Scholarly article on topic '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'

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 Academic research paper on "Basic medicine"

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Academic research paper on topic "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"

European Heart Journal (2017) 0, 1-20 doi:10.1093/eurheartj/ehx383

CURRENT OPINION

EUROPEAN SOCIETY OF CARDIOLOGY*

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 Thielmann1*^, Vikram Sharma2,3^, Nawwar Al-Attar4, Heerajnarain Bulluck3, Gianluigi Bisleri5, Jeroen JH Bunge6, Martin Czerny7,

89 10 11 12

Peter Ferdinandy , , Ulrich H. Frey , Gerd Heusch , Johannes Holfeld ,

11 13 14 15

Petra Kleinbongard , Gudrun Kunst , Irene Lang , Salvatore Lentini ,

16,17 18 19

Rosalinda Madonna , , Patrick Meybohm , Claudio Muneretto , Jean-Francois Obadia20, Cinzia Perrino21, Fabrice Prunier22, Joost P.G. Sluijter23, Linda W. Van Laake24, Miguel Sousa-Uva25, and Derek J. Hausenloy3,26,27,28,29,30*

"'Department of Thoracic and Cardiovascular Surgery, West-German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, 45122, Essen, Germany; 2Department of Internal Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA; 3The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London WC1E 6HX, UK; 4Scottish National Advanced Heart Failure Service, Golden Jubilee National Hospital, Agamemnon Street, G81 4DY, Clydebank, UK; 5Division of Cardiac Surgery, Queen's University, 99 University Avenue, Kingston, Ontario K7L 3N6, Canada; 6Department of Intensive Care, Erasmus Medical Center,'s-Gravendijkwal 230, 3015 CE Rotterdam, Holland; Department of Cardiac Surgery, University Heart Center Freiburg-Bad Krozingen, Hugstetterstrasse 55, Freiburg, D-79106, Germany; 8Department of Pharmacology and Pharmacotherapy, Semmelweis University, Ulloi ut 26, H - 1085 Budapest, Hungary; 9Pharmahungary Group, Szeged, Graphisoft Park, 7 Zahony street, Budapest, H-1031, Hungary; 10Department of Anaesthesia and Intensive Care Medicine, University Hospital Essen, Hufelandstr. 55, 45122 Essen, Germany; 11Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstr. 55, 45122 Essen, Germany; 12University Clinic of Cardiac Surgery, Innsbruck Medical University, Christoph-Probst-Platz 1, Innrain 52, A-6020 Innsbruck, Austria; 13Department of Anaesthetics, King's College Hospital and King's College London, Denmark Hill, London, SE5 9RS, UK; 14Internal Medicine II, Division of Cardiology, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Vienna, Austria; Department of Cardiac Surgery, The Salam Center for Cardiac Surgery, Soba Hilla, Khartoum, Sudan, Italy; Center of Aging Sciences and Translational Medicine— CESI-Met and Institute of Cardiology, Department of Neurosciences, Imaging and Clinical Sciences "G. D"'Annunzio University, Via dei Vestini, 66100 Chieti, Italy; 17The Center for Cardiovascular Biology and Atherosclerosis Research, Department of Internal Medicine, The University of Texas Medical School at Houston, 6431 Fannin Street, MSB 1.240, Houston, TX 77030, USA; 18Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; 19Department of Cardiac Surgery, University of Brescia Medical School. P.le Spedali Civili, 1., Brescia, 25123, Italy; 20Department of Cardiothoracic Surgery, Louis Pradel Hospital, 28 Avenue du Doyen Jean Lepine, 69677 Bron Cedex, Lyon, France; 21Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Corso Umberto I 40 - 80138 Naples, Italy; 22Department of Cardiology, Institut MITOVASC, University of Angers, University Hospital of Angers, 2 rue Lakanal, 49045 Angers Cedex 01, Angers, France; 23Cardiology and UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands; Department of Cardiology, Division of Heart and Lungs and Regenerative Medicine Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands; 25Department of Cardiothoracic Surgery, Hospital da Cruz Vermelha, Lisbon, Portugal; 26The National Institute of Health Research University College London Hospitals Biomedical Research Centre, Maple House Suite A 1st floor, 149 Tottenham Court Road, London W1T 7DN, UK; Cardiovascular and Metabolic Disorder Research Program, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, 8 College Road, Singapore 169857, Singapore; 28National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital Drive, Singapore 169609, Singapore; 29Yong Loo Lin School of Medicine, National University Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore; and 30Barts Heart Centre, St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE, UK

