CLINICAL STUDIES
Myocardial perfusion and oxygen consumption in reperfused noninfarcted dysfunctional myocardium after unstable angina
Direct evidence for myocardial stunning in humans
Bernhard L. Gerber, MD*,1,
William Wijns, MD ,
Jean-Louis J. Vanoverschelde, MD, FACC*,
Guy R. Heyndrickx, MD,
Bernard De Bruyne, MD,
Jozef Bartunek, MD and
Jacques A. Melin, MD*
* Division of Cardiology and Positron Emission Tomography Laboratory, University of Louvain Medical School, Brussels, Belgium
Cardiovascular Center, Onze Lieve Vrouw-Ziekenhuis, Aalst, Belgium
Manuscript received December 2, 1998;
revised manuscript received June 29, 1999,
accepted August 27, 1999.
Reprint requests and correspondence: Dr. William Wijns, Cardiovascular Center, Onze-Lieve Vrouwziekenhuis, Moorselbaan 164, B-9300 Aalst, Belgium
william.wijns{at}olvz-aalst-.be
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Abstract
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OBJECTIVES
To positively establish the diagnosis of myocardial stunning in patients with unstable angina and persistent wall motion abnormalities after reperfusion by coronary angioplasty.
BACKGROUND
Although myocardial stunning is thought to occur in several clinical conditions, definite proof of its existence in humans is still lacking, owing to the difficulty of measuring myocardial blood flow (MBF) in absolute terms.
METHODS
We studied 14 patients with unstable angina due to proximal left anterior descending coronary artery disease who presented persistent anterior wall motion abnormalities despite revascularization of the culprit lesion by percutaneous coronary angioplasty (PTCA) and who did not have clinical evidence of necrosis. Dynamic positron emission tomography (PET) with [13N]-ammonia and [11C]-acetate was performed 48 h after PTCA to determine absolute MBF and oxygen consumption (MVO2). Regional wall thickening and regional cardiac work were determined using two-dimensional echocardiography. Improvement of segmental wall motion abnormalities was followed for a median of 4 months (1.5 to 14 months).
RESULTS
As judged from the changes in segmental wall motion score, regional dysfunction was spontaneously reversible in 12/14 patients and improved from 2.2 ± 0.3 to 1.2 ± 0.3 at late follow-up (p < 0.001). With PET, [13N]-ammonia MBF was similar among dysfunctional and remote normally contracting segments (85 ± 29 vs. 99 ± 20 ml·min–1·100g–1, p = not significant [n.s.]), thus demonstrating a perfusion-contraction mismatch. Despite the reduced contractile function, dysfunctional myocardium presented near normal levels of MVO2 (6.5 ± 4.2 vs. 8.0 ± 1.9 ml·min–1·100g–1, p = n.s.). Consequently, the regional myocardial efficiency (regional work divided by MVO2) of the dysfunctional myocardium was found to be markedly decreased as compared with normally contracting myocardium (6 ± 6% vs. 26 ± 6%, p < 0.001).
CONCLUSIONS
This study demonstrates that human dysfunctional myocardium capable of spontaneously recovering contractile function after unstable angina endures a state of perfusion-contraction mismatch. These data for the first time provide unequivocal direct evidence for the existence of acute myocardial stunning in humans.
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Abbreviations and Acronyms
| | ECG | = electrocardiogram | | LAD | = left anterior descending coronary artery | | MBF | = myocardial blood flow | | MVO2 | = myocardial oxygen consumption | | PET | = positron-emission tomography | | PTCA | = percutaneous coronary angioplasty |
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Reversible postischemic dysfunction, or myocardial stunning (1,2), is the contractile dysfunction that persists after reperfusion despite the absence of irreversible myocardial damage and despite restoration of normal or near-normal coronary flow (3). Myocardial stunning is a well-defined experimental entity that can be observed in several animal species (4) following reperfusion after complete coronary occlusions (1,5–7) or after prolonged low flow ischemia (8). Although myocardial stunning is thought to occur in several clinical conditions (9) such as during unstable angina (10–14), after coronary spasm (15–17) or after exercise induced ischemia (18–22), definite evidence of its existence in humans is still lacking, mainly owing to the difficulty of measuring myocardial blood flow (MBF) in absolute terms. We used positron-emission tomography (PET) and dynamic imaging using 13N-ammonia to assess MBF noninvasively in an attempt to establish the diagnosis of myocardial stunning positively in patients with unstable angina and persistent wall motion abnormalities after reperfusion by coronary angioplasty.
