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Annu. Rev. Med. 1991. 42:1-8 Copyright © 1991 by Annual Reviews Inc. All rights reserved
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STUNNED AND HIBERNATING MYOCARDIUM Robert A. Kloner, M.D., Ph.D., and Karin Przyklenk, Ph.D.
The Heart Institute, The Hospital of the Good Samaritan, Los Angeles, California 90017; and Section of Cardiology, University of Southern California, Los Angeles, California 90033 KEY
WORDS:
myocardial ischemia, myocardial rcpcrfusion, myocardial infarc tion, thrombolysis, angioplasty
ABSTRACT
Myocardium that is not functioning may be dead (infarct or scar), viable but stunned (postischemic ventricular dysfunction), viable but hibernating (chronic low flow state), or acutely ischemic. Stunned myocardium has clearly been documented (a) in experimental studies of brief coronary artery occlusion followed by reperfusion, and (b) in myocardial infarct models in which early reperfusion salvages viable tissue. Recent clinical studies have confirmed the existence of stunned myocardium in humans. Evidence supporting the concept of hibernating myocardium comes from clinical studies in which patients with chronic low flow ischemia exhibit improvement in left ventricular function (sometimes immediately) fol lowing revascularization. INTRODUCTION
There are several possible causes for a regional wall motion abnormality of the left ventricle. The contractile abnormality may be due to infarcted tissue or scar; if so, coronary artery revascularization will not improve the wall motion abnormality. Regional contractile dysfunction may arise when viable myocardium has been affected by a period of low blood flow. The abnormality in function will then be resolved once sufficient blood flow is 0066-4219/91/0401--0001$02.00
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
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KLONER & PRZYKLENK
restored. This latter situation could be the result of (a) clinically active ischemia with angina pectoris and ischemic ST segment abnormality on the electrocardiogram; (b) "hibernating" myocardium-that is, a chronic low flow state in which clinically active ischemia (as evidenced by chest pain or ECG change) may not be present at the time the wall motion abnormality is observed; or (c) "stunned" myocardium in which clinically active ischemia is no longer present but the wall motion abnormality persists for a prolonged period following reperfusion. This review discusses the concepts of stunned and hibernating myocardium. THE STUNNED MYOCARDIUM
Stunned myocardium refers to dysfunction of viable ventricular myo cardium salvaged by reperfusion. This concept was first described in exper imental studies (I). For example, a coronary artery occlusion of 15 minutes followed by reperfusion in an experimental canine model does not cause cell necrosis. Myocytes subjected to such a mild ischemic insult are said to be reversibly injured and, when viewed by light microscopy, appear essentially normal following reperfusion. Such models of brief and tran sient ischemia mimic the syndrome of angina in that the ischemia is not associated with myocardial cell death. While the cells appear normal by routine histology, abnormalities of both systolic and diastolic function persist for 6-48 hours after reflow (2-4). In addition to these wall motion abnormalities, stunned myocardium is also characterized by transient depression of myocardial ATP levels and by the appearance of vacuoles adjacent to the mitochondria in ultrastructural studies (2). Stunned myocardium has also been observed following more prolonged periods of ischemia. When a two-hour myocardial infarct is reperfused in the experimental laboratory, viable but previously ischemic tissue is sal vaged in the subepicardium. This layer of tissue does not necessarily begin active contraction immediately: in fact, active left ventricular wall thickening in the infarct-related area does not occur until 48 hours after reperfusion, with further improvement in function throughout the initial two weeks after reflow. In contrast, transmural infarcts created by per manent coronary occlusion (no reperfusion) failed to develop active con traction over a two-week period of time (5). While the stunned myocardium does not, by definition, resume active contraction following reperfusion, it can be recruited or stimulated to contract with inotropic agents such as dopamine, dobutamine, iso proterenol, and epinephrine. Thus the stunned myocardium maintains its potential to contract, and if needed clinically (as might be the case in a
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
STUNNED AND HIBERNATING MYOCARDIUM
3
patient who has had early reperfusion therapy for acute myocardial infarc tion but who remains in severe heart failure or cardiogenic shock) it can be recruited to improve overall left ventricular function (6, 7). Why should the heart react to even brief episodes of ischemia in such a peculiar fashion? Several theories have been suggested to explain the phenomenon of stunning (8). Investigations have demonstrated that reper fusion is associated with a burst of cytotoxic, oxygen-derived free radical production (9). These oxygen radicals, including the superoxide anion and hydroxyl radical, can contribute to lipid peroxidation of membranes, which in turn alters both membrane structure and function. One theory of the mechanism of stunned myocardium claims that oxygen free radical damage to the sarcolemmal membrane makes the heart more susceptible to calcium overload, and the resulting relative contracture of the myofilaments impairs organized relaxation and contraction. Another theory suggests that oxygen radicals limit the ability of the sarcoplasmic reticulum to take up calcium. This could deplete calcium stores within the sarcoplasmic reticulum and reduce its ability to release sufficient calcium to the crucial sites along actin-myosin filaments. Such events would result in an electrical mechanical dissociation. Which (if any) of these theories is correct remains to be determined; however, there is ample evidence in the literature sup porting both the role of oxygen free radicals (10) and abnormalities in calcium homeostasis (11) in the pathophysiology of myocardial stunning. What types of patients are likely to demonstrate stunned myocardium? One group of patients who may exhibit postischemic dysfunction are those who have received thrombolytic therapy for acute myocardial infarction. Several clinical studies have reported that wall motion abnormalities may not improve immediately or dramatically following thrombolytic therapy (12). For example, Touchstone et al (1 3) observed very little improvement in regional wall motion over the first three days following intravenous streptokinase therapy. However, between three and ten days ofreperfusion there were dramatic improvements in function. Several studies have sug gested that improvement in regional wall motion may not be observed until 10-16 days after thrombolysis (12). Thus, one cannot predict the ultimate return of cardiac function after thrombolytic therapy from the results during the first few days after treatment. There is some indirect evidence from clinical studies that stunned myo cardium can be stimulated to contract. Satler and colleagues (14) observed that small doses of isoproterenol increased ejection fraction to a greater extent in patients who were successfully reperfused than in those patients in whom reperfusion treatment was unsuccessful. The incremental increase
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
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KLONER & PRZYKLENK
in ejection fraction in the reperfused group may have been related to the presence of salvaged but stunned myocardium. The improvements in function occurring over the course of 10-16 days after thrombolytic therapy may initially appear small. For example, in many of the clinical trials, the initial ejection fraction at the time of thrombolysis is approximately 45-50% , while 10-16 days later the ejection fraction tends to increase to �50-55% . Are these modest improvements in function clinically meaningful? What happens to left ventricular funtion if reperfusion is not achieved? Guerci et al (15) reported a 4% increase in left ventricular ejection fraction 10 days after patients received tissue plasminogen activator for evolving acute myocardial infarction. In contrast, patients who received placebo actually had a 5% decrease in ejection fraction. Furthermore, the increase in left ventricular ejection fraction observed in patients receiving tissue plasminogen activator was associated with a smaller incidence of clinical congestive heart failure compared with those patients who received placebo. Thus the gradual improvement in function of stunned myocardium does translate to event ual improvement in clinical symptoms. A second important group of patients who may exhibit stunned myo cardium are those who develop ischemia during exercise treadmill tests. Stunned myocardium can occur when experimental animals with a partial coronary stenosis are subjected to exercise (16). Recent evidence from two dimensional echocardiographic exercise treadmill tests suggests that the same phenomenon occurs in humans. Robertson and coworkers inves tigated a small group of patients who demonstrated persistent regional wall motion abnormalities by echocardiography at 30 minutes after ter mination of exercise (17). These wall motion abnormalities persisted well beyond the incidence of angina or electrocardiographic changes, and they were common in patients with double and triple vessel coronary artery disease. We have also reported a high prevalence of persistent wall motion abnormalities 30 minutes after exercise in a large cohort of patients with documented coronary artery disease (18). Some studies have suggested that stunned myocardium may also be present in patients with unstable angina (12). Finally, a fourth group of patients who may demonstrate stunned myocardium are those who under go heart surgery with cardiopulmonary bypass. As cardiology consultants are aware, many of these patients require inotropic support for hours to days following cardiac surgery. Despite cardioplegia, such initial inotropic support following surgery suggests that these hearts initially may be stunned after cardiopulmonary bypass. What potential therapies are available for stunned myocardium? Experi-
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
STUNNED AND HIBERNATING MYOCARDIUM
5
