Myocardial Injury After Noncardiac Surgery

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Intraoperative cardiovascular management of the patient undergoing noncardiac surgery has become an area of widespread interest given the fact that cardiac death is the leading cause of postoperative death within the first 30 postoperative days. Among patients 45 years of age or older undergoing in-hospital noncardiac surgery, complications of cardiac death, nonfatal myocardial infarction (MI), heart failure, or ventricular tachycardia represent the most common complications and occur in up to 5% of cases. Of these, perioperative MI is the most common. In addition, there is a larger group of patients who have an elevation in troponin (Tn) but no symptoms and no evidence of myocardial ischemia on an electrocardiogram (ECG). These patients are labeled as having myocardial injury after noncardiac surgery (MINS) when there is no evidence of a nonischemic etiology (e.g., venous thromboembolism [VTE], sepsis, atrial fibrillation with rapid ventricular response [RVR]). It is estimated that of the over 200 million annual surgeries performed worldwide, approximately 100 million involve patients over 45 years of age and at risk for MI or myocardial injury. Of these, around 1.1 million suffer a perioperative symptomatic MI, whereas another 2.2 million have asymptomatic MI and 4.6 million have myocardial injury. ^{, ,} The 30-day postoperative mortality in these three groups is 9.7%, 12.5%, and 7.8%, respectively. In other words, annually over 750,000 deaths within 30 days of noncardiac surgery result from myocardial insults (1.5 times the amount of deaths attributed to COVID-19 in the United States at the time this chapter was written). Thus: Is MINS important?

DEFINITIONS

According to the 2018 Joint Task Force of the European Society of Cardiology (ESC), American College of Cardiology Foundation (ACCF), American Heart Association (AHA), and World Health Federation (WHF), myocardial infarction (MI) is defined as a clinical (or pathologic) event in the setting of myocardial ischemia in which there is evidence of myocardial injury.

Myocardial injury occurs when there is evidence of elevated cardiac troponin (cTn) with at least one value above the 99th percentile reference limit. The myocardial injury is considered acute if there is a rise and/or fall in cTn values. Importantly, other clinical manifestations do not have to be present. Myocardial injury can include situations of myocardial ischemia, which encompass infarction or simply injury without infarction. Myocardial injury after noncardiac surgery (MINS) is defined as myocardial cell injury during the first 30 days after noncardiac surgery from an ischemic etiology (i.e., no evidence of a nonischemic etiology like sepsis, VTE, cardioversion, or chronically elevated Tn) and is independently associated with mortality. The definition of MINS includes both symptomatic and asymptomatic MI and patients with postoperative elevations in cTn who do not have symptoms, ECG abnormalities, or other criteria that meet the universal definition previously described and have no evidence of a nonischemic etiology for their Tn elevation. It is estimated that MINS occurs in about 8 million patients worldwide every year and is an independent risk factor for death and cardiovascular complications during the first postoperative year. Table 62.1 summarizes perioperative risks factors associated with MINS.

PATHOPHYSIOLOGY

The pathogenesis of MINS is not fully understood. Although likely a heterogenous disease, it has been proposed that a mismatch in the supply demand of oxygen in the perioperative context of pain and inflammation plays a major role. Many risk factors have been identified, but the most common originating pathologies are either underlying obstructive coronary artery disease (CAD), which can cause elevations of cTn because of supply/demand mismatch, or an acute thrombus. Patient characteristics and their physiologic response to the stress of surgery and anesthesia likely contribute to the development of MINS. In addition, increased levels of cortisol, catecholamines, platelet reactivity, procoagulant factors, and coronary artery shear stress are all present in the postoperative period and may contribute to an increased propensity for thrombotic events. Oxygen supply/demand imbalance leading to myocyte stress, ischemia, and subsequent infarction is likely common in the perioperative period; this imbalance may be present with or without symptoms. Oxygen demand may increase secondary to tachycardia caused by bleeding, pain, and catecholamines or increased wall stress from hypertension caused by pain or vasoconstriction. Oxygen supply can be decreased secondary to anemia, hypotension, hypoxemia, hypercarbia, fluid shifts (bleeding or volume overload), or coronary vasoconstriction ( Fig. 62.1 ). Again, the term MINS does not encompass Tn elevation secondary to nonischemic etiologies such as VTE, sepsis, and atrial fibrillation possibly exacerbated by renal dysfunction. Three large prospective cohort studies in which adjudicators attempted to evaluate each case of an elevated Tn for evidence of a nonischemic etiology found that over 85% of Tn elevations after surgery were likely because of myocardial ischemia, and 11% to 14% were of nonischemic etiology. ^{, ,}

In the Optical Coherence Tomographic Imaging of Thrombus (OPTIMUS) study that included only non-ST segment elevation MI (NSTEMI) patients, coronary thrombus was the culprit lesion in 13% of the perioperative MI cases and in 67% of the nonoperative MIs. Considering this data, and the fact that prior large studies have found that ST segment elevation MI (STEMI) accounts for 11% to 21% of perioperative MIs, ^{, ,} it can be assumed that up to 30% of perioperative MIs are caused by thrombosis. The prospectively designed multicenter Coronary CTA Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study found that obstructive or extensive CAD was present in 72% of the patients who had a perioperative MI, and the remaining had at least one coronary artery plaque with less than 50% stenosis. Overall, these data support the idea that up to a third of MINS cases are caused by de novo thrombosis (i.e., not present preoperatively), whereas the rest of the cases are because of supply/demand mismatch. This indicates that surgical and perioperative factors have an important role in producing thrombosis or supply/demand imbalance in patients who did not have active ischemia at the onset of surgery.

