Inflammatory mediators appear to be the most intriguing yet confusing subject, regarding the management of patients with acute coronary syndromes (ACS). The current inflammatory concept of atherosclerotic coronary artery disease (CAD) led many investigators to concentrate on systemic markers of inflammation, as well as imaging techniques, which may be helpful in risk stratification and prognosis assessment for cardiovascular events. In this review, we try to depict many of the recently studied markers regarding stable angina (SA), their clinical usefulness, and possible future applications in the field.
Angina is chest discomfort caused by myocardial ischemia without necrosis, further qualified by its precipitating factors, time course to relief, and clinical characteristics, such as pain radiation and quality. Typical angina may be triggered by increased activity (exercise, sexual activity), emotional stress (anger, fright, or stress), or cold, wind, and fever. The discomfort of exertional angina is relieved by rest within 1–5 min or more rapidly with sublingual nitroglycerin and attacks usually last from 2 to 10 min. Characteristically, there is heaviness or pressure retrosternally, with possible radiation to the ulnar aspect of the left arm, neck, jaw, midabdomen, right arm, or shoulders. The average frequency of angina attacks in patients is about 2 per week. Many patients voluntarily cut back their activities to avoid further episodes. Clinically, chronic stable angina (SA) is generally caused by one or more significant obstructive lesions in coronary arteries, defined as stenosis of >50% of the diameter of the left main coronary artery or stenosis of >70% of the diameter of a major epicardial vessel. Precipitating circumstances remain similar between episodes, thresholds may be predicted by patients, and relief patterns become known. Since stenoses are fixed, the angina is due to demand ischemia and seems to be the most common symptom in patients with coronary artery disease (CAD).
Almost 7 million Americans suffer and 400,000 new cases are added each year, resulting in very high economic burden estimated at 1.3% of the NHS budget in the UK and $75 billion in 2000 in the USA [
Distribution of PubMed search results within the last 6 years, per calendar year, with the search terms “biomarkers AND stable angina.”
Distribution of PubMed search results within the last 6 years, per calendar year, with the search terms “biomarkers AND acute coronary syndrome.”
Recently, the Euro heart survey for SA [
In this review article, we try to broach into the majority of the novel biochemical (Table
Summary of the most important data in this review, regarding biomarker use for risk stratification of SA patients.
Biomarker | Study | Comments |
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hs-CRP | Cushman et al., 2005 [ |
Elevated CRP levels were independently associated with increased 10-year risk of CHD in intermediate-Framingham-risk men and high-Framingham-risk women. |
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GDF-15 | Kempf et al., 2009 [ |
GDF-15 remained an independent predictor of CHD mortality in SA patients ( |
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Neopterin | Estévez-Loureiro et al., 2009 [ |
Neopterin was found to be independent predictor of LV dysfunction in SA patients ( |
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IL-6 | Tanindi et al., 2011 [ |
IL-6 levels were correlated with severe LAD stenosis ( |
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IL-10 | Cavusoglu et al., 2011 [ |
Baseline elevated IL-10 levels were an independent predictor of adverse outcome in ACS patients. |
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IL-17 | Liang et al., 2009 [ |
Significant correlation was found between plasma MPO and IL-17 levels in all study participants ( |
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MPO | Liang et al., 2009 [ |
No significant difference between the control (24.2 ± 5.7 |
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SDF-1; CXCL-12 | Stellos et al., 2011 [ |
No correlation of SDF-1 with any biochemical parameter (except an inverse correlation with cholesterol levels, |
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PCT |
Sinning et al., 2011 [ |
Increased PCT levels in ACS group than in SA group ( |
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Fetuin-A | Bilgir et al., 2010 [ |
Decreased fetuin-A levels in SA group than in controls. Higher fetuin-A levels in SA patients, compared to AMI patients (1.67 ± 0.20 ng/mL versus 1.56 ± 0.21 ng/mL, |
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Lp-PLA2 | Ikonomidis et al., 2011 [ |
Major risk factor for CHD and also fatal cardiovascular events, mainly in lipidemic middle-aged men. |
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MMP-8, MMP-9 | Jönsson et al., 2011 [ |
Both MMP-8 and MMP-9 levels did not correlate with clinical characteristics. No difference in serum or plasma levels of MMP-8/MMP-9 between SA patients and controls. |
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TIMP-1, TIMP-2 | Brunner et al., 2010 [ |
No significant difference in TIMP-1/TIMP-2 levels between SA groups and controls. |
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Copeptin | Von Haehling et al., 2012 [ |
Higher baseline copeptin levels in patients with family CAD history. Patients with serum level ≥20.4 pmol/L suffered more events of the combined primary endpoint and of all-cause death in 90 days. |
ACS: acute coronary syndrome; CHD: chronic heart disease; CAD: coronary artery disease; SA: stable angina; AMI: acute myocardial infarction; STEMI: ST-elevation myocardial infarction; NSTEMI: non-ST elevation myocardial infarction; LV: left ventricle; LAD: left anterior descending artery; CRP: C-reactive protein; GDF-1: growth differentiation factor-1; IL-6: interleukin-6; IL-10: interleukin-10; IL-17: interleukin-17; MPO: myeloperoxidase; SDF-1: stromal-cell derived factor-1; CXCL-12: C-X-C motif ligand 12; PCT: procalcitonin; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of metalloproteinases.
