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3 Is (Infection, Immunity, Inflammation) and Atherothrombosis: New Directions for Improving Patient Care

Executive Summary

The NHLBI and the Center for Anti-Inflammatory Therapeutics (CAT) at the Henry M. Goldman School of Dental Medicine (GSDM) jointly convened a workshop on September 7, 2010, in Boston, MA titled “3 Is (Infection, Immunity, Inflammation) and Atherothrombosis: Improving Patient Care.” The purpose of the workshop was

  • to assess what is known about the role of infection, immunity, inflammation and their interactions in the development and progression of atherothrombotic diseases;
  • to review emerging technologies that may help shape the field in the future; and
  • to identify research needs related to infection, immunity, and inflammation directed at improving prevention and treatment of atherothrombotic cardiovascular disease (ATCVD). 

This conference was a public and private partnership to engage in an innovative and productive intellectual collaboration in identifying research priorities related to the 3 Is and atherothrombosis (AT) to speed up the development and adoption of new diagnostic, preventive, and treatment modalities into clinical practice for improving patient care.

The workshop was organized into three panels each with a specific task:

Panel 1: define the state-of-the-art in knowledge of inflammation and atherothrombosis
Panel 2: define the state-of-the-art in knowledge of immunity and atherothrombosis
Panel 3: define the state-of-the-art in knowledge of infection and atherothrombosis

It is currently estimated that about half of the population in the USA and Europe will die from ATCVD, which is poised to become the number one cause of death globally. Despite this enormous public health impact, our understanding and treatment strategies regarding ATCVD remain inadequate. These sobering facts make ATCVD a central research priority of the NHLBI. This workshop addressed the important roles that the 3 Is play in the initiation and progression of ATCVD. Its goal was to spur public and private interests in developing novel targeted therapies to reduce this public health burden. Multidisciplinary experts in the field reviewed the background data in areas of (1) inflammation and AT, (2) immune interactions in AT, (3) infection and AT, and 4) interplay of the 3 Is in AT. The workshop derived a consensus on the opportunities, and provided recommendations for research involving the 3Is in AT, its biomarkers, and therapeutic approaches that would target new signaling pathways and networks.


The public health costs of ATCVD are staggering. Effective research and therapeutic approaches are crucially needed. Based considerably on NHLBI funded research over decades, inflammation is now understood to play a major role in every stage of the atherothrombotic process that is the underlying cause of most cardiovascular (CV) events. While LDL cholesterol has been proven to play a causal role in atherogenesis and LDL lowering strategies are highly effective, half of all heart attacks and strokes occur among individuals without overt elevations of cholesterol level. Recent epidemiological and clinical studies, therefore, have focused on inflammatory biomarkers and have established the role of proinflammatory cytokines such as interleukins 1 (IL-1) and 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) in the AT and coronary artery disease (CAD).  While the underlying molecular mechanisms linking these markers to AT and CAD remain uncertain, clinical evidence has accumulated demonstrating that inflammatory biomarkers such as high-sensitivity CRP (hs-CRP) predict risk of recurrent as well as initial CV events. However, currently available therapies are insufficient to stem the proinflammatory cytokine-mediated AT and CAD.

Innate and adaptive immune responses participate in most aspects of atherothrombotic disorders. Oxidized low density lipoprotein (ox-LDL) is seen as non-self by the innate immune system and leads to activation of signaling pathways that promote atherosclerosis. These neo-epitopes are also recognized by natural antibodies that are essential components of the innate immune response. The innate immune system also interacts with the hemostatic system, elaborates inflammatory cytokines, and precipitates thrombosis. Recent evidence has also highlighted the potential participation of mast cells in atherosclerosis.  Dysfunction in the unfolded protein response (UPR) pathway has been linked to atherosclerotic plaque instability through increased macrophage cell death.  The role of pattern recognition receptors (PRR) including Toll-like receptors (TLRs) in controlling atherogenesis and the role of the macrophage UPR in the necrotic core of advanced atherosclerotic lesions are rapidly being recognized. In addition, metabolic disease has been linked to pathological activation of TLRs.

Evidence has accumulated suggesting links between infection with pathogens such as Chlamydia pneumonia, Helicobacter pylori, periodontal pathogen i.e. Porphyromonas gingivalis, as well as cytomegalovirus (CMV), herpes simplex virus (HSV) types 1 and 2, and hepatitis A virus and AT in humans. These findings have drawn interest concerning the possible role of infectious agents in the initiation and progression of atherosclerosis, and in precipitating plaque rupture complicating the course of ATCVD with acute myocardial infarction and death.


