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Cardiovascular Research 2007 74(3):343-355; doi:10.1016/j.cardiores.2007.01.014
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Copyright © 2007, European Society of Cardiology

Reperfusion injury in humans: A review of clinical trials on reperfusion injury inhibitory strategies

Maurits T. Dirksena, Gerrit J. Laarmana,*, Maarten L. Simoonsb and Dirk J.G.M. Dunckerb

aAmsterdam Department of Interventional Cardiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
bDepartment of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands

* Corresponding author. Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Oosterpark 9, 1090 HM Amsterdam, The Netherlands. Tel.: +31 20 5993032; fax: +31 20 5993120. Email address: g.j.laarman{at}olvg.nl

Received 14 June 2006; revised 9 January 2007; accepted 11 January 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Ca2+-overload (Table 2)
 3. Miscellaneous
 4. Mechanical modulation of...
 5. What is the...
 6. Summary, conclusion and...
 References
 
The principal therapy in patients with myocardial infarction to limit infarct size is myocardial reperfusion by mechanical or pharmacological intervention. Reperfusion has been proposed to cause myocardial injury beyond that caused by the preceding ischaemia, termed "reperfusion injury" (RI). While the precise mechanism of RI is still incompletely understood, a large number of clinical studies have been performed over the past decade targeting some of the postulated mechanisms of RI. These clinical studies were based on experimental data demonstrating significant myocardial salvage. Nevertheless, clinical benefits were absent or very limited. The purpose of this review is to provide an overview of the various strategies that inhibit RI and to discuss potential mechanisms that may contribute to the discrepancy between the promising pre-clinical data and the rather disappointing results obtained from prospective clinical trials. There are numerous differences between the experimental models and clinical studies, including the fact that experimental studies typically use abrupt occlusion and reperfusion protocols in animals with previously healthy myocardium that apparently do not predict the therapeutic efficacy of novel cardioprotective agents in a clinical setting with pre-existing progressive coronary disease, intermittent coronary occlusion, and relatively late reperfusion. However, discrepancies also exist between experimental studies. Future experimental studies of reperfusion injury should use models that mimic the clinical situation more closely. Furthermore, future large clinical trials should only be performed in cases where the drug under investigation proved to reduce RI in a series of well-designed (possibly multicenter) experimental studies and in clinical trials with predefined subgroups.

KEYWORDS Reperfusion injury; Review; Experimental; Clinical; Acute myocardial infarction; Reperfusion


   1. Introduction
Top
 Abstract
 1. Introduction
2. Ca2+-overload (Table 2)
 3. Miscellaneous
 4. Mechanical modulation of...
 5. What is the...
 6. Summary, conclusion and...
 References
 
Preventing acute myocardial infarction (AMI) or limiting infarct size is critical to improve immediate and long-term outcome of patients with an acute coronary syndrome and to avoid the development of heart failure. Currently, the single established strategy to limit infarct size is early reperfusion with percutaneous coronary intervention (PCI) or thrombolytic therapy [1]. The importance of early reperfusion is not surprising as the primary insult is a decrease in oxygen supply resulting in a decrease of free energy from ATP-hydrolysis beyond a critical level required for maintaining cell processes such as ion channel function. However, despite its clear benefit, reperfusion itself has been proposed to cause irreversible myocardial damage, termed "reperfusion injury" (RI), beyond that caused by the preceding period of ischaemia, implying that optimization of reperfusion therapy could further limit infarct size (Table 1).


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  		Table 1 List of acronyms of randomized clinical trials in alphabetical order

 
The mechanism of RI remains incompletely understood, but may include (i) cytosolic and mitochondrial Ca2+-overload, (ii) release of reactive oxygen species (ROS), (iii) an acute inflammatory response, and (iv) shift in substrate use [2–8]. In concert, these perturbations might produce irreversible damage to cardiomyocytes that are severely ischaemic but still salvageable at the time of reperfusion. Consequently, these pathways have been the therapeutic targets in experimental and clinical studies. Furthermore, despite restoration of epicardial coronary patency and blood flow, reperfusion after prolonged coronary occlusion is associated with secondary impairment of microcirculatory flow ("no-reflow" phenomenon), that is due to endothelial dysfunction, neutrophil plugging and oedema, but may also be aggravated by distal (micro-)embolization [9,10].