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Methods
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Patient selection.
The study comprised 14 patients (7 men and 7 women, mean age 63 ± 12 years, range 43 to 79 years) admitted to the coronary care unit for unstable coronary syndromes due to proximal left anterior descending coronary artery (LAD) disease. The individual clinical characteristics of this study population are summarized in Table 1. Patients were considered eligible for inclusion in the study if they presented with: 1) one-vessel disease with severe proximal LAD stenosis or occlusion with successful revascularization of the culprit lesion by balloon angioplasty or stenting, 2) persistent contractile dysfunction of the anterior wall after coronary revascularization, and 3) no signs of myocardial necrosis defined as no Q-waves on the electrocardiogram (ECG) and no elevation of creatine phosphokinase levels. The study protocol was approved by the Ethical Committee of the University of Louvain Medical School and all patients gave informed consent to the investigative nature of this study.
Study protocol.
Patients were enrolled in the study if resting echocardiograms displayed persisting contractile dysfunction in the anterior wall on the day after coronary revascularization. Positron-emission tomography was obtained as soon as possible after coronary angioplasty to obtain measurements of resting MBF and oxygen consumption in the dysfunctional area. Echocardiographic studies of contractile function of the anterior wall were performed at the time of the PET study and at regularly scheduled control visits after angioplasty over a period of six months or until complete normalization of anterior wall dysfunction.
Two-dimensional echocardiography.
Two-dimensional echocardiograms were analyzed in digitized cinequad loop format on a computer workstation. Regional wall motion was analyzed both qualitatively (regional wall motion) and quantitatively (percent wall thickening) by the consensus of two experienced observers (B.L.G. and J.L.V.O.). Regional wall motion was interpreted in 16 myocardial segments (23) and graded either as normal 1), hypokinetic 2) or akinetic 3). Intraobserver concordance for wall motion score was 84% (kappa = 0.68) whereas interobserver concordance was 83% (kappa = 0.62). A wall motion score for the segments supplied by the LAD was calculated by summing up the scores of the mid- and basal level of the septal, antero-septal and anterior wall and of the septal, anterior and lateral part of the apex. End-diastolic and end-systolic internal dimensions of the left ventricle were measured on parasternal M-mode images. Systolic wall thickening of the midanterior and mid-lateral segments was calculated from high quality digitized two-dimensional echocardiographic frames as the difference between systolic (R-wave of the ECG) and diastolic (time of aortic valve closure) thickness and expressed in percent of the diastolic wall thickness. Meridional wall stress and regional mechanical work (24) of both the anterior (dysfunctional) and lateral (remote) wall were also calculated by use of the following equations:
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RW = –  m·d ln(1/Wth)
where LVD (cm): left ventricular dimension, LVP (mm Hg): left ventricular pressure, RW (mJ/cm3): regional work, Wth (cm): wall thickness, m (g/cm2): meridional wall stress. The intraobserver reproducibility calculated as intraclass correlation coefficient was 0.85, while interobserver variability was 0.86. Contractile efficiency (%) was computed as the ratio of regional work to regional myocardial oxygen consumption (MVO2).
Pet.