The inability of the coronary arteries to increase blood flow in response to increased cardiac metabolic demands is the baseline dysfunction in SA. Normally, coronary endothelium excretes nitric oxide (NO) from its cells as a response to physical activity or any other demanding cardiac effort. Atherosclerosis damages the endothelium and makes endothelial cells permeable to cholesterol as well as other harmful substances, resulting in dysfunctional NO release and atherosclerotic plaque formation. In patients with stable CAD, the process of atherosclerosis involves a fundamentally different histopathology compared with ACS or UA. In chronic stable CAD, we have the formation of a small lipid core with a very thick fibrous cap and a low proclivity to rupture, causing narrowing of the arterial lumen as time goes by and producing symptoms, whereas in ACS/UA the principal histopathologic picture is that of a large lipid core subtended by a thinned, inflamed cap, which harbors the high-risk or vulnerable plaque with a high proclivity for rupture. When these plaques rupture or suffer “fissuring,” clot formation takes over (less in stable CAD, more in ACS/UA) with the usual acute ischemic consequences. The type of exposed substrates to circulation plays a major role in thrombosis formation, as platelets adhere more to exposed collagen and not to foam cells (as in SA). It has been recognized that myocardial ischemia results from an imbalance between myocardial energy supply, from insufficient sources of oxygen and substrate (glucose, free fatty acids), and myocardial oxygen demand. Usually this is simply referred to as an imbalance between myocardial oxygen supply and demand, but it should be clear that substrate supply, utilization, and enzymatic activities, along with other variables involved in metabolism and mitochondrial function, play a major role in the pathogenesis of myocardial ischemia in SA and ACS and during reperfusion ischemic injury. Many of the global relationships and positive feedback loops relating to the inequality of myocardial oxygen supply and demand have not changed in many years, although molecular, electrophysiological, conceptual, and technological advances have been changed considerably. Myocardial energy imbalance is central to all ischemic syndromes: SA, AMI, and cardiogenic shock. The variables determining myocardial oxygen supply are altered by negative feedback loops from complications of poor left ventricular function. Those factors affecting myocardial oxygen demand (heart rate, afterload, preload, and contractility) are altered by positive feedback loops from those events perpetuating systemic features. An increase in left ventricular end-diastolic pressure (LV-EDP) or volume (LV-EDV) increases preload according to Laplace’s Law. Both negative feedback on oxygen supply and positive feedback on oxygen demand tend to increase the inequality between the two and may jeopardize poorly perfused myocardial tissue (Figure
Schematic approach of the current established mechanisms in stable angina pathophysiology (LV: left ventricle; LV-EDP: left ventricular end-diastolic pressure; LV-EDV: left ventricular end-diastolic volume).
During the past decades, various types of serum marker levels were widely used in the risk management of CAD. Mainly, these were markers of myocardial necrosis, such as aspartate transaminase in the 1950s, creatinine kinase (CK) in the 1960s, CK-MB in the 1970s, and troponins in the 1980s, primarily used as diagnostic tests with high negative and positive predictive value. Cardiac troponins are a clear example in clinical medicine where urgent clinical decision and marker measurement are closely related. Although a vast variety of other markers are routinely checked among patients with CAD, their true clinical use in terms of decision-making is not clear. As an example, serum creatinine has been estimated among people with suspected CAD for decades, but only in the last decade has its potential prognostic value been considered.
In patients with SA, circulating biomarkers have been recommended as potentially useful in risk stratification. As an example, the Centers for Disease Control/American Heart Association statement for health-care professionals recommended that one biomarker among SA patients (C-reactive protein, CRP) may be useful as an independent prognostic marker. On the other hand, there is a variability observed between clinicians and centers in which biomarkers are evaluated among SA patients, and only anecdotal evidence exists for biomarker use in common everyday clinical practice other than clinical studies.
There are various possible pathophysiologic mechanisms by which these markers may interfere with prognosis in SA patients, but this is of secondary importance taking into account the urgent clinical decision-making. The primary issue is to understand, if possible, each responsible mechanism of risk prediction and secondarily which marker is better.
