Translational research in coronary artery disease

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TRANSLATIONAL RESEARCH IN CORONARY ARTERY DISEASE TRANSLATIONAL RESEARCH IN CORONARY ARTERY DISEASE Pathophysiology to Treatment Edited by Wilbert S Aronow, MD, FACC, FAHA Professor of Medicine New York Medical College Valhalla, NY, USA and John Arthur McClung, MD, FACP, FACC, FAHA, FASE Director, Non-Invasive Cardiology Laboratory Professor of Clinical Medicine & Public Health New York Medical College Valhalla, NY, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125, London Wall, EC2Y 5AS 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability 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 ISBN: 978-0-12-802385-3 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress For Information on all Academic Press publications visit our website at http://store.elsevier.com/ Publisher: Mica Haley Acquisition Editor: Stacy Masucci Editorial Project Manager: Shannon Stanton Production Project Manager: Julia Haynes Designer: Matt Limbert Typeset by MPS Limited, Chennai, India www.adi-mps.com Printed and bound in the USA List of Contributors Nader G Abraham PhD  Department of Pharmacology, New York Medical College, Valhalla, NY, USA Chhaya Aggarwal MD  Division of Cardiology, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY, USA Chul Ahn PhD, MS  Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, USA Wilbert S Aronow MD  Division of Cardiology, Department of Medicine, Westchester Medical Center/ New York Medical College, Valhalla, NY, USA Lewis C Becker MD  Department of Medicine, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD, USA Deepak L Bhatt MD, MPH  Division of Cardiovascular Medicine, Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA, USA William H Frishman MD  Division of Cardiology, Department of Medicine, Westchester Medical Center/ New York Medical College, Valhalla, NY, USA Sachin Gupte MD, PhD  Department of Pharmacology, New York Medical College, Valhalla, NY, USA Michael E Halkos MD, MSc  Division of Cardiothoracic Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA Thomas H Hintze PhD  Department of Physiology, New York Medical College, Valhalla, NY, USA Sei Iwai MD  Division of Cardiology, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY, USA Jason T Jacobson MD  Division of Cardiology, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY, USA Diwakar Jain MD  Division of Cardiology, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla NY, USA Parag H Joshi MD, MHS  The Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA Sotirios K Karathanasis PhD  Cardiovascular and Metabolic Diseases, MedImmune, Gaithersburg, MD, USA Elizabeth Kertowidjojo MD, PhD, MPH  Department of Physiology, New York Medical College, Valhalla, NY, USA Sahil Khera MD  Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, NY, USA Dhaval Kolte MD, PhD  Division of Cardiology, Brown University/Rhode Island Hospital, Providence, RI, USA Brian G Kral MD, MPH  Department of Medicine, Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD, USA Steven L Lansman MD, PhD  Department of Surgery, Section of Cardiothoracic Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY, USA Seth S Martin MD, MHS  The Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA John Arthur McClung MD  Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, NY, USA Jawahar L Mehta MD, PhD  Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA Erin D Michos MD, MHS  The Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA Julio A Panza MD  Division of Cardiology, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY, USA Sulli Popilskis DVM  Department of Anesthesiology, New York Medical College, Valhalla, NY, USA Naga Venkata Pothineni MD  Department of Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA Khaled Qanud MD  Department of Physiology, New York Medical College, Valhalla, NY, USA Petra Rocic PhD  Department of Pharmacology, New York Medical College, Valhalla, NY, USA Amar Shah MD  Department of Radiology, Westchester Medical Center/New York Medical College, Valhalla, NY, USA Mala Sharma MD  Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, NY, USA Steve K Singh MD, MSc  Division of Cardiothoracic Transplant and Assist Devices, Texas Heart Institute, Baylor College of Medicine, Houston, TX, USA Su Song PhD  Department of Physiology, New York Medical College, Valhalla, NY, USA