Academic Press is an imprint of Elsevier 32 Jamestown Road, London NW1 7BY, UK 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands This book is printed on acid-free paper ϱ Copyright ß 2010, Elsevier Inc All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: permissions@elsevier.com Alternatively you can submit your request online by visiting the Elsevier web site at http://www.elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-380983-4 ISSN: 0065-2423 For information on all Academic Press publications visit our website at www.elsevierdirect.com Printed and bound in USA 10 11 12 10 CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors’ contributions begin SARIKA ARORA (65), Department of Biochemistry, Lady Hardinge Medical College & Associated Hospitals, New Delhi, India C.H BRIDTS (87), Department of Immunology‐Allergology‐Rheumatology, Faculty of Medicine, University of Antwerp, Antwerpen, Belgium THOMAS M CONNOLLY (1), Discovery Translational Medicine, Wyeth Research, Collegeville, Pennsylvania, USA P.K DABLA (65), Department of Biochemistry, Lady Hardinge Medical College & Associated Hospitals, New Delhi, India L.S DE CLERCK (87), Department of Immunology‐Allergology‐Rheumatology, Faculty of Medicine, University of Antwerp, Antwerpen, Belgium K.J DE KNOP (87), Department of Immunology‐Allergology‐Rheumatology, Faculty of Medicine, University of Antwerp, Antwerpen, Belgium JORIS R DELANGHE (23), Department of Clinical Chemistry, Ghent University, Gent, Belgium D.G EBO (87), Department of Immunology‐Allergology‐Rheumatology, Faculty of Medicine, University of Antwerp, Antwerpen, Belgium MASSIMO FRANCHINI (47), Servizio di Immuno-ematologia e Medicina Trasfusionale, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy M.M HAGENDORENS (87), Department of Paediatrics, Faculty of Medicine, University of Antwerp, Antwerpen, Belgium ix x CONTRIBUTORS ALAN R HIPKISS (123), School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, The University of Birmingham, Edgbaston, Birmingham, United Kingdom ISHMAEL KASVOSVE (23), Department of Chemical Pathology, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe JASBIR KAUR (103), Department of Ocular Biochemistry, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India GIUSEPPE LIPPI (47), Laboratorio di Analisi Chimico-Cliniche, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy GWINYAI MASUKUME (23), Department of Chemical Pathology, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe MEDHA RAJAPPA (103), Department of Ocular Biochemistry, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India PARUL SAXENA (103), Department of Ocular Biochemistry, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India BHAWNA SINGH (65), Department of Biochemistry, G.B Pant Hospital, New Delhi, India MARIJN M SPEECKAERT (23), Department of Clinical Chemistry, Ghent University, Gent, Belgium REINHART SPEECKAERT (23), Department of Clinical Chemistry, Ghent University, Gent, Belgium W.J STEVENS (87), Department of Immunology‐Allergology‐Rheumatology, Faculty of Medicine, University of Antwerp, Antwerpen, Belgium GIOVANNI TARGHER (47), Sezione di Endocrinologia, Dipartimento di Scienze Biomediche e Chirurgiche, Universita` di Verona, Verona, Italy CONTRIBUTORS xi RICHA VAISHYA (65), Department of Biochemistry, G.B Pant Hospital, New Delhi, India M.M VERWEIJ (87), Department of Immunology‐Allergology‐Rheumatology, Faculty of Medicine, University of Antwerp, Antwerpen, Belgium XINKANG WANG (1), Discovery Translational Medicine, Wyeth Research, Collegeville, Pennsylvania, USA J.M WALSHE (151), Department of Neurology, The Middlesex Hospital, London, United Kingdom PREFACE I am pleased to present volume fifty of Advances in Clinical Chemistry series for the year 2010 In this first volume for the new decade, an array of interesting topics is presented This volume leads off with an interesting review on the identification of potential biomarkers in vulnerable atheromatous plaques Rupture of these plaques is associated with a host of coronary artery syndromes including myocardial infarction and stroke The second review explores the unique relationship of haptoglobin polymorphism and its functionally distinct phenotypes in vaccination, as well as susceptibility or resistance to common infection The role of bilirubin as a physiological antioxidant is presented in the next chapter in support of its reported protective role in prevention of cardiovascular morbidity and mortality The oxidation theme is continued in the next chapter as the role of NAD(P)H oxidase is investigated as the major source of superoxide in vascular cells and myocytes The importance of this key enzyme in the pathophysiology of coronary artery disease is elucidated The next chapter deals with the application of microarray technology in the component-resolved diagnosis of IgE-mediated allergies An excellent chapter on pathology of vision loss, specifically ocular disease and the biochemical mechanisms, involved with angiogenesis The identification and elucidation of these unique markers may potentially