mental studies indicate that many pharmacologic agents can be used to treat postischemic dysfunction. Inotropic drugs can stimulate the stunned myocardium to contract (6, 7). Drugs that can overcome the stunning phenomenon arc more directly therapeutic. Agents that can improve the function of stunned myocardium include oxygen free radical scavenging agents, such as superoxide dismutase and catalase; allopurinol, which blocks the formation of the superoxide anion (19); calcium blockers, including nifedipine, verapamil, diltiazem, and amlodipine (20); angio tensin converting enzyme inhibitors, such as captopril (21); and prosta glandins (22). Whether or not these pharmacological therapies will prove beneficial in clinical instances of stunned myocardium remains to be determined. THE HIBERNATING MYOCARDIUM
The concept of hibernating myocardium is both similar to and different from the concept of stunned myocardium. In both situations a wall motion abnormality of the left ventricle is present, and in both situations viable myocardium exhibiting abnormal contractile function is present. In stunned myocardium, blood flow has been restored and ischemia is relieved, but the wall motion abnormality persists even after reperfusion (8). Hibernating myocardium is characterized by chronic, sublethal ischemia with persistent dysfunction of viable tissue while blood flow is reduced. Once flow is restored, however, function of hibernating myo cardium recovers (23, 24). Some investigators have hypothesized that the hibernating myocardium is a protective process, depressing the tissue's contractile function in order to reduce oxygen demand in the setting of reduced oxygen supply (23, 24). In a sense, this concept is a clinical construct used to explain the finding that some patients with chronic ventricular wall motion abnormalities exhibit improvement in contractile function following revascularization procedures (coronary artery bypass surgery, angioplasty). However, whether the heart is truly hibernating from a biochemical perspective remains to be fully explored. In fact, little is known regarding the basic science of the hibernating myocardium. In one study, Fedele et al (25) subjected pigs to an 80% reduction in coronary artery diameter for three hours. They observed a transient decline in coronary venous pH and a transient increase in coronary venous PC02 during the first 5-20 minutes of coronary stenosis; both levels returned to baseline by 1-3 hours. Lactate consumption prior to the stenosis changed to lactate production post stenosis, but lactate consumption was gradually restored within three
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
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KLONER & PRZYKLENK
hours. While regional oxygen consumption declined at five minutes after stenosis, it returned to baseline values within an hour. Regional left ven tricular function was depressed throughout the study. These data suggest a time-dependent adjustment in cardiac metabolism that occurs rapidly after partial stenosis and may help reverse some of the metabolic sequelae of ischemia. Clinical evidence supporting the concept of hibernating myocardium comes largely from studies that demonstrate resolution of chronic wall motion abnormalities following coronary artery bypass surgery or angio piasty (23, 24). Rahimtoola (23) recently reviewed the clinical studies supporting the concept of hibernating myocardium. Some of these studies suggested that, unlike the gradual recovery of stunned myocardium, the improvement in function following revascularization of hibernating myo cardium occurs immediately. For example, Carlson et al (26) observed that regional ejection fraction improved immediately following angioplasty of patients with unstable angina pectoris. Cohen et al (27) reported the results of angioplasty in 12 patients with severe regional wall motion abnormalities who had an element of "reversible chronic ischemia" defined by angina, improvement in function following postextrasystolic potentiation, or thallium uptake in the nonfunctioning zone. They observed that following angioplasty there was an immediate increase in left ventricular ejection fraction and an immediate reduction in the per centage of the left ventricular circumference showing asynergy, findings that support the concept of hibernating myocardium. It is conceivable that the immediate recovery of function observed in some of these patients was due to pretreatment with calcium channel blockers (20). Additional evidence supporting this phenomenon, as well as a technique that may be utilized to identify hibernating myocardium, comes from positron emission tomography (PET) (28). PET can evaluate regional myocardial blood flow with tracers such as rubidium, and can detect the presence of ongoing active metabolism with tracers such as fluoro deoxyglucose. Hibernating myocardium is characterized by an area of the left ventricle showing depressed function and reduced uptake of rubidium (reduced flow) but active or increased fluorodeoxyglucose uptake. Tillisch et' al (29) utilized PET scanning and found that such regions could predict the reversibility of the left ventricular dysfunction after coronary artery bypass surgery in 85% of left ventricular segments. However, zones of the myocardium that lacked ongoing metabolism (could not take up ftuoro deoxyglucose) correctly predicted irreversibility of left ventricular function. It is clear that identifying hibernating myocardium is important since the revascularization of viable but dysfunctional tissue will lead to ultimate recovery of left ventricular function.