David Spielvogel MD  Department of Surgery, Section of Cardiothoracic Surgery, Westchester Medical Center/ New York Medical College, Valhalla, NY, USA Gilbert H.L Tang MD, MSc, MBA  Department of Surgery, Section of Cardiothoracic Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY, USA Sohaib Tariq MD  Division of Cardiology, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY, USA ix Preface These first years of the new millennium have witnessed an explosion in translational research in the field of cardiovascular disease in general and coronary artery disease in particular During this time, our understanding of the pathophysiology, the available diagnostic modalities, and the appropriate therapeutic interventions has changed considerably This is a time, too, during which the promise of stem cell therapy has remained unfulfilled, largely as a result of an insufficient knowledge of the many signaling pathways that underpin the programming, homing, and differentiation of pluripotent cell lines Despite this, remarkable advances have been made in vascular biology and the genetics of coronary disease, our understanding of lipid chemistry and inflammation, the electrophysiological manifestations of ischemic disease, and the development of novel means of revascularization and treatments for ischemic shock These new developments promise to completely reinvent our approach to the prevention, diagnosis, and treatment of coronary disease over the course of the decade to come They have also laid the groundwork for a more carefully designed series of experiments and clinical trials that will finally realize the benefits of cellular plasticity as a therapeutic modality This is as it needs to be, for despite the significant improvements made in the diagnosis and treatment of coronary disease in developed nations, the emergence of coronary disease in the developing world is now becoming a major public health problem Given the complexity of human biology, it is a truly remarkable thing that the human organism responds as well as it does to the pharmacologic and interventional strategies that have been developed for the treatment of coronary disease over the course of the last half century For those of us privileged to have had our careers unfold during this time of unparalleled growth in knowledge and therapeutic potential, it has been an extraordinary journey What we have witnessed to date, however, serves only as a prelude to even more remarkable discoveries that will build exponentially on what we now know This book has attempted to encapsulate in one volume the major advances of the recent past in order to provide the reader with a concise, but comprehensive, view of where we are and where we are going To this end, we have organized it in such a fashion as to begin with the most promising work in basic science, subsequent to which we transition into diagnostic modalities and ultimately into new therapies We have concluded with a chapter on biostatistics which presents the reader with a precise review of the techniques currently used for the development and analysis of clinical data We have crafted this volume to be of particular use to cardiovascular scientists and practitioners alike as well as to biomedical faculties and students of all stripes who have an interest in learning about and furthering the progress of coronary artery research We hope that you will find it useful in your own education as well as the education of others who care for our patients and who continue to develop and improve the therapies for them Wilbert S Aronow and John Arthur McClung xi Biographies Wilbert S Aronow, MD, is Professor of Medicine at New York Medical College/Westchester Medical Center, Valhalla, NY, USA Dr Aronow received his MD from Harvard Medical School He has edited 13 books and is author or coauthor of 1453 papers, 301 commentaries or Letters to the Editor, and 1004 abstracts and is presenter or copresenter of 1374 talks at meetings Dr Aronow is a Fellow of the ACC, the AHA, the ACP, the ACCP, the AGS (Founding Fellow of Western Section), and the GSA He has been a member of 112 editorial boards of medical journals, coeditor of two journals, deputy editor of one journal, executive editor of three journals, associate editor for nine journals, and guest editor for seven other medical journals He has received each year from 2001 to 2015 an outstanding teacher and researcher award