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Does Dobutamine Stress Echocardiography Induce Damage During Viability Diagnosis of Patients with Chronic Regional Dysfunction After Myocardial Infarction?
Does Dobutamine Stress Echocardiography Induce Damage During Viability Diagnosis of Patients with Chronic Regional Dysfunction After Myocardial Infarction? Stephan Beckmann, MD, Wolfgang Bocksch, MD, Christian Mu¨ller, MD, and Michael Schartl, MD, Berlin, Germany
Experimental hibernating-model investigations of animals have shown that myocardial necrosis can be induced by longer-term intracoronary dobutamine infusion. This study was designed to determine whether myocardial infarction could be ascertained in patients with chronic regional wall motion abnormalities and greater than 75% stenosis in the supplying coronary artery through dobutamine stress echocardiography. Twenty patients with coronary artery disease and regional resting wall motion abnormalities were examined with a standard dobutamine protocol (5 to 50
The 1980s Rahimtoola
1
introduced the term “hibernating myocardium,” which he described as a reversible impairment of the myocardial and left ventricular pump function resulting from a reduced coronary blood flow. Because a revascularization through coronary bypass surgery or percutaneous transluminal coronary angioplasty can lead to improvement in regional pump function,2,3 the identification of viable myocardium plays a major role in making decisions concerning revascularization measures. In addition to radionuclear imaging,4 dobutamine echocardiography has begun to play an increasing role in this process.5– 8 Animal experiments demonstrated that hypoperfused viable myocardium exhibits a contractile reserve during inotropic stimulation with dobutamine.9 In the clinical arena contractile reserve during dobutamine stress echocardiography has been used to predict recovery of regional From the Department of Cardiology, Virchow Clinic and German Heart Institute Berlin, and the Institute of Clinical Chemistry and Biochemistry of the Virchow Clinic, Humboldt University. Presented in part at the 68th Annual Scientific Session of the American Heart Association, November 1995, Anaheim, California. Reprint requests: M. Schartl, MD, Department of Cardiology, Virchow-Clinic and German Heart Institute Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Copyright © 1998 by the American Society of Echocardiography. 0894-7317/98 $5.00 1 0 27/1/86094
mg/kg/min). Exclusion criteria were an acute coronary syndrome, severe heart failure, and severe hypertension. Creatine kinase (CK, CKMB), myoglobin, and troponine-I were measured before and at each of the first 7 hours after beginning of infusion. Fourteen of these 20 patients exhibited viable myocardium. The serum markers CK, CKMB, myoglobin, and troponin-I demonstrated no increase beyond the reference range, suggesting that with this protocol, no myocardial necrosis was induced. (J Am Soc Echocardiogr 1998; 11:181-7.)
myocardial function in patients with chronic ischemic heart disease.5– 8 The most conclusive evidence is obtained by not only infusing low-dose dobutamine but also by administering high doses (40 mg/kg body weight/min) as well.8,10 In animal experiments, intracoronary dobutamine infusion provided inotropic stimulation despite a continued decrease in subendocardial blood flow.9 In addition, Schulz et al.11 was able to show that metabolic adaptations of the myocardium occurring during longer-term hypoperfusion could be overcome by dobutamine infusion. Obvious cases of infarction were observed after longer periods of dobutamine infusion.12 In the case of postischemic cardiac dysfunction (stunned myocardium) no such deleterious effect could be detected.13 In light of the increasing importance of dobutamine echocardiography in detecting viable hibernating myocardium, we investigated patients with chronic resting regional wall motion abnormalities and coronary artery disease exhibiting more than 75% diameter stenosis of the corresponding coronary artery. This study was designed to determine whether myocardial infarction could be ascertained in these patients during intravenous high-dose dobutamine infusion. The serum markers for possible myocardium necrosis resulting from dobutamine infusion were creatine kinase (CK, CKMB), myoglobin, and troponin-I. 181
182 Beckmann et al.
METHODS Patient Population Patients with coronary artery disease and regional resting wall motion abnormalities were the subjects of this study. Twenty patients were enrolled. The criteria for inclusion were an age of 18 years or more, incidence of a significant coronary artery disease with a greater than 75% diameter stenosis in at least one epicardial coronary arterial branch, and a proven regional left ventricular resting wall motion abnormality in the region supplied by the stenosed coronary artery. In addition, sufficient image quality of all left ventricular segments was required. Exclusion criteria were an acute myocardial infarct within the preceding 4 weeks, an unstable angina pectoris, severe heart failure, significant valvular heart disease, cardiomyopathy, severe hypertension (systolic and diastolic blood pressure exceeding 200/120 mm Hg), left bundle branch block, previous aortocoronary bypass surgery, and lack of patient consent. Antianginal medication was discontinued 24 hours before the study. Written informed consent was obtained from all subjects.
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angina pectoris, dyspnea, systolic blood pressure to below 85 or above 220 mm Hg, systolic blood pressure decrease of more than 20 mm Hg from one infusion stage to the next, more than two mV ST segment depressions in the ECG, or significant arrhythmias (six beats of supraventricular tachycardia or three beats of ventricular tachycardia). Echocardiographic Image Processing and Analysis
Before enrollment in the study all patients scheduled for diagnostic cardiac catheterization were screened by twodimensional echocardiography. Patients with clear endocardial border delineation in the parasternal and apical views, resting wall motion abnormalities, and significant stenoses in the supplying coronary arteries were recruited. High-dose dobutamine stress echocardiography was performed within 1 week after diagnostic catheterization. Venous blood samples were taken from an antecubital vein through an indwelling venous catheter. The following venous blood sampling times were chosen: shortly before the beginning of dobutamine infusion and 1, 2, 3, 4, 5, 6, and 7 hours after the initiation of infusion. Each time a 12-lead electrocardiogram (ECG) was also recorded. The protocol was approved by an institutional review committee (Virchow-Clinic, Humboldt University).
