Inflammatory biomarkers for predicting cardiovascular disease

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Inflammatory biomarkers for predicting cardiovascular disease

Lee Stoner, Adam A. Lucero, Barry R. Palmer, Lynnette M. Jones, Joanna M.Young, James Faulkner

PII: S0009-9120(13)00275-0DOI: doi: 10.1016/j.clinbiochem.2013.05.070Reference: CLB 8412

To appear in: Clinical Biochemistry

Received date: 26 December 2012Revised date: 27 May 2013Accepted date: 30 May 2013

Please cite this article as: Stoner Lee, Lucero Adam A., Palmer Barry R., Jones LynnetteM., Young Joanna M., Faulkner James, Inflammatory biomarkers for predicting cardio-vascular disease, Clinical Biochemistry (2013), doi: 10.1016/j.clinbiochem.2013.05.070

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http://dx.doi.org/10.1016/j.clinbiochem.2013.05.070

http://dx.doi.org/10.1016/j.clinbiochem.2013.05.070

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ACCEPTED MANUSCRIPTStoner et al Page 1

INFLAMMATORY BIOMARKERS FOR PREDICTING CARDIOVASCULAR DISEASE

Running title: Inflammatory Biomarkers

Lee Stoner1*

, Adam A. Lucero1, Barry R. Palmer

2, Lynnette M. Jones

3, Joanna M. Young

4, James Faulkner

1

1School of Sport and Exercise, Massey University, Wellington, New Zealand.

2Institute of Food, Nutrition and Human Health, Massey University, New Zealand.

3School of Physical Education, Sport and Exercise Sciences, University of Otago, Dunedin, New Zealand.

4Lipid and Diabetes Research Group, Diabetes Research Institute, Christchurch, New Zealand.

*Corresponding Author: Lee Stoner, Ph.D.

Email: [email protected]

Telephone: +64.4.801.5799 ext 6240

Fax: +64.4.801.4994

Address: School of Sport and Exercise, Private Bag 756, Massey University, Wellington 6140, New Zealand.

Word Count: 9,488

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ABSTRACT

The pathology of cardiovascular disease (CVD) is complex; multiple biological pathways have been implicated,

including, but not limited to, inflammation and oxidative stress. Biomarkers of inflammation and oxidative stress

may serve to help identify patients at risk for CVD, to monitor the efficacy of treatments, and to develop new

pharmacological tools. However, due to the complexities of CVD pathogenesis there is no single biomarker

available to estimate absolute risk of future cardiovascular events. Furthermore, not all biomarkers are equal; the

functions of many biomarkers overlap, some offer better prognostic information than others, and some are better

suited to identify/predict the pathogenesis of particular cardiovascular events. The identification of the most

appropriate set of biomarkers can provide a detailed picture of the specific nature of the cardiovascular event. The

following review provides an overview of existing and emerging inflammatory biomarkers, pro-inflammatory

cytokines, anti-inflammatory cytokines, chemokines, oxidative stress biomarkers, and antioxidant biomarkers. The

functions of each biomarker are discussed, and prognostic data are provided where available.

Keyword: biomarkers, inflammation, oxidative stress, cardiovascular disease, chemokines, cytokines

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INTRODUCTION

Multiple biological pathways have been implicated in the etiology of cardiovascular disease (CVD), including, but

not limited to inflammation and oxidative stress. The identification of biological markers of inflammation and

oxidative stress may assist the physician in monitoring the efficacy of treatments, and facilitate the development of

new pharmacological tools for patients at risk of CVD. However, due to the complexities of CVD pathogenesis there

is no single biomarker available to estimate absolute risk of future cardiovascular events. Furthermore, not all

biomarkers are equal; the functions of many biomarkers overlap, some offer better prognostic information than

others, and some are better suited to identify/predict the pathogenesis of particular cardiovascular events. The

following review provides an overview of existing and emerging biomarkers of inflammation and oxidative stress.

BIOMARKER DEFINITION

The US National Institutes of Health/Food and Drug Administration in 2001 defined a biomarker as a characteristic

that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or

pharmacological responses to a therapeutic intervention [1]. The levels of an ideal biomarker should be measurable

in a sample such as blood, urine, or tissue biopsy and should relate to a clinical phenotype either causally or

indirectly.

INFLAMMATORY BIOMARKERS

Atherosclerosis, the precursor to CVD, is recognized as a chronic inflammatory disease of large arteries [2, 3].

While the process of atheroma formation has been extensively reviewed elsewhere [4], some of the relevant steps in

atheromatous plaque development are briefly outlined here. Pathological studies show the abundant presence of

inflammatory cells, like monocyte-derived macrophages and T-lymphocytes at the site of rupture or superficial

erosion [3, 5]. These morphological characteristics are preceded by dysfunction of activated endothelial cells, which

produce adhesion molecules that interact with inflammatory cells [3, 6]. The ability of monocyte-derived

macrophages to secrete various cytokines, chemokines, growth-factors, and disintegrins, then leads to activation and

proliferation of smooth muscle cells (SMCs), lesion progression, and finally to the weakening of a vulnerable plaque

by matrix degradation of its fibrous cap [5]. Once inflammation has been triggered and cytokine release is initiated

at the onset of atherosclerotic lesion development, a number of factors that are found in the atherosclerotic plaque

can participate in maintaining and amplifying cytokine production, including: adipokines, angiotensin II (ANG II),

heat shock proteins (HSPs), immune complexes, reactive oxygen species (ROS), and pro-inflammatory cytokines

(Table 1).

ADVANCED GLYCATION END PRODUCTS (AGEs)

AGEs, the products of non-enzymatic glycation and oxidation of proteins and lipids, accumulate in the vessel wall

following oxidative stress [7]. AGEs may exert their pathogenic effects by engaging cellular binding sites/receptors.

The interaction of AGEs with macrophages activates macrophages in an NF-κB-dependent fashion, leading to the

induction of platelet-derived growth factor (PDGF), insulin-like growth factor (IGF)-I, and pro-inflammatory

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cytokines, such as interleukin-1β (IL-1β) and tumour necrosis factor- α (TNF-α) [8]. Binding of AGEs to the

endothelial receptor for advanced glycation end products (RAGE) results in the depletion of cellular antioxidant

defence mechanisms (e.g., glutathione, vitamin C) [9] and the generation of reactive oxygen species (ROS) [10]. As

a consequence of the increased cellular oxidative stress, AGE-activated endothelial cells express pro-coagulant

tissue factor and adhesion molecules such as E-selectin, intracellular cell-adhesion molecule-1 (ICAM-1), and

vascular cell-adhesion molecule-1 (VCAM-1) [9, 11].

Increased levels of AGEs have been positively associated with increased arterial stiffness in relatively

healthy adults [12], and have been shown to predict all-cause [13] and cardiovascular mortality in older adults [13-

15]. Semba et al [13] reported a hazard ratio (HR) of 2.11 (95% CI: 1.27–3.49, P=0.003) for 1,013 adults aged 65 or

above with the highest tertile for adjusted plasma carboxymethyl-lysine (CML, a dominant AGE). Notably, the HR

was lower for all-cause mortality (HR: 1.84, 95%CI: 1.30-2.50, P=0.006), suggesting that high plasma CML may be

more specifically involved in CVD.

ANGIOTENSIN II (ANG II)

ANG II is the main effector of the renin-angiotensin-aldosterone system [16]. Vasoconstrictor action and anti-

natriuretic properties allow ANG II to regulate blood pressure and salt and fluid volume homeostasis [16]. ANG II

is also pro-inflammatory, inducing the production of ROS, pro-inflammatory cytokines, and adhesion molecules.

ANG II stimulates ICAM-1 and VCAM-1 expression in endothelial cells and SMCs [17-20], as well as E- and P-

selectin expression in endothelial cells [21, 22]. ANG II also enhances the functional adhesion of monocytes to

endothelial cells [23, 24] and stimulates MCP-1 production in SMCs and monocytes [25, 26]. In addition, ANG II

enhances the vascular expression of TNF-α, IL-6, and IL-1β as well as chemokines and chemokine receptors [27-

29]. These effects are primarily mediated by angiotensin II type 1 receptors (AT1R) and opposed by AT2R receptors

(AT2R); the latter receptors are also associated with pro-apoptotic and neuroprotective effects [16, 27, 30].

Increased ANG II levels have been reported in patients with hypertension [31], chronic heart failure (CHF)

[32] and unstable angina (UA) [33]. Conversely, both angiotensin-converting enzyme (ACE) inhibitors

and angiotensin II receptor blockers (ARBs) have been shown to favorably reduce left ventricular mass [34], intima-

media thickness [35] and arterial stiffness [36]. ACE inhibitors have also been shown to improve survival following

myocardial infarction (MI) [37], and to reduce the risk of cardiovascular events in patients with stable CAD [38].