Indirect evidence for the existence of RI stems from observations that reperfusion is associated with hypotension, temporary increase of chest pain, ST segment deviation and arrhythmias. However, direct evidence for the existence of RI stems from animal studies in which pharmacological agents administered just prior to reperfusion limit infarct size [3,11–15]. Pre-clinical studies, although sometimes equivocal, spurred a large number of clinical trials. The latter yielded mostly disappointing results and hence the existence of lethal RI in the clinical setting remains controversial [3,11–13,16].

The goal of the present review article is to discuss potential reasons why clinical studies have generally failed to show a beneficial effect of pharmacological interventions, despite beneficial effects reported in many experimental studies. In addition, we propose some guidelines for improving future pre-clinical and clinical trials. In-depth overviews of the mechanisms of RI have been published previously [2,5,13,17], and are beyond the scope of this article.


   2. Ca2+-overload (Table 2)
Top
 Abstract
 1. Introduction
 2. Ca2+-overload (Table 2)
3. Miscellaneous
 4. Mechanical modulation of...
 5. What is the...
 6. Summary, conclusion and...
 References
 
Intracellular Ca2+ increases during prolonged ischaemia and subsequent reperfusion. Ca2+-overload during ischaemia is partially due to activation of the Na+/Ca2+-exchanger and opening of L-type Ca2+-channels, in conjunction with inhibition of sarcolemmal and sarcoplasmic reticular Ca2+-pumps [13]. During reperfusion, the Na+/H+-exchanger is activated to restore intracellular pH. However, the extrusion of H+ initiates a net influx of Na+ into the cardiomyocyte, which via the Na+/Ca2+-exchanger leads to further increase in Ca2+-influx during early reperfusion [13]. The Ca2+-overloaded myocytes enter into a state of hypercontracture when exposed to oxygen and energy, after reperfusion [13,14,18]. Furthermore, Ca2+-overload induces protease activation, gap-junction dysfunction and membrane rupture that cumulatively contribute to cell death [19].


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  		Table 2 Randomized clinical trials on calcium homeostasis in patients with AMI

 
2.1 Ca2+-channel blockers and magnesium
Blockade of the L-type Ca2+-channel can prevent Ca2+-overload during prolonged ischaemia and reperfusion [20]. In experimental models of coronary occlusion, Ca2+-antagonists limit irreversible myocardial damage and reduce the degree of stunning, provided these agents are administered prior to ischaemia [21,22]. MgSO4 also possesses Ca2+-channel blocking properties, which may aid in preventing Ca2+-overload during reperfusion [20] and may protect against reactive oxygen species [23]. Interestingly, intracellular Mg2+ levels are depressed during AMI [24], while supplemental Mg2+ has been reported to reduce infarct size when administered prior to reperfusion [25,26].

2.1.1 Clinical trials
Clinical evidence regarding the benefit of Ca2+-channel blockers in the setting of AMI remains inconclusive when treated with Ca2+-channel blockers on top of reperfusion therapy, despite their beneficial effects in reversible ischaemic syndromes [27]. Two of three small pilot studies showed improvement of left ventricular function (echocardiography)(Table 2) [21,22,28–30]. The DATA trial showed improved clinical outcome (n=59), despite a lack of efficacy of diltiazem on infarct size or left ventricular function [24]. There is no indication for Ca2+-channel blockers as an adjunct to reperfusion therapy as large randomized trials are lacking. Trials on the use of MgSO4 (an endogenous Ca2+-antagonist) in patients with AMI showed similarly negative results in over 60,000 patients (Table 2) [31–34].