Positron-emission tomography was performed using ECAT III and ECAT EXACT HR tomographs (25). Absolute MBF was quantified using 13N-ammonia and MVO2 using 11C-acetate. One dynamic midventricular transaxial study was analyzed per patient. Two large irregular volumes of interest were drawn onto the anterior (dysfunctional) and lateral (remote) wall of the myocardium, respectively. In each volume of interest, absolute regional myocardial perfusion was quantified by use of a three-compartment model (26), and regional oxidative metabolism was estimated from the rapid exponential clearance rate of the 11C-activity from the myocardium to derive kmono. MVO2 was calculated based on the relationship between MVO2 and kmono that had been determined in prior studies (27).
Statistical analysis.
Values are expressed as means ± one standard deviation. Comparisons between wall motion score at baseline and after follow-up and of differences of parameters between the dysfunctional anterior and remote lateral wall were made using the Student t test for paired samples. All tests were two-tailed and a p value of less than 0.05 was considered indicative of statistical significance.
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Results
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Baseline clinical and angiographical characteristics.
The individual clinical and angiographical characteristics of the study population are shown in Table 1. In 12 patients the initial clinical presentation corresponded to unstable angina of the Braunwald class 2B and 3B (28). The two remaining patients presented with features typical of acute myocardial infarction (ST elevation and chest pain nonresponsive to IV nitrates and heparin) which completely resolved during thrombolysis. In each case, no anterior Q-waves developed and cardiac enzymes always remained within the normal limits for our laboratory (<160 IU/ml). Coronary angiography and successful revascularization of the LAD were performed at a median of four days (range 1 to 23 days) after the onset of the acute coronary syndrome. The proximal LAD was occluded in six patients and showed >80% stenosis in the remaining eight patients. Revascularization was performed using balloon angioplasty in 13 patients and using directional atherectomy in 1 patient. Three patients underwent implantation of an endovascular stent. All patients presented complete akinesis of the anterior and apical wall at contrast angiography. Mean ejection fraction at the time of coronary angioplasty was 59 ± 12%. All patients were treated with IV nitrates, heparin and aspirin before undergoing coronary angioplasty. Additional treatment consisted of beta-adrenergic blocking agents in eight patients and calcium antagonists in four patients. The peak creatine kinase enzyme level averaged 134 ± 142 U/ml. The ECG at the time of the PET study displayed ample and negative T-waves in 12 patients. No patient had pathological Q-waves or ST elevation or depression at the time of the PET study.
Contractile function at baseline and spontaneous recovery over time.
Tomographic and echocardiographic acquisitions were performed 2 ± 2 days (range 1 to 7 days) after coronary revascularization (Fig. 1). At the time of the PET study, all patients displayed severe dysfunction of the LAD-dependent anterior wall with complete akinesis of the mid- and apical-anterior segments. The average wall motion score for the LAD-dependent segments was 2.2 ± 0.3. Serial echocardiographic follow-up was obtained in 13 of the 14 patients. The remaining patient was lost to follow-up. The median time of follow-up was four months (range 1.5 to 14 months). The time course of recovery of LAD-dependent wall-motion score, assessed by repeated echocardiographic studies is illustrated in Figure 2. Slow spontaneous improvement of the contractile dysfunction (improvement of wall motion score from 2.2 ± 0.3 before percutaneous coronary angioplasty [PTCA] to 1.2 ± 0.3 after follow-up, p < 0.001) occurred over time in all patients but with an interindividual variability. Eight patients completely normalized contractile function, presenting less than one hypokinetic segments at late follow-up. In four patients, hypokinesis persisted in more than one (all apical) segment. Finally, the recovery of contractile function was incomplete in one patient (Patient 10) who remained akinetic in the anterior and anteroseptal wall. Repeated coronary angiography and cardiac catheterization were obtained in 10 patients and also demonstrated complete normalization of contractile function in all patients.
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Figure 1 Graph illustrating the delay between first occurrence of symptoms and coronary revascularization and the time points when PET studies were performed and when functional follow-up was completed. PET = positron-emission tomography.
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Figure 2 Plot illustrating the time course of spontaneous recovery of contractile function of the stunned myocardium after coronary angioplasty.
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Absolute myocardial perfusion and its relationship to wall thickening.