E-SELECTIN

E-selectin is a member of the cellular adhesion molecule family, which also includes VCAM and ICAM-1. Each has

a plasma soluble form, which can serve as a surrogate marker for increased expression of CAM’s on vascular

endothelial cells, and reflect inflammation and activation of endothelial cells [39]. The selectin family has three

members: L-, P- and E-selectin, of which the latter is of particular interest, as it is found only on the endothelium

[40, 41]. E-selectin promotes endothelial-leukocyte interactions [42]. The adherence of certain leukocytes to the

intimal surface seems to be a subsequent event in atherogenesis, and this phenomenon is mediated in part by E-

selectin [40].

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Increased levels of E-selectin have been observed in patients with acute coronary syndromes (ACS) [43],

CAD [44, 45], and UA [46, 47]. However, other studies have failed to show elevated levels of E-selectin in patients

with ACS [48] or UA [49]. An epidemiological study reported raised E-selectin levels in subjects with CAD,

although this was lost in multivariate analysis with included traditional risk factors [50]. In the British Regional

Heart Study of 643 men [51], Malik et al. reported an odds ratio (OR) of 1.13 (95% CI: 0.78-1.62) for adjusted E-

selectin, concluding that measurement of this molecule is unlikely to add much predictive information to that

provided by more established risk factors. Taken together, these findings indicate that the prognostic value of E-

selectin remains unclear [52].

HEAT SHOCK PROTEIN (HSPs)

HSPs are a group of highly conserved proteins found in the cells of all organisms, from the simplest of prokaryotes

to the most complex mammals, including man [53]. HSPs are grouped into various families according to their

molecular weight: namely the 110, 90, 70, 60, 40 kDa and low molecular weight families. HSP synthesis is

increased in response to many environmental stresses (stress-inducible), including raised temperature, oxidative

stress, nutritional deficiency, ultraviolet radiation, chemicals, viruses and ischemia-reperfusion injury [54]. Although

stress-inducible, HSPs constitute 5–10% of the total protein content in healthy growth conditions [55, 56]. HSPs

function as molecular chaperones, guiding newly formed polypeptides through folding/unfolding steps to achieve

correct functional configuration [57]. They are also involved in protein transport across intracellular membranes and

the repair of denatured proteins.

The inflammatory component of atherosclerosis might, at least in part, involve immune reactivity to HSPs

[58, 59]. HSP60 and HSP70 families have been most widely investigated. Studies have shown that HSP60 localizes

selectively in atherosclerotic lesions as opposed to non-atherosclerotic regions of the arterial wall [60]. Animal

models of atherosclerosis have shown a very early role for HSP60 in the development of the disease [61]. HSP60

might be an important auto-antigen in atherosclerosis and may play a role similar to that of oxLDL in triggering an

autoreactive T-cell response. Elevated HSP60 levels predict the progression of atherosclerosis in hypertensive

patients [62] and are associated with early atherosclerosis in clinically normal subjects [63, 64]. HSPs also have

prognostic significance in predicting morbidity and mortality due to atherosclerosis. In a cohort of 79 men with

documented CAD, significantly higher levels of anti-HSP65 antibodies were found in those who went on to have

cardiovascular events [65]. Similarly, anti-HSP65 antibodies predicted cardiovascular events (OR: 2.1, 95% CI: 1.2

to 3.9) in 386 age- and sex-matched, high risk patients, independent of conventional cardiovascular risk factors and

other inflammatory markers [66].

MATRIX METALLOPROTEINASES (MMPs)

MMPs are a family of endopeptidases, secreted by a variety of inflammatory or tumour cells as zymogens (pro-

MMPs), subsequently activated by proteinases [67]. Expression of pro-MMPs is strictly regulated [68], and their

action is inhibited by specific tissue inhibitors of metalloproteinases (TIMPs) [69]. MMPs are expressed

predominantly in macrophages, and also in vascular SMCs, lymphocytes, and endothelial cells [70]. MMPs play an

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important role in diverse physiological processes such as organ development, angiogenesis, and tissue repair, and

contribute to pathology including inflammation and cancer [71]. In vascular pathology, MMPs play a role in

vascular remodelling, aneurysm formation, post-angioplastic restenosis, progression of atherosclerosis, and plaque

destabilization [72]. Several studies have indicated that MMPs can directly or indirectly affect the activity of various

cytokines that participate in inflammation and repair processes, including IFN-β, vascular endothelial growth factor

(VEGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) [73]. Of particular interest in the

context of atherosclerosis are the effects of MMPs on TGF- β, IL-1 β, and TNF-α. By activating TGF-β in vivo,

MMPs would restrain, rather than augment, inflammation. This might, at least in part, account for reduced

macrophage infiltration in atherosclerotic lesions of MMP-3-deficient apoE-/-

mice [74].

MMPs have been reported to be elevated in patients following MI [75], UA [76] and sudden cardiac death

(SCD) [77], and are considered particularly important in ACS [76, 78-80]. MMPs weaken coronary plaque caps by

degrading the extracellular matrix (ECM) at certain locations, often in the shoulder areas of the plaque [81]. Focal

destruction of the ECM renders the plaque less resistant to mechanical stresses imposed during systole, thereby

making the plaque vulnerable to rupture. Disruption of an atherosclerotic plaque accounts for more than two-thirds

of acute cardiovascular events [82, 83].

MYELOPEROXIDASE (MPO)

MPO is a heme protein that is secreted by phagocytic white blood cells when they become activated. The principal

sources of MPO are activated neutrophils and monocytes. MPO is proposed to be an active mediator of

atherogenesis [84]. In support of a pro-atherogenic role of MPO in vivo, expression of human MPO in macrophages

of LDL receptor-deficient mice led to a 2-fold increase in atherosclerotic lesion size [85]. MPO has also been

identified in human plaques [86] and has been found to exert potent pro-atherogenic effects. These include oxidation

of LDL, rendering it atherogenic [87], as well as oxidative modification of apolipoprotein AI (ApoAI), attenuating

its capacity to promote cholesterol efflux [88, 89]. MPO activity also diminishes nitric oxide (NO) bioavailability,

which leads to endothelial dysfunction [90, 91] – the precursor to atherosclerosis [92, 93].

MPO levels were independently predictive of mortality in acute MI patients [94, 95]. MPO levels are also

higher in patients with CAD and can predict future cardiovascular events in this cohort, even after correction for

traditional risk factors and CRP [94, 96, 97]. Elevated MPO levels also predicted future risk of CAD in apparently

healthy individuals [98]; however, the association of MPO with future CAD was weaker than that of traditional

cardiovascular risk factors and CRP.

PLATELET ENDOTHELIAL CELL ADHESION MOLECULE-1 (PECAM-1)

Also known as CD31, PECAM-1is a member of the immunoglobulin gene superfamily [99]. PECAM-1 is expressed

at high density at the lateral borders of endothelial cells and at lower density on the surface of hematopoietic and

immune cells [100]. PECAM-1 is involved in angiogenesis [101], integrin regulation [102], apoptosis [103] and

more importantly, transendothelial migration of monocytes [104], and also plays an important role in plaque

formation and thrombosis [105].

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PECAM-1 gene polymorphisms and elevated PECAM-1 levels are associated with atherosclerosis, CAD

and MI [106-109]. PECAM-1 may contribute to the pathogenesis of atherosclerosis through its ability to mediate

leukocyte infiltration. Oxidized LDL has been shown to promote monocyte migration through cytokine-stimulated

endothelial cells in vitro by a mechanism involving up-regulation of endothelial cell PECAM-1 and down-regulation

of VE-cadherin [110]. Furthermore, in light of the fact that diabetic patients exhibit a higher incidence of

atherosclerosis, it is of relevance that high glucose and insulin levels can promote increased monocyte migration

through cultured endothelial cells in a PECAM-1–dependent manner [111, 112].

INTRACELLULAR CELL-ADHESION MOLECULE-1 (ICAM-1)

Soluble ICAM-1 is expressed on the surface of endothelial cells, leukocytes and SMCs in reaction to stimuli such as

shear stress, bacterial toxins, pro-inflammatory cytokines and oxidants. ICAM-1 can be induced by IL-1 and TNF-α

and is expressed by the vascular endothelium, macrophages and lymphocytes. ICAM-1 mediates attachment of

circulating leukocytes to the endothelium and their subsequent transmigration and accumulation in the arterial

intima [113, 114], processes critical to the development and progression of atherosclerosis [3]. The circulating

soluble form of ICAM-1 (sICAM-1) released from endothelial cell membranes may therefore reflect on-going

atherosclerosis.

