Elsevier

Clinical Biochemistry

Volume 46, Issue 15, October 2013, Pages 1353-1371
Clinical Biochemistry

Review
Inflammatory biomarkers for predicting cardiovascular disease

https://doi.org/10.1016/j.clinbiochem.2013.05.070Get rights and content

Highlights

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

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

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

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

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

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.

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.

Section snippets

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

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 hematopoiesis [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

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], [138], [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

Adiponectin

Adiponectin is a protein produced by adipocytes and present at high concentration in human peripheral circulation [207], [208], [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

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

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 have been associated with subclinical atherosclerosis [287] and a range of CVD [154], [206], [281], [282], [288], [289], [290], [291]. IL-8 has been associated with a number of CVD [168], [189], [277], [278], [279], [280], [281], [282]

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

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

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

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

References (443)

  • K. Kozuka et al.

    Endothelial markers and adhesion molecules in acute ischemic stroke—sequential change and differences in stroke subtype

    Atherosclerosis

    (2002)
  • K.G. Shyu et al.

    Circulating intercellular adhesion molecule-1 and E-selectin in patients with acute coronary syndrome

    Chest

    (1996)
  • T.A. Mehta et al.

    Heat shock proteins in vascular disease—a review

    Eur J Vasc Endovasc Surg

    (2005)
  • D. Whitley et al.

    Heat shock proteins: a review of the molecular chaperones

    J Vasc Surg

    (1999)
  • A.G. Pockley

    Heat shock proteins as regulators of the immune response

    Lancet

    (2003)
  • S.D. Shapiro

    Matrix metalloproteinase degradation of extracellular matrix: biological consequences

    Curr Opin Cell Biol

    (1998)
  • Y. Inokubo et al.

    Plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 are increased in the coronary circulation in patients with acute coronary syndrome

    Am Heart J

    (2001)
  • H. Kai et al.

    Peripheral blood levels of matrix metalloproteases-2 and -9 are elevated in patients with acute coronary syndromes

    J Am Coll Cardiol

    (1998)
  • B. Shao et al.

    Myeloperoxidase impairs ABCA1-dependent cholesterol efflux through methionine oxidation and site-specific tyrosine chlorination of apolipoprotein A-I

    J Biol Chem

    (2006)
  • H.M. Abu-Soud et al.

    Nitric oxide is a physiological substrate for mammalian peroxidases

    J Biol Chem

    (2000)
  • T.J. Mocatta et al.

    Plasma concentrations of myeloperoxidase predict mortality after myocardial infarction

    J Am Coll Cardiol

    (2007)
  • M.C. Meuwese et al.

    Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: the EPIC-Norfolk Prospective Population Study

    J Am Coll Cardiol

    (2007)
  • A.J. Atkinson et al.

    Biomarkers and surrogate endpoints: preferred definitions and conceptual framework

    Clin Pharmacol Ther

    (2001)
  • G.K. Hansson

    Inflammation, atherosclerosis, and coronary artery disease

    N Engl J Med

    (2005)
  • R. Ross

    Atherosclerosis — an inflammatory disease

    N Engl J Med

    (1999)
  • S.E. Nissen et al.

    Intravascular ultrasound: novel pathophysiological insights and current clinical applications

    Circulation

    (2001)
  • G. Basta et al.

    Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes

    Cardiovasc Res

    (2004)
  • A. Bierhaus et al.

    Advanced glycation end product-induced activation of NF-κB is suppressed by α-lipoic acid in cultured endothelial cells

    Diabetes

    (1997)
  • S.F. Yan et al.

    Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond

    Circ Res

    (2003)
  • G. Basta et al.

    Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses

    Circulation

    (2002)
  • R.D. Semba et al.

    Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults

    Am J Hypertens

    (2009)
  • R.D. Semba et al.

    Plasma carboxymethyl-lysine, an advanced glycation end product, and all-cause and cardiovascular disease mortality in older community-dwelling adults

    J Am Geriatr Soc

    (2009)
  • R. Meerwaldt et al.

    Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients

    J Am Soc Nephrol

    (2005)
  • R.D. Semba et al.

    Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women

    Aging Clin Exp Res

    (2009)
  • A. Costanzo et al.

    Endothelial activation by angiotensin II through NFκB and p38 pathways: involvement of NFκB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin

    J Cell Physiol

    (2003)
  • L. Pastore et al.

    Angiotensin II stimulates intercellular adhesion molecule-1 (ICAM-1) expression by human vascular endothelial cells and increases soluble ICAM-1 release in vivo

    Circulation

    (1999)
  • M.E. Pueyo et al.

    Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-κB activation induced by intracellular oxidative stress

    Arterioscler Thromb Vasc Biol

    (2000)
  • P.E. Tummala et al.

    Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: a potential link between the renin–angiotensin system and atherosclerosis

    Circulation

    (1999)
  • M. Grafe et al.

    Angiotensin II-induced leukocyte adhesion on human coronary endothelial cells is mediated by E-selectin

    Circ Res

    (1997)
  • X.-L. Chen et al.

    Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells

    Circ Res

    (1998)
  • Y. Funakoshi et al.

    Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells

    Hypertension

    (2001)
  • W. Ni et al.

    Monocyte chemoattractant protein-1 is an essential inflammatory mediator in angiotensin II-induced progression of established atherosclerosis in hypercholesterolemic mice

    Arterioscler Thromb Vasc Biol

    (2004)
  • L. Boring et al.

    Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis

    Nature

    (1998)
  • C. Savoia et al.

    Angiotensin type 2 receptor in hypertensive cardiovascular disease

    Curr Opin Nephrol Hypertens

    (2011)
  • R.E. Schmieder et al.

    Angiotensin II related to sodium excretion modulates left ventricular structure in human essential hypertension

    Circulation

    (1996)
  • H. Zheng et al.

    Exercise training normalizes enhanced sympathetic activation from the paraventricular nucleus in chronic heart failure: role of angiotensin II

    Am J Physiol Regul Integr Comp Physiol

    (2012)
  • G.G. Neri Serneri et al.

    Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component

    Circ Res

    (2004)
  • B. Ariff et al.

    Candesartan- and atenolol-based treatments induce different patterns of carotid artery and left ventricular remodeling in hypertension

    Stroke

    (2006)
  • Y. Lacourciere et al.

    Effects of perindopril on elastic and structural properties of large arteries in essential hypertension

    Can J Cardiol

    (2004)
  • Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group

    Circulation

    (1998)
  • Cited by (0)

    View full text