© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Negative inotropic mediators released from the heart after myocardial ischaemia–reperfusion
aMedizinische Klinik, Kardiologie, Angiologie, Pneumologie, Charité, Campus Mitte, Humboldt-Universität zu Berlin, Schumannstr. 20–21, D-10098 Berlin, Germany
bKlinik für Innere Medizin B, Ernst-Moritz-Arndt-Universität, Greifswald, Germany
* Corresponding author. Tel.: +49-30-450-513153; fax: +49-30-450-513932 verena.stangl{at}charite.de
Received 2 May 2001; accepted 26 July 2001
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Abstract |
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 Top Abstract 1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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The heart responds to ischaemic stimuli with release of negative inotropic mediators such as cytokines, platelet-activating factor, oxygen free radicals, arachidonic acids, nitric oxide, adenosine, and still unidentified "cardiodepressant factors" that modulate myocardial performance via autocrine and paracrine coupling. This review summarises experimental and clinical data on the role of negative inotropic mediators that are released from cardiac cells (including cardiomyocytes, endothelial cells, and resident mast cells) after myocardial ischaemia-reperfusion.
KEYWORDS Cytokines; Free radicals; Ischemia; Macrophages; Myocytes; Nitric oxide; Reperfusion
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1. Introduction |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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It is now well recognised that the heart — besides acting as a pump — also performs autocrine and paracrine functions. Endothelial cells, as one prime example, under physiological and pathophysiological circumstances, release a number of substances that modulate vascular tone, homeostasis, and myocardial contraction. An increasing volume of clinical and experimental data is available to evidence that the heart contributes to regulation of vasomotion after myocardial ischaemia by releasing diffusible agents such as nitric oxide, prostaglandins, adenosine, endothelin. Nevertheless, the role of cardiac autoregulation in the context of changes in postischaemic contractile state is less clear. However, recent clinical data as well as experimental studies have demonstrated that, after myocardial ischaemia, cardiac cells release a variety of diffusible negative inotropic factors that exert important autocrine and paracrine effects on myocardial contractile function. Evidence exists that cardiodepressant mediators generated in the ischaemic and reperfused region not only aggravate ischaemia-induced contractile depression, but also diffuse to the intact, non ischaemic part of the myocardium, thereby inducing global myocardial dysfunction.
Myocardial ischaemia triggers production and release from the heart of these negative inotropic mediators, which include cytokines, platelet-activating factor (PAF), oxygen free radicals, arachidonic acids, and nitric oxide (NO). These autacoids apparently contribute to the phenomenon of reperfusion injury, which is defined as myocardial cellular dysfunction induced by the re-establishment of coronary perfusion — in contrast to myocardial damage brought about during the preceding ischaemic episode. The present overview describes the role of cardiodepressant substances released from cardiac cells — particularly cardiomyocytes, endothelial cells, and infiltrating monocytes — after myocardial ischaemia.
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2. Cytokine-mediated contractile depression following myocardial ischaemia |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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Cytokines, a group of low-molecular-weight polypeptides, play a crucial role in inflammatory reactions during myocardial ischaemia–reperfusion injury. Furthermore, it is becoming increasingly apparent that proinflammatory cytokines also exert direct negative inotropic effects via paracrine and autocrine modulation. Tumor necrosis factor-
(TNF-), interleukin (IL)-6 and IL-1 are the primary regulators of these changes in contractility, often acting in synergistic and cascade-like reactions.
2.1 TNF-
It is now well established that TNF- is generated in the myocardium subsequent to ischaemia and reperfusion, and that it is involved in postischaemic cardiac contractile depression [1–3]. Initial reports indicated that TNF- levels rose in experimental ischaemia-reperfusion in rat macrophages [4], and that TNF- mRNA increased 1 h after reperfusion [5]. Subsequently, Gurevitch and coworkers were the first to demonstrate a significant release of TNF- in the rat coronary effluent at 1 min after reperfusion [6]. It was possible to directly correlate these TNF- levels with postischaemic depression in myocardial mechanical performance. Meldrum later demonstrated that TNF- protein is elevated in the myocardium itself after crystalloid-perfused global ischaemia-reperfusion [2,7]. These studies indicate that the myocardium synthesises and releases TNF- in response to ischaemia and reperfusion. The extent remains to be elucidated to which paracrine release of TNF- contributes to postischaemic depression in myocardial contractile performance; the amount of tissue damage also requires further elucidation. Experimental studies provide evidence, however, that anti-TNF strategies — i.e. inhibition or neutralisation of TNF- by adenosine [8,9] or by a monoclonal anti-TNF- antibody [10] — not only eliminate TNF- from the effluent but also reduce myocardial ischaemia–reperfusion injury, with enhancement of recovery of cardiac function.
TNF- is a polypeptide hormone with a wide range of biological activities. It is produced in response to stress: i.e. infection, inflammation, tissue injury, and shock. Hypoxia may represent the basis of TNF- production in ischaemia–reperfusion [11]. Other biochemical pathways, however, may play important roles in formation of this cytokine, including increase in cGMP [12], platelet activating factor [13], lactic acidosis [14], and -receptor stimulation [15]. Activation of protease-activated receptor-2 has recently been shown to be involved in TNF- release after ischaemia–reperfusion [16]. Kapadia and colleagues have suggested that myocardial-resident macrophages and cardiomyocytes themselves are capable of producing TNF- [17].
TNF- has potent negative inotropic effects (Fig. 1) [18]. Contractile dysfunction induced by TNF- appears to be biphasic (i.e. immediate and delayed): which implies at least two different underlying mechanisms [19]. The early cardiodepressant effect occurs within minutes, is NO-independent, and appears to be mediated, at least in part, by sphingosine [20]. Sphingosine is rapidly produced in cardiomyocytes exposed to TNF- via sphingomyelin catabolism [21]. Sphingosine has furthermore been shown to inhibit the sarcoplasmic ryanodine receptor that reduces Ca2+-induced Ca2+ release and myocardial contractility [22]. In addition, the acute effects of TNF- are most probably due to direct cytotoxicity, disruption of excitation–contraction coupling, desensitising of the β-receptor, and interaction with other putative negative inotropic substances such as IL-1β [2,7]. The delayed effect on contractile state requires hours of TNF- exposure, and is likely mediated by NO [2]. TNF- indeed induces nitric oxide synthase (iNOS), which promotes NO production. NO inhibits calcium influx via cGMP-dependent inhibition of L-type Ca2+ channels, desensitises the myofilaments to Ca2+, and subsequently decreases contractile force [23,24]. It has furthermore been recently suggested that cytokine-induced negative inotropic effects (including TNF-) may be due to the formation of peroxynitrite, which is generated via interaction of superoxide and NO in the heart [25] (see Section 6). These findings evidence that TNF- can act not only as immune-cell mediator with endocrine effects, but can also exert cardiodepressive action via paracrine or autocrine mechanisms.
