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Cardiovascular Research 1998 38(3):549-558; doi:10.1016/S0008-6363(98)00061-3
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

"Myocardial stunning"

remaining questions1

Dirk J Dunckera, Rainer Schulzb, Roberto Ferraric, David Garcia-Doradod, Carlo Guarnierie, Gerd Heuschb and Pieter D Verdouwa,*

aExperimental Cardiology, Thoraxcenter, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, Netherlands
bDepartment of Pathophysiology, University of Essen, Essen, Germany
cFondazione Clinica del Lavoro, Brescia, Italy
dHospital General Universitairi, Vall d'Hebron, Barcelona, Spain
eDepartment of Biochemistry, University of Bologna, Bologna, Italy

* Corresponding author. Tel.: +31-10-408-8029; fax: +31-10-436-5607; e-mail: verdouw@tch.fgg.eur.nl

Received 12 December 1997; accepted 19 February 1998


   1 What is stunning and why is it important?
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 1 What is stunning...
2 What are the...
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 References
 
The pivotal importance of myocardial perfusion for the maintenance of myocardial contractile function was already recognized some 60 years ago [1], but the functional and metabolic consequences of brief as well as long coronary artery occlusions have become unravelled only in the last twenty years. Until the mid seventies, coronary artery occlusions of different duration were used to describe the transition of reversible to irreversible damage [2, 3]. It was more or less assumed that function of ischaemic myocardium would recover almost instantaneously upon reperfusion or did not recover completely because myocardium had become infarcted due to the long duration of occlusion (>30 min). In the seventies, the technology became available to determine regional myocardial function by sonomicrometry and using this technique Heyndrickx et al. [4]described that in awake dogs following a 15 min coronary artery occlusion recovery of regional myocardial contractile function was not immediate as it took more than 12 h, while the electrocardiogram had normalized almost instantaneously. In that period there was some scepsis about the concept that myocardial function would not recover immediately upon reperfusion, illustrated by the rejection of a manuscript, in which the observation that myocardial function did not return completely to control within 30 min in a dog model of transient ischaemia was labelled as probably being an artefact [5, 6]. In 1982, Braunwald and Kloner [7]coined the term "myocardial stunning", for this phenomenon of "delayed recovery of regional myocardial contractile function after reperfusion despite the absence of irreversible damage and despite restoration of normal flow". Thus, the paper by Heyndrickx et al. [4]triggered tremendous research efforts to unravel the mechanisms of stunning which has greatly contributed to our current knowledge about the role of many of the cellular processes during and after ischaemia.


   2 What are the most pressing questions about myocardial stunning?
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 1 What is stunning...
 2 What are the...
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Over the years a number of mechanisms have been forwarded to explain stunning, including loss of and reduced ability to synthesize high-energy phosphates, impairment of microvascular perfusion, impairment of sympathetic neural responsiveness, generation of oxygen-derived free radicals, activation of leukocytes, reduction in the activity of creatine kinase, and disturbances in calcium homeostasis [8]. At the present time, the release of oxygen-derived free radicals [9]and calcium overload [10, 11]are considered to be key events in the pathogenesis of stunning, while prostacyclin [12]and ACE inhibition and the consequent augmentation of bradykinin [13]can modulate the severity of stunning. However, there are several controversies regarding these triggers and modulators that remain to be solved.

In this article we will discuss the characteristics and clinical relevance of stunned myocardium. It is beyond the scope of this article to give a comprehensive overview of stunning, but rather to provide the reader with areas of consensus and controversy and make recommendations for future research. For an overview, we refer to one of the many excellent monographs or Review papers (see Refs. [14–17]).

2.1 What are the remaining controversies of established triggers and modulators of myocardial stunning?
2.1.1 Oxygen-derived free radicals
In the setting of a single brief coronary artery occlusion, several laboratories have reported that anti-oxidants attenuate myocardial stunning when administered either before the coronary occlusion or just prior to reperfusion [9]. However, when administration was started 1 minute after the onset of reperfusion, anti-oxidants failed to protect the reperfused myocardium [18]. Using spin trap, {alpha}-phenyl N-tert-butyl nitrone and electron paramagnetic resonance spectroscopy, generation of free radicals has been directly demonstrated in reperfused myocardium particularly during the initial minutes of reperfusion [19]. Although stunning could thus be viewed as a form of reperfusion injury, the severity of stunning and the duration of dysfunction have been shown to depend on the duration and severity of ischaemia [20], which is supported by observations that the magnitude of free radical formation is inversely related to the collateral blood flow during ischaemia [21]and directly related to the duration of ischaemia [22]. Hence, it remains debatable whether stunning can be viewed as a pure form of reperfusion injury or whether it should be viewed as a consequence of events that took place during the preceding ischaemic episode.

What is the source of radicals? Sofar the source of free radical formation that leads to stunning has remained largely unknown [23]. Free radicals could potentially be derived from a number of sources: (i) the enzyme xanthine oxidase, (ii) activated neutrophils, and (iii) the arachidonate cascade. Xanthine oxidase appears to be a source of free radical generation in dogs, but its role in stunning in rabbits, swine and humans is unlikely since myocardial levels of the enzyme in these species are negligible [24]. Although there have been reports to the contrary [25], there is now general consensus that there is no important role for neutrophil-derived free radicals in stunning [26]. Alternatively, free radicals could be derived from autooxidation of catecholamines, or accumulation of reducing equivalents, and particularly from ischaemia-induced damage of the mitochondrial electron transport chain, but all these possibilities have sofar remained largely unexplored [23].

In conclusion, free radicals produced during the initial minutes of reperfusion contribute to myocardial stunning. The duration and severity of ischaemia determine at least in part the magnitude of free radical formation. However, the source of free radicals remains unclear.

2.1.2 Ca2+
Although a pivotal role of calcium in myocardial stunning is widely accepted, the exact nature of how calcium contributes to stunning is still incompletely understood [14, 15]. Studies in isolated hearts have shown that Ca2+ levels are elevated after 10 min of ischaemia [27, 28], but possibly already as early as after 1–2 min [29, 30]. Upon reperfusion, Ca2+ levels do not recover immediately [28]and may even increase further [30–32], Whether elevated calcium levels contribute to the overshoot in function during early reperfusion which precedes the prolonged depression of function remains controversial [30, 33]. Calcium-antagonists administered either before ischaemia or just prior to reperfusion attenuate myocardial stunning in isolated perfused hearts [11]. In vivo studies also support a role for calcium in myocardial stunning since numerous studies have shown a beneficial effect of calcium-antagonists in vivo (see Refs. [10, 11, 34]). However, in vivo studies could not show a beneficial effect when calcium-antagonists were administered just prior to or at the onset of reperfusion, questioning the importance of an increase in cytosolic calcium during early reperfusion [10].

2.1.3 How do free radicals and Ca2+ produce stunning?
The mechanism by which free radicals and Ca2+ produce stunning is still incompletely understood. Recent evidence suggests that it m include activation of Ca2+-dependent protease activity and consequent troponin I proteolysis [35]. It could thus be possible that free radicals together with increased Ca2+ levels present during ischaemia and early reperfusion may act in concert to damage the proteins of the contractile machinery [35]or sarcoplasmic reticulum [36].

2.1.4 Angiotensin converting enzyme and prostacyclin
The activity of angiotensin I converting enzyme (ACE) is increased during acute coronary artery occlusion [37], which results in increased production of angiotensin II and increased breakdown of bradykinin. Angiotensin II is a potent vasoconstrictor and positive inotropic agent which may aggravate ischaemia, while bradykinin stimulates prostacyclin production which can mitigate stunning [13]. Consequently, increased ACE activity during coronary artery occlusion could aggravate myocardial stunning. Indeed, several investigators have reported improved recovery of contractile function by several different ACE inhibitors administered before occlusion or immediately before reperfusion (see Refs. [38, 39]). Ehring et al. [13]studied the role of bradykinin in the beneficial effects of the ACE inhibitor ramiprilat in open-chest dogs. The effect of ramiprilat on the recovery of postischaemic wall thickening was shown to be bradykinin-mediated, but since bradykinin can promote synthesis of both prostacyclin and nitric oxide the authors further investigated which of these two pathways was involved in the attenuation of stunning. The cyclo-oxygenase inhibitor indomethacin, but not the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester abolished the protective effect of ramiprilat, indicating that attenuation of stunning by ramiprilat involves a cascade of bradykinin and prostaglandins but not nitric oxide. These findings imply that an endogenous production of prostacyclin during ischaemia and reperfusion attains cardioprotective levels. This is also supported by observations that both exogenous [40, 41]and stimulated endogenous [42]production of prostacyclin protect against myocardial stunning. The mechanism by which prostacyclin exerts protection is still unclear.