Absolute myocardial perfusion and wall thickening in the anterior dysfunctional and remote regions are shown in Figures 3 and 4. At the time of the PET study, wall thickening in the anterior wall was reduced to 9 ± 8% of the thickening of the remote lateral wall (p < 0.001, Fig. 3A). In contrast, absolute myocardial blood perfusion in the dysfunctional anterior wall was well preserved at 87 ± 27% of the remote region and, on average, did not significantly vary between the dysfunctional anterior and the remote normally contracting segments (85 ± 29 vs. 99 ± 20 ml·min–1·100g–1, p = NS, Fig. 3B). The values of blood flow were within the 95% confidence limits (60 to 138 ml·min–1·100g–1) of the remote region in all but two patients. One of these two patients (Patient 10) displayed incomplete recovery of wall motion at follow-up. Figure 4 illustrates the relationship between reduction of wall thickening and reduction of myocardial perfusion observed in our patients. This figure clearly demonstrates the discrepancy between preserved perfusion and reduced wall thickening that is characteristic of a contraction-perfusion mismatch.
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Figure 3 (A) Bar graph showing percentage of wall thickening in the stunned anterior and remote normally contracting region. Wall thickening was significantly reduced (p < 0.001) in the stunned myocardium. (B) Bar graph showing resting MBF in the stunned anterior and remote normally contracting region. There was no significant reduction of MBF in the anterior as compared with the remote myocardium. MBF = myocardial blood flow.
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Figure 4 Relationship between absolute MBF and wall thickening in the anterior region (closed circles) with respect to the remote lateral region (open circles). In the anterior region, wall thickening was found to be reduced to 9% of the remote, whereas blood flow was maintained at 87% of the remote region, thus illustrating a perfusion-contraction mismatch. MBF = myocardial blood flow.
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Myocardial oxygen consumption and regional work.
Figure 5 illustrates the average values of resting regional work and oxygen consumption in both the anterior and remote regions. The anterior wall performed only 13 ± 11% of the contractile work performed by the normally contractile remote region (0.6 ± 0.6 J/beat vs. 5.4 ± 1.6 J/beat, p < 0.001). In contrast, MVO2 did not significantly vary between the anterior and remote regions 6.5 ± 4.2 vs. 8.0 ± 1.9 ml·min–1·100g–1, p = n.s.). Consequently, the regional mechanical efficiency of the anterior wall was found to be reduced as compared with the remote region (6 ± 6% vs. 26 ± 6%, p < 0.001, Fig. 6).
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Figure 5 Bar graph showing contractile work (left) and MVO2 (right) of the dysfunctional anterior and remote lateral region. Contractile work was significantly (p < 0.001) reduced in the anterior with respect to the remote region, whereas MVO2 was found to be well-preserved. MVO2 = myocardial oxygen consumption.
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Figure 6 Bar graph showing contractile efficiency in the dysfunctional anterior and remote lateral regions. Anterior contractile efficiency was significantly (p < 0.001) lower than remote contractile efficiency.
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Discussion
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In this study we attempted to positively demonstrate the presence of myocardial stunning in 14 patients with unstable coronary syndromes with proximal LAD disease and persistent anterior wall dysfunction despite revascularization of the culprit LAD lesion. Contractile function spontaneously recovered over time, confirming the absence of myocardial necrosis in 12 out of 14 patients. Absolute myocardial perfusion was measured using PET at the time of dysfunction and was not found to be significantly reduced in the dysfunctional region. Myocardial oxygen consumption remained preserved, thus indicating a reduced contractile efficiency of the dysfunctional tissue under resting conditions.
Myocardial stunning in man.
