with persistent postoperative dysfunction showed a modest degree of improvement in wall motion (by only 1 grade) with dobutamine. The other 13 patients (87%) showed no significant changes. In the whole group of 39 patients, the degree of improvement in anterior wall motion after revascularization correlated well with that seen during the dobutamine challenge (r=.72, P<.001).
Subgroup Analysis in Patients With ≤35% LVEF
Because identification of potentially reversible left ventricular dysfunction is most important in patients with a low LVEF, a subgroup analysis was performed in the 26 patients with a LVEF ≤35% (Table 4⇓). In this subgroup, 13 patients had reversible anterior wall dysfunction after revascularization, while the remaining 13 patients had persistent dysfunction. On average, mean values for myocardial blood flow in both anterior and lateral regions were similar to those found in the entire population. However, myocardial glucose uptake in the dysfunctional segments was significantly higher in patients with than in those without reversible dysfunction (45±17 versus 31±19 μmol·min−1·100 g−1, P<.05).
The aim of the present study was to characterize the flow and metabolic and functional (inotropic reserve) correlates of the reversibility of left ventricular ischemic dysfunction in patients undergoing coronary revascularization and to test the hypothesis that, even in unselected patients, regional contraction is disproportionately reduced compared with resting perfusion. The findings can be summarized as follows: (1) chronically but reversibly dysfunctional myocardium shows almost normal resting myocardial perfusion compared with remote, normally contracting myocardium from the same patients and with values in normal volunteers; (2) myocardial FDG uptake and normalized glucose uptake are higher in reversibly compared with persistently dysfunctional myocardium; and (3) reversibly dysfunctional myocardium displays recruitable inotropic reserve when challenged by the administration of a low dose of dobutamine.
Myocardial Blood Flow in the Hibernating Myocardium
Several clinical studies have shown that prolonged regional contractile dysfunction due to coronary artery disease did not always result from irreversible tissue damage and, to some extent, could be reversed by restoration of blood flow.1 2 13 These observations have led to the speculation that chronically underperfused myocardium could remain viable if its energy requirements were actively downregulated to match the decreased supply. This intriguing condition, which is often referred to as “chronic myocardial hibernation,” thus requires the achievement of a new steady state between reduced supply and decreased demand. Results of studies in open-chest anesthetized pigs undergoing 1 to 5 hours of partial coronary occlusion have recently shown partial support of this hypothesis. Several investigators have indeed reported on the successful development of sustained low-flow perfusion-contraction matching (also called short-term hibernation) in the pig heart.14 15 16 17 Ischemia was produced by incomplete coronary occlusion leading to a 20% to 70% reduction of transmural myocardial blood flow. Intriguingly, despite the continuing low flow and a sustained decrease of segmental wall thickening, the metabolic hallmarks of ischemia (lactate production and decreased phosphocreatine) improved over time and no myocardial necrosis ensued.14 15 16 17 It should be noted, however, that this condition was remarkably unstable, because superimposition of a chronotropic or inotropic stress invariably resulted in increased lactate production, decreased phosphocreatine, and eventually myocardial infarction.17
Although these findings suggest that a precarious steady state between reduced oxygen supply and decreased oxygen demand can be achieved and maintained for some time under particular experimental conditions, no data are presently available to indicate that such a perfusion-contraction matching can persist for weeks or months in chronic animal preparations, let alone in patients with coronary artery disease. On the contrary, most investigators who have succeeded thus far in reproducing chronic (>1 week) but reversible regional left ventricular ischemic dysfunction in the experimental laboratory have always ended up with models of perfusion-contraction mismatch. Canty and Klocke18 examined the temporal response of regional function after ameroid implantation in conscious dogs. In their model, regional contraction was found to decrease progressively during the course of ameroid occlusion. Yet, at the time of ameroid occlusion, the measurements of regional endocardial blood flow showed a dissociation between flow and function. Liedtke et al19 achieved sustained reduction in segmental shortening without necrosis in swine undergoing a 50% reduction of the LAD flow velocity for 7 days. In these experiments, too, the decrease in segmental function was progressive over time and was not associated with reduced subendocardial blood flow by day 4.19 More recently, Shen and Vatner20 examined the time course of regional dysfunction after ameroid implantation in chronically instrumented pigs. Here again, the resulting progressive segmental dysfunction was not associated with permanent subendocardial blood flow reduction but rather appeared to result from repeated transient episodes of acute ischemia followed by stunning. Although the above studies do not entirely dismiss the possibility that chronic perfusion-contraction matching could be achieved in intact animals, they suggest that, as with our previous observations in patients with noninfarcted dysfunctional collateral-dependent myocardium, repetitive intermittent episodes of ischemia followed by stunning could be an alternative mechanism leading to chronic regional ischemic dysfunction.
