Inflammatory markers and coronary artery disease

doi:10.1016/j.coph.2004.01.002

Current Opinion in Pharmacology

Volume 4, Issue 2, April 2004, Pages 124-131

https://doi.org/10.1016/j.coph.2004.01.002 Get rights and content

Abstract

In the past decade, the important role of inflammatory processes in the development and progression of atherosclerosis has been clearly established. Over the past two years, different circulating (inflammatory) biomarkers indicating the instability of atherosclerotic plaques have been identified. These new markers do not only serve as diagnostic tools for the identification of patients with unstable angina or acute myocardial infarction but also help us to identify high-risk patients. As a result, different markers are used clinically for risk stratification in stable coronary artery disease as well as in acute coronary syndromes.

Introduction

Atherosclerosis is widely accepted as a chronic inflammatory disease initiated by different vascular and extravascular sources 1., 2.. Because a large number of epidemiologic studies have reported associations between various ‘inflammatory’ factors and coronary artery disease (CAD), many systemic markers of inflammation have been investigated and linked to predict future cardiovascular events and identify patients at risk. The present review summarizes findings gained in several clinical trials. Moreover, we discuss novel inflammatory biomarkers used to identify patients at risk with either stable or activated CAD (e.g. pregnancy-associated plasma protein-A [PAPP-A], myeloperoxidase [MPO]), as well as anti-inflammatory markers (e.g. interleukin [IL]-10).

Section snippets

Patients with unidentified or documented stable coronary heart disease

In a recent meta-analysis, fibrinogen, leukocyte count, albumin and C-reactive protein (CRP) were associated with CAD [3]. However, other markers of the inflammatory cascade are also predictive for development of CAD or cardiovascular events, including D-dimer, IL-6, plasminogen activator, intercellular adhesion molecules, tumour necrosis factor-α (TNF-α), lipoprotein phospholipase A₂ [4], IL-18 [5] and the metalloproteinase PAPP-A [6]. Serum amyloid A — another acute-phase reactant — is

Patients with acute coronary syndromes

Approximately 1.4 million patients with acute coronary syndromes (ACS) without ST-segment elevation are hospitalized annually in the US [42] Markers of myocyte necrosis, such as creatine kinase-myocardial band and cardiac troponin, are invaluable diagnostic tools for such patients and are routinely used for risk stratification. However, even cardiac troponin, a highly specific marker of cardiac myocyte necrosis, has a relatively low diagnostic sensitivity for ACS, with only 22% to 50% of

Conclusions

In stable patients with suspected or documented CAD, CRP appears to represent the most effective and efficient marker of low grade inflammation for the prediction of future cardiovascular events. Furthermore, there are several ongoing trials to investigate whether CRP levels can also be used for monitoring different therapeutic strategies in addition to our classical risk markers (e.g. LDL cholesterol). In patients with ACS, however, the use of novel, more specific inflammatory markers (e.g.

Update

Evidence suggests that placental growth factor, a member of the vascular endothelial growth factor family, acts as a primary inflammatory instigator of atherosclerotic plaque instability. Very recently, we were able to demonstrate that elevated levels of placental growth factor independently predict adverse events both in a cohort of patients with angiographically confirmed ACS and in a more heterogeneous cohort of patients presenting to an emergency department with acute chest pain [82].

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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of special interest
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of outstanding interest

Acknowledgements

There is no conflict of interest in connection with this article. This study was supported by the Deutsche Forschungsgemeinschaft SFB 553 Project C5.

