ESC Joint Working Groups on Cardiovascular Surgery and the Cellular Biology of the Heart Position Paper: Peri-operative myocardial injury and infarction in patients undergoing coronary artery bypass graft surgery

Matthias Thielmann*, Vikram Sharma, Nawwar Al-Attar, Heerajnarain Bulluck, Gianluigi Bisleri, Jeroen JH Bunge, Martin Czerny, Péter Ferdinandy, Ulrich H. Frey, Gerd Heusch, Johannes Holfeld, Petra Kleinbongard, Gudrun Kunst, Irene Lang, Salvatore Lentini, Rosalinda Madonna, Patrick Meybohm, Claudio Muneretto, Jean-Francois Obadia, Cinzia Perrino, Fabrice Prunier, Joost P.G. Sluijter, Linda W. Van Laake, Miguel Sousa-Uva, and Derek J. Hausenloy*


Introduction
Coronary artery disease (CAD) is one of the leading causes of death and disability in Europe and worldwide. For patients with multi-vessel CAD, coronary artery bypass graft (CABG) surgery is a common approach for coronary revascularization, and is of proven symptomatic and prognostic benefit. Due to an aging population, higher prevalence of co-morbidities (such as diabetes mellitus, heart failure, hypertension, and renal failure), and a growing requirement for concomitant surgical procedures (such as valve and aortic surgery), higher risk patients are undergoing surgery. [1][2][3] This has resulted in an increased risk of peri-operative myocardial injury (PMI) 4 and Type 5 myocardial infarction (MI), both of which are associated with worsened clinical outcomes following CABG surgery. The aetiology and determinants of PMI and Type 5 MI are multi-factorial (see Tables 1 and 2 for summary). Although diagnostic criteria have been proposed for Type 5 MI (based on an elevation in cardiac biomarkers in the 48h post-operative period and electrocardiogram/angiography/imaging evidence of MI 5,13 ), there is currently no clear definition for prognostically significant PMI, in terms of the level of post-operative cardiac biomarker elevation, which is associated with worsened clinical outcomes following CABG surgery.
Therefore, the aim of this European Society of Cardiology (ESC) Joint Working Groups (WG) Position Paper is to provide a set of recommendations to better define the level of cardiac biomarker elevation following CABG surgery at which PMI should be considered prognostically significant, and therefore prompt further clinical evaluation. We also provide guidance on how to manage patients with PMI and Type 5 MI.

Defining type 5 myocardial infarction
Type 5 MI has been defined in the Third Universal Definition of MI (2012) as an elevation of cardiac troponin (cTn) values >10Â 99th percentile upper reference limit (URL) during the first 48 h following CABG surgery, in patients with normal baseline cardiac cTn values (<99th percentile URL) together with either: (a) new pathological Q waves or new left bundle branch block (LBBB), or (b) angiographic documented new graft or new native coronary artery occlusion, or (c) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality (RWMA). 13 In general, Type 5 MI is mainly due to an ischaemic event arising from either a failure in graft function, an acute coronary event involving the native coronary arteries, or inadequate cardioprotection. The incidence of Type 5 MI following CABG surgery varies depending on the diagnostic criteria which are used to define it. When assessed by elevations in cardiac biomarkers and new electrocardiogram (ECG) evidence of Q waves Table 1 Causes of peri-operative myocardial injury in patients undergoing coronary artery bypass graft surgery or LBBB, the incidence has been reported to range from 5 to 14%, 4 whereas it ranges from 20 to 30% when using cardiac magnetic resonance (CMR) to detect new loss of viable myocardium. [14][15][16] The current definition of Type 5 MI does have several limitations: (1) The selection of a cTn elevation of 10Â URL as a threshold for diagnosing Type 5 MI was arbitrarily chosen. Elevated cTn of 10Â URL occurs in over 90% of all patients undergoing CABG surgery. 8,12 (2) Type 5 MI requires the presence of ECG/angiography/imaging evidence of MI, and ignores post-surgical isolated elevations in cardiac biomarkers which may still be prognostically significant (i.e. biomarker elevations in the absence of ECG/angiographic or other imaging evidence of MI). (3) The diagnostic criteria for Type 5 MI can also be quite challenging in the setting of CABG surgery for several reasons: (i) In a substantial number of patients, the ECG may not be interpretable and many of the ECG changes following CABG surgery may be non-specific for MI. [15][16][17] (ii) Coronary angiography is rarely performed post-surgery to diagnose very early graft failure; and (iii) Echocardiography is the most practical imaging modality for detecting new loss of viable myocardium or new RWMA following CABG surgery, but it may not be diagnostic in many cases.
