Aernoud Fiolet

53 Viewing Atherosclerosis through a Crystal Lens INