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. 1–3 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 48-h 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. Table 1 Causes of peri-operative myocardial injury in patients undergoing coronary artery bypass graft surgery Injury related to primary myocardial ischaemia (mainly graft-related) Plaque rupture in native coronary artery or graft Thrombus formation in the native coronary artery or graft Acute graft failure due to occlusion, kinking, overstretching, anastomotic stenosis or spasm of the grafted blood vessel Arterial graft spasm Myocardial injury related to unfavourable haemodynamics or oxygen supply Tachyarrhythmia Cardiogenic or hypovolaemic shock Severe respiratory failure Severe anaemia Left ventricular hypertrophy Coronary artery or graft micro-embolism Inadequate cardioprotection from cardioplegia Myocardial injury not related to myocardial ischaemia Cardiac handling during surgery Direct injury to the myocardium Surgical myectomy Inflammatory injury due to cardiopulmonary bypass Multifactorial or indeterminate myocardial injury Heart failure Severe pulmonary embolism Sepsis Critically ill patients Renal failure Adapted from reference 6. Table 2 Predictors of peri-operative myocardial infarction/graft-failure Patient factors Advanced age 6 Female sex 7 Impaired LV systolic function prior to surgery 6 Left main stem or 3-vessel CAD 6 , 7 Pre-operative MI 6 Unstable angina 6 , 8 , 9 Previous history of coronary revascularisation Poor target coronary artery quality 6 , 10 Uncontrolled hyperglycaemia 10 , 11 EUROSCORE >6 9 Surgery factors Longer surgery time 6 Prolonged cardio-pulmonary bypass and/or aortic cross clamp time 6 , 8 , 9 , 11 Coronary endarterectomy Concomitant aortic and/or valve surgery Inadequate myocardial protection during CABG 12 Incomplete revascularisation 9 Poor vein graft quality Small internal thoracic artery 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 >10× 99th percentile upper reference limit (URL) during the first 48 h following CABG surgery, in patients with normal baseline cardiac cTn values ( 10× 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 on-pump 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 ≥3× URL within 24 h of CABG surgery. Above isolated 10× 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. Table 3 Major recent studies showing elevations in creatine kinase-MB fraction to be associated with mortality post-coronary artery bypass grafting surgery Study Type of study and surgery Number of patients Cardiac biomarker (time) Time from CABG when biomarker level taken Major findings Costa et al. 19 (ARTS trial) Multi-centre prospective study CABG only 496 CK-MB 6,12,18 h 5× URL 7.0% 30 d mortality 10.5% 1 yr mortality Klatte et al. 20 (GUARDIAN Trial) Multi-centre prospective study CABG only 2394 CK-MB ECG 8, 12, 16, 24 h 5× URL + new Q waves worse 6 mth mortality (8.0% vs. 3.1%) Steuer et al. 21 Prospective single centre, CABG only 4911 CK-MB 24 h >61 ug/L Relative Hazard 1.3 to 1.4 for late mortality (up to 6 years) Brener et al. 12 Retrospective single centre analysis, CABG only 3812 CK-MB 24 h ≤1× URL 7.2% 3 yr mortality 1–3× URL 7.7% 3 yr mortality 3–5× URL 6.3% 3 yr mortality 5–10× URL 7.5% 3 yr mortality >10× URL 20.8% 3 yr mortality >10× URL predicted 3 yr mortality (HR 1.3) Marso et al. 22 Single centre registry post-hoc analysis CABG only 3667 CK-MB Single measurement mean 15.2 h ≤1× URL 0.6% 30 d mortality >1–3× URL 1.1% 30 d mortality >3× URL 2.2% 30 d mortality >4× URL associated with increased long-term mortality 5.1 yr (RR 1.3) Ramsay et al. 23 Multi-centre prospective randomized trial CABG only 800 CK-MB 4,8, 16, 20,24, 30, 36 h Day 2, 4, 7, 30 0–5× URL 0.9% 30 d mortality 5–10× URL 0.7% 30 d mortality 10–20× URL 0.9% 30 d mortality >20× URL 6.0% 30 d mortality AUC and peak CK-MB correlated very well. Engoren et al. 24 Retrospective analysis CABG only 1161 CK-MB 10–18 h >8× URL HR 1.3 increased 1 yr mortality Newall et al. 7 Observational cohort study CABG only 2860 CK-MB Single value up to 24 h 3–6× URL HR 2.1 for 1 yr mortality >6× URL HR 5.0 for 1 yr mortality Mahaffey et al. 25 Pooled analysis of four trials CABG only 1406 CK-MB Single value up to 24 h 0.46 μg/L (>46× URL) at 48 h after surgery was the optimum discriminator for long-term cardiac mortality (28 mths, OR 4.93) Kathiresan