In conclusion, recovery of postischaemic function can be enhanced by ACE inhibitors, administered either prior to ischaemia or at the onset of reperfusion, indicating the involvement of ACE in the development of stunning. The mechanism by which ACE modulates stunning is likely via blunting of bradykinin-mediated release of prostacyclin.

2.2 Do we know all the triggers?
To date no study has demonstrated that optimal treatment, which should consist of a combination of inhibitors of all known triggers, completely prevents stunning. It therefore cannot be excluded that yet unknown factors contribute to stunning.

2.3 What are the controversies regarding abnormalities in excitation-contraction coupling?
2.3.1 Decreased Ca2+-transients or decreased myofilament responsiveness to calcium?
Since electrical activation is back to normal at a time when contractile function is still depressed [4], it is clear that stunned myocardium is characterized by abnormalities in excitation-contraction coupling. However, despite intense research efforts there is still some controversy as to the exact nature of these abnormalities. Contractile abnormalities can result from either a decrease in calcium-availability, e.g., resulting from sarcoplasmic reticular dysfunction or a decreased responsiveness of the myofilaments to calcium (e.g., resulting from proteolysis of troponin I [43]. Maximal calcium uptake into the sarcoplasmic reticulum (SR) vesicles was reduced at 60 min reperfusion following 8 times 5 min LAD occlusion in canine myocardium [44]. Similarly, in isolated rat hearts following 10 min global no-flow ischaemia and 60 min reperfusion maximal calcium uptake into the SR was reduced [45]. In contrast, in biopsies from pig myocardium subjected to 2 times 10 min LAD occlusion followed by 30 min reperfusion, maximum Ca2+ uptake in the SR was actually higher at a time when segment shortening was depressed by more than 50% [46]. The reason for differences between those studies is unclear at present, but might relate to the species used (rat vs. dog. vs. pig) or the time point at which SR function was analyzed (30 min vs. 60 min reperfusion).

In most isolated buffer-perfused heart preparations following 10 to 20 min of ischaemia and 10 to 20 min of reperfusion, both end-diastolic and peak-systolic intracellular calcium concentrations have returned to control values [28, 30, 47–49], and in only one study remained peak-systolic calcium concentration slightly increased [50]. Thus, whereas the calcium transient appears to be normal, Ca2+-sensitivity as well as maximum Ca2+ developed force of the myofibrils were decreased in isolated ferret hearts following 15 min global no-flow ischaemia and 30 min reperfusion [30]. Similar results were obtained in isolated trabeculae excised from rat hearts following 20 min of global no-flow ischaemia [51], and in isolated skinned cardiomyocytes from porcine hearts subjected to 45 min of regional low-flow ischaemia [52]. The reported decrease in calcium sensitivity, i.e. –log[Ca2+]i for the half maximal tension, in these studies averaged 2–3%. Data in isolated myocytes, trabeculae and hearts are consistent, but controversial findings arise from the anaesthetized pig preparation in vivo. While calcium sensitivity, as reflected by the contractile responses to postextrasystolic potentiation and to intracoronary calcium infusion was nearly unchanged at 30 min reperfusion following 90 min of moderate low-flow ischaemia [53], indirect evidence for an altered calcium sensitivity at the identical reperfusion time point but following 2 times 10 min total coronary occlusion comes from another study [54], using the thiadiazinone-derivative EMD 60263 (a calcium-sensitizing agent which is devoid of phoshodiesterase inhibiting properties) [55]. In the presence of combined {alpha}- and β-adrenoceptor blockade, this drug produced a preferential increase in regional function of the stunned as compared to normal myocardium, which is consistent with the hypothesis that Ca2+-sensitivity is decreased in stunned compared to normal myocardium. Although direct in vivo evidence that EMD 60263 increases Ca2+-sensitivity was not obtained in that study, adrenergic receptor dependent mechanisms were excluded. The reason for the observed differences in calcium sensitivity among these two later studies could in part have resulted from the different protocols to induce myocardial stunning [53, 54]. The data on the maximal calcium-activated force in stunned myocardium in vivo also remain controversial. In a recent study in anaesthetized swine [53], the absolute increases in regional myocardial work in response to postextrasystolic potentiation and to intracoronary calcium infusion were reduced at 30 min reperfusion following 90 min of moderate low-flow ischaemia; the contractile responses to postextrasystolic potentiation and to intracoronary calcium infusion, when expressed as a fraction of the maximal increase, however, were unchanged. In contrast, the maximal calcium-activated segment shortening was not different from control in an in situ canine heart preparation following 15 min coronary occlusion and 30 min reperfusion [56]. Reasons for the observed differences in maximal calcium-activated regional myocardial function among these later two studies in vivo are unclear, but may include differences in species (pig vs. dog), in protocols to induce myocardial stunning (complete versus partial coronary artery occlusions, duration of occlusion) and in the parameters used for assessing regional myocardial function (shortening vs. work) as well as their calculations (absolute value vs. normalized value).

