Patients presenting with symptoms suggestive of an acute coronary syndrome (ACS) encompass a heterogeneous group of patients with a variable clinical background, different severity of the underlying coronary artery disease, large variation in clinical course and variable risk of subsequent cardiac events. In a substantial proportion of patients with an initial suspicion of ACS, the diagnosis will eventually be ruled out, and the patients will be found to have other cardiac or non-cardiac diagnoses. Thus, patients presenting with symptoms suggestive of ACS constitute a diagnostic, prognostic and therapeutic challenge. Biomarkers, together with the ECG, play crucial roles for early diagnosis of ACS and assessment of the prognosis and are important for tailoring the treatment to the individual patient.
Acute coronary syndrome
Acute coronary syndrome is an umbrella term for acute myocardial infarction (AMI) and unstable angina (UA) and is characterized by abrupt and unpredictable reductions in coronary blood flow causing myocardial ischemia at rest or decreasing levels of exertion and in case of AMI, measurable amounts of myocardial necrosis. ACS is subdivided based on the ECG-changes at presentation in ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS). NSTE-ACS is further divided in non-ST-segment elevation myocardial infarction (NSTEMI) and UA depending on whether myocardial necrosis is demonstrated or not.
Key events for the development of ACS are in most cases a disruption of an atherosclerotic plaque and thrombus formation causing partial or complete occlusion of the infarct-related artery or distal embolization in the coronary tree . However, ACS (and so called type II/secondary AMI) may occur in the absence of plaque rupture and thrombosis in conditions causing supply-demand mismatch to the myocardium, e.g., hypotension, anemia, infection and tachyarrhythmia .
The incidence of ACS is declining in most developed countries [3, 4]. Lifestyle adjustments in the general population, e.g., reduction in smoking and of serum cholesterol levels, have contributed to the reduction in incidence . Among patients with AMI, the relative occurrence of STEMI has decreased and the occurrence of NSTEMI has increased, and NSTEMI is now more common than STEMI . The decrease in incidence has been paralleled by an impressive improvement in mortality, e.g., in Sweden the standardized 30-day mortality in STEMI went from 12.9% to 6.3% between 1996 and 2007 . During the same period there has been an increasing use of evidence-based therapies in ACS, such as revascularization (PCI and CABG), anti-platelet and anti-coagulant agents, ACE-inhibitors and statins .
Biomarkers in ACS
Measurements of biomarkers in serum or plasma might be used for diagnosis, prognosis and selection of appropriate treatment. A multitude of biomarkers has been suggested and evaluated for these purposes [8, 9]. The biomarkers can be grouped in areas reflecting different pathophysiological mechanisms operating in ACS (Figure 1). Biomarkers available (or expected to soon be available) for use in clinical routine are summarized in Table 1. However, currently only a few of them have gained widespread use.