As such, the diagnosis of Type 5 MI in the 48 h post-operative period may be quite challenging, unless it presents with obvious graft failure or a significant ischaemic event. Therefore, in many cases, patients may sustain prognostically significant PMI, but this may be overlooked. The Society for Cardiovascular Angiography and Interventions (SCAI) has proposed a new definition for clinically relevant MI, which takes into account isolated elevations in either creatine kinase-MB fraction (CK-MB) or cTn within 48 h of CABG surgery. 18 With respect to CK-MB, these recommendations propose a peak elevation > _10Â URL in isolation or > _5Â URL with new pathologic Q-waves in > _2 contiguous ECG leads or new persistent LBBB. A substantially higher cut-off for cTn elevation of > _70Â URL in isolation or > _35Â URL with new pathologic Q-waves in > _2 contiguous ECG leads or new persistent LBBB is also proposed in that paper. 18 Again, these threshold levels were arbitrarily chosen, and further studies are required to validate their new definition of clinically relevant MI, and explore their relationship to clinical outcomes postsurgery. In addition, these recommendations do not take into consideration isolated elevations of cardiac biomarkers below these thresholds, which may still be clinically relevant and prognostically significant.

Defining peri-operative myocardial injury
Peri-operative myocardial injury is defined as an isolated elevation in cardiac biomarkers (CK-MB and/or cTn) greater than the upper limit of normal, in the 48-h post-operative period. However, this level of cardiac biomarker elevation occurs in virtually all patients undergoing CABG surgery, and there is no clear consensus on the level of cardiac biomarker elevation above which, it is either clinically relevant or prognostically significant. A recent publication has proposed defining PMI as an isolated elevation in cTn <10Â the URL within 48 h of CABG surgery, 5 but this definition does not include those patients who have isolated cTn elevations >10Â URL in the absence of ECG/ angiographic or other imaging evidence of MI. Therefore, in this ESC Joint WG Position Paper we provide recommendations for defining prognostically significant PMI following CABG surgery, which should prompt further clinical evaluation to exclude Type 5 MI. In this paper, we mainly focus on those patients undergoing elective isolated onpump or off-pump CABG surgery, as the presence of prognostically significant PMI is more challenging to define in patients presenting with an acute coronary syndrome (with elevated pre-operative cardiac biomarkers), and those having concomitant valve or aortic surgery. However, patients presenting with an acute coronary syndrome are become increasingly rare since many undergo primarily percutaneous intervention.
Isolated elevations in creatine kinase-MB fraction and mortality post-coronary artery bypass graft surgery A large number of early studies have assessed the prognostic significance of isolated elevations in CK-MB following CABG surgery in the absence of ECG/angiographic or other imaging evidence of MI ( Table 3 and Figure 1). These studies have demonstrated a graded increase in short, medium, and long-term mortality beginning with an isolated CK-MB elevation > _3Â URL within 24 h of CABG surgery. Above isolated 10Â URL elevations, there appears to be a progressive increase in short-term (30 days) and longer-term mortality (1 year and over), which is independent of other evidence of MI. 20,23,29 In most centres, CK-MB has now been replaced by the use of cardiac troponins, as the latter are more sensitive and specific for detecting PMI and Type 5 MI following CABG surgery. 32,33 Hence, we have elected to not use isolated CK-MB elevations post-surgery to define prognostically significant PMI.

Isolated elevations in cTnT and cTnI and mortality post-coronary artery bypass graft surgery
Cardiac troponins have greater sensitivity and specificity for myocardial necrosis, when compared to CK-MB, and have been found to be superior to CK-MB in predicting mortality post-CABG surgery. 30,[34][35][36][37] However, the interpretation of isolated changes in cTn levels in the post-operative period, in the absence of ECG/angiographic or other imaging evidence of MI, can be quite challenging given the different cTn assays used, the introduction of high-sensitive assays for cTn, and the presence of renal dysfunction.