In conclusion, the weight of current in vitro and in vivo evidence suggests that calcium availability in stunned myocardium is normal, but that stunned myocardium is characterized by decreased Ca2+ responsiveness, resulting from either a decrease in Ca2+ sensitivity or maximum Ca2+-activated force or both.

2.4 Is vascular stunning related to myocardial stunning?
Maximal coronary blood flow responses to endothelium-independent vasodilators have been reported to be unchanged in reperfused myocardium after single or multiple brief (5–10 min) periods of myocardial ischaemia [57, 58], but to be reduced after 15 min of ischaemia [59, 60]in dogs. However, in swine 10–30 min coronary occlusions fail to blunt the vasodilator responses to intracoronary infusions of maximum doses of adenosine [61–63]. However, 30 min of low flow ischaemia (which produced no infarction) resulted in a shift of the coronary pressure-flow relation (obtained during maximum coronary vasodilation with adenosine) towards higher coronary pressures with no change in the slope [63]. These findings suggest an increase in extravascular compressive forces, which could be the result of oedema formation or relaxation abnormalites.

Several studies have reported significant blunting of endothelium-dependent vasodilation in canine myocardium stunned by single or multiple brief (≤15 min) coronary artery occlusions [64–66]. In contrast, Ehring et al. [67]reported that a 15 min coronary occlusion in open-chest dogs did not blunt the vasodilation produced by the endothelium-dependent vasodilator acetylcholine; however, a 60 min occlusion reduced acetylcholine mediated vasodilation in necrotic tissue (TTC negative), but also in myocardial tissue which survived the prolonged ischaemic period (viable, TTC positive) but remained severely stunned. In open-chest swine, blunting of endothelium-dependent vasodilation was related to the duration of occlusion. Whereas 10–15 min coronary occlusions did not modify the maximum coronary vasodilation produced by the endothelium-dependent vasodilator ATP [61, 62], 30 min of low flow ischaemia (which produced no infarction) decreased the slope of the pressure-flow relation during maximum vasodilation with ATP, suggesting that maximum endothelium-dependent vasodilation was blunted [63]. These findings suggest that occlusion of sufficiently long duration can reduce flow reserve of stunned myocardium by increasing the extravascular compressive forces and impair endothelial function. In addition to impaired blood flow regulation, endothelial dysfunction may also directly affect contractile function [68]. Therefore, it cannot be excluded that endothelial stunning contributes to a delay in recovery of function of viable myocardium following occlusions that are sufficiently long to also produce irreversible damage. However, since coronary occlusions less than 15 min in duration clearly produce myocardial stunning at a time when there is no indication of "vascular stunning", it is evident that vascular abnormalities are no prerequisite and hence unlikely contributors to the pathogenesis of myocardial stunning.