2.2 Na+/H+ exchange inhibitors
Experimental studies have demonstrated marked limitation of infarct size when NHE-inhibitors are administered prior to ischaemia [35]. However the efficacy of NHE-inhibitors administered just prior to reperfusion remains controversial [36].

2.2.1 Clinical trials
Except for a pilot study in 100 patients with cariporide [37], NHE-inhibitors generally failed to demonstrate any benefit on infarct size or clinical outcome when given after onset of ischaemia in the setting of AMI (ESCAMI trial (n=1389) with eniporide and CASTEMI trial (n=247) with caldaret (Table 2) [38,39]. However, when the NHE-inhibitor cariporide was given before ischaemia in patients undergoing CABG, a reduction in peri-operative cardiac enzyme release was observed in the GUARDIAN CABG subgroup [40] and the large EXPEDITION study (n=5761)[41]. This was associated with an improvement in outcome in the GUARDIAN CABG subgroup, whereas the EXPEDITION trial showed an overall increase in mortality, and inexplicably, strokes [41]. Nevertheless, GUARDIAN and EXPEDITION support the concept that that irreversible myocardial damage is reduced by NHE inhibitors administered prior to the onset of ischaemia. The results of these trials are consistent with animal studies that show that NHE-inhibitors are principally only effective when given before ischaemia.

2.3 Anti-inflammatory strategies (Table 3)
Key events in the inflammatory response to ischaemia-reperfusion are the production of reactive oxygen species (ROS), complement activation, neutrophil activation and endothelial dysfunction. These processes may produce irreversible cardiomyocyte damage directly, but also indirectly via myocardial oedema and capillary plugging by polymorphonuclear cells (PMN) causing "no-reflow" [42,43].


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  		Table 3 Randomized clinical trials on anti-inflammatory agents in patients with AMI

 
2.3.1 Clinical trials
Studies using anti-inflammatory strategies have generally yielded disappointing results and will not be discussed in detail in this manuscript. These clinical trials are summarized in Table 3. Thus, pilot trials with anti-oxidants (a recombinant human SOD and edaravone, a ROS scavenger) in the setting of primary PCI for AMI failed to demonstrate efficacy (Table 3) [44,45]. In addition, despite equivocal experimental data regarding a causal role of PMNs in lethal RI, clinical trials were initiated using drugs that inhibit PMN tethering and activation [46–51], inhibit PMN adhesion molecules [52], or preserve endothelial function (Table 3) [53]. Disappointing results were reported in these 8 (predominantly phase II) clinical trials with agents that inhibit PMN activation and endothelial dysfunction [46–53]. Finally, complement inhibition with a monoclonal antibody (anti-C5), pexelizumab, was investigated in patients with AMI in the COMMA [54], the COMPLY [55] and the APEX-AMI trial [56]. All three trials failed to demonstrate a limitation of infarct-size (total CK-MB) or composite clinical endpoint. However, the COMMA-trial did show an unexplained decrease in overall mortality with pexelizumab (Table 3) [54].

2.4 Adenosine
Adenosine exerts a multitude of actions that can protect the myocardium against RI, including anti-ischaemic effects via pharmacological preconditioning, inhibition of PMN-activation and ROS formation, anti-inflammatory properties, preservation of endothelium and microvascular flow [57]. Adenosine has demonstrated marked cardioprotection in animal studies, when administered before ischaemia. Conversely, administration after the onset of ischaemia has yielded variable results [58–60], that may in part be due to co-administration of lidocaine [59–61] or collateral flow level [50].

