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Ann Thorac Surg 1999;68:1898-1904
© 1999 The Society of Thoracic Surgeons
a Departments of Pharmacology and Toxicology, and Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Address reprint requests to Dr Gross, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226
e-mail: ggross{at}post.its.mcw.edu
Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sept 21–24, 1997.
Abstract
Prolonged reversible postischemic contractile dysfunction that follows single or multiple brief periods of regional or global ischemia has been termed "stunned myocardium," and is thought to be the result of a decreased responsiveness of the cardiac myofilaments to calcium. A number of hypotheses have been proposed to explain the pathogenesis of stunned myocardium; however, the two major theories that are supported by the most experimental evidence suggest that the generation of oxygen-derived free radicals and a disturbance in calcium homeostasis are responsible for the postischemic contractile dysfunction observed. These mechanisms are not mutually exclusive, and data are available that support both theories. Evidence exists that indicates that one may pharmacologically enhance the recovery of stunned myocardium by use of oxygen radical scavengers, adenosine agonists, calcium channel blockers, and openers of the ATP-sensitive potassium channel, including the volatile anesthetic isoflurane. Ischemic preconditioning (IPC) has also been shown to produce delayed protection against myocardial stunning, and a novel pharmacological agent, monophosphoryl lipid A, has been shown to mimic the effect of IPC. Because stunning appears to occur in a number of clinical settings, it is important to understand the mechanisms involved and to develop pharmacological therapy that will result in an improved clinical outcome.
The first evidence to suggest that brief periods of ischemia result in prolonged regional postischemic contractile dysfunction was provided by Heyndrickx and colleagues in conscious dogs [1] by use of ultrasonic crystals. These investigators found that dogs subjected to 5 to 15 minutes of coronary artery occlusion, followed by 24 hours of reperfusion, had prolonged decreases in regional contractile function for at least 3 to 6 hours, and that these values did not return to control until 24 hours later. This depression in contractile function appeared to occur independent of changes in regional myocardial blood flow and was not associated with any evidence of myocardial infarction. In anesthetized dogs, Przyklenk and Kloner [2] found a depression in regional wall thickening that persisted for 30 hours after a 15-minute coronary artery occlusion. Subsequently, other investigators [3] found decreases in high-energy phosphates and cellular ultrastructure after brief periods of ischemia. Taken together, these results led Braunwald and Kloner [4] to coin the term "stunned myocardium" to describe these prolonged changes in regional contractile function, metabolism, and cellular ultrastructure that occurred after a transient period of ischemia. Because there are a number of procedures in which stunned myocardium has been shown to occur in humans, such as after coronary artery bypass operation, angioplasty, and thrombolysis, a number of experimental models have been developed to mimic these situations (Table 1), and there have been numerous studies performed in an attempt to determine the mechanisms responsible for stunned myocardium, with the goal of developing new pharmacological therapy to alleviate postischemic dysfunction for therapeutic benefit [5]. Thus, the focus of this discussion is to present the major theories that have been proposed to explain the pathogenesis of myocardial stunning and to outline some therapeutic approaches that may be useful in combating this potentially deleterious sequela resulting from transient ischemic episodes. Some of the major proposed mechanisms, endogenous mediators, and potential therapeutic approaches for alleviating stunning are summarized in Table 2.
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The role of oxygen-derived free radicals in stunned myocardium was first demonstrated by Myers and associates [6], Gross and associates [7], and Przyklenk and Kloner [8] in anesthetized open chest dogs. These investigators found that administration of the free radical scavengers, superoxide dismutase (SOD), and catalase, enzymes that catalyze the dismutation of the superoxide anion ( ·O2-) to O2 and H2O2, and H2O2 to O2 and H2O, respectively, significantly improved the recovery of regional contractile function after 15 minutes of coronary artery occlusion and 3 hours of reperfusion (Fig 1). Subsequently, Bolli and associates [9] and Farber and associates [10], using dimethylthiourea, mercaptopropionylglycine (MPG) and desferrioxamine, agents that scavenge or inhibit hydroxyl radical ( ·OH) formation, also improved functional recovery of stunned myocardium in anesthetized dogs. These results and those obtained from other studies performed in other species, including pigs and rabbits, with oxygen radical scavengers provided suggestive but indirect evidence for a causitive role for oxygen-derived free radicals in the pathogenesis of myocardial stunning [5].
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Finally, since all of the earlier studies concerning the role of oxygen-derived free radicals in myocardial stunning were performed in anesthetized animals in which the confounding effects of anesthesia, surgical trauma, temperature, and neurohormonal factors may influence the results and possibly produce artifacts, Bolli’s group tested the oxyradical hypothesis in the conscious, unanesthetized dog. Li and associates [14] subjected conscious dogs to 15 minutes of regional ischemia, and found that there was a burst of free radicals produced which peaked at 2 to 3 minutes of reperfusion and that several antioxidants reduced this burst of radicals and enhanced the recovery of wall function following reperfusion. Thus, these results and those of numerous other laboratories clearly support the hypothesis, which suggests that the generation of oxygen-derived free radicals plays a major role in the pathogenesis of stunned myocardium.