Myocardial stunning is an experimentally observed (1,5) postischemic event that is characterized by persisting contractile dysfunction of the postischemic but reperfused myocardium with a spontaneous recovery over time (2). In the experimental setting, stunning was demonstrated to be an oxygen radical mediated reperfusion injury to the calcium channels and contractile proteins, resulting in intracellular calcium overload and reduced excitation coupling of the contractile myofilaments of the stunned myocyte (3). It is generally accepted among clinical cardiologists that myocardial stunning is a phenomenon that occurs as frequently as ischemia itself in many patients with various cardiac diseases. Stunning therefore has been postulated to exist in a variety of situations (9,29) such as in reperfused myocardial infarction (30–32), after unstable angina (10–14) or in coronary spasm (15–17), following recovery of exercise-induced ischemia (18–20,33) or after cardiopulmonary bypass surgery. However, unlike the situation in animals, full reperfusion is rarely achieved in humans (34), and it is likely that other pathophysiological situations such as myocellular necrosis, ongoing ischemia and short-term hibernation may coexist within dysfunctional human myocardium. Hence, the presence of myocardial stunning in the clinical situation has most often been inferred, and direct evidence for the ocurrence of myocardial stunning in man is still lacking (9).
Positive diagnosis of the occurrence of myocardial stunning in man.
By definition, the positive diagnosis of myocardial stunning requires documentation of the reversibility of the dysfunction as well as the analysis of the relationship between perfusion and contraction, demonstrating a perfusion contraction mismatch (35) at the time when reperfusion has been performed and dysfunction persists (9). To provide such evidence, it is important to carefully select patients in whom evidence of ongoing ischemia or necrosis is definitely lacking. In this study, we therefore chose to select patients with unstable angina but without any signs of myocardial infarction, as demonstrated by the absence of enzymatic elevation or electrocardiographic Q-waves on the 12-lead ECG, who presented with persisting wall motion abnormalities despite successful PTCA of the culprit lesion of the proximal LAD and complete akinesis of the anterior wall that persisted until the PET studies were performed.
At the time of the study, the majority of the patients presented with negative T-waves in the precordial chest derivations of the 12-lead ECG. Previous work from de Zwaan et al. (36) and Renkin et al. (12) has indicated that when this particular ECG pattern occurs in the presence of a severe proximal LAD stenosis, it is often associated with resting segmental dysfunction that slowly recovers after recanalization and may represent the electrophysiological correlate of functional stunning. In this study, we also demonstrated a slow and spontaneous recovery of contractile function that was gradual over time. Several authors had previously demonstrated such complete recovery of contractile function in patients after attacks of unstable angina (10–14) or myocardial infarction. The time course of recovery of contractile function is still poorly known but was shown to span between several hours (13) and two weeks (37) after reflow. In our study, the recovery of contractile function appeared to be slower and, in some patients, took up to four months to occur. This slower recovery of function was confirmed by reports of Renkin et al. (12) and de Feijter et al. (38) and most likely resulted from more severe or more pronounced previous ischemic attacks, as previously reported in experimental animal studies (39,40). To positively demonstrate a state of myocardial stunning beyond the demonstration of spontaneous recovery of contractile function, we also had to demonstrate the presence of a contraction-perfusion mismatch (35) at the time of dysfunction. Therefore quantitative measurements of absolute myocardial perfusion were performed using PET and 13N-ammonia. While contractile dysfunction persisted, we found that perfusion was completely restored in the majority of patients, thus illustrating the presence of a perfusion-contraction mismatch. Previous studies addressing the issue of myocardial perfusion in patients with reperfused myocardium only concentrated on patients with reperfused infarction (41–43). As expected from the known admixture of necrotic and normal tissue after infarction, all these studies concur in demonstrating reduced perfusion in the dysfunctional tissue. With regard to unstable angina or coronary spasms, only a few case reports have been published (44,45), none providing quantitative measurements of MBF at the time of postischemic dysfunction. This study therefore represents the first unequivocal demonstration that myocardial stunning occurs in humans and, in particular, following attacks of unstable angina.
Myocardial oxygen consumption and efficiency in stunned myocardium.