STUNNED AND HIBERNATING MYOCARDIUM
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
Literature Cited 1. Braunwald, E., Kloner, R. A. 1982. The stunned myocardium-prolonged, post ischemic ventricular dysfunction. Cir culation 66: 1146-49 2. Kloner, R. A., Ellis, S. G., Lange, R., Braunwald, E. 1983. Studies of exper imental coronary artery rcpcrfusion. Effects of infarct size, myocardial func tion, biochemistry, ultrastructure and microvascular damage. Circulation 68: 18-115 3. Heyndrickx, G. R., Millard, R. W., McRitchie, R. J., Maroko, P. R., Vatner, S. F. 1975. Regional myocardial function and electrophysiological alter ations after brief coronary artery oc clusion in conscious dogs. J. c/in. In vest. 56: 978-85 4. Charlat, M. L., O'Neill, P. G., Hartley, C. J., Roberts, R., Bolli, R. 1989. Pro longed abnormalities of left ventricular diastolic wall thinning in the "stunned" myocardium in conscious dogs: Time course and relations to systolic function. J. Am. Call. Cardiol. 13: 185-94 5. Ellis, S. G., Henschke, C. I., Sandor, T., Wynne, 1., Braunwald, E., Kloner, R. A. 1983. Time course of functional and biochemical recovery of myocardium salvaged by reperfusion. J. Am. Call. Cardiol. I: 1047-55 6. Arnold, 1. M. 0., Braunwald, S., San dor, T., K10ner, R. A. 1985. Inotro pic stimulation of reperfused myocard ium with dopamine: effects on infarct size and myocardial function. J. Am. Call. Cardial. 6: 1026-34 7. Becker, L. C., Levine, J. H., DiPaula, A. F., Guarnieri, T., Aversano, T. 1986. Reversal of dysfunction in postischemic stunned myocardium by epinephrine and postextrasystolic potentiation. J. Am. Call. CardiaI. 7: 580-89 8. Kloner, R. A., Przyklenk, K., Patel, B. 1989. Altered myocardial states: The stunned and hibernating myocardium. Am. J. Med. 86(Suppl. 1A): 14--2 2 9. Bolli, R., leroudi, M. 0., Patel, B. S., Aruoma, O. I., Halliwell, B., et al. 1989. Marked reduction of free radical gen eration and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Circ. Res. 65: 607-22 10. Kloner, R. A., Przyklenk, R., Whit taker, P. 1989. Deleterious effects of oxygen radicals in ischemia/reper fusion. Resolved and unresolved issues. Circulation 80: 1115-27 II. Krause, S. M., Jacobus, W. E., Becker, L. C. 1989. Alterations in cardiac sar coplasmic reticulum calcium transport
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in the postischemic "stunned" myo cardium. Circ. Res. 65: 526-30 Patel, B., Kloner, R. A., Przyklenk, K., Braunwald, E. 1988. Postischemic myo cardial "stunning": a clinically relevant phenomenon. Ann. Intern. Med. 108: 627-29 Touchstone, D. A., Beller, G. A., Nygaard, T. W., Tedesco, c., Kaul, S. 1989. Effects of successful intravenous reperfusion therapy on regional myo cardial function and geometry in humans: a tomographic assessment using two-dimensional echocardiography. J. Am. Call. Cardiol. 13: 1506-13 Satler, L. F., Kent, K. M., Fox, L. M., et al. 1986. The assessment of contractile reserve after thrombolytic therapy for acute myocardial infarction. Am. Heart J. Il l : 821-25 Guerci, A. D., Gerstenblith, G., Brinker, 1. A., et al. 1987. A randomized trial of intravenous tissue plasminogen acti vator for acute myocardial infarction with subsequent randomization to elec tive coronary angioplasty. N. Engl. J. Med. 317: 1613-18 Homans, D. C., Sublett, E., Dai, X.-Z., Bache, R.I. 1986. Persistence of regional left ventricular dysfunction after exer cise-induced myocardial ischemia. J. c/in. invest. 77: 66-73 Robertson, W. S., Feigenbaum, H., Armstrong, W. F., Dillun, 1. c., O'Don nell, J., McHenry, P. W. 1983. Exercise echocardiography: a clinically practical addition in the evaluation of coronary artery disease. J. Am. Call. Cardiol. 2: 1085-91 Kloner, R. A., Allen, J., Zheng, Y., Ruiz, C. 1990. Myocardial stunning fol lowing exercise treadmill testing in man. J. Am. Call. CardiaI. 15: 203A Bolli, R. 1988. Oxygen-derived free rad icals and postischemic myocardial dys function ("Stunned Myocardium"). J. Am. Call. Cardiol. 12: 239-49 Przyklenk, K., Ghafari, G. 8., Eitzman, D. T., Kloner, R. A. 1989. Nifedipine administered post reperfusion ablates systolic contractile dysfunction of post ischemic "stunned" myocardium. J. Am. Call. Cardiol. 13: 1176--83 Westlin, W., Mullane, K. 1988. Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals? Circulation 77(6): 30-39 Farber, N. E., Gross, G. J. 1989. Pro staglandin E I attenuates postischemic contractile dysfunction after brief cor onary occlusion and reperfusion. Am. Heart. J. 118: 17-24
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
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23. Rahmitoola, S. H. 1989. The hiber nating myocardium. Am. Heart J. 117: 211-21 24. Braunwald, E., Rutherford, 1. D. 1989. Reversible ischemic left ventricular dys function: evidence for the "hibernating myocardium." J. Am. Call. Cardiol. 8: 1467-70 25. Fedele, F. A., Gerwitz, H., Capone, R. J., Sharaf, B., Most, A. S. 1988. Meta bolic response to prolonged reduction of myocardial blood flow distal to a severe coronary artery stenosis. Circulation 78: 729-35 26. Carlson, E. B., Cowley, W. J., Wolfgang, T. c., Vetrovec, O. W. 1989. Acute changes in global and regional rest left ventricular function after success-
27.