Received 3 November 2016; revised 30 January 2017; editorial decision 19 June 2017; accepted 20 June 2017

* Corresponding authors. Tel: +49-201-723-8-4908, Fax: +49-201-723-6800, Email: matthias.thielmann@uni-due.de (M.T.); Tel: +65 66015121/65166719, Fax: +65 6221 2534, Email: derek.hausenloy@duke-nus.edu.sg (D.J.H.) ^ The first two authors are the Joint First Authors.

© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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 MI5,13), there is currently no clear definition for prognos-tically significant PMI, in terms of the level of post-operative cardiac

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

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>10x 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

Table 2 Predictors of peri-operative myocardial

infarction/graft-failure

Adapted from reference 6.

Patient factors

Advanced age6 Female sex7

Impaired LV systolic function prior to surgery6 Left main stem or 3-vessel CAD6,7 Pre-operative MI6 Unstable angina6,8,9

Previous history of coronary revascularisation Poor target coronary artery quality6,10 Uncontrolled hyperglycaemia10,11 EUROSCORE >69 Surgery factors Longer surgery time6

Prolonged cardio-pulmonary bypass and/or aortic cross clamp

time6,8,9,11

Coronary endarterectomy

Concomitant aortic and/or valve surgery

Inadequate myocardial protection during CABG12

Incomplete revascularisation9

Poor vein graft quality

Small internal thoracic artery

Table 1 Causes of peri-operative myocardial injury in patients undergoing coronary artery bypass graft surgery

biomarkers and new electrocardiogram (ECG) evidence of Q waves 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 ofviable myocardium.14-16

The current definition ofType 5 MI does have several limitations:

(1) The selection of a cTn elevation of 10x URL as a threshold for diagnosing Type 5 MI was arbitrarily chosen. Elevated cTn of 10x 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. bio-marker 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.15-17 (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 >10x URL in isolation or>5x URL with new pathologic Q-waves in >2 contiguous ECG leads or new persistent LBBB. A substantially higher cut-off for cTn elevation of >70x URL in isolation or>35x 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 post-surgery. 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<10x the URL within 48 h of CABG surgery,5 but this definition does not include those patients

who have isolated cTn elevations >10x 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 >3x URL within 24h of CABG surgery. Above isolated 10x 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 cTnTand cTnI and mortality post-coronary artery bypass graft surgery

Cardiac troponins have greater sensitivity and specificity for myocar-dial necrosis, when compared to CK-MB, and have been found to be superior to CK-MB in predicting mortality post-CABG surgery.30,34-37 However, the interpretation of isolated changes in cTn levels in the post-operative period, in the absence of ECG/angio-graphic 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 short-term 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>7x URL41 and cTnI levels >20x URL29,41 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

Table 3 Major recent studies showing elevations in creatine kinase-MB fraction to be associated with mortality post-coronary artery bypass grafting surgery

Type of study and Number of Cardiac Time from CABG surgery patients biomarker when biomarker

(time) level taken

Major findings

Costa et al.19 (ARTS trial)

Klatte et al.20 (GUARDIAN Trial)

Steuer et al.21

Brener et al.12

Marso et al.22

Ramsay et al.