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In addition to its direct effects on myocardial contractility, TNF-
may play a critical role in initiating the cytokine cascade responsible for release of other putative negative inotropic cytokines such as IL-6 — as well as for myocyte intracellular adhesion molecule-1 induction and subsequent neutrophil-induced injury [26]. TNF- may furthermore induce cardiac myocyte apoptosis through type-1 (TNFR1) and type-2 (TNFR2) TNF receptors [27].
2.2 Interleukin (IL)-1
The interleukin-1 family performs a function as main mediator of the inflammatory reaction. IL-1 and IL-1β bind to the same two receptors and accordingly exhibit similar biological activity. Whereas IL-1 primarily remains associated at the cell membrane, IL-1β is secreted in blood. After acute myocardial infarction in men, IL-1β is the primary cytokine that appears in plasma. Shortly after initial signs of myocardial injury, an IL-1β peak has been observed that precedes the IL-6 peak by 4–9 h. Possible interrelation between IL-1β and IL-6 in the course of inflammation subsequent to myocardial injury has been suggested [28].
In addition, synergistic activities of the proinflammatory cytokines IL-1 and TNF- are a commonly reported phenomenon (Fig. 1) [29]. Although the receptors for TNF- and IL-1 are clearly different, the post-receptor events are astonishingly similar. IL-1β such as TNF- increase NO production in rat cardiocytes by induction of iNOS expression [30,31]. This IL-1β-induced NO formation in cardiomyocytes requires several hours, suggesting de-novo protein synthesis of iNOS [32]. This cytokine acting via an NO-independent mechanism has furthermore been shown to cause downregulation of calcium regulating genes [33]. Since the resulting iNOS expression and downregulation of calcium-regulating genes is a long-lasting process, correlation with prolonged depression of myocardial contractility associated with this cytokine has been suggested [32]. Besides this delayed action mechanism, IL-1β has also been shown to induce direct negative inotropic effects in the isolated perfused rat heart within 30 min [34]. In isolated papillary muscles, however, Finkel et al. have reported that — in contrast to TNF- and IL-6 — IL-1 produces only slight negative inotropic effects [23]. The significance of this cytokine in postischaemic contractile depression remains to be elucidated.
2.3 IL-6
Elevated IL-6 levels have been demonstrated in patients with acute myocardial infarction, particularly during reperfusion. These findings imply that IL-6 may play a role in the pathogenesis of ischaemic heart disease [28,35–39]. These data are supported by experimental results that evidence induction of IL-6 mRNA in the ischaemic reperfused canine myocardium. IL-6 induction was apparently accelerated by reperfusion (i.e. within the first 3 h) [40,41].
After initial reports hypothesising that IL-6 is evidently a marker rather than a mediator of myocardial injury [42], an increasing number of experimental observations now suggest that IL-6 may act as a direct cardiodepressant substance under certain conditions. Finkel et al. reported that IL-6 such as TNF- inhibited contractility in hamster papillary muscles [23]. Furthermore, addition of IL-6 to human pectinate muscles (dissected from atrial appendages at the time of bypass surgery) resulted in a concentration-dependent, negative inotropic effect within 2–3 min: one that remained constant for 
20 min and proved to be completely reversible after washout [43]. In cultured chick ventricular myocytes, IL-6 acutely decreased peak systolic Ca2+-transient and contractility [44]. These is some evidence that this acute cardiodepressant effect of IL-6 may result from enhanced production of NO and subsequent cGMP-mediated decrease in L-type Ca2+-channel current [23,43,44]. The rapid onset and reversibility of these negative inotropic effects argue against iNOS activation, which requires several hours for gene expression. However, some evidence exists that IL-6 also induces iNOS in cardiomyocytes, and that this effect may contribute to sustained depression of myocardial contractility [44].
Not only mononuclear cells in the ischaemic and reperfused myocardium have been shown to produce IL-6: adult cardiac myocytes in vitro and in vivo [26,41,45] have also demonstrated this tendency. Rat cardiac myocytes respond to hypoxic stress to augment significantly the production of IL-6, which suggests a regulatory role of cardiomyocytes in contractile dysfunction after ischaemia [46]. In addition, IL-6 is reported to be secreted by endothelial cells [47] and vascular smooth-muscle cells [48], which may be potential sources of elevated serum IL-6 levels after myocardial ischaemia–reperfusion.
2.4 Other cytokines
IL-2 and IL-8 mRNA are induced after reperfusion of ischaemic myocardium in animal models [1,49,50]. These cytokines are released from the myocardium during reperfusion after ischaemia and after myocardial infarction [42,51–53]. However, there is no substantial evidence for any relevant role of IL-2 or IL-8 as mediator in regulation of myocardial contractility.
In conclusion, these data indicate that several proinflammatory cytokines whose expression and release by the heart is triggered by ischaemia–reperfusion may participate in myocardial contractile depression after ischaemia and/or have worsening effects. The negative inotropic effects of TNF-, IL-1β, and IL-6 appeared to be both immediate (2–5 min) and delayed, with effects beginning a number of hours after exposure suggesting transcriptional regulation (Fig. 1).
It is noteworthy that cytokines function as intercellular communication molecules and act within a network of interrelated and interacting signals. Thus, several authors have hypothesised a sequential activation of cytokines in myocardial ischaemia. This hypothesis would suggest that TNF- released early in ischaemia from preformed stores in cardiac mast cells [26] and/or IL-1β act as upstream cytokine inducer of IL-6 in ischaemia–reperfusion [28,41]. Both TNF- and IL-1β are proinflammatory cytokines that exhibit feedback induction of themselves and synergistically depress cardiac function. In addition, it has been reported that TNF- and IL-1β reduce adrenergic stimulation of myocardial contractility in certain models via a decrease in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels [54–57].