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Citation Excerpt :
Early risk stratification is essential in patients with CAD for better medical care, particularly in those with ACS. Inflammatory biomarkers are usually used for risk stratification among CAD patients [23]. Pentraxin-3 may be identified as an early marker of local inflammation in the vasculature [24].
Studies on the prognostic significance of circulating pentraxin-3 level in patients with coronary artery disease (CAD) have yielded conflicting results. The aim of this meta-analysis was to evaluate the prognostic value of circulating pentraxin-3 level in CAD patients.
We made a systematic literature search in Pubmed, Embae, CNKI, Wanfang, and VIP database from their inception to January 10, 2019 for prospective cohort studies that investigated the association between pentraxin-3 level and adverse outcomes in patients with CAD. The outcome measures were all-cause mortality, cardiac death, and cardiac events (cardiac death, nonfatal myocardial infarction, heart failure or coronary revascularization). Multivariable-adjusted risk ratio (RR) with 95% confidence intervals (CI) was pooled for the highest versus the lowest pentraxin-3 group to summarize the predictive value.
Nine studies were included, enrolling 5,174 CAD patients. Overall, CAD patients with the highest pentraxin-3 level had an increased risk of all-cause mortality (RR 1.81; 95% CI 1.43–2.28), cardiac death (RR 1.77; 95% CI 1.38–2.26), and cardiac events (RR 1.61; 95% CI 1.16–2.25). However, elevated pentraxin-3 level appeared to not significantly increase the risk of cardiac events (RR 1.63; 95% CI 0.71–3.72) in stable CAD subgroup.
In CAD patients, elevated circulating pentraxin-3 level is possibly an independent predictor of all-cause mortality, cardiac death, and cardiac events. However, interpretation of these findings should be with caution due to the small number of studies analyzed.
Resolvins as proresolving inflammatory mediators in cardiovascular disease
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Currently, these diseases represent the greatest threat to the worldwide human health and welfare; in fact, coronary artery disease (CAD) remains to be the leading cause of death in the world [77]. There is extensive epidemiologic literature supporting the association between inflammation and CAD [18,77,102,105]. Current evidence supports that inflammatory cells and proteins, and inflammatory responses from vascular cells play a major role in the development and propagation of CAD, since they are major forces underlying the onset of coronary plaques, their unstable progression and eventual rupture.
Cardiovascular disease (CVD) represents a global burden with a prevalence that continues increasing progressively. CVD comprises a group of disorders of the heart and blood vessels including coronary heart disease, cerebrovascular disease and peripheral arterial disease. This group of disorders is associated with an inflammatory process which can participate in the pathophysiology of these diseases. Inflammation resolution is an active process involving the participation of pro-resolving mediators such as lipoxins, resolvins, protectins and maresins. Pro-resolving mediators are bioactive molecules generated from omega-3 polyunsaturated fatty acids (PUFAs); among these eicosapentaenoic acid (EPA; C20:5n3) and docosahexaenoic acid (DHA; C22:6n3) are the precursors of resolvins. Pro-resolving mediators orchestrate the correct resolution of inflammation and also stimulate tissue regeneration. Their deregulation can lead to chronic inflammation involving CVD. The discovery of these novel lipid mediators opens a new range of possibilities for the design of anti-inflammatory agents with therapeutic potential for a wide variety of diseases. The present work summarizes the available data about the general characteristics, structure and biosynthesis of resolvins and their relation as protective compounds in CVD.
TNF-α -308G>A and IL-6 -174G>C polymorphisms in Tunisian patients with coronary artery disease
2010, Clinical Biochemistry
Our aim was to evaluate the contribution of tumor necrosis factor (TNF)-α −308G > A and interleukin (IL)-6 −174G > C gene promoter variants to the presence of coronary artery disease (CAD) in Tunisians.
Study subjects comprised 418 angiographically proven CAD patients and 406 age-, gender-, and ethnic origin-matched controls. Genotyping was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.
There were no significant differences in the allelic distribution of TNF-α −308A (19.6% vs. 19.0%, P = 0.73), and IL-6 −174C (15.6% vs. 14.3%, P = 0.47) promoter polymorphisms between CAD patients and control subjects, respectively. In addition, single locus analysis revealed no differences in genotype frequencies between the two study groups, and the combined distribution of both genotypes did not differ significantly between controls and CAD patients (P > 0.05).
There is no allelic or genotypic association of TNF-α −308G > A and IL-6 −174G > C promoter polymorphisms with CAD in Tunisians, thereby confirming an ethnic-selective contribution of both gene variants to CAD presence.
Cholesterol crystals piercing the arterial plaque and intima trigger local and systemic inflammation
2010, Journal of Clinical Lipidology
Citation Excerpt :
This event then leads to the disruption of the plaque cap and overlying endothelium, triggering a systemic inflammatory response (Fig. 4). The local production of interleukin (IL)-6 molecule by lymphocytes occurs in response to intimal injury that then circulates to the liver and signals the production of hs-CRP, which is an acute-phase reactant.3,4,18,19 Plaque rupture may occur suddenly or slowly on the basis of the size of the lipid pool.
The response to arterial wall injury is an inflammatory process, which over time becomes integral to the development of atherosclerosis and subsequent plaque instability. However, the underlying injurious agent, critical to this process, has not received much attention. In this review, a model of plaque rupture is hypothesized with two stages of inflammatory activity. In stage I (cholesterol crystal-induced cell injury and apoptosis), intracellular cholesterol crystals induce foam cell apoptosis, setting up a vicious cycle by signaling more macrophages, resulting in accumulation of extra cellular lipids. This local inflammation eventually leads to the formation of a semi-liquid, lipid-rich necrotic core of a vulnerable plaque. In stage II (cholesterol crystal-induced arterial wall injury), the saturated lipid core is now primed for crystallization, which can manifest as a clinical syndrome with a systemic inflammation response. Cholesterol crystallization is the trigger that causes core expansion, leading to intimal injury. We recently demonstrated that when cholesterol crystallizes from a liquid to a solid state, it undergoes volume expansion, which can tear the plaque cap. This observation of cholesterol crystals perforating the cap and intimal surface was made in the plaques of patients who died with acute coronary syndrome. We have also demonstrated that several agents (ie, statins, aspirin, and ethanol) can dissolve cholesterol crystals and may be exerting their immediate benefits by this direct mechanism. Also, because recent studies have demonstrated that high-sensitivity C-reactive protein may be a reliable marker in selecting patients for statin therapy, it could reflect the presence of intimal injury by cholesterol crystals. This was demonstrated in an atherosclerotic rabbit model. Therefore, we propose that cholesterol crystallization could help explain in part both local and systemic inflammation associated with atherosclerosis.
Plasma levels of myeloperoxidase are not elevated in patients with stable coronary artery disease
2008, Clinica Chimica Acta
Plasma and serum levels of myeloperoxidase (MPO), a redox-active hemoprotein released by polymorphonuclear neutrophils (PMN) upon activation, is now recognized as a powerful prognostic determinant of myocardial infarction in patients suffering acute coronary syndromes. However, there is limited information on whether systemic MPO levels are also elevated and of discriminating value in patients with stable coronary artery disease (CAD) representing different ethnic groups.
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Las funciones de riesgo cardiovascular constituyen la mejor herramienta para establecer prioridades en prevención primaria. Después de descartarse la original de Framingham por sobrestimar excesivamente el riesgo real, las funciones adaptadas de REGICOR y SCORE son las dos disponibles en España, aunque la función de REGICOR es la única validada en nuestra población. La estimación del riesgo ha mostrado su utilidad en la toma de decisiones, especialmente para el tratamiento de la hipercolesterolemia; sin embargo, el hecho de que la mayoría de los acontecimientos cardiovasculares se den en individuos clasificados en el grupo de riesgo moderado refleja la escasa capacidad de discriminación de los factores de riesgo clásicos. Con todo, los nuevos elementos propuestos para el cálculo del riesgo (proteína C-reactiva, detección de calcio intracoronario, índice íntima-media carotídea, índice tobillo/brazo) no mejoran la capacidad predictiva de los factores de riesgo clásicos. La alternativa más sólida parece entonces la identificación del «paciente vulnerable» basada en los marcadores de placa vulnerable (inestable o de alto riesgo), sangre vulnerable (tendencia a la trombosis) y miocardio vulnerable (eléctricamente inestable o arritmogénico). Discutimos la posible efectividad de la utilización combinada de las funciones de riesgo, junto con nuevos marcadores de riesgo y pruebas no invasivas, para aumentar la precisión de la selección de pacientes candidatos a prevención primaria de las enfermedades cardiovasculares.
Cardiovascular risk functions are regarded as the best tools for establishing priorities in primary prevention. Since the original Framingham risk chart fell into disuse because it greatly overestimated the real risk, the adjusted REGICOR and SCORE functions have become widely available in Spain, although the REGICOR function is the only one that has been validated for use in the Spanish population. Risk estimates have been shown to be useful for decision-making, particularly on the treatment of hypercholesterolemia. However, the fact that the majority of cardiovascular events occurs in individuals classified as being at a medium risk is evidence for the poor discriminative ability of classical risk factors. Despite the use of new parameters proposed for estimating cardiovascular risk, such as the C-reactive protein level, the detection of coronary calcification, the carotid intimamedia thickness and the ankle-brachial index, there has been no improvement in the predictive capacity of classical risk factors. The most promising alternative seems to be the identification of “vulnerable patients” using markers of vulnerable plaque (ie, unstable or highrisk plaque), vulnerable blood (ie, with a tendency for thrombosis), and vulnerable myocardium (ie, electrically unstable or with a tendency for arrhythmia). In this article, we discuss whether the combined use of cardiovascular risk functions, novel risk markers and noninvasive tests can be effective in increasing the accuracy of patient selection for the primary prevention of cardiovascular disease.