All testing was conducted with a Vingmed CFM 750 (Vingmed Sound) rigged to a 3.25 MHz probe. For each view, one cardiac cycle was digitally transferred to a Macintosh IIci computer with commercially available software (Echoloops, Vingmed sound). Repeated images were obtained in all views before each incremental increase in infusion rate and during the following resting phase and were transferred digitally and stored on a magneto-optical disk. The echocardiographic images were displayed on the monitor as cineloops in quad-screen format and simultaneously evaluated in a synchronized-beat mode. The left ventricle was divided into 16 segments according to the recommended American Society of Echocardiography 16segment model.14 Wall motion was scored on systolic wall thickening and endocardial movement according to the following system: 1 5 normal; 2 5 hypokinetic; 3 5 akinetic; and 4 5 dyskinetic. A segment was judged to be normal if it displayed a normal systolic thickening and inward movement at rest with a hyperdynamic response on dobutamine. Initial improvement of one grade or more in a segment with resting wall motion abnormality with lowdose dobutamine was taken as evidence of viable myocardium. Deterioration during higher-dose infusion in this segment or a new occurrence of wall motion abnormality in an at-rest normal segment was considered to be an indication of ischemia. A fixed regional wall motion abnormality, unchanged during dobutamine administration, was classified as a scar. Left ventricle segments were assigned to the supply area of a certain coronary artery according to previously published guidelines.15
Dobutamine Stress Echocardiography
Coronary Angiography
The dobutamine echocardiography was performed according to a standard protocol. First, resting echocardiography was performed with the patient in the left decubitus position. Dobutamine was infused in 3-minute stages as follows: 5, 10, 20, 30, 40, and 50 mg/kg/min. If the maximum stress heart rate was not reached and there were no indications of ischemia, fractionated doses of atropine (maximum 1 mg) were injected intravenously. Echocardiographic images were obtained in the standardized parasternal long- and short-axis (midventricular) views as well as in apical two- and four-chamber views at each infusion stage and stored digitally. During infusion a 12-lead ECG was recorded and blood pressure was measured at each stress level. Heart rate was observed continuously by a single-lead ECG monitor. The following situations were grounds for termination of testing: 85% of the predicted maximum heart rate,
Coronary angiography was performed in all patients by use of the Judkins technique. All angiograms were analyzed by two experienced investigators blinded to the echocardiographic data. A more than 75% lumen diameter stenosis of a major epicardial coronary artery was defined as significant.
Protocol
Assessment of Serum Markers The venous blood samples were centrifuged, and the serum was stored at a temperature of 270° C. Assays and assignment of values were performed by staff who were unfamiliar with the patients’ clinical and echocardiographic data. Total CK and CKMB were determined kinetically after immunoinhibition with a Cobas Mira selective analyzer from Roche Diagnostica. The total CK reference range was below 70 U/L for women and below 80 U/L for men; the CKMB reference range was below 10 U/L and below 6% of the total CK.
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Myoglobin was measured with a latex-enhanced immunoassay with a Turbitimer from Behringwerke. The reference range was below 80 mg/L, the lower detection limit below 50 mg/L. Mass concentration of cardiac troponin-I was determined by immunoassay by use of a Stratus II analysis system from Dade. Two specific monoclonal antibodies for cardiac troponin-I were used in this assay. Cardiac troponin-I cannot be detected in healthy volunteer subjects. Parametric analysis of these assays performed in hospitalized patients with no myocardial infarction revealed an upper limit for the reference range of 0.60 ng/ml (97.5 percentile). The immunoassay has no detectable cross reactivity with the human skeletal muscle troponin-E.16 Statistical Analysis The mean values and standard deviations of all continuous variables were calculated. Significant variation of total CK, CKMB, myoglobin, and troponin-I was calculated with a Wilcoxon test. A value of p # 0.05 was considered statistically significant.
RESULTS Patient Population Fifteen men and 5 women with a mean age of 55 6 10.3 years and a history of myocardial infarction were included. The investigation was conducted at a mean interval of 20.5 6 36.7 weeks after the myocardial infarction. Twelve patients had suffered an anterior wall myocardial infarction and eight a posterior or lateral wall infarction. In the postinfarction period a stable angina pectoris developed in 10 patients. Seven patients presented with dyspnea during exercise. All patients were receiving antianginal medication, (Wblockers, 9; diltiazem, 1; nifedipin, 2; nitrates, 11; and verapamil, 1), which was discontinued 24 hours before the investigation. All patients exhibited greater than 75% diameter coronary artery stenoses (.75%: included left anterior descending 14, right 3, and left circumflex 7; .90% included left anterior descending 12, right 3, and left circumflex 6 patients). Hemodynamic Response to Dobutamine The mean maximum dobutamine dose was 38.5 6 9.8 mg/kg/min. Table 1 shows that no significant increase in heart rate or blood pressure occurred during low-dose dobutamine infusion. However, a significant increase was recorded with maximum dobutamine stimulation. Six patients were stimulated with the maximum dobutamine dose of 50 mg/kg/ min; one patient received atropine. Infusion was discontinued on grounds of reaching the maximum stress heart rate in nine, angina pectoris in four,
Beckmann et al. 183
Table 1 Hemodynamic response to dobutamine infusion Heart rate (beats/min)
SBP (mm Hg)
DBP (mm Hg)
Baseline rest 71.6 6 13.8 129.5 6 19.0 80.0 6 9.2 Low-dose (5 mg/ 73.3 6 13.6 132.5 6 21.9 78.0 6 9.5 kg/min) Peak dose 131.4 6 17.0* 147.7 6 31.1* 75.8 6 14.4 SBP, Systolic blood pressure; DBP, diastolic blood pressure. Data are expressed as mean value 6 SD. *p , 0.05 versus baseline.
dyspnea in one, blood pressure reduction in one, and regional wall motion abnormalities in five patients. Severe cardiac arrhythmias did not occur. Electrocardiography The ECGs of 15 patients exhibited signs of old myocardial infarctions. Four patients displayed pathologic Q waves in II, III, and aVF, one patient in I, aVL, and V5 and V6. In 10 patients there was insufficient R slope in the thoracic leads. Significant ST segment depression in II, III, and aVF developed in three patients, and in one patient in V1 through V4 during dobutamine stimulation. All these dobutamine-induced ECG changes resolved after the test and no sign of acute myocardial infarction was seen. Results of Dobutamine Echocardiography One hundred nineteen of the 320 evaluated segments exhibited a regional wall motion abnormality at rest (70 akinetic, 49 hypokinetic). Figure 1 shows that responses to the dobutamine stimulation varied. A biphasic response (improvement with low-dose dobutamine and deterioration during peak stimulation) was recorded in 20 resting akinetic and 27 resting hypokinetic segments. Improvement with low-dose as well as peak-dose dobutamine was shown by nine hypokinetic and nine akinetic segments. Forty one segments remained akinetic, nine segments hypokinetic. Four hypokinetic segments became akinetic without intervening improvement. In the resting phase after the dobutamine infusion the preexisting wall motion abnormalities displayed no expansion. Application of the above-cited definitions yielded indications of ischemia and viable myocardium in 10 patients. Four patients exhibited only viable myocardium, one patient exhibited only ischemia, and five patients had visible scars with no indication of viable myocardium. Protein Marker Variation in Blood None of the patients displayed an increase in the monitored protein markers beyond the reference
184 Beckmann et al.
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Figure 1 Segmental wall motion in 119 dyssynergic segments at baseline and during dobutamine infusion.
range. Tables 2 and 3 present mean values and their standard deviations.