Disruption in calcium homeostasis
Although the evidence is overwhelming in support of the oxyradical hypothesis in myocardial stunning [5], the mechanism(s) by which oxygen-derived free radicals produce a decrease in contractile dysfunction at the cellular level is still not totally clear. Since calcium is the major ion involved in force generation in the myocardium, it is likely that a change in extracellular calcium influx, intracellular calcium release, or reuptake by the sarcoplasmic reticulum or an alteration in myofilament sensitivity to calcium is responsible for the reduction in regional function observed in stunned myocardium. Evidence exists to support the hypothesis that calcium overload occurs in stunned myocardium either as a result of enhanced calcium influx during ischemia and/or reperfusion or as a result of a decrease in reuptake into the sacroplasmic reticulum, and that this increase in intracellular calcium may lead to a reduction in myofilament sensitivity to this ion. Evidence is also available that suggests that the contractile proteins may be damaged due to proteolysis via calcium overload and activation of calpain I, a calcium-activated neutral protease found in cardiac muscle. Finally, data have recently been obtained that directly link the oxyradical hypothesis and the calcium hypothesis in the pathogenesis of stunned myocardium.
Calcium overload and myocardial stunning
Evidence to suggest that a transient period of calcium overload during early reperfusion may be responsible for stunned myocardium was presented initially by Kusuoka and associates [15] in isolated isovolumic ferret hearts perfused in the Langendorff mode. These hearts were subjected to 15 minutes of global ischemia and reperfusion. The authors found that there was a decrease in maximal calcium-activated pressure and a decrease in sensitivity to Ca2+ in stunned hearts. ATP concentrations in the myocardium did not correlate with the recovery of function. Furthermore, Marban and associates [16] directly measured intracellular free Ca2+ concentrations in ferret hearts during 15 minutes of ischemia and after reperfusion. They found that intracellular Ca2+ significantly increased during ischemia and decreased rapidly during reperfusion [16]. Thus, based on these results in isolated ferret hearts, these investigators concluded that an increase in intracellular calcium is responsible for stunning; however, the mechanism by which calcium overload produced this reversible injury was unknown.
Support for the idea of an increase in calcium influx through L-type channels as being responsible for the transient calcium overload, which is thought to occur in stunned myocardium, has emerged from several studies, in which it has been shown that L-type calcium channel blockers attenuate stunning [17–19]. Przyklenk and Kloner [22] found that pretreatment with verapamil in anesthetized dogs subjected to 15 minutes of coronary artery occlusion and 3 hours of reperfusion almost completely blocked stunning. Similarly, Lamping and Gross [23] found that intravenous nifedipine produced an improvement in postischemic function in dogs subjected to 15 minutes of coronary artery occlusion and reperfusion. Przyklenk and associates [19] also found that administration of nifedipine 30 minutes after reperfusion enhanced segment shortening to nearly 90% to 100% of control values. These results are surprising because one would predict that the calcium overload observed in stunning should have occurred long before the nifedipine was given, so it is difficult to ascribe this effect to blockade of cellular calcium overload. Although these results suggest a role for L-type sarcolemmal calcium channels and a resultant calcium overload in stunned myocardium, it is likely that in many of these studies, a reduction in myocardial oxygen consumption occurred as a result of the negative inotropic and possibly chronotropic effects of these agents in the ischemic area, and the improvement in postischemic function was the result of the antiischemic effect of these compounds.
Sarcoplasmic reticulum and myocardial stunning
Several studies have addressed the role of the sarcoplasmic reticulum (SR) calcium transport processes in stunned myocardium [20, 21]. Because calcium is known to be sequestered by an active transport process via an energy-dependent SR calcium-adenosine triphosphatase (Ca2+-ATPase) and released from the SR via the ryanodine receptor or calcium-release channel, a defect in one or both of these mechanisms might be responsible for the abnormal function observed in the stunned heart. In this regard, Krause and associates [27] subjected canine hearts to multiple 5-minute periods (8 to 12) of coronary artery occlusion interspersed with 10-minute periods of reflow, followed by a final 60-minute period of reperfusion. These authors found a marked reduction in postischemic systolic shortening and demonstrated that there was a reduction in oxalate-dependent calcium transport or SR reuptake and a decrease in Ca2+-ATPase activity and its ability to be activated by calcium. More recently, Valdivia and associates [28] studied the effect of regional stunning on SR function in anesthetized pigs subjected to 10 minutes of coronary artery occlusion followed by 2 hours of reperfusion. Both the rate of calcium uptake by SR vesicles and the density of high-affinity ryanodine binding sites were reduced by 37% to 38% in the stunned region as compared with the normal region. The open probability of the ryanodine-sensitive calcium-release channel was also significantly reduced in SR isolated from the stunned area. Taken together, these results suggest that a defect in SR calcium uptake and release may be partially responsible for the contractile dysfunction observed in stunned myocardium. The mechanism by which the transient calcium overload that has been shown to occur during ischemia and early reperfusion produces this depression in SR function in stunned myocardium is still unknown, but may involve phosphorylation of the ryanodine receptor by a calcium calmodulin-dependent protein kinase and a subsequent decrease in the open probability of the calcium-release channel [21]. Alternatively, it is possible that a transient increase in intracellular calcium may activate a calcium-sensitive neutral protease (calpain), which may partially cleave the ryanodine receptor protein and reduce its ability to release SR calcium [21].