from the medical residents and from 2001 to 2015 from the cardiology fellows at Westchester Medical Center/New York Medical College He has received awards from the Society of Geriatric Cardiology, the Gerontological Society of America, New York Medical College including the 2014 Chancellor’s Research Award, the F1000 Faculty Member of the Year Award for the Faculty of Cardiovascular Disorders in 2011, 2013, and 2014, the Walter Bleifeld Memorial Award for distinguished contributions to clinical research from the International Academy of Cardiology in July, 2010, and a Distinguished Fellowship Award from the International Academy of Cardiology in July, 2012 He has been a member of four national guidelines committees including being a coauthor of the 2010 AMDA guidelines for heart failure, cochair and first author of the 2011 ACC/AHA expert consensus document on hypertension in the elderly, coauthor of the 2015 AHA/ACC/ASH scientific statement on treatment of hypertension in patients with coronary artery disease, and is currently a member of the writing group of the ACC/AHA guideline for the management of patients with hypertension He was a coauthor of a 2015 position paper from the International Lipid Expert Forum He was a consultant to the ACP Information and Educational Resource (PIER) on the module of aortic stenosis He is currently a member of the Board of Directors of the ASPC, and a member of the ACCP Cardiovascular Medicine and Surgery Network Steering Committee John Arthur McClung, MD, is Professor of Clinical Medicine in the School of Medicine and Professor of Clinical Public Health in the School of Health Sciences and Practice at New York Medical College in Valhalla, New York, where he also serves on the clinical faculty of the Westchester Medical Center Dr McClung received his AB from the Johns Hopkins University in 1971 and his MD from New York Medical College in 1975, where he received the Sprague Carlton Award and the Cor et Manus Award of Distinction He has been on the faculty of New York Medical College since 1979 and served as its Chief of the Critical Care Section of the Department of Medicine from 1982 until 1990 In 1988, he completed the Intensive Bioethics Course at Georgetown University and went on to the Advanced Bioethics Course in 1990 He is board certified in Internal Medicine, Cardiovascular Disease, and Echocardiography and currently serves as the Director of the Noninvasive Cardiology Laboratory at the Westchester Medical Center, a position that he has held since 2006 He is a past Director of the Cardiovascular Fellowship Training Program at New York Medical College from 2001 until 2014, and was a member of the New York Medical College Committee for the Protection of Human Subjects from 1987 until 2008, serving as its chair for the last years He is currently a member of the New York Academy of Sciences and a Fellow of the American College of Physicians, the American College of Cardiology, the American Heart Association and its Council on Clinical Cardiology, and the American Society of Echocardiography He is a past Fellow of the Society for Cardiac Angiography and Interventions and serves on the Board of Directors of the Physicians’ Home since 2009 He is a member of the Iota Chapter of ΑΩΑ and is a past Councilor for the New York State Chapter of the American College of Cardiology, where he served as the chair of its nominating committee He has served as a manuscript reviewer for the European Journal of Endocrinology, Drugs & Aging, Catheterization and Cardiovascular Diagnosis, the Journal of Clinical Ethics, and Cardiology in Review In 1990, Dr McClung founded the Division of Clinical Ethics of the Department of Medicine at New York Medical College and served as its chief until 1995 He has published articles and book chapters on endothelial function in diabetes mellitus, heme oxygenase, cardiomyopathy, multiple topics in echocardiography, and multiple topics in clinical cardiology He has also published articles and book chapters on ethical issues in the areas of cardiopulmonary resuscitation, bioethics consultation, and end of life care xiii C H A P T E R Endothelial Biology: The Role of Circulating Endothelial Cells and Endothelial Progenitor Cells John Arthur McClung1 and Nader G Abraham2 Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, NY, USA Department of Pharmacology, New York Medical College, Valhalla, NY, USA In Lewis Carroll’s Alice in