Up to 1954, with the first report that the enzyme, glutamic oxaloacetic transaminase, could be used for diagnosis of AMI , the clinical diagnosis relied solely on the history and on development of diagnostic Q-waves in the ECG. Today, elevated levels of a marker of myocardial damage, particularly cardiac troponin I (cTnI) or cardiac troponin T (cTnT), is a prerequisite for the diagnosis of AMI . An ideal biomarker for diagnosis of AMI should (adopted from ): 1) exist in high concentration in the myocardium; 2) not exist in any other tissue, neither under normal, nor under pathological conditions; 3) not be measurable in plasma under normal conditions; 4) be released only after irreversible damage to the myocardium; 5) be released in direct proportion to the extent of myocardial necrosis; 6) be rapidly released and persist in the plasma long enough to allow a convenient diagnostic time window; and 7) be suitable for development of rapid, reliable and inexpensive methods for measurement. Cardiac troponins fulfill most, but not all, of these requirements. The development of high sensitivity cardiac troponin assays has increased the analytical sensitivity with almost three orders of magnitude compared to the first generation assays, and has made it evident that cardiac troponins indeed are measurable in plasma also under normal conditions . The previous belief that cardiac troponins are only released after irreversible myocardial damage is seriously challenged . The vast majority of patients diagnosed with UA in the pre-troponin era have slight elevations of cardiac troponin, and using the most sensitive assays available it can be questioned whether ‘true’ UA does exist, i.e., without any evidence of myocardial damage (=cardiac troponin elevation) [14, 15]. Furthermore, the cardiac troponin assays with high analytical sensitivity have also shown that cardiac troponins are released at least as early as the previously thought ‘earlier’ markers myoglobin and heart fatty acid binding protein [16, 17]. Therefore, it has been difficult to prove that adding another marker of myocardial damage to cardiac troponin, provide any clinically meaningful benefit over using cardiac troponin alone for diagnosis [16, 17]. However, some 10%–20% of patients with AMI still had non-elevated levels of cardiac troponin at presentation to the emergency room, necessitating serial measurements over at least a 3-h period  in order to be able to reliably rule out AMI. Hence, there is still an unmet clinical need to be able to diagnose ACS, and particularly AMI, with certainty already on admission. Therefore it seems logical to add a marker that reflects some other important pathophysiological aspect of ACS, such as ischemia, activation of the coagulation system or the plaque rupture. However, to find a marker of ischemia has been notoriously difficult, and studies of the suggested marker so far, ischemia modified albumin (IMA), have failed to convincingly and consistently show added clinically relevant diagnostic value although some initial studies showed positive results . The IMA assay was approved by FDA but is no longer available for clinical use. In a study evaluating multiple markers for early diagnosis of AMI , neither of the three markers suggested to indicate plaque rupture, myeloperoxidase (MPO), matrix metalloproteinase 9 (MMP-9) and pregnancy-associated plasma protein-A (PAPP-A) added any clinically meaningful diagnostic information to that of cTnT alone, nor did CD40L and D-dimer. In a systematic review of the literature on novel biomarkers for diagnosing ACS , not a single marker thought to reflect inflammation in general, plaque rupture or activation of the coagulation system or platelets, demonstrated supportive evidence in diagnosing ACS alone or in combination with cardiac troponin (except for MMP-9 in one study ). For a few other markers, heart fatty acid-binding protein (marker of myocardial injury), B-type natriuretic peptide (a marker of ventricular wall stress) and Copeptin (the C-terminal end of the prohormone of vasopressin), the various studies have shown conflicting results [17, 18]. Thus, so far there is inadequate evidence to support routine use, either alone or in combination with cardiac troponin, of any of these novel biomarkers for diagnosing ACS.
Early prognostic evaluation is essential for the application of appropriate treatment and further management. However, when assessing the risk for new cardiac events it is important to define which event or events are of interest, since the biomarkers’ predictive ability might differ considerably between different endpoints. Generally, more biomarkers are predictive of mortality than of AMI. Therefore, information from studies only using composite endpoints may be difficult to interpret and even misleading. Furthermore, to be clinically useful the biomarker must add independent prognostic information to what is already available in routine practice, i.e., the patient history and the ECG. Another important issue to consider when comparing different studies on the prognostic value of risk markers is in which populations the study were performed. Patients enrolled in randomized clinical trials are often highly selected and with established ACS, whereas most observational studies have less restricted inclusion criteria. Generally, the relative risk or odds ratio for a clinical event associated with a positive marker is higher in observational studies. A large number of biomarkers have been shown to predict death or the combined endpoint death/AMI, while much fewer have been shown to be predictive of AMI (Table 1).