DISCUSSION This investigation demonstrated that patients with suspected hibernating myocardium developed no clinical, echocardiographic, or electrocardiographic infarct when subjected to a widely used dobutamine infusion schedule with doses up to 50 mg/kg/min. Protein markers such as CK, CKMB, myoglobin, and troponin-I revealed no increase beyond the reference range. Serious side effects did not occur during dobutamine infusion. These results suggest that both low-dose and high-dose dobutamine can be infused to evaluate this patient population.
Detection of Viable Myocardium With Dobutamine Echocardiography Reports of the application of dobutamine echocardiography to detect viable myocardium have been published since the beginning of the 1990s.17–23 In the case of chronic regional dysfunction (hibernation) with stenosis in the supplying coronary artery, reversibility during low-dose dobutamine infusion (5 to 10 mg/kg/min) is a reliable predictor of left ventricular functional recovery after revascularization.7,24 –26 Afridi et al.8 demonstrated that optimal prediction of reversibility of such a wall motion abnormality is possible only if examination with both low- and highdose dobutamine procedures is performed. Patients who experienced a biphasic response in segments with resting wall motion abnormalities (improvement of pump function during low-dose dobutamine
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infusion and subsequent deterioration with a higher dosage of dobutamine) had the best prognosis for recovery after revascularization. On the basis of these findings the subjects of our investigation were examined under both low- and high-dose dobutamine procedures, since both are required for complete patient evaluation. Both our study and the abovecited investigations revealed no serious side effects of dobutamine infusion. Dobutamine and Hibernation Since the 1930s acute myocardial ischemia has been known to result in contractile dysfunction.27 The extent of the abnormal contraction closely corresponds to reduction of blood flow.28 Although total coronary artery occlusion without collateral blood supply leads to necrosis, with moderate ischemia reduced contractile function may lead to reduced myocardial energy consumption as a compensatory mechanism to preserve cell integrity.29 Rahimtoola1 introduced the term hibernating myocardium to describe this phenomenon. During ischemia in experimental animals an initial drop of the concentration of myocardial phosphocreatine is followed in the course of recovery by the attainment of a near-normal value.11 In such short-term hibernation patterns, an inotropic reserve exists that can be activated by intracoronary dobutamine infusion only, however, at the expense of impairing metabolic recovery.11 Infusion of (2.5 mg/min) dobutamine in anesthetized swine over longer periods demonstrated a subendocardialto-subepicardial redistribution of blood flow. Moreover, myocardial infarction affecting up to 26.3% 6 7.3% of the tested myocardial segments were induced.12 In this study enzyme markers and electrocardiographic examination failed to reveal infarction during intravenous dobutamine infusion. Several explanations for the differences between the animal experiments and our data can be considered. Contrasting with the short-term hibernation pattern with reduced coronary flow,12 a nearly normal resting blood flow can be ascertained in human beings in segments with resting wall motion abnormalities and demonstrated viable myocardium.30 –32 A more severe stenosis of a coronary artery need not affect normal resting blood flow, but it does entail progressive depletion of coronary flow reserve.33 Even a minor increase in the oxygen requirement may then induce ischemia.34 Thus chronic resting wall motion abnormalities coupled with severe coronary stenosis in conjunction with normal resting blood flow and limited coronary flow reserve could be a manifestation of recurrent ischemia or of repetitive stunning.30 Data from recent
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Table 2 Creatine kinase (CK) and CKMB in venous blood (U/L)
Rest End of Infusion 1 hour* 2 hours 3 hours 4 hours 5 hours 6 hours 7 hours
CK (U/L)
SD
CKMB (U/L)
SD
29.6 28.8 29.2 29.0 29.6 30.7 30.5 30.6 31.2
10.3 9.5 9.5 9.9 9.7 9.8 9.9 9.4 9.4
8.8 7.9 7.6 7.4 7.7 7.8 7.7 6.9 6.5
3.8 2.9 3.5 2.5 2.3 2.6 2.6 2.7 1.4
SD, Standard deviation. *Hours after the initiation of infusion.
Table 3 Myoglobin (mg/L) and troponin-I (ng/ml) in venous blood
Rest End of Infusion 1 hour* 2 hours 3 hours 4 hours 5 hours 6 hours 7 hours
Myoglobin (mg/L) SD
Troponin I (ng/ml)
SD
,50 ,50 ,50 ,50 ,50 ,50 ,50 ,50 ,50
0.21 0.20 0.19 0.16 0.24 0.15 0.25 0.23 0.21
0.28 0.26 0.30 0.26 0.31 0.25 0.31 0.29 0.37
SD, Standard deviation; myoglobin ,50 mg/L refers to an empirical value below the range of measurement. *Hours after the initiation of infusion.
animal experiments have corroborated this assumption.35 W-Adrenergic stimulation does not lead to infarction in cases of stunned myocardium,13,36 so no increases in enzyme markers or infarct-induced ECG changes are to be expected when repetitive stunning is presumed. Unlike the case of intracoronary dobutamine administration, intravenous dobutamine infusion in animals with coronary stenosis and reduced subendocardial flow leads to an increase both of subendocardial and subepicardial blood flow.37 Similarly, positron emission tomography evaluation in human beings demonstrated increased myocardial blood flow during intravenous infusion of 10 mg/ kg/min of dobutamine in segments with F-18 glucose/N-13 ammonium mismatches (i.e., regions of viable myocardium).31 Intravenous dobutamine dosages of up to 40 mg/kg/min were associated with an increase in myocardial blood flow in segments with resting wall motion abnormalities and ischemia.38 The various responses of subendocardial blood flow to intracoronary and intravenous dobutamine infu-
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186 Beckmann et al.