28.
29. .
ful coronary angioplasty: comparative results in stable and unstable angina. J. Am. Call. Cardiol. 13: 1262-69 Cohen, M., Charney, R., Hershman, R., Fuster, V., Gorlin, R., Francis, X. 1988. Reversal of chronic ischemic myocardial dysfunction after transluminal coronary angioplasty. J. Am. Call. Cardiol. 12: 1193-98 Schelbert, H. R., Buxton, D. 1988. Insights into coronary artery disease gained from metabolic imaging. Cir culation 78: 496-505 Tillisch, J., Brunken, R., Marshall, R., et al. 1986. Reversibility of cardiac wall motion abnormalities predicted by posi tron tomography. N. Engl. J. Med. 314: 884--88
Annu. Rev. Med. 1991. 42:1-8 Copyright © 1991 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
STUNNED AND HIBERNATING MYOCARDIUM Robert A. Kloner, M.D., Ph.D., and Karin Przyklenk, Ph.D.
The Heart Institute, The Hospital of the Good Samaritan, Los Angeles, California 90017; and Section of Cardiology, University of Southern California, Los Angeles, California 90033 KEY
WORDS:
myocardial ischemia, myocardial rcpcrfusion, myocardial infarc tion, thrombolysis, angioplasty
ABSTRACT
Myocardium that is not functioning may be dead (infarct or scar), viable but stunned (postischemic ventricular dysfunction), viable but hibernating (chronic low flow state), or acutely ischemic. Stunned myocardium has clearly been documented (a) in experimental studies of brief coronary artery occlusion followed by reperfusion, and (b) in myocardial infarct models in which early reperfusion salvages viable tissue. Recent clinical studies have confirmed the existence of stunned myocardium in humans. Evidence supporting the concept of hibernating myocardium comes from clinical studies in which patients with chronic low flow ischemia exhibit improvement in left ventricular function (sometimes immediately) fol lowing revascularization. INTRODUCTION
There are several possible causes for a regional wall motion abnormality of the left ventricle. The contractile abnormality may be due to infarcted tissue or scar; if so, coronary artery revascularization will not improve the wall motion abnormality. Regional contractile dysfunction may arise when viable myocardium has been affected by a period of low blood flow. The abnormality in function will then be resolved once sufficient blood flow is 0066-4219/91/0401--0001$02.00
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
2
KLONER & PRZYKLENK
restored. This latter situation could be the result of (a) clinically active ischemia with angina pectoris and ischemic ST segment abnormality on the electrocardiogram; (b) "hibernating" myocardium-that is, a chronic low flow state in which clinically active ischemia (as evidenced by chest pain or ECG change) may not be present at the time the wall motion abnormality is observed; or (c) "stunned" myocardium in which clinically active ischemia is no longer present but the wall motion abnormality persists for a prolonged period following reperfusion. This review discusses the concepts of stunned and hibernating myocardium. THE STUNNED MYOCARDIUM
Stunned myocardium refers to dysfunction of viable ventricular myo cardium salvaged by reperfusion. This concept was first described in exper imental studies (I). For example, a coronary artery occlusion of 15 minutes followed by reperfusion in an experimental canine model does not cause cell necrosis. Myocytes subjected to such a mild ischemic insult are said to be reversibly injured and, when viewed by light microscopy, appear essentially normal following reperfusion. Such models of brief and tran sient ischemia mimic the syndrome of angina in that the ischemia is not associated with myocardial cell death. While the cells appear normal by routine histology, abnormalities of both systolic and diastolic function persist for 6-48 hours after reflow (2-4). In addition to these wall motion abnormalities, stunned myocardium is also characterized by transient depression of myocardial ATP levels and by the appearance of vacuoles adjacent to the mitochondria in ultrastructural studies (2). Stunned myocardium has also been observed following more prolonged periods of ischemia. When a two-hour myocardial infarct is reperfused in the experimental laboratory, viable but previously ischemic tissue is sal vaged in the subepicardium. This layer of tissue does not necessarily begin active contraction immediately: in fact, active left ventricular wall thickening in the infarct-related area does not occur until 48 hours after reperfusion, with further improvement in function throughout the initial two weeks after reflow. In contrast, transmural infarcts created by per manent coronary occlusion (no reperfusion) failed to develop active con traction over a two-week period of time (5). While the stunned myocardium does not, by definition, resume active contraction following reperfusion, it can be recruited or stimulated to contract with inotropic agents such as dopamine, dobutamine, iso proterenol, and epinephrine. Thus the stunned myocardium maintains its potential to contract, and if needed clinically (as might be the case in a
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
STUNNED AND HIBERNATING MYOCARDIUM
3