2.5 Clinical correlates and human evidence
Experimental data are corroborated by clinical situations associated with ischaemia–reperfusion in which serum concentrations of several cytokines have been found to increase [51,58–60]. It has been clearly demonstrated by sampling coronary sinus blood and by myocardial biopsies that the myocardium is able to release biologically active amounts of cardiodepressant cytokines following ischaemia–reperfusion. A number of authors (although not all) have in cases of angina pectoris determined measurable levels of cytokines TNF-, IL-1β, and IL-6 in patient's serum. As a rule, these levels were higher for unstable than for stable angina pectoris [61–64]. Numerous publications have also reported that TNF-, IL-1β, and IL-6 levels increase in acute myocardial infarction in men [28,35,58,60,61,65–67]. Until now, however, it has not been definitely established whether these high cytokine levels are associated with functional impairment elicited by inotropic effects. The hypothesis that this may indeed be the case has been supported by experimental data on human myocardial trabeculae (obtained at the time of cardiac surgery): these results indicate that TNF- and IL-1β dose-dependently depress contractile function [68]. Further support for this hypothesis arises from clinical studies that have reported significant association of TNF- and IL-6 elevation with damage severity, in the sense of increased infarct size, signs of heart failure, increased enzymatic infarct, as well as large perfusion defects in thallium scintigraphy [59,60,69–71]. It has also proved possible to demonstrate that successful reperfusion of coronary arteries leads to a significant decrease in plasma TNF- levels [72]. In contrast, other authors have found no correlation between serum levels of these cytokines and the extent of myocardial damage [36,63,73].
Coronary artery bypass grafting is another situation associated with ischaemia–reperfusion injury, in which proinflammatory cytokines have been shown to be elevated [74–76]. Many studies, although not all [76], have evidenced increased TNF- and IL-6 levels during and after coronary bypass surgery [42,51]. Some clinical data suggest that these elevated plasma levels contribute to cardiac dysfunction and haemodynamic instability following coronary bypass surgery [43,45,77,78].
Whereas anti-cytokine strategies — employing TNF- antibodies or soluble TNF- receptors, for example — have been implemented in patients with sepsis and heart failure, to date, no human data are available for myocardial ischaemia–reperfusion.
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3. Platelet-activating factor (PAF) |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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PAF (1,-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent active phosphoglyceride with a wide spectrum of diverse biological proinflammatory properties. It is now well established that this lipid mediator is deeply involved in the pathogenesis in myocardial reperfusion injury [79–82]. PAF is released from the ischaemic myocardium of rat, dog, sheep, and pig hearts in vivo [81,83–85]. Investigations with isolated buffer-perfused hearts have revealed the cardiac origin of PAF released in significant amounts during ischaemia–reperfusion [86–88].
In various models of myocardial ischaemia–reperfusion injury, several specific PAF receptor antagonists have been found to markedly attenuate myocardial postischaemic contractile dysfunction [81,88–92]. These data suggest that PAF is generated in response to ischaemia–reperfusion [83,86,93] and is an important mediator in the pathogenesis of reperfusion injury.
As stated earlier, studies using isolated crystalloid-perfused heart preparations indicate that the heart itself is able to synthesise and release PAF in significant amounts during reperfusion. Several cell types in the heart — including cardiomyocytes as well as endothelial cells and monocytes/macrophages — have been shown to produce this lipid mediator upon stimulation [94–98]. PAF does not exist in a stored form, but is rapidly synthesised during ischaemia–reperfusion from membrane phospholipids after sequential activation of phospholipase A2 (Lyso-PAF) and acetyl transferase [86,99]. The effects of PAF are mediated through specific PAF cell surface receptors that belong to the superfamily of G protein-coupled receptors [82]. There is evidence that most of the cells that produce PAF also possess PAF receptors and serve as targets for PAF action [82]. Since cardiomyocytes not only produce PAF but also possess specific binding sites for PAF [100], a role of this mediator in autocrine/paracrine modulation of myocardial contractility after ischaemia–reperfusion is likely.
The underlying mechanisms involved in PAF-induced harmful effects after ischaemia and reperfusion have proven to be multifactorial, since this phospholipid modulates coronary circulation, pre- and afterload, the conduction system, and the contractile properties of the myocardium: either directly or via generation of secondary mediators (Fig. 2) [101]. In vivo and in isolated hearts, the decrease in myocardial contractility mediated by PAF may be attributed to both negative inotropic effects and coronary vasoconstriction [102,103]. A direct effect of PAF on cardiac contractility has been suggested by experiments involving intracoronary infusion of PAF in pigs. PAF infusion in this context has induced a marked reduction in cardiac output in the absence of significant vascular effects [104]. Investigations in papillary muscles and isolated cardiomyocytes have confirmed that PAF is a potent cardiodepressant mediator. In guinea pig papillary muscles, PAF has induced a direct negative inotropic effect [105–107]. Several authors have described this effect of PAF on myocardial contractility to be biphasic with a transient, slightly positive inotropic effect (within 2–3 min) followed by a negative effect [105–108]. This positive inotropic effect was blocked by beta-blockers in guinea pig and human papillary muscle, which suggests a stimulation of beta-receptors by endogenous catecholamines [105,109]. In isolated adult or neonatal cardiomyocytes, PAF was shown to decrease twitch tension and velocity of contraction and relaxation, as well as to increase spontaneous beating rate [110,111]. These effects of PAF were receptor-mediated, as shown by the use of specific PAF-receptor antagonists. The underlying mechanism of the negative inotropic effect of PAF is most likely not due to a decrease in myofilament sensitivity, since we have recently demonstrated that PAF inhibited cell contraction and systolic intracellular Ca2+ concentrations in isolated field-stimulated rat cardiomyocytes in a time- and concentration-dependent manner [112].
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PAF possesses not only cardiodepressant properties but also arrhythmogenic effects, induces coronary artery vasoconstriction, and acts as a potent chemoattractant for platelets and leukocytes. This behaviour may exacerbate postischaemic myocardial injury by capillary plugging and via damage induced by the formation of free radicals or proteolytic enzymes [86,113–118]. In addition, it has been shown that PAF stimulates the release of other biologically active mediators such as eicosanoids (leukotrienes and thromboxane), superoxide anions, and TNF-
. These effects can furthermore enhance myocardial dysfunction (Fig. 2) [13,84,92,114,119]. In conclusion, the finding that the heart produces PAF after ischaemia, expresses PAF receptors, and proves sensitive to the potent negative inotropic action of PAF suggests that this mediator acts in a paracrine and autocrine manner to regulate its own contractility in response to ischaemic injury [82]. However, it must be considered that alterations in cardiac function induced by PAF in vivo may result either from direct action exerted on the heart — or from indirect effects such as changes in coronary circulation, variation in preload and afterload pressures, and modulation of the conduction system. Moreover, paracrine effects due to myocardial release of PAF must be distinguished from alterations secondary to PAF-induced platelet and neutrophil activation, and secretion of other mediators.