ICAM-1 has been implicated in mature atherosclerotic lesions [115]; however, its role in initiation and

formation of lesions is overshadowed by the contribution of VCAM-1 [116, 117]. Nonetheless, in several cross-

sectional studies, ICAM-1 levels were reported to be higher in patients with CAD [118-121], and have been

significantly associated with death due to cardiovascular events in patients with CAD [45]. Furthermore, higher

levels of ICAM-1 have been shown to predict future cardiovascular events, including SCD in those free of clinical

CVD at baseline [77, 122-124].

VASCULAR CELL ADHESION MOLECULE-1 (VCAM-1)

VCAM-1 is expressed on both large and small vessels after the endothelial cells are stimulated by cytokines [125].

These molecules facilitate the rolling, adhesion and migration of leukocytes across the endothelial barrier. Up-

regulation of VCAM-1 in endothelial cells by cytokines occurs as a result of increased gene transcription (e.g., in

response to TNF-α and IL-1) and through stabilization of mRNA (e.g., IL-4).

In large prospective studies of healthy individuals, sICAM-l, but not sVCAM-1, appears consistently

related to incident CAD [50, 51, 122, 126, 127]. sICAM-l correlates with acute phase reactants like CRP, and

provides similar predictive information to CRP in settings of primary prevention [126]. sICAM-l, therefore, appears

as a general marker of a pro-inflammatory status [128]. By contrast, VCAM-1 is not expressed in baseline

conditions, but is rapidly induced by pro-atherosclerotic conditions in animal models and in humans [129].

Therefore, it seems that sVCAM-1 does not appear as a risk factor in healthy individuals, but emerges as a strong

risk predictor in patients suffering from pre-existing disease. Support for a different role of ICAM-1 and VCAM-1

according to the type of population comes from studies on peripheral arterial disease (PAD); in healthy individuals,

ICAM-1 predicts symptomatic disease [123], whereas in patients with established disease, VCAM-1 is a better

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marker of the extent and severity of atherosclerosis [130, 131]. In a prospective cohort of 1,246 CAD patients,

VCAM, ICAM, and E-selectin were independently higher in patients with future death from cardiovascular causes

[45]. However, sVCAM-1 levels revealed the strongest association with future death from cardiovascular causes,

and in a Cox regression model that simultaneously controlled for all inflammatory and soluble adhesion markers,

only VCAM-1 remained independently significant for future cardiovascular events (HRR: 2.8, 95% CI: 1.4-5.4, P =

0.003). VCAM-1 has also been reported to predict future cardiovascular events patients with CAD [45, 51], type 2

diabetes [132, 133] or UA [47].

SUMMARY

MMPs play a role in plaque destabilization [72] and have been reported to be elevated in patients following the

development of CVD [75-77], in particular ACS [76, 78-80]. MMPs may be useful for prognosis in patients with

ACS. Conversely, a number of the biomarkers may be particularly useful for illuminating the early stages of

atherosclerosis. MPO may exert important oxidative effects [87-89], including diminished NO bioavailability [90,

91], which may lead to lead to endothelial dysfunction, the precursor to atherosclerosis [92, 93]. However, while

elevated MPO levels have been reported to predict future risk of CAD in apparently healthy individuals [98], this

association with CAD was weaker than that of traditional cardiovascular risk factors. Likewise, AGE has been found

to induce pro-inflammatory cytokines [8], and following binding to RAGE, results in the production of ROS [10],

which would also lead to endothelial dysfunction. Not surprisingly, AGE has been associated with raised central

arterial stiffness, an early marker of CVD [134, 135], as well as CVD mortality [13], though further longitudinal,

predictive studies are warranted. ANG II has also been found to induce the production of ROS, as well as pro-

inflammatory cytokines, and adhesion molecules. High levels of ANG II have been found in hypertensive patients,

and ARBs have been shown to reduce intima-media thickness [35] and arterial stiffness [36], suggesting the ANG II

may be involved in the early development of atherosclerosis. However, the predictive capacity of this molecule

remains to be determined. Lastly, it has been postulated that the inflammatory component of atherosclerosis might,

at least in part, involve immune reactivity to HSPs [57]. HSPs represent an emerging, potentially exciting

biomarker, but longitudinal predictive studies are required. HSPs have been associated with early atherosclerosis in

clinically normal subjects [63, 64], but the majority of the literature has looked at individuals with pre-existing

disease [62, 65, 66],

The cellular adhesion molecule family, including E-selectin, VCAM and ICAM-1, serve has soluble

markers for the increased expression of CAM’s on vascular endothelial cells, and reflect inflammation and

activation of endothelial cells [39]. However, while these markers may represent the early onset of inflammation,

their prognostic value remains unclear [52]. For example, it has been reported that adjusted E-selectin levels are

unlikely to add much predictive information to that provided by more established risk factors [51]. Likewise,

VCAM-1 does not appear as a risk factor in healthy individuals, but does emerge as a strong risk predictor in

patients suffering from pre-existing disease [129].

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CYTOKINES

Most cytokines are glycoproteins that are secreted by cells using classical secretory pathways. Cytokines consist of

more than 50 secreted factors involved in intercellular communication, which regulate fundamental biological

processes including body growth, lactation, adiposity, and haematopoiesis [73, 136]. They are especially important

for regulating inflammatory and immune responses and have crucial functions in controlling both innate and

adaptive immunity. Indeed, the pathogenesis of atherosclerosis involves a complex interplay between cytokines,

chemokines and adhesion molecules, leading to monocyte infiltration and multiple other leukocyte responses within

the arterial wall [2, 73].

Once produced, cytokines are rapidly trapped by neighbouring cells via their high-affinity receptors.

Accordingly, measuring the levels of circulating cytokines is not necessarily a perfect surrogate end point.

Nevertheless, a variety of plasma inflammatory markers have been shown to predict future cardiovascular risk. They

may be useful for risk stratification and also to identify patients who might benefit from targeted therapy. Cytokines

are often classified according to their pro- or anti-inflammatory activities (see Table 2 and Table 3). The balance

between pro- and anti-inflammatory cytokines has emerged as a major determinant of plaque stability [73].

PRO-INFLAMMATORY CYTOKINES

CD40/CD40L

CD40 ligand (CD40L) is a trimeric, transmembrane protein of the TNF family, and together with its receptor CD40

is an important contributor to the inflammatory processes that lead to atherosclerosis, plaque destabilization, and

thrombosis [137-139]. A large variety of immunological and vascular cells express CD40 and/or CD40L [140].

CD40L directly regulates platelet-dependent inflammatory and thrombotic responses that contribute to the

pathogenesis of atherothrombosis [141]. Both CD40 and CD40L are present in human atherosclerotic plaques.

Interestingly, only membrane CD40L is on the surface of platelets [142], but non-platelet derived CD40L [143] can

activate endothelial cells and upregulate adhesion molecules, pro-inflammatory cytokines and chemokines in vitro.

This might limit vascular inflammation following the cleavage of CD40L from the surface of activated platelets

[143].

It has been reported that apparently healthy women with elevated levels of CD40L have an increased risk

of MI, stroke, or cardiovascular death, a finding that remained after adjustment for traditional cardiovascular risk

factors [144]. Furthermore, among patients with carotid atheroma, sCD40L levels predicted the presence of an

intraplaque lipid pool on high resolution carotid magnetic resonance imaging [145]. Platelet stimulation is the major

source of circulating CD40L, suggesting that the CD40L levels may be of greatest predictive value among those

with ACS. Consistent with this hypothesis, sCD40L levels identify patients at risk of having recurrent ischemic

events [146]. The CAPTURE study demonstrated that elevated levels of CD40L identified the subgroup of patients

with ACS who were at highest risk of death or nonfatal MI over a 6-month follow-up [146].

C-REACTIVE PROTEIN (CRP)

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C-reactive protein (CRP), an acute-phase protein, is a potentially important etiological factor in inflammation and

atherosclerosis [147]. Production occurs primarily in the liver, by the hepatocytes as part of the acute phase response

upon stimulation by IL-6, and to a lesser degree by TNF-α and IL-1β, originating at the site of inflammation. Among

other effects, recombinant CRP has been shown to enhance the expression of ICAM-1, VCAM-1, E-selectin, and

MCP-1 in endothelial cells [148, 149]. CRP has been extensively studied, and there is now robust evidence from

primary prevention cohorts and among patients presenting with ACS that elevated CRP levels predict future

cardiovascular events [150]. The lack of correlation between LDL-cholesterol and CRP observed in the Women’s

Health Study allowed the identification of a subgroup of subjects with increased incidence of CAD, but normal lipid

profiles [151]. CRP levels also were found to correlate only marginally to Lp-PLA2 [152, 153] and MCP-1 [154],

and were unrelated to CD40L in patients with UA.

