Abnormal elevation of myocardial necrosis biomarkers after coronary artery bypass grafting without established myocardial infarction assessed by cardiac magnetic resonance

Myocardial necrosis biomarkers are frequently elevated after cardiac revascularization procedures. However, the diagnosis of acute myocardial infarction (MI) after a revascularization procedure is still a controversial issue. This inability to diagnose MI makes it more difficult to establish a specific therapeutic strategy. With the appearance of high-sensitivity troponins, a myriad of false-positive diagnoses for myocardial infarction have emerged. In 2000 and 2007 in an attempt to standardize the criteria for diagnosing MI, the European Society of Cardiology, the American College of Cardiology, the American Heart Association, and the World Heart Federation formed a joint task force to address this issue, but the task force was unable to make a satisfactory decision. Therefore, the problem still remained. To reduce diagnostic mistakes, in 2012, this same group arbitrarily raised the cutoff point to 10 times the 99th percentile, but with no solid scientific basis for doing so [1]. Troponin (cTnI) and the creatine kinase isoform (CK-MB) do not reflect, alone, the occurrence of MI related to occlusion of the graft or native artery or varying degrees of myocardial injury. Release of myocardial necrosis markers may be related to incomplete myocardial protection; reperfusion injury; a systemic inflammatory state, including inevitable postsurgical trauma; the handling of intramyocardial vessels; and cardiac defibrillator use [2, 3]. Cardiac troponin may also be increased when nonsurgical damage is present, such as sepsis and thromboembolic phenomena [1]. cTnIs have also been found elevated in athletes after marathons [4]. This makes the identification of small areas of injury very difficult to assess in clinical practice [5].

Parallel to the increased sensitivity of troponin assays, imaging methods have achieved better accuracy for exclusion of the diagnosis of myocardial infarction. Thus, due to the limitations on the interpretation of biomarkers after coronary artery bypass grafting (CABG) and the difficulty of excluding MI, cardiac magnetic resonance imaging (CMR) has enabled a more detailed evaluation of the myocardium.

Therefore, in this study, we aimed to examine the release of biomarkers after CABG in patients with no evidence of late enhancement on CMR.

Details of the study design, protocol, patient selection, and inclusion criteria have been previously reported [6]. Briefly, patients with preserved left ventricular function and angiographic coronary artery stenosis of more than 70% confirmed by a visually reviewed document, and with multiple-vessel involvement, and documented ischemia were included. Stress testing or evaluation of stable angina according to the Canadian Cardiovascular Society guidelines (Class II or III) established the presence of ischemia. All patients were candidates for on-pump coronary artery bypass grafting (ONCAB). Patients were excluded if they had undergone any previous mechanical interventions, and had experienced recent thromboembolic events, systemic inflammatory disease, or kidney failure.

Between March 2012 and April 2014, 326 consecutive patients who met the inclusion criteria were screened. Of these patients, 107 (32.8%) were excluded (Fig. 1). Of the 219 remaining patients, 148 were referred for CABG (75 ONCAB and 73 OPCAB [off-pump coronary artery bypass]), and 71 patients were referred for PCI (percutaneous coronary intervention). Of the 75 ONCAB patients enrolled in this study, 21 were excluded and 54 completed the study protocol. These 54 patients had no evidence of MI on CMR assessed by LGE. The main reasons for exclusion of the patients are presented in Fig. 1.

The clinical, demographic, and angiographic characteristics are summarized in Table 1. The mean age was 61.3 (± 8.3) years, and 39 (72.2%) were male. In addition, 24 (44.4%) patients had a diagnosis of type 2 diabetes mellitus and 13 (24.1%) had a history of myocardial infarction. Regarding smoking, 18 patients (33.34%) stopped smoking during the inclusion period of the study. The angiographic screening showed that 17 (31.5%) patients had stenosis of the left main coronary artery, 43 (80%) had obstructive lesions in 3 epicardial branches, and 11 (20.4%) had a concomitant bi-arterial obstructive pattern. Additionally, the mean SYNTAX Score was 28. Anginal symptoms were present in 47 (87%) patients, and 15 (27.8%) had grade III angina, according to the Canadian Cardiovascular Society (CCS) scale. Left ventricular ejection fraction was assessed by CRM performed before the procedure and averaged 66 ± 8.6 (Table1).