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Inflammatory markers and coronary artery disease

Abstract

Introduction

Section snippets

Patients with unidentified or documented stable coronary heart disease

Patients with acute coronary syndromes

Conclusions

Update

References and recommended reading

Acknowledgements

Am J Cardiol

Am J Pathol

Lancet

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Circulation

Br J Haematol

Circ Res

J Biol Chem

Circulation

JAMA

Inflammation in atherosclerosis

Nature

Inflammatory markers of coronary risk

N Engl J Med

Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies

JAMA

Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group

N Engl J Med

Pregnancy-associated plasma protein A as a marker of acute coronary syndromes

N Engl J Med

Association between serum amyloid A proteins and coronary artery disease: evidence from two distinct arteriosclerotic processes

Circulation

The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina

N Engl J Med

Population distributions of C-reactive protein in apparently healthy men and women in the United States: implication for clinical interpretation

Clin Chem

Lack of seasonal variation in C-reactive protein

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Absence of diurnal variation of C-reactive protein concentrations in healthy human subjects

Clin Chem

Measurement of serum C-reactive protein concentration in myocardial ischaemia and infarction

Br Heart J

Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group

Lancet

Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men

N Engl J Med

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JAMA

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Inflammation and atherosclerosis

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Low density lipoprotein and very low density lipoprotein are selectively bound by aggregated C-reactive protein

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C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries

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A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis

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Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells

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