et al. 37 Prospective single centre study CABG only 136 cTnT CK-MB Immediately post-op, 6–8 h and 18–24 h post-op cTnT >1.58 μg/L at 18–24 h was the optimum discriminator for 1 year cardiac mortality (OR 5.45) Elevations in CK-MB were not predictive of mortality Nesher et al. 39 Retrospective observational single centre study Cardiac surgery (CABG and/or valve) 1918 cTnT Single sample 13× URL 6.8% 30 day mortality Muehlschlegel et al. 26 Retrospective analysis CABG only 1013 cTnT Daily from day 1 to 5 24 h cTnT rise > 110× URL HR 7.2 of 5 yr mortality cTnT at 24 h were independent predictors of 5 year mortality in a multivariate model (No additional benefit of measuring cTn beyond 24 h). Majority of patients had peak cTnI and CK-MB levels at 24 h. ECG changes alone did not predict 5 year mortality. Mohammed et al. 40 Prospective single centre study, retrospective analysis CABG only 847 cTnT 6–8 and 18–24 h A cTnT of 10× URL rise in hs-TNT + ECG/ECHO evidence of recent MI or regional ischaemia predicted 30 day (HR 4.9) and long-term mortality (median follow-up 1.8 years) (HR 3.4). > 10× URL rise in hs-cTnT was seen in 90% patients. Gober et al. 42 Retrospective study from registry data CABG only 290 cTnT CK-MB 8,16 h post op cTnT > 0.8 ng/mL (>80× URL) at 6–8 h was predictive of in hospital adverse outcomes and long term (4yr) mortality (OR 4.0). However, cTnT measured at 6–8 h was inferior to cTnT taken at 20 h in its prognostic ability. AUC, area under the curve; CABG, coronary artery bypass grafting; CMR, cardiac MRI; CK-MB, creatine kinase-MB fraction; d, day; ECG, electrocardiogram; ECHO, echocardiocardiogram; HR, hazards ratio; h, hour; LGE, late gadolinium enhancement; LV, left ventricle; MACE, major adverse cardiac events; MI, myocardial infarction; mth, month; ng, nanogram; ONBEAT, on-pump beating heart; CABG ONSTOP, on-pump CABG; OR, odds ratio; post-op, post-operative; PMI, perioperative myocardial injury; RR, relative risk; TEE, transoesophageal echocardiogram; cTnI, Troponin I; cTnT, Troponin T; UA, unstable angina; URL, upper reference limit; yr, year. Table 5 Major recent studies showing elevations in Troponin I to be associated with mortality post-coronary artery bypass grafting surgery Study Type of study and surgery Number of patients Cardiac biomarker (time) Other features Major findings Greenson et al. 43 Single centre prospective study; CABG or Aortic valve replacement 100 cTnI CK-MB Pre-op, 24 h and 48 h, then daily until discharge or 1 week Peak cTnI > 60 ng/mL (> 120× URL) predictive of cardiac events up to 30 days post op Holmvang et al. 35 Single centre prospective study, CABG only 103 cTnT cTnI CK-MB Myoglobin Every 2 h in first 20 h, 24, 30, 36 and 48 h, 72 and 98 h ECG changes unable to differentiate between patients with or without graft failure. CK-MB and cTnT (but not cTnI or Myoglobin) levels were significantly higher in patients with graft failure vs. those without. Optimal discrimination values were 30 mcg/L for CK-MB (sensitivity 67%, specificity 65%) and 3 mcg/L for cTnT (sensitivity 67%, specificity 76%). In multivariate analysis cTnT > 3 mcg/L was significantly associated with graft failure (sensitivity of 75% compared to 20% for clinical criteria) Eigel et al. 44 Prospective single centre study; CABG only (Excluded MI within 7 days) 540 cTnI Prior to induction of anaesthesia and at termination of CPB cTnI level > 0.495 ng/L (> 9.9× URL for assay) measured at the end of CPB was predictive of in-hospital adverse outcomes (MI/death) Lasocki et al. 45 Single centre prospective study; CABG or valve surgery (Acute MI 100× URL 44% in hospital mortality Thielmann et al. 46 Single centre prospective study: CABG only 2,078 cTnI 1, 6, 12,24 h post op cTnI was a more sensitive and specific marker of graft failure at a level above 21.5 ng/mL (> 43× URL ng/mL) at 12 h and 33.4 ng/mL (>66.8× URL) at 24 h, compared to myoglobin and CK/CK-MB. CK-MB and EKG changes (ST-segment deviations or new Q wave) did not predict graft failure Paparella et al. 47 Prospective Single centre study; CABG only (Patients with UA/MI 260× URL (13 ng/L) predicted in-hospital mortality but not 2 year mortality; Peak cTnI generally observed 24 h after surgery Onorati et al. 9 Prospective single centre study; CABG only 776 cTnI ECG changes (New Q wave or reduction in R waves > 25%) & ECHO feature of MI Pre-op and 12, 24, 48 and 72 h