TROPONIN MONITORING

Troponins are classified in 3 subgroups: C, T, and I. Troponin T (TnT) and troponin I (TnI) are integral parts of the cardiac muscle and contribute to excitation-contraction coupling. The skeletal version of these troponins differs, which has led to the development of specific assays to measure the cardiac version. In normal conditions, cTn are undetectable in serum. After cardiomyocyte necrosis, however, troponins are released into the circulating blood typically after 3 to 4 hours and remain elevated for up to 14 days. In patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), there is a greater prevalence of persistently elevated cTn compared with patients who do not have the disease. Although the mechanism is not fully understood, kidney disease-related subclinical cardiac damage is likely the cause, possibly exacerbated by reduced clearance.

One of the major pitfalls of studies assessing incidence of MINS is the lack of preoperative Tn assessments. Because many patients have detectable Tn concentrations in the preoperative setting, the “harm-threshold” for high-sensitivity troponin (hs-Tn) depends on the baseline value. For instance, hs-TnT is considered to be elevated when peak postoperative concentration increases by at least 5 ng/L from the baseline value to at least 20 ng/L, or when it exceeds 65 ng/L irrespective of the baseline value.

Although TnT test assays are universal, TnI tests are generic and, therefore, threshold values must be referenced with a local laboratory. Two versions of the TnT are currently in use (the fourth- and fifth-generation high-sensitivity tests). The VISION cohort evaluated fourth-generation TnT changes, in which a peak postoperative concentration of more than 0.03 ng/mL (harm threshold) predicted a fourfold increase in 30-day mortality.

Preoperative Tn elevation is a poor prognostic sign and is associated with significant increased mortality at 3 years postoperatively. Hs-TnT has been found to be elevated preoperatively in 2% of patients aged 50 years and close to 40% in those older than 70 years. ESRD, sepsis (11%), atrial fibrillation (9%), pulmonary thromboembolism (3%), and electric cardioversion (1%) are among the nonischemic etiologies for Tn elevation. In noncardiac surgical patients in whom baseline Tn was elevated, an adjusted hazard ratio (HR) for mortality at 1 year was 2.5 (95% confidence interval [CI] 2.0–3.2, p < .001).

EVIDENCE REGARDING TROPONIN ELEVATION

Different studies have evaluated whether the postoperative Tn elevation is because of MI or MINS. The incidence of MINS ranges between 8% to 19%, whereas MI accounts for 40% of cases when a nonhigh-sensitivity troponin (nhs-Tn) assay is used, and 20% to 30% when an hs-Tn assay is used. Several factors have been identified that could explain the differences in the incidence of MINS among studies and the percentage of MINS events that are labeled as MI. First, among those, almost no studies have compared baseline preoperative Tn against postoperative values. Second, the incidence of MINS depends on the Tn assay employed (nhs-Tn or hs-Tn). Third, pain control after surgery usually masks what otherwise could be considered an MI with ECG changes; had patients been symptomatic, they would likely have been labeled as MIs or would have had effective interventions.

Several other large studies have assessed the incidence of Tn elevation after noncardiac surgery. The VISION Study was a prospective cohort study that included a representative sample of patients at least 45 years of age or older undergoing in-hospital noncardiac surgery, and all of the participants had Tn measurements after surgery. So far, two cohorts have been reported.

In the first cohort (n = 15,065), a nonhigh-sensitivity, fourth-generation cardiac Tn assay was measured during the first 3 postoperative days. Patients were assessed for ischemic symptoms, had at least 1 ECG obtained, and had two independent adjudicators to determine whether there was evidence of a nonischemic cause of the Tn elevation. Ultimately, 93% of patients with a Tn elevation had an ischemic etiology for their Tn elevation, whereas 8% suffered MINS. A limitation of this study is that preoperative Tn measurements were not obtained systematically. In the second VISION cohort (n = 21,842), a hs-cTn assay was measured and 40.4% of the subjects had a preoperative Tn measurement. In this cohort, 11% had evidence of a nonischemic etiology for their elevated Tn, and among the patients who had an elevated perioperative Tn measurement, 13.8% had a preoperative hs-TnT measurement. In this cohort with hs-TnT measurements, 3904 patients (17.9%) were labeled as having suffered MINS, and among these patients, 21.7% fulfilled the definition of MI.

A prospective study of more than 2000 subjects at increased cardiovascular risk comparing preoperative and postoperative Tn values was published in 2017. Hs-cTn was measured before and after routine noncardiac surgery. Perioperative myocardial injury (absolute increase in hs-cTnT of ≥14 ng/L above preoperative values) occurred in 16% of surgeries. Of these, 6% had typical chest pain, 18% had an ischemic symptom, and 29% had one or more of the following: an ischemic symptom, a diagnostic change on an ECG, or evidence of loss of myocardial viability on imaging.