Unwanted silent crosstalk: Troponinemia and surgeons

Abstract

The release of serum cardiac troponins (cTn) following major non-cardiac surgery (MNCS) is associated with significant adverse postoperative outcomes. This phenomenon comprises myocardial injury after non-cardiac surgery (MINS) or perioperative myocardial infarction that may occur regardless of the presence of obstructive coronary artery disease (CAD). However, there is no consensus on its diagnostic criteria or therapeutic guidelines. The 30-day mortality following MNCS is 2%-6% and more than half of these deaths are attributable to the major adverse cardiovascular events (MACEs). Although MINS is an independent predictor of MACEs, it is not the only prognostic tool. The release of cTn may be secondary to perioperative tachycardia, hypotension, anemia, hypoxia, sepsis, inflammation, and profound stress. In the latter, an adrenergic surge, independent of underlying CAD, can cause a noticeable release of cTn. Even low levels of cTn elevation within the first three days after high-risk surgery are correlated with a significant increase in the short- and long-term mortality rates. Therefore, awareness of this phenomenon is of utmost value for better perioperative management and prognostication. The patient, surgery (type, duration, and urgency), and cTn (timing, type, and frequency) should be considered in MINS identification and interpretation. Appropriate management necessitates index of suspicion and multidisciplinary stepwise actions.

Key Words: Troponinemia; Perioperative; Major non-cardiac surgery; Myocardial injury after non-cardiac surgery; Surgery; Mortality; Cardiac biomarker

Core Tip: The Major non-cardiac surgery is associated with a significant risk of perioperative mortality. This adverse outcome relies mainly on the occurrence of myocardial injury in the perioperative settings. Myocardial injury after non-cardiac surgery remains widely unrecognized, partly because there is no universal consensus on its definition and diagnostic criteria. However, a working diagnosis can be established based on an elevated post-operative cardiac troponin level within 30 days of surgery after excluding other non-ischemic causes, regardless of whether the patient has symptoms or electrocardiogram findings. There is growing consensus for proactive surveillance to mitigate the burden of perioperative cardiovascular complications.

INTRODUCTION

The major non-cardiac surgery (MNCS) carries a significant risk of mortality and morbidity[1]. It has been reported that one myocardial infarction (MI) may occur in every 100 surgeries[2]. The MI and ischemic myocardial injury that do not fulfil the universal definition of MI comprise a phenomenon called myocardial injury after non-cardiac surgery (MINS), which occurs in up to 20% of patients undergoing MNCS[2-5]. This minireview aims to highlight the importance of detecting MINS in the surgical setting and to address their pathophysiology, diagnosis, and therapy.

DISCUSSION

Globally, among the 200 million patients who undergo MNCS annually, approximately eight million experience MINS, and one million are projected to die within 30 days, primarily due to major adverse cardiovascular events (MACEs) such as cardiac arrest, congestive heart failure, and stroke[2,3,6]. The 30-day mortality rate following MNCS ranges from 2%-6%, with more than half of these deaths attributable to MACEs[4]. Additionally, most perioperative MIs within one year are linked to high rates of MACEs and all-cause mortality[7,8]. Key determinants of adverse outcomes after MNCS include patient age, comorbidities, physical status, surgical type, and urgency[9]. Some studies have also identified sex differences and blood type as potential risk factors for MINS[10,11].

The characteristics of perioperative conditions that contribute to the occurrence of MINS include several factors such as: A mean arterial pressure < 65 mmHg or low systolic blood pressure (< 90 mmHg) maintained for at least 15 minutes, low blood hemoglobin (< 11 g/dL), high blood sugar (> 180 mg/dL), sympathetic activation, systemic inflammation, increased stress hormone production, enhanced cytokine/acute phase reactant activity, hypercoagulable state, altered platelet reactivity, and procoagulant production (Figure 1)[1,2,4]. The frequency, duration, and severity of hypotensive episodes, early or during MNCS, along with other risk factors, are key determinants of MINS development[12]. Moreover, prolonged surgical time (≥ 3 hours) and emergency surgery are associated with a 2- to 3-fold increased risk of MINS, respectively[13].

Figure 1 Causes, pathophysiology and outcomes of troponinemia including myocardial injury after non-cardiac surgery. MINS: Myocardial injury after non-cardiac surgery; cTn: Cardiac troponin; ECG: Electrocardiogram; URL: Upper reference limit.

MINS is a crucial independent predictor of MACEs, but not the only one (Figure 1)[2-4,14]. Identifying these events in the perioperative period is notoriously difficult. This is because MINS could occur in the absence of obstructive coronary artery disease (CAD) in approximately 30% of patients, and only up to 40% of these injuries meet the standard criteria for MI[6,12]. MINS remains widely unrecognized. However, a working diagnosis can be established based on an elevated post-operative cardiac troponin (cTn) level within 30 days of surgery after excluding other non-ischemic causes[8].