Several papers have demonstrated that most of the in vitro effects of recombinant CRP previously reported

in the literature were most likely artifactual and due to the presence of sodium azide [155] or contamination by

bacterial products [149] in the commercial CRP preparation used in the experiments. Moreover, in vivo experiments

assessing the direct role of CRP on atherosclerosis in CRP transgenic apoE-/-

mice failed to observe any effect [156],

or reported a very small effect in male, but not female mice [157]. There is even some evidence that CRP might be

protective against atherosclerosis [158, 159] and has a clear anti-inflammatory activity that protects mice from

lethality due to LPS challenge [160]. It is therefore unlikely that CRP is a mediator of atherosclerosis and its

complications, even though it appears to be a strong independent predictor of cardiovascular events.

INTERFERON-GAMMA (IFN- γ)

IFN-γ is a Th1 cytokine that is produced by T and NK cells following synergistic activation by IL-12 and IL-18.

Previous studies have shown that IFN-γ plays a major role in atherosclerosis. IFN-γ receptor deficiency was

associated with a reduction in atherosclerotic lesion size in apoE-/-

mice [161], and cholesterol diet-induced

atherosclerosis in LDLr-/-

mice was significantly reduced in the absence of IFN-γ [162]. Moreover, IFN-γ

administered intraperitoneally promoted atherosclerosis in apoE-/-

mice [163]. It has been suggested that IFN-γ may

affect atherosclerosis in a gender-specific manner, IFN-γ being pro-atherogenic only in males [164]. However, two

studies show conflicting effects of IFN-γ on atherosclerosis in female mice [161, 165]. In humans, IFN-γ levels

significantly correlate with CRP (r = 0.782, P<0.001, [166]) and TNF-α (r = 0.702, P value not reported, [167]),

have been shown to be raised in patients with MI [166, 168], PAD [169], CAD [120, 170], and CHF [171], and

predict death following MI (OR 1.119, 95% CI: 1.005-1.246, P=0.040) [167].

INTERLEUKIN-1 (IL-1)

Interleukins are an important group of inflammatory mediators, released from various cells into the blood and

interstitium where they bind to interleukin receptors on cell surfaces and can induce cellular activation. Some

interleukins are well-documented as aggravating (e.g., IL-6) the inflammatory response, while others are

documented to reduce (e.g, IL-10) inflammation. The pathogenic role of IL-1 has been investigated in apoE-/-

mice

fed a cholesterol-rich diet receiving subcutaneous administration of recombinant human IL-1Ra [172], and in LDLr-

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/- mice [173] or apoE

-/- mice [174] crossed with transgenic mice expressing high levels of IL-1R. Over-expression of

IL-1Ra increased total cholesterol levels by ~50%, and in spite of this, decreased the size of atherosclerotic lesions

by 50–70%. In contrast, IL-1ra knockout C57BL/6J mice fed a cholesterol/cholate diet had a threefold decrease in

non-HDL cholesterol and a trend toward increased foam-cell lesion area compared with wild-type littermate controls

[173]. Taken together, these results clearly indicate that IL-1 contributes to atherosclerosis in mice.

Increased levels of IL-1 have been reported in patients with CAD [121], UA [175], acute MI [176], and

have been associated with adverse events following coronary stenting [177]. Patti et al [176] investigated IL-1

receptor antagonist (IL-1Ra) values in patients (N = 44) who reported to the emergency department with acute MI.

IL-1Ra values were elevated (>230 pg/ml) in 82% of patients, compared to 57% with raised CRP, 57% with raised

troponin I, 48% with raised myoglobin, and 41% with raised creatine kinase. These findings suggest that IL-1 may

be a sensitive marker of clinical instability in patients with CAD.

INTERLEUKIN (IL-6)

IL-6 is a pleiotropic cytokine produced by a variety of cells including fibroblasts, endothelial cells, mononuclear

phagocytes, neutrophils, hepatocytes, lymphocytes (T and B) and neural tissue - neurons, astrocytes and glial cells

[178]. IL-6 acts on a wide range of tissues influencing cell growth and differentiation, including angiogenesis, re-

vascularisation, and healing. In healthy individuals, IL-6 is expressed at low levels, kept in check by a complex

network that comprises glucocorticoids, catecholamines and secondary sex steroids [179].While the specific role of

IL-6 in the progression of atherosclerosis remains unclear, IL-6 has been shown to enhance fatty lesion development

in mice [180], and positively correlates with the degree and number of atherosclerotic plaques in ApoE knockout

mice [181]. IL-6 also mediates the synthesis and secretion of CRP [182], and is involved in the induction of MMP

[183], therefore playing an important role in the instability of vulnerable plaque. However, IL-6 also induces the

synthesis of IL-1Ra and release of soluble TNF receptor leading to reduced activity of pro-inflammatory cytokines

[184-186]. Taken together, these findings suggest that IL-6 levels in a physiological range are necessary to keep

inflammatory responses in check [179].

IL-6 levels appear to be predictive of death due to CVD [187], and are elevated in patients with stable CAD

[120], UA [76, 188] acute MI [76, 189, 190] and CHF [191], and are associated with adverse outcomes in patients

with ACS [190, 192, 193]. Patients with persistently elevated IL-6 levels demonstrate a worse in-hospital outcome

following admission with UA [194]. In the FRISC II trial, IL-6 was an independent predictor of mortality among

patients presenting with ACS, even when high sensitivity CRP was included in the analysis [195]. Interestingly,

elevated IL-6 levels appeared to have utility in terms of directing subsequent care. Early invasive strategies in

patients with elevated IL-6 levels led to a 65% relative reduction in mortality at 1 year [195]. In contrast, among

patients with lower levels of IL-6, randomization to an early invasive strategy did not confer any benefit over a

conservative strategy.

TUMOR NECROSIS FACTOR-α (TNF-α)

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TNF-α is a cytokine with a wide range of pro-inflammatory activities [196, 197]. It is primarily produced by

macrophages, endothelial cells, and SMCs of atherosclerotic arteries [198]. TNF-α may influence the atherosclerotic

process both by causing metabolic perturbations and by increasing the expression of cellular adhesion molecules.

TNF-α induces the expression of surface leukocyte adhesion molecules [199, 200], chemokines [201] and enhances

the production of cytokines and growth factors [202]. TNF-α also stimulates new vessel formation and induces

features characteristic of developing atheroma.

Disturbances in the TNF-α metabolism have been implicated in metabolic disorders, such as obesity and

insulin resistance [203], indicating that perturbations of TNF-α metabolism may affect the onset of non-insulin-

dependent diabetes mellitus and play a role in the development of cardiovascular disorders. Indeed, increased

plasma concentrations of TNF-α have been found in patients with premature CAD [121, 204, 205], acute MI [206],

PAD [169], and CHF [191].

ANTI-INFLAMMATORY CYTOKINES

ADIPONECTIN

Adiponectin is a protein produced by adipocytes and present at high concentration in human peripheral circulation

[207-209]. Adiponectin exerts important cardiovascular functions, including anti-inflammatory, anti-apoptotic and

anti-hypertrophic effects [210]. Adiponectin also controls monocyte adhesion to the vascular endothelium [211] and

is an important regulator of endothelial nitric oxide synthase (eNOS) [212]. In humans, adiponectin levels appear to

be closely correlated with forearm reactive hyperaemia (endothelial function)[213], flow-mediated-dilation

(endothelial function) [214] and carotid intima-media thickness [214, 215]. Anti-inflammatory actions include

reduced TNFα-stimulated expression of E-selectin, nuclear factor-κB, VCAM-1 and IL-8 [211, 216, 217]. These

anti-inflammatory and anti-atherogenic properties appear to have important protective effects at the cardiovascular

level [207-209].

Adiponectin is reduced in the serum of both diabetic and obese individuals, and is further decreased in

patients with CAD [218, 219]. Improvement of glycaemic control with diet, weight loss and hypoglycaemic agents,

has resulted in normalization of adiponectin levels [220], suggesting an intimate connection between this adipokine

and metabolic control. In patients with CHF, levels of adiponectin were inversely related to mortality independent of

other risk markers [221]. High levels of adiponectin have also been associated with lower risk for MI [222], even

after correction for HDL- and LDL-cholesterol and BMI. Furthermore, elevated circulating concentrations of

adiponectin are associated with a lower risk for CAD independently of other well-known risk factors [223].


IL-4 is a pleiotropic cytokine produced by Th2 lymphocytes, eosinophils, basophils, and mast cells. Since IL-4

inhibits the synthesis of pro-inflammatory cytokines it is generally considered anti-inflammatory [224-228].