Decreased myofilament sensitivity to calcium
A number of recent publications support the concept that transient calcium overload in stunned myocardium results in a decreased sensitivity or responsiveness of the cardiac myofilaments to intracellular calcium [22–24]. Carrozza and associates [22] found in isolated buffer-perfused ferret hearts that a reduced myofilament responsiveness to calcium, as reflected by Fmax or the maximum calcium-activated force, occurred after a transient calcium overload as measured by aequorin. In a model of regional ischemia in open chest pig hearts in which in vitro measurement of myofilament sensitivity to calcium was assessed in permeabilized myocytes obtained from tissue biopsies harvested from normal and stunned myocardium, Hofmann and associates [23] found that the calcium-tension relationships were shifted to the right, which suggested that there was a decreased myofilament sensitivity to calcium in the stunned area. More recently, Miller and associates [24] determined whether the decrease in myofilament sensitivity to calcium occurred during ischemia per se or during the subsequent reperfusion period in permeabilized myocytes prepared from stunned pig hearts. These investigators found that the calcium sensitivity of the myocytes was not altered during ischemia but was decreased after reperfusion [24]. These results support the concept that reperfusion injury is responsible for myocardial stunning.
Although it is well established that the contractile proteins show a decreased sensitivity to calcium in stunned myocardium, the mechanism(s) responsible for this observation is not clear. However, recent evidence from Marban’s laboratory [25–27] suggest two viable hypotheses: proteolysis of the myofibrils due to activation of the calcium-dependent protease calpain I [25, 26] or a direct effect of oxygen free radicals on the myofilaments [27]. Using skinned cardiac trabeculae obtained from rat myocardium, Gao and associates [25] showed that the myofilaments showed a decreased sensitivity to calcium after stunning and that a similar decrease was observed in normal myofilaments exposed to 5 or 30 minutes of calpain I. A specific calpain I inhibitor, calpastatin, prevented these detrimental effects on skinned trabeculae. These data were suggestive of a role for calpain I in stunning but were not definitive because these investigators did not show that calpain I was activated in stunned myocardium or that the calpain I inhibitor attenuated stunning. In a more recent study, Gao and associates [26] showed that the contractile protein troponin I (TnI) was selectively degraded in stunned myocardium, and that this degradation, as well as stunning, could be prevented by a low calcium/acidotic reperfusion buffer in intact hearts. These authors also showed that calpain I selectively degrades TnI similar to that observed in stunned hearts, and that this effect of calpain I could be blocked by calpastatin in skinned trabeculae. Taken together, these data strongly support a role for proteolysis of contractile and other regulatory cellular proteins in myocardial stunning.
Link between the oxyradical and calcium hypothesis in stunning
Although prolonged exposure of skinned muscle fibers to oxygen free radicals has been shown to depress peak force generation and myofilament sensitivity to calcium [28], these results cannot readily be extrapolated to the situation in stunned myocardium, where the large increase in free radical production is transient and only lasts for a few minutes upon the initiation of reperfusion. Therefore, Gao and associates [27] subjected trabeculae obtained from rats to two oxygen radical-generating systems: H2O2 + Fe3+ to produce the hydroxyl radical, and xanthine oxidase (XO) + purine (P) to produce superoxide for 10 to 20 minutes. The results showed that the hydroxyl radical-generating system reduced activator calcium availability, whereas the superoxide generating system decreased myofilament calcium sensitivity. Because the superoxide anion appeared to more closely produce effects similar to those observed in stunned myocardium, it was concluded that this free radical may be the most important one involved in the pathogenesis of stunning.
Endogenous mediators and myocardial stunning
A discussion of the mechanisms of myocardial stunning would not be complete without mentioning several endogenous systems that are thought to be activated and may contribute to the calcium overload that may be responsible for stunning or alternatively may dampen the effects of myocardial stunning. These include adenosine, the ATP-sensitive potassium channel (KATP channel), and the sodium-hydrogen (Na-H) antiport or exchanger.
