Diagnostic dilemma of perioperative myocardial infarction after coronary artery bypass grafting: A review

Abstract

Coronary artery bypass grafting (CABG) is one of the most commonly performed cardiac procedures in the United States (US) and Europe. In the US, perioperative morbidity and mortality related to CABG are below 5%. One of the most significant complications following CABG, however, is perioperative myocardial infarction (PMI). Cardiac biomarkers, intra- and post-operative echocardiography, and electrocardiography are routinely used to monitor for evidence of PMI. In this review, we seek to summarize how each of these modalities is used in the clinical setting to differentiate PMI from expected procedure-related changes, and how these findings impact patients’ outcomes. We conclude that while no perfect diagnostic test for the detection of clinically meaningful PMI exists, using a combination of existing modalities with knowledge of expected post-procedure changes allows for early and reliable detection. Future development is needed to create more sensitive and specific modalities for the detection of PMI in patients undergoing CABG.

1. Introduction

Coronary artery bypass grafting (CABG) remains one of the most commonly performed cardiac operations in the United States and Europe. In an analysis of the Society of Thoracic Surgeons database, isolated CABG accounted for 55% of total cases in the United States in 2017 [1]. Through decades of innovation and refinement, CABG has become one of the safest cardiac procedures performed with a reported in-hospital mortality in all-comers of around 1.8% [1]. Despite this excellent safety profile, postoperative changes concerning for ischemia, including perioperative myocardial infarction (PMI), remain a significant concern. Depending on the definition used, the incidence of PMI ranges from 5 to 30% [2]. Published in 2018, the Fourth Universal Definition of Myocardial Infarction remains the accepted standard in contemporary practice (Table 1) [3]. The primary challenge remains differentiating expected post-operative changes that mimic ischemia in patients following CABG from acute PMI.

Table 1:

Criteria for Myocardial Infarction Type 5 ≤48h after coronary artery bypass grafting. cTn cardiac troponin, URL upper reference limit

Fourth Universal Definition of Myocardial Infarction Type 5
Elevation of cTn as main criteria:
• Patients with normal pre-procedure cTn: Elevation of cTn >10 times the 99th percentile URL
• OR Patients with elevated baseline cTn and stable or falling cTn: Rise of the post-prodecure cTn by >20% with absolute value of >10 times the 99th percentile URL
Additionally at least one of the following criteria:
• Occurrence of new pathological Q waves
• Imaging evidence of an ischemic incidence detected by loss of viable myocardium or new regional wall motion abnormality
• New graft occlusion or new native coronary artery occlusion documented by angiography
Further meeting the criteria for MI Type 5:
• Isolated new pathological Q waves accompanied by rising cTn values, but <10 times the 99th percentile URL

Myocardial injury following CABG can be seen in up to a quarter of patients and the mechanisms of injury are diverse [4]. In the postoperative setting, cardiac enzyme assays, echocardiography, and electrocardiography are routinely used to monitor for these acute ischemic events, and to differentiate them from expected procedure-related changes. Where normal postoperative changes end and clinically significant events begin, remains uncertain. Direct intraoperative manipulation of the heart, for example, can lead to subclinical injury through microembolization with downstream microinfarcts [5,6]. Further injury can be caused by suboptimal myocardial protection and inadequate cardioplegic perfusion [7].

In this review, we summarize the current evidence regarding detection of common procedure-related injuries and deviations. We seek to inform on how these changes manifest as measured by cardiac enzyme release, echocardiography, and electrocardiography (ECG), with these being the primary diagnostic methods recommended by the current guidelines for patients undergoing CABG (Table 2) [8]. We then set out to discuss the clinical significance of these changes as they apply to patient outcomes.