sion might be attributed to changes in global hemodynamics during stimulation of ischemic and nonischemic segments of the left ventricle by intravenous dobutamine.39 These global hemodynamic changes did not occur during intracoronary infusion of 2.5 mg/kg/min.12 Moreover, dobutamine can lead indirectly, through metabolic change and b-receptors, to vasodilation of coronary arteries.28 Since we also administered dobutamine intravenously in our investigation, this is another possible explanation for the absence of infarction when applying a high-dose dobutamine protocol. In addition, in our study the maximum infusion period was approximately 20 minutes, whereas dobutamine was infused for a period of more than 90 minutes in the investigations by Schulz et al.12 Evaluation of Protein Markers in Detection of Myocardial Necrosis This study used CK, the isoenzyme CKMB, myoglobin, and troponin-I as serum markers of myocardial necrosis. These markers showed no increases beyond the reference range in the first 7 hours after dobutamine echocardiography was performed. CK, CKMB,40 myoglobin,41,42 and troponin-I43 are sensitive markers for myocardial necrosis. Troponin-I also provides high specificity for cardiac necrosis.44 In the time frame we investigated, incidence of myocardial necrosis coincides with increases of these proteins.40 – 44 Increases of myoglobin in the serum have even been reported in the absence of ECG changes.42 Therefore the lack of an increase of any of the serum markers used in our study can be interpreted as an indication of the absence of significant myocardial necrosis. Limitations of the Study Not all patients showed signs of viable myocardium on echocardiographic criteria during dobutamine infusion. However, the purpose of the investigation was to detect the occurrence of dobutamine-induced myocardial necrosis under clinical conditions without preselection of patients. However, patients whose dobutamine echocardiogram is negative with respect to viability also often display small amounts of viable myocardium, which does not suffice for improvement of function.6 A check of subsequent postrevascularization improvement was not conducted because the literature contains much evidence that dobutamine echocardiography is a good predictor of viable myocardium.7,8 At-rest measurements of blood flow could not be consulted to confirm pathophysiologic positron emission tomography findings because they were not available at the time of the study.
Clinical Implications On the basis of the data presented here, the frequently used dobutamine infusion protocol can be applied to examine patients for viable myocardium in the chronic stage after myocardial infarction without demonstrated risk of myocardial infarction. Therefore, alteration of the dobutamine protocol to prevent myocardial necrosis is not necessary for this group of patients, and this population can be studied with both low-dose and high-dose dobutamine. REFERENCES 1. Rahimtoola SH. The hibernating myocardium. Am Heart J 1989;117:211–21. 2. Brundage BH, Massie BM, Botvinick EH. Improved regional ventricular function after successful surgical revascularization. J Am Coll Cardiol 1984;3:902– 8. 3. Cohen M, Charney R, Hershman R, Fuster V, Gorlin R. Reversal of chronic ischemic dysfunction after transluminal coronary angioplasty. J Am Coll Cardiol 1988;12:1193– 8. 4. Dilsizian V, Bonow R. Current diagnostic technique of assessing myocardial viability in patients with hibernating and stunned myocardium. Circulation 1993;87:1–20. 5. Baer F, Voth E, Deutsch H, Schneider C, Schicha H, Sechtem U. Assessment of viable myocardium by dobutamine transesophageal echocardiography and comparison with fluorine-18 fluordesoxyglucose positron emission tomography. J Am Coll Cardiol 1994;24:343–53. 6. Arnese M, Cornel J, Salustri A, et al. Prediction of improvement of regional left ventricular function after surgical revascularization. Circulation 1995;91:2748 –52. 7. Cigarroa C, deFilippi C, Brickner M, Alvarez L, Wait M, Grayburn P. Dobutamine stress echocardiography identifies hibernating myocardium and predicts recovery of left ventricular function after coronary revascularization. Circulation 1993;88:430 – 6. 8. Afridi I, Kleinman N, Raizner A, Zoghbi W. Dobutamine echocardiography in myocardial hibernation. Optimal dose and accuracy in predicting recovery of ventricular function after coronary angioplasty. Circulation 1995;91:663–70. 9. Schulz R, Miyazaki S, Miller M, et al. Consequences of regional inotropic stimulation of ischemic myocardium on regional myocardial blood flow and function in anesthetized swine. Circ Res 1989;64:1116 –26. 10. Senior R, Lahiri A. Enhanced detection of myocardial ischemia by stress dobutamine echocardiography utilizing the “biphasic” response of wall motion thickening during low and high dose dobutamine infusion. J Am Coll Cardiol 1995;26: 26 –32. 11. Schulz R, Guth B, Pieper K, Heusch G. Recruitment of an inotropic reserve in moderately ischemic myocardium at the expense of metabolic recovery. A model of short-term hibernation. Circ Res 1992;70:1282–95. 12. Schulz R, Rose J, Martin C, Broddle O, Heusch G. Development of short-term myocardial hibernation. Its limitation by the severity of ischemia and inotropic stimulation. Circulation 1993;88:684 –95. 13. Bolli R, Zhu W, Myers M, Hartley C, Roberts R. Betaadrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration. Am J Cardiol 1985;56:964 – 8.