Wonderland, the king responds to the query of the White Rabbit as to where to begin by saying, “Begin at the beginning… and go on till you come to the end: then stop.” When dealing with cell turnover, the definition of the beginning is an open question, as a result of which, simply for purposes of discussion, this review will begin with the endothelial progenitor cell and go on from there mature human umbilical vein cells (HUVECs) which were CD133 negative [3] Concurrently, Gehling et  al isolated CD133+ cells from peripheral blood that, when plated on fibronectin for 14 days, were able to generate colony-forming units (CFUs) of apparently both hematopoietic and endothelial lineage cells [4] Shortly thereafter, Hill et  al described a similar, but not identical, assay in which circulating mononuclear cells were cultured for days with the nonadherent cells and were subsequently plated on fibronectin Colonies were counted days later and demonstrated an endothelial phenotype by histochemical staining for von Willebrand factor, VEGFR-2, and CD31 [5] The number of colonies generated correlated negatively with the Framingham risk score and positively with the flow-mediated brachial index Other investigators, using a similar technology, demonstrated that these cells could be incorporated into the damaged endothelium of a ligated left anterior descending coronary artery in a rat model [6] A commercial assay using this technology was subsequently devised that used a 5-day protocol and has subsequently become known as the CFU-Hill Colony Assay In contradistinction to the CFU assay, Lin et al plated human monocytes from which the nonadherent cells were removed at 24 h [7] The remaining adherent cells were cultured and observed to have expanded significantly in bone marrow (BM) transplant recipients over the course of a month Similarly, Vasa et  al evaluated WHAT ARE ENDOTHELIAL PROGENITOR CELLS? Since Asahara et  al first isolated and described a population of what were termed “endothelial progenitor cells” (EPCs) in the peripheral blood at the end of the last century [1,2], a wealth of research has been generated that has further characterized these cells and in so doing raised more questions about both their identity and their behavior Asahara’s original work identified a population of cells that were CD34 positive as well as vascular endothelial growth factor receptor-2 (VEGFR-2) positive that were capable of differentiating into endothelial cells in vitro, migrating in vivo to sites of vascular injury, and that enhanced the formation of new endothelium when infused into an organism Given that both CD34 and VEGFR-2 are also expressed on mature endothelial cells, Peichev et  al demonstrated a population of circulating cells that also expressed CD133 in contradistinction to presumably Translational Research in Coronary Artery Disease DOI: http://dx.doi.org/10.1016/B978-0-12-802385-3.00001-2 2016 Elsevier Inc All rights reserved © 2012 1.  Endothelial Biology: The Role of Circulating Endothelial Cells and Endothelial Progenitor Cells the migratory capability of monocytes cultured for days on fibronectin in which the adherent cells were isolated rather than the nonadherent cells [8] These cells demonstrated significant migratory potential that appeared to be inversely proportional to the number of risk factors in a population of patients with coronary artery disease (CAD) Hur et  al plated monocytes on endothelial basal medium and noted the appearance of spindle shaped cells similar to the original Asahara reports that increased in number for 14 days, after which replication ceased and the cells gradually disappeared by 28 days [9] Another population of cells appeared after 2–4 weeks of incubation that rapidly replicated and demonstrated no evidence of senescence These “late” EPCs, in contradistinction to “early” EPCs, were observed to successfully form capillaries when plated on Matrigel and were more completely incorporated into HUVEC monolayers Notwithstanding, both early and late EPCs were equally effective at improving perfusion to an ischemic limb in a mouse model Combining these two populations of cells was even more effective at enhancing ischemic limb perfusion [10] Late EPCs have also been described as “outgrowth endothelial cells” (OECs) or “endothelial colony-forming cells” (ECFCs) by other investigators [7,11] Using the approach of Lin and Vasa in which nonadherent cells were