Table 2:

Current US guidelines on the use of postoperative echocardiography, electrocardiography, and enzyme assays following cardiac surgery. CK-MB creatine kinase myocardial band, CABG coronary artery bypass grafting, TEE transesophageal echocardiogram

Criteria	Class of Recommendation	Level of evidence	Guideline
Enzymes	IIa	B	Measurement of biomarkers of myonecrosis (e.g. CK-MB, troponin) is reasonable in the first 24h after CABG.
ECG	I	B	Continuous monitoring of the electrocardiogram for arrhythmias should be performed for at least 48 hours in all patients after CABG.
	IIa	B	Continuous ST-segment monitoring for detection of ischemia is reasonable in the intraoperative period for patients undergoing CABG.
	IIb	B	Continuous ST-segment monitoring for detection of ischemia is reasonable in the intraoperative period for patients undergoing CABG.
Echo	I	B	Intraoperative TEE should be performed for evaluation of acute, persistent, and life-threatening hemodynamic disturbances that have not responded to treatment.
	I	B	Intraoperative TEE should be performed in patients undergoing concomitant valvular surgery.
	I	C	A fellowship-trained cardiac anesthesiologist (or experienced board-certified practitioner) credentialed in the use of perioperative TEE is recommended to provide or supervise anesthetic care of patients who are considered to be at high risk.
	IIa	B	Intraoperative TEE is reasonable for monitoring of hemodynamic status, ventricular function, regional wall motion, and valvular function in patients undergoing CABG.

2. Cardiac biomarkers for the detection of myocardial injury

It has been shown that uncomplicated CABG is associated with a postoperative change in cardiac biomarkers. In 1985, Graeber and others demonstrated that direct trauma through surgical manipulation is associated with an increase in the release of creatine kinase myocardial band (CK-MB) [9]. Other series have demonstrated similar elevations in CK-MB and troponin T (TnT) as a result of cardiopulmonary bypass and aortic cross-clamping [10]. In fact, the Fourth Universal Definition of Myocardial Infarction states that in all patients undergoing CABG, a procedure-related elevation of cardiac troponin should be expected, and thus enzyme release alone cannot be used as a marker for PMI [3].

In general, enzyme elevation observed following CABG is considered to be of less clinical significance when compared to patients who present with acute myocardial ischemia unrelated to cardiac surgery [11]. Utilizing contrast-enhanced magnetic resonance imaging (MRI), several studies have shown that these expected small enzymatic changes after CABG are not associated with imaging evidence of myocardial ischemia [12,13].

The amount of enzymatic release, however, may influence outcomes. In a large meta-analysis of 18,908 patients, Domanski et al. showed that the 30-day mortality is doubled in patients with a CK-MB level of 4–5 times the upper limit of normal (ULN) when compared to patients showing a CK-MB level of 1 time the ULN or less within 24 hours of surgery [14]. Similar trends were seen with troponin elevation. Other series have demonstrated a similar graded relationship between enzymatic release and mortality [15–19].

There is still no consensus, however, on the preferred biomarker and threshold to discriminate between insignificant injury and an event of clinical or prognostic significance. Currently the Fourth Universal Definition uses TnT or Troponin I (TnI) as the cardiac biomarkers of choice. CK-MB is recommended only when a troponin assay is unavailable. [3] The cut-offs used in the published studies vary substantially (Table 3).

Table 3:

Major studies suggesting cut-off between enzyme elevation with and without increased mortality or combined outcomes. CK-MB creatine kinase myocardial band, ULN Upper Limit of Normal, TnT Troponin T, TnI Troponin I, MACE major adverse cardiovascular event