A second important question addressed in this study concerns resting oxidative metabolism and mechanical efficiency in the dysfunctional stunned myocardium. Under normal conditions, MVO2 has been shown to be tightly correlated with the contractile work. The relation between oxygen consumption and decreased contractile function in the dysfunctional but stunned myocardium is still a matter of debate (46). Experimental observations in animal models of myocardial stunning have indeed yielded some conflicting results. While some studies reported unchanged (47,48) or even increased (49) MVO2 in stunned myocardium, others (50–52) reported reduced oxygen consumption in the stunned myocardium. Some of these discrepancies may be explained by the inherent difficulty of directly measuring oxygen consumption in the heart in vivo and thus by measurement errors or methodological issues. Indeed, reductions of absolute oxygen consumption were moderate—less than 25% of preischemic levels—and therefore out of proportion with the depressed postischemic regional work. These reductions seem to parallel the levels of perfusion that may also be found to be slightly reduced after reperfusion, as previously discussed. In this study, resting oxygen consumption was found to be maintained in the dysfunctional regions despite the reduced mechanical work performed by the stunned myocardium. Thus, the stunned human myocardium was found to have, as previously demonstrated in animal studies (48,52), a reduced mechanical efficiency.
Study limitations.
This study has some limitations that are related to the use of PET for the measurements of perfusion and oxygen consumption in dysfunctional myocardium. Because part of the study was performed using a single slice tomograph, dynamic data were acquired at a single tomographic level, corresponding to the midventricular level of the heart. It is therefore assumed that the anterior wall at this tomographic level was representative of the entire territory of the LAD. Also, in an attempt to compensate for the limited spatial resolution of the PET imaging device, all individual time-activity curves were corrected for partial-volume and spillover effects. Although such corrections are a definite prerequisite for the measurement of MBF and metabolism in absolute terms (26), particularly when dealing with dysfunctional or thin myocardial walls, none of the currently available methods are perfect. In this study, we used a specially developed Monte-Carlo simulation to generate individual correction factors for each myocardial region of interest. This approach has been validated in dogs over a wide range of thickness and thickening conditions and allows accurate estimations of individual recovery coefficients and spillover factors (26). Because quantitative measurements of myocardial perfusion using PET encompass transmural wall thickness, subendocardial blood flow can not be assessed presently. Our observations of perfusion-contraction mismatch can, therefore, not be extended to the subendocardial level. Finally, in our study one patient (Patient 10) did not spontaneously recover function during the time of observation. While the exact reason for this is not entirely clear, this patient had presented with ST elevations and received thrombolysis, yet without apparent increase of creatine phosphokinase levels and without pathologic Q-waves on the ECG. Despite the absence of such objective signs of infarction, it is likely that the patient had undergone an unrecognized but significant amount of myocellular necrosis in the anterior wall, explaining the limited recovery of function after reperfusion. It is also possible that this patient had undergone microvascular damage from the no-reflow phenomenon, which might explain the reduced perfusion (41 ml/min/100g) observed at the time of the study. This latter diagnosis may also apply to another patient (Patient 8) who also presented with reduced perfusion (38 ml/min/100g) and limited recovery of contractile function. Thus, the diagnosis of myocardial stunning, which clearly applies to all other 12 patients in our study, is not applicable to these latter 2 patients, although they fulfilled the inclusion criteria for our study.
Conclusions.
This study demonstrated that human dysfunctional myocardium capable of spontaneously recovering contractile function after an unstable coronary syndrome endures a state of perfusion-contraction mismatch. This study therefore provides unequivocal direct evidence for the existence of myocardial stunning in humans.
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Acknowledgments
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We gratefully acknowledge the work of Raymond Bausart for technical assistance in tomographic acquisitions and of our radiochemists, Benoît Georges and Daniel Labar, for radioisotope production.
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Footnotes
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This study was supported, in part, by grants (number 3-4540-95) from the "Fonds National de la Recherche Scientifique et Médicale" and by the "Action de Recherche Concertée" (number 96/01-199).
1 Dr. Gerber was supported by a grant from the "Fonds de Développement Scientifique" of the University of Louvain, Belgium. 
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