2.5 Can we discard alterations in metabolism as a cause for myocardial stunning?
Although the stunned myocardium is characterized by a number of metabolic alterations, such as a decreased ATP level and altered substrate utilization which can last for hours to days [69, 70], there is no evidence that postischaemic impairment of oxidative phosphorylation (mitochondrial stunning), energy transport or utilization are the cause for myocardial stunning. Nonetheless, in in vivo studies oxygen consumption is high in regionally stunned myocardium relative to the amount of systolic shortening or external work. This reduced contractile efficiency (or oxygen wastage) is at least in part caused by an increase in wall stress of the regionally stunned myocardium (due to regional wall thinning in conjunction with an increase in ventricular volume) or a shift from external work to potential work (energy stored in the myocardium after closure of the aortic valve and which is converted to heat) [71]. The increase in wall stress and the shift from external to potential work appear to result from the lower contractile state of the regionally stunned myocardium because intravenous dobutamine restores the contractile efficiency of regionally stunned myocardium [72]. Studies in isolated rat hearts perfused with several carbon substrates indicate that oxygen consumption is not elevated relative to the rate-pressure product when ischaemia lasted less than 80% of the time required to produce contracture [73, 74]. Taken together these studies suggest that the apparent oxygen in vivo wastage is due to the lower contractile state of regionally stunned myocardium in vivo, resulting in a higher wall stress and shift from external to potential work, and not to ischaemia-reperfusion-induced alterations in muscle properties per se.

2.6 Is inotropic reserve of stunned myocardium normal?
Several studies have demonstrated the presence of recruitable inotropic reserve in stunned myocardium. Becker et al. [75]titrated an intravenous dose of epinephrine to produce a maximal increase in systolic segment shortening of stunned canine myocardium. The postischaemic maximal response remained somewhat below the maximal response to epinephrine given before the 15 min ischaemia period, but a similar trend was observed in the remote normal myocardium. Ito et al. [56]infused calcium into the coronary artery of open-chest swine before and after a 15-min coronary artery occlusion. Before stunning calcium increased segment shortening from 26 to 37%, while following stunning segment shortening increased from 12 to 35%, indicating normal contractile reserve in stunned myocardium. To minimize the influence of loading conditions Krams et al. [76]used end-systolic pressure-segment relations to study the effect of dobutamine on maximal elastance (Emax) of stunned myocardium (in which Emax had decreased to 40% of baseline) and found that dobutamine increased Emax to 170% of pre-ischaemia baseline in both normal myocardium and myocardium stunned by two 10 min coronary artery occlusions in open-chest pigs. However, in another study in open-chest pigs the maximum increases in regional myocardial work in response to intracoronary calcium infusion were reduced at 30 min reperfusion following 90 min of moderate low-flow ischaemia, which did not produce myocardial necrosis, as verified by TTC staining [53]. It is possible that the different results in the latter study are related to the degree and duration of flow reduction.

In conclusion, all studies clearly indicate the presence of contractile reserve in stunned myocardium, but whether contractile reserve is normal remains controversial.

2.7 Is recruitment of inotropic reserve harmful?
Several studies [56, 75, 77]have shown that after termination of inotropic stimulation, resulting in an increase in contractile function at or above pre-stunning baseline levels for up to 3 hours, contractile function did not decrease below values prior to the onset of inotropic stimulation indicating that stimulation per se did not exert a deleterious effect on stunned myocardium. Also partial restoration of systolic shortening in dogs by xamoterol during the 8 h reperfusion period following 15 min ischaemia in open-chest dogs did not result in irreversible damage as compared to the placebo group [78]. These findings are corroborated by metabolic studies, as McFalls et al. [79]observed that dobutamine restored mechanical efficiency of stunned porcine myocardium without evidence of anaerobic metabolism. Similarly, Kida et al. [80]reported that in stunned porcine myocardium ATP loss was not aggravated when a high dose of dobutamine was infused throughout the 120-min reperfusion period. These studies indicate that inotropic stimulation of intermediate duration (8 h) does not aggravate postischaemic contractile and metabolic abnormalities in stunned myocardium. However, there is currently no information regarding the potentially harmful effects of inotropic stimulation of stunned myocardium during periods exceeding 8 h.