Author, year	Journal	Study design	No. of patients	Enzymes investigated	Cut-off	Outcomes
Petäjä, 2009 [21]	The Annals of Thoracic Surgery	Meta-Analysis	29,483 21,657 (CK-MB)	1) CK-MB 2) Troponin	1) ≥ 5–8×ULN 2) no threshold suggested for troponin	40-month mortality
Klatte, 2001 [16]	Journal of the American College of Cardiology	Prospective	2,349	CK-MB	5–10× ULN	6-month mortality
Costa, 2001 [17]	Circulation	Retrospective	496	CK-MB	>5× ULN	30-day mortality
Brener, 2002 [18]	Journal of the American College of Cardiology	Retrospective	3,812	CK-MB	>10× ULN	3-year mortality
Marso, 2003 [19]	European Heart Journal	Post-hoc analysis	3,667	CK-MB	≥ 4× ULN	5-year mortality
Steuer, 2002 [60]	European Heart Journal	Prospective	4,911	CK-MB	61 μg/L	5-year mortality
Januzzi, 2002 [61]	Journal of the American College of Cardiology	Prospective	224	TnT	≥1.58 ng/mL	In-hospital death or cardiogenic shock
Muehlschlaegel, 2009 [62]	European Heart Journal	Prospective	1,013	1) TnI 2) TnT 3) CK-MB	1) 6.9 μg/L 2) 3.3 μg/L 3) no threshold suggested	5-year mortality
Mohammed, 2009 [63]	Circulation	Prospective	847	TnT	≥1.60 ng/mL	30-days composite outcome of death, heart failure, need for vasopressor
Engoren, 2005 [64]	European Journal of Cardio-Thoracic Surgery	Retrospective	1,161	CK-MB	>40 ng/mL	1-year mortality
Newall, 2006 [65]	Journal of Cardiothoracic Surgery	Observational, prospective	2,860	CK-MB	≥3× ULN	1-year mortality
Ramsay, 2005 [15]	The Journal of Thoracic and Cardiovascular Surgery	Prospective, randomized	800	CK-MB	>20× ULN	Combined outcome of severe postoperative left ventricular dysfunction and mortality within 30 days
Farooq, 2013 [66]	International Journal of Cardiology	Retrospective	474	CK-MB	≥3× ULN	4-year mortality
Nesher, 2008 [67]	The Annals of Thoracic Surgery	Retrospective	1,918	TnT	≥ 0.8 μg/L	In-hospital MACE (death, PMI, low-output syndrome)
Eigel, 2001 [68]	European Journal of Cardio-Thoracic Surgery	Prospective	540	TnI	>0.495 ng/L	Myocardial infarction and/or death peri-/ postoperatively
Onorati, 2005 [57]	The Annals of Thoracic Surgery	Prospective	776	TnI	>3.1 μg/L	In-hospital and 1-year mortality
Fellahi 2003 [69]	Anesthesiology	Prospective	202	TnI	≥13 ng/mL	2-year mortality
Kathiresan, 2004 [70]	The American Journal of Cardiology	Prospective	136	1) TnT 2) CK-MB	1) ≥1.58 ng/mL 2) no threshold suggested	1-year mortality

The level at which enzyme release becomes clinically meaningful is difficult to characterize. In a pooled analysis of four major trials including 4,401 patients, short-term mortality was only influenced by a CK-MB level of 10 times above the ULN [20]. This is in contrast to the results of a systematic review of biomarkers after CABG, in which 23 studies and 29,483 patients were included. These authors demonstrated that the elevation of CK-MB over 5 times the ULN has a prognostic impact on the risk of long-term mortality [21].

Some authors have attempted to determine the appropriate enzyme cut-off by correlating them with angiographic findings. Holmvang et al. investigated elevation of biochemical markers and compared them with angiographic findings following CABG. In this series, protocol-driven repeat angiography was performed in 108 patients prior to discharge, regardless of clinical symptoms or ECG changes. Patients with uneventful CABG had median enzyme elevations of 25 μg/L for CK-MB, 6.9 μg/L for TnI, and 0.9 μg/L for TnT [22]. In another prospective study that used angiography to confirm PMI following CABG, Thielmann and colleagues suggest that a TnI cut-off 10.5 ng/mL is able to discriminate between patients with and without PMI or acute graft failure [23]. Finally, in a meta-analysis performed by Biancari and others, control angiography performed in the setting of potential PMI was negative in 31.7% of patients (n=39,266 patients across 9 studies) [24].

While most existing studies compare maximum peaks of enzyme elevation after CABG [21], more recent studies have investigated the temporal relationship of enzyme release. Alam et al. found that while there were two peaks of TnI after 6 and 24 hours, only the 24-hour peak appears to be associated with PMI diagnosed by ECG and contrast-enhanced cardiovascular MRI. The authors suggest that the first peak is likely a consequence of non-specific injury to the myocardial tissue [25]. Similar studies have confirmed these findings [13,26,27].