As with CK-MB, there appears to be a graded increase in shortterm and long-term mortality following CABG surgery, based on the magnitude of post-operative cTnI or cTnT levels ( Tables 4 and 5).
Overall, there is a clear association between isolated elevations of cTnT > _7Â URL 41 and cTnI levels > _20Â URL 29,41 with significant increases in short-term (30 days) and long-term (one year and over) mortality after CABG surgery (Tables 4, 5 and Figure 2). Importantly, these findings were shown to be independent of ECG/angiography/ imaging evidence of MI, confirming that isolated elevations of cTn following CABG surgery can predict mortality. The studies that have been used to define these thresholds used various generations of 'standard' cTnT and cTnI assays, and currently there is lack of sufficient data to accurately determine these thresholds for the high sensitivity-cTnT or cTnI assays. Hence, the above threshold for cTnT does not apply to the high-sensitive cTnT assay, and so for this assay, additional ECG and/or imaging evidence of MI appears to be required to identify those CABG patients at a higher risk of mortality when > _10Â URL hs-cTnT elevation is measured. 8 The majority of studies have reported isolated elevations between 24 and 48 h postsurgery as being the most discriminatory for predicting clinical outcomes. 27,30,[36][37][38]42 Whether it is necessary to measure the AUC cTn elevation or whether a single time-point measurement of cTn is sufficient to predict post-surgical outcomes, is not clear. Recent evidence suggests that the AUC of high-sensitive cTnT may be a good surrogate for MI size. 54 In summary, we recommend, that for patients with a pre-operative cTn <1Â URL, isolated elevations of 'standard' cTn assays (cTnT > _7Â URL and cTnI > _20Â URL) within the 48 h post-operative period (in the absence of ECG/angiographic or other imaging evidence of MI), may be indicative of prognostically significant PMI, and require further clinical evaluation to determine whether there is evidence for Type 5 MI. This is particularly so if there is additional clinical evidence for MI such as disproportionate chest pain, unusual ECG changes or new regional wall motion abnormalities on echocardiography in a territory that is dependent on a graft, or dependent on a major ungrafted vessel. However, these threshold values for cTnT and cTnI in defining prognostically significant PMI, may vary from site to site and the actual cTn assay used, and should be established for individual sites. Also, it is important to note that isolated elevations in cTn below these thresholds may still be clinically significant, but their impact on post-CABG mortality appears to be small. For patients with additional ECG/angiography/imaging evidence of MI, an elevation of cTnT or cTnI > _10Â URL should be used to define Type 5 MI, as per the 3rd Universal Definition of MI. For the newest generation of high-sensitive cTn assays, the threshold level above which clinical outcomes post-surgery can be predicted remains to be determined.
Other biomarkers for quantifying peri-operative myocardial injury As mentioned above, cTn elevations between 24 and 48 h have been most clearly shown to correlate with mortality post-CABG surgery. However, this may be too late to identify prognostically significant PMI or Type 5 MI, as interventions at this stage may fail to salvage a substantial volume of myocardium at risk. Also, cTn elevation in this early time period (<24 h) may be due to non-ischaemic causes, making it a less reliable marker of regional ischaemia in the first 24 h.
Newer cardiac biomarkers are therefore needed to improve the diagnosis of PMI following CABG surgery with respect to earlier diagnosis, and improving specificity for regional ischaemia, thereby allowing prompt implementation of medical or surgical treatment and to maximise myocardial salvage. Myoglobin, heart-type fatty acidbinding protein, 55,56 copeptin, 57 microRNAs (miR-499 and miR-1), 58,59 and cardiac myosin-binding protein C 60 have been shown to be associated with PMI following CABG surgery. Some of these are not specific for myocardial necrosis, but they seem to provide additional power in combination with conventional cardiac biomarkers for detecting PMI following CABG surgery. Interestingly, new peptides have been identified via a phage display peptide library screen that might be useful in the future to predict PMI after CABG surgery. 49 Although these new biomarkers seem to be extremely sensitive for detecting PMI, technological improvements for early detection, and large validation cohorts are needed to speed-up their clinical application.