2.8 Is there a relation between stunning and ischaemic preconditioning?
Several studies in isolated hearts have shown that ischaemic preconditioning improves postischaemic recovery of global left ventricular function [81]. However, interpretation of these studies is difficult since the duration of ischaemia was likely associated with irreversible damage [82], making it impossible to distinguish between reduction of infarct size and attenuation of stunning. Evidence that ischaemia preconditioning can attenuate stunning during the first window of protection is therefore limited [83]. Interpretation of studies using multiple occlusions of 5–15 min is hampered by the alterations in baseline contractile function [84, 85]. Only if very brief (≤2 min) preconditioning stimuli are used, which do not produce significant changes in function can a comparison be made, although it cannot be excluded that such a brief stimulus is insufficient to protect the myocardium against stunning. However, there does appear to be protection against stunning in the second window of preconditioning [86, 87], although this may be species and/or stunning protocol dependent [86–88]. The mechanism of the second window of protection likely involves free radicals [89, 90].

Matsuda et al. [91]demonstrated that at 2 h of reperfusion, in dogs a 15 min coronary artery occlusion had lost its protective effect against infarction produced by a 40 min occlusion. Also, restoration of contractile function of stunned myocardium with dobutamine had no effect on infarct limitation [92]. Protection by preconditioning against stunning has so far only been shown in dogs during the second window of protection. Conversely, there is general consensus that reversible postischaemic contractile dysfunction is not required to precondition the myocardium (see also Ref. [93]).

2.9 Does stunning contribute to hibernation?
Hibernating myocardium is characterized by chronic, yet reversible contractile dysfunction in the setting of coronary artery disease [94, 95]. Whereas myocardial hibernation was originally seen as a chronic, adaptive reduction of myocardial contractile function during persistent ischaemia, repetitive stunning has been proposed as an alternative mechanism underlying hibernation [96–98]. This alternative explanation was based on experimental [97]and clinical [96, 98]findings of depressed regional contractile function with normal or almost normal resting blood flow, but impaired coronary reserve. There is evidence to suggest that exercise-induced ischaemia with subsequent stunning can occur in patients with coronary artery obstruction [99]. Furthermore, episodes of stress-induced ischaemia with subsequent stunning have been observed in an experimental study in conscious pigs with chronic ameroid coronary constriction [97]. Thus it would appear that episodes of exercise- or stress-induced ischaemia with subsequent stunning can bring the myocardium into a state of persistent contractile dysfunction at near normal blood flows. However, blood flow and function must be continuously monitored to definitively demonstrate this, and this has not been done so far. Furthermore, there is evidence that hibernation exists in the original sense, i.e., an adaptation to persistent ischaemia [100–102]. This is particularly true since in the clinical setting, both hibernation and stunning are likely to coexist [14].

2.10 What is the clinical importance of myocardial stunning?
In 1993 Braunwald ended his contribution [103]to Kloner and Przyklenk's "Stunned myocardium" with the words "As to the question of whether myocardial stunning is important from a clinical standpoint – my answer is a resounding yes, I certainly believe that it is. Indeed, I think that an awareness of this phenomenon, its manifestations, consequences, treatment, and prevention, is essential to optimal management of patients with ischaemic heart disease." Indeed, if we were to perform an acute 10–15 min coronary artery occlusion followed by abrupt reperfusion in a normal human heart, which has not experienced any prior ischaemic episodes, it is very likely that myocardial stunning will develop similar to that observed in animal hearts. In conscious animals large differences exist between the severity of stunning after similar ischaemic insults [88], with stunning being less in baboons than in pigs and dogs, and because of the similarity of the human and non-human primate hearts it is quite feasible that the human heart is more resistant to stunning than that of the two most frequently studied large animals hearts.