2.4.1 Clinical trials
Following a promising non-randomized pilot trial (n=45)[62], the AMISTAD-I [63] and II [64] trials investigated the effect of adenosine in combination with lidocaine as an adjunct to reperfusion therapy in patients with AMI. The first AMISTAD trial included 236 patients who were randomly assigned to either placebo or adenosine with lidocaine on top of thrombolysis for AMI. Although adenosine treatment did not modify overall infarct size (SPECT), the anterior infarct subgroup showed significant reduction. Consequently, the AMISTAD-II was conducted exclusively in patients (n=2084) with anterior AMI. Although adenosine did not show an overall benefit, the authors reported a trend towards a modest limitation in infarct size in the high-dose adenosine subgroup compared to placebo (Table 3) [64]. The ADMIRE (n=608; reperfusion by thrombolysis) and the ATTACC (n=311 with anterior MI; reperfusion by PCI) trials also failed to observe beneficial effects of adenosine treatment on infarct size or clinical outcome, although a trend towards greater myocardial salvage assessed by SPECT was apparent in the ADMIRE trial (Table 3) [65,66].

The anti-inflammatory and coronary vasodilator actions of adenosine may limit no-reflow following reperfusion and hence reduce secondary myocardial ischaemia [58]. A pilot study (n=54) investigated the effects of intracoronary adenosine administered just before reperfusion in patients with AMI [67]. No-reflow was observed in 1 patient in the adenosine group and in 7 patients in the placebo group (p<0.05), which was associated with significant improvement in ventricular function (echocardiography) and clinical improvement.

Taken together, clinical trials with adenosine as an adjunct to reperfusion therapy have failed to show a significant beneficial effect. However, the potential of adenosine to improve microvascular function and reduce infarct size when administered before the onset of ischaemia (similar to the experimental studies), e.g. in the setting of CABG, deserves further investigation [68].

2.5 Metabolic interventions: glucose–insulin–potassium (Table 4)
The concept of glucose–insulin-K+-therapy (GIK) was introduced 44 years ago by Sodi-Pallares and thought to be protective by stabilization of the membrane [69]. From observations that glucose is a preferential energy source during ischaemia and reperfusion the concept emerged that GIK therapy may limit infarct size [70–73]. Additionally, GIK decreases circulating levels of free fatty acids and myocardial free fatty acids uptake, possibly limiting toxic concentrations in ischaemic myocardium [74]. Finally, insulin can exert anti-RI effects by activation of Akt and p70s6 kinases [75]. GIK has been shown to be protective against RI following AMI in the majority of animal studies, also when administered after the onset of ischaemia [75–78].


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  		Table 4 Randomized clinical trials with glucose–insulin–potassium (GIK) in patients with AMI

 
2.5.1 Clinical trials
Meta-analysis of trials from the pre-thrombolytic era suggests therapeutic benefit of GIK treatment [72]. Six recent trials also showed some benefit of GIK, but only in specific subgroups (Table 4) [71,79–82]. In the ECLA study (n=407) GIK therapy, starting 10–11 h after onset of symptoms, improved clinical outcome in the reperfused patients (62% of total study population) [66]. In the CREATE-ECLA-trial (n=20,000; reperfusion therapy in 83%), GIK treatment failed to improve 30-days clinical outcome although there was a trend towards improved clinical outcome in patients undergoing reperfusion therapy by PCI (9% of all patients) [79]. Conversely, the Pol-GIK-trial in a low-risk AMI patient population (Killip I-II) was terminated prematurely because of an increase in mortality in GIK-treated patients [80]. The REVIVAL study evaluated GIK treatment started within 10 h of start of symptoms in 312 patients undergoing reperfusion therapy. No infarct size reduction as assessed by SPECT was shown, although GIK-treated patients with diabetes (n=35) showed improved myocardial salvage [83].

Recent studies performed in the Netherlands yielded similar results for GIK treatment on top of primary PCI in the setting of AMI (Table 4) [81,82]. Analysis of the total study population in the GIPS-I (n=904) and patients without clinical evidence of heart failure in the GIPS-II (n=889) failed to demonstrate a reduction in 30-days mortality or limitation in enzymatic infarct size, despite significant reduction in the subgroup with patients without evidence of heart failure in the GIPS-I [81,82].