facilitate early diagnosis or treatment options A comprehensive review on mitochondrial dysfunction and protein alteration is next presented The identification of these new biomarkers of both diagnostic and prognostic significance will increase in importance as the world’s population ages This volume concludes with an interesting review on monitoring copper in Wilson’s disease I extend my appreciation to each contributor of volume fifty and thank colleagues who contributed to the peer review process I also extend thanks to my Elsevier editorial liaison, Gayathri Venkatasamy, for dedicated support I sincerely hope the first volume of the new decade will be enjoyed by our readership As always, comments and suggestions for future review articles for the Advances in Clinical Chemistry series are always appreciated In keeping with the tradition of the series, I would like to dedicate volume fifty to my mother Florence GREGORY S MAKOWSKI xiii ADVANCES IN CLINICAL CHEMISTRY, VOL 50 BIOMARKERS OF VULNERABLE ATHEROMATOUS PLAQUES: TRANSLATIONAL MEDICINE PERSPECTIVES Xinkang Wang1 and Thomas M Connolly Discovery Translational Medicine, Wyeth Research, Collegeville, Pennsylvania, USA Abstract Background on Atherosclerosis and Vulnerable Plaques Concept of Biomarkers Imaging Biomarkers for Vulnerable Plaques 4.1 Ultrasound 4.2 Computed Tomography (CT) 4.3 Positron Emission Tomography (PET) 4.4 Magnetic Resonance Imaging (MRI) 4.5 Optical Imaging Circulating Biomarkers for Vulnerable Plaques 5.1 Nonspecific Inflammatory Biomarkers 5.2 Inflammatory Cytokines/Chemokines 5.3 Adhesion Molecules 5.4 Matrix Metalloproteinases 5.5 Other Inflammatory Markers 5.6 Redox Biomarkers FDA Perspectives of Biomarkers Conclusion References 4 8 9 10 11 12 12 13 13 14 15 Abstract In cardiovascular disease rupture of a vulnerable atherosclerotic plaque is the major causative factor of acute coronary syndromes, myocardial infarction and stroke, and can ultimately lead to death Identification of biomarkers that could accurately predict the risk of plaque rupture would Corresponding author: Xinkang Wang, e-mail: wangxk2000@yahoo.com 0065-2423/10 $35.00 DOI: 10.1016/S0065-2423(10)50001-5 Copyright 2010, Elsevier Inc All rights reserved WANG AND CONNOLLY be a significant advance in guiding treatment of patients with this disease The use of these biomarkers would also facilitate the development of new drugs to treat cardiovascular disease, particularly those that act through novel mechanisms There is currently a lack of specific biomarkers for vulnerable plaque, and thus, it is an area of intense research including the concepts of live detection versus retrospective characterization, molecular imaging, and biochemical biomarker discovery This review will focus on recent advances on both imaging and circulating molecular biomarkers in atherosclerosis The use of combinations of different imaging modalities (such as molecular, functional, and anatomical) and modalities with circulating/biochemical markers is the current trend and will likely provide the most useful information for the assessment of the vulnerability of atherosclerotic plaques Background on Atherosclerosis and Vulnerable Plaques Atherosclerosis is a disease of medium and large arteries and involves endothelial dysfunction, inflammation, and the buildup of lipid deposits, fibrous tissue, and cellular debris to form a large and growing mass termed a ‘‘plaque.’’ As the atheromatous plaque grows, the vessel may undergo a remodeling to enlarge its dimension Significant stenosis may occur only after the plaque makes up a significant portion of the intima and then the reduced lumen makes it more difficult for blood to flow through the artery with a resulting reduced oxygen supply to the target organ Furthermore, erosion or rupture of an unstable plaque exposes the blood to thrombogenic stimuli which can lead to thrombus formation and complete occlusion and ensuing cardiovascular (CV) event The formation of a plaque in an artery, or atherosclerotic vascular disease, is a major health problem with over 200 million cases worldwide It is the causative factor that leads to coronary artery disease (CAD; myocardial infarction and angina), peripheral vascular diseases (PAD; critical limb ischemia and intermittent claudication), and cerebral vascular disease (CVD; ischemic strokes) Coronary heart disease (CHD) represents the number one and stroke is the number three cause of death in the United States and most Western countries It is estimated that annually 785,000 individuals in the United States suffer a first heart attack and an estimated 935,000 had a total attack in 2006 [1] Atherosclerosis is a complex and progressive disease The progression of the disease and composition of the plaque are influenced by inflammatory cells and the mediators they secrete, and can be further affected by a metabolic condition such as diabetes (glucose), homocysteine, smoking status, BIOMARKERS OF VULNERABLE ATHEROMATOUS PLAQUES and coagulation mediators The complex interaction among inflammatory cells, vascular cells, various