If there are no other cardiovascular complications, a period of transient depressed regional function is well tolerated by the animal. This appears to be even more true for man, for which a number of reasons can be forwarded: (i) man are studied in the awake state (the same ischaemic insult causes less severe stunning in awake than in anaesthetized animals) [104], (ii) the ischaemic episodes may be too short in duration, (during PTCA or exercise-induced angina) to produce significant postischaemic dysfunction [105], (iii) the large majority of patients in which stunning might occur suffers from coronary artery disease which triggers formation of collaterals, (iv) many patients are already using antiischaemic drugs which will attenuate stunning, (v) in patients formation of oxygen derived free radicals upon reperfusion may be less because of a pre-existing flow-limiting stenosis, which modifies the abruptness of reperfusion, and (vi) there is evidence that via the second window of protection prior ischaemia attenuates stunning. However, so far there is no evidence for the latter phenomenon in man. For these reasons and also because of its transient nature several investigators consider stunning not as a serious clinical problem [106].

Some investigators and clinicians dispute the proof for the existence of stunning in man. Indeed, it is not only sufficient to demonstrate the existence of (transient) dysfunction because a major requirement of stunning is that dysfunction occurs in the presence of normal perfusion. Despite the progress made by the advent of developments in positron emission tomography, thallium-201 imaging, technetium Tc-99m sestamibi imaging and dobutamine echocardiography we still cannot exclude that impaired perfusion, particular in the subendocardium, underlies the dysfunction seen in patients [107]. Thus even with the most advanced technology it remains next to impossible to show that the transient dysfunction as we see following percutaneous transluminal coronary angioplasty, unstable and variant angina and exercise-induced exercise (demand ischaemia) is not caused by subendocardial ischaemia [108–115]. Transient depression of global myocardial function is not uncommon after open heart surgery and has frequently been treated successfully with positive inotropic agents for periods up to 48 h [116, 117]. With the current knowledge about the pathogenesis of the dysfunction it is logical to assume that stunning may be the underlying cause, because stimulation with positive inotropic agents in the presence of ischaemia would more often lead to irreversible damage and to chronic impairment of function.

In case there is a need to avoid further deterioration of global function by preventing myocardial stunning a number of agents such as antioxidants, calcium-antagonists and ACE-inhibitors are available. However, it must be reminded that the effectiveness of these agents has predominantly been shown in the animal laboratory and that to our knowledge only one clinical report on their effectiveness has been published [118]and that report was not without problems [119, 120]. If stunning has already been established, positive inotropic agents can be administered for at least a few hours, provided that ischaemia due to residual stenosis of the culprit vessel has been excluded. Conversely, one should be aware that an increase in wall motion during postinfarct stress-testing does not preclude residual ischaemia, as recruitment of function of stunned myocardium may mask ischaemia-included contractile dysfunction.

In conclusion, there is indirect evidence for the occurrence of myocardial stunning in a number of clinical entities. However, until accurate assessment of myocardial perfusion (including transmural distribution of myocardial blood flow to detect subendocardial hypoperfusion), myocardial contractile function and tissue damage can be made, stunning will have to await definitive prove in the clinical setting. The clinical importance of stunning may have been overestimated (i) in view of necessity of treatment of stunning only when global left ventricular function is grossly impaired, (ii) many patients with ischaemic heart disease are already using antiischaemic drugs that antagonize triggers of myocardial stunning (e.g. ACE inhibitors, β-blockers, Ca2+-antagonists, anti-oxidants). Perhaps the importance of stunning lies in its identification as a cause for temporary dysfunction in patients which does not require treatment.


   3 Conclusion
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In the last 20 years myocardial stunning has been one of the most extensively studied topics in cardiovascular research. The transient postischaemic depression after reversible ischaemia appears to be more severe in experimental studies than in man. The importance of stunning may therefore not be so much the direct clinical relevance (unless there is a serious impairment of global ventricular function) but what we learned from the changes in cellular processes that occur during ischaemia and upon reperfusion.

Time for primary review 27 days.


   Acknowledgements
 
We thank the other members of the EU Biomed II concerted action "New Ischaemic Syndromes" (C. Ceconi, M. Galinanes, S. Haunso, D.J. Hearse, D. Kremastinos, J.W. de Jong, P. Menasche, M. Ovize, H.M. Piper, P.A. Poole-Wilson, T.J.C. Ruigrok, K. Schwartz) for their comments and suggestions.


   Notes
 
1 On behalf of participants of the EEC Biomed Concerted Action ‘The New Ischaemic Syndromes’. Back


   References
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