The results of the present study extend these observations to patients with chronic left ventricular dysfunction and a past history of myocardial infarction. In this study, we prospectively included every single patient with chronic anterior wall dysfunction, poor LVEF, and severe coronary artery disease who was referred to our institution for diagnostic cardiac catheterization. To avoid potential selection bias, only two major selection criteria were required for inclusion into the study: the suitability of the diseased vessels for either CABG or PTCA and the possibility of obtaining good-quality echocardiograms before and after revascularization. The majority of the patients (82%) had few or no ischemic symptoms. In these patients, we found that resting myocardial blood flow was similar among reversibly dysfunctional and remote normal segments (84±27 versus 82±22 mL·min−1·100 g−1), whereas it was decreased in segments with persistent postrevascularization dysfunction. On an individual patient basis, all but 4 patients (83%) with reversible dysfunction after revascularization had normal levels (ie, within the range of normal volunteers) of absolute myocardial blood flow to the dysfunctional area. These figures are quite similar to those previously reported by other investigators by use of either relative13 21 or quantitative PET imaging.22 23 24 25 Taken together, these data thus indicate that, in the large majority of patients with myocardial hibernation, the loss of regional contraction is out of proportion to the reduction in myocardial blood flow (perfusion-contraction mismatch). Accordingly, we would like to suggest that chronic reversible dysfunction in these patients is not caused by chronic (ie, permanent) underperfusion but rather is the consequence of repeated episodes of severe ischemia followed by stunning, with the functional recovery being incomplete because of renewed episodes of ischemia.
Myocardial FDG and Glucose Uptake in the Hibernating Myocardium
This study confirms that myocardial FDG uptake is higher in reversibly as opposed to persistently dysfunctional myocardium.13 21 According to previous observations from our group, the uptake of FDG by the hibernating myocardium is intimately related to both the presence and amount of structurally altered cardiomyocytes, which, in addition to their increased reliance on glucose, also show considerable glycogen accumulation.22 This raises intriguing questions about the biochemical fate of exogenous glucose in these cells. Although it was originally suggested that the maintained glucose uptake in hibernating myocardium resulted from stimulation of anaerobic metabolism by chronic ischemia, this explanation now appears unlikely in view of the normal or nearly normal levels of absolute myocardial perfusion and oxygen consumption measured in these segments. It would also hardly explain the accumulation of glycogen, a quite unusual finding in the setting of ongoing ischemia, which would rather be expected to result in the opposite. FDG uptake by dysfunctional but metabolically active myocardium has been shown to be relatively independent of the hormonal milieu and dietary conditions.26 Preliminary observations by Schwaiger et al27 suggest that this could involve a switch in the subtype of glucose transporters expressed at the surface of the cardiomyocytes from the insulin-responsive glucose transporter GLUT-4 to the insulin-insensitive unidirectional glucose transporter GLUT-1. Although this remains speculative, reexpression of GLUT-1 might be just one part of the many phenotypic changes shown to occur in chronically dysfunctional myocardium28 and be the molecular basis for both the maintained FDG uptake and the accumulation of glycogen.
Some peculiar aspects of FDG imaging in our study warrant discussion. Whereas the results of our investigation confirm those of previous studies,13 21 29 ie, that relative FDG imaging is useful to predict functional recovery after revascularization, the results in terms of absolute levels of regional glucose uptake were quite disappointing. Indeed, despite our efforts to minimize interpatient variability by use of the hyperinsulinemic euglycemic glucose clamp technique,8 the range of absolute glucose uptake in both remote normal and dysfunctional segments was so large that it precluded any valid delineation of the different patient subgroups. Although these discrepancies may be related to individual differences in the myocardial insulin responsiveness, they may also reflect some more fundamental limitations to the use of FDG and PET for the assessment of glucose metabolism. The basic assumption underlying the use of FDG and PET for measuring myocardial glucose metabolism is that glucose uptake can be derived from the measured rates of FDG uptake by correction of the FDG data with a lumped constant that accounts for the differences in transport and phosphorylation between FDG and glucose. It has been postulated that this lumped constant was insensitive to changes in dietary state and hormonal conditions and was not affected by ischemia, reperfusion, or both. Because glucose analogues are favored over glucose in most membrane transport systems, while at the same time glucose is favored over its analogues by most plant and mammalian hexokinases, the value of the lumped constant is unlikely to remain constant under all conditions. Greater translocation of the glucose transporters to the plasma membrane, as occurs with insulin stimulation or ischemia,30 or changes in the relative affinity of the hexokinase for glucose and FDG, as occurs with insulin,31 are likely to affect the lumped constant and consequently the reliability of the metabolic information derived from FDG studies. In fact, significant changes in the lumped constant with insulin,32 33 catecholamines,33 and changes in substrate availability33 have been reported in isolated hearts and are likely to occur in humans as well. Whether these factors also affect the lumped constant on a regional basis, however, remains unknown. In this regard, the better predictive accuracy of relative imaging as opposed to absolute uptake measurements in our study could indicate that there is indeed less regional than interpatient variability.
