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J Am Coll Cardiol, 2002; 39:420-427 © 2002 by the American College of Cardiology Foundation |
* MRC Clinical Sciences Centre and Division of Cardiology, National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
Manuscript received May 14, 2001; revised manuscript received October 19, 2001, accepted November 2, 2001.
* Reprint requests and correspondence: Prof. Paolo Camici, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, England W12 0NN, United Kingdom.
paolo.camici{at}csc.mrc.ac.uk
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Abstract |
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BACKGROUND: In animal models of stunning, MBF and MMRO2 are normal or near normal, and the severity of stunning is related to the degree of the preceding ischemia.
METHODS: Myocardial blood flow and MMRO2 were measured using positron emission tomography and oxygen 15-labelled water (H215O) and oxygen 15-labelled oxygen (15O2), respectively, in 14 patients with CAD and normal left ventricular (LV) function. Global ejection fraction and regional LV systolic function (SF) were measured using quantitative echocardiography during and after dobutamine-induced ischemia.
RESULTS: Ejection fraction and SF were reduced 30 min after dobutamine (both: p < 0.01) but recovered by 120 min. Myocardial blood flow (ml/min per g) to regions with reversible LV dysfunction was normal at baseline and during dysfunction (0.88 [0.82 to 0.99] and 1.09 [0.75 to 1.37], respectively, p = NS) as was MMRO2 (ml/min per 100 g) (16.64 [10.16 to 16.18] and 11.68 [8.43 to 15.30] respectively, p = NS). Left ventricular dysfunction was related to stenosis severity and peak MBF. Regions were divided into those subtended by a stenosis of <50%, 50% to 80% and >80% luminal diameter. Systolic function 30 min after dobutamine was 93.9% (83.4% to 104.4%) (p = NS), 85.4% (80.0% to 90.9%) and 67.4% (56.2% to 78.7%) (both: p < 0.001), respectively. Peak MBF was 2.0 (1.71 to 2.31), 1.75 (1.65 to 1.85) (p = 0.01 compared with <50%) and 1.47 (1.33 to 1.60) (p = 0.03 compared with 50% to 80% and p = 0.002 compared with <50%), respectively.
CONCLUSIONS: In patients with CAD, dobutamine produces prolonged, but reversible, LV dysfunction when MBF is normal, confirming stunning. This stunning is related to the severity of the coronary stenosis and the reduction in peak MBF. Myocardial oxygen consumption to stunned myocardium is normal.
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Methods |
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70% stenosis in at least one major epicardial coronary artery assessed using quantitative coronary angiography (QCA-CMS, Medis, Leiden, the Netherlands) within the preceding four months. Patients were excluded if there was a history of myocardial infarction or unstable angina in the preceding four months or if it was not possible to obtain echocardiograms of sufficient quality for quantitative analysis. All patients were taking aspirin in addition to their anti-anginal medication (Table 1).
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Echocardiography. Two-dimensional echocardiography was performed by one operator (E.B.) with the patient in the left lateral position using commercially available equipment with a P3-2 Broadband phased array transducer (HDI 3000, ATL Ltd., Bothell, Washington). Images were recorded at baseline and then 30, 45, 60 and 120 min after peak dobutamine. To minimize beat-to-beat variability, all recordings were made in held midexpiration (9) and recorded onto super VHS videotape for off-line analysis. Left ventricular contractile function was assessed in the apical two-chamber (AP2CH) and apical four-chamber (AP4CH) views according to the guidelines from the American Society of Echocardiography (10).
Dobutamine stress. Dobutamine was infused at incremental doses (starting at 5 µg/kg per min and increased at 3-min intervals to 10, 15, 20, 30 and 40 µg/kg per min) until patients experienced chest pain, were limited by other symptoms, achieved a target heart rate (calculated as 220 – age in years), systolic blood pressure fell by >20 mm Hg or significant arrhythmias were induced. The electrocardiogram (ECG) was monitored continuously, and blood pressure and a 12-lead ECG recorded every 3 min during stress and every 5 min during recovery.