discarded and adherent cells were retained, investigators were able to culture a subpopulation of cells that appeared to be identical to Hur’s late EPCs, both morphologically and in their migratory behavior Late EPCs appear to be distinctly superior to other EPC subpopulations in promoting angiogenesis, both in vitro and in vivo [12] In addition to having a much higher rate of proliferation and resistance to apoptosis, this subpopulation has also been noted to have increased telomerase activity [11] Sieveking et  al generated both early and late EPCs out of a single population of mononuclear cells that were plated on fibronectin with the nonadherent cells removed after 24 h [13] Both early and late EPCs were observed to be CD34, CD31, CD146, and VEGFR-2 positive, however, only early EPCs expressed CD14 and CD45 Late EPCs formed branched interconnecting vascular networks, while early EPCs were observed to exhibit a marked augmentation of angiogenesis by a paracrine mechanism These results are summarized in Figure 1.1 [14] Thus, there appear to be at least four different methodologies for isolating putative EPCs from monocytes plated on fibronectin The CFU assay cultures cells that are not adherent to the medium which form colonies at 4–9 days that are consistent with an early EPC phenotype Hur et  al were able to grow both early and late EPCs from monocytes that were not separated Hematopoietic stem cell CD133 CD133 CD34 CD133 Early EPC CD34 CD14 Late EPC (OEC) CD45 CD14 ? CD133 CD11b CD14 CD34 CD34 KDR CD45 CD34 CD14 KDR Culture Colony-forming unit Flow cytometry Early EPC Characteristics Late EPC 3–5 days Duration 7–14 days Heterogenous Morphology Homogenous Antigen markers CD34/KDR CD31/vWf +++ Secretion of angiogenic cytokines + Low In vivo angiogenic effects High CD14/CD45/KDRLow CD31/vWf FIGURE 1.1  Antigenic cell surface markers of “Early” EPC and “Late” EPC (OEC) “Early” EPCs form CFUs and most of these go on to have hematopoetic rather than endothelial phenotypes OEC, outgrowth endothelial cells; KDR, VEGFR-2 Source: From Ref [14] Used by permission out by their ability to either adhere or not to adhere to the medium Sieveking et al were able to grow both early and late EPCs from only adherent monocytes Hence, it appears that nonadherent cells can generate only early EPC colonies, while adherent cells have the capability of generating both early EPC and OEC (Figure 1.2) In addition to BM-derived cells, a recent study isolated a rare vascular endothelial stem cell in the blood vessel wall of the adult mouse that is CD117+ and c-kit+, and has the capacity to produce tens of millions of daughter cells that can generate functional blood vessels in vivo that connect to the host circulation [16] The cellular regeneration of both the vascular and other components of a mouse digit tip in the context of CFU transplantation has been found to be composed of tissue-derived cells only [17] All of these various cells have reparative capability when acting together, but precisely how this occurs is a matter of intense current research TRANSLATIONAL RESEARCH IN CORONARY ARTERY DISEASE Mechanisms, Known and Unknown PB-MNC Method A CFU-EC Method B Method C CAC ECFC Adherence deplete on FN Colonies appear d4–9 Discard nonadherent cells d4, cells enumerated Colonies appear d7–21 No colony formation [24] HGF markedly enhances angiogenesis [25] G-CSF and GM-CSF enhance the migration of endothelial cells, and both have anti-inflammatory activity on vascular endothelium as well [26–28] MMP-9 appears to be required for EPC mobilization, migration, and vasculogenesis, and IL-8 enhances both endothelial cell proliferation as well as survival [29,30] Among other things, MIF appears to induce EPC mobilization [31] Ang-1 is expressed from hematopoetic stem cells [32] Along with VEGF, Ang-1 has been implicated in the recruitment of vasculogenic stem cells, and when BM mononuclear cells are enhanced by Ang-1 gene transfer, angiogenesis is improved both qualitatively and quantitatively [33,34] TP has been demonstrated to both enhance endothelial cell migration and protect EPCs from apoptosis [18,35] Early EPCs also have been shown to be repositories of both eNOS and iNOS which play a role in ischemic preconditioning and chronic myocardial ischemia, respectively [36,37] More recently, prostacyclin (PGI2) has been identified as being secreted in very high levels by late (OEC) EPC [38] MECHANISMS, KNOWN