It has been convincingly demonstrated, that patients with, compared to without, elevation of cTnI or cTnT have a higher mortality, both short- and long-term. The odds ratio for death for patients with elevated cTnT and cTnI was 3.0 (95% CI 1.6–5.5) and 2.6 (95% CI 1.8–3.6), respectively, in a meta-analysis of randomized clinical trials . In a separate analysis of observational cohort studies the corresponding odds ratios were 5.1 (95% CI 3.2–8.4) and 8.5 (95% CI 3.5–21.1) . Furthermore, there seems to be a dose-response relation, since mortality increases by increasing levels of troponin [22, 23]. In contrast to most other biomarkers, patients with elevated cardiac troponin also have an increased risk of suffering a new AMI. However, there seems to be more of a threshold effect for the risk of a new MI, every reliable elevation of cardiac troponin is associated with an increased risk of a new MI in non-STE ACS . Information about the association between troponin level and risk of re-hospitalization and congestive heart failure, respectively, are limited.
C-reactive protein (CRP) is an acute phase protein, which is synthetized in the liver and increases within 4–6 h after tissue damage or in response to inflammation. It is a commonly used marker in clinical routine for the diagnosis and monitoring of bacterial infection, tissue damage and inflammatory diseases. The currently used high-sensitivity CRP assays have high analytical sensitivity and assay precision, allowing reliable measurement of CRP also at levels found in healthy individuals. CRP has gained interest as a prognostic marker in ACS with the recognition that atherosclerosis is an inflammatory disease. The optimal decision limit as well as the optimal time point for risk stratification, however, is still unclear. Most studies so far have used 3 or 10 mg/L as the decision limit. In AMI, CRP peaks about 24–48 h after onset and the peak level is related to the infarct size . In ACS patients the CRP level is independently associated with long-term risk of death [25, 26], however, for short-term risk the results are contradicting . The ability of CRP to predict non-fatal AMI is questioned  and few studies have studied the incremental value of CRP in relation to usual risk prediction . Measurement of CRP for risk stratification of patients with ACS has received a class IIa recommendation in the National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines , but has not gained widespread use in clinical practice.
The B-type natriuretic peptide
The B-type natriuretic peptide (BNP) and the N-terminal part of its prohormone (NT-proBNP) are mainly released from myocytes in the cardiac ventricles in response to increased stretch and wall tension . However, the natriuretic peptides might also rise in response to a number of other stimuli, among them ischemia per se and cytokines [30, 31]. BNP and NT-proBNP have received widespread use for diagnosis of heart failure and evaluation of acute dyspnea. However, BNP and NT-proBNP also rise early after the onset of symptoms in patients with ACS and the levels of natriuretic peptides have been shown to be strong and independent predictors of mortality in a number of studies [32, 33]. However, despite the convincing evidence as markers for risk prediction , the lack of diagnostic value of natriuretic peptides in ACS have so far prevented a more widespread use of BNP or NT-proBNP also in ACS.
Measurements of renal function such as serum creatinine and estimation of creatinine clearance have been shown to carry independent prognostic information in ACS . However, creatinine concentration is an unreliable estimate of the glomerular filtration rate (GFR). The level of creatinine is influenced by factors such as age, gender, muscle mass, physical activity, and diet. Because of the non-linear relationship between creatinine concentration and GFR, it is also too insensitive to detect small decreases in GFR and mild renal dysfunction. Cystatin C is an endogenous inhibitor of cathepsins, which are cysteine proteases. Cystatin C is produced in all nucleated cells at a constant rate and is freely filtered by the glomerulus without secretion or subsequent reabsorption to the blood flow and therefore, has been suggested as a better marker of GFR than serum creatinine, which has been verified in several, but not all comparative studies . However, Cystatin C might also be a systemic marker of ongoing inflammatory processes since cathepsins are proinflammatory . The predictive value of Cystatin C in ACS patients has been evaluated in several studies and Cystatin C has been shown to be an independent predictor of mortality and in some, but not all, a better marker than serum creatinine [36–39].
Growth-differentiation factor-15 (GDF-15) is a distant member of the transforming growth factor-β cytokine superfamily that is induced in the myocardium following pathological stress associated with inflammation or tissue injury . An increasing number of studies have shown that the level of GDF-15 is a strong and independent predictor of mortality in patients with ACS [41–43].