Echocardiographic analysis. The videotaped images were analyzed using a PC-based digitizing program (Thoraxcenter, Erasmus University, Rotterdam, the Netherlands) (9). Three consecutive beats (excluding extrasystolic and post-extrasystolic beats) were analyzed for each time point. Endocardial borders (excluding papillary muscles) were traced at end diastole, timed as the closure of the mitral valve leaflets and, at end systole, defined as the point of maximal inward excursion of the endocardial contour. The centerline method was used to assess regional LV function calculated as the difference between the end-diastolic and end-systolic endocardial tracings. The deviation from the centerline of 100 chords around the LV circumference is calculated after correction for the end-diastolic circumference and expressed as a percentage-shortening fraction (SF). Each apical view of the LV is divided into six segments, and the SF of the chords in each segment is averaged so that a total of 12 values are obtained (six AP4CH and six AP2CH). Post-ischemic dysfunction (SFdysfunction) was defined as a reduction in SF of >30% at 30 min after peak dobutamine and other regions that did not demonstrate post-ischemic dysfunction defined as nondysfunctional (SFnorm). Left ventricular volumes at end diastole and end systole were calculated using the biplane disk method and global ejection fraction (EF) derived as previously described (11). The coefficient of repeatability for this method is 2.6% as assessed by the method of Bland and Altman (12).
PET scanning procedure. Positron emission tomography scans were performed using an ECAT 931-08/12 15-slice tomograph (CTI/Siemens, Knoxville, Tennessee). After a 20-min transmission scan, the blood pool was imaged by inhalation of tracer amounts of 15O-labelled carbon monoxide ([C15O] 3 MBq·ml–1 at 500 ml·min–1 for 4 min). Myocardial blood flow was then measured using H215O (10 MBq/kg) as previously described (13). The measurement of regional MMRO2 was performed using a build-up method as previously described (14); following a background frame of 30 s, 15O2 was inhaled for 5 min, and 10 additional 30-s frames were acquired. The scans were repeated after dobutamine stress (Fig. 1).
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To correct for the changes in MBF secondary to the increase in cardiac workload, MBF and MMRO2 was also corrected for the rate pressure product (RPP) (13).
Statistical analysis. Data are presented as mean ± 95% confidence intervals. The primary end points were based on the effects of pharmacologic stress on the echocardiographic parameters of LV function (EF, SFdysfunction and SFnorm) and MBF at baseline, peak stress and during recovery. All echocardiographic data met the assumption of homogeneity of variances required for analysis of variance (ANOVA). Echocardiographic parameters, MBF and hemodynamic parameters were compared using one-way ANOVA with a design for repeated measures, with Bonferroni’s test to correct for multiple comparisons.
The values of MBF and MMRO2 in SFdysfunction and SFnorm regions were compared using an unpaired t test. The values of regional LV function for each stenosis severity subset were compared by one-way ANOVA with a design for repeated measures as described above. The change of regional function 30 min after peak stress compared with baseline for each subset of stenosis severity was assessed using an unpaired t test. A value of p < 0.05 was considered significant for all analyses.
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Results |
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Global EF. At 30 and 45 min after dobutamine stress, EF was 59.1% (55.8% to 62.4%) and 61.2% (58.2% to 64.2%) (p < 0.001 and p < 0.05 vs. baseline, respectively) (Fig. 2, A). At 1 h and 2 h after peak stress, EF was 62.8% (60.4% to 65.3%) and 64.7% (61.4% to 68.0%) (both: p = NS vs. baseline). In nine of the 14 patients, global EF was reduced by >5% at 30 min.