Workshop participants identified a set of research and policy priorities designed to facilitate the adoption of clinically important advances in patient care. It was concluded that future research should focus on clarifying the causal relationship between the 3 Is and their interactions in ATCVD. Specific recommendations included:

  • Improve the understanding of AT as a dynamic inflammatory response to subendothelial apolipoprotein B-containing lipoproteins through activation of endothelial cells, smooth muscle cells, macrophages, lymphocytes and mast cells, leading to plaque formation and progression; support basic, translational, and clinical research on AT in the context of this inflammatory response; and develop therapeutic approaches that target new signaling pathways and networks.
  • Study the causative factors that induce proinflammatory cytokines responsible for the acute phase protein response and the intracellular signaling pathways that lead to cytokine-induced expression of elevated levels of CRP, coagulation factors, and protease inhibitors in animal models and clinical setting of CVD; investigate the proinflammatory cytokines that exert potent effects on genetic reprogramming of vascular endothelial cells expressing organ-specific vascular bed phenotype.
  • Investigate the role of novel modifications on cell signaling and cell phenotype in AT induced by oxidants, reactive lipids, methyl groups, and small ubiquitin-like modifier (SUMO) proteins.
  • Study whether excess n−3 fatty acids supplementation suppress pro-resolving mediators (SPM) pathways and enhance auto oxidation and proinflammatory mediators; investigate whether essential fatty acids deficiencies prolong resolution of recurring bouts of acute inflammation.
  • Study mechanisms by which naturally occurring antibodies could be atheroprotective and identify new drug targets in the realm of host defenses; develop, validate, and translate molecular imaging approaches to study regional inflammation in intact subjects to probe pathophysiology and support the development of novel anti-inflammatory strategies.
  • Support studies that focus on the mechanisms and endpoints involved in the progression of lesions to clinically dangerous stage such as fibrous cap thinning, superficial erosion of the intima, and necrotic core formation involving apoptosis and defective efferocytosis (removal of dead cells), and support the development of animal models that better mimic plaque disruption and luminal thrombosis.
  • Support experimental, preclinical, and clinical studies to discover a new set of cell-based biomarkers that would accurately delineate the propensity of plaques to advance and rupture in the near term; support studies that will identify imaging or biomarker endpoints that reflect the progression of a coronary silent plaque to clinically dangerous plaque (vulnerable); and develop new drug targets to block acute CV events.
  • Investigate the role of a select group of inflammatory mediators like IL-1, IL-6, TNF-alpha in AT and define new targets for drug and diagnostic development; study potential biomarkers of immunity, infection, inflammation, and atherosclerosis for diagnosis, risk stratification, and targeted personalized therapies (including intracellular modulators) for the treatment of ATCVD.
  • Investigate in intervention trials whether the changes in cellular and molecular markers in peripheral blood as a result of periodontitis are indeed causally related to CV events, and whether periodontal therapy and maintenance of periodontal health will reduce the risk for such events.
  • Investigate genetic predispositions for periodontal disease and atherosclerosis; identify modifier genes that predispose to susceptibility for a host response to periodontitis and other chronic inflammatory states; support genome-wide association studies (GWAS) in large population to probe mechanisms that link periodontal diseases and CVD and the studies of the role of nucleotide binding oligomerization domain-like (NOD) and inflammasome pathways in AT.
  • Coordinate and synergize the investments of various NIH institutes and centers in the field of AT. Broaden and utilize the NHLBI ancillary studies program for mechanistic studies on AT.

Publication Plans

The conference organizers plan to write a detailed summary of the meeting for publication in an appropriate peer-reviewed journal. Efforts will be made to publish the full proceedings of the meeting. The video contents will be posted at the conference site located at the Boston University public site with a link on the NHLBI public site.

Participating Division and Institute

  • Division of Cardiovascular Science (DCVS), NHLBI
  • Center for Anti-Inflammatory Therapeutics (CAT), GSDM, Boston University


  • Salomon Amar, DMD, PhD, Boston University School of Dental Medicine (Chair)
  • Richard A. Cohen, MD, Whitaker Cardiovascular Institute, Boston University
  • Ahmed A.K. Hasan, MD, PhD, NHLBI
  • Peter Libby, MD, Brigham and Women’s Hospital, Harvard Medical School
  • Joseph Loscalzo, MD, PhD, Brigham and Women’s Hospital, Harvard Medical School
  • Steven Shoelson, MD, PhD, Joslin Diabetes Center, Harvard Medical School

Panel Members

  • Gerald Byrne, MD, PhD, University of Tennessee
  • Linda K. Curtiss, PhD, The Scripps Research Institute
  • Jane Freedman, MD, Whitaker Cardiovascular Institute
  • Bingbing Jiang, MD, Harvard School of Medicine
  • Gwendolyn Randolph, PhD, Columbia University
  • Paul M. Ridker, MD, MPH, Brigham and Women’s Hospital
  • Charles Serhan, PhD, Harvard Medical School
  • Ira Tabas, MD, PhD, Columbia University
  • Joseph Vita, MD, Whitaker Cardiovascular Institute
  • Joseph Witztum, MD, University of California San Diego School of Medicine


  • Michael Domanski, MD
  • Debra Egan, MS, MPH
  • Ahmed A.K. Hasan, MD, PhD
  • Ruth Kirby, RN, BS
  • Michelle Olive, PhD
  • Yves Rosenberg, MD, MPH
  • Pothur Srinivas, PhD, MPH

Staff Contact

Last Updated: January 2011

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