Adenosine is an endogenous substance that is released during ischemia and has been shown by numerous laboratories to be cardioprotective against myocardial infarction and stunning. Yao and Gross [29] clearly showed in a canine model of stunned myocardium produced by multiple, brief periods of ischemia and reperfusion that blockade of the adenosine A1 receptor by the selective antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX) worsened the recovery of regional segment shortening, whereas administration of the selective adenosine A1 receptor agonist, cyclopentyl adenosine (CPA), markedly enhanced the recovery of function. The selective adenosine A2 receptor agonist, CGS 21680, had no effect on the recovery of regional segment function. These results are in agreement with those previously published by Lasley and Mentzer [30], in which they showed a cardioprotective effect of adenosine in isolated rat hearts that was mediated via A1 receptor activation. These results suggest that the adenosine A1 receptor plays an important cardioprotective role in stunned myocardium.
Similarly, the KATP channel has been shown to exert a marked cardioprotective effect against infarction and stunning in numerous animals models [31]. Auchampach and associates [32] determined the role of the KATP channel in stunned myocardium of anesthetized dogs subjected to a single 15-minute coronary artery occlusion followed by 180 minutes of reperfusion. These investigators found that the KATP channel opener, aprikalim, produced a marked enhancement of postischemic function, whereas two sulfonylurea KATP channel antagonists, glibenclamide and tolbutamide, worsened the recovery of segment function (Fig 2).
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Preconditioning and myocardial stunning
Ischemic preconditioning (IPC) produced by single or multiple brief periods of coronary artery occlusion has been shown to produce a powerful but relatively short-lived (30- to 90-minute) cardioprotective effect to reduce infarct size in all species tested thus far [35], and a delayed protective effect against infarction that is manifested 12 to 24 hours after the initial brief ischemic insult in rabbits and dogs. In contrast, Ovize and associates [36] have clearly demonstrated in dogs that IPC does not preserve contractile function during a 15-minute coronary artery occlusion, and does not prevent myocardial stunning in the initial few hours after reflow. However, Sun and associates [37] in Bolli’s group found that 10 2-minute coronary artery occlusions separated by 2 minutes of reperfusion resulted in an attenuation of stunning in conscious pigs subjected to the same stunning protocol 1 to 2 days later. An adenosine receptor blocker, 8-p-sulfophenyl theophylline (8-SPT), did not block this delayed protective effect; however, there was an increased expression of heat-shock protein (HSP 70) mRNA and HSP 70 protein 24 hours after the initial preconditioning period. Furthermore, Yao and associates [38] have recently shown that monophosphoryl lipid A (MLA), a nontoxic endotoxin derivative, produces a delayed protective effect against stunning similar to that produced by brief periods of ischemia. This protective effect has been shown to be mediated via the KATP channel because its effect was blocked by glibenclamide. Thus, based upon these results, several questions arise as to whether blocking the effects of acute stunning pharmacologically is beneficial or detrimental to the heart over a prolonged period of time, and whether we can successfully elicit the second window of protection by use of safe and efficacious pharmacological agents such as MLA.
Summary
The most important factors and sites identified to be involved in myocardial stunning are summarized in Figure 4. There is little doubt that oxygen-derived free radicals are involved in the pathogenesis of acute stunning and that there is a disruption in calcium homeostasis, as reflected by a transient calcium overload, a decrease in SR function, and damage to the contractile proteins via calcium-activated proteases such as calpain I. This injury to the myofilaments most likely leads to a decrease in sensitivity to calcium and the decrease in postischemic contractile function, which is characteristic of stunned myocardium. In this regard, the severity of damage to the myofilaments and possible mechanisms involved in eliciting stunning may be determined by the intensity and/or duration of the ischemic insult. A number of pharmacological approaches can be used to prevent stunning, such as adenosine A1 agonists, KATP channel openers, free radical scavengers, calpain inhibitors, and antagonists of the sodium-hydrogen exchanger (Table 2). However, the recent observation that stunning produces a delayed protective effect against further stunning may lead to rethinking treatment strategies against this phenomenon.
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We thank Donna Sloane for her excellent secretarial assistance in the preparation of this manuscript. Portions of the authors’ work were supported by National Institutes of Health grants HL-08311 and HL-54280.
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Significantly (p < 0.05) different from vehicle-pretreated dogs; §significantly (p < 0.05) different from glyburide-treated dogs; 
significantly (p < 0.05) different from dogs receiving gylburide and isoflurane. (Reproduced by permission of Lippincott-Raven Publishers from Kersten JR, Schmeling TJ, Hettrick DA, Pagel PS, Gross GJ, Waritier DC. Mechanism of myocardial protection by isoflurane. Role of adenosine triphosphate-regulated potassium (KATP) channels. Anesthesiology 1996;85:794–807.)