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MBF. Baseline MBF to regions that exhibited reduced systolic function after dobutamine (SFdysfunction) was 0.88 (0.82 to 0.99) ml/min per g and 0.89 (0.81 to 0.90) ml/min per g in SFnorm regions (p = NS). Myocardial blood flow corrected for the RPP was 1.07 (1.01 to 1.23) ml/min per g and 1.05 (1.00 to 1.12) ml/min per g, respectively (p = NS). At peak stress, MBF increased both in SFdysfunction and SFnorm regions (1.44 [1.25 to 1.64] ml/min per g and 1.71 [1.62 to 1.81] ml/min per g, respectively, both: p < 0.001 vs. baseline) (Fig. 3A), but the increase in SFdysfunction regions was significantly lower than it was in SFnorm regions (p = 0.01). After dobutamine, MBF to SFdysfunction regions was 1.09 (0.75 to 1.37) ml/min/g (p = NS compared with baseline), and in SFnorm regions it was 1.11 (1.04 to 1.27) ml/min per g (p < 0.001 compared with baseline). This difference, however, was absent when MBF was corrected for RPP (Fig. 3B).
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Relation between stenosis severity and degree of myocardial dysfunction. The degree of myocardial dysfunction was assessed for regions subtended by coronary arteries of differing stenosis severities (16). Stenosis severity was categorized as <50%, 50% to 80% and >80% of the luminal diameter. When all 14 patients were assessed, regional function 30 min after peak stress did not change compared with baseline in regions subtended by a stenosis of <50% (96.3% [87.6 to 105.1] of baseline SF, p = NS). In regions subtended by arteries with a stenosis of 50% to 80% and in those with >80% stenosis, SF was 89.4% (84.0% to 94.8%) and 88.3% (77.3% to 99.4%) of baseline SF, respectively (both: p < 0.01 vs. baseline).
The relation between the stenosis severity and severity of regional LV dysfunction 30 min after dobutamine was also assessed in the nine patients with >5% reduction in global EF. In these patients, the severity of regional LV dysfunction was related to the degree of stenosis and inversely to the increase in MBF at peak dobutamine (Fig. 4). For regions subtended by an artery with a <50% stenosis (n = 24), SF was 93.9 (83.4 to 104.4) of baseline function 30 min after peak stress (p = NS) with a peak MBF of 2.01 (1.71 to 2.31) ml/min per g.
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Discussion |
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MBF and myocardial dysfunction. Myocardial stunning is defined as the post-ischemic LV dysfunction that persists in the absence of irreversible damage despite normal or near-normal myocardial perfusion (1,2). Prerequisites for confirming stunning involve both the demonstration of fully reversible LV dysfunction and normal or near-normal MBF when LV function is impaired. A number of studies have reported reversible LV dysfunction after exercise-induced ischemia in patients with CAD (8,11,17). Only one study using SPECT has demonstrated an absence of perfusion defects in regions with reversible LV dysfunction (8). Single photon emission computed tomography offers qualitative, or at best semiquantitative, data regarding relative changes in perfusion and, therefore, that study could only demonstrate a lack of major differences in MBF between dysfunctional and remote regions. More recently, Gerber et al. (18) have demonstrated normal absolute MBF using PET and the flow tracer nitrogen 13-labelled ammonia in patients with reversible LV dysfunction after an episode of unstable angina who were successfully treated by angioplasty. In contrast with that study (18) we were able to assess resting LV function and have demonstrated reversible LV dysfunction that is similar in duration to other published work (8,11,17). We have also shown that myocardial ischemia in patients with stable angina is not usually due to an absolute reduction in MBF but to a blunted rise in peak MBF compared with regions that do not develop dysfunction. In this setting ischemia fulfills the classic definition of an imbalance between demand and supply.
MMRO2 and stunning. Little data exist regarding MMRO2 to human stunned myocardium. The results of many animal studies support the theory of an "oxygen paradox" (19) whereby, despite a marked reduction in myocardial function, there is maintained oxygen consumption. In an isolated heart preparation using global ischemia to induce stunning MMRO2 has been found to be unchanged from baseline (20,21). In a conscious, chronically instrumented canine model of post-ischemic dysfunction, Laxson et al. (22) found no change in MMRO2 to stunned myocardium from baseline. Similar results have been demonstrated in an anesthetized, open-chested canine (19). Using PET and the tracer 1-11C-acetate as an indirect assessment of regional and global MMRO2, oxygen consumption to stunned myocardium has also been shown to be preserved in anesthetized dogs (23). In contrast with these findings, others have found a decrease in MMRO2 in proportion to the corresponding reduction in ventricular function (24).