Role of electrocardiogram for detecting type 5 myocardial infarction following coronary artery bypass graft surgery
The appearance of new Q waves or LBBB on ECG following CABG surgery remain part of the diagnostic criteria for Type 5 MI. 5 Using ECG, the incidence of Type 5 MI is in the range of 5 to 14%. New STsegment elevation or depression may indicate ongoing regional ischaemia, and warrant further diagnostic work-up. However, in many post-surgical patients the ECG may not be interpretable, and ECG changes may be non-specific or transient. A number of clinical studies have found that ECG changes alone are not always predictive of poorer outcomes following CABG surgery, 23,26,49 although the additional presence of ECG evidence of PMI with an elevation in cTn appears to be associated with significantly worse outcomes. 8,9 Interestingly, a number of studies have shown that many cases of Type 5 MI detected by CMR occur in the absence of new ECG changes (Q waves or LBBB), illustrating the difficulties in relying on ECG changes to detect Type 5 MI. 15,61 Role of cardiac imaging for detecting type 5 MI following coronary artery bypass graft surgery Although several cardiac imaging modalities exist for detecting new loss of viable myocardium or new regional wall motion abnormalities following CABG surgery, only coronary angiography allows for immediate final decision making (conservative, vs. redo CABG vs. percutaneous coronary intervention).

Echocardiography to detect type 5 myocardial infarction following coronary artery bypass graft surgery
Echocardiography is the most practical imaging modality for detecting new RWMA following surgery. 13 However, image quality can be reduced after CABG surgery, due to the presence of pleural or pericardial effusions, inflammation or assisted ventilation, and in these cases transoesophageal echocardiography may be preferable. 62 Endocardial visualisation might also be enhanced by the use of contrast agents, especially when 2 or more myocardial segments are not visualised by standard echocardiography. 63 Moreover, detection of RWMA might be improved by more advanced echocardiography imaging modalities such as tissue Doppler imaging or speckle tracking. 64 However, a large retrospective analysis found that RWMA detected by TEE were not able to predict those patients with graft failure as documented by coronary angiography. 65 One major limitation of echocardiography is that new RWMA may reflect   Myocardial nuclear imaging and cardiac computed tomography to detect type 5 myocardial infarction following coronary artery bypass graft surgery Radionuclide single-photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging can allow the direct assessment and quantification of myocardial viability before and after CABG surgery, 66,67 although given the relatively low spatial resolution of this imaging technique, small areas of non-viable myocardium (especially subendocardial MI), which are commonly found with Type 5 MI, may be missed. Other radionuclide imaging approaches are currently under intense investigation, and will likely be tested in the next few years. 68 New loss of viable myocardium may be also visualised by cardiac CT. 69 Multi-slice CT coronary angiography is another useful noninvasive imaging modality that can be utilized to evaluate graft patency following CABG surgery. 10,11,70,71 However, the radiation dose and the risks of cumulative ionising radiation need to be weighed against the obvious advantages of an early and accurate diagnosis. 72 Cardiac magnetic resonance to detect type 5 myocardial infarction following coronary artery bypass graft surgery Cardiovascular magnetic resonance (CMR) imaging is a well validated imaging technique with high spatial resolution, for the accurate assessment of both myocardial function and viability, which has proven to be an excellent tool in the diagnosis of Type 5 MI. 73 The presence of new areas of late gadolinium enhancement (LGE), on CMR performed in the first couple of weeks following CABG surgery can detect the presence of new non-viable myocardial tissue required for diagnosing Type 5 MI (see Table 6). These clinical studies suggest that Type 5 MI occurs in 20-30% of all patients undergoing elective CABG surgery. Interestingly, the pattern of LGE observed on CMR post-CABG surgery reflects the multi-factorial aetiology of Type 5 MI with examples of transmural infarction (suggesting native artery or graft failure), subendocardial infarction (suggesting inadequate cardioprotection), and patchy areas of infarction (suggesting coronary microembolisation or non-ischaemic myocardial necrosis). 16,17,77 Overall, there is a good correlation between elevations in cardiac biomarkers post-surgery and new LGE mass quantified by CMR (see Table 6). However, in some patients with absence of LGE on CMR, there was still a significant elevation in AUC cTnI, suggesting that not all post-operative cTnI release represents irreversible myocardial injury, 15 or that the tissue loss was too small to be detected by CMR. 78 Therefore, the prognostic significance of post-surgical elevations in cardiac biomarkers in the absence of MI on LGE-CMR remains to be determined. One study has demonstrated that a single cTnI value at 1 h post-surgery accurately predicted new LGE on CMR, increasing the clinical utility of measuring cardiac biomarkers and implementing a change in management to avoid future complications. 61 .  In most patients with LGE on CMR, in-hospital patient management was not changed. In one study, a rise in both CK-MB and cTnI to >5Â URL in patients with new LGE on CMR had an inverse linear relation with lack of improvement in global left LV function post-CABG surgery, and a pooled analysis of percutaneous coronary intervention (PCI) and CABG patients suggested that new LGE on CMR increased by three-fold the risk of MACE-death, non-fatal MI, admission to hospital for unstable angina or worsening heart failure, or occurrence of ventricular arrhythmia (defined as ventricular fibrillation or sustained ventricular tachycardia). 79 At least one clinical study 76 has used the mass of LGE on CMR as a surrogate endpoint to assess the cardioprotective efficacy of a novel therapy during CABG surgery, although in this particular study the anti-inflammatory agent, Elafin, failed to reduce the mass of LGE ( Table 6).