However, a body of evidence indicates that IL-4 may also play a role in atherosclerosis through induction of

inflammatory responses, such as upregulation of VCAM-1 [229] and MCP-1 [230]. Consistent with this hypothesis,

transplantation of bone marrow stem cells from IL-4-deficient LDLr-/-

mice decreased atherosclerotic lesion

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formation in a site-specific manner [231]. In contrast, IL-4 deficiency in C57BL/6 mice fed an atherogenic diet did

not affect the development of early lesions [232]. Findings are more consistent in human studies. Szkodzinski et al

[233] investigated 53 patients with acute MI undergoing percutaneous coronary intervention; higher IL-4

concentrations significantly characterized left ventricular dysfunction (ejection fraction <30%) when measured prior

to (specificity = 79%, P <0.001) or immediately post (specificity = 67%, P <0.001) surgery. IL-4 has also been

shown to be elevated in patients with CAD [120]. Furthermore, in type 2 diabetic subjects, mixed modality physical

exercise upregulates IL-4 and IL-10 and down-regulates inflammatory markers (hs-CRP, IL-1β, IL-6, TNF-α and

IFN- γ) [234, 235].


IL-10 is a pleiotropic cytokine produced by Th2 cells, B cells, monocytes, and macrophages that inhibits a broad

array of immune parameters including the expression Th1 cytokines, antigen presentation, and antigen-specific T-

cell proliferation [236]. IL-10 also has potent anti-inflammatory properties on macrophages [237] and plays an

active role in limiting the inflammatory response in the vessel wall [238]. The role of endogenous IL-10 has been

clearly established in mouse models of atherosclerosis. IL-10 deficiency in C57BL/6 mice fed an atherogenic

cholate-containing diet promotes early atherosclerotic lesion formation, characterized by increased infiltration of

inflammatory cells and by increased production of pro-inflammatory cytokines [239]. Furthermore, in IL-10

deficient LDLr -/-

mice, it was found that IL-10 is instrumental in the prevention of atherosclerotic lesion

development [240].

Decreased IL-10 levels have been reported in patients with acute MI [168], UA [241] and other ACS [242].

Heeschen et al [242] assessed the prognostic impact of CRP and IL-10 in patients (n = 547) presenting with ACS;

IL-10 was inversely correlated with CRP (r = -0.31, P = 0.49), and patients with elevated IL-10 (>3.5 pg/mL) had

decreased risk for MI and death at 24 hours (HR: 0.19, 95% CI: 0.04-0.88) and 6 months (HR: 0.43, 95% CI: 0.25-

74). Notably, the predictive value of IL-10 was restricted to patients with elevated CRP levels, indicating the

complex interplay between inflammatory and anti-inflammatory molecules.

TRANSFORMING GROWTH FACTOR (TGF-β)

TGF-β is a potent anti-inflammatory, immunosuppressive and pro-fibrotic cytokine, with major effects on the

biology of SMCs. Three TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3) are expressed by cells in the vessel wall

and are capable of modulating vascular development and remodelling by altering cell differentiation, proliferation,

migration, extracellular matrix production, and the activities of immune cells [243] [244]. TGF-β appears to

determine the extent to which developing atherosclerotic lesions are stabilized by a collagen-rich fibrous cap.

Indeed, SMCs in stable lesions express greater amounts of TGF- β than unstable lesions [245]. In mice, specific

inhibition of TGF-β signalling in T cells leads to the development of atherosclerotic plaques with a phenotype that

may potentially increase plaque vulnerability to rupture [246-248]. There is also evidence that TGF-β1 down-

regulates inflammatory cytokine-induced expression of VCAM-1[249], leukocyte adhesion to the endothelium

[250], decreases macrophage activity by releasing IL-1 Ra [251], and is inversely correlated (-0.27, P=0.05) to CRP

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[252]. Taken together, these findings suggest that TGF-β plays a pivotal role in the maintenance of normal blood

vessel wall architecture, and protects against vulnerability to atherosclerosis

In humans, genetic polymorphisms and defective TGF-β signalling have been linked to the development of

a number of cardiovascular diseases, including CAD [253], CHF [254], aortic aneurysm [255, 256], hypertrophic

cardiomyopathy [257], hypertension [258, 259], rheumatic heart disease [260], stroke [261, 262], as well as acute

MI [253, 263, 264] and SCD [77, 265]. Decreased levels of TGF-β1 have been reported in patients with CAD, CVD

and PAD compared to controls [252], and in patients receiving regular haemodialysis, a 1 ng/mL reduction in TGF-

β1 concentration was associated with a 9% increase in the relative risk of a cardiovascular events [252].

SUMMARY

The balance between pro- and anti-inflammatory cytokines may be important for risk stratification and also to

identify patients who might benefit from targeted therapy. The pro-inflammatory cytokines, CD40/CD40L, CRP,

and IFN-γ, appear to play an important role in atherosclerosis, has been shown to be elevated in patients with several

CVDs [120, 166, 168-171], and to predict death following MI [167]. TNF-α may play a particularly important role

in metabolic disorders such as obesity and insulin resistance [203], and increased plasma concentrations of TNF-α

have been found in patients with a range of CVD [121, 169, 191, 204-206]. CD40L levels identify patients at risk of

having recurrent ischemic events [146], and elevated levels of CD40L identified the subgroup of patients with ACS

who were at highest risk of death or nonfatal MI [146], suggesting that CD40L may be of greatest predictive value

among those with ACS. Even though CRP appears to be a strong independent predictor of cardiovascular events

[150], the validity of this biomarker remains unclear; there is evidence that CRP might be protective against

atherosclerosis [158-160], and commercial CRP preparation may be contaminated by the presence of sodium azide

[155] or bacterial products [149].

Two promising anti-inflammatory cytokines include adiponectin and TGF-β. Adiponectin appears to play a

role in regulating endothelial function [211-213] and has been inversely correlated with flow-mediated dilation

(endothelial function) and carotid intima-media thickness [214, 215], two widely used and early markers of

atherosclerosis. High levels of adiponectin have been associated with a lower risk for CAD [222] and MI [223].

TGF-β appears to play a pivotal role in the maintenance of normal blood vessel wall architecture and decreased

levels of TGF-β1 have been reported in patients with several CVD [77, 191, 253, 254, 261-265].

Interleukins are an important group of inflammatory mediators, some of which aggravate the inflammatory

response, while others reduce inflammation. IL-1 and IL-6 are thought to be pro-inflammatory. Increased levels of

IL-1 have been documented in patients with a range of CVD [121, 175-177], and may serve as a sensitive marker of

clinical instability in CAD patients [176]. Raised levels of IL-6 levels have also been reported in patients with a

range of CVD [76, 120, 188-193], and have been associated with worse in-hospital outcomes following admission

with UA [194]. Conversely, IL-4 and IL-10 are considered anti-inflammatory. While findings from IL-4 studies are

inconstant, the role of endogenous IL-10 has been clearly established in mouse models of atherosclerosis, and

decreased IL-10 have been reported in patients with ACS [168, 241, 242]. Measurement of IL-1, IL-6 and IL10 may

be useful for indicating the complex interplay between inflammatory and anti-inflammatory processes.

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CHEMOKINES

Chemokines belong to a large group of structurally related and secretable, largely basic, chemotactic cytokines [266,

267]. Chemokines are pro-inflammatory, characterized by their ability to cause directed migration of leukocytes into

inflamed tissue. These chemotactic cytokines seem not only to be raised in the circulation, but also within

atherosclerotic lesions [73]. Furthermore, several other leukocyte responses such as cell proliferation, enzyme

secretion and induction of ROS, have been observed in vitro after chemokine stimulation [73]. Chemokines may

also interfere with SMC migration and growth, as well as platelet activation [268, 269].

INTERLUKIN-8 (IL-8)

While a wide variety of cell types are potential sources of IL-8, the principal cellular sources are typically

monocytes and macrophages [270, 271]. IL-8 induces angiogenesis [272, 273] and functions as a chemoattractant

for neutrophils and T lymphocytes, which also produce IL-8 [274]. Injection of an IL-8 inhibitor in rabbits and rats

significantly reduced neutrophil migration towards inflammatory foci [275]. In irradiated mice reconstituted with

bone marrow cells lacking the murine homologue of the IL-8 receptor CXCR2, the lesion size, as well as the amount

of macrophages within the plaques, was reduced [276].

IL-8 has been associated with acute MI [168, 189], UA [277, 278], CHF [279], and CAD [280-282]. Inoue

et al [280] evaluated the serum levels of 10 cytokines as potential markers of long-term outcomes in patients with

angiographically identified stable CAD; IL-8 was the only cytokine to predict cardiovascular events, doing so

independently of the other nine cytokines. More recently, Pronzinsky et al [168] investigated the prognostic value

of IL-1β, IL-6, IL-7, IL-8, and IL-10 in 40 patients presenting with acute MI complicated by cardiogenic shock . IL-

8 showed the highest diagnostic accuracy for infarct-related mortality over the subsequent 96 hours, with an area

under the curve (AUC) of 0.80 ± 0.08, followed by IL-6 (AUC 0.79 ± 0.08), IL-10 (AUC 0.76 ± 0.08) and IL-7

(AUC 0.69 ± 0.08). Moreover, physical exercise has reported to decrease IL-8 and MCP-1 levels in patients with

metabolic syndrome [283], suggesting that the protective effect of physical exercise might be due, in part, to the

suppression inflammatory molecules.