Engoren et al. ' Newall et al.7

Mahaffey et al.2

Multi-centre prospec- 496

tive study CABG only

Multi-centre prospec- 2394

tive study CABG only

Prospective single 4911

centre, CABG only

Retrospective single 3812

centre analysis, CABG only

Single centre registry 3667

post-hoc analysis CABG only

Multi-centre prospec- 800

tive randomized trial CABG only

Retrospective analysis 1161 CABG only

Observational cohort 2860

study CABG only

Pooled analysis of four 1406

trials CABG only

Muehlschlegel et al. Prospective single centre study CABG only Petaja et al.27 Meta-analysis

CABG and/or valve

Vikenes et al.28

surgery Prospective single centre study

21 657

CK-MB ECG

CK-MB CK-MB

6,12,18 h

8, 12, 16, 24h

<1 x URL 0.0% 30 d mortality 1.1% 1 yr mortality 1-3 x URL 0.5% 30 d mortality 0.5% 1 yr mortality >3-5x URL 5.4% 30 d mortality 5.4% 1 yr mortality >5x URL 7.0% 30 d mortality 10.5% 1 yr mortality <5x URL 3.4% 6 mth mortality (RR 1.0) >5-10x URL 5.8% 6 mth mortality (RR 1.69) >10-20x URL 7.8% 6 mth mortality (RR 2.28) >20x URL 20.2% 6 mth mortality (RR 5.94 >5x URL + new Q waves worse 6 mth mortality

(8.0% vs. 3.1%) >61 ug/L Relative Hazard 1.3 to 1.4 for late mortality (up to 6 years)

<1 x URL 7.2% 3 yr mortality 1-3 x URL 7.7% 3 yr mortality 3-5 x URL 6.3% 3 yr mortality 5-10x URL 7.5% 3 yr mortality >10x URL 20.8% 3yr mortality >10x URL predicted 3yr mortality (HR1.3) Single measurement mean <1 x URL 0.6% 30 d mortality

15.2 h

4,8,16, 20,24, 30, 36 h Day 2, 4, 7, 30

10-18 h

Single value up to 24 h

Single value up to 24 h

Daily from day 1 to 5

>1-3 x URL 1.1% 30 d mortality >3x URL 2.2% 30 d mortality >4x URL associated with increased long-term mortality 5.1 yr (RR 1.3) 0-5 x URL 0.9% 30 d mortality 5-10x URL 0.7% 30 d mortality 10-20x URL 0.9% 30 d mortality >20x URL 6.0% 30 d mortality AUC and peak CK-MB correlated very well. >8x URL HR 1.3 increased 1 yr mortality

3-6x URL HR 2.1 for 1 yr mortality >6x URL HR 5.0 for 1 yr mortality

<3x URL 2.5% 30 d mortality; 3.7% 6 mth mortality 3-5 x URL 2.9% 30 d mortality; 4.7% 6 mth mortality

5-8x URL 3.1% 30 d mortality; 6.1% 6 mth mortality

>8x URL 8.6% 30 d mortality; 9.6% 6 mth mortality 24 h 1.23 for each 25 mg/L increase of 5 yr mortality ECG changes alone did not predict 5 year mortality.

Variable (peak or absolute CK-MB >5x URL -RR of short term mortality value at various time 3.69% (CI 2.17-6.26); RR of long term (6-60 m) points post-op) mortality 2.66% (CI 1.95-3.63)

1-3, 4-8, 24, 48 and 72 h CK-MB elevation > 5 x URL was associated with worst long term event free survival (median follow-up 92 mths).

Continued

Table 3 Continued

Type of study and Number of Cardiac Time from CABG surgery patients biomarker when biomarker

(time) level taken

Major findings

Domanski et al.

Soraas et al.

Farooq et al. SYNTAX trial substudy

CABG and/or valve

surgery Meta-analysis CABG only

18 908

CK-MB (<24 h)

Registry analysis, single centre study CABG only

Post hoc analysis of 474

SYNTAX trial data; CABG only

Single value < 24 h

7,20, 44 h

6, 12h

(CK-MB was measured only if CK>2x URL

1-5 x URL 1.69% RR of 30 d mortality 5-10x URL 2.98% RR of 30 d mortality 10-20x URL 4.47% RR of 30 d mortality 20-40x URL 8.73% RR of 30 d mortality >40x URL 27.01% RR of 30 d mortality CK-MB levels were significantly associated with 1 year mortality; there was a non-significant trend for association with 5 year mortality There was no difference in mortality between those

with CK-MB >7.8x URL vs. <4x URL CK-MB levels at 44 h postoperatively had a greater

predictive value for mortality than at 7 or 20 h. Peak CK-MB levels predicted long-term mortality (median 6.1 years) after univariate but not multivariate analysis (including cTnl). CK-MB <3/>3x URL separated patients into low and high-risk groups based on 4-year mortality (All-cause mortality 2.3% vs. 9.5% P = 0.03). CK-MB >3x URL was associated with significantly higher frequency of high SYNTAX Score tertile (>33)