Most recently, investigators have started to examine new biomarkers for early detection of PMI, as well as for distinguishing between different etiologies of myocardial injury. Several series exist investigating biomarkers such as heart-type fatty acid binding protein (hFABP), myoglobin, copeptin, cardiac-myosin-binding protein and microRNAs [2]. HFABP, in particular, seems to be promising. It rises earlier than Troponin and CK-MB, so myocardial injury can be detected rapidly in the early postoperative phase [28–30]. Jo et al. evaluated the ability of hFABP to discriminate between PMI versus myocardial manipulation during cardiac surgery. The authors compared patients undergoing either CABG, valve surgery, or closure of a septal defect, and found significantly larger amounts of CK-MB and TnT in valve surgery than in CABG, but similar amounts of hFABP in both procedures, concluding that hFABP might be more predictive for ischemia than TnT and CK-MB [31]. Further investigations are needed prior to widespread adoption of hFABP.

3. The use of echocardiography to detect perioperative CABG-related changes

Echocardiography is the most commonly used imaging modality after CABG and critical for the early detection of myocardial injury. Nonetheless, the imaging quality of transthoracic echocardiography in the early postoperative phase is limited by ventilation, inflammation and pleural or pericardial effusions and therefore transesophageal echocardiography (TEE) should be the preferred method. [2]

Though it is not mandated by current guidelines [32], a multi-national survey demonstrated that 60–70% of anesthesiologists use intraoperative TEE for CABG cases, and any co-existing significant valvular disease, decreased ejection fraction, or high-risk patient increases the risk-benefit profile [33].

After uncomplicated CABG, post cardiopulmonary bypass improvement of wall motion can be expected to be seen immediately following reperfusion of heart [34]. Swaminathan et al. studied 1,412 patients undergoing CABG and examined the relationship between 16-segment wall-motion score (WMS) calculated from post-procedural echo and clinical outcomes at 2-year follow-up. The authors found that post cardiopulmonary bypass WMS did not change in 812 patients (58%), worsened in 219 patients (16%), and improved in 368 patients (26%). Kaplan-Meier analysis showed that patients with worsened WMS after CABG experienced significantly lower cardiac event-free survival when compared with patients with either no change or improvement in WMS (P= 0.004). Cox proportional hazards regression modeling revealed a significant association between deterioration in WMS and major adverse cardiac events (hazard ratio= 1.47, 95% confidence interval=1.06–2.03; P= 0.02) [35].

A prospective study of 633 patients undergoing CABG compared intraoperative TEE with ECG in the detection of myocardial infarction. The authors found that TEE was more than twice as sensitive at identifying patients with myocardial infarction compared with ECG and a multivariable model, which included patient characteristics and ischemia, revealed that only the presence of wall-motion abnormality detected by TEE was an independent predictor of myocardial infarction (odds ratio= 2.35; 95% confidence interval= 1.30–4.20) [36].

Though sensitive, wall motion changes are not specific for PMI. Persistent wall motion changes may be due to ongoing ischemia or myocardial stunning after cardiopulmonary bypass [37]. In a retrospective study of 5,998 patients, 39 presented with signs of early graft failure and underwent angiography. In these patients, new intraoperative wall motion abnormalities predicted graft failure confirmed by angiography, such as occlusion, kinking, and incomplete revascularization, with a low sensitivity of 15.6%, a specificity of 57.1%, and positive and negative predictive values of 62.5% and 12.9%, respectively [38].

Additionally, there are regional wall motion changes that are commonplace after CABG and cardiac surgery in general and may not be indicative of ischemia. An example is the presence of abnormal or decreased septal motion observed frequently on echocardiography in post-CABG patients. This can be attributed to changes in the geometry of the septum after pericardiotomy, myocardial stunning, increased right ventricular pressure or volume, pacing, and new intraventricular conduction delay, all of which may be temporary and benign [39].

Reduced right ventricular (RV) function in patients undergoing CABG is another common echocardiographic finding [40,41] accompanied with either unchanged or improved left ventricular function [42]. RV dysfunction can be due to many factors after CABG such as poor myocardial protection, air embolism, graft failure, ventilatory problems, acute respiratory distress syndrome, and volume overload [41] and is not specific for ischemia. Prior studies have demonstrated that regional changes in the free wall and septum of the RV after cardiac surgery may be due to geometric rather than functional changes secondary to the pericardiotomy in cardiac surgery and can occur without a change of systolic function [40,43,44].