3.1 Clinical correlates and human evidence
There is only a small body of clinical data — mutually contradictory in some cases — on the release of PAF after myocardial ischaemia in humans. Intravascular release of PAF has been detected in the blood of patients with coronary artery disease who undergo atrial pacing to evaluate ischaemia severity [120]. In myocardial infarction, plasma levels of PAF have been shown to be elevated in part via increased production of PAF by neutrophils [121,122]. Moreover, acute myocardial infarction has been shown to be associated with depression of plasma acetyl hydrolase activity, which in turn may allow a prolonged half-life of newly synthesised PAF [123]. A study investigating the relationship between PAF and cardiopulmonary sequelae in patients undergoing coronary bypass surgery has reported that increased levels of PAF in patients with unstable angina, left main coronary artery disease, or recent myocardial infarction are associated with the need for increased inotropy and prolonged ventilatory support following surgery [124]. In contrast, other studies failed to detect increased PAF levels in the peripheral blood after myocardial infarction [125,126].
To date, no clinical trials have investigated the protective effect of PAF antagonists in human phenomena associated with ischaemia–reperfusion. A recent study has investigated the effects of lexipafant, the PAF-receptor antagonist, on lysis-induced hypotension in cases of acute myocardial infarction. This study — which was not designed to investigate infarct size, ventricular function, or arrhythmias — established no beneficial effects of the PAF antagonist with respect to these parameters [127]. In contrast, the PAF antagonist BN 52021 significantly ameliorated postischaemic graft function in patients after lung transplantation, an intervention associated with ischaemia–reperfusion injury [128]. As a result, the significance of the release of PAF after myocardial ischaemia among humans is still unclear, and of the importance of this mediator as a negative inotropic substance in such a situation.
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4. Oxygen free radicals |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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Myocardial ischaemia and reperfusion are characterised on the one hand by increased generation of reactive oxygen species — including superoxide anion (O2–), hydrogen peroxide (H2O2), and hydroxyl radicals (·OH) — and on the other by a decrease in endogenous anti-oxidant mechanisms [129–133]. Free radical release, which is weak during ischaemia but increases substantially during reperfusion, overwhelms cellular defences and induces oxidative tissue damage [129]. It has proved possible to directly detect this increased formation of reactive oxygen species during ischaemia–reperfusion in isolated hearts and in vivo, by using electron paramagnetic resonance techniques [130,133,134]. In closed-chest dogs undergoing coronary artery occlusion followed by reperfusion, oxygen radical generation has been detected in the coronary sinus, beginning during the initial minutes of reperfusion and lasting up to 1 h [135].
The hypothesis that these reactive oxygen species are involved in post-ischaemic contractile depression has been supported by experimental studies using antioxidant mechanisms. Various antioxidants such as catalase, superoxide dismutase, glutathione peroxidase, and vitamin E have been shown to enhance the recovery of contractile functions after ischaemia, in both experimental and clinical studies [130,136–141]. However, the pattern emerging from these studies is not consistent, since some investigations using antioxidants failed to afford protection against ischaemia–reperfusion injury [141–144]. Differences in the severity of ischaemia–reperfusion injury, and in the subsequent levels of oxidative stress — as well as interaction of antioxidants with reactive oxidant species — may, at least in part, be responsible for these apparently conflicting data [141]. This is analogous to the effects of nitric oxide, which performs regulatory functions and also exerts cytotoxic effects, depending on the enzymatic source and relative amounts of nitric oxide generated [145]. Nevertheless, recent experiments that have involved overexpression of superoxide dismutase and catalase with transgenic animals, provide direct evidence that antioxidant strategies may indeed play a significant role in preventing post-ischaemic contractile failure [146,147].
There are various sources of oxygen free radicals in the post-ischaemic heart, including mitochondrial respiration, activated polymorphonuclear neutrophils, xanthine oxidase activity, auto-oxidation of catecholamines and arachidonic-acid metabolism [135,148,149]. Free radicals are chemical species with an unpaired electron: a characteristic that renders them reactive and capable of inducing oxidative modifications on other molecules. Oxidative stress associated with enhanced formation of free radicals accordingly induces membrane lipid peroxidation of cardiac organelles, leads to oxidation of sulfhydryl groups of structural proteins and enzymes, and induces mitochondrial damage [134]. These changes are believed to alter membrane permeability and configuration in addition to functional modifications of cellular proteins [141]. Functional consequences in cardiomyocytes are depression in sarcolemmal Ca2+-pump ATPase and Na+-K+-ATPase activities on the one hand, which leads to reduced Ca2+-efflux and enhanced Ca2+-influx [150,151]. On the other hand, these consequences include depression of the sarcoplasmic reticulum Ca2+-pump ATPase, with subsequent inhibition of Ca2+ sequestration from the cytoplasm in cardiomyocytes [152]. All these changes result in intracellular Ca2+ overload and cell death.
Oxygen free radicals are thus generated during myocardial ischaemia–reperfusion and apparently have deleterious effects on the contractile state of the myocardium. The question, however, arises: Is it appropriate to consider these reactive species as cardiodepressant substances? In vivo, exogenous oxygen free radicals generated by the xanthine–xanthine oxidase system or by activated polymorphonuclear neutrophils have been shown to depress cardiac function and myocardial contractility [153,154]. In anaesthetised rats, bolus injections of xanthine oxidase with substrate have transiently reduced myocardial contractility [155]. In isolated Langendorff-perfused guinea pig hearts, purine/XO has induced a negative inotropic effect [156]. Exogenous oxygen free radicals generated by xanthine oxidase [153] or activated polymorphonuclear neutrophils [157] have furthermore produced concentration-dependent decreases in contractility in isolated perfused rabbit hearts. Moreover, oxygen radicals in skinned muscle fibres from pig myocardium have been shown to attenuate contractility [158]. On the cellular level, the xanthine and xanthine oxidase system has been demonstrated to lead to arrest of contraction in mouse cardiac myocytes [159], and to produce a strong decrease in contractility and spontaneous beating rate in rat cardiomyocytes [160]. These experimental data support the assumption that oxygen free radicals are cardiac depressant mediators.