patient who has had early reperfusion therapy for acute myocardial infarc tion but who remains in severe heart failure or cardiogenic shock) it can be recruited to improve overall left ventricular function (6, 7). Why should the heart react to even brief episodes of ischemia in such a peculiar fashion? Several theories have been suggested to explain the phenomenon of stunning (8). Investigations have demonstrated that reper fusion is associated with a burst of cytotoxic, oxygen-derived free radical production (9). These oxygen radicals, including the superoxide anion and hydroxyl radical, can contribute to lipid peroxidation of membranes, which in turn alters both membrane structure and function. One theory of the mechanism of stunned myocardium claims that oxygen free radical damage to the sarcolemmal membrane makes the heart more susceptible to calcium overload, and the resulting relative contracture of the myofilaments impairs organized relaxation and contraction. Another theory suggests that oxygen radicals limit the ability of the sarcoplasmic reticulum to take up calcium. This could deplete calcium stores within the sarcoplasmic reticulum and reduce its ability to release sufficient calcium to the crucial sites along actin-myosin filaments. Such events would result in an electrical mechanical dissociation. Which (if any) of these theories is correct remains to be determined; however, there is ample evidence in the literature sup porting both the role of oxygen free radicals (10) and abnormalities in calcium homeostasis (11) in the pathophysiology of myocardial stunning. What types of patients are likely to demonstrate stunned myocardium? One group of patients who may exhibit postischemic dysfunction are those who have received thrombolytic therapy for acute myocardial infarction. Several clinical studies have reported that wall motion abnormalities may not improve immediately or dramatically following thrombolytic therapy (12). For example, Touchstone et al (1 3) observed very little improvement in regional wall motion over the first three days following intravenous streptokinase therapy. However, between three and ten days ofreperfusion there were dramatic improvements in function. Several studies have sug gested that improvement in regional wall motion may not be observed until 10-16 days after thrombolysis (12). Thus, one cannot predict the ultimate return of cardiac function after thrombolytic therapy from the results during the first few days after treatment. There is some indirect evidence from clinical studies that stunned myo cardium can be stimulated to contract. Satler and colleagues (14) observed that small doses of isoproterenol increased ejection fraction to a greater extent in patients who were successfully reperfused than in those patients in whom reperfusion treatment was unsuccessful. The incremental increase
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
4
KLONER & PRZYKLENK
in ejection fraction in the reperfused group may have been related to the presence of salvaged but stunned myocardium. The improvements in function occurring over the course of 10-16 days after thrombolytic therapy may initially appear small. For example, in many of the clinical trials, the initial ejection fraction at the time of thrombolysis is approximately 45-50% , while 10-16 days later the ejection fraction tends to increase to �50-55% . Are these modest improvements in function clinically meaningful? What happens to left ventricular funtion if reperfusion is not achieved? Guerci et al (15) reported a 4% increase in left ventricular ejection fraction 10 days after patients received tissue plasminogen activator for evolving acute myocardial infarction. In contrast, patients who received placebo actually had a 5% decrease in ejection fraction. Furthermore, the increase in left ventricular ejection fraction observed in patients receiving tissue plasminogen activator was associated with a smaller incidence of clinical congestive heart failure compared with those patients who received placebo. Thus the gradual improvement in function of stunned myocardium does translate to event ual improvement in clinical symptoms. A second important group of patients who may exhibit stunned myo cardium are those who develop ischemia during exercise treadmill tests. Stunned myocardium can occur when experimental animals with a partial coronary stenosis are subjected to exercise (16). Recent evidence from two dimensional echocardiographic exercise treadmill tests suggests that the same phenomenon occurs in humans. Robertson and coworkers inves tigated a small group of patients who demonstrated persistent regional wall motion abnormalities by echocardiography at 30 minutes after ter mination of exercise (17). These wall motion abnormalities persisted well beyond the incidence of angina or electrocardiographic changes, and they were common in patients with double and triple vessel coronary artery disease. We have also reported a high prevalence of persistent wall motion abnormalities 30 minutes after exercise in a large cohort of patients with documented coronary artery disease (18). Some studies have suggested that stunned myocardium may also be present in patients with unstable angina (12). Finally, a fourth group of patients who may demonstrate stunned myocardium are those who under go heart surgery with cardiopulmonary bypass. As cardiology consultants are aware, many of these patients require inotropic support for hours to days following cardiac surgery. Despite cardioplegia, such initial inotropic support following surgery suggests that these hearts initially may be stunned after cardiopulmonary bypass. What potential therapies are available for stunned myocardium? Experi-
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
STUNNED AND HIBERNATING MYOCARDIUM
5