Mid-regional part of the prohormone of adrenomedullin
Adrenomedullin is a 52-amino-acid peptide that is expressed by various tissues including the vessels and the myocardium. Adrenomedullin exhibits protective effects on the heart and the vasculature . The stable mid-regional part of its prohormone, MR-proADM, is elevated in various cardiovascular pathologies and has been shown to be strongly predictive of mortality in populations with cardiovascular disease, especially heart failure  but also AMI .
Selection of therapy
A large number of therapeutic options are available in the management of patients with ACS. However, some of these are rather costly and have potential serious side effects. Therefore, identification of those who benefit most from a particular therapy has become important. The beneficial effects of antithrombotic treatment with low molecular weight heparins, antiplatelet therapy with glucoprotein IIb/IIIa receptor inhibitors, and an invasive approach with early revascularization in NSTE-ACS have all been shown to be predominantly present in patients with elevated troponin [47–49]. Hence, the cardiac troponin level has been incorporated in the treatment algorithms in recent guidelines .
For other biomarkers there are limited data in the literature, GDF-15 has been shown to identify those who benefit from revascularization in one study , likewise Il-6 . For NT-proBNP the results are conflicting regarding revascularization [52, 53].
Search for new markers
There is an intense search for new biomarkers in the cardiovascular field. There has been a rapid development of technologies for proteomic studies and currently many proteomic studies observe 1000–5000 proteins . In analogy with genome-wide association studies, hypotheses free association studies (‘whole proteome scanning’) are underway to identify completely new biomarkers in the cardiovascular field [54, 55].
MicroRNA constitutes a whole new class of biomarkers. MicroRNAs are short, non-coding RNAs that regulate gene expression at the post-transcriptional level and play a role in normal development and physiology, as well as in disease development, including in the cardiovascular system . MicroRNAs are measurable also in circulating blood and are relatively stable. There are some promising results indicating the potential use of some microRNAs (e.g., miR-1, miR-133, miR-208, miR-328 and miR-499) for (early) diagnosis of AMI . However, the studies are so far very small, and the suggested microRNAs need to be evaluated in comparison with cardiac troponin in large multicenter studies.
Combination of biomarkers with cardiac imaging
Rapid and non-invasive imaging techniques, i.e., computerized tomography (CT) coronary angiography and cardiac magnetic resonance imaging, giving detailed anatomical, but also functional, information of the heart are rapidly evolving. Therefore, the combination of imaging with biomarkers seems logical for both diagnostic and prognostic purposes. The optimal combination of measurements of biomarkers and CT coronary angiography for early diagnosis and risk assessment of patients with suspicion of ACS are evaluated in ongoing clinical studies, e.g., the ROMICAT II study .
New applications for biomarkers
Studies using very sensitive cardiac troponin assays have shown that chronically elevated levels above the 99th percentile level of healthy individuals are common among patients with structural heart disease [58, 59]. It is sometimes difficult in clinical practice to differentiate these chronic elevations from acute elevations. Therefore, a marker capable of separating acute from chronic myocardial injury in a single blood sample would be clinically very useful. Likewise, a biomarker capable of separating primary atherothrombotic AMI (AMI type 1) from secondary AMI due to supply/demand imbalance (AMI type 2) would be clinically helpful , since the treatment and management are different between the two forms of AMI. The distinction between the two forms is sometimes difficult, e.g., in the patient with preexisting coronary artery disease with chest pain, rapid atrial fibrillation, unspecific ST-segment depression in the ECG and rising levels of troponin.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.
Research funding: None declared.
Employment or leadership: Dr. Lindahl has served as a consultant for Beckman Coulter Inc., Siemens Healthcare Diagnostics, Roche Diagnostics, Radiometer Medical, bioMérieux Clinical Diagnostics, Philips Healthcare, Fiomi diagnostics AB, and has received a research grant from Roche Diagnostics.