In older men and women, elevated CRP has been associated with an increased 10-year risk of CAD, regardless of the presence or absence of other common cardiac risk factors [
It is a cytokine involved in cell-differentiation and embryogenesis and belongs to the superfamily of proteins called “
A large-scale study regarding the use of GDF-15 levels in SA patients published by Schaub et al. [
Our suggestion is that these findings, albeit novel and useful, have to be validated by more studies and also different researchers, in a multicenter basis, because most of the available data has been reported by the same research group.
Neopterin is a marker of macrophage activation, atherosclerotic plaque progression, fibrous cap disruption, and intracoronary thrombus formation. It is a pteridine derivative and a byproduct of the guanosine triphosphate-biopterin pathway. Neopterin has been studied in the concept of discovering a connection between the inflammatory process and left ventricular (LV) function, as depicted by left ventricular ejection fraction (LVEF) [
Interleukin-6 is a 22–27 kD glycoprotein secreted by activated monocytes, vascular smooth muscle cells, and adipose tissue and acts as both an inflammatory and anti-inflammatory cytokine in response to a stressful insult of any kind such as trauma, infection, and burns. Inflammation has been accepted to play a role at all stages of atherosclerotic CAD including progression and rupture of the plaque [
This cytokine is studied in relationship between other biomarkers and conventional risk factors in order to assess its clinical value. In a recent study including 34 patients with SA, levels of IL-6 were correlated with severe stenosis of the left anterior descending artery (LAD) and a higher Gensini score (as an objective score of CAD severity). Interestingly, when patient groups were compared, STEMI and NSTEMI groups had significantly higher IL-6 levels than the SA group (
Larger studies combining objective coronary angiographic parameters and histologic findings may be helpful in evaluating the use of IL-6 as risk predictor.
Interleukin-10 is not a new member in ACS research, but there is growing controversial literature regarding its prognostic value. This cytokine is mainly expressed in monocytes and type 2 T helper cells (
It is a 150 kD peroxidase enzyme stored in azurophilic granules of the neutrophil, secreted at sites of inflammation, interfering in the pathway of cell oxidation, and has a well-documented role in atherosclerotic disease, in terms of plaque progression and vulnerability, along with matrix metalloproteinases (MMPs) [
In a 3,000 patients’ population study, high levels of MPO were an independent predictive risk factor for developing CAD in healthy individuals (OR for the highest quartile of MPO 1.36, 95% CI 1.07–1.73) [
Direct comparison of MPO levels between studies is obtrusive, because the sampling and laboratory assays for MPO levels seem to differ. In conclusion, this data suggests that MPO is a powerful marker of acute coronary inflammation and also a strong mediator for neutrophil activation. As research groups remain in controversy, we need more data to integrate the use of MPO in everyday clinical practice.
Interleukin-17 is a 155-amino acid protein that is a disulfide-linked, homodimeric, secreted glycoprotein with a molecular mass of 35 kD. It is a potent mediator in delayed-type reactions by increasing chemokine production in various tissues to recruit monocytes and neutrophils to the site of inflammation. Interestingly, IL-17 bears no resemblance to any other known proteins or structural domains [
The role of IL-17 in SA or CAD remains under investigation. It is established that Th17 cells producing IL-17 are involved in the pathogenesis of atherosclerosis inducing vascular endothelial cell apoptosis, but the exact pathway is not clear [
In a small population study [
The stromal cell-derived factor-1 (SDF-1) is a small cytokine that belongs to the larger family of intecrines, chemokines that can be classified into two subgroups, the CC and the CXC family, with SDF-1 belonging to the latter. It is secreted in response to any vascular injury or ischemia and regulates recruitment of CXCR4+ cells on the vascular wall and there is evidence for its crucial role in tissue regeneration and revascularization, reflecting a possible cardioprotective effect after myocardial infarction
When SDF-1 was compared with classic cardiovascular risk factors such as arterial hypertension, diabetes, smoking, or hyperlipidemia, there was no association found and no correlation with any biochemical parameter (except an inverse correlation with cholesterol levels,
Based on currently available data, SDF-1 can discriminate SA from ACS in the presence of nonvalvular arrhythmias, but not SA from acute ischaemic episodes
Procalcitonin is a peptide precursor of calcitonin, composed of 116 amino acids and produced by parafollicular cells (C cells) of the thyroid gland and by the neuroendocrine cells of the lung, intestine, and liver. It is a well-established biomarker in critically ill patients, in terms of predicting mortality, sepsis, and septic shock development, distinguishing bacterial from nonbacterial infections and being helpful in reducing unnecessary antibiotic therapy [
Recently [
Serum PCT levels might be a representative marker for the patients’ inflammatory status and could be used for risk stratification in CAD, but there are few available data regarding SA.