AUC, area under the curve; CABG, coronary artery bypass grafting; CMR, cardiac MRI; CK-MB, creatine kinase-MB fraction; d, day; ECG, electrocardiogram; ECHO, echocar-diocardiogram; 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.

sensitivity-cTnT or cTnl 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 Ml appears to be required to identify those CABG patients at a higher risk of mortality when>10x URL hs-cTnT elevation is measured.8 The majority of studies have reported isolated elevations between 24 and 48 h post-surgery as being the most discriminatory for predicting clinical outcomes.27,30,36-38,42 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 Ml size.54

In summary, we recommend, that for patients with a pre-operative cTn <1 x URL, isolated elevations of 'standard' cTn assays (cTnT >7x URL and cTnl >20x URL) within the 48 h post-operative period (in the absence of ECG/angiographic or other imaging evidence of Ml), may be indicative of prognostically significant PMI, and require further clinical evaluation to determine whether there is evidence for Type 5 Ml. This is particularly so if there is additional clinical evidence for Ml 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 cTnl in defining prognostically significant PMl, 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 Ml, an elevation of cTnT or cTnl >10x URL should be used to define Type 5 Ml, as per the 3rd Universal Definition of Ml. 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 PMl or Type 5 Ml, as interventions at this stage may fail to salvage a substantial volume of myocardium at risk. Also, cTn elevation in this

Elevations in CK-MB levels and 30-days mortality

1 to <5 i

5 to <10

10 to <20 -■—

20 le <40

II 5 III 1$ 20 ¡5 JO 35 -HI 4)1 Я <5

Relative risk of mortality (95%CI)

Elevations in Troponin I levels and 30-days mortality ■ URL

lto<S ||—

5 to <10 1" ■

10 10 <20 *-

20 to <40 ■

£40 -*-

I 5 II 15 21 JO 15 411 45 <0 55

Relative risk of mortality (95%CI)

Figure 1 Relationship between creatine kinase-MB fraction elevation post-coronary artery bypass graft surgery with relative risk of mortality at 30 days (adapted from meta-analysis by Domanski etaL29).

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).

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 acid-binding protein,55,56 copeptin,57 microRNAs (miR-499 and miR-1),58,59 and cardiac myosin-binding protein C60 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 bio-markers 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 ST-segment 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

Table 4 Major recent studies showing elevations in Troponin T to be associated with mortality post-coronary artery bypass grafting surgery

Study Type of study and Number of Cardiac Time from CABG Major findings

surgery patients biomarker (time) when biomarker level taken

Januzzi et at.36 Prospective single centre 224 cTnT Immediately post-op, cTnT level in the highest quintile (>1.58 ng/mL; >15 x URL) immediately post-op or at 18-24 h

study CK-MB 6-8 h predicted in-hospital death.

CABG only and 18-24 h CK-MB levels did not offer additional prognostic benefit to cTnT in multivariate analysis

Lehrke et at.38 Prospective single centre study CABG and/or valve surgery 204 cTnT 4, 8 h then every day for 7 days cTnT >0.46 |ig/L (>46x URL) at 48 h after surgery was the optimum discriminator for long-term cardiac mortality (28 mths, OR 4.93)

Kathiresan et at.37 Prospective single centre 136 cTnT Immediately post-op, cTnT >1.58 |ig/L at 18-24 h was the optimum discriminator for 1 year cardiac mortality (OR 5.45)

study CK-MB 6-8 h and Elevations in CK-MB were not predictive of mortality

CABG only 18-24 h post-op

Nesher et al.39 Retrospective observational single centre study Cardiac surgery (CABG and/or valve) 1918 cTnT Single sample <24 h cTnT level >0.8 |ig/L (8x URL) was most discriminatory for MACE (30 day death, electrocardio- gram-defined infarction, and low output syndrome) (OR 2.7) 0-3.9x URL 0.5% 30day mortality 5-5.9x URL 1.6% 30day mortality 6-7.9x URL 1.0% 30day mortality 8-12.9x URL 1.8% 30day mortality >13x URL 6.8% 30day mortality