Regarding the regional assessment of MMRO2 to acutely stunned myocardium in man, little data exist. In the recent study by Gerber et al. (18), regional MMRO2 to dysfunctional, but viable, segments was not different from remote regions. Due to the aforementioned time course of recovery in LV function in this study, there was no baseline data comparing a basal MMRO2. There is, therefore, no study to date in the human assessing regional MMRO2 to acutely stunned myocardium, assessing values both before ischemia and in the post-ischemic period during the post-ischemic LV dysfunction. Our data would support the hypothesis that the stunned myocardium shows a marked reduction in function, and during this dysfunction there was a trend for a reduction in MMRO2, although this difference did not achieve statistical significance. Overall, the oxygen utilization is inappropriately high for the degree of dysfunction seen. It would appear that this is due to inappropriate energy requirements for excitation-contraction coupling (20), and it has been suggested that, as well as the functional stunning that is seen, a "metabolic stunning" occurs (21).
Myocardial dysfunction and the severity of ischemia. We have demonstrated a relation between the degree of regional myocardial dysfunction and the impairment of peak MBF during stress. In animal models, where ischemia is usually induced by coronary ligation to reduce regional myocardial perfusion, it is generally accepted that the severity of myocardial stunning is related to the intensity and duration of the preceding bout of ischemia (25,26), although the former is more important (7). In patients with CAD, demand ischemia follows an inadequate increase in blood flow to meet an increase in myocardial work. In this study dobutamine was used to increase myocardial work as the movement of exercise precludes satisfactory PET imaging to be acquired. We have previously demonstrated that the resultant degree of LV dysfunction is similar after either form of demand-ischemia, although it is not possible to quantify the degree or duration of ischemia in an individual patient (17). Furthermore, dobutamine stress results in a progressive blunting of myocardial hyperemia with increasing coronary artery stenosis severity (27). This has been further confirmed in the present study, where myocardial regions subtended by a coronary artery with a higher-grade stenosis have a greater attenuation in peak MBF. In addition, such regions have now been shown to exhibit more marked reversible systolic dysfunction.
Although we have demonstrated a reduction in peak MBF with increasing stenosis severity, it is not possible to define the degree to which MBF must be reduced before ischemia ensues. Without continuous flow measurements, it is not possible to assess the true duration of ischemia since noninvasive markers of ischemia are unreliable. The occurrence and duration of chest pain is subjective and unlikely to be a valid marker. ST-segment depression with dobutamine has been demonstrated to have a sensitivity of only about 50% (28) and would, therefore, not enable an accurate estimation of the duration of ischemia (28).
Study limitations. In this study the assessment of MBF and MMRO2 after dobutamine was made immediately before the echocardiographic data acquisition 30 min after the end of the dobutamine infusion and not simultaneously. It is impossible to collect echocardiographic and PET data concurrently due to movement artefact and patient positioning. We believe that by demonstrating normal MBF before showing that LV function was still reduced confirms the presence of stunning. Our data are in accordance with reports from other workers using SPECT to assess myocardial perfusion who demonstrated no perfusion abnormalities 30 min after an ischemic episode (8).
We noted that for all 14 patients there was no significant difference in the degree of stunning between regions subtended by coronary arteries with a stenosis of 50% to 80% or >80%. However, in those patients in whom the overall EF was reduced >5%, there was a significant relation between the degree of stunning and the severity of the preceding episode of ischemia. This is most likely because many of the stenoses >80% were total occlusions and regions with normal resting function subtended by these arteries probably had a good collateral supply, thus reducing or preventing ischemia and, hence, stunning, although we did not assess the degree of collateralization. Finally, it is recognized that not all patients with stable CAD develop myocardial stunning (11).
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Footnotes |
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p < 0.05.