In correlation to the majority of substances released after myocardial ischaemia, oxygen free radicals are also signalling molecules and mediate a series of events leading to tissue injury during reperfusion. A link therefore exists between the well-established role of oxygen free radicals and that of PAF in ischaemia and reperfusion injury. Results indeed evidence that generation of free radicals stimulates the synthesis of PAF by the endothelium in the isolated perfused guinea pig heart, and that PAF receptor antagonists blunt the mechanical and electrical alterations induced by oxygen radicals [161]. In addition, free radicals promote activation and adherence of polymorphonuclear neutrophils to the vascular endothelium via adhesion molecule expression [162]. The superoxide radical has furthermore been shown to inactivate nitric oxide [163].
In conclusion, the concept that oxygen free radicals play a role as endogenous regulators of contractile function in ischaemia–reperfusion is based on the following phenomena: first, free radicals are generated and released from the heart and infiltrating neutrophils during ischaemia and reperfusion. Second, antioxidant strategies have beneficial effects with regard to the recovery of contractile function. Third, exogenous addition of oxidants induces cardiodepressant effects. Accumulating evidence accordingly suggests that oxygen free radicals released during reperfusion after myocardial ischaemia not only induce marked biochemical and metabolic abnormalities in experimental contexts and in humans, but also directly modulate myocardial contractile state. It is therefore justified to assign oxygen radicals to the group of endogenously released cardiac depressant substances.
4.1 Clinical correlates and human evidence
Studies have described enhanced generation — particularly during the early reperfusion period — of reactive oxygen species during acute coronary syndromes, and after thrombolysis, coronary angioplasty, or bypass surgery in men [133,164–166]. There is some evidence that this oxidative stress is related to transient left ventricular dysfunction or stunning [167]. In patients after coronary bypass grafting, a direct correlation has been reported between the duration of the aortic clamping period and the release of oxidized glutathione (GSSG) into the coronary sinus and an inverse correlation between the degree of GSSG release and the recovery of hemodynamic function after surgery [165]. Therapeutic antioxidative approaches have disclosed no consistent, favourable effects. On the one hand, beneficial effects on the clinical course in the postoperative phase after bypass surgery have been described [168]. Treatment with allopurinol in the perioperative phase of a bypass operation has, for example, led to significant improvement of cardiac function in comparison to placebo [169,170]. After myocardial infarction, treatment with allopurinol, on the other hand, was associated with increased mortality [171]. Two clinical studies have investigated the effects of recombinant human superoxide dismutase (h-SOD) among patients undergoing thrombolysis or angioplasty for acute myocardial infarction [172–174]. Both studies failed to show significant improvement in left ventricular ejection fraction. A recently published randomised study (EMIP-FR) on the administration of trimetazidine during the initial 48 h after myocardial infarction likewise revealed no beneficial effects of this antioxidant substance with regard to short- and long-term outcome [175]. Although free radicals are released in massive quantities after ischaemia–reperfusion, and are also in some cases associated with poor cardiac function, this approach accordingly offers at present no promising clinical therapeutic approaches.
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5. Arachidonic acid and metabolites |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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Under physiological conditions the cardiac content of unesterified arachidonic acids is very low. Ischaemia and reperfusion enhance membrane phospholipid degradation by the action of phospholipase A2, and thereby contribute to the accumulation of arachidonic acid in the ischaemic myocardium [176]. Phospholipase A2 is activated by an increase in intracellular Ca2+ concentrations that occur during reperfusion. Free radical-induced peroxidation of membrane phospholipids may further accelerate phospholipase A2-mediated hydrolysis [177]. Investigations with isolated heart preparations have elucidated that arachidonic acids are liberated after myocardial ischaemia [178–180]. Reperfusion of previously ischaemic myocardium was found to further increase the cardiac levels of arachidonic acids [178]. The extent of post-ischaemic arachidonic acid accumulation appears to positively correlate with the degree of ischaemia and reperfusion-induced damage [178,181].
Arachidonic acid molecules can be derived from membrane phospholipids of each cell type in the heart, but investigations with isolated, energy-depleted cardiomyocytes have suggested that cardiac muscle cells themselves are probably the major site of myocardial arachidonic acid accumulation [182]. Arachidonic acid and its metabolites exert distinct effects on cell membrane channels, receptors, and gap junctions, with hypoxia being an important stimulus to arachidonic acid metabolism. Findings on the direct effects of arachidonic acids on cardiac contractility are not consistent. Damron et al. have reported on the one hand that arachidonic acids enhance myocyte shortening by increasing the amplitude and the duration of the intracellular Ca2+ transient: which suggests that arachidonic acids themselves mediate almost positive inotropic effects in cardiac muscle [183]. Petit-Jaques et al., on the other hand, have shown that arachidonic acid exogenously administered to frog ventricular cells causes a significant inhibition of the L-type calcium channel current previously stimulated by isoproterenol [184]. A recent study has demonstrated that arachidonic acids induce marked intracellular acidosis in neonatal and adult cardiomyocytes. Since the contractility of cardiac muscle is known to be extremely sensitive to intracellular acidosis, the authors have suggested that this free fatty acid produces the negative inotropic effect during cardiac ischaemia through induction of acidosis [185].
Arachidonic acids also act indirectly via production of eicosanoids in the heart by the action of cyclooxygenase, lipoxygenase, and cytochrome P450 monooxygenase. Eicosanoids are most likely produced by endothelial cells, although some conversion of arachidonic acid into eicosanoids in cardiomyocytes has been discussed [186]. The pathogenetic role of various eicosanoids in cardiac dysfunction is equivocal; contractility however, does not seem to be influenced by most of the eicosanoids to a considerable degree. Leukotrienes (LT) are endogenously produced by the heart: production that is significantly increased after global ischaemia–reperfusion [187–189]. The family of LT includes LT B4, a powerful chemoattractant, and LT C4, D4, and E4, which are potent coronary vasoconstrictors. Polymorphonuclear neutrophils invading the damaged areas of the reperfused heart are the most likely source of LT, but synthesis and release of LT have also been verified in endothelial cells, myocytes, and resident mast cells [187,190]. Since LT receptor antagonists have significantly improved recovery of contractile function after myocardial ischaemia–reperfusion, it has been suggested that these arachidonic acid metabolites also have cardiodepressant properties [187]. Most studies on the cardiodepressant effects of leukotrienes favour the assumption that these mediators exert only a minor, if at all direct, cardiodepressive effect.
