Biomarkers for early diagnosis of acute myocardial infarction and unstable angina

Mueller C
Eur Heart J. 2013 Dec 18. [Epub ahead of print]

The risk of dying and the benefit of revascularisation are largest in the first hours after an acute coronary syndrome (ACS), be it acute myocardial infarction (AMI) or unstable angina (UA). Hence, early diagnosis is critical. About two-thirds of the patients presenting to the emergency department (ED) with acute chest pain or other symptoms suggestive of ACS will turn out not to have ACS. Therefore, both rule-in and rule-out are important.

Current standard of care

Clinical assessment and 12-lead ECG are indispensable, but insufficiently accurate to diagnose ACS. Measurement of a biomarker that reflects and quantifies cardiomyocyte injury is therefore mandatory when ACS is suspected.
When considering the clinical value of biomarkers, it is important to emphasize that ACS includes two distinct clinical entities: AMI (ischaemic chest pain at rest with cardiomyocyte necrosis) and UA (ischaemic chest pain at rest or minimal exertion without cardiomyocyte necrosis). These entities differ substantially in their risk to the patient and the documented benefit of early revascularisation.

Cardiac troponin

Cardiac troponin (cTn) I or T are heart-specific proteins, and can therefore be used as markers of myocardial damage. In AMI cTnI and cTnT are released from necrotic heart tissue into peripheral blood, and can be detected. A major limitation of the conventional cTn assays is their low sensitivity at the time of presentation of the patient, due to a delayed increase in circulating levels. Thus serial sampling for 6-9 hours is needed.

Sensitive and high-sensitivity cardiac troponin assays, and the 99th percentile

Recent improvements of assay technology have lead to sensitive and high-sensitivity (hs) cTn assays that detect cTn in a substantial number of healthy persons and that give a more precise definition of what is ‘normal’. A decision value for AMI has previously been defined as the 99th percentile of cTn in a normal population of healthy individuals. Thus, the accuracy of the tests affects the diagnosis of AMI.
Study data have consistently shown that sensitive cTn and hs-cTn assays increase the accuracy of the diagnosis of AMI at the time of presentation to the ED. These tests allow a more rapid rule-in or rule-out. It is, however, as yet unclear whether hs-cTn assays provide a clinically meaningful advantage over sensitive cTn assays.
Hs-cTn assays have been introduced into clinical practice in Europe, but still await approval in the United States. Existing concerns mostly revolve around the use of the 99^th percentile.

High-sensitivity cardiac troponin: timing of serial measurements and the ESC guidelines

The higher detection sensitivity of AMI at presentation allows for a shorter time interval between measurements. This can substantially reduce time to decision and total treatment costs in the ED. The ESC guideline outlined a 3-hour rule-out protocol, based on hs-cTn (or sensitive cTn), and the patient being pain-free and with a GRACE score below 140. Time since chest pain onset is a modifier, as pain onset is considered the beginning of cardiomyocyte damage, thus release of cTn into the circulation. Thus time since pain onset can help interpret cTn finding, although this concept still needs prospective testing.

Rapid rule-out and rule-in protocols

Different rule-out and rule-in protocols have been evaluated in observational studies. Approaches with as little as 1-hour protocols  have shown good results, by making maximum use of the diagnostic value of hs-cTn. These innovative methods still require external validation before implementation in the clinic.

Unstable angina in the high-sensitivity cardiac troponin era

Improved detection of cTn can alter incidences of AMI and UA; as small AMIs were previously misclassified as UA.s Most patients with UA do not show hs-cTn changes. The absence of distal coronary embolisation of the culprit lesion may be a key differentiating pathophysiological feature between UA and AMI. Since the risk of death and the benefit of early revascularisation appears to be lower in UA, the current classification that put UA and AMI together as ACS may need to be reconsidered. UA diagnosed in the hs-cTn era may be better placed as a subgroup of severe stable CAD.

Unstable angina in the high-sensitivity cardiac troponin era

Heart-type fatty acid-binding protein (h-FABP) is another protein that is released into the circulation in response to cardiomyocyte injury, and more rapidly than cTns. Thus, h-FABP was considered an early sensitive marker of AMI. Most of the promising data on the clinical value of h-FABP was however obtained before the clinical introduction of hs-cTn assays. h-FABP does not appear to have relevant added prognostic value on top of hs-cTnT. It is under current investigation whether h-FABP is useful in patients presenting very early (<1-2 h ) after chest pain onset.

Biomarkers reflecting endogenous stress: copeptin

Copeptin is part of the vasopressin prohormone and appears to quantify the individual endogenous stress level and mortality risk in AMI and other medical conditions. Copeptin may already identify AMI very early after symptom onset, before cTn is detectable. The time course of endogenous stress and detectable cardiomyocyte damage appears reciprocal, thus copeptin seems to be the ideal marker to compensate for the sensitivity deficit of conventional cTn assays in early presenters. Indeed, copeptin showed substantial added diagnostic value on top op fourth generation cTnT, but in combination with sensitive cTnI or hs-cTnT this benefit seems to be smaller. It may still prove useful in a dual-marker strategy for very early rule-out of AMI.

Other complimentary prognostic biomarkers

Other prognostic biomarkers such as natriuretic peptides, midregional pro-adrenomedullin, and GDF-15 are powerful predictors of mortality in patients with suspected or established ACS, but their diagnostic value seems limited. It remains to be established how the pathophysiological information these measures contain, can be benefitted from clinically.

Biomarkers associated with plaque instability

Plaque rupture precedes cardiomyocyte damage by minutes to maybe hours in ACS. Thus biomarkers of plaque instability may serve useful as early AMI markers. To date, no markers have been identified to have early diagnostic value for AMI.

Thus, hs-cTn measured at presentation and after 3 h are currently standard of care. Future approaches may involve even more rapid hs-cTn assays, possibly in combination with copeptin measurement.