Perioperatively, analgesics frequently mask classic ischemic cardiac symptoms, and electrocardiogram (ECG) ischemic changes are often subtle or transient, complicating the clinical picture of MINS[7]. Moreover, the diagnostic value of perioperative cardiac biomarkers is controversial in this setting. There are several factors that can affect the interpretation of these biomarkers. The release of cTn from cardiomyocytes could be induced by perioperative systemic conditions such as sepsis, inflammation, and profound stress. For instance, the adrenergic surge during surgery, independent of underlying CAD, can initiate cTn release, underscoring that, while cTn is a heart-specific marker, it is not a disease-specific marker[14].

Even a low level of cTn elevation (e.g., 0.02 ng/mL) within the first three days after MNCS is associated with a significant increase in the five-year mortality rate[15]. It has been noticed that the absolute risk of 30-day mortality varies with cTn value (i.e., 1.0% for a cTn value ≤ 0.01 ng/mL; 4.0% for a value of 0.02 ng/mL; and 16.9% for a value ≥ 0.30 ng/mL)[16]. Of note, an isolated elevation in cTn is an independent predictor of mortality within a year following MNCS[8,15]. This cTn elevation correlated with a six-fold increase in the risk of death[17]. Supporting this, the VISION study confirmed the relationship between peak postoperative cTn levels and 30-day mortality[17,18]. Moreover, the interval between the peak cTn measurement and death was generally 1 to 2 weeks, suggesting a potential window for clinical intervention to reduce mortality risk[15,18]. The relationship between cTn elevation and mortality risk was also directly related to the magnitude of its increase[17,18]. Yet, it remained independent of preoperative risk factors typically associated with postoperative death (i.e., the Revised Cardiac Risk Index)[8,15,19].

A key unresolved issue is whether cTn measurement should be implemented routinely or only in high-risk surgical populations. Coric and Smith[20] reported that abnormal cTn has high sensitivity (86%) but low specificity (32%) for detecting MACEs, resulting in a 56% false-positive rate. Patients with abnormal cTn levels have a 23% risk of MACEs, and the “number needed to measure” to detect one patient with MACE is 4.4[20]. Incorporating additional biomarkers, such as serum NT-pro-BNP alongside cTn, may enhance predictive and discriminative capacity for improved risk stratification[21].

The pathophysiology of MINS is heterogeneous. Table 1 outlines the criteria for the universal definition of MI and myocardial injury[22]. Only one quarter to one third of MINS cases are attributable to coronary thrombosis (type I MI), while the majority result from a supply-demand mismatch (type II MI), often due to tachycardia, hypotension, anemia, or hypoxia[12]. Other perioperative conditions, including pulmonary embolism, sepsis, trauma, and renal failure, can also elevate serum cTn levels. Consequently, clinicians require additional tools to differentiate ischemia-related cTn elevations from other causes of “troponinemia” in surgical settings[6,14].

Table 1 Summary of the criteria for universal definition of myocardial infarction and myocardial injury.

Variable	Definition
Myocardial injury	Detection of an elevated cTn value above the 99th percentile URL. The injury is considered acute if there is a rise and/or fall of cTn values
Type 1 MI	Detection of a rise and/or fall of cTn values with at least 1 value above the 99th percentile URL and with at least 1 of the below mentioned findings1. Identification of a coronary thrombus by angiography including intracoronary imaging or by autopsy
Type 2 MI	Detection of a rise and/or fall of cTn values with at least 1 value above the 99th percentile URL, requiring at least 1 of the below mentioned findings1. Identification of an imbalance between myocardial oxygen supply and demand unrelated to acute coronary atherothrombosis
Type 3 MI	Sudden cardiac death, with symptoms suggestive of myocardial ischemia accompanied by presumed new ischemic ECG changes or ventricular fibrillation but die before blood samples for biomarkers can be obtained, or before increases in cardiac biomarkers can be identified, or MI is detected by autopsy examination
Type 4 MI (cardiac procedural-related)	An increases of cTn values (> 99th percentile URL) in patients with normal baseline values (≤ 99th percentile URL) or a rise of cTn values > 20% of the baseline value when it is above the 99th percentile URL but it is stable or falling. Type 4 MI can be further classified into three subgroups
Type 5 MI (CABG-related MI)	An elevation of cTn values > 10 times the 99th percentile URL in patients with normal baseline cTn values In patients with elevated preprocedure cTn in whom cTn levels are stable (≤ 20% variation) or falling, the postprocedure cTn must rise by > 20%. The absolute postprocedural value still must be > 10 times the 99th percentile URL. In addition to one of these elements: Development of new pathological Q waves, angiographic documented new graft occlusion or new native coronary artery occlusion, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology

¹Symptoms of acute myocardial ischemia; new ischemic electrocardiogram changes; development of pathological Q waves; imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology.