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14. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantification of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 – 67. 15. Segar D, Brown S, Sawada S, Ryan T, Feigenbaum H. Dobutamine stress echocardiography: correlation with coronary lesion severity as determined by quantitative angiography. J Am Coll Cardiol 1992;19:1197–202. 16. Bodor GS, Porter S, Landt Y, Ladenson JH. Development of monoclonal antibodies for an assay of cardiac troponin-I and preliminary results in suspected cases of myocardial infarction. Clin Chem 1992;38:2203–14. 17. Pierard LA, De Landsheere CM, Berthe C, Rigo P, Kulbertus HE. Identification of viable myocardium by echocardiography during dobutamine infusion in patients with myocardial infarction after thrombolytic therapy: comparison with positron emission tomography. J Am Coll Cardiol 1990;15:1021–31. 18. Smart S, Sawada S, Ryan T, et al. Low-dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation 1993;88:405–15. 19. Barilla F, Gheorgiade M, Alam M, Khaja F, Goldstein S. Low-dose dobutamine in patients with acute myocardial infarction identifies viable but not contractile myocardium and predicts the magnitude of improvement in wall motion abnormalities in response to coronary revascularization. Am Heart J 1991;122:1522–31. 20. Salustri A, Elhendy A, Garyfallydis P, et al. Prediction of improvement of ventricular function after first acute myocardial infarction using low-dose dobutamine stress echocardiography. Am J Cardiol 1994;74:853– 6. 21. Watada H, Ito H, Oh H, et al. Dobutamine stress echocardiography predicts reversible dysfunction and quantifies the extent of irreversibly damaged myocardium after reperfusion of anterior myocardial infarction. J Am Coll Cardiol 1994;24: 624 –30. 22. Takeuchi M, Araki M, Nakashima Y, Kuroiwa A. The detection of residual ischemia and stenosis in patients with acute myocardial infarction with dobutamine stress echocardiography. J Am Soc Echocardiogr 1994;7:242–52. 23. Smart S, Knickelbine T, Carlos M, Stoiber T, Wynsen J, Sagar K. Safety of dobutamine stress echocardiography during the first week after acute myocardial infarction [abstract]. Circulation 1995;92:1– 411. 24. La Canna G, Alfieri O, Giubbini R, Gargano M, Ferrari R, Visioli O. Echocardiography during infusion of dobutamine for identification of reversible dysfunction in patients with chronic coronary artery disease. J Am Coll Cardiol 1994;23: 617–26. 25. Perrone-Filardi P, Pace L, Prastaro M, et al. Dobutamine echocardiography predicts improvement of hypoperfused dysfunctional myocardium after revascularization in patients with coronary artery disease. Circulation 1995;91:2556 – 65. 26. Meluzin J, Cigarroa C, Brickner E, et al. Dobutamine echocardiography in predicting improvement in global left ventricular systolic function after coronary bypass or angioplasty in patients with healed myocardial infarcts. Am J Cardiol 1995; 76:877– 80. 27. Tennant R, Wiggers C. The effect of coronary occlusion on myocardial contraction. Am J Physiol 1935;112:351– 61. 28. Vatner SF, McRitchie RJ, Braunwald E. Effects of dobutamine on left ventricular performance, coronary dynamics, and dis-
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Experimental hibernating-model investigations of animals have shown that myocardial necrosis can be induced by longer-term intracoronary dobutamine infusion. This study was designed to determine whether myocardial infarction could be ascertained in patients with chronic regional wall motion abnormalities and greater than 75% stenosis in the supplying coronary artery through dobutamine stress echocardiography. Twenty patients with coronary artery disease and regional resting wall motion abnormalities were examined with a standard dobutamine protocol (5 to 50
The 1980s Rahimtoola
1
introduced the term “hibernating myocardium,” which he described as a reversible impairment of the myocardial and left ventricular pump function resulting from a reduced coronary blood flow. Because a revascularization through coronary bypass surgery or percutaneous transluminal coronary angioplasty can lead to improvement in regional pump function,2,3 the identification of viable myocardium plays a major role in making decisions concerning revascularization measures. In addition to radionuclear imaging,4 dobutamine echocardiography has begun to play an increasing role in this process.5– 8 Animal experiments demonstrated that hypoperfused viable myocardium exhibits a contractile reserve during inotropic stimulation with dobutamine.9 In the clinical arena contractile reserve during dobutamine stress echocardiography has been used to predict recovery of regional From the Department of Cardiology, Virchow Clinic and German Heart Institute Berlin, and the Institute of Clinical Chemistry and Biochemistry of the Virchow Clinic, Humboldt University. Presented in part at the 68th Annual Scientific Session of the American Heart Association, November 1995, Anaheim, California. Reprint requests: M. Schartl, MD, Department of Cardiology, Virchow-Clinic and German Heart Institute Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Copyright © 1998 by the American Society of Echocardiography. 0894-7317/98 $5.00 1 0 27/1/86094
mg/kg/min). Exclusion criteria were an acute coronary syndrome, severe heart failure, and severe hypertension. Creatine kinase (CK, CKMB), myoglobin, and troponine-I were measured before and at each of the first 7 hours after beginning of infusion. Fourteen of these 20 patients exhibited viable myocardium. The serum markers CK, CKMB, myoglobin, and troponin-I demonstrated no increase beyond the reference range, suggesting that with this protocol, no myocardial necrosis was induced. (J Am Soc Echocardiogr 1998; 11:181-7.)
myocardial function in patients with chronic ischemic heart disease.5– 8 The most conclusive evidence is obtained by not only infusing low-dose dobutamine but also by administering high doses (40 mg/kg body weight/min) as well.8,10 In animal experiments, intracoronary dobutamine infusion provided inotropic stimulation despite a continued decrease in subendocardial blood flow.9 In addition, Schulz et al.11 was able to show that metabolic adaptations of the myocardium occurring during longer-term hypoperfusion could be overcome by dobutamine infusion. Obvious cases of infarction were observed after longer periods of dobutamine infusion.12 In the case of postischemic cardiac dysfunction (stunned myocardium) no such deleterious effect could be detected.13 In light of the increasing importance of dobutamine echocardiography in detecting viable hibernating myocardium, we investigated patients with chronic resting regional wall motion abnormalities and coronary artery disease exhibiting more than 75% diameter stenosis of the corresponding coronary artery. This study was designed to determine whether myocardial infarction could be ascertained in these patients during intravenous high-dose dobutamine infusion. The serum markers for possible myocardium necrosis resulting from dobutamine infusion were creatine kinase (CK, CKMB), myoglobin, and troponin-I. 181
182 Beckmann et al.
METHODS Patient Population Patients with coronary artery disease and regional resting wall motion abnormalities were the subjects of this study. Twenty patients were enrolled. The criteria for inclusion were an age of 18 years or more, incidence of a significant coronary artery disease with a greater than 75% diameter stenosis in at least one epicardial coronary arterial branch, and a proven regional left ventricular resting wall motion abnormality in the region supplied by the stenosed coronary artery. In addition, sufficient image quality of all left ventricular segments was required. Exclusion criteria were an acute myocardial infarct within the preceding 4 weeks, an unstable angina pectoris, severe heart failure, significant valvular heart disease, cardiomyopathy, severe hypertension (systolic and diastolic blood pressure exceeding 200/120 mm Hg), left bundle branch block, previous aortocoronary bypass surgery, and lack of patient consent. Antianginal medication was discontinued 24 hours before the study. Written informed consent was obtained from all subjects.