mental studies indicate that many pharmacologic agents can be used to treat postischemic dysfunction. Inotropic drugs can stimulate the stunned myocardium to contract (6, 7). Drugs that can overcome the stunning phenomenon arc more directly therapeutic. Agents that can improve the function of stunned myocardium include oxygen free radical scavenging agents, such as superoxide dismutase and catalase; allopurinol, which blocks the formation of the superoxide anion (19); calcium blockers, including nifedipine, verapamil, diltiazem, and amlodipine (20); angio tensin converting enzyme inhibitors, such as captopril (21); and prosta glandins (22). Whether or not these pharmacological therapies will prove beneficial in clinical instances of stunned myocardium remains to be determined. THE HIBERNATING MYOCARDIUM
The concept of hibernating myocardium is both similar to and different from the concept of stunned myocardium. In both situations a wall motion abnormality of the left ventricle is present, and in both situations viable myocardium exhibiting abnormal contractile function is present. In stunned myocardium, blood flow has been restored and ischemia is relieved, but the wall motion abnormality persists even after reperfusion (8). Hibernating myocardium is characterized by chronic, sublethal ischemia with persistent dysfunction of viable tissue while blood flow is reduced. Once flow is restored, however, function of hibernating myo cardium recovers (23, 24). Some investigators have hypothesized that the hibernating myocardium is a protective process, depressing the tissue's contractile function in order to reduce oxygen demand in the setting of reduced oxygen supply (23, 24). In a sense, this concept is a clinical construct used to explain the finding that some patients with chronic ventricular wall motion abnormalities exhibit improvement in contractile function following revascularization procedures (coronary artery bypass surgery, angioplasty). However, whether the heart is truly hibernating from a biochemical perspective remains to be fully explored. In fact, little is known regarding the basic science of the hibernating myocardium. In one study, Fedele et al (25) subjected pigs to an 80% reduction in coronary artery diameter for three hours. They observed a transient decline in coronary venous pH and a transient increase in coronary venous PC02 during the first 5-20 minutes of coronary stenosis; both levels returned to baseline by 1-3 hours. Lactate consumption prior to the stenosis changed to lactate production post stenosis, but lactate consumption was gradually restored within three
Annu. Rev. Med. 1991.42:1-8. Downloaded from www.annualreviews.org Access provided by New York University - Bobst Library on 02/10/15. For personal use only.
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hours. While regional oxygen consumption declined at five minutes after stenosis, it returned to baseline values within an hour. Regional left ven tricular function was depressed throughout the study. These data suggest a time-dependent adjustment in cardiac metabolism that occurs rapidly after partial stenosis and may help reverse some of the metabolic sequelae of ischemia. Clinical evidence supporting the concept of hibernating myocardium comes largely from studies that demonstrate resolution of chronic wall motion abnormalities following coronary artery bypass surgery or angio piasty (23, 24). Rahimtoola (23) recently reviewed the clinical studies supporting the concept of hibernating myocardium. Some of these studies suggested that, unlike the gradual recovery of stunned myocardium, the improvement in function following revascularization of hibernating myo cardium occurs immediately. For example, Carlson et al (26) observed that regional ejection fraction improved immediately following angioplasty of patients with unstable angina pectoris. Cohen et al (27) reported the results of angioplasty in 12 patients with severe regional wall motion abnormalities who had an element of "reversible chronic ischemia" defined by angina, improvement in function following postextrasystolic potentiation, or thallium uptake in the nonfunctioning zone. They observed that following angioplasty there was an immediate increase in left ventricular ejection fraction and an immediate reduction in the per centage of the left ventricular circumference showing asynergy, findings that support the concept of hibernating myocardium. It is conceivable that the immediate recovery of function observed in some of these patients was due to pretreatment with calcium channel blockers (20). Additional evidence supporting this phenomenon, as well as a technique that may be utilized to identify hibernating myocardium, comes from positron emission tomography (PET) (28). PET can evaluate regional myocardial blood flow with tracers such as rubidium, and can detect the presence of ongoing active metabolism with tracers such as fluoro deoxyglucose. Hibernating myocardium is characterized by an area of the left ventricle showing depressed function and reduced uptake of rubidium (reduced flow) but active or increased fluorodeoxyglucose uptake. Tillisch et' al (29) utilized PET scanning and found that such regions could predict the reversibility of the left ventricular dysfunction after coronary artery bypass surgery in 85% of left ventricular segments. However, zones of the myocardium that lacked ongoing metabolism (could not take up ftuoro deoxyglucose) correctly predicted irreversibility of left ventricular function. It is clear that identifying hibernating myocardium is important since the revascularization of viable but dysfunctional tissue will lead to ultimate recovery of left ventricular function.