post-op cTnI >3.1 μg/L (> 310× URL) at 12 h predicted increased in-hospital and 12 month mortality; Additional ECG and ECHO criteria of MI predicted worst outcome Thielmann et al. 31 , 48 Prospective single centre study CABG only patients undergoing re-angiography post-op 94 cTnI CK-MB Pre-op, 1, 6, 12, 24, 36 and 48 h post-op cTnI was the best discriminator between PMI ′in general′ and ′inherent′ release of cTnI after CABG with a cut-off value of 10.5 ng/mL (> 21× URL) and between graft-related and non-graft-related PMI with a cut-off value of 35.5 ng/mL (>71× URL). CK-MB level and ECG changes/TEE could not differentiate between those with or without graft failure. Croal et al. 49 Prospective CABG+ valve/other cardiac surgery 1365 cTnI ECG changes 2 and 24 h cTnI at 24 h best predictor ≥53× URL 2.37 OR 30-day mortality, 2.94 OR 1 yr mortality, 1.94 OR 3 yr mortality ≥27× URL 1.05 OR 30-day mortality, 1.14 OR 1 yr mortality, 1.37 OR 3 yr mortality Provenchère et al. 50 Prospective single centre study CABG and/or valve surgery 92 cTnI 20 h post op cTnI levels were not predictive of 1 year mortality in a multivariate model. Fellahi et al. 51 Prospective single centre study; CABG only 202 cTnI Per-op and 24 h post-op cTnI ≥ 13 ng/mL (≥ 21.66 x URL) did not predict in-hospital mortality, but was predictive of 2 year mortality (18% vs. 3%; OR 7.3). Best cut off to predict death ranged from 12.1 to 13.4 ng/mL (20.16–21.66× URL) Adabag et al. 34 Retrospective analysis CABG and/or valve surgery 1186 cTnI CK-MB Ever 8 h for 24 h post-op, longer if no peak in 24 h cTnI level independently associated with operative (30 day) mortality; CK-MB had a weaker association with operative mortality Muehlschlegel et al. 26 Prospective single centre study CABG only surgery 1013 cTnI Daily from day 1 to 5 24 h cTnI rise ≥ 138× URL HR 2.8 for 5 yr mortality cTnT at 24 h were independent predictors of 5 year mortality in a multivariate model (No additional benefit of measuring cTn beyond 24 h). ECG changes alone did not predict 5 year mortality. Petaja et al. 41 Meta-analysis CABG and/or Cardiac surgery 2348–3271 cTnI Up to 7 days post op Short-term mortality ( 10× URL) Van Geene et al. 53 Registry retrospective analysis;CABG and/or valve surgery 938 (Separate validation subset, n = 579) cTnI 1 h post-op 1 h post-op cTn values correlated with hospital mortality with the best cut-off value of 4.25 μ/L (Type of assay and URL for assay not known) Domanski et al. 29 Meta-analysis CABG only 18,908 cTnI 4.8 yr follow-up period). Cumulative area under to curve for cTn release up to 72 h was the best predictor of mortality in this model (HR 1.45). Peak cTnI of > 13 ng/mL (URL not defined) did not predict mid-term mortality. AUC, area under the curve; CABG, coronary artery bypass grafting; CMR, cardiac MRI; CK-MB, creatine kinase-MB fraction; d, day; ECG, electrocardiogram; ECHO, echocardiocardiogram; HR, hazards ratio; h, hour; LGE, late gadolinium enhancement; LV, left ventricle; MACE, major adverse cardiac events; MI, myocardial infarction; mth, month; ng, nanogram; ONBEAT, on-pump beating heart; CABG ONSTOP, on-pump CABG; OR, odds ratio; post-op, post-operative; PMI, perioperative myocardial injury; RR, relative risk; TEE, transoesophageal echocardiogram; cTnI, Troponin I; cTnT, Troponin T; UA, unstable angina; URL, upper reference limit; yr, year. Figure 2 Relationship between Troponin I elevation post-coronary artery bypass graft surgery with relative risk of mortality at 30 days (adapted from meta-analysis by Domanski et al. 29 ). In summary, we recommend, that for patients with a pre-operative cTn 6.6 µg/L (165× URL) at 24 h detection of Type 5 MI on LGE-CMR. cTnI better than CK-MB for quantifying myocardial injury Lim et al. 61 28 CABG cTnI and CK-MB At 1, 6, 12, 24 h after surgery 9/28 (32%) CMR day 7 (4–10) cTnI > 83.3× URL at 1 h and peak cTnI/CK-MB at 24 h correlated with new LGEcTnI better than CK-MB in predicting new LGE at both 1 and 24 hNone of the 9 patients with new LGE had Q waves on ECGPre-op CMR performed van Gaal et al. 75 32 CABG cTnI and CK-MB At 1, 6, 12, 24 h after surgery 9/32 (28%) CMR day 7 (4–10) and 6 months. New mean LGE mass 8.7 g on acute scan—no significant change in LGE mass at 6 months There was a strong correlation between the absolute peak cTnI 24 h post-procedure and LGE. Pre-op CMR performed Alam et al. 76 69 CABG (Elafin