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angina pectoris, dyspnea, systolic blood pressure to below 85 or above 220 mm Hg, systolic blood pressure decrease of more than 20 mm Hg from one infusion stage to the next, more than two mV ST segment depressions in the ECG, or significant arrhythmias (six beats of supraventricular tachycardia or three beats of ventricular tachycardia). Echocardiographic Image Processing and Analysis
Before enrollment in the study all patients scheduled for diagnostic cardiac catheterization were screened by twodimensional echocardiography. Patients with clear endocardial border delineation in the parasternal and apical views, resting wall motion abnormalities, and significant stenoses in the supplying coronary arteries were recruited. High-dose dobutamine stress echocardiography was performed within 1 week after diagnostic catheterization. Venous blood samples were taken from an antecubital vein through an indwelling venous catheter. The following venous blood sampling times were chosen: shortly before the beginning of dobutamine infusion and 1, 2, 3, 4, 5, 6, and 7 hours after the initiation of infusion. Each time a 12-lead electrocardiogram (ECG) was also recorded. The protocol was approved by an institutional review committee (Virchow-Clinic, Humboldt University).
All testing was conducted with a Vingmed CFM 750 (Vingmed Sound) rigged to a 3.25 MHz probe. For each view, one cardiac cycle was digitally transferred to a Macintosh IIci computer with commercially available software (Echoloops, Vingmed sound). Repeated images were obtained in all views before each incremental increase in infusion rate and during the following resting phase and were transferred digitally and stored on a magneto-optical disk. The echocardiographic images were displayed on the monitor as cineloops in quad-screen format and simultaneously evaluated in a synchronized-beat mode. The left ventricle was divided into 16 segments according to the recommended American Society of Echocardiography 16segment model.14 Wall motion was scored on systolic wall thickening and endocardial movement according to the following system: 1 5 normal; 2 5 hypokinetic; 3 5 akinetic; and 4 5 dyskinetic. A segment was judged to be normal if it displayed a normal systolic thickening and inward movement at rest with a hyperdynamic response on dobutamine. Initial improvement of one grade or more in a segment with resting wall motion abnormality with lowdose dobutamine was taken as evidence of viable myocardium. Deterioration during higher-dose infusion in this segment or a new occurrence of wall motion abnormality in an at-rest normal segment was considered to be an indication of ischemia. A fixed regional wall motion abnormality, unchanged during dobutamine administration, was classified as a scar. Left ventricle segments were assigned to the supply area of a certain coronary artery according to previously published guidelines.15
Dobutamine Stress Echocardiography
Coronary Angiography
The dobutamine echocardiography was performed according to a standard protocol. First, resting echocardiography was performed with the patient in the left decubitus position. Dobutamine was infused in 3-minute stages as follows: 5, 10, 20, 30, 40, and 50 mg/kg/min. If the maximum stress heart rate was not reached and there were no indications of ischemia, fractionated doses of atropine (maximum 1 mg) were injected intravenously. Echocardiographic images were obtained in the standardized parasternal long- and short-axis (midventricular) views as well as in apical two- and four-chamber views at each infusion stage and stored digitally. During infusion a 12-lead ECG was recorded and blood pressure was measured at each stress level. Heart rate was observed continuously by a single-lead ECG monitor. The following situations were grounds for termination of testing: 85% of the predicted maximum heart rate,
Coronary angiography was performed in all patients by use of the Judkins technique. All angiograms were analyzed by two experienced investigators blinded to the echocardiographic data. A more than 75% lumen diameter stenosis of a major epicardial coronary artery was defined as significant.
Protocol
Assessment of Serum Markers The venous blood samples were centrifuged, and the serum was stored at a temperature of 270° C. Assays and assignment of values were performed by staff who were unfamiliar with the patients’ clinical and echocardiographic data. Total CK and CKMB were determined kinetically after immunoinhibition with a Cobas Mira selective analyzer from Roche Diagnostica. The total CK reference range was below 70 U/L for women and below 80 U/L for men; the CKMB reference range was below 10 U/L and below 6% of the total CK.
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Myoglobin was measured with a latex-enhanced immunoassay with a Turbitimer from Behringwerke. The reference range was below 80 mg/L, the lower detection limit below 50 mg/L. Mass concentration of cardiac troponin-I was determined by immunoassay by use of a Stratus II analysis system from Dade. Two specific monoclonal antibodies for cardiac troponin-I were used in this assay. Cardiac troponin-I cannot be detected in healthy volunteer subjects. Parametric analysis of these assays performed in hospitalized patients with no myocardial infarction revealed an upper limit for the reference range of 0.60 ng/ml (97.5 percentile). The immunoassay has no detectable cross reactivity with the human skeletal muscle troponin-E.16 Statistical Analysis The mean values and standard deviations of all continuous variables were calculated. Significant variation of total CK, CKMB, myoglobin, and troponin-I was calculated with a Wilcoxon test. A value of p # 0.05 was considered statistically significant.
RESULTS Patient Population Fifteen men and 5 women with a mean age of 55 6 10.3 years and a history of myocardial infarction were included. The investigation was conducted at a mean interval of 20.5 6 36.7 weeks after the myocardial infarction. Twelve patients had suffered an anterior wall myocardial infarction and eight a posterior or lateral wall infarction. In the postinfarction period a stable angina pectoris developed in 10 patients. Seven patients presented with dyspnea during exercise. All patients were receiving antianginal medication, (Wblockers, 9; diltiazem, 1; nifedipin, 2; nitrates, 11; and verapamil, 1), which was discontinued 24 hours before the investigation. All patients exhibited greater than 75% diameter coronary artery stenoses (.75%: included left anterior descending 14, right 3, and left circumflex 7; .90% included left anterior descending 12, right 3, and left circumflex 6 patients). Hemodynamic Response to Dobutamine The mean maximum dobutamine dose was 38.5 6 9.8 mg/kg/min. Table 1 shows that no significant increase in heart rate or blood pressure occurred during low-dose dobutamine infusion. However, a significant increase was recorded with maximum dobutamine stimulation. Six patients were stimulated with the maximum dobutamine dose of 50 mg/kg/ min; one patient received atropine. Infusion was discontinued on grounds of reaching the maximum stress heart rate in nine, angina pectoris in four,
Beckmann et al. 183
Table 1 Hemodynamic response to dobutamine infusion Heart rate (beats/min)
SBP (mm Hg)
DBP (mm Hg)
Baseline rest 71.6 6 13.8 129.5 6 19.0 80.0 6 9.2 Low-dose (5 mg/ 73.3 6 13.6 132.5 6 21.9 78.0 6 9.5 kg/min) Peak dose 131.4 6 17.0* 147.7 6 31.1* 75.8 6 14.4 SBP, Systolic blood pressure; DBP, diastolic blood pressure. Data are expressed as mean value 6 SD. *p , 0.05 versus baseline.