Honorarium: None declared.
Fuster V, Badimon L, Badimon J, Chesebro J. The pathogenesis of coronary artery disease and the acute coronary syndromes (second of two parts). N Engl J Med 1992;326:310–8.Google Scholar
Schmidt M, Jacobsen J, Lash T, Bøtker H, Sørensen H. 25 year trends in first time hospitalisation for acute myocardial infarction, subsequent short and long term mortality, and the prognostic impact of sex and comorbidity: a Danish nationwide cohort study. Br Med J 2012;344:e356.Google Scholar
Vamos EP, Millett C, Parsons C, Aylin P, Majeed A, Bottle A. Nationwide study on trends in hospital admissions for major cardiovascular events and procedures among people with and without diabetes in England, 2004–2009. Diabetes Care 2012;35:265–72.Google Scholar
Wilhelmsen L, Welin L, Svärdsudd K, Wedel H, Eriksson H, Hansson PO, et al. Secular changes in cardiovascular risk factors and attack rate of myocardial infarction among men aged 50 in Gothenburg, Sweden. Accurate prediction using risk models. J Intern Med 2008;263:636–43.Google Scholar
Rogers WJ, Frederick PD, Stoehr E, Canto JG, Ornato JP, Gibson CM, et al. Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J 2008;156:1026–34.Google Scholar
Jernberg T, Johanson P, Held C, Svennblad B, Lindbäck J, Wallentin L. Association between adoption of evidence-based treatment and survival for patients with ST-elevation myocardial infarction. J Am Med Assoc 2011;305:1677–84.Google Scholar
Karmen A, Wroblewski F, LaDue JS. Transaminase activity in human blood. J Clin Invest 1954;34:126–33.Google Scholar
Adams J, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation 1993;88:750–63.Google Scholar
Mousavi N, Czarnecki A, Kumar K, Fallah-Rad N, Lytwyn M, Han S-Y, et al. Relation of biomarkers and cardiac magnetic resonance imaging after marathon running. Am J Cardiol 2009;103:1467–72.CrossrefGoogle Scholar
Wilson SR, Sabatine MS, Braunwald E, Sloan S, Murphy SA, Morrow DA. Detection of myocardial injury in patients with unstable angina using a novel nanoparticle cardiac troponin I assay: observations from the PROTECT-TIMI 30 Trial. Am Heart J 2009;158:386–91.Google Scholar
Venge P, Johnston N, Lindahl B, James S. Normal plasma levels of cardiac troponin I measured by the high-sensitivity cardiac troponin I access prototype assay and the impact on the diagnosis of myocardial ischemia. J Am Coll Cardiol 2009;54:1165–72.PubMedCrossrefGoogle Scholar
Eggers KM, Oldgren J, Nordenskjöld A, Lindahl B. Diagnostic value of serial measurement of cardiac markers in patients with chest pain: limited value of adding myoglobin to troponin I for exclusion of myocardial infarction. Am Heart J 2004;148:574–81.PubMedCrossrefGoogle Scholar
Eggers KM, Venge P, Lindahl B. High-sensitive cardiac troponin T outperforms novel diagnostic biomarkers in patients with acute chest pain. Clin Chim Acta 2012;413:1135–40.Google Scholar
McCann CJ, Glover BM, Menown IB, Moore MJ, McEneny J, Owens CG, et al. Novel biomarkers in early diagnosis of acute myocardial infarction compared with cardiac troponin T. Eur Heart J 2008;29:2843–50.PubMedCrossrefGoogle Scholar
Apple FS, Smith SW, Pearce LA, Murakami MM. Assessment of the multiple-biomarker approach for diagnosis of myocardial infarction in patients presenting with symptoms suggestive of acute coronary syndrome. Clin Chem 2009;55:93–100.PubMedGoogle Scholar
Heidenreich PA, Alloggiamento T, Melsop K, McDonald KM, Go AS, Hlatky MA. The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a meta-analysis. J Am Coll Cardiol 2001;38:478–85.CrossrefPubMedGoogle Scholar
Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000;343:1139–47.Google Scholar