MONOCYTE CHEMOATTRACTANT-1 (MCP-1)

MCP-1, also known chemokine ligand 2 (CCL2), is produced by a variety of cell types, either constitutively or after

induction by oxidative stress, cytokines, or growth factors [284]. MCP-1 is one of the key chemokines that regulate

migration and infiltration of monocytes and macrophages, and appears to play a principal role in atherosclerotic

lesions. In mice over-expressing apolipoprotein B, deletion of the MCP-1 gene protected against monocyte

recruitment [285]. Similarly, in MCP-1-deficient LDLr-/-

mice, macrophage recruitment is diminished, suggesting

that MCP-1 attracts monocytes into the vessel wall [286].

MCP-1 has been associated with subclinical atherosclerosis (coronary artery calcium score) [287], CAD

[154, 281, 282, 288], PAD [154], ACS [288-290], UA [291], MI [206, 290], SCD[290] and UA [291]. de Lemos

[290] et al investigated MCP-1 levels in 2,279 patients presenting with ACS; MCP-1 levels above the 75th

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percentile (238 pg/ml) were associated with an increased risk of MI or death (HR: 1.53, 95% CI: 1.09-2.14) during

follow-up (10 months) after adjustment for traditional risk factors, including CRP. Martinovic et al [288] assessed

serum MCP-1 levels in 263 patients admitted to hospital for non-invasive diagnostic procedures; elevated MCP-1

levels were found in patients with CAD or increased coronary risk factors. In addition, endothelial activation

markers such as soluble adhesion molecules, soluble intercellular adhesion molecule and soluble E-selectin were

also increased in these patients. This suggests that elevated MCP-1 levels might serve as a direct marker of

inflammatory activity for those at risk for CVD [292].

MIGRATION INHIBITORY FACTOR (MIF)

MIF is a pleiotropic inflammatory T cell and macrophage cytokine. Originally discovered and named as an inhibitor

of macrophage migration, MIF has now been shown to be a key player in acute and chronic immune-inflammatory

conditions, including atherosclerosis [293], rheumatoid arthritis [294], sepsis [295], and asthma [296]. There is also

evidence that MIF plays a key role in metabolic and inflammatory processes underlying metabolic disorders [297].

MIF is widely expressed in numerous types of tissue, and can act in an autocrine and paracrine fashion to stimulate

its own synthesis and the synthesis of other pro-inflammatory mediators [298]. An up-regulation of MIF has been

observed in endothelial cells, SMCs, and macrophages during progression of atherosclerosis [299, 300]. Inhibition

of MIF in apoE-/-

mice by treatment with neutralizing MIF antibodies resulted in a shift in the cellular composition

of neointimal plaques toward a more stable phenotype with reduced macrophage and increased SMCs content [301],

as well reduced circulating levels of inflammatory markers (fibrinogen, MIF and IL-6) [299].

In humans, the prognostic capacity of MIF in predicting future cardiac events remains elusive. One study

[302] demonstrated that high MIF levels were a marginal, but significant predictor of MI and SCD, while another

[303] reported a lack of association between serum levels of MIF and incident CAD. However, these data are based

on a group of subjects without pre-existing CAD. A more recent study [304] examined whether high circulating

levels of MIF are related to future cardiovascular events in patients with stable CAD and, after controlling for

conventional risk factors, MIF was a significant predictor of cardiovascular events in patients with type 2 diabetes

mellitus (HR: 3.3, 95% CI: 1.6–8.3), but not in patients without diabetes.

SUMMARY

Several chemokines have been widely investigated, including IL-8, MCP-1 and MIF. Of these, IL-8 and MCP-1

have shown particular promise as cardiac biomarkers. MCP-1 levels might serve as a direct marker of inflammatory

activity for those at risk for CVD [292], and hasve been associated with subclinical atherosclerosis [287] and a range

of CVD [154, 206, 281, 282, 288-291]. IL-8 has been associated with a number of CVD [168, 189, 277-282], and

appears to be a sensitive marker of long-term outcomes in patients with stable CAD [280]. The prognostic capacity

of MIF for predicating future cardiovascular events may be limited to those with pre-existing CVD or diabetes

[304].

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OXIDATIVE STRESS

Oxidative stress results when free radical formation is unbalanced in proportion to protective antioxidants [305].

Free radicals are formed during a variety of biochemical reactions and cellular functions (such as mitochondria

metabolism). Examples of free radicals (oxidizing molecules) are hydrogen peroxide, hydroxyl radical, NO, singlet

oxygen, superoxide anion and peroxyl radical. Free radicals are highly reactive, unstable molecules that have an

unpaired electron in their outer shell. They bind with electrons from other molecules, potentially initiating chain

reactions as successive molecules lose and gain electrons. They oxidize various cellular components including

DNA, proteins, lipids/fatty acids and AGEs [306]. These reactions between cellular components and free radicals

lead to DNA damage, mitochondrial malfunction, cell membrane damage and eventually cell death (apoptosis).

Antioxidants are molecules or compounds that act as free radical scavengers (Table 4). Most antioxidants

are electron donors and react with the free radicals to form innocuous end products such as water. These

antioxidants bind and inactivate the free radicals. Thus, antioxidants protect against oxidative stress and prevent

damage to cells.

OXIDATIVE STRESS BIOMARKERS

ISOPROSTANES

Isoprostanes are cellular non-enzymatic products resulting from free radical–catalyzed peroxidation of arachidonic

acid [307, 308]. In contrast to enzymatically generated prostaglandins, which are generated from free arachidonic

acid, isoprostanes can be generated on intact cholesteryl esters and phospholipids, which are major components of

lipoprotein particles and cell membranes. Following generation, isoprostanes are released by phospholipase activity,

circulate in plasma, and are ultimately excreted in urine. F2 isoprostanes are stable, specific and unique end-products

(up to 64 species can be generated) of lipoprotein metabolism.

F2 isoprostane levels are raised by traditional risk factors, including cigarette smoking, diabetes mellitus,

obesity and hypertension [307], and correlate with unstable carotid plaques [309]. A recent systematic review [310]

assessed the role of F2 isoprostane as a biomarker for CVD. Of the 22 eligible studies retrieved, 20 studies showed

a significant association between F2-isoprostanes and CVD, of which only 4 were population based studies, and

only 2 were prospective. Thus, while F2 isoprostanes may be considered the gold standard in measuring oxidative

stress in vivo [311], prognostic data remain limited. Furthermore, the relative sophistication and expense required to

perform isoprostane assays inhibits widespread use.

LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 (Lp-PLA2)

Lp-PLA2 is a member of phospholipase A2 superfamily [312]. The secreted isoform was first identified on the basis

of its ability to degrade platelet-activating factor (PAF), hence it is also known as PAF-acetylhydrolase [313]. Lp-

PLA2 is secreted by various inflammatory cells, including monocyte-macrophages, T-cells, and mast cells [314]. It

cleaves the ester bond of oxidized phospholipids (OxPLs) at the sn-2 position to give rise to two potentially pro-

inflammatory products, free oxidized fatty acids and lysophosphatidylcholine [315]. The biological role of Lp-PLA2

has been controversial with seemingly contradictory, with anti- or pro-atherogenic functions being proposed. The

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anti-atherogenic properties of Lp-PLA2 were suggested because of the enzymatic catabolism of biologically active

oxidized phospholipids in LDL and degradation of the unrelated polar phospholipid, PAF [316, 317]. To this end,

Lp-PLA2 was reported to alter biological properties of minimally modified LDL by abrogating the ability of LDL to

promote endothelial cell binding of monocytes [317]. In contrast, Lp-PLA2 may directly promote atherogenesis by

generating potent pro-inflammatory and pro-atherogenic products, such as lysophosphatidylcholine and oxidized

free fatty acids from oxidation of LDL [315, 318, 319], an important step in atherogenesis.

Seemingly conflicting evidence has been found in population and clinical studies. For example, loss-of-

function mutations have been found to be associated with a higher risk for CVD in Japanese populations [320,

321].Three subsequent studies [152, 322, 323] reported that high levels of Lp-PLA2 independently predicted CAD

or cardiovascular events. However, in all studies, Lp-PLA2 levels were strongly correlated with LDL cholesterol

levels, and the predictive value of Lp-PLA2 was attenuated substantially after adjusting for LDL cholesterol and

traditional risk factors. Further study is required to determine the extent to which Lp-PLA2 levels provide

independent information beyond traditional risk assessments such as the Framingham risk model.