dyspnea in one, blood pressure reduction in one, and regional wall motion abnormalities in five patients. Severe cardiac arrhythmias did not occur. Electrocardiography The ECGs of 15 patients exhibited signs of old myocardial infarctions. Four patients displayed pathologic Q waves in II, III, and aVF, one patient in I, aVL, and V5 and V6. In 10 patients there was insufficient R slope in the thoracic leads. Significant ST segment depression in II, III, and aVF developed in three patients, and in one patient in V1 through V4 during dobutamine stimulation. All these dobutamine-induced ECG changes resolved after the test and no sign of acute myocardial infarction was seen. Results of Dobutamine Echocardiography One hundred nineteen of the 320 evaluated segments exhibited a regional wall motion abnormality at rest (70 akinetic, 49 hypokinetic). Figure 1 shows that responses to the dobutamine stimulation varied. A biphasic response (improvement with low-dose dobutamine and deterioration during peak stimulation) was recorded in 20 resting akinetic and 27 resting hypokinetic segments. Improvement with low-dose as well as peak-dose dobutamine was shown by nine hypokinetic and nine akinetic segments. Forty one segments remained akinetic, nine segments hypokinetic. Four hypokinetic segments became akinetic without intervening improvement. In the resting phase after the dobutamine infusion the preexisting wall motion abnormalities displayed no expansion. Application of the above-cited definitions yielded indications of ischemia and viable myocardium in 10 patients. Four patients exhibited only viable myocardium, one patient exhibited only ischemia, and five patients had visible scars with no indication of viable myocardium. Protein Marker Variation in Blood None of the patients displayed an increase in the monitored protein markers beyond the reference
184 Beckmann et al.
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Figure 1 Segmental wall motion in 119 dyssynergic segments at baseline and during dobutamine infusion.
range. Tables 2 and 3 present mean values and their standard deviations.
DISCUSSION This investigation demonstrated that patients with suspected hibernating myocardium developed no clinical, echocardiographic, or electrocardiographic infarct when subjected to a widely used dobutamine infusion schedule with doses up to 50 mg/kg/min. Protein markers such as CK, CKMB, myoglobin, and troponin-I revealed no increase beyond the reference range. Serious side effects did not occur during dobutamine infusion. These results suggest that both low-dose and high-dose dobutamine can be infused to evaluate this patient population.
Detection of Viable Myocardium With Dobutamine Echocardiography Reports of the application of dobutamine echocardiography to detect viable myocardium have been published since the beginning of the 1990s.17–23 In the case of chronic regional dysfunction (hibernation) with stenosis in the supplying coronary artery, reversibility during low-dose dobutamine infusion (5 to 10 mg/kg/min) is a reliable predictor of left ventricular functional recovery after revascularization.7,24 –26 Afridi et al.8 demonstrated that optimal prediction of reversibility of such a wall motion abnormality is possible only if examination with both low- and highdose dobutamine procedures is performed. Patients who experienced a biphasic response in segments with resting wall motion abnormalities (improvement of pump function during low-dose dobutamine
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infusion and subsequent deterioration with a higher dosage of dobutamine) had the best prognosis for recovery after revascularization. On the basis of these findings the subjects of our investigation were examined under both low- and high-dose dobutamine procedures, since both are required for complete patient evaluation. Both our study and the abovecited investigations revealed no serious side effects of dobutamine infusion. Dobutamine and Hibernation Since the 1930s acute myocardial ischemia has been known to result in contractile dysfunction.27 The extent of the abnormal contraction closely corresponds to reduction of blood flow.28 Although total coronary artery occlusion without collateral blood supply leads to necrosis, with moderate ischemia reduced contractile function may lead to reduced myocardial energy consumption as a compensatory mechanism to preserve cell integrity.29 Rahimtoola1 introduced the term hibernating myocardium to describe this phenomenon. During ischemia in experimental animals an initial drop of the concentration of myocardial phosphocreatine is followed in the course of recovery by the attainment of a near-normal value.11 In such short-term hibernation patterns, an inotropic reserve exists that can be activated by intracoronary dobutamine infusion only, however, at the expense of impairing metabolic recovery.11 Infusion of (2.5 mg/min) dobutamine in anesthetized swine over longer periods demonstrated a subendocardialto-subepicardial redistribution of blood flow. Moreover, myocardial infarction affecting up to 26.3% 6 7.3% of the tested myocardial segments were induced.12 In this study enzyme markers and electrocardiographic examination failed to reveal infarction during intravenous dobutamine infusion. Several explanations for the differences between the animal experiments and our data can be considered. Contrasting with the short-term hibernation pattern with reduced coronary flow,12 a nearly normal resting blood flow can be ascertained in human beings in segments with resting wall motion abnormalities and demonstrated viable myocardium.30 –32 A more severe stenosis of a coronary artery need not affect normal resting blood flow, but it does entail progressive depletion of coronary flow reserve.33 Even a minor increase in the oxygen requirement may then induce ischemia.34 Thus chronic resting wall motion abnormalities coupled with severe coronary stenosis in conjunction with normal resting blood flow and limited coronary flow reserve could be a manifestation of recurrent ischemia or of repetitive stunning.30 Data from recent
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Table 2 Creatine kinase (CK) and CKMB in venous blood (U/L)
Rest End of Infusion 1 hour* 2 hours 3 hours 4 hours 5 hours 6 hours 7 hours
CK (U/L)
SD
CKMB (U/L)
SD
29.6 28.8 29.2 29.0 29.6 30.7 30.5 30.6 31.2
10.3 9.5 9.5 9.9 9.7 9.8 9.9 9.4 9.4
8.8 7.9 7.6 7.4 7.7 7.8 7.7 6.9 6.5
3.8 2.9 3.5 2.5 2.3 2.6 2.6 2.7 1.4
SD, Standard deviation. *Hours after the initiation of infusion.