vs. placebo) cTnI At 2, 6, 24 and 48 h after surgery 25% CMR day 5 No difference in AUC cTnI or new LGE mass with Elafin (potent endogenous neutrophil elastase inhibitor—an anti-inflammatory agent) No data on LGE mass given Pre-op CMR performed Hueb et al. 14 136 CABG (on pump vs. off pump) cTnI and CK-MB At 6, 12, 24, 36, and 48 h after surgery 13/69 (19%) (on pump) CMR day 6 14/67 (21%) (off pump) on CMR day 6 No data on LGE mass given CK-MB better than cTnI in predicting patients with LGE following CABG surgery The best cut-off for cTnI in predicting Type 5 MI (new LGE on CMR) for on-pump CABG was 162.5× URL and for off-pump CABG was 112.5× URL. The best cut-off for CK-MB in predicting LGE (Type 5 MI) for on-pump CABG was 8.5× URL and for off-pump CABG was 5.1× URL. New Q waves in ECG present in only 7/136 (5%) patients Pre-op CMR performed AUC, area under the curve; CABG coronary artery bypass grafting; CMR, cardiac MRI; CK-MB, creatine kinase-MB fraction; d, day; ECG, electrocardiogram; ECHO, echocardiocardiogram; HR, hazards ratio; h, hour; LGE, late gadolinium enhancement; LV, left ventricle; MACE, major adverse cardiac events; MI, myocardial infarction; mth, month; ng, nanogram; ONBEAT, on-pump beating heart; CABG ONSTOP, on-pump CABG; OR, odds ratio; post-op, post-operative; PMI, perioperative myocardial injury; RR, relative risk; TEE, transoesophageal echocardiogram; cTnI, Troponin I; cTnT, Troponin T; UA, unstable angina; URL, upper reference limit; yr, year. 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 >5× 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 peri-operative 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 post-operative 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-graft-related 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 45× URL at 12 h and >70× 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-surgical period (>45× URL at 12 h and >70× 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. 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 >45× URL at 12 h and >70× 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. Figure 3 Proposed algorithm for managing patients with possible peri-operative myocardial injury and Type 5 myocardial infarction following coronary artery bypass graft surgery. CPB, cardiopulmonary bypass; RWMA, regional wall motion abnormality; TEE, transeophageal echocardiography; LCOS, low-cardiac output syndrome; VT, ventricular tachycardia; VF, ventricular fibrillation; IABP, intra-aortic balloon pulsation; ECLS, Extracorporeal Life Support; URL, upper reference limit. 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. The graft or native coronary artery occlusion was identified late, in which case consider viability assessment first. 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. 102–108 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 ≥7× URL and/or cTnI ≥20× 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. Table 7 Overview of definitions for peri-operative myocardial injury and Type 5 myocardial infarction Diagnostic criteria Cardiac biomarker Threshold for isolated elevation in cardiac biomarker (with no ECG or imaging changes of MI) Threshold for elevation in cardiac biomarker with ECG and imaging changes of MI Universal definition 13 Type 5 MI Troponins only N/A ≥10× URL Universal definition 5 Peri-operative myocardial injury Troponins only 70× 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. Funding European Cooperation in Science and Technology (COST EU-ROS) and Hungarian Scientiﬁc Research Fund (OTKA K 109737 and ANN 107803) to P.F; British Heart Foundation (grant number FS/10/039/28270), the Rosetrees Trust, and National Institute for Health Research University College London Hospitals Biomedical Research Centre to D.J.H.; Italian Ministry of Health (GR-2009-1596220) and the Italian Ministry of University (RBFR124FEN) to C.P.; Netherlands Organization for Health Research and Development (ZonMW Veni 91612147) and Netherlands Heart Foundation (Dekker 2013T056) to L.V.L.; German Research Foundation (He 1320/18-3; SFB 1116 B8 to G.H.). Conflict of interest: D.H., M.T., V.S., J.B., G.K., R.M., J.S., F.P., P.K., P.M., N.A., S.L., C.P., G.B., J.O., U.F., M.C., U.F., J.F.O., C.M., L.V.L., M.S.N. have no disclosures. G.H. served as consultant for Servier. P.F. is an owner of Pharmahungary Group, a group of R&D companies.