Muehlschlegel et at26 Retrospective analysis CABG only 1013 cTnT Daily from day 1 to 5 24 h cTnT rise > 110 x U RL H R 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 cTnl 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 < 1.60 (<160x URL) had good negative predictive value for poor 30day outcomes (death or heart failure)

Petaja et al.41 Meta-analysis CABG and/or valve surgery 2,547 cTnT <48 h post op >7-16 x URL: Short term mortality 3.2% vs. 0.5% for <7-16 x URL elevation (RR 4.68-6.4); Long term mortality (12-28 mth) 16.1% vs. 2.3% (RR 5.7-10.09). (Pooled RR of mortality could not be calculated)

Soraas et al.30 Registry analysis, single centre study CABG only 1,350 cTnT CK-MB 7,20, 44 h post op Patients with peak cTnT > 5.4x URL had much higher long-term mortality (median 6.1 years) than those with <5.4x URL cTnT elevation. cTnT levels at 44 h postoperatively had a greater predictive value for long-term mortality than at 7 or 20 h. PeakTrop T levels predicted long-term mortality after multivariate analysis.

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Myocardial nuclear imaging and cardiac computed tomography to detect type 5 myocardial infarction following coronary artery bypass graft surgery

Radionuclide single-photon emission computed tomog aphy (SPECT) and positron emission tomography (PET) imaging can allow the di rect 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

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 bio-marker (time) Other features Major findings

Greenson et al.43 Single centre prospective 100 cTnl Pre-op, 24 h and 48 h, Peak cTnl > 60 ng/mL (> 120x URL) predictive of cardiac events up to 30 days

study; CABG or Aortic CK-MB then daily until dis- post op

valve replacement charge or 1 week

Holmvang et al.35 Single centre prospective 103 cTnT Every 2 h in first 20 h, ECG changes unable to differentiate between patients with or without graft failure.

study, CABG only cTnl CK-MB Myoglobin 24, 30, 36 and 48 h, 72 and 98 h CK-MB and cTnT (but not cTnl 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 Ml within 7 days) 540 cTnl Prior to induction of anaesthesia and at termination of CPB cTnl level > 0.495 ng/L (> 9.9 x URL for assay) measured at the end of CPB was predictive of in-hospital adverse outcomes (Ml/death)

Lasocki et al.45 Single centre prospective study; CABG or valve surgery (Acute Ml < 7 days were excluded) 502 cTnl ECG changes 20 h post-op cTnl < 32.5 x URL ~2.5% in hospital mortality cTnl > 32.5x URL ~22.5% in hospital mortality cTnl > 100x URL 44% in hospital mortality

Thielmann et al.46 Single centre prospective study: CABG only 2,078 cTnl 1, 6, 12,24 h post op cTnl was a more sensitive and specific marker of graft failure at a level above 21.5 ng/mL (> 43 x URL ng/mL) at 12 h and 33.4 ng/mL (>66.8x URL)at24h, 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 < 7 days included) 230 cTnl Pre-op, 1,6,12,24 and 36 h post-op, daily from day 2 to 7 cTnl >260x URL (13 ng/L) predicted in-hospital mortality but not 2year mortality; Peak cTnl generally observed 24 h after surgery

Onorati et al.9 Prospective single centre 776 cTnl Pre-op and 12,24,48 cTnl >3.1 |ig/L (> 310x URL) at 12h predicted increased in-hospital and

study; CABG only ECG changes (New Q wave or reduction in R waves > 25%) & ECHO feature of Ml and 72 h post-op 12 month mortality; Additional ECG and ECHO criteria of Ml predicted worst outcome

