Author + information
- aDivision of Cardiology, Massachusetts General Hospital, Boston, Massachusetts
- bBaim Institute for Clinical Research, Boston, Massachusetts
- cDepartment of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. James L. Januzzi, Jr., Massachusetts General Hospital, Cardiology/Internal Medicine, 33 Fruit Street, Yawkey 5984, Boston, Massachusetts 02114.
For the evaluation of acute chest pain, measurement of cardiac troponin to seek presence of acute myocardial infarction (MI) has become the standard of care (1,2). Fundamental to the value of troponin for diagnosis of MI is the high and increasing sensitivity of assays for its measurement. With greater refinements in assay technology, high-sensitivity cardiac troponin (hs-cTn) assays can now measure troponin concentrations in ≥50% of normal individuals, and possess high precision at very low concentrations of the marker, such as the 99th percentile for a normal patient population (3). Further, assay sensitivity continues to increase: incredibly, some preclinical hs-cTn assays may detect measurable troponin in 100% of normal subjects.
Although such increased sensitivity provides unique opportunities to diagnose or exclude acute MI, it comes with challenges. Though there is value from being able to detect minute concentrations of troponin, with hs-cTn assays it is possible to recognize acute myocardial necrosis in patients that previously had a “negative” troponin as measured with a conventional method. Indeed, such a circumstance not infrequently occurs when a patient presents to the emergency department with a noncardiac complaint, and a troponin is ordered as part of a barrage of blood tests. When acute myocardial necrosis is detected in patients without other obvious signs or symptoms of MI, it often leads to cognitive dissonance and frustration with the test. With hs-cTn assays, this is inevitably going to increase in frequency. As the late Dr. Bob Jesse once famously wrote: “When troponin was a lousy assay, it was a great test. Now that it’s a great assay, it’s a lousy test” (4).
In framing how clinicians might generally consider abnormal troponin concentrations, it is worthwhile to start by defining terms. Current consensus documents define MI by a rise or fall in troponin concentration above the 99th percentile related to coronary ischemia (5). This is most often due to plaque rupture and intracoronary thrombosis (type 1 MI) or supply-demand imbalance, typically from increased demand in the context of obstructed coronary arteries (type 2 MI). The latter category may be challenging to correctly diagnose, but in both cases, coronary ischemia is the sine qua non: in the absence of ischemia, all forms of MI are excluded. Yet, the circumstance of an elevated troponin in patients without MI continues to be common. Of course, although analytical false positives may rarely occur and lead to an abnormal troponin without classical MI, clinicians have grown accustomed to the circumstance of elevated troponin without obvious acute coronary ischemia. In addition to (often incorrectly) assuming such a circumstance was a type 2 MI (despite lack of clinical criteria to assign this diagnosis), other terms have been used to label this circumstance, including “troponinemia,” or even worse, “troponinitis”; these inaccurate terms are merely descriptive, providing nothing more than the fact that the test is abnormal—and the clinician using the term has not considered why.
To address this variation in practice and provide guidance for how to interpret abnormal troponin concentrations in the absence of an acute MI, the fourth universal definition of MI has now defined nonischemic troponin elevation as “myocardial injury,” which may be an acute or chronic diagnosis (5). Several mechanisms may contribute to myocardial injury, including cardiomyocyte turnover, nonischemic myocyte necrosis, apoptosis, myocardial strain, proteolytic fragmentation, increased cell membrane permeability, and exocytotic release of cytosolic troponin. We can detect injury—but is it important, or can we simply trivialize its presence by calling it a nonsensical term such as “troponinemia” that lacks a treatment imperative?
In this issue of the Journal, Eggers et al. (6) examine the prognostic implications of myocardial injury without MI among patients included in the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry, who were admitted with suspected acute coronary syndrome, but were discharged without a specified diagnosis. Of the 48,872 patients included in the study, 20.1% had troponin concentrations >99th percentile (6). Over a median follow-up of 4.9 years, 25% of patients with myocardial injury experienced a major adverse event (defined as all-cause mortality, nonfatal MI, readmission for heart failure or stroke), compared with 13% in patients with troponin concentrations ≤99th percentile. Major adverse event rates increased with increasing concentrations of troponin. Even in the absence of cardiovascular comorbidities, kidney impairment, left ventricular dysfunction, or significant coronary artery disease, patients with troponin concentrations in the highest stratum had a 3-fold increased risk of major adverse events when compared to patients with normal troponin concentrations (6). Strengths of the study include the large cohort size (almost 50,000 patients), adjustment for several cardiovascular and noncardiovascular comorbidities that may cause an abnormal troponin concentration, and inclusion of both fatal and nonfatal cardiovascular endpoints.
This study adds to the growing body of evidence that suggests myocardial injury is not only associated with an increased risk of all-cause mortality, but also cardiovascular mortality, MI, heart failure, and stroke (6,7). Armed with this prognostic information, physicians must decide if any diagnostic testing or treatments should be implemented when a patient with myocardial injury is encountered in clinical practice. Eggers et al. (6) advocate for “liberal referral for echocardiography and invasive or non-invasive coronary imaging, depending on the individual pre-test probability of coronary artery disease” when a patient with myocardial injury is encountered. It is logical to consider such an approach, in order to avoid missing unsuspected coronary disease as the cause of injury; however, given the many triggers for injury that are not coronary in origin, physicians should consider the cost implications and the risks of overtesting and fact there is currently no evidence (randomized or otherwise), that revascularization would benefit patients with myocardial injury in the absence of obvious coronary ischemia.
Of course, it would be desirable to have a defined set of medical therapies to manage myocardial injury, however none are yet accepted. Undertaking a thorough history and physical examination is crucial when evaluating patients in this circumstance and addressing whatever medical disarray exists. To the extent that injury may reflect whatever burden of medical conditions is present at the time of diagnosis, it is sensible to optimize medical therapies for cardiovascular comorbidities such as hypertension, hyperlipidemia, and diabetes mellitus, and ensuring guideline-directed medical therapy goals for high-risk conditions such as heart failure are met. Statins may have a role to reduce incidence of cardiac injury, in parallel with improved prognosis (8): in the West of Scotland Coronary Prevention Study, pravastatin reduced troponin concentrations by an average of 13%, and reduction in troponin at 1 year was associated with favorable improvement in coronary risk (8). More recently an international trial randomized 1,754 patients with myocardial injury after noncardiac surgery to dabigatran 110 mg twice daily versus placebo. Dabigatran was associated with lower major vascular event rates (a broad composite of vascular mortality, MI, nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism) when compared with placebo (11% vs. 15%; p = 0.0115).
With an aging population of patients with cardiovascular disease burdened by medical complexity, coupled with higher and higher sensitivity troponin assays, recognition of myocardial injury will increase in frequency. As articulated by the fourth universal definition of MI (5) and emphasized by Eggers et al., (6) myocardial injury is not a benign condition and should not be trivialized with awkward and nonsensical monikers such as “troponinemia”; it is injury, and should be referred to as such. Information on definitive management for these high-risk patients will depend on outcome of much-needed clinical trials currently planned or ongoing.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Januzzi has received grant support from Roche Diagnostics, Abbott Diagnostics, Singulex, Prevencio, and Cleveland Heart Labs; has received consulting income from Roche Diagnostics, MyoKardia, Abbott, and Critical Diagnostics; and has participated in clinical endpoint committees/data safety monitoring boards for Boehringer Ingelheim, Amgen, AbbVie, Janssen, Abbott, and Siemens Diagnostics. Dr. McCarthy has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2019 American College of Cardiology Foundation
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