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J Am Coll Cardiol, 2005; 46:937-954, doi:10.1016/j.jacc.2005.03.074 (Published online 7 September 2005).
© 2005 by the American College of Cardiology Foundation
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STATE-OF-THE-ART PAPER

Atherothrombosis and High-Risk Plaque

Part I: Evolving Concepts

Valentin Fuster, MD, PhD, FACC*, Pedro R. Moreno, MD, FACC*,*, Zahi A. Fayad, PhD, FACC*, Roberto Corti, MD, FACC{dagger} and Juan J. Badimon, PhD, FACC*

* Zena and Michael A. Wiener Cardiovascular Institute and the Marie-Josee and Henry R. Kravis Cardiovascular Health Center, The Mount Sinai School of Medicine, New York, New York
{dagger} Department of Cardiology, University Hospital Zurich, Zurich, Switzerland

Manuscript received July 14, 2004; revised manuscript received January 4, 2005, accepted March 4, 2005.

* Reprint requests and correspondence: Drs. Pedro R. Moreno and Valentin Fuster, Mount Sinai School of Medicine, Box 1030, New York, New York, 10029 (Email: pedro.moreno{at}msnyuhealth.org).

Atherothrombosis is a complex disease in which cholesterol deposition, inflammation, and thrombus formation play a major role. Rupture of high-risk, vulnerable plaques is responsible for coronary thrombosis, the main cause of unstable angina, acute myocardial infarction, and sudden cardiac death. In addition to rupture, plaque erosion may also lead to occlusive thrombosis and acute coronary events. Atherothrombosis can be evaluated according to histologic criteria, most commonly categorized by the American Heart Association (AHA) classification. However, this classification does not include the thin cap fibroatheroma, the most common form of high-risk, vulnerable plaque. Furthermore, the AHA classification does not include plaque erosion. As a result, new classifications have emerged and are reviewed in this article. The disease is asymptomatic during a long period and dramatically changes its course when complicated by thrombosis. This is summarized in five phases, from early lesions to plaque rupture, followed by plaque healing and fibrocalcification. For the early phases, the role of endothelial dysfunction, cholesterol transport, high-density lipoprotein, and proteoglycans are discussed. Furthermore, the innate and adaptive immune response to autoantigens, the Toll-like receptors, and the mechanisms of calcification are carefully analyzed. For the advanced phases, the role of eccentric remodeling, vasa vasorum neovascularization, and mechanisms of plaque rupture are systematically evaluated. In the final thrombosis section, focal and circulating tissue factor associated with apoptotic macrophages and circulatory monocytes is examined, closing the link between inflammation, plaque rupture, and blood thrombogenicity.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  AHA = American Heart Association
  apo = apolipoprotein
  CAM = cell adhesive molecule
  CRP = C-reactive protein
  HDL = high-density lipoprotein
  IEL = internal elastic lamina
  LDL = low-density lipoprotein
  MMP = matrix metalloproteinase
  NCP = non-collagenous bone-associated protein
  OPN = osteopontin
  TCFA = thin-cap fibroatheroma
  TF = tissue factor
  TLR = toll-like receptor




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