Recruitment of Inotropic Reserve
Previous experimental work has shown that reversibly injured (including stunned4 and short-term5 and chronically hibernating34 ) myocardium retains the ability to temporarily improve function on stimulation with catecholamines or calcium, whereas infarcted myocardium usually remains unchanged. This diverging contractile response in dysfunctional but viable and infarcted myocardium has also been observed in patients with coronary artery disease and left ventricular ischemic dysfunction, and it is increasingly used clinically for identification of reversible dysfunction. Earlier investigators attempting to predict the reversibility of left ventricular ischemic dysfunction after revascularization used the response of global LVEF to an inotropic stimulus (epinephrine or postextrasystolic potentiation) at the time of cardiac catheterization as an index of myocardial viability.35 36 37 Although this approach was shown by several investigators to allow accurate prediction of reversible dysfunction, its clinical applicability has been limited by the need to resort to cardiac catheterization to measure left ventricular function. Recent refinements in noninvasive imaging, particularly in digitized echocardiography, and the use of standardized dobutamine infusion protocols have allowed successful application of these concepts, on a larger scale, to almost any patient with left ventricular ischemic dysfunction.
In the present study, we focused on the potential flow and metabolic correlates of the ability of reversibly dysfunctional myocardium to augment contractile performance in response to an inotropic stimulus. Our data confirm that most reversibly dysfunctional segments do retain the ability to improve function on stimulation with dobutamine. It is noteworthy, however, that not every segment with reversible postrevascularization dysfunction did improve functionally with dobutamine. In the present study, 5 of 24 patients with improved function after revascularization showed no change in regional contraction during low-dose dobutamine, whereas 2 other patients even experienced worsening of their regional wall motion. Interestingly, none of the flow and metabolic parameters analyzed allowed distinction between patients with and without a positive response to dobutamine. It is therefore possible that mechanisms not evaluated in this study, such as the severity of the underlying cardiomyocyte alterations (particularly the loss of myofilament and contractile material),22 the extent of impairment of myocardial perfusion reserve,3 and the β-receptor density and affinity, contributed to this observation.
The present study has some limitations that should not be ignored. First, we did not obtain follow-up angiograms in every patient to ascertain that complete revascularization of the dysfunctional segments had indeed been achieved. Therefore, we cannot rule out the possibility that incomplete revascularization, graft closure, or restenosis contributed to the lack of functional improvement in patients with persistent postoperative dysfunction. However, in those patients who were prospectively followed up angiographically after revascularization, these events were rare, and thus, they can be expected to be rare in the group as a whole. As with previous studies from our laboratory, data were acquired at a single tomographic level. Although static images from several different levels of the left ventricular myocardium were usually obtained, only one tomographic level was used for dynamic imaging. It is therefore assumed that this tomographic level was representative of the entire anterior ischemic area. Also, in an attempt to compensate for the limited spatial resolution of the PET imaging devices, all individual time-activity curves were corrected for partial-volume and spillover effects. Although it has been shown previously that these corrections were a definite prerequisite to the measurement of myocardial blood flow and metabolism in absolute terms,10 particularly when dealing with dysfunctional or thin myocardial walls, none of the currently available methods can be considered to be perfect. In the present study, we used a specially developed Monte Carlo simulation to generate individual correction factors for each myocardial region of interest.9 This approach has been validated in dogs over a wide range of thicknesses and thickening conditions and allows accurate estimation of individual recovery coefficients and spillover factors.9 10 Implementation of these correction factors is probably responsible for the relatively high flow values measured in our study in both reversibly injured and permanently damaged segments. It should be emphasized, however, that these corrections did not contribute to the differences in myocardial blood flow seen among patients with and without postoperative functional improvement, since the magnitude of correction, if changed at all, was greater in those with persistent dysfunction. Finally, only patients with stable coronary artery disease and left ventricular dysfunction were enrolled in this study. Although most patients had sustained at least one previous myocardial infarction, the most recent occurring 13 days before the PET study, none were studied during the acute phase of infarction (<3 days). Therefore, the conclusions of the present study can be applied only to patients with chronic coronary artery disease and presumably not to those with recent (<3 days) myocardial infarction.
This study supports the contention that myocardial hibernation is not the consequence of a permanent reduction of transmural myocardial perfusion at rest and confirms that myocardial FDG uptake is maintained in this condition. This study also shows that the hibernating myocardium displays recruitable inotropic reserve when challenged by the administration of a low dose of dobutamine.
This work was supported in part by grants 3-4523-89 and 3-4540-95 from the Fonds National de la Recherche Scientifique et Me´dicale, by the Action de Recherche Concerte´e No. 91/96-146, and by Concerted Action of European Economic Community on PET Investigations of Cellular Degeneration and Regeneration. Dr Gerber is supported by a grant from the Fonds de De´veloppement Scientifique of the University of Louvain.
Selected Abbreviations and Acronyms
|CABG||=||coronary artery bypass graft surgery|
|LAD||=||left anterior descending coronary artery|
|LVEF||=||left ventricular ejection fraction|
|PET||=||positron emission tomography|
|PTCA||=||percutaneous transluminal coronary angioplasty|
- Received December 4, 1995.
- Revision received February 8, 1996.
- Accepted February 16, 1996.
- Copyright © 1996 by American Heart Association
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