GIK has also been investigated as adjunctive therapy to CABG [84]. A review of 91 studies indicates a benefit of insulin or GIK in 74 of these studies [85]. Despite the reports in which GIK treatment suggested additive benefit on clinical outcome and peri-operative infarct size, GIK is currently not used routinely in clinical practice because of a lack of unequivocally positive results [85].


   3. Miscellaneous
Top
 Abstract
 1. Introduction
 2. Ca2+-overload (Table 2)
 3. Miscellaneous
4. Mechanical modulation of...
 5. What is the...
 6. Summary, conclusion and...
 References
 
Various other cardioprotective agents, such as trimetazidine, angiotensin converting enzyme (ACE)-inhibitors and nicorandil, have been evaluated in the setting of AMI. None of these trials showed satisfactory proof of infarct size reduction in adequately sized trials (Table 5) [86–90]. Consequently none of these agents is currently being used in AMI, and await evaluation in larger trials.


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  		Table 5 Randomized clinical trials with miscellaneous agents in patients with AMI

 

   4. Mechanical modulation of reperfusion
Top
 Abstract
 1. Introduction
 2. Ca2+-overload (Table 2)
 3. Miscellaneous
 4. Mechanical modulation of...
5. What is the...
 6. Summary, conclusion and...
 References
 
Gradual reinstitution of blood flow during reperfusion has been shown to limit RI in the setting of experimental ischaemia-reperfusion [91]. Recently, this phenomenon was extended when Zhao et al. showed that infarct size in dogs was reduced by a sequence of brief re-occlusions following prolonged ischaemia [92]. This phenomenon, termed "postconditioning", has been confirmed in several other animal species [93,94], and probably involves a reduced inflammation and oxidative stress [92], and the activation of reperfusion injury salvage kinase pathways [93,94] resulting in reduced mitochondrial permeability [95].

4.1 Clinical trials
Staat et al. investigated the effect of postconditioning in 30 patients with AMI and reported limitation of enzyme release and improvement of myocardial perfusion [95], supporting the concept that lethal myocardial RI in humans may be limited by (mechanical) intervention [95]. However, these promising initial results await confirmation in large trials.


   5. What is the cause of the predominantly negative clinical trials?
Top
 Abstract
 1. Introduction
 2. Ca2+-overload (Table 2)
 3. Miscellaneous
 4. Mechanical modulation of...
 5. What is the...
6. Summary, conclusion and...
 References
 
A reconciliation of the discordance between the often positive findings in pre-clinical studies and the predominantly negative clinical trials requires a careful assessment of differences in methodology and biology between experimental and clinical studies.

5.1 Co-morbid conditions
5.1.1 Concomitant disease
In contrast to the majority of pre-clinical studies, in which healthy young animals are typically employed, ischaemic heart disease and myocardial infarction in humans is principally a disease of the middle-aged and elderly. The co-morbid conditions leading to ischaemic heart disease (e.g. atherosclerosis, hypercholesterolemia, hypertension and diabetes), advanced age, and impaired nutritional status and that are typically absent in pre-clinical studies, may blunt the efficacy of cardioprotective therapies [53,96,97].

5.1.2 Preconditioning
The hearts of healthy animals in the pre-clinical studies have not been exposed to ischaemia prior to infarction. In contrast, brief ischaemic episodes and gradual occlusion preceding myocardial infarction, as occurs clinically during episodes of pre-infarct angina pectoris [98], may modulate the protective effects of pharmaco-therapy by inducing ‘ischaemic preconditioning’ [11]. Conversely, subsets of patients may have become tolerant to preconditioning due to repeated ischaemic episodes in which pharmacological protection may provide an important contribution to cardioprotection [99].