In this prospective trial based on current guidelines, we found distinct results when cTnI and CK-MB were simultaneously analyzed in patients after surgical myocardial procedures. All patients had elevated cTnI above the 99th percentile after surgery, with the majority having more than 10 times, reaching an average of 70 times this threshold. Conversely, we found the release of CK-MB predominantly below the recommended threshold of 10 times the 99th percentile. Therefore, our findings conflict with the recommendations of the 2012 European Society of Cardiology/American College of Cardiology/American Heart Association/World Heart Foundation Joint Task Force for the diagnosis of myocardial infarction after surgical revascularization.

In this scenario, the EKG remained similar before and after interventions independently of the release of biomarkers. In addition, CMR likewise remained unchanged, without a new delayed enhancement after the procedure.

Over the last decade, elective CABG has progressed to a very standardized and safe surgical procedure with low mortality and low rates of myocardial events [14]. Thus, the present study focused on the possible reasons why our patients, after ONCAB, had elevated troponin above MI levels without the appearance of late enhancement in cardiac magnetic resonance imaging. As we know, perioperative elevation of specific cardiac biomarkers may be due to MI, but may also be associated with routine cardiac surgical procedures.

A study aimed at identifying the release of biomarkers following myocardial revascularization conducted by Pegg et al. [15] identified excessive troponin release in the absence of late enhancement by CMR. On the other hand, they noted that CK-MB behaved as foreseen by the current guideline. Thus, their results confirm the findings of the present study. Likewise, Van Gaal et al. [16], in a study comparing cTnI elevation and appearance of new late enhancement in CMR after CABG, found late enhancement in 28.1% of their patients. However, troponin elevation was found in 100% of patients based on the definition of myocardial infarction by the third Task Force [1]. Similar results were observed by Fellahi et al. [17] who, in an accurate analysis, found 14% troponin elevation in the absence of late enhancement. This lower percentage of discordance was probably due to the use of less-sensitive troponin assays. Wang et al. [18] applying EKG and echocardiography as the gold standard to detect AMI after CABG identified 21% of patients with new regional changes in wall motion on echocardiography without the corresponding change on EKG. The echocardiographic findings were consistent with the Troponin Task Force definition. Conversely, EKG data from our study were consistent with CK-MB release and discordant with troponin release.

The evident release of cTnI in the absence of myocardial necrosis is still questioned in the literature. As a confounding factor, advances in cTnI accuracy after high-sensitivity cTnI onset have been recently observed [18]. It can be postulated that this increase in sensitivity may be related to the power to detect changes in myocyte membrane permeability, which may result from non-physiological intraoperative events, contributing to the increase of cTnI plasma levels in the cytosol even in the absence of necrotic damage (Type 5 troponin elevation) [11, 19]. Therefore, a possible deleterious effect of extracorporeal circulation may contribute to the occurrence of discrete and “diffuse” myocardial damage. This damage can compromise subcellular structures that are difficult to identify, evidencing a clear limitation of CMR analysis.

With the emergence of high-sensitivity troponins, the relationship between the increase in the sensitivity thereof and the increasing rise in false diagnoses has already been described [2]. Currently, there is extensive discussion among manufacturers about the heterogeneity of their troponin kits and the influence of laboratory practices on the use of these kits. The multiplicity of troponin kits, each having different reference values, which use different reagents, different epitopes to bind antibodies, and different incubation times, leads to great difficulty in finding uniformity in the acquired information and studies [20‐22]. Unlike that observed with CK-MB, the lack of standardization for calibration of the different tests for assessment of cTnI precludes the establishment of a universal threshold cutoff for the 99th percentile [20].

In this study, different from CK-MB findings, troponin was significantly increased in the absence of myocardial infarction on cardiac resonance imaging. Thus, CK-MB was more accurate than cTnI for excluding procedure-related MI. These data suggest a higher troponin cutoff for the diagnosis of CABG-related MI.