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Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing. The reason for this failure can be attributed to a number of factors including the inadequacy of the animal ischemia–reperfusion injury models used in the preclinical cardioprotection studies and the inappropriate design and execution of the clinical cardioprotection studies. This important issue was the main topic of discussion of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop, the outcome of which has been published in this article as the “Hatter Workshop Recommendations”. These have been proposed to provide guidance on the design and execution of both preclinical and clinical cardioprotection studies in order to facilitate the translation of future novel cardioprotective strategies for patient benefit.
Ischemic heart disease (IHD) is the leading cause of death worldwide. As such, novel therapeutic strategies for protecting the heart against ischemia–reperfusion injury (IRI) are urgently needed to: reduce myocardial injury, preserve cardiac function, prevent the development of heart failure, and improve clinical outcomes in patients with IHD [42, 66]. However, a major obstacle to this process has been the inability to successfully translate novel cardioprotective strategies discovered in the research laboratory setting directly into the clinical arena .
This important issue was the main topic of discussion of the 6th Hatter Institute International Workshop on Cardioprotection, which was held this year in Mauritius, an Island in which diabetes and associated IHD are major contributors to overall morbidity and mortality. It was organized together with the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. The main agenda of this International Workshop was to discuss and formulate a set of recommendations for the design and execution of future studies on cardioprotection in both the research laboratory and the clinical setting, in order to facilitate the translation of future novel cardioprotective strategies for patient benefit. One crucial aspect of this endeavour was to recognise the limitations in the design and execution of current experimental laboratory and clinical cardioprotection studies, a feature which was also highlighted by the NHLI Working Group in 2004 .
It is well accepted that the majority of animal models of IRI currently used to investigate novel cardioprotective strategies are inadequate representations of the clinical setting [7, 33, 36, 56], given the size and age of the animals used as well as their lack of co-morbidities and co-treatments. Ideally, one would have to prove efficacy of a certain cardioprotective intervention in animal experiments by the reduction in myocardial infarct (MI) size and/or improvement of prognosis under all mimicked clinical circumstances; however, this is unrealistic and it was agreed that the following recommendations should be proposed.
It is clear from the previously published preclinical literature that an abundance of novel cardioprotective strategies have been discovered. However, the investigation of a particular novel cardioprotective strategy using a systematic, step-wise, collaborative approach has been lacking. Therefore, the formation of a collaborative network of research laboratories to test a single novel cardioprotective strategy in a range of animal MI models may be required to determine whether consistent cardioprotection is observed across species and laboratories. This would have the potential advantage of increasing the probability of a successful translation into the clinical setting, or alternatively, discouraging the initiation of a clinical trial that is destined to be unsuccessful. In 2002, this approach was used to investigate the cardioprotective effect of an adenosine A1 agonist. In this study, a multicentre randomised controlled double-blind experimental animal study was performed in three different laboratories .
The pathophysiology of IRI obviously varies with the clinical setting. The purest example of classical IRI is the IHD patient presenting acutely with a complete thrombotic coronary artery occlusion (a STEMI) who undergoes PCI reperfusion therapy. Although IRI may contribute to the myocardial injury sustained in a number of other clinical settings such as CABG surgery, cardiac arrest and transplantation, other factors such as manual handling of the heart and coronary embolization  may come into play. They need to be taken into consideration when analysing the results. It should be noted, however, that the problem of distal embolization may also occur with PCI and the contribution of IRI per se to this form of injury is probably minor. Clearly, the appropriate animal IRI model should be selected to test the novel cardioprotective strategy to match the intended clinical setting in which it is to be applied to (see Table 1).
An alternative approach to measure the AAR is to assess the hypokinetic segments of the left ventricle using venticulography at the time of PCI [57, 60], although this technique may overestimate the AAR by including areas of myocardial stunning. Cardiac MRI (CMR) may be a promising imaging technique for measuring the AAR. Animal studies have reported that enhanced signal intensity on retrospective T2-weighted CMR from increased myocardial oedema  correlates with the AAR in reperfused myocardial infarcts [1, 27]. Preliminary clinical studies suggest that the enhanced T2 signal intensity on CMR scans performed in the first week following PCI correlates with the AAR as measured by the BARI coronary angiography jeopardy score  and nuclear myocardial scans . In addition, myocardial salvage as measured by CMR has been linked to clinical outcomes in PCI-treated STEMI patients . The concern with CMR is whether the novel cardioprotective strategy itself may influence the extent of myocardial oedema by reducing it, thereby resulting in an underestimate of the AAR. In this case, CMR may be ineffective as a technique for measuring AAR post PCI. Whichever technique is used to measure the AAR it is essential to use the AAR as a co-variate for analysing MI size reduction, given that patients presenting with the larger areas at risk are those most likely to benefit from the novel cardioprotective strategy.
Despite excellent cardioprotection using cold blood cardioplegia, significant peri-operative myocardial injury still occurs in patients undergoing CABG surgery ± valve surgery. The cause of this myocardial injury is multi-factorial being attributed to global ischemia–reperfusion injury, coronary embolization and prolonged aortic cross-clamp time. The extent of peri-operative myocardial injury can be assessed by measuring serum cardiac enzymes such as CK-MB, troponin-T and troponin-I, the elevation of which has been associated with worse clinical outcomes post-surgery [9, 13, 29]. Surgeons are therefore continually seeking ways to minimise IRI, particularly as more high-risk patients are being operated upon and it is becoming increasingly clear that even mild to moderate elevations in CK-MB and troponin are associated with increased intermediate and long-term mortality.