AND UNKNOWN Early outgrowth Asahara, Hill Early outgrowth Asahara, Dimmeler Late outgrowth Hebbel, Ingram FIGURE 1.2  Methodologies for the generation of various cell types from tissue culture of BM-derived circulating mononuclear cells PB-MNC, peripheral blood mononuclear cells; CFU-EC, CFU endothelial cells; CAC, circulating angiogenic cells; ECFC, OEC; FN, fibronectin Source: Adapted by permission from Macmillan Publishers Ltd; Ref [15] PARACRINE EFFECTS OF BM-DERIVED CELLS CFU derived early EPCs secrete a number of agents, among them matrix metalloproteinase (MMP)-9, interleukin (IL)-8, macrophage migration inhibitory factor (MIF), angiopoeitin-1 (Ang-1), and thymidine phosphorylase (TP) in higher amounts than in early EPCs from adherent monocytes [18] Early EPCs cultured from nonadherent monocytes secrete VEGF, stromal cell-derived factor-1 (SDF-1), insulin-like growth factor-1 (IGF-1), and hepatocyte growth factor (HGF) [19] Early EPCs cultured from adherent monocytes secrete VEGF, HGF, granulocyte colony stimulating factor (G-CSF), and granulocyte macrophage colony stimulating factor (GM-CSF) [20] Both VEGF and SDF-1 promote migration and tissue invasion of progenitor cells to a site of injury as well as enhance migration of mature endothelial cells [21–23] IGF-1 promotes angiogenesis and inhibits apoptosis Mobilization of BM-Derived Cells Under stable physiologic conditions, circulating EPC precursors exist in a niche in the BM that is defined by a combination of low oxygen tension, low levels of reactive oxygen species (ROS), and high levels of SDF-1 [39–41] In the face of myocardial ischemia, VEGF and SDF-1 are expressed in human and rat models, respectively [42,43] This, as well as vascular trauma, initiates a complex mechanism that involves the release of multiple chemokines [44–46] Among other effects, this release activates the phosphoinositide 3-kinase (PI3K)/Akt pathway to increase the production of nitric oxide (NO) which in turn activates MMPs [47,48] MMPs, and in particular MMP-9 via release of soluble kit ligand, disrupt the integrins that form the scaffold that retains the stem cells in the marrow, allowing them to respond to the enhanced SDF-1 gradient and move out into the circulation (Figure 1.3) [50,51] Once released from the marrow, development of these cells is enhanced, in part, by the release of Ang-1 by pericytes and by EPC themselves which can also enhance their survival by means of the downstream activation of the PI3K/Akt pathway (Figure 1.4) [53] Vasculogenesis and Angiogenesis Originally thought by Asahara et  al to be a process mediated solely by BM-derived cells, vasculogenesis refers to de novo vessel formation by in situ incorporation, TRANSLATIONAL RESEARCH IN CORONARY ARTERY DISEASE 1.  Endothelial Biology: The Role of Circulating Endothelial Cells and Endothelial Progenitor Cells FIGURE 1.3  Schematic representation of the mobilization of BM-derived EPC by ischemic stimuli Ischemia activates the PI3K/Akt pathway to increase the production of NO which in turn activates MMP-9 disrupting the integrin scaffold in the BM and allowing EPC to respond to the enhanced SDF-1 gradient and move out into the circulation Source: Adapted from Ref [49] Used by permission FIGURE 1.4  Cell survival induced by activation of the PI3K/Akt pathway by Ang-1 elaboration by pericytes The release of Ang-1 enhances survival of the in situ endothelial cell by allowing it to resist active inflammation mediated by Ang-2 as well as serving as a chemoattractant for EPC ABIN-2, A20-binding inhibitor of NF-kappa-B activation 2; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; Tie-2, tyrosine kinase receptor Source: By permission from Macmillan Publishers Ltd; Ref [52] TRANSLATIONAL RESEARCH IN CORONARY ARTERY DISEASE ... jtcvs.2013.09.033 TRANSLATIONAL RESEARCH IN CORONARY ARTERY DISEASE C H A P T E R 19 Biostatistics Used for Clinical Investigation of Coronary Artery Disease Chul Ahn Department of Clinical Sciences,... uncommon clinical finding with an incidence rate of 1.5–4.9% in adults Cross-Sectional Study Exposure and disease are determined at one specific point in time in a given population in a cross-sectional... situations in coronary artery disease Here, we present a few RCT designs commonly used in coronary artery disease research More detailed information on the types of RCT designs can be found in Ahn
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