Despite it being a frequent occurrence in emergency departments (ED) around the world, chest pain triage remains a challenge for patients and physicians alike. Responsible for 6–10% of all presentations to acute healthcare providers [
1‐
4], the presenting complaint of chest pain results in a high rate of admissions (1:3, according to data from the UK [
5]), but a paradoxically low probability (10%) of a final diagnosis of acute myocardial infarction (AMI) [
6]. The inability to make a rapid and accurate diagnosis not only causes financial but also medical, psychological and social burden to the affected patient and the healthcare system. Only 32% of patients with an ultimate diagnosis of AMI have diagnostic ECG changes of ST-elevation or depression that facilitate immediate triage [
7,
8], in many cases—and healthcare environments—directly to heart attack centres. The remaining two-thirds of all patients eventually diagnosed with an acute coronary syndrome (ACS) present with non-ST elevation myocardial infarction (NSTEMI) [
6]. Consequently, triage has become reliant on quantifying the biomarker cardiac Troponin (cTn). This is enshrined in the Universal Definition of Myocardial Infarction [
9] (now in its fourth iteration [
10]) by mandating the detection of a cardiac biomarker rise and/or fall for the diagnosis of AMI. Historically, patients tested with contemporary cTn assays had to wait for at least 12 h for a reliable diagnosis—on the basis that the cardiac-restrict troponin isoforms (cTnI and cTnT) are released slowly after myocardial injury and reach their respective peak concentration after 18 h [
11,
12]. To facilitate earlier rule-in and rule-out of AMI, the cTn assay vendors then increased the analytic performance—to achieve high-sensitivity (hs), or, in simple terms, quantify cTn in the majority of patients. The ability to detect ever-lower concentrations of cTn enables direct rule-out of AMI in a specific subgroup—i.e. in patients with symptoms for more than 3 h, a normal ECG and an undetectable cTn level. While the European guidelines recommend the ‘measurement of a biomarker of cardiomyocyte injury, preferably high-sensitivity cardiac Troponin’ in all patients with suspected NSTEMI [
13], the clinical implications of using hs-cTn assays include a 2-fold increase of detection of type 2 AMI, ~ 20% relative increase in detection of type 1 AMI and—all according to the ESC’s 2015 guideline—‘elevations up to 3-fold the upper reference limit (URL)… may be associated with a broad spectrum of conditions’. The very definition of a hs-cTn assay—according to the International Federation of Clinical Chemistry and Laboratory Medicine Task Force on Clinical Applications of cardiac Bio-Markers (IFCC TF-CB)—includes (1) a CV ≤ 10% at the 99th centile value and (2) the ability to measure at least 50% of healthy individuals with concentrations above the assay’s limit of detection (LoD) [
14,
15]. Acknowledging the underlying biology, the ESC hence advocates the use of its 0/1 h rule-out/rule-in algorithm only in patients presenting > 3 h after chest pain onset. Several publications have recently reported on the variable effectiveness of the ESC algorithm in clinical practice—many patients have to undergo a second blood draw for a more refined triage, and only 20–30% of patients benefit from immediate rule-out/-in using the cut-offs published [
16‐
19]. Taken together, technological advances result in many more patients being tested ‘Troponin-positive’, without necessarily being ‘AMI-positive’—while impressive with respect to assay development, cTn was inherently unsuited for early diagnosis of acute myocardial injury and this has not been mitigated by moving detection limits to ever-lower levels.