In summary, LGE-CMR post-CABG surgery has provided important insights into the pathophysiology of Type 5 MI. From a clinical perspective however, its utility for diagnosing Type 5 MI is limited given that it is not widely available, and may be impractical in the early post-operative phase.

Managing the patient with perioperative myocardial injury and type 5 myocardial infarction
There is limited evidence from clinical studies comparing strategies on how best to manage either prognostically significant PMI or Type 5 MI following CABG surgery. The key issue in the immediate postoperative period is to identify patients with regional ischaemia due to graft-failure or an acute coronary event in the native coronaries, as this group of patients may benefit from urgent revascularisation. 80 Graft failure post-CABG surgery is associated with higher mortality ($15%), 81 and is potentially amenable to intervention (PCI or redo-CABG). 80 Early intervention in these patients may reduce the extent of Type 5 MI, thereby improving clinical outcomes. 81 For non-graftrelated PMI, there is currently no specific therapy available, only general supportive measures.

General management of peri-operative myocardial injury and type 5 myocardial infarction
General supportive measures apply both to graft-related as well as non-graft-related PMI and Type 5 MI. It is important to note that while there are several risk-stratification models to determine the risk of mortality in the patients undergoing CABG surgery based on pre-operative risk factors, such as EuroSCORE, EuroSCORE II, and STS score, there are currently no validated prediction models to determine which patients are at high-risk of PMI or Type 5 MI following CABG surgery. If patients at high risk of PMI or Type 5 MI can be identified, customised management pathways comprising more aggressive monitoring, investigations and/or treatment approaches may result in improved clinical outcomes. The ultimate treatment would be urgent coronary revascularisation, either interventional or surgical. 80 Non-graft-related PMI is most often related to inappropriate myocardial protection, excessive surgical manipulation, inflammation, and air or plaque embolisation. 82 Treatment of anaemia, pain and tachycardia can increase coronary blood flow and/or decrease myocardial oxygen consumption, thereby limiting Type 2 MI. Observational studies have shown an association between transfusion and worse outcome, including infections, ischaemic complications, and mortality. 83,84 In contrast, a recent multi-centre randomised trial comparing a liberal (haemoglobin, Hb <9 g/dL) vs. a restrictive (Hb <7.5 g/dL) transfusion threshold in CABG surgery patients, showed a lower 30-day mortality in the liberal group, although it was not the primary outcome of the study. 85 The incidence of PMI was similar in the two groups, but peak values of cardiac biomarkers were not reported. Two recent large multicentre randomised controlled trials showed no benefit of routine intra-operative high dose dexamethasone or methylprednisolone on major adverse events, and its use did not reduce the incidence of Type 5 MI. 86,87 Beta-blockers can be used to treat tachycardia, diminish myocardial oxygen consumption and prevent arrhythmias, and are recommended prior to and early after CABG surgery in practice guidelines, 88 however, hypotension due to systolic dysfunction or PMI may limit their use.
In cases of overt heart failure, pharmacological haemodynamic optimisation and/or mechanical support may be indicated. Due to safety concerns, inotropes are reserved for patients with inadequate peripheral tissue perfusion or hypotension. The b-agonist dobutamine, phosphodiesterase inhibitors like milrinone or enoximone, and the calcium sensitiser levosimendan can all be used to treat postoperative refractory low cardiac output syndrome and decompensated heart failure.
