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3 Is (Infection, Immunity, Inflammation) and Atherothrombosis: New Directions for Improving Patient Care
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
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:
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 agenda and other materials can be found here.
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:
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
Last Updated: January 2011