Recent investigations suggest that epoxyeicosatrienoic acids (EETs) — which are products of the cytochrome P-450 monooxygenase metabolism of arachidonic acid — are involved in the regulation of contractile function after myocardial ischaemia [191]. Four regio-isomeric EETs (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) have been characterised and are produced in the heart [192,193]. Appreciably positive inotropic effects on isolated cardiomyocytes, as well as inhibitory effects on cardiac L-type Ca2+ channels, have been described after extracellular addition of EETs [194–197]. Since arachidonic acid and its metabolites are elevated in the ischaemic myocardium, a potential role of EETs in regulation of post-ischaemic cardiac contractile function may be assumed. Further research is required for detailed information on the effects of these cytochrome P-450 metabolites on myocardial contractility under physiological and ischaemic conditions.
5.1 Clinical correlates and human evidence
There is some evidence that the concentrations of phospholipase A2 involved in the formation of arachidonic acid cascade metabolites gradually increase during the acute stage of myocardial infarction in men [198,199]. These phospholipase A2 levels were higher in severe cases with heart failure, and were significantly correlated with left ventricular ejection fraction [199]. It has been accordingly suggested that activation of phospholipase A2 is directly related to the extent of tissue injury. Nevertheless, clinical data are lacking on the significance of arachidonic acid, or its metabolites: i.e. as negative inotropic substances after myocardial ischaemia–reperfusion in conjunction with infarct or bypass surgery.
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6. Nitric oxide |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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Nitric oxide (NO) is released under physiological and pathophysiological conditions by coronary and endocardial endothelial cells, as well as by cardiomyocytes. This highly reactive gas is recognised as a nearly ubiquitous autocrine and paracrine chemical messenger [200,201]. Accumulating evidence suggests that NO also regulates myocardial function [202]. NO is generated from L-arginine by a family of NO synthases (NOS). Whereas NOS activation on a Ca2+-independent inducible basis (iNOS, located in the cytosol) usually requires several hours, the Ca2+-dependent constitutive endothelial NOS (eNOS, located in the cell membrane) is easily activated by hypoxia or ischaemia and leads to rapid release of NO. Neuronal NOS (nNOS), another constitutive isoform, has been identified in cardiac neurons and cardiomyocytes [203–205]. Although some authors described increased expression of nNOS in myocardial ischaemia [206,207], the physiological role of nNOS-derived NO in ischaemia–reperfusion remains to be elucidated. In addition to the NOS-dependent NO formation, NO can be generated by a nonenzymatic pathway during ischaemia–reperfusion injury via reduction of nitrate to NO [208].
NO acts primarily by stimulating the soluble guanylate cyclase and through subsequent elevation of intracellular cGMP. Small increases in cGMP levels predominantly inhibit phosphodiesterase III, with subsequent diminished breakdown of cAMP — whereas high cGMP levels activate cGMP-dependent protein kinase. Accordingly, physiologically low concentrations of NO apparently increase contractility, while high concentrations induce negative inotropic effects via inhibition of voltage-dependent calcium channels [202,209–211]. In addition, some data suggest another mechanism by which NO depresses myocardial function: namely, via reaction with superoxide to form the toxic product peroxynitrite. Peroxynitrite inhibits contractile function in cardiac myocytes and in isolated hearts [212,213]. It has been shown that myocardial ischaemia and reperfusion results in the generation of peroxynitrite. Treatment with NO synthase inhibitors or superoxide dismutase has prevented formation of peroxynitrite after ischaemia, and was associated with significantly improved recovery of contractile function during reperfusion [214]. In corroboration, studies have shown both in vitro and in vivo that enhanced formation of peroxynitrite in the myocardium is deleterious to cardiac function and contributes to ischaemia and reperfusion injury [215,216].
It is not only exogenous NO that has been reported to show concentration-dependent biphasic effect on cardiac myocyte contraction [202,209]: activation of NOS expression also has the same effect [209,217–219]. The cytokine-induced NO-dependent cardiodepressive effect should be seen in this context, consistent as it is with the negative inotropic effect of NO at high concentrations.
There is some evidence that NO release after brief ischaemia followed by reperfusion is more likely reduced [220,221], and that increased NO release comes about only after longer ischaemia–reperfusion, primarily as a result of upregulation of iNOS activity [222–224]. Wang et al. have detected increased NO release from isolated rat hearts after 30 min of global ischaemia. After pre-treatment with an NOS inhibitor, a fourfold increase in postischaemic functional recovery has been observed [215]. Similar data have been obtained for the isolated working rabbit heart [225]. In an in vivo model (dog), it has furthermore been shown that enhanced NO release reduces myocardial contractility in the ischaemic heart [226]. These experimental data suggest that NO exerts pronounced detrimental effects on myocardial postischaemic contractile state. On the other hand, it has been reported that inhibition of NOS enhanced the degree of myocardial depression following brief ischaemia in conscious dogs, independently of changes in coronary flow [227]. These findings imply that NO produced significant protective effects against myocardial stunning [227]. The underlying reason for these conflicting results of NO in modulating postischaemic cardiac function may be explained by the multifactor NO mechanism of action under these pathophysiological circumstances: NO not only directly influences contractility in the sense of a positive or negative inotropic effect (dependent on the concentration of NO): it also inhibits neutrophil-mediated injury, preserves endothelial function, and may react with superoxide to form peroxynitrite [215]. Thus, the effects on myocardial function in vivo of endogenous NO generation and the impact of its release from the heart after myocardial ischaemia remains controversial.
6.1 Clinical correlates and human evidence
Hardly any clinical data are available on the significance of NO release with respect to human myocardial contractility during phenomena associated with ischaemia–reperfusion. Akiyama et al. have shown that myocardial production of nitrite and nitrate — i.e. oxidative products of NO — was increased in patients with acute anterior infarction [228]. Their data suggest that the myocardium constitutes the source of increased plasma levels of plasma-oxidation products of NO. No information is currently available on the functional relevance of an increased release of NO after myocardial ischaemia in humans.