In patients with insufficient coronary perfusion (before surgery or insufficient graft perfusion), the intra-aortic balloon pump (IABP) may provide improvement of haemodynamics while underlying cause(s) of instability can be addressed and is still being used in high risk patients or in patients with difficulties weaning off cardiopulmonary bypass. 89 A recent meta-analysis showed benefit of a pre-operative intra-aortic balloon pump insertion in patients undergoing CABG surgery on 30-day mortality, and this may be considered in selected unstable high-risk patient preoperatively. 90 Advanced mechanical support may be indicated in severe cardiac failure, where inotropes, vasopressors and IABP fail to restore adequate output. Extracorporeal Life Support (ECLS or ECMO) may be a bridge to recovery of cardiac function, or bridge to decisions about further long-term mechanical support (LVAD) and future transplantation. Unfortunately, survival in ECLS treated patients is only 20-40%. 91 Managing the patient with suspected graft-related failure The incidence of early graft failure is $3%, 92 and the rate of graft occlusion before discharge varies from 3 to 12% for vein grafts (3 to 4% for radial arteries and 1 to 2.5% for internal mammary arteries 48 ). It is often difficult to distinguish graft-related from non-graft-related PMI and Type 5 MI, and surgeons rely on elevations in cardiac biomarkers, unexplained low cardiac output syndrome (LCOS), persistent ischaemic ECG changes, recurrent ventricular tachycardia and fibrillation, and new echocardiographic RWMAs to detect graft failure following CABG surgery. A variety of patient symptoms and objective findings should raise suspicion of regional ischaemia due to early graft failure, and trigger prompt evaluation with an ECG, measurement of cardiac biomarkers, coronary angiography or other appropriate cardiac imaging. These include the presence of typical or atypical chest pain, unexplained shortness of breath, haemodynamic instability as well as difficulty in weaning off cardiopulmonary bypass, refractory arrhythmia or persistent circulatory failure. Unfortunately, all of the above can be present following CABG surgery, even in the absence of regional ischaemia, hence none of these findings are sensitive or specific enough in isolation to accurately identify the presence of regional ischaemia, and so the appropriate diagnostic or management pathway should be determined in each patient taking the whole clinical picture in consideration. Equally, regional ischaemia may be present even in the absence of the above findings. The assessment of regional ischaemia following CABG surgery remains a considerable challenge for managing PMI and Type 5 MI.
The main cause of early graft failure post CABG surgery is graft occlusion but other causes include graft kinking and anastomotic stenosis. 46 A graft-related cause is identified in 60-80% of coronary angiograms performed for this indication, and consecutive re-revascularisation is performed in 50-70% of graft-related Type 5 MI. 81,[92][93][94][95] However, in one study, 24-35% of patients undergoing coronary angiography after CABG for early graft dysfunction had patent grafts. 93 One retrospective series found that an urgent post-CABG coronary angiogram was required in 1.8% patients, and more than half of these patients needed re-intervention, and, in spite of this, had high mortality. 96 In multi-variate analysis, younger patients, female patients, smaller patients, and patients receiving a combined arterial and venous revascularisation were at a higher risk for an unplanned post-surgical coronary angiogram. 96 When detected, potentially correctable abnormalities included early graft thrombosis, anastomotic stenosis, bypass kinks, overstretching or tension, significant spasm or incomplete revascularization. Compared with native coronary PCI, bypass graft PCI has been shown to be independently associated with higher in-hospital mortality. 97 In the CathPCI registry, patients undergoing bypass graft PCI more frequently required intra-aortic balloon pump counter pulsation, longer fluoroscopy time, and larger amount of contrast medium; and less frequently achieved TIMI flow grade 3 poststenting, were more likely to receive blood transfusions, and had higher rates of post-procedural complications and in-hospital mortality. 97 In one of the few studies that investigated the appropriate treatment for patients with early graft failure following CABG surgery, the major findings were that: (i) patients with prompt re-intervention for early graft failure after CABG surgery had a higher number of graft/ patient failure than in patients managed conservatively; (ii) even with more graft failure per patient, there was a trend towards smaller size of MI in the early aggressive re-intervention group than in the conservative group; and (iii) coronary angiography was a good tool to discriminate the aetiology of postoperative infarction (graft-related or non-graft-related). 81 Early graft failure has been shown to be associated with a higher elevations in cTnI (about >45Â URL at 12 h and >70Â URL elevation at 24 h for cTnI). 35,46,48 However, it is important to appreciate that there may be a significant overlap between patients with or without graft failure even at this level of biomarker elevation. 35,46,48 Another important finding from these studies is that ECG and/or imaging evidence of MI did not appear to reliably identify those with early graft failure following surgery. Therefore, high cTnI elevations in the post-

