Role of Insulin Resistance and Hyperglycemia in the Development of Atherosclerosis Sameer Bansilal, MD, Michael E. Farkouh, MD, MSc, and Valentin Fuster, MD, PhD* Insulin resistance (IR) is the underlying defect in >90% of patients with type 2 diabetes mellitus and the major pathologic mechanism for the associated suscepti- bility to premature cardiovascular disease (CVD). The progression of IR to diabetes parallels the progression of endothelial dysfunction to atherosclerosis. The downregu- lation of the antiatherogenic phosphatidylinositol-3-kinase–mediated insulin recep- tor–signaling pathway, and maintained activity of the proatherogenic mitogenic- activated protein kinase pathway in insulin-resistant states, leads to accelerated atherosclerosis. Efforts to prevent or slow the epidemic of atherothrombotic CVD must focus on the reversal of the disturbances in glucose and lipid homeostasis through the amelioration of IR. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99[suppl]:6B–14B) In 1988, Reaven 1 used the term “syndrome X” to describe a constellation of metabolic and hemodynamic changes associ- ated with coronary artery disease (CAD) and postulated a causal effect of impaired insulin-mediated glucose disposal and compensatory hyperinsulinemia. Insulin resistance (IR) syndrome, as it has come to be known, leads to a cluster of dyslipidemia, hypertension, and hypercoagulability. IR is the underlying defect in 90% of patients with type 2 diabetes mellitus and the major pathologic mechanism for the associ- ated susceptibility to premature cardiovascular disease (CVD). IR assessed by homeostasis model assessment has been shown to be predictive of CVD. In long-term follow-up of patients with type 2 diabetes, IR was independently predic- tive of CVD, with a 1-unit increase in IR assessed by homeostasis model assessment associated with a 5.4% in- creased risk for CVD (Figure 1). 2,3 The Insulin Resistance and Atherosclerosis Study (IRAS) also demonstrated the relation between IR and atherosclerosis in the carotid ar- tery. 4 Direct evidence of this association between IR and atherosclerosis, however, has been elusive because of the difficulties with measuring IR in large populations of pa- tients. Atherosclerosis To elucidate the pathogenetic role of IR and hyperglycemia in the development of atherosclerosis, it is necessary to review the process of the formation of an atherosclerotic plaque. Multiple hypotheses proposed to explain the devel- opment of atherosclerosis have now been integrated, and the term “atherothrombosis” is used to describe the unifying hypotheses. This process involves the intima of large and medium-sized systemic arteries, including the carotid, aor- tic, coronary, and peripheral arteries. Atherothrombotic plaques are initiated because of endothelial dysfunction and progress to incorporate varying proportions of extracellular matrix, cholesterol, and proteoglycans. The innate and adaptive immune responses mediated via class A scavenger receptor, CD36, and toll-like receptor 4 mediate the release of cytokines and the recruitment of macrophages and fibro- blasts (Figure 2). Further changes in the media and adven- titia, including eccentric vascular remodeling, calcification, and growth of vasa vasorum followed ultimately by plaque rupture or erosion, have led to the classification of plaques into 6 progressive stages. Figure 3 outlines the American Heart Association’s (AHA) definition and histologic classi- fication of atherosclerotic lesions. 5 The development of atherothrombotic plaques has been further characterized into 5 phases to correlate with the temporality of their development and the association with clinical events (Fig- ure 4). 6 The early phase consists of the foam cell (type I), which develops into a fatty streak (type II) with the addition of smooth muscle cells and lipid droplets. Type III lesions represent an intermediate stage between type II and type IV lesions (atheroma). Atheroma and fibroatheroma (type Va) represent the onset of phase 2, which consists of lesions that are stenotic or may be prone to rupture because of their high lipid content, increased inflammation, and thin fibrous caps. Phase 3 involves the process of rupture or erosion, resulting in the formation of the mural, nonobstructive thrombi (type VI) lesions. During phase 4, type VI lesions may further undergo acute complications, with fixed or repetitive occlu- sive thrombosis. Type Vb lesions (in which the lipid core The Zena and Michael A. Wiener Cardiovascular Institute and The Marie-Josee and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, New York, New York, USA. *Address for reprints: Valentin Fuster, MD, PhD, The Zena and Mi- chael A. Wiener Cardiovascular Institute and The Marie-Josee and Henry R. Kravis Cardiovascular Health Center, Mount Sinai School of Medicine, Box 1030, One Gustave L. Levy Place, New York, New York 10029-6574. E-mail address: valentin.fuster@mssm.edu. 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2006.11.002