Lindahl B, Diderholm E, Lagerqvist B, Venge P, Wallentin L. Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy. J Am Coll Cardiol 2001;38:979–86.CrossrefPubMedGoogle Scholar
James SK, Oldgren J, Lindbäck J, Johnston N, Siegbahn A, Wallentin L. An acute inflammatory reaction induced by myocardial damage is superimposed on a chronic inflammation in unstable coronary artery disease. Am Heart J 2005;149:619–26.CrossrefPubMedGoogle Scholar
He L-P, Tang X-Y, Ling W-H, Chen W-Q, Chen Y-M. Early C-reactive protein in the prediction of long-term outcomes after acute coronary syndromes: a meta-analysis of longitudinal studies. Heart 2010;96:339–46.CrossrefPubMedGoogle Scholar
James SK, Armstrong P, Barnathan E, Califf R, Lindahl B, Siegbahn A, et al. Troponin and C-reactive protein have different relations to subsequent mortality and myocardial infarction after acute coronary syndrome: a GUSTO-IV substudy. J Am Coll Cardiol 2003;41:916–24.CrossrefPubMedGoogle Scholar
Christenson RH. Preamble: National Academy of clinical biochemistry laboratory medicine practice guidelines for utilization of biomarkers in acute coronary syndromes and heart failure. Clin Biochem 2008;41:208–9.CrossrefPubMedGoogle Scholar
Lindahl B, Lindbäck J, Jernberg T, Johnston N, Stridsberg M, Venge P, et al. Serial analyses of N-terminal pro-B-type natriuretic peptide in patients with non-ST-segment elevation acute coronary syndromes: a Fragmin and fast Revascularisation during InStability in coronary artery disease (FRISC)-II substudy. J Am Coll Cardiol 2005;45:533–41.CrossrefGoogle Scholar
Wiviott SD, de Lemos JA, Morrow DA. Pathophysiology, prognostic significance and clinical utility of B-type natriuretic peptide in acute coronary syndromes. Clin Chim Acta 2004;346:119–28.Google Scholar
James SK, Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong P, et al. 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: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation 2003;108:275–81.Google Scholar
Santopinto JJ, Fox KA, Goldberg RJ, Budaj A, Piñero G, Avezum A, et al. Creatinine clearance and adverse hospital outcomes in patients with acute coronary syndromes: findings from the global registry of acute coronary events (GRACE). Heart 2003;89:1003–8.CrossrefGoogle Scholar
Ferraro S, Marano G, Biganzoli Elia M, Boracchi P, Bongo Angelo S. Prognostic value of cystatin C in acute coronary syndromes: enhancer of atherosclerosis and promising therapeutic target. Clin Chem Lab Med 2011;49:1397–404.PubMedGoogle Scholar
Jernberg T, Stridsberg M, Venge P, Lindahl B. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol 2002;40:437–45.PubMedCrossrefGoogle Scholar
Kilic T, Oner G, Ural E, Yumuk Z, Sahin T, Bildirici U, et al. Comparison of the long-term prognostic value of Cystatin C to other indicators of renal function, markers of inflammation and systolic dysfunction among patients with acute coronary syndrome. Atherosclerosis 2009;207:552–8.Google Scholar
García Acuña JM, González-Babarro E, Grigorian Shamagian L, Peña-Gil C, Vidal Pérez R, López-Lago AM, et al. Cystatin C provides more information than other renal function parameters for stratifying risk in patients with acute coronary syndrome. Rev Esp Cardiol 2009;62:510–9.CrossrefPubMedGoogle Scholar
Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, et al. The transforming growth factor-β superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006;98:351–60.PubMedCrossrefGoogle Scholar
Wollert K, Kempf T, Peter T, Olofsson S, James S, Johnston N, et al. Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007;115:962–71.Google Scholar