NITROTYROSINES

Nitrotyrosine, one of the most important mediators of MPO, plays a key role in the process of oxidation seen early

on in atherosclerosis [324, 325]. Nitrotyrosine accumulation reflects a loss of balance between oxidant formation

and antioxidant defence mechanisms [325]. Nitrotyrosine originates as tyrosine in both a free and protein-bound

form. The protein-bound form that is involved in atherosclerosis is attached to LDL. This molecule is then nitrated

to form the biologically active nitrotyrosine, and occurs in a highly efficient manner in human serum [326]. Once

modified, the nitrated form of LDL is collected and consumed by macrophages via phagocytosis. The end product of

this degradation is the deposition of cholesterol and foam cells that are vital in plaque development.

Several animal studies have linked nitrotyrosine to inflammation. Mice injected with Klebsiella pneumonia

produced an inflammatory fluid rich in nitrotyrosine [326]. Rats genetically engineered to be spontaneously

hypertensive have been shown to have an increased production of nitrotyrosine [327]. A study that links the

association of nitrotyrosine with the oxidative stress of renal failure showed an increase in nitrotyrosine serum levels

in uremic mice [328]. In humans, nitrotyrosine levels are raised in patients afflicted with diseases associated with

high oxidative stress such as diabetes mellitus [329], and multiple studies have reported that raised levels are

detected in atheromatous plaques [329, 330]. Nitrotyrosine has also been found to be elevated in patients with PAD

[331], CAD [332-334], and MI [335]. Systemic levels of protein-bound nitrotyrosine have been reported to be

associated with the presence of CAD even following multivariable adjustments for traditional risk factors and CRP

(OR:4.4, 95%CI: 1.8-10.6, P<0.001)[332].

OXIDIZED LDL (oxLDL)

oxLDL is thought to be a very early trigger of vascular inflammation and a major cause of injury to the endothelium

[336]. LDL accumulation and modification in the sub-endothelium triggers monocyte and lymphocyte recruitment.

Thereafter, activated macrophages and lymphocytes secrete abundant amounts of cytokines that in turn can activate

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endothelial cells, SMCs, and macrophages/lymphocytes to foster cytokine production, leading to a self-perpetuating

inflammatory process that becomes less dependent on the presence of oxLDL [337]. In addition, oxLDL cholesterol

has been demonstrated to induce the production of endothelin-1 (ET-1) in human macrophages and increases ET-1

release from endothelial cells by inducing ET-1 gene expression [338]. oxLDL may therefore indirectly contribute

to endothelial dysfunction in atherosclerosis [339].

Elevated levels of oxLDL have been associated with CVD [340], ACS [341-345], acute MI [346-348], UA

[347, 349], PAD [350], CHF [351, 352], transient ischemic stroke (TIA) [340, 353, 354], CAD [343, 355, 356], and

the severity of CAD [357-359]. In a recent study by Tsimikas et al [340], oxLDL levels were found to be

significantly raised in patients with incident CVD versus controls, and after adjustment for traditional risk factors

were found to be associated with higher risk for CVD (HR: 1.18, 95% CI: 1.02-1.37, P=0.028) and stroke (HR: 1.32,

95% CI: 1.11-1.58, P=0.002) after a 15 year follow up. The time course of change in oxLDL has been measured in

patients following acute MI [360] and TIA [353]; oxLDL levels were high during admission to hospital, but

approached normal levels at the time of discharge. These findings suggest that plasma oxLDL is released into the

circulation following plaque rupture [361, 362].

ANTIOXIDANT BIOMARKERS

COENZYME Q10 (CoQ10)

CoQ10, present in all cellular membranes [363], originates from endogenous synthesis as well as from food intake

and oral supplements [364]. Tissues generally synthesize CoQ10 from farnesyl diphosphate and tyrosine [365]. Iron,

magnesium, and vitamin B6 are cofactors for CoQ10 biosynthesis. CoQ10 can be obtained from dietary sources of

meat, fish, vegetables, and fruits. CoQ10 is an important antioxidant; its reduced form, ubiquinol, protects

membrane phospholipids and mitochondrial membrane proteins, as well as DNA, from free-radical-induced

oxidative damage [366-368]. Not only can ubiquinol act to remove oxygen radicals, but it can also reduce

tocopheryl radicals and semi dehydroascorbate back to tocopherol and ascorbate, respectively [369, 370]. The

ubiquinone formed in this process is reduced back to ubiquinol in the electron transport chain by metabolic supply

of NADH or NADPH [371, 372]. Ubiquinol has also been reported to protect LDL from oxidation [373].

Myocardial tissues of CVD patients are reported to be deficient in CoQ10 [374-376]. Littarru et al [377]

first reported its deficiency in heart disease. These authors reported that 75% of cardiac surgery patients had

decreased CoQ10 in the blood and myocardium. Folkers et al [374] reported low myocardial CoQ10 in patients with

aortic and mitral wall disease, diabetic cardiopathy, and congenital valvular defects. The same group of authors

[375] reported that, compared with people with less-severe CHF (Class I and II), people with more-severe CHF

(class III and IV) had lower plasma and myocardial CoQ10, suggesting an increased risk of CoQ10 deficiency as

heart disease worsens. Decreased CoQ10 levels have also been reported in patients with hyperlipidemia [378] and

diabetes [379].

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GLUTATHIONE (GSH)

GSH is an important intracellular antioxidant required for normal functioning of immune cells [380]. Certain

cellular functions, such as the DNA synthetic response, are very sensitive to ROS and are favoured in high levels of

GSH [381]. A study by Kinscherf et al [382] found that individuals with intermediate level of GSH (20-30 nmol/mg

protein) had, on average, a significantly higher number of CD4+ T-cells than those with either higher or lower

intracellular GSH levels. This indicates that the immune system is very sensitive to changes in GSH levels and that

the mean GSH levels of healthy human subjects are approximately optimal. Low GSH levels have also been

associated with impaired immune function, including impaired T cell proliferation and activation, as well as

decreased IL-2 production, impaired IL-2 responses and a shift to Th2 response as compared to Th1[383].

Decreased levels of GSH have been reported in patients with CHF [384, 385] and acute MI [383, 386]. In patients

reporting with a first acute MI, plasma-reduced GSH was independently associated with future cardiovascular

events (HR: 0.42, 95% CI: 0.18-0.99, P=0.04) [383].

SUPEROXIDE DISMUTASE (SOD)

In mammals, there are 3 isoforms of superoxide dismutase (SOD). Each isoform is the product of a distinct gene but

catalyses the same reaction. The 3 isoforms are: the cytosolic or copper-zinc SOD (CuZn-SOD SOD-1), the

manganese SOD (Mn-SOD or SOD-2) localized in the mitochondria, and the extracellular form of SOD (EC-SOD

or SOD-3). EC-SOD is the only antioxidant enzyme localized on the surface of the vascular lumen [387]. Studies in

nonvascular cells suggest the different isoforms of SOD have distinctive roles [388]. An important function of EC-

SOD in the arterial wall may be the preservation of NO bioactivity [389-391]; NO is considered the most important

molecule governing endothelial function and health [93, 392-395]. NO reacts with superoxide at a rate three times

faster than dismutation of superoxide by SOD [396, 397]. Moreover, EC-SOD degrades superoxide at a rate 4-5

times faster than antioxidants such as vitamin C or E [398]. Studies using rabbit aortas or bovine coronary arteries

have shown that inhibition of vascular SOD activity results in a rapid impairment of NO-mediated vasodilation,

suggesting that SOD levels are critical for the ability of NO to modulate vascular tone [390, 391].

The role of SOD in cardiovascular events was initially the subject of controversy [399]. Arterial expression

and/or activity of CuZn-SOD and Mn-SOD increases in several animal models of hypertension [400, 401], as well

as in the initial phases of atherosclerosis, but is decreased in the later stages of this disease [402]. Knock-out

experiments showed neonatal lethality of mice lacking Mn-SOD and reduced lifespan in mice lacking CuZn-SOD

[403-406]. EC-SOD-deficient mice had higher blood pressures in two hypertension models compared with wild-type

animals [407]. Over-expression studies of SODs strongly suggest a protective role of these enzymes in many

diseases, as well as in aging [404-406]. Indeed, SOD was reported to be increased in the initial stages of CAD to

protect and prevent lipid peroxidation, but it decreased thereafter with the severity of disease [408]. Studies in

patients with stable CAD [409, 410], UA [411] , MI [412] and SCD [413] have reported substantially reduced levels

of vascular EC-SOD.

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SUMMARY

A number of biomarkers have emerged that may be used to represent the balance between free radical formation and

protective antioxidants. Oxidative stress biomarkers include F2 isoprostane, LpPLA1, Nitrotyrosine, and oxLDL.