RV dysfunction has been associated with worse outcomes after CABG when accompanied by hemodynamic deterioration [45]. It is important to note, however, that isolated findings of RV dysfunction without hemodynamic changes may be benign. Also, there are known limitations to RV quantification by intraoperative two-dimensional (2D) TEE. 2D linear indices commonly used to assess RV function, such as tricuspid annular plane systolic excursion (TAPSE) and tissue doppler peak systolic annular velocity (S’), which evaluate the function of the RV free wall, may be limited in the evaluation of global RV function. Therefore, more advanced modalities such as three-dimensional (3D) echo and 2D-speckle tracking echocardiography (2D-STE) may be preferred to comprehensively assess RV function peri-procedurally after CABG [40,41,46] (Figure 1). Investigators have described a significantly reduced TAPSE and free wall strain after CABG post-operatively with 2D echocardiography with preserved ejection fraction seen on RV ejection fraction from 3D echocardiography, occurring despite successful revascularization of the right coronary artery [46,47]. It remains to be seen if these novel parameters will be prognostically significant.

Figure 1:

Advanced modalities for intraoperative evaluation of right ventricular function (A): Two-dimensional speckle tracking echocardiography (2D-STE); (B): Three-dimensional (3D) echocardiography. EDA end-diastolic area, ESA end-systolic area, FAC fractional area change, GLS global longitudinal strain, EDV end-diastolic volume, ESV end-systolic volume, EF Ejection Fraction

In summary, TEE is a powerful tool to assess ischemia during CABG, and regional wall motion changes in the left and right ventricle have been shown to affect clinical outcomes. However, some changes may also be benign, although these should be a diagnosis of exclusion. Furthermore, the clinical picture is important and echocardiographic interpretation and duration of findings should be corroborated with the hemodynamic scenario. Considerations such as checking the graft anastomosis, increasing the mean arterial pressure to optimize myocardial oxygen delivery, or adding vasopressor and/or inotropic support should be taken when echocardiographic changes persist, worsen, or are accompanied by hemodynamic instability.

4. Electrocardiographic changes

Due to its low cost and wide availability, ECG is one of the most commonly used diagnostic modalities in the post-operative setting. There are a number of rhythm disturbances that can be observed following CABG including right bundle branch block (RBBB), left bundle branch block (LBBB), atrioventricular block, ST-segment elevation or depression, T-wave changes, and new Q waves. While some of these changes are of clinical significance and can impact long-term survival following surgical revascularization, most are transient and benign.

With a reported incidence ranging between 3.4% and 55.8%, conduction disturbances following CABG are relatively common. The most frequent abnormalities are RBBB and LBBB. Other than ischemia, one of the main reasons behind conduction disturbances is insufficient myocardial protection [48]. Recent improvements in cardioplegic techniques, however, have led to a significant decrease in the manifestation of conduction defects on ECG [49]. In addition to the type of cardioplegia used, direct trauma to the myocardium has been shown to increase the incidence of conduction defects [48].

In a 2006 meta-analysis of five studies investigating the impact of various postoperative conduction disturbances including RBBB, LBBB, and atrioventricular block in CABG patients, Kumbhani and others found no difference in long-term survival when compared with patients without conduction abnormalities on routine ECG (relative risk [RR]= 1.35, 95% CI= 0.85–2.01, p=0.23) [48]. In a separate large retrospective series including 2000 patients, the authors found no significant difference in 5 year cardiac survival between patients with RBBB or LBBB when compared with a matched cohort without conduction disturbances [50]. In order to investigate the significance of conduction disturbances for the detection of myocardial ischemia, Seitelberger et al. compared the occurrence of RBBB with CK-MB levels. The authors found higher CK-MB levels in patients with new RBBB on postoperative ECG when compared with matched controls (22.7±3.2 vs. 13.4±0.8, P<0.01), but lower than those with ECG signs of PMI (33.4±7.6 vs. 22.7±3.2, P<0.05) [51]. They concluded that RBBB could be indicative for ischemia. This conclusion, however, is limited by the lack of specificity of CK-MB in the detection of myocardial ischemia.

