Elevated cTn levels of unknown etiology can predict major adverse outcomes in suspected ACS

Cardiac Troponin Elevation in Patients Without a Specific Diagnosis

Literature - Eggers KM, Jernberg T, Lindahl B et al. - JACC 2019;73(1):1-9

Introduction and methods

Elevated cardiac troponin (cTn) levels predict adverse outcomes, both cardiac and noncardiac conditions. However, since not all elevated cTn levels are associated with adverse outcomes [1-2], a higher cTn level warrants the search for the underlying cause. In some patients, etiology of elevated cTn levels remains unknown. It has been reported that 31% of patients discharged from the emergency department have no specified diagnosis but do have cTn levels above the 99th percentile are [3] and this may be similarly high in those who are admitted [4]. This scenario has been named troponinemia. Scientific studies investigating this condition are, however, largely lacking.

This retrospective registry-based cohort study therefore investigated clinical characteristics of patients with elevated cTn levels of unknown etiology and their long-term risk of fatal and non-fatal events. This study is part of the Tailoring Of Treatment in All comers with Acute Myocardial Infarction (TOTAL-AMI) project, which used data from the SWEDEHEART registry, a nationwide registry including consecutive patients admitted to Swedish coronary units or other specialized facilities because of suspected acute coronary syndrome (ACS).

This study included all patients acutely admitted between January 2005 and August 2013, who had been discharged without a specified diagnosis. 48.872 Participants were divided into four groups based on cTn levels: those with cTn levels ≤99th percentile and the remaining patients stratified by tertiles calculated separately for each assay. Three clinically relevant subcohorts were separately evaluated to investigate the association of higher cTn groups with adverse events. Subcohort 1 consisted of patients without previous MI, previous coronary revascularization, previous stroke, and known congestive heart failure (HF). In subcohort 2 patients with an eGFR <60 ml/min/1.73 m2 were further excluded and subcohort 3 also excluded patients who had a left ventricular ejection fraction (LVEF) ≤0.50% or significant coronary artery disease (CAD), defined as ≥50% coronary stenosis according to invasive angiography. Outcomes for this analysis were all-cause mortality, MI, CV mortality, non-CV mortality, and hospitalization for HF and ischemic stroke. Major adverse events (MAE) were also assessed, defined as the composite of all-cause mortality and all non-fatal outcomes.

Main results

Clinical characteristics and cTn levels

  • The discharge diagnoses most commonly reported were unspecified chest pain (79.0%) and observation for suspected MI (16.0%).
  • 9800 (20.1%) patients had cTn level >99th percentile, and 18.2%, 17.2% and 30.8% fell in clinical subcohorts 1,2 and 3, respectively.
  • The prevalence of most CV risk factors tended to increase across groups with higher cTn levels, as did the prevalence of previous manifestations of CVD and non-CV comorbidities. Current smoking showed a decreasing prevalence with increasing cTn levels.
  • Among patients who underwent echocardiography (n=10.627), left ventricular dysfunction was more often seen in higher cTn groups, whereas in patients who underwent coronary angiography (n=4.989), only a weak association between the extent of CAD and cTn levels was found .

cTn levels and clinical outcomes

  • In total, 15.4% experienced an MAE during a median follow-up of 4.9 years.
  • The incidence rates for MAE and the assessed single outcomes increased in a stepwise fashion across groups with higher cTn levels. In an unadjusted Kaplan-Meier analysis, MAE rates diverged early and constantly over time.
  • In the total population, MAE risk was mainly driven by the risks of CV mortality, MI and readmission for HF; the outcomes that consistently showed the highest HR’s in all tertiles. Investigating subcohort 1 and subcohort 2 revealed similar MAE risk patterns as the total cohort.
  • In subcohort 3, MAE rates were particularly high if cTn levels were in the highest tertile. Compared with patients with cTn ≤99th percentile, the HR for MAE across increasing assay-specific cTn tertiles were 1.25 (95%CI: 0.67-2.35), 1.26 (95%CI: 0.54-2.94), and 3.57 (95%CI: 2.30-5.54) , respectively.
  • Male and older patients, and those with diabetes, renal dysfunction, lower BMI, previous manifestations of CVD, or COPD, showed significantly higher risk for experiencing a MAE, irrespective of cTn. Risk of MAE was significantly elevated in those with previous or present cancer, when tertiles 1-3 and 2-3 were considered, but not in tertile 3 alone.


This retrospective registry-based cohort study demonstrated that elevated cTn levels can predict major adverse outcomes in patients acutely admitted with suspected ACS in whom no definite diagnosis can be established, even in the absence of significant CAD or left ventricular dysfunction. These data indicate that careful work-up is necessary in these patients and the term troponinemia is not useful and should be avoided.


1. Giannitsis E, Katus HA. Cardiac troponin level elevations not related to acute coronary syndromes. Nat Rev Cardiol 2013; 10:623–34.

2. Mair J, Lindahl B, Hammarsten O et al. How is cardiac troponin released from injured myocardium? Eur Heart J Acute Cardiovasc Care 2018;7:553–60.

3. Hochholzer W, Reichlin T, Twerenbold R et al. Incremental value of high-sensitivity cardiac troponin T for risk prediction in patients with suspected acute myocardial infarction. Clin Chem 2011; 57:1318–26.

4. Eggers KM, Lindahl B, Melki D et al. Consequences of implementing a cardiac troponin assay with improved sensitivity at Swedish coronary care units: an analysis from the SWEDEHEART registry. Eur Heart J 2016;37:2417–24.

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