5.1.3 Concomitant medication
The concomitant medication used during routine clinical practice, and which is typically absent in experimental studies, may influence the effectiveness of agents directed against RI [49,53]. Current reperfusion therapy of acute myocardial infarction involves treatment with vasodilators (including nitroglycerin, opiates, nitroprusside or dobutamine), medication with specific effects on thrombus formation, coagulation and platelet activation (heparin, aspirin, clopidogrel and GPIIb/IIIa receptor blockers), substitution of lost electrolytes and diuretics in case of increased filling pressures. It remains unclear whether these drugs have an effect on RI or modify the cardioprotective effects of the drug under investigation, but heparin and GPIIb/IIIa receptor blockers could influence the effect of agents RI inhibitory drugs on adherence and extravasation of PMNs via modulation of chemotactic cytokines such as CD11/CD18 and ICAM-1 receptors [100]. Conversely, sub-analyses of patients treated with or without GPIIb/IIIa receptor blockers in the PARI-MI and LIMIT-AMI trial did not reveal a different effect of the reperfusion inhibitory substrate interfering with this same pathway of PMN accumulation, adhesion and activation [49,53]. Nevertheless observations that GPIIb/IIIa receptor blockers improved microvascular flow may suggest that GPIIb/IIIa receptor blockers influence inflammation [101]. Similarly, the effect of agents such as NHE-blockers and adenosine on RI could be superseded by the effects of standard concomitant medication in patients with coronary artery disease influencing the cellular electrolyte homeostasis, such as beta-blockers, Ca2+-blockers and ACE-inhibitors [102,103]. Finally, it should be noted that many patients that encounter an AMI are already treated for hypercholesterolemia and hypertension. Recently, it was demonstrated that statin treatment started before ischaemia reduced infarct size in a rat ischaemia-reperfusion model [104]. Several experimental studies showed a possible effect of widely used anti-hypertensive and/or anti-anginal medication on RI, such as ACE-inhibitors and Ca2+-channel blockers.

In conclusion, co-morbid conditions are likely to modulate the efficacy of new cardioprotective drugs under investigation, but these are typically not taken into account in experimental studies. Future experimental studies should take into account these co-morbid conditions.

5.2 Determinants of infarct size
The main determinants of infarct size include the area at risk, the severity of ischaemia, the duration of ischaemia, and the mode of reperfusion [105]. In contrast to the clinical setting, these factors can either be controlled or accurately determined in the experimental models.

5.2.1 Location and size of the area at risk
In contrast to pre-clinical studies in which infarct size is related to the anatomical area at risk, clinical studies typically express infarct size as a percent of the left ventricle, resulting in greater infarct size variability. Furthermore, animal studies primarily examine anterior infarction, while the majority of clinical trials included both patients with anterior as well as inferior wall infarctions. Interestingly, there are some trials indicating beneficial effects of a reperfusion inhibitory drug in patients with anterior wall infarction [37,39,63]. The explanation for this localized feature is unknown and may be related to anatomical and biological differences, including area at risk size and degree of collateral flow.

5.2.2 Severity of ischaemia
The severity of ischaemia is dependent on both the degree of residual antegrade flow and collateral flow [106,107]. In animal studies total coronary occlusions are typically used. In contrast, in clinical studies coronary obstruction is variable, either gradual or abrupt, intermittent or constant, partial or complete, thereby increasing infarct size variability. In addition, collateral blood flow in individual humans demonstrates a high degree of variability (e.g. young patient versus an older patient with chronic coronary artery disease) [108], but is rarely determined in clinical studies, which will increase infarct size variability.

5.2.3 Duration of ischaemia
The majority of animal studies use a prospectively determined duration of ischaemia ranging from 30–90 min. In the clinical setting, the exact duration of ischaemia and the onset of reperfusion are difficult to establish, particularly in thrombolytic trials, but the duration of ischaemia is typically much longer (>2 h from onset of symptoms to reperfusion, see Tables 2–5GoGoGo) compared to the laboratory setting. This may result in extensive ischaemic damage, leaving less room for RI limiting strategies [53,96]. Indeed, this is supported by clinical event reduction in patients treated early (within 3.17 h) in the AMISTAD-II trial [109]. However, other clinical studies could not confirm such a benefit in the subgroup of patients with re-established flow within 2 h of symptom onset [49,53].