There is only a small body of data, including contradictory results to some extent, on alterations of iNOS expression or activity in coronary heart disease. Whereas the expression of iNOS as well as iNOS immunoreactivity have been shown to be increased in explanted heart tissues or biopsies from patients with ischaemic heart disease [229,230], others found little, if any, iNOS activity in myocardial tissue from patients with ischaemic heart disease [231].
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7. Adenosine |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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Adenosine, a metabolite of adenine nucleotide, is released by the heart, from cardiomyocytes, endothelial cells, and smooth muscle cells, in accordance with the increased severity of ischaemia. It carries out a variety of biological functions that are mediated by several G protein-coupled cell surface receptors. Adenosine is primarily a chemical mediator of coronary hyperaemic flow in the ischaemic myocardium via A2 receptors located on endothelial cells and smooth muscle cells. In addition, adenosine induces negative chronotropic, dromotropic, and inotropic effects via A1 receptors [232,233]. Adenosine-mediated regulation of myocardial contractility after ischaemia comprises several mechanisms of action. Adenosine accordingly antagonises the positive inotropic effect of catecholamines by inhibiting catecholamine-induced stimulation of adenylyl cyclase activity, and it inhibits exocytotic release of catecholamines in the ischaemic heart by activation of presynaptic adenosine receptors [233–235]. Moreover, there is evidence that adenosine also produces direct negative inotropic effects in the heart [236–240]. The underlying mechanism, however, has been elucidated to only a partial extent; there are especially controversial data involving interaction with proteinkinase C (PKC). On the one hand, Lester et al. have reported that adenosine receptor-induced PKC activation mediates a negative inotropic effect in rat cardiomyocytes [241]. On the other hand, adenosine A1 receptor activation apparently attenuates the PKC-dependent negative inotropic effect and during ischaemia adenosine prevents activation of PKC [242,243]. There is evidence that an adenosine-mediated decrease in myocardial contractility vanishes after longer periods of ischaemia [240]. This loss of adenosine-induced negative inotropic effect during ischaemia has been attributed to activation of protein kinase C and prostacylin release [240]. Adenosine accordingly appears to be involved in the regulation of myocardial contractility after ischaemia.
The role of adenosine as a postischaemically released negative inotropic substance, however, remains to be elucidated, since this nucleotide mediates a variety of other biological functions that can mask contractile effects. Adenosine replenishes high-energy phosphate stores in endothelial cells and cardiomyocytes, inhibits oxygen free radical formation and neutrophil activation, and adapts coronary perfusion to the oxygen demand of cardiac muscle, etc. (for review, see Ref. [244]). These beneficial effects are the basis for the cardioprotective action of adenosine, which is well documented for ischaemia–reperfusion. In both in vitro and in vivo work it has proved possible to conclude that adenosine enhances myocardial function after ischaemia, and that it reduces infarct size: not only for endogenously produced but also for exogenously administered adenosine [244,245].
7.1 Clinical correlates and human evidence
In corroboration with experimental studies, there is some evidence that exogenous adenosine has beneficial effects on the one hand when administered before or during acute myocardial ischaemia, by virtue of its reduction of ischaemic periods and infarct size, and by improving functional recovery [244,246]. On the other hand, its benefits are also seen in conjunction with cardioplegia through reduction of inotropic support after surgery and in improvement of postoperative myocardial function [244,245]. There are presently no data available on the importance of inotropic effects of exogenous or endogenous adenosine in situations associated with ischaemia–reperfusion.
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8. ‘Cardiodepressant factors’ |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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8.1 Factors released after hypoxia-modulating myocardial contractility
Since the first description by Brutsaert et al. that endothelial cells influence myocardial contractile function [97], numerous reports have produced evidence on the role of endocardial and coronary endothelial lining in modulating myocardial contraction under physiological and pathophysiological conditions [247–249]. The heart contains large quantities of coronary vascular endothelium in close proximity to the myocardium, which likewise suggests physiologically relevant crosstalk between endothelial cells and cardiomyocytes after myocardial ischaemia. Ramaciotti and colleagues have proposed that oxygen tension and coronary flow are important regulatory factors that influence the release of diffusible mediators from endothelial cells [250]. Shah et al. have reported that endothelial cells superfused with hypoxic buffer for 1–6 h release a stable, low-molecular-mass (<0.5 kDa) substance that induces pronounced inhibition of cardiac myocyte shortening without relevant changes of cytosolic Ca2+ transients [251,252]. In an in-vitro motility assay, the substance released during hypoxia depressed the translocation of actin filaments over myosin molecules and reduced the actin-activated cardiac myosinATPase activity in solution [252]. More recently, the same authors showed that hypoxic coronary effluent of rat hearts also significantly inhibits myocyte twitch shortening and decreases diastolic length, without inducing significant changes in intracellular Ca2+-transients. The effect was reversible upon reoxygenation [253]. The authors concluded that the heart during hypoxia likely releases an unidentified stable substance that acts predominantly by Ca2+-independent modification of myofilament function. These investigations suggest the close and dynamic interaction between myocardial and endothelial cells, likewise during regulation of contractile state after myocardial ischaemia.
8.2 Negative inotropic substance(s) (NIS) released after ischaemia
We have recently shown that stable negative inotropic substance(s) (NIS) of yet unknown chemical structure are released during reperfusion of isolated hearts after ischaemia. These mediator(s) induce a pronounced decrease in myocardial contractility in sequentially perfused second hearts used as a bioassay [254,255]. In isolated rat cardiomyocytes, NIS reduces systolic cell shortening and Ca2+ transients through reduction of Ca2+ influx through L-type Ca2+ current (ICa, see Fig. 3) [256]. It remains to be elucidated by which mechanism NIS blocks ICa. Since neither cGMP nor cAMP tissue levels, nor PKA nor PKC activity are modified by NIS, it is unlikely that dephosphorylation of subunits of L-type Ca2+ channel is involved. We favour the hypothesis that NIS interacts with the Ca2+ channel more directly: e.g. by plugging the pore or by binding to the channel protein. The negative inotropic effect is rapid in onset, reversible within 5 min upon washout, and counteracted by catecholamine release after ischaemic periods longer than 10 min [257].
