Myocardial inflammation, injury and infarction during on-pump coronary artery bypass graft surgery

Approximately 400,000 coronary artery bypass graft (CABG) operations are performed each year in the United States of America [1]. Cardiopulmonary bypass (CPB) during these procedures is known to induce systemic and myocardial inflammation [2, 3]. Inflammatory cytokines such a tumour necrosis factor alpha (TNF-α) depress cardiac function after CPB [4], whereas elevations of interleukin(IL)-6 and IL-8 are proportional to levels of myocardial injury and apoptosis [5]. Elevated cardiac troponin concentrations have been identified in up to 100% of patients undergoing CABG [6]. However, corresponding cardiac magnetic resonance (CMR) evidence of myocardial necrosis is evident in only 28% of patients, suggesting that troponin release may reflect reversible injury resulting from other processes such as inflammation or ischaemia-reperfusion injury rather than infarction [7]. The identification of clinically relevant peri-operative myocardial injury and infarction can be challenging but is important because it predicts short, medium and long-term mortality [8, 9].

The universal definition of myocardial infarction defines procedural (type 5) myocardial infarction as a > 10-fold elevation above the 99th centile of cardiac troponin within 48 h of CABG surgery accompanied by new pathological Q waves or left bundle branch block, angiographically documented new graft or new native coronary artery occlusion, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality [10]. Elevation of plasma cardiac troponin concentration is required but in the absence of these other clinical features, is insufficient to make the diagnosis of type 5 myocardial infarction.

The latest generation of high-sensitivity cardiac troponin I (cTnI) assays have been widely adopted since the introduction of the third universal definition of myocardial infarction. Our group has contributed to work demonstrating the ability of these assays to define normal plasma concentrations in healthy populations and to identify at-risk patients presenting with chest pain and very small elevations in cTnI concentration that would pass undetected by older contemporary assays [11]. This increased sensitivity may have consequences for the identification and diagnosis of myocardial infarction in patients undergoing CABG surgery.

Using a comprehensive panel of blood and imaging biomarkers, we here explored the relationship between perioperative myocardial inflammation, injury and infarction in order to characterise and to diagnose type 5 myocardial infarction with high-sensitivity cTnI assays.

The Elafin Myocardial Protection from Ischemia Reperfusion (EMPIRE, ISRCTN 82061264) randomized controlled clinical trial investigated the effect of Elafin, a neutrophil elastase inhibitor, on myocardial injury during on-pump CABG surgery [12]. This single centre clinical trial was performed with the approval of the national research ethics committee (11/MRE00/5), in accordance with the Declaration of Helsinki (2000), under a Clinical Trial Authorization (27,586/0015/001–0001) from the Medicine and Healthcare products Regulatory Authority (MHRA, United Kingdom), and the written informed consent of all participants. The authors had no conflicts on interests.

Baseline characteristics have been reported according to treatment group previously [12]. Consecutive patients were assessed for eligibility and 53% consented to participate (Fig. 1 and Table 1). Pre-existing (previously unidentified) myocardial infarction was common with 27% (21/79 who underwent pre-surgery MRI) of patients having pre-operative LGE. Two patients died in the early post-operative period from graft failure and cardiac arrest and a further 6 patients were diagnosed with a myocardial infarction by the clinical team based on ECG changes and troponin release giving a total of 8 (9%) patients who were clinically diagnosed with type 5 myocardial infarction. Unrecognised type 5 myocardial infarction was identified in a further 10 patients (total of 18; 21%) with new LGE on CMR.

Overall 25.3% of patients required intra-aortic balloon pump counterpulsation, inotropes or vasoactive support in the first 48 h, 33% required red cell transfusion, and 31% developed atrial fibrillation prior to discharge (Table 2).

We believe this is the first in depth and detailed investigation of high-sensitivity cardiac troponin release and perioperative myocardial inflammation, injury and infarction in patients undergoing CABG surgery. This study was performed on a highly characterised and phenotyped population using the current gold standard techniques to detect myocardial inflammation, injury and infarction [11]. We have demonstrated that patients undergoing CABG surgery invariably have plasma hs-cTnI concentrations >10-fold the 99th centile that is not attributable to inflammatory or ischemic injury alone. Peri-operative type 5 myocardial infarction is often unrecognised and is associated with a delayed 24-h peak in plasma hs-cTnI concentrations.

Using the latest generation high-sensitivity assay, we have shown that cTnI release is >10-fold the upper limit of normal (99th centile) in all patients following CABG surgery. Importantly, we describe two patterns of release with an early 6-h peak and a more delayed 24-h peak. We suggest these peaks reflect perioperative myocardial injury and infarction respectively as demonstrated by late gadolinium enhancement on cardiac magnetic resonance imaging. There appears to be no single discriminatory threshold for troponin concentration that could reliably discriminate clinically overt myocardial infarction. Our data indicate that the profile, rather than peak, of troponin release may be more important when attempting to distinguish between myocardial injury and type 5 myocardial infarction.