Table 6
Major studies using cardiac magnetic resonance to assess Type 5 myocardial infarction following coronary artery bypass graft surgery even in the absence of ECG and/or imaging evidence of MI, should raise the suspicion of early graft failure. However, it is important to have earlier markers of graft failure to allow the implementation of a change in management in order to limit PMI and improve clinical outcomes post-CABG surgery. In this regard, some studies have shown that post-operative cTn levels at 1 h post-surgery may be used to predict Type 5 MI on CMR, but the role of this measurement in detecting early graft failure has not been investigated. 61 The detection of graft dysfunction by intraoperative transit time flow measurement (TTFM) within the graft may allow early detection of graft failure and thereby provide a potential strategy for limiting PMI and Type 5 MI. 98,99 In addition, this approach has been shown to predict graft failure at 1 month 100 and 6 months post-CABG surgery. 101 In summary, strategies aimed at earlier identification of patients with significant on-going regional ischaemia could salvage viable myocardium. Anaesthesiologists and intensivists should be involved in this process. Early coronary angiography and on-site consultation of an interventional cardiologist and cardiac surgeon should result in a decision on the management of the individual patient, taking into account the extent of ischaemia, coronary anatomy, and comorbidities.
We present a management algorithm ( Figure 3) providing guidance on when to perform coronary angiography for suspected PMI or Type 5 MI. It proposes emergent coronary angiography in case of clear signs of acute myocardial ischaemia or unexplained haemodynamic compromise immediately post-surgery, and urgent coronary angiography in case of recurrent ventricular arrhythmias, unexplained LCOS or persistent ischaemic ECG changes. Furthermore, high cTn elevations in the post-surgical period (such as cTnI >45Â URL at 12 h and >70Â URL elevation at 24 h) even in the absence of ECG and/or imaging evidence of MI, should raise the suspicion of early graft failure. This proposed algorithm aligns well with the current ESC/EACTS guidelines on myocardial revascularization (2014), which support emergency PCI in early post-operative graft failure to limit the extent of myocardial injury. 80 Additionally, the current ESC/EACTS guidelines favour PCI to the body of the native vessel or IMA graft while avoiding PCI to an occluded vein graft or graft anastomosis site and reserve re-do surgery to patients with coronary anatomy unsuitable for PCI. 80 Future studies aiming at earlier and more precise identification of patients with suspected graft-related ischaemia should allow one to refine this algorithm further.

Decision making following coronary angiography post-surgery
Once coronary angiography following CABG in cases of suspected graft failure, the treatment strategy (conservative vs. revascularisation) depends on many factors, and the decision needs to be made in close consultation with the Heart Team (intensivists, surgeons and cardiologists). These factors include the coronary anatomy, graft occlusion vs. native vessel occlusion, extent of myocardial ischaemia, extent of viable myocardium, clinical symptoms, haemodynamic status and inotrope support, and age and co-morbidities.
A conservative strategy should be considered if: • All grafts are patent.
• There are no lesions in native coronary arteries potentially involved in post-operative myocardial ischaemia. • In cases of venous graft occlusion anastomosed on non-major left anterior descending (LAD) coronary artery with no lesion suitable for PCI on the related native coronary artery.
Revascularisation by PCI should be considered if: • There is early graft dysfunction.
• There are suitable lesions in native coronary arteries involved in the post-operative myocardial ischaemia.
• In the presence of severe cardiogenic shock emergency PCI or ECLS should be considered.
If PCI is chosen there are certain risks and technical challenges. PCI should be performed on lesions in the native vessels supplying the ischaemic region, and should be avoided in the occluded vein graft or graft anastomosis site, except when lesions on the native vessels are not suitable for PCI.
Revascularization by redo CABG surgery should be considered if: • The coronary anatomy is unsuitable for PCI • There is involvement of a large extent of ischaemia (e.g. LAD territory).