Eggers KM, Kempf T, Venge P, Wallentin L, Wollert KC, Lindahl B. Improving long-term risk prediction in patients with acute chest pain: the Global Registry of Acute Coronary Events (GRACE) risk score is enhanced by selected nonnecrosis biomarkers. Am Heart J 2010;160:88–94.Google Scholar
Schaub N, Reichlin T, Twerenbold R, Reiter M, Steuer S, Bassetti S, et al. Growth differentiation factor-15 in the early diagnosis and risk stratification of patients with acute chest pain. Clin Chem 2012;58:441–9.CrossrefPubMedGoogle Scholar
Ishimitsu T, Ono H, Minami J, Matsuoka H. Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disorders. Pharmacol Ther 2006;111:909–27.Google Scholar
Adlbrecht C, Hülsmann M, Strunk G, Berger R, Mörtl D, Struck J, et al. Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients. Eur J Heart Fail 2009;11:361–6.PubMedCrossrefGoogle Scholar
Dhillon OS, Khan SQ, Narayan HK, Ng KH, Struck J, Quinn PA, et al. Prognostic value of mid-regional pro-adrenomedullin levels taken on admission and discharge in non-ST-elevation myocardial infarction. The LAMP (Leicester Acute Myocardial Infarction Peptide) II Study. J Am Coll Cardiol 2010;56:125–33.CrossrefGoogle Scholar
Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group. J Am Coll Cardiol 1997;29:43–8.CrossrefGoogle Scholar
Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet 1999;354:1757–62.Google Scholar
Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, et al. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. J Am Med Assoc 2001;286:2405–12.Google Scholar
Hamm CW, Bassand J-P, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054.Google Scholar
Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. J Am Med Assoc 2001;286:2107–13.Google Scholar
James S, Lindbäck J, Tilly J, Siegbahn A, Venge P, Armstrong P, et al. Troponin-T and N-terminal pro-B-type natriuretic peptide predict mortality benefit from coronary revascularization in acute coronary syndromes: a GUSTO-IV substudy. J Am Coll Cardiol 2006;48:1146–54.CrossrefGoogle Scholar
Windhausen F, Hirsch A, Sanders GT, Cornel JP, Fischer J, van Straalen J, et al. N-terminal pro-brain natriuretic peptide for additional risk stratification in patients with non-ST-elevation acute coronary syndrome and an elevated troponin T: an Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS) substudy. Am Heart J 2007;153:485–92.Google Scholar
Hoffmann U, Truong QA, Fleg JL, Goehler A, Gazelle S, Wiviott S, et al. Design of the Rule Out Myocardial Ischemia/Infarction Using Computer Assisted Tomography: a multicenter randomized comparative effectiveness trial of cardiac computed tomography versus alternative triage strategies in patients with acute chest pain in the emergency department. Am Heart J 2012;163:330–8.Google Scholar
Eggers KM, Lind L, Ahlström HK, Bjerner T, Ebeling Barbier C, Larsson A, et al. Prevalence and pathophysiological mechanisms of elevated cardiac troponin I levels in a population-based sample of elderly subjects. Eur Heart J 2008;29:2252–8.CrossrefGoogle Scholar
Eggers KM, Lagerqvist B, Venge P, Wallentin L, Lindahl B. Persistent cardiac troponin I elevation in stabilized patients after an episode of acute coronary syndrome predicts long-term mortality. Circulation 2007;11:1907–14.CrossrefGoogle Scholar
About the article
Bertil Lindahl is Professor of Cardiology, at the Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Sweden. He has published more than 180 original and review articles.
Published Online: 2013-03-23
Published in Print: 2013-09-01
This article is based on a contribution given at the EuroMedLab Milano 2013 Congress, May, 2013.