All patients in our study exhibited at least 50-fold rise from baseline troponin and all but 4 had at least 100-fold increase. Many factors contribute to myocardial injury in the perioperative period including manipulation of the heart during on-pump surgery, cardioplegia, ischemia and patients specific factors including severity of underlying coronary artery disease and myocardial function. The average increase in cTnI concentration from baseline was nearly 2000. The third universal definition for type 5 myocardial infarction occurring during CABG surgery stipulates a cardiac marker elevation of ≥10-fold the upper limit of normal (99th centile). In our study, all patients undergoing on-pump surgery fulfil this criterion and this threshold is therefore unhelpful and has no value. This leads to the questions of whether a higher single threshold should be employed or whether alternative criteria looking at the profile of cTnI release may be more discriminatory.

Our data would not support the approach of increasing the troponin threshold to be more discriminatory. For example, increasing the threshold to >100-fold 99th centile would have excluded 64% of patients with LGE proven macro-infarction and included 43% of patients without. Our data support the findings by other groups that multiple time-point sampling to detect a late rise in troponin concentration is more discriminatory for type 5 myocardial infarction [18‐20]. Selvanayagam et al. demonstrated a late peak in troponin levels in patients with new LGE compared to those without (20.3 ± 11.9 versus 11.3 ± 11.0 h) [18]. Both Pegg et al. and Lim et al. demonstrated that subjects with new LGE showed a trend for continuous increase of troponin up to 24 h whereas those without new LGE showed peaks at 6 to 12 h [19, 20]. We have here found two distinct cTnI concentration peaks at 6 and 24 h. Patients with ECG or LGE evidence of infarction were much more likely to have a peak cTnI at 24 h compared to those without. In our study, an ECG demonstrating infarction was highly specific (98%) for detecting the formation of LGE. However both ECG and cTnI profile in isolation had relatively low sensitivity for such detection. This may be because greater volume of infarction must occur in order to cause a change in the electrical or biochemical profile. We suggest that the most effective and practical method for diagnosing type 5 myocardial infarction involves cTnI testing at 6 and 24 h combined with ECG evidence of infarction. Additional use of CMR is not practical nor cost effective in the clinical setting. However, patients with a late rise in cTnI could be targeted for additional diagnostic testing such as echocardiographic imaging or angiography. Such patients may also benefit from additional anti-platelet treatment, but further studies would be required for validation.

A previous study reported new LGE in up to 78% of patients undergoing CABG surgery, but the investigators did not perform pre-operative CMR [21]. We identified LGE in 27% of pre-operative MRI scans in patients with no prior clinical history of myocardial infarction suggesting the presence of sub-clinical infarction is common even in stable patients. Consistent with our work, Pegg and colleagues also reported new LGE from preoperative scans in 8/40 (20%) of patients participating in a study of a novel hybrid method of on-pump beating heart CABG surgery [19].

Although it might have been anticipated that the magnitude of myocardial injury would correlate with CPB time, there was no association with AUC cTnI release. Furthermore there was no correlation with inflammatory cytokine release or myocardial inflammation. This suggests that injury is not mediated by inflammation alone. Other processes influence the cTnI injury such as microemboli, surgical manipulation of the heart and patient specific factors. Our data also confirm that substantial cTnI release occurs in the perioperative period without imaging evidence of infarction and new scar formation consistent with reversible myocardial injury.

We used USPIO contrast for the first time to assess in vivo myocardial inflammation following CABG surgery, similar to macrophage infiltration in patients with type 1 myocardial infarction [15]. The average pan-myocardial USPIO uptake was higher than that of healthy myocardium from controls. However it would be expected that inflammation would not be uniform throughout the heart given variation in the distribution and severity of coronary disease and surgical factors. Using the average USPIO uptake in the three segments with the highest uptake, we identified a 2-fold increase compared to the pan-myocardial values. Macrophage recruitment into the myocardium correlated weakly with hsCRP suggesting that humoral and cellular inflammation are co-ordinated. However there was no correlation with hs-cTnI or CPB time indicating that the magnitude of myocardial inflammation was not dependent on degree of myocardial injury or ischemia time. The determinants and the sequelae of higher levels of cellular inflammation post-CABG surgery require further study.

Our study has some limitations. This was a sub-analysis of the EMPIRE study [12]. In this trial, there was no demonstrable effect from the intervention (the neutrophil elastase inhibitor, elafin) on a range of clinical and surrogate outcome measures. However we cannot exclude the possibility of a weak effect on the current outcome measures. Some patients had difficulty lying flat and breath-holding in the MRI scanner for post-operative scans. This sometimes resulted in reduced scan quality. Since the USPIO-enhanced scans were carried out at later time points (5 to 14 days post-surgery), this may have hindered our ability to identify some of the correlations with our early (first 48 h) biomarker assessments.

All patients undergoing CABG surgery demonstrate >10-fold elevation above the 99th centile of cardiac troponin indicating the current universal definition of type 5 myocardial infarction lacks specificity. Differing levels of myocardial inflammation post CABG surgery occurred, and did not correlate directly with the length of CPB, hs-cTnI release or circulating cytokines. A peak hs-cTnI at 6 h following CABG appears to be related to the surgical process and non-specific myocardial injury whilst a continuing increase at 24 h suggesting myocardial infarction. We would suggest cTnI sampling at 6 and 24 h post CABG surgery together with ECG assessment for the routine detection and diagnosis of type 5 myocardial infarction.