Thielmann et al.31'48 Prospective single centre 94 cTnl Pre-op, 1,6, 12, 24, 36 cTnl was the best discriminator between PMI 'in general' and 'inherent' release of

study CK-MB and 48 h post-op cTnl after CABG with a cut-off value of 10.5 ng/mL (> 21 x URL) and between graft-related and non-graft-related PMI with a cut-off value of 35.5 ng/mL

Table 5 Continued

Study Type of study and Number of Cardiac bio-

surgery patients marker (time)

CABG only patients

undergoing re-angiogra-

phy post-op

Croal et at.49 Prospective 1365 cTnl

CABG+ valve/other car- ECG changes

diac surgery

Provenchère et al.50 Prospective single centre 92 cTnl

CABG and/or valve

surgery

Fellahi et al.51 Prospective single centre 202 cTnl

study;

CABG only

Adabag et al.34 Retrospective analysis 1186 cTnl

CABG and/or valve CK-MB

surgery

Muehlschlegel et al26 Prospective single centre 1013 cTnl

CABG only surgery

Petaja et al.41 Meta-analysis 2348-3271 cTnl

CABG and/or Cardiac

surgery

Hashemzadeh et al.52 Prospective single centre 320 cTnl

CABG +/- Valve surgery

(Excluded Ml within 7

Van Geene et al.53 Registry retrospective 938 (Separate vali- cTnl

analysis;CABG and/or dation subset,

valve surgery n = 579)

Domanski et al.29 Meta-analysis 18,908 cTnl

CABG only

Other features Major findings

(>71 x URL). CK-MB level and ECG changes/TEE could not differentiate between those with or without graft failure.

2 and 24 h cTnl at 24 h best predictor

>53 x URL 2.37 OR 30-day mortality, 2.94 OR 1 yr mortality, 1.94 OR 3 yr mortality

>27x URL 1.05 OR 30-day mortality, 1.14 OR 1 yr mortality, 1.37 OR3yr mortality

20 h post op cTnl levels were not predictive of 1 year mortality in a multivariate model.

Per-op and 24 h post- cTnl >13 ng/mL (> 21.66 x URL) did not predict in-hospital mortality, but was op 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 x URL)

Ever 8 h for 24 h post- cTnl level independently associated with operative (30day) mortality; CK-MB had op, longer if no a weaker association with operative mortality

peak in 24 h

Daily from day 1 to 5 24 h cTnl rise > 138x 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.

Up to 7 days post op Short-term mortality (<6 mths) 8.1% > 21 x URL vs. 1.5% <21 x URL Long-term mortality (6-36 mths): 10.6% vs. 3.1% (RR 1.06-11.00%)

Immediately and 20 h 20 h post-op cTnl had better prognostic value than immediate post-op levels, post-op 20 h cTnl level was an independent predictor of in-hospital mortality above a

value of 14 ng/mL (>1 Ox URL)

1 h post-op 1 h post-op cTn values correlated with hospital mortality with the best cut-off

value of 4.25 |i/L (Type of assay and URL for assay not known)

<24 h post op 5 to < 10x URL 1.00 RR of 30 d mortality

10to<20x URL 1.89 RR of 30 d mortality 20 to < 40x URL 2.22 RR of 30 d mortality

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In most patients with LGE on CMR, in-hospital patient management was not changed. In one study, a rise in both CK-MB and cTnl to >5x 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 Ml, 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 study76 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-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 orType 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 myo-cardial 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 <9g/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 dexametha-sone 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 dobut-amine, phosphodiesterase inhibitors like milrinone or enoximone, and the calcium sensitiser levosimendan can all be used to treat postoperative refractory low cardiac output syndrome and decompen-sated 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%, 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 arteries48). 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-revas-cularisation is performed in 50-70% of graft-related Type 5 MI.81,92-95 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 revascular-ization. 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 post-stenting, 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>45x URL at 12h and >70x 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

Study Number of patients Type of surgery Cardiac biomarkers Incidence of Ml (LGE on CMR) Major findings

Steuer et al.17 23 CABG CKMB/cTnT/cTnl Days 1, 2, and 4 after surgery 18/23 (78%) CMR 4-9 days First study to use CMR to visualise PMI following CABG surgery. Median LGE mass in patients with PMI was 4.4g (2.5% of LV). Mixed pattern of LGE with transmural, subendocardial and patchy features. Moderate correlation between elevations in CK-MB, cTnT, cTnl at day 1 and LGE mass. Four patients with transmural LGE all had CK-MB >5 x URL No pre-op CMR scan performed which may explain the higher than expected incidence of LGE on post-surgery CMR.