Similar to the setting of a STEMI in which patients with a larger MI are most likely to benefit from a cardioprotective intervention, the same may apply to patients undergoing CABG surgery. Therefore, the patients most likely to benefit from a cardioprotective strategy during CABG surgery are those who are most at risk of sustaining significant peri-operative myocardial injury. This group includes patients undergoing 3-vessel CABG surgery with or without valve surgery, redo CABG surgery patients, patients with significant LVH or LV systolic dysfunction, patients with an additive Euroscore of ≥6 and diabetic patients. We believe that it is this group of higher-risk patients who should be selected for studies of novel cardioprotective strategies as they are more likely to experience a greater degree of myocardial IRI from the prolonged cross-clamp and cardio-pulmonary bypass times.
A variety of cardioprotective strategies have been tried in the CABG surgery setting in the past. Although the majority of these were unsuccessful, one of the most potentially promising treatment strategies was cariporide, but unfortunately it had off-target cerebral side effects . In the setting of CABG surgery, the novel cardioprotective strategy can be applied either prior to myocardial ischemia (cross-clamping of the aorta), during myocardial ischemia in the cardioplegia solution or at the time of myocardial reperfusion (unclamping the aorta). As noted previously, the preclinical testing of the novel cardioprotective strategy in an animal IRI model which closely resembles the CABG setting should have been previously utilised to verify efficacy (see Table 1).
There are a number of novel cardioprotective strategies which have shown promise in initial proof-of-concept clinical studies. The question is which of these should be taken forward into phase 2/3 clinical studies. Following discussion in the Workshop, it was agreed that the two most promising novel cardioprotective strategies were remote ischemic conditioning (RIC) and cyclosporine-A (CsA).
For RIC, in which cycles of brief ischemia and reperfusion applied to the upper or lower limb protect the myocardium from lethal IRI, there exist extensive preclinical data in a range of animal models including in vivo murine, rat, rabbit and porcine models of MI (reviewed in [20, 56]). RIC is a non-invasive virtually cost-free cardioprotective strategy which has been shown to be effective when applied both prior to or during the index myocardial ischemia  as well as at the onset of myocardial reperfusion , lending itself to the clinical settings of CABG surgery , planned PCI , and STEMI patients receiving PCI , settings in which initial proof-of-concept studies have already been successfully performed.
CsA has the advantage of targeting an end-effector of IRI, as opposed to the ever-expanding list of cardioprotective agents which tend to target G-protein coupled receptors and intracellular kinases and other mediators, which may be down-regulated or ineffective in the presence of co-morbidities. Because the main site of action of CsA is probably the mPTP, a purported mitochondrial channel which mediates cardiomyocyte death at the onset of myocardial reperfusion, most of the preclinical data in support of its role as a cardioprotective agent have been as an adjunct to myocardial reperfusion [19, 22]. Similarly, there exist extensive preclinical data in a range of animal models including in vitro and in vivo models of MI, as well as in a rabbit model of post-cardiac arrest . However, the in vivo porcine MI model has produced mixed results with CsA for an unclear reason [28, 35, 54]. CsA has also been demonstrated to be effective in human atrial tissue models of simulated IRI . Again, a preliminary proof-of-concept clinical study has demonstrated that a single intravenous bolus of CsA given prior to PCI can limit MI size in STEMI patients .
Other potentially novel cardioprotective strategies for which there exist both preclinical data and initial proof-of-concept clinical studies are glucagon-like peptide 1 , PKC-δ inhibition , atrial natriuretic peptide , and ischemic postconditioning .
Clearly, for all these novel cardioprotective strategies preclinical studies are required to determine whether cardioprotection is maintained in the presence of certain confounding factors such as age, sex, diabetes, the metabolic syndrome, hyperlipidemia, hypertension and so forth. In this regard, a recent preclinical study suggests that CsA-mediated cardioprotection at the time of myocardial reperfusion was ineffective in Zucker obese rats . This intriguing finding requires confirmation and the mechanism underlying this observation needs further investigation.
In summary, for both CsA and RIC large multi-centred randomised controlled clinical trials are required to confirm their cardioprotective benefit in the clinical setting and investigate whether these interventions impact on clinical outcomes for patient benefit.
In order to overcome the obstacles to translation of novel cardioprotective strategies discovered in laboratories into the clinical setting for patient benefit, a set of recommendations may facilitate this process. These are outlined below and include preclinical cardioprotection studies and clinical cardioprotection studies in PCI patients. Clearly, similar recommendations may be introduced for other clinical settings of IRI such as CABG surgery, sudden cardiac arrest, cardiac transplantation, as more evidence becomes available from ongoing studies.
We would like to thank the Working Group of Cellular Biology of the Heart of the European Society of Cardiology for their kind support of this Workshop.
Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
M. Marber, London, UK, served as guest editor for the manuscript and was responsible for all editorial decisions, including the selection of reviewers. The policy applies to all manuscripts with authors from the editor’s institution.
Report of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop together with the Working Group of Cellular Biology of the Heart of the European Society of Cardiology.