Unlike bundle branch, new Q waves are usually clinically significant, and have a known impact on patient outcomes. In fact, new Q waves remains one of the defining characteristics for PMI when appearing together with the release of myocardial necrosis biomarkers [3]. In an analysis of the Coronary Artery Surgery Study, Chaitman and others found that new Q waves on ECG were independently associated with increased in-hospital mortality [52]. Similarly, a post-hoc analysis of the Bypass Angioplasty Revascularization Investigation (BARI) trial found that cardiac-related mortality was highest in patients with new Q wave abnormalities on the initial post-operative ECG [53].

What is less clear, is the independent prognostic significance of new Q waves in absence of biomarkers. Crescendi et al. showed a significant impact on patient outcomes when Q waves manifested on ECG in combination with cardiac biomarker release. In the absence of biomarker release, however, Q waves alone were not related to adverse cardiac outcomes [54]. In a more contemporary cohort study of 1,464 patients undergoing cardiac surgery, Mauermann et al. analyzed Q waves according to their location and found that Q waves per se were not associated with increased all-cause mortality and cardiac events. Only for new Q waves in anterior locations they found a highly significant association with postoperative outcome. These results held true in a subgroup analysis of isolated CABG patients [55].

In non-surgical patients, ST-segment elevations are an important indicator for a major ischemic event and of prognostic importance. After CABG, however, they can be observed in the setting of pericardial injury, such as pericarditis or a nonspecific inflammatory reaction secondary to cardiac trauma [56]. Loeb et al. assessed the frequency and clinical importance of new ST-elevations in patients without other evidence of acute PMI and found an incidence of 12.6% early after CABG. These non-ischemic postoperative ST-elevations had no prognostic significance for hospital stay and 30-day mortality compared to patients without ST-elevation [56]. In the above-mentioned BARI analysis, which included 1427 patients who underwent CABG, new ST-segment elevations were detected in 15.1% of patients and ST-segment depression in 15.4%. The authors found that ST-changes had no correlation with 5-year cardiac mortality.

5. Combining the findings of biomarkers, echocardiography and electrocardiography

When used in isolation, biomarkers, echocardiography, and electrocardiography show poor sensitivity in the detection of PMI. When used in combination, however, these modalities may offer a clearer picture. This is reflected in the Fourth Universal Definition of Myocardial Infarction, where cardiac enzymes need to be accompanied by other diagnostic criteria [3]. As previously shown, Q waves are predictive for ischemic changes in particular if accompanied by enzyme elevation. Onorati et al., in their prospective study, showed that patients with TnI elevation and associated ECG or echocardiographic changes had a lower survival and lower freedom of cardiac events compared to TnI elevation only (38.5 ± 14.8% vs 72.7 ± 15.0%; p = 0.023) [57]. As there is no comprehensive single test available, this seems currently the most promising method to rule out ischemia mimicking signs.

6. Future perspectives

Moving forward new cardiac biomarkers with higher specificity for perioperative ischemia are required. This is especially true for the detection of ischemia in the early postoperative phase (<24 hours). Circulating microRNAs appear promising and their early detection for PMI have been associated with decreased morbidity and mortality [58]. Another potential innovation are peptide biomarkers which have shown excellent sensitivity (90%) and specificity (86%) in the preoperative prediction of PMI and identification of high-risk patients [59]. Further studies should build on these promising opportunities.

7. Conclusion

There are several diagnostic methods currently used for the assessment of myocardial injury after CABG. Cardiac enzyme assays, intra- and post-operative echocardiography and electrocardiography represent the mainstay of modalities used in the differentiation of clinically significant events from expected post-operative findings. For clinical practice it is of importance to know about expected procedure-related changes. The distinction between those and acute coronary artery or graft-related problems is essential for making a decision regarding reintervention. Unfortunately, there is no definite marker to determine the source of injury. As demonstrated in this review, using a combination of biomarker values, echocardiographic signs, and ECG provides the most diagnostically conclusive information. Still several mechanisms of injury are not yet fully understood and further investigation will help to improve optimizing outcomes.