Selvanayagam et al.15 53 CABG cTnl 9/26 (35%) New median LGE mass in patients with PMI was 6.3±3.6g on pump and 6.4

(on pump vs. off pump) At 1,6,12, 24, 48 and 120h after surgery (on pump) CMR day 6 (range 4-17) 12/27(44%) (off pump) CMR day 6 (range 4-17) ± 4.0 g off pump Moderate correlation between elevations in AUC cTnl and LGE mass (r2 = 0.4). Only 4 of the 21 patients with LGE on CMR had new Q waves on ECG. Pre-op CMR revealed 47-53% patients had LGE priorto surgery (mean LGE mass 19g).

Pegget al.16'74 40 CABG cTnl and CK-MB 6/17(35%) New median LGE mass in patients with PMI was 8.2 ± 5.2g ONSTOP and

(ONBEAT—on pump At 1,6,12,24,48, and 120h (ON BEAT) 9.8 ± 9.0 g ON BEAT

beating heart vs. after surgery CMR day 6 or 7 (range 6-11.5) Good correlation between AUC and 24 h cTnl, CK-MB and new LGE

ONSTOP—on pump 12/23 (52%) mass.

cardioplegia) (ONSTOP) CMR day 6 or 7 (range 6-11.5) Mixed pattern of LGE with transmural and subendocardial features. Pre-op CMR revealed 100% patients had LGE priorto surgery. cTnl value >6.6 |ig/L (165 x URL) at 24 h detection of Type 5 Ml on LGE-CMR. cTnl better than CK-MB for quantifying myocardial injury

Lim et al.61 28 CABG cTnl and CK-MB At 1, 6,12, 24 h after surgery 9/28 (32%) CMR day 7 (4-10) cTnl > 83.3x URL at 1 h and peak cTnl/CK-MB at 24 h correlated with new LGEcTnl 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 cTnl 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 8.7g on acute scan—no significant change in LGE mass at 6 months There was a strong correlation between the absolute peak cTnl 24 h postprocedure and LGE. Pre-op CMR performed

Alam et al.76 69 CABG cTnl 25% No difference in AUC cTnl or new LGE mass with Elafin (potent endoge-

(Elafin vs. placebo) At 2, 6, 24 and 48 h after surgery CMR day 5 nous neutrophil elastase inhibitor—an anti-inflammatory agent) No data on LGE mass given

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surgical period (>45x URL at 12h and >70x URL elevation at 24h), 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, th is approach has been shown to predict graft

100 101 failure at 1 month and 6 months post-CABG surgery.

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 haemody-namic 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 x URL at 12 h and >70x 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.

Coronary angiography and heart team consultation

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.

• 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 cardio-plegic 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

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 Type 5 MI

Universal definition5 Peri-operative myocardial injury SCAI18

Clinically relevant MI ESC Joint WG Criteria Prognostically significant peri-operative myocardial injury

Troponins only Troponins only CK-MB and Troponins Troponins only

<10x URL

>10x URL (CK-MB)

>70x URL (cTn)

>7x URL(cTnT)

>20 x URL(cTnl)

(Does not apply to hs-cTnT)

>10x URL N/A

>5x URL (CK-MB) >35x URL (troponin) >10x URL

URL, upper reference limit.

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 follow-

102_108

ing acute ischaemia-reperfusion injury. 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 Ml 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

111 112 outcomes with RIPC at short- or more long-term 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 hospitalization113 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

112 115

recruited patients undergoing CABG surgery. , There are also other causes of biomarker release such as bypass graft failure48 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 protectomiRs117 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>7x URL and/or cTnI >20x 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/angiog-raphy/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 (>70x 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.

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