Adopted from Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol 2018; 72: 2231-2264. cTn: Cardiac troponin; ECG: Electrocardiogram; MI: Myocardial injury; URL: Upper reference limit.

Postoperative cTn elevation is a strong predictor of 30-day and one-year mortality [odds ratio (OR) = 3.52 and adjusted OR = 2.53], respectively[17]. After major abdominal surgery, a doubling of postoperative cTn compared to baseline is a robust predictor of 30-day complications and prolonged hospitalization[16,23]. Elevated cTn is a powerful predictor of MACEs and mortality within one year following non-cardiac, non-vascular surgery, with risk levels similar to those observed after major vascular surgery[8,17]. Moreover, in orthopedic surgery, elevated cTn is associated with a one-year mortality OR of 2.14[17].

The VISION study, which measured cTn at 5 post-surgery time points (6-72 hours), found that even cTn levels in the upper normal range, below the diagnostic threshold of 0.04 ng/mL, were associated with increased mortality[18,20]. The study reported 8% of patients who experienced MINS. Only 16% of MINS patients exhibited ischemic symptoms, and two-thirds lacked ischemic ECG findings. The presence of ischemic symptoms further increased mortality risk by 55%[12]. In the POISE trial, two-thirds of patients with perioperative MI were asymptomatic. Since cardiac markers were measured only on the third postoperative day, additional asymptomatic MIs may have been missed[24,25], highlighting the importance of timely cTn measurement in the perioperative period.

The use of high-sensitivity troponin T (hs-TnT) assays has revealed a greater disease burden and provides more relevant prognostic values than that have been detected with a conventional cTn[18]. Mortality rates increase substantially with higher hs-TnT levels, rising from 3% at 20-65 ng/L to 29% at levels above 1000 ng/L[18,19,26]. The incidence of MINS detected increases from 8%-19% with conventional cTn assays to 20%-30% with hs-TnT assays[26,27]. Consequently, hs-TnT testing as a point-of-care screening tool may be invaluable for early and accurate diagnosis and prognosis of MINS[18,27].

Given this evidence, physicians should consider monitoring cTn levels during the postoperative period in at-risk patients. This monitoring can help identify vulnerable patients who could benefit from cardiovascular optimization. For patients diagnosed with MINS who are not at high risk of bleeding, prescribing dabigatran, low-dose aspirin, and statins could be considered[3,12,28]. However, the rates of mortality and major cardiovascular and cerebrovascular events in patients with unrecognized MINS are high even with aspirin-statin therapy and specialized clinic follow-up[29]. The POISE trial showed that while beta-blockers were associated with a decrease in the post-operative MI, they also increased the incidence of stroke, indicating a need for careful risk-benefit analysis[24].

Following MINS, coronary angiography (CAG) should be considered in patients who have recurrent events and those with heart failure, though currently only a small number of patients with perioperative MI (21%) or MINS (8%) undergo CAG[12,24]. The risk of CAG with stenting (percutaneous coronary intervention) must be weighed cautiously in patients shortly after surgery, as withdrawing antiplatelet therapy can lead to catastrophic in-stent thrombosis[12,28]. Therefore, unnecessary CAG and overtreatment should be avoided, as both have diverse pathophysiological mechanisms and impact unrelated to the primary condition itself.

Major cardiology societies emphasize the importance of early detection of MINS. The American Heart Association recommends measuring cTn within the first 2-3 days postoperatively in high-risk patients. The European Society of Cardiology advises both preoperative and postoperative hsTnT testing for 2-3 days, along with NT-pro-BNP testing, in high-risk individuals undergoing intermediate- or high-risk non-cardiac surgery. The Canadian Cardiovascular Society similarly recommends daily postoperative cTn testing for 2-3 days in high-risk patients[1,3]. This consensus underscores the necessity for proactive surveillance to reduce the burden of perioperative cardiovascular complications. Involving a cardiologist in MINS management has been shown to significantly reduce 30-day mortality compared with those without cardiologist involvement (hazard ratio 0.62)[30].

Recently, machine learning algorithms have shown promise by continuously updating the probabilities of myocardial injury and death during the perioperative period. These tools could be integrated with alarm systems and decision support platforms to guide interventions and potentially reduce complications[31].

CONCLUSION

Awareness of the phenomenon of MINS is of utmost value for better perioperative management and prognostication. The patient, surgery (type, duration, and urgency), and cTn (timing, type, and frequency) should be considered in MINS identification and interpretation. Appropriate management requires a high index of suspicion and a stepwise, multidisciplinary approach.