The biological role of Lp-PLA2 has been controversial with seemingly contradictory anti-atherogenic [316, 317] and

pro-atherogenic [315, 318, 319] functions being proposed. F2 isoprostane levels are raised by traditional risk factors

[307], correlate with unstable carotid plaques [309], and a recent systematic review reported a significant

association between F2-isoprostanes and CVD. However, prognostic data remain limited and the expense required

to perform isoprostane assays inhibits widespread use. Alternatively, oxLDL is thought to be an early trigger of

vascular inflammation and has been associated with a range of CVD [340-359]. oxLDL levels have also been

associated with higher risk for CVD, even after adjustment for traditional risk factors [340]. Raised nitrotyrosine

levels may also be used to indicate an imbalance between oxidant formation and antioxidant defence mechanisms

[325], and raised levels have been reported in patients with several CVD [331-335]. Nitrotyrosine levels may play a

particularly prominent role in diseases associated with high oxidative stress, such as diabetes mellitus [329].

Prominent antioxidant biomarkers include coQ10, GSH, and SOD. Decreased levels of coQ10 have been

reported in patients presenting with CVD [375, 376], and have been associated with CVD risk factors, including

hyperlipidemia [378] and diabetes [379]. Levels of GSH and SOD may be indicative of the stage of CVD. Up-

regulation of vascular EC-SOD may indicate the initial stages of CVD [408], whereas substantially decreased levels

may indicate stable CVD [409-413]. Decreased levels of GSH have been reported in patients presenting with CHF

[384, 385] and acute MI [383, 386], and reduced GSH levels were associated with future cardiovascular events in

patients with acute MI [383]. Further investigation is required to elucidate the prognostic capacity of these

potentially useful biomarkers.

CONCLUSIONS

Not surprisingly - due to the complexities of CVD pathogenesis - a single biomarker cannot be used to estimate

absolute risk of future cardiovascular events. Furthermore, particular biomarkers are more suited for the prognosis of

particular cardiovascular events, or for a given stage of a given CVD and it should also be recognized that the

functions of many biomarkers overlap. For example, soluble ICAM-1 reflects in part endothelial function and in part

inflammation, HSP60 might play a role similar to that of oxLDL in triggering an autoreactive T-cell response, and

MMPs can directly or indirectly affect the activity of various cytokines. Therefore, biomarkers should be selected

for a specific stage of a given CVD, and a particular biomarker should not be considered in isolation. Simultaneous

measurements of disease appropriate biomarkers over time can provide a more detailed picture of the specific nature

of the cardiovascular event.

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TABLES

TABLE 1. Inflammatory biomarkers

Biomarker Role Associated with End

point

AGEs Macrophage activation CAD[414], CVD[13-15]

ANG II Induce production of

ROS, cytokines, &

adhesion molecules

CHF[32], HT[31],

UA[33]

E-selectin Leukocyte recruitment ACS[43], CAD[44, 45],

MI[46], UA[47],

SCD[45]

HSP Amplify cytokine

production

CAD[65], MI[66],

SCD[66], Stroke [66]

ICAM-1 Adhesion; leukocyte

recruitment

CAD[118, 120, 121, 124,

415], PAD[123, 130],

[77, 122-124], UA[46]

MMPs Plaque rupture ACS[76, 78-80], MI [75],

UA[76], SCD[77]

MPO LDL-uptake; MMP

activation; plaque

rupture; endothelial

dysfunction

ACS[96], CAD[97, 98],

MI[94, 95]

PECAM-1 Leukocyte

migration/motility

CAD[106-108], MI[109]

VCAM-1 Adhesion; leukocyte

recruitment

ACS, CAD[51, 120],

PAD[130], SCD[45, 77],

stroke[48], UA[46, 47]

ACS, acute coronary syndromes; AGEs, advanced glycation end products; ANG, angiotensin; CAD, coronary artery

disease; CHF, chronic heart failure; CVD, cardiovascular disease; HSP, heat shock protein; HT, hypertension,

ICAM, intracellular cell-adhesion molecule; MI, myocardial infarction; MMPs, matrix metalloproteinases; MPO,

myeloperoxidase; PAD, peripheral arterial disease; PECAM, platelet endothelial cell adhesion molecule; SCD,

sudden cardiac death; UA, unstable angina; VCAM, vascular cell adhesion molecule.

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TABLE 2. Pro-inflammatory cytokines


point

CD40 Thrombosis; MMP

expression; endothelial

dysfunction

ACS[146], MI[144],

SCD[146], stroke[144]

CRP Thrombosis; LDL-

uptake; endothelial

dysfunction

ACS[150], CAD[120,

151, 322, 332, 416],

CHF[417-421], MI[45,

76, 151, 386, 422-424],

PAD[425-433],

SCD[151], stroke[151,

423, 434-438], UA[76,

439-441]

IFN-γ Antiviral;

immunoregulatory;

macrophage activation

CAD[120, 170],

CHF[171], MI[166, 168],

PAD[169]

IL-1 EC & SMC activation CAD [121], UA[175],

MI[176, 206]

IL-6 Induction of acute phase

proteins; plaque rupture;

SMC proliferation

ACS[195], CAD[120,

187], CHF[191], MI [76,

189, 190], UA[76, 188]

IL-8 Chemokine; deactivate

circulating leukocytes

MI[168, 189], UA [277,

278], CHF [279], CAD

[280-282], PAD[169]

MCP-1 Chemokine; leukocyte

recruitment

ACS[288-290],

CAD[154, 281, 282,

288], CVD[287], MI[206,

290], PAD[154, 169],

SCD[290], UA[291]

MIF Chemokine;

immunoregulatory;

macrophage activation

MI[302, 304], SCD[302,

304], UA[304].

TNF-α Leukocyte adhesion, new

vessel formation,

atheroma

CAD[121, 204, 205],

CHF[191], MI[168, 206],

PAD[169]

ACS, acute coronary syndromes; CAD, coronary artery disease; CHF, chronic heart failure; CRP, C-reactive

protein; CVD, cardiovascular disease; EC, endothelial cell; IFN, interferon; IL, interleukin; MCP; monocyte

chemoattractant protein; MI, myocardial infarction; MIF, migration inhibitory factor; PAD, peripheral arterial

disease; SCD, sudden cardiac death; SMC, smooth muscle cell; TNF, tumour necrosis factor-α; UA, unstable

angina.

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TABLE 3. Anti-inflammatory cytokines


point

Adiponectin Anti-inflammatory; anti-

apoptotic; anti-

hypertrophic

CAD[218, 219],

CHF[221], MI[222]

IL-4 Inhibits Th1; proliferation

& differentiation of B

cells

MI[233], CAD [120]

IL-10 Inhibits Th1; proliferation

& differentiation of T

cells

ACS[242], MI[166,

168],UA [241],

TGF-β Immunosuppressive; pro-

fibrotic

SCD[77, 265], CAD

[253], CHF[191, 254],

MI [263, 264],

stroke[261, 262]

ACS, acute coronary syndromes; CAD, coronary artery disease; CHF, chronic heart failure; HT, hypertension; IFN,

interferon; IL, interleukin; MI, myocardial infarction; SCD, sudden cardiac death.

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TABLE 4. Oxidative stress biomarkers


point

CoQ10 Antioxidant; oxidative

phosphorylation; protects

membrane phospholipids

CVD[375, 376],

CHF[375, 376]

GSH Antioxidant; immune

function

MI[383, 386], CHF[384]

Isoprostanes Oxidant CVD [310], MI [307,

308]

Lp-PLA2 LDL oxidation;

inflammation

ACS[442], CAD[152,

153, 322, 323]

Nitrotyrosines Oxidant; mediates MPO;

inflammation

PAD[331], CAD[332-

334], MI[335, 443]

CVD[325]

oxLDL Inflammation; monocytes

& lymphocyte

recruitment; endothelial

dysfunction

ACS [341-345], CAD

[343, 355-359], CHF

[351, 352], CVD [340], ,

MI[346-348], PAD

[350], stroke[340, 353,

354], UA [347, 349]

SOD Major antioxidant

defence against O2- NO

preservation

CAD[409, 410],

MI[412] UA[411],

SCD[413]

ACS, acute coronary syndromes; CAD, coronary artery disease; CHF, chronic heart failure; CoQ10, coenzyme Q10;

CVD, cardiovascular disease; GSH glutathione; Lp-PLA2, lipoprotein-associated phospholipase A2; MI, myocardial

infarction; O2- superoxide anions; oxLDL, oxidized LDL; NO, nitric oxide; PAD, peripheral arterial disease; SCD,

sudden cardiac death; SOD, superoxide dismutase; UA, unstable angina.

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Highlights

1. Inflammatory/oxidative biomarkers can elucidate cardiovascular events/risk

2. A single biomarker cannot estimate absolute risk of future cardiovascular events

3. This review provides an overview of existing and emerging biomarkers

4. The functions of each biomarker are discussed, along with prognostic data

5. The complexity surrounding the interactions of potential biomarkers is presented

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Inflammatory biomarkers for predicting cardiovascular disease

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