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The chemical structure of NIS remains unknown. As evidenced by data recently reported by us, the substance(s) are most likely not proteins. It has proved possible to exclude mechanisms based on generally recognised cardioactive mediators such as oxygen free radicals, nitric oxide, and adenosine. In addition, the substance(s) so far unidentified are stable, heat-resistant and dialyzable molecules of low molecular weight (<0.5 kDa), as evidenced by treatment of postischaemic coronary effluent as recently described [254–256].
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9. Discussion |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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Ischaemia–reperfusion injury is a clinical problem associated with measures undertaken to establish blood flow and to minimise damage to the myocardium after severe myocardial ischaemia, such as observed after myocardial infarction and coronary bypass surgery. Myocardial ischaemia and reperfusion injury have been shown to result in reversible contractile dysfunction (stunning), reperfusion arrhythmias, microvascular damage, apoptosis and necrotic cell death (lethal reperfusion injury), which may occur either together or separately [258,259]. Two main mechanisms are involved in the pathogenesis of ischaemia–reperfusion injury: namely, oxidative stress and Ca2+ overload [135,260]. The principal mediators of this phenomenon are oxygen free radicals and neutrophils that are reintroduced in the previously ischaemic tissue. Upon reflow, oxygen free radicals are generated in large amounts, overwhelming cellular defences and inducing oxidative tissue damage. Activated neutrophils amplify cellular dysfunction by the release of lytic enzymes [135].
In addition, potent mediators, in part substances of the inflammatory cascade, are released during myocardial reperfusion from the heart itself: a process that may further worsen myocardial dysfunction in autocrine and paracrine forms by virtue of negative inotropism. These mediators generated in the ischaemic and reperfused myocardium by cardiomyocytes, endothelial cells, and infiltrating monocytes/macrophages not only aggravate damage to the previously ischaemic tissue, but may also diffuse to the intact, non-ischaemic part of the heart, particularly during the early reperfusion period. The result is induction of global myocardial dysfunction.
The variety of these endogenous negative inotropic mediators raises the question as to whether they act independently of each other or synergistically at the target cells. In vivo, an individual cardiodepressive factor cannot be evaluated independently of all other influencing factors. Many mediators produce not only a direct effect on myocardial contractility (e.g. through blocking of L-type Ca2+ channels, or by inhibition of excitation contraction coupling): they also indirectly modulate contractility by induction and release of other, potentially negative inotropic substances. In this manner, for example, PAF stimulates the release of TNF-, free radicals, and eicosanoids. Cytokines in particular constitute a sophisticated regulatory network acting in cascade fashion in which a mediator may have considerable effects on both the production and the action of other mediators. The resulting change in homeostasis is the consequence of complicated interaction between various cytokines and hormones [28,35,38].
It is furthermore worthy of note that many mediators, including cytokines and PAF, frequently act via various mechanisms in a negative inotropic manner — and that rapid modulation of the contractile state is in most cases opposed by delayed contractile failure that is based on gene expression. These circumstances could well prove significant in the development of myocardial stunning.
In order to be able to assess the pathophysiological relevance of these effects on contractility, it is also essential to consider the fact that the various mediators frequently have other effects as well. These effects include induction or hindrance of apoptosis and hypertrophy, as well as alteration of vasoreactivity, all of which can indirectly influence myocardial functions. Oxygen free radicals and cytokines, for example, are among the most potent stimuli that elicit cardiomyocyte apoptosis, and may accordingly modulate contractility by induction of apoptotic cell death [2,27,261]. PAF and a number of arachidonic metabolites are likewise strong vasoconstrictors and may accordingly modulate haemodynamics and, indirectly, the myocardial contractile state.
In arriving at a teleological interpretation of these phenomena, it may profitably be taken into consideration that negative inotropic effects of substances released after myocardial ischaemia may further jeopardise the pump function of the heart. On the other hand, the release after myocardial ischaemia of mediators that decrease contractility may be interpreted as a mechanism to reduce myocardial O2 consumption and, in turn, may consequently facilitate the myocardial oxygen supply–demand balance. In addition, mediators that decrease the intracellular Ca2+ transient, such as NIS, may play protective roles by antagonizing the Ca2+ overload observed during reperfusion after ischaemia [262]. Inhibition of Ca2+ overload may reduce lethal ischaemic cellular injury. The decrease in [Ca2+]c may therefore represent an important compensatory mechanism of the myocardium for limiting ischaemic injury during reperfusion. It has been shown for cytokines such as TNF- that they produce potentially deleterious effects with progressive left ventricular dysfunction when administered exogenously [263]. Other results, however, have concluded that the extent of myocardial infarction in mice that lacked TNF receptors was increased — which indicates that TNF receptor stimulation can exert a beneficial effect in myocardial infarction [264]. These studies have emphasised the view that intervention with a potentially negative effect, under certain circumstances, can lead to beneficial results in a physiological context [265].
In conclusion, cardiac cells — including cardiomyocytes, endothelial cells, and resident mast cells — respond to ischaemic stimuli with release of mediators that influence myocardial performance via autocrine–paracrine coupling. Cytokines, PAF, free radicals, arachidonic acid and metabolites, NO, adenosine as well as still unidentified ‘cardiodepressant mediators’ represent the main negative inotropic substances generated and released under these conditions. Further investigation is required to elucidate the relationship between the various cardiodepressant mediators of the extent and/or severity in ischaemia–reperfusion injury. The objective of such further work will be to evaluate the effects of pharmacological intervention on the production of these mediators, particularly in reperfusion/thrombolysis, and to assess the prognostic significance of circulating levels of cardiodepressant substances. Contractile failure after myocardial infarction represents a major clinical problem associated with high mortality rates, particularly in the initial hours and days after infarction. Identification of mediators — as well as recognition of cellular targets associated with myocardial contractile dysfunction and amenable to pharmacological manipulation — may consequently enable novel therapeutic strategies.
Time for primary review 28 days.
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References |
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TopAbstract1. Introduction2. Cytokine-mediated contractile...3. Platelet-activating factor...4. Oxygen free radicals5. Arachidonic acid and...6. Nitric oxide7. Adenosine8. 'Cardiodepressant factors'9. DiscussionReferences |
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- Herskowitz A.S., Choi S., Ansari A.A., Wessellingh S. Cytokine mRNA expression in the postischemic/reperfused myocardium. Am J Pathol (1995) 146:419–428.[Abstract]
- Meldrum D.R. Tumor necrosis factor in the heart. Am J Physi