• There is failure of LIMA or a Y-graft to the left system.
If redo CABG is being considered there are certain risk and technical challenges. Recurring cardiopulmonary bypass (CPB) with cardioplegic arrest may intensify acute myocardial ischaemia-reperfusion injury, already sustained, and a period of recovery using ECLS, may be beneficial in the initial 24-48 h after treatment. Redo CABG surgery may also be considered using 'beating heart surgery' (without cardiac arrest and cardioplegia) under cardiopulmonary bypass support, in order to limit additional acute myocardial ischaemia-reperfusion injury.
Using peri-operative myocardial injury and type 5 myocardial infarction to assess the cardioprotective efficacy of novel therapies in the setting of coronary artery bypass graft surgery Cardioprotective strategies such as ischaemic preconditioning (IPC), ischaemic post-conditioning (IPost), remote ischaemic preconditioning (RIPC), and a number of drugs including volatile anesthetics which recruit the signal transduction pathways underlying conditioning, have been shown to attenuate myocardial injury following acute ischaemia-reperfusion injury. [102][103][104][105][106][107][108] Ischaemic cardioplegic arrest on cardiopulmonary bypass with subsequent reperfusion was therefore considered an ideal and well controlled clinical setting to translate findings from animal experiments to humans. In fact, a number of smaller studies have reported reduced MI size with IPC, IPost, and RIPC (for review see reference 102), and cyclosporine A. 109,110 These studies used biomarker release (CK, CK-MB, and cTn) to quantify PMI. It is important to note that the majority of studies have measured the magnitude of PMI to assess the cardioprotective efficacy of novel therapies, and did not investigate whether the new intervention was able to reduce the incidence of Type 5 MI or mortality. Two moderately sized trials also reported improved clinical outcomes with RIPC at short-111 or more long-term 112 as a secondary endpoints.
In contrast to these encouraging phase II a studies, two recent larger phase III trials assessing RIPC neither confirmed reduced biomarker (cTnT or cTnI) release nor improved clinical outcomes during hospitalization 113 or at one year follow-up. 114 In both these neutral trials, less than 50% of patients had only CABG surgery, and the others had either additional or only valvular surgery. Valvular surgery causes greater traumatic injury than CABG, and the contribution of trauma to total biomarker release may have diluted a potential cardioprotective effect of remote ischaemic preconditioning. In contrast to these larger trials, the original positive phase II trials had only recruited patients undergoing CABG surgery. 112,115 There are also other causes of biomarker release such as bypass graft failure 48 or microembolization of atherothrombotic debris, 77 which are not associated with subsequent reperfusion injury and from which, therefore, no protection by conditioning or drugs is expected. More disconcerting than the lack of reduction in biomarker release is the lack of improved clinical outcomes, which retrospectively also confirms the lack of reduced biomarker release in the two recent phase III trials. 116 Therefore, the search for novel biomarkers specific to cardioprotection by ischaemic conditioning such as protectomiRs 117 is of particular interest.

Recommendations for defining and managing prognostically significant peri-operative myocardial injury
In this ESC Joint WGs Position paper, we have provided recommendations for defining prognostically significant PMI ( Table 7). In summary, we would recommend that isolated elevations in cTnT > _7Â URL and/or cTnI > _20Â URL in the 48-h post-operative period may indicate the presence of prognostically significant PMI, and should prompt clinical evaluation to exclude Type 5 MI. Where ECG/angiography/imaging evidence of MI is available, lower levels of biomarker elevation (cTn x10 URL) should be considered for diagnosing prognostically significant PMI, as per the Universal MI definition.
We have also proposed an algorithm for managing CABG patients with or without suspected graft failure based on elevations in cardiac biomarkers ( Figure 3). Isolated elevations in cTn (>70Â URL in the 48 h post-operative period), even in the absence of any other feature of MI, may be indicative of graft failure and warrant further investigation with coronary angiography and re-revascularization by PCI or CABG surgery if indicated. More studies are needed to establish thresholds, especially for hs-cTnT elevations, which can be used in conjunction with clinical features and imaging findings, to predict those patients with regional ischaemia or graft failure. Furthermore, studies are required to better define the role of coronary angiography post-CABG surgery to detect early graft failure.