5.2.4 Mode of occlusion and reperfusion
In experimental studies, ischaemia-reperfusion is typically produced by a mechanically induced abrupt and total coronary occlusion and reperfusion. This contrasts with the more unpredictable coronary occlusion in the clinical setting that may be either gradual or acute. Reperfusion by thrombolysis is gradual and intermittent [33] and may result in incomplete reperfusion due to persistence of the coronary stenosis [110,111]. Importantly, the repetitive-intermittent ischaemia caused by both thrombolysis (incomplete reperfusion) and PCI (balloon dilatation and stent implantation) may induce postconditioning, a feature that is typically avoided in experimental studies [112]. In support of this concept, a study in which coronary occlusion and reperfusion was produced by formation and lysis of a thrombus failed to show cardioprotection by the drug under investigation [42].

In conclusion, several determinants of infarct size have been identified in the experimental setting and are typically controlled or measured and accounted for. In contrast, these determinants are frequently overlooked in clinical studies of AMI, thereby acting as confounders and hampering detection of a protective effect by the drug under investigation.

5.3 Treatment related aspects
5.3.1 Distal embolization
Impaired post-procedural perfusion could be, at least in part, the result of embolization of plaque debris and thrombus into the distal microvasculature rather than of the result RI [96,113–115]. Macro- and micro-embolization are both associated with reduced myocardial reperfusion, more extensive myocardial damage and a poor prognosis [115,116]. This embolization can occur spontaneously or as a result of intracoronary manipulation (wires, balloon dilatation and stent implantation). The plaque and thrombus content is washed out into the distal microvasculature [114,117] in 10–15% of patients [115,116,118], where they mechanically "plug" the microvasculature, but can also produce spasm and local inflammation [113].

To prevent plaque and thrombus wash-out several distal protection devices are currently under evaluation, two of which did not show improvement in microvascular flow, infarct size or event-free survival [119,120].

5.3.2 Timing of drug administration
Pre-clinical studies demonstrated that several drugs are beneficial when given before the onset of ischaemia but do not consistently exhibit a beneficial effect when given just prior to reperfusion [12,42,96,121]. Clinical trials suggest a similar trend as the majority of drugs administered in the setting of an AMI before the onset of reperfusion failed to limit infarct size or improve outcome (Tables 2–5GoGoGo), compared to administration prior to ischaemia, in the setting of CABG. Thus, patients pretreated before CABG showed reduced peri-operative MI [40,41,122], suggesting that these drugs may simply not be effective against RI in the setting of AMI.

5.3.3 Does medication reach the jeopardized myocardium in sufficiently concentrations?
Another explanation for the inconsistent results, is that drugs may not reach the area at risk in sufficiently high concentrations prior to reperfusion. This concept is supported by pre-clinical studies with NHE-inhibitors, reporting that higher doses are required with delayed administration [123] while resulting in only modest effects [124,125]. The importance of sufficient dosing is also suggested by the observations that benefits occurred only in the high dose groups in several clinical studies [39,64,126].

In conclusion, there is evidence from CABG studies that cardioprotection in humans does occur when pharmacological agents are administered prior to ischaemia. Furthermore, there is some experimental evidence that a sufficiently high concentration during the first few minutes after reperfusion can result in infarct size limitation. The inability to meet these requirements might contribute to the failure to observe RI limitation in the majority of clinical studies.

5.4 Methodology and study design
5.4.1 Choice of endpoints
The primary endpoint of the majority of animal experiments is infarct size, expressed as a percentage of area at risk [12,106,127]. Clinical endpoints, such as mortality, would require unacceptably large numbers of animals. Histochemical staining with tetrazolium salts has been thoroughly validated, and remains the golden standard. In clinical trials the primary endpoints often include mortality, recurrent ischaemia, congestive heart failure and stroke. However, reperfusion therapy (PCI and thrombolysis) has reduced mortality after AMI to low levels (4–6%) [128], making further significant reductions by adjunctive agents difficult to achieve. Although all methods to assess infarct size, including serum markers and imaging modalities, have their limitations [127], in phase II "proof of concept" trials infarct size is considered the most appropriate surrogate end-point for evaluating the efficacy of RI-inhibitory drugs.