Fetuin-A has been recognized as an anti-inflammatory cytokine and modulator in the atherosclerotic process [
This 50 kDa protein is a phospholipase
There is growing data regarding the positive correlation of Lp-PLA2 levels and cardiovascular risk. In the West of Scotland Coronary Prevention Study (WOSCOPS), almost 6,600 hyperlipidemic middle-aged males were followed up for 5 years and inflammatory markers were measured. The strongest predictor of an adverse cardiovascular outcome was Lp-PLA2, independently from traditional markers such as CRP (relative risk of 1 SD increase = 1.18, 95% CI: 1.05–1.33,
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that belong to a larger family of proteases known as the metzincin superfamily. They are incriminated for plaque development in atherosclerotic disease and also in plaque rupture and subsequent atherothrombosis [
The levels of MMPs have been consequently evaluated in different CAD patients, including SA and ACS. In a recent study, levels of both MMP-2 and MMP-9 were significantly higher in patients with ACS compared to SA or healthy controls with normal coronary arteriography, which might indicate that the release of these two MMPs is related to the pathophysiology of ACS only [
In conclusion, since the neutrophil release of MMP-9 is thought to be an early marker of neutrophil activation, these findings may depict a persistent neutrophil activation in SA patients but not clarify MMPs value in risk stratification.
They are the main regulators of matrix metalloproteinase activity and compromise a family of four protease inhibitors, TIMP-1, TIMP-2, TIMP-3, and TIMP-4. The balance between TIMPs and MMPs is thought to be decisive for plaque stability. Interestingly, reduced amounts of TIMP-1 and TIMP-2 (the main endogenous regulators of MMP-8 and MMP-9 activity) have been reported in unstable atherosclerotic lesions compared to stable atherosclerotic lesions [
There is very limited and also controversial data regarding SA patients, with a few clinical studies reporting increased plasma levels of TIMP-1 in SA patients [
Copeptin is the C-terminal of provasopressin, composed of 39 amino acids and secreted from neurohypophysis in response to stimuli (hemodynamic or osmotic type). It has been recently proposed by several study groups as an early marker of AMI risk stratification and prognosis in chronic heart failure [
In a large cath lab cohort (2,700 patients; SA group
In short, copeptin may be a useful prognostic tool for the prediction of major adverse cardiovascular events such as AMI, stroke, and all-cause mortality in CAD patients, but these findings cannot be extrapolated in SA. Further studies should investigate copeptin exclusively in SA patients and the optimal cutoff value.
MicroRNAs (also known as miRs or miRNAs) are RNAs of a non-coding molecule approximately 25-NT-long, that negatively regulate gene expression by binding to 39 untranslated regions of targeted messenger RNAs [
In a study by Latronico and Condorelli [
Further studies are needed, with larger populations, to address the potential utility of plasmatic miRNAs as biomarkers of SA, as well as to clarify the mechanisms of their release in serum.
Compared to a simple exercise electrocardiography testing (XECG), perfusion imaging with 201Thallium or 99mTechnetium-sestamibi raises sensitivity, but prognostic value is less established [
With the increasing use of hybrid single photon emission computed tomography (SPECT/CT) devices, myocardial perfusion imaging (MPI) and coronary artery calcium (CAC) scoring can be easily combined and performed in a single session. However, in symptomatic patients with a very high CAC score, it is still unclear if MPI will provide any benefit in terms of the resulting implications for treatment as well as short-term prognosis. In a recent study by Prescott et al. [
In the ongoing iPOWER study [
In a recently published meta-analysis on the diagnostic accuracy and posttest outcomes of XECG and SPECT [
There is growing evidence suggesting that the use of a fixed marker panel combined with classical, easy, accessible data prior to testing may augment prognostic strength and accuracy in clinical practice [
Moreover, taking into account the very low reported mortality rates in SA, in the era of new available pharmacological agents (i.e., ranolazine) [
With the emergence of novel, sensitive biomarkers of inflammation, myocyte necrosis, vascular damage, and hemodynamic stress, it is becoming possible to characterize noninvasively the participation of different contributors in any individual patient. Although there are several novel biomarkers proposed for risk stratification in SA and our understanding for the specific biochemical role of each marker in the disease is still limited, it is plausible that elevated levels of circulating markers of inflammation reflect an intensification of focal inflammatory processes that destabilize vulnerable plaques.
Cardiac serum and imaging biomarkers provide a convenient and noninvasive means in clinical practice, in order to gain insights into the underlying causes and consequences of stable CAD that mediate the risk of recurrent or new events and may be targets for specific therapeutic interventions.
The authors declare that there is no conflict of interests regarding the publication of this paper.
George Tsaknis performed the literature search and wrote and drafted the paper; Iraklis Tsangaris critically reviewed the paper; and Ignatios Ikonomidis and Argirios Tsantes had the main concept idea and critically reviewed the paper.