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Biomarkers in the prognostic stratification of non ST elevation acute coronary syndromes

An article from the e-journal of the ESC Council for Cardiology Practice

Four components can be identified in acute coronary syndromes: 1) the presence of vascular damage; 2) the activation of inflammatory cells; 3) the formation of a subocclusive or occlusive thrombus; 4) the development of transient or irreversible myocardial dysfunction resulting in hemodynamic stress.
Biomarkers reflecting the severity of these four components predict the risk of major adverse cardiac events and their predictive value is additive.
At the present time however, only troponin levels impact on in-hospital clinical decision making.

Acute Coronary Syndromes (ACS)

I - Components of acute coronary syndromes

1) The presence of vascular damage

Coronary atherosclerosis is highly prevalent in the population, yet it may remain clinically silent for many years or all through life. Nevertheless the greater the extent and severity of vascular damage, the higher the risk of acute coronary events happening and recurring.

2) The activation of inflammatory cells

The transformation of a stable atherosclerotic plaque into an unstable atherosclerotic plaque is frequently associated with the activation of inflammatory cells. This transformation is not limited to the culprit stenosis (responsible for clinical symptoms), but it can be wideaspread -throughout the whole coronary circulation and may even involve remote arterial districts as well as the myocardium (1).

3) The formation of a subocclusive or occlusive thrombus

The more intense and persistent the activation of inflammatory cells, the greater the thrombogenic stimulus. Thrombus formation is influenced not only by the intensity of inflammation, but also by the intensity of the thrombotic response.

4) The development of transient or irreversible myocardial dysfunction resulting in hemodynamic stress

The more intense the thrombotic response, the greater the risk of persistent coronary occlusion and of subsequent recurrences.The consequence of transient or permanent coronary thrombosis, in the absence of compensatory collateral circulation recruitment, is transient or irreversible myocardial dysfunction. The greater is the extent of myocardial dysfunction, the worse is the outcome for the patient.

II - Risk stratification of patients with non ST elevation acute coronary syndromes

Symptoms, signs and ECG findings

For many years cardiologists have based prognostic stratification of patients with non ST elevation acute coronary syndromes on symptoms, signs and ECG findings.
These tools remain of paramount importance, as they allow the identification of very high risk patients; for instance those with recurrent ischemic episodes in spite of maximal medical treatment or those who develop evidence of heart failure during myocardial ischemia, in particular in the presence of ST depression. In this subset of patients a step up of treatment is dictated by the clinical presentation and no further risk stratification is needed.

Biomarkers : an additive prognostic value

In the past ten years several studies have consistently demonstrated that in the remaining patients risk stratification can be based on biomarkers reflecting the severity of the four components of acute coronary syndromes mentioned above.
Indeed, lower values of creatinine clearance (2)- a marker of vascular damage- are associated with a worse outcome.
Furthermore, higher serum levels of several markers of activation of inflammatory cells, including C-reactive protein (3), myeloperoxidase (4), plasma-associated pregnancy protein A (5) and placental growth factor (6), are associated with a worse medium and long-term outcome, in particular mortality.
With regard to thrombus formation, higher serum levels of troponins (7), caused by coronary microembolisation reflecting the thrombotic burden, or higher serum levels of sCD40 ligand (8)- a marker of platelet activation- have consistently been associated with a higher recurrence rate of coronary instability.
Finally, raised levels of brain natriuretic peptide-a marker of ischemic burden- as well as of the degree of underlying impairment of left ventricular function (9), hence a marker of hemodynamic stress, have been associated with a worse short and medium-term outcome, including mortality and recurrence of coronary instability.
One most note that the prognostic value of biomarkers of the four components of acute coronary syndromes is additive (10,11).

Biomarkers : variable clinical utility

However, the clinical utility of these four classes of biomarkers varies.

1) Biomarkers of vascular damage

Biomarkers of vascular damage do not impact on in hospital clinical decision making, but they are important for long term management.

2) Biomarkers of inflammation

Biomarkers of inflammation do not impact on clinical decision making yet. Indeed, the increased risk conferred by inflammation is not abated by currently available therapeutic regimens, including a very early invasive approach (12).
Recent circumstantial evidence suggests that it might be partially reduced with high doses of statins, thanks to their anti-inflammatory action; however, this notion needs to be tested in prospective studies. More importantly, a better knowledge of the triggers and molecular mechanisms of inflammation associated to acute coronary syndromes is warranted in order to design specific anti-inflammatory treatments.

3) Biomarkers of thrombotic burden

Biomarkers of thrombotic burden impact on in-hospital clinical decision making and should be measured in all patients with a non ST elevation acute coronary syndrome clinical decision making.  Indeed, Patients with raised serum levels of troponins exhibit a better outcome if treated with a potent antithrombotic regimen and an invasive approach, while patients with normal levels are not penalised if treated with a cheaper and more comfortable conservative approach.
To measure this biomarker, different essays are commercially available and it is impossible to define a fixed cut off value. However the cut off value for each essay should exceed the concentration corresponding to a total analytical imprecision of 10%.

4) Hemodynamic stress

Biomarkers of hemodynamic stress of do not impact on in hospital clinical decision making, but they are important for long term management.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.


1. Abbate A, Bonanno E, Mauriello A, Bussani R, Biondi-Zoccai GG, Liuzzo G, Leone AM, Silvestri F, Dobrina A, Baldi F, Pandolfi F, Biasucci LM, Baldi A, Spagnoli LG, Crea F. Widespread myocardial inflammation and infarct-related artery patency. Circulation. 2004;110:46-50.

2. Jernberg T, Lindahl B, James S, Larsson A, Hansson LO, Wallentin L. Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome. Circulation. 2004;110:2342-2348.

3. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 1994;331:417–424.

4. Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Münzel T, Simoons ML, Hamm CW, Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation. 2003;108:1440-1445.

5. Heeschen C, Dimmeler S, Hamm CW, Fichtlscherer S, Simoons ML, Zeiher AM. Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. J Am Coll Cardiol. 2005;45:229-237

6. Heeschen C, Dimmeler S, Fichtlscherer S, Hamm C W, Berger J, Simoons ML., Zeiher AM., Prognostic value of placental growth factor in patients with acute chest pain. JAMA. 2004;291:435-441.

7. Hamm CW, Ravkilde J, Gerhardt W, Jorgensen P, Peheim E, Ljungdahl L, Goldmann B, Katus HA. The prognostic value of serum troponin T in unstable angina. N Engl J Med. 1992;327:146-50.

8. Heeschen C, Dimmeler S,Hamm CW, VAN DEN Brand MJ, Boersma E, Zeiher AM, Simoons ML. Solubile CD40 ligand in acute coronary syndromes. N Engl J Med. 2003;348:1104-1111.

9. de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001;345:1014 –1021.

10. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L, FRISC Study Group. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. N Engl J Med. 2000;343:1139-1147.

11. James SK., Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong P, Barnathan ES., Califf R, Topol EJ.,. Simoons ML, Wallentin L, N-terminal pro–brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease. Circulation. 2003;108:275-281.

12. Mueller C, Buettner HJ, Hodgson JM, Marsch S, Perruchoud AP, Roskamm H, Neumann FJ. Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a very early invasive strategy in 1042 consecutive. Circulation. 2002;105:1412-1415.



Vol4 N°05

Notes to editor

Prof. F. Crea
Rome , Italy
Past-Chairman of the ESC Working Group on Coronary Pathophysiology and Microcirculation

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.