5.5 Biases
A ‘publication bias’ may also contribute to the discrepancy between the weight of pre-clinical versus clinical data. Thus, negative trial results are obviously less exciting and often more difficult to get published. Similarly, there may be bias in the evaluation of available experimental data before starting a clinical trial [42]. Thus, clinical trials were often initiated even though drugs showed inconsistent results in experimental animal studies [12].


   6. Summary, conclusion and future perspectives
Top
 Abstract
 1. Introduction
 2. Ca2+-overload (Table 2)
 3. Miscellaneous
 4. Mechanical modulation of...
 5. What is the...
 6. Summary, conclusion and...
References
 
Experimental observations that drugs are capable of limiting infarct size when administered just prior to or at the onset of reperfusion have prompted a large number of clinical trials investigating the therapeutic potential of several agents against RI in the setting of AMI, that generally have been disappointing. Potential explanations for the discrepant findings between pre-clinical and clinical studies are summarized in Table 6. Future studies into novel drugs that have shown promise in the experimental setting, including Na+/Ca2+-exchange inhibitors, protease inhibitors, and cyclic GMP mimetics, should take these factors into account.


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  		Table 6 Major differences between animal versus clinical trials

 
Fig. 1 depicts a flow-chart from pre-clinical studies to large randomized double-blind clinical trials that is recommended for future evaluation of RI limiting strategies. For example, timing of drug administration, animal species (species with or without collaterals) and mode of occlusion and reperfusion should be rationally chosen [129]. Furthermore, animal experiments should consider the impact of co-morbid conditions and co-medication on the cardioprotective efficacy of novel agents [12]. The occlusion of arteries should mimic thrombotic occlusion in contrast to arterial clamping, and reperfusion should mimic thrombolysis or PCI.


Figure 1
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  		Fig. 1 Flow-chart for suggested development of new reperfusion inhibitory drugs. *Prospective patient stratification with or without all confounding factors as mentioned in Table 6, e.g.: TIMI flow grade 0–1, pre-infarct angina, concomitant medication, young, anterior wall infarction, etc; # administration of agent before the onset of ischemia, during ischemia but minutes before reperfusion and at reperfusion.

 
To prevent inappropriate clinical trials, an expert Working Group recently proposed that clinical trials with new agents should be initiated only after the therapy proves to be reproducibly effective in multiple animal models, ideally performed in a randomized, blinded and multicenter approach analogous to clinical trials [12,121]. Only then clinical testing should be started, initially focussing on predefined subgroups for proof of concept, before conducting a large scale clinical trial. First, studies should be performed in patients undergoing CABG to allow detection of cardioprotection by drugs when administered prior to ischaemia. Subsequently, studies should be considered in subgroups of AMI patients that are more similar to the animal experimental, e.g. patients with naïve vessels (young, no previous cardiac history, without pre-infarct angina), anterior wall infarction, and a totally occluded infarct-related artery and no co-medication at presentation. Large scale clinical trials should only be performed after such initial trials turn out positive.

In conclusion, the evidence presented in this review suggests that future studies pertaining to limitation of ischaemia-reperfusion injury in patients with AMI have a very low likelihood of success. However, the limitation of myocardial infarct size reported in experimental studies when administered prior to ischaemia and reperfusion warrants further investigation into this field, taking into account the lessons taken from the animal experimental and clinical studies as presented in this review article.


   Acknowledgement
 
The authors would like to thank Carla Nederhof for providing indispensable administrative support.


   Notes
 
Time for primary review 31 days


   References
Top
 Abstract
 1. Introduction
 2. Ca2+-overload (Table 2)
 3. Miscellaneous
 4. Mechanical modulation of...
 5. What is the...
 6. Summary, conclusion and...
 References
 

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