Table 3 Myoglobin (mg/L) and troponin-I (ng/ml) in venous blood
Rest End of Infusion 1 hour* 2 hours 3 hours 4 hours 5 hours 6 hours 7 hours
Myoglobin (mg/L) SD
Troponin I (ng/ml)
SD
,50 ,50 ,50 ,50 ,50 ,50 ,50 ,50 ,50
0.21 0.20 0.19 0.16 0.24 0.15 0.25 0.23 0.21
0.28 0.26 0.30 0.26 0.31 0.25 0.31 0.29 0.37
SD, Standard deviation; myoglobin ,50 mg/L refers to an empirical value below the range of measurement. *Hours after the initiation of infusion.
animal experiments have corroborated this assumption.35 W-Adrenergic stimulation does not lead to infarction in cases of stunned myocardium,13,36 so no increases in enzyme markers or infarct-induced ECG changes are to be expected when repetitive stunning is presumed. Unlike the case of intracoronary dobutamine administration, intravenous dobutamine infusion in animals with coronary stenosis and reduced subendocardial flow leads to an increase both of subendocardial and subepicardial blood flow.37 Similarly, positron emission tomography evaluation in human beings demonstrated increased myocardial blood flow during intravenous infusion of 10 mg/ kg/min of dobutamine in segments with F-18 glucose/N-13 ammonium mismatches (i.e., regions of viable myocardium).31 Intravenous dobutamine dosages of up to 40 mg/kg/min were associated with an increase in myocardial blood flow in segments with resting wall motion abnormalities and ischemia.38 The various responses of subendocardial blood flow to intracoronary and intravenous dobutamine infu-
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186 Beckmann et al.
sion might be attributed to changes in global hemodynamics during stimulation of ischemic and nonischemic segments of the left ventricle by intravenous dobutamine.39 These global hemodynamic changes did not occur during intracoronary infusion of 2.5 mg/kg/min.12 Moreover, dobutamine can lead indirectly, through metabolic change and b-receptors, to vasodilation of coronary arteries.28 Since we also administered dobutamine intravenously in our investigation, this is another possible explanation for the absence of infarction when applying a high-dose dobutamine protocol. In addition, in our study the maximum infusion period was approximately 20 minutes, whereas dobutamine was infused for a period of more than 90 minutes in the investigations by Schulz et al.12 Evaluation of Protein Markers in Detection of Myocardial Necrosis This study used CK, the isoenzyme CKMB, myoglobin, and troponin-I as serum markers of myocardial necrosis. These markers showed no increases beyond the reference range in the first 7 hours after dobutamine echocardiography was performed. CK, CKMB,40 myoglobin,41,42 and troponin-I43 are sensitive markers for myocardial necrosis. Troponin-I also provides high specificity for cardiac necrosis.44 In the time frame we investigated, incidence of myocardial necrosis coincides with increases of these proteins.40 – 44 Increases of myoglobin in the serum have even been reported in the absence of ECG changes.42 Therefore the lack of an increase of any of the serum markers used in our study can be interpreted as an indication of the absence of significant myocardial necrosis. Limitations of the Study Not all patients showed signs of viable myocardium on echocardiographic criteria during dobutamine infusion. However, the purpose of the investigation was to detect the occurrence of dobutamine-induced myocardial necrosis under clinical conditions without preselection of patients. However, patients whose dobutamine echocardiogram is negative with respect to viability also often display small amounts of viable myocardium, which does not suffice for improvement of function.6 A check of subsequent postrevascularization improvement was not conducted because the literature contains much evidence that dobutamine echocardiography is a good predictor of viable myocardium.7,8 At-rest measurements of blood flow could not be consulted to confirm pathophysiologic positron emission tomography findings because they were not available at the time of the study.
Clinical Implications On the basis of the data presented here, the frequently used dobutamine infusion protocol can be applied to examine patients for viable myocardium in the chronic stage after myocardial infarction without demonstrated risk of myocardial infarction. Therefore, alteration of the dobutamine protocol to prevent myocardial necrosis is not necessary for this group of patients, and this population can be studied with both low-dose and high-dose dobutamine. REFERENCES 1. Rahimtoola SH. The hibernating myocardium. Am Heart J 1989;117:211–21. 2. Brundage BH, Massie BM, Botvinick EH. Improved regional ventricular function after successful surgical revascularization. J Am Coll Cardiol 1984;3:902– 8. 3. Cohen M, Charney R, Hershman R, Fuster V, Gorlin R. Reversal of chronic ischemic dysfunction after transluminal coronary angioplasty. J Am Coll Cardiol 1988;12:1193– 8. 4. Dilsizian V, Bonow R. Current diagnostic technique of assessing myocardial viability in patients with hibernating and stunned myocardium. Circulation 1993;87:1–20. 5. Baer F, Voth E, Deutsch H, Schneider C, Schicha H, Sechtem U. Assessment of viable myocardium by dobutamine transesophageal echocardiography and comparison with fluorine-18 fluordesoxyglucose positron emission tomography. J Am Coll Cardiol 1994;24:343–53. 6. Arnese M, Cornel J, Salustri A, et al. Prediction of improvement of regional left ventricular function after surgical revascularization. Circulation 1995;91:2748 –52. 7. Cigarroa C, deFilippi C, Brickner M, Alvarez L, Wait M, Grayburn P. Dobutamine stress echocardiography identifies hibernating myocardium and predicts recovery of left ventricular function after coronary revascularization. Circulation 1993;88:430 – 6. 8. Afridi I, Kleinman N, Raizner A, Zoghbi W. Dobutamine echocardiography in myocardial hibernation. Optimal dose and accuracy in predicting recovery of ventricular function after coronary angioplasty. Circulation 1995;91:663–70. 9. Schulz R, Miyazaki S, Miller M, et al. Consequences of regional inotropic stimulation of ischemic myocardium on regional myocardial blood flow and function in anesthetized swine. Circ Res 1989;64:1116 –26. 10. Senior R, Lahiri A. Enhanced detection of myocardial ischemia by stress dobutamine echocardiography utilizing the “biphasic” response of wall motion thickening during low and high dose dobutamine infusion. J Am Coll Cardiol 1995;26: 26 –32. 11. Schulz R, Guth B, Pieper K, Heusch G. Recruitment of an inotropic reserve in moderately ischemic myocardium at the expense of metabolic recovery. A model of short-term hibernation. Circ Res 1992;70:1282–95. 12. Schulz R, Rose J, Martin C, Broddle O, Heusch G. Development of short-term myocardial hibernation. Its limitation by the severity of ischemia and inotropic stimulation. Circulation 1993;88:684 –95. 13. Bolli R, Zhu W, Myers M, Hartley C, Roberts R. Betaadrenergic stimulation reverses postischemic myocardial dysfunction without producing subsequent functional deterioration. Am J Cardiol 1985;56:964 – 8.
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