STUNNED AND HIBERNATING MYOCARDIUM
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Literature Cited 1. Braunwald, E., Kloner, R. A. 1982. The stunned myocardium-prolonged, post ischemic ventricular dysfunction. Cir culation 66: 1146-49 2. Kloner, R. A., Ellis, S. G., Lange, R., Braunwald, E. 1983. Studies of exper imental coronary artery rcpcrfusion. Effects of infarct size, myocardial func tion, biochemistry, ultrastructure and microvascular damage. Circulation 68: 18-115 3. Heyndrickx, G. R., Millard, R. W., McRitchie, R. J., Maroko, P. R., Vatner, S. F. 1975. Regional myocardial function and electrophysiological alter ations after brief coronary artery oc clusion in conscious dogs. J. c/in. In vest. 56: 978-85 4. Charlat, M. L., O'Neill, P. G., Hartley, C. J., Roberts, R., Bolli, R. 1989. Pro longed abnormalities of left ventricular diastolic wall thinning in the "stunned" myocardium in conscious dogs: Time course and relations to systolic function. J. Am. Call. Cardiol. 13: 185-94 5. Ellis, S. G., Henschke, C. I., Sandor, T., Wynne, 1., Braunwald, E., Kloner, R. A. 1983. Time course of functional and biochemical recovery of myocardium salvaged by reperfusion. J. Am. Call. Cardiol. I: 1047-55 6. Arnold, 1. M. 0., Braunwald, S., San dor, T., K10ner, R. A. 1985. Inotro pic stimulation of reperfused myocard ium with dopamine: effects on infarct size and myocardial function. J. Am. Call. Cardial. 6: 1026-34 7. Becker, L. C., Levine, J. H., DiPaula, A. F., Guarnieri, T., Aversano, T. 1986. Reversal of dysfunction in postischemic stunned myocardium by epinephrine and postextrasystolic potentiation. J. Am. Call. CardiaI. 7: 580-89 8. Kloner, R. A., Przyklenk, K., Patel, B. 1989. Altered myocardial states: The stunned and hibernating myocardium. Am. J. Med. 86(Suppl. 1A): 14--2 2 9. Bolli, R., leroudi, M. 0., Patel, B. S., Aruoma, O. I., Halliwell, B., et al. 1989. Marked reduction of free radical gen eration and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Circ. Res. 65: 607-22 10. Kloner, R. A., Przyklenk, R., Whit taker, P. 1989. Deleterious effects of oxygen radicals in ischemia/reper fusion. Resolved and unresolved issues. Circulation 80: 1115-27 II. Krause, S. M., Jacobus, W. E., Becker, L. C. 1989. Alterations in cardiac sar coplasmic reticulum calcium transport
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23. Rahmitoola, S. H. 1989. The hiber nating myocardium. Am. Heart J. 117: 211-21 24. Braunwald, E., Rutherford, 1. D. 1989. Reversible ischemic left ventricular dys function: evidence for the "hibernating myocardium." J. Am. Call. Cardiol. 8: 1467-70 25. Fedele, F. A., Gerwitz, H., Capone, R. J., Sharaf, B., Most, A. S. 1988. Meta bolic response to prolonged reduction of myocardial blood flow distal to a severe coronary artery stenosis. Circulation 78: 729-35 26. Carlson, E. B., Cowley, W. J., Wolfgang, T. c., Vetrovec, O. W. 1989. Acute changes in global and regional rest left ventricular function after success-
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