lipoproteins/particles, and diverse local and circulating mediators mark the vast complexity of the atherosclerosis process While the most severe and ultimate fate of atherosclerosis may be vessel occlusion (mostly by atherothrombosis), the rate of atherosclerosis progression is difficult to predict and varies among individuals Early atherosclerosis is thought to be initiated with the initial infiltration of inflammatory cells through the compromised endothelium and their progression to become subendothelial macrophages, which accumulate cholesterol to form foam cells and subsequently form fatty streak [2, 3] Over time an intermediate lesion of atherosclerosis develops when smooth muscle cells migrate into the subendothelium, proliferate, and lay down extracellular matrix to form the fibrous cap With the persistence of various risk factors, such as high levels of LDL, inflammation, shear stress, and other oxidative stresses, the lesion grows Multiple cellular components including macrophages, T cells and smooth muscle cells, and various mediators produced by these cells continuously drive the progression and remodeling of the atherosclerotic lesion [2, 3] The stability of the atheroma may be weakened due to the digestion of the fibrous cap by proteases including matrix metalloproteinases (MMPs), which can ultimately lead to plaque erosion, rupture, and possible occlusion of the vessel by thrombosis [4] It is noted that less than 70% patients with acute coronary syndrome (ACS) had significant stenotic plaques (as defined by angiography) [5, 6] and that many acute myocardial infarctions (AMI) occur due to occlusion of coronary arteries without significant structural stenosis [7] Thus, plaque dimensions (in particular stenotic phenotype) and clinical outcome are not always closely related Histopathological studies of postmortem specimens suggest distinct composition and characteristics for high-risk/vulnerable plaques that could serve for diagnosis prior to their rupture, including a thin fibrous cap, a large lipid-rich core, and increased macrophage activity Recent advances have provided a better understanding of the molecular/ biochemical mechanisms of atherosclerosis development and in imaging technologies that provide better insights on plaques prone to rupture, prone to erosion, or with calcified nodules (additional factor of plaque vulnerability) [8] The plaque prone to erosion is often rich in proteoglycans, though in most cases it lacks a distinguishing structure such as a lipid pool or necrotic core In plaques that have lipid-rich cores, the fibrous cap is usually thick and rich in smooth muscle cells [8, 9] The plaque with a calcified nodule often protrudes into the lumen and is associated with loss and/or dysfunction of endothelial cells over a calcified nodule and thus the loss of fibrous cap, which makes the plaque at high risk or vulnerable [8, 9] WANG AND CONNOLLY Concept of Biomarkers An NIH working group has 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’’ [10] A biomarker may be measured in blood, urine, or a tissue, or may be a recording of a process Key criteria are that the biological variables measured be done quantitatively and with acceptable reproducibility, sensitivity, and specificity Biomarkers can be used for disease diagnosis, therapeutic target validation, target engagement, pharmacokinetics and pharmacodynamics relationship (as both drug efficacy and safety parameters), and patient selection and stratification [11] Imaging Biomarkers for Vulnerable Plaques Multiple diagnostic imaging modalities have been developed and applied to detect atherosclerotic plaques Table summarizes key features of each modality, including advantages and limitations of their applications in atherosclerosis [12–27] While earlier methods provided anatomical information, the field is currently shifting toward imaging techniques that provide information on plaque and vessel composition as well The imaging modalities are summarized as invasive and noninvasive categories, of which the invasive methodologies include angiography, intravascular ultrasound (IVUS), angioscopy, optical coherence tomography (OCT), and noninvasive methodologies include ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging [24, 25, 27, 28] This review will focus on noninvasive imaging methodologies and their applications in atherosclerosis In addition, molecular imaging has been rapidly advancing and there is great interest and potential for its application in the molecular and functional aspects of atherosclerosis such as inflammation, protease activity, and angiogenesis Some potential applications of molecular imaging in atherosclerosis are also reviewed/highlighted in the following sections along with each imaging modalities 4.1 ULTRASOUND Surface ultrasound has been successfully used to noninvasively assess plaques in the carotid artery because of its high sensitivity and the proximity of this artery to the body surface, thus allowing for excellent penetration Liver Cu – mg/g WW 400 300 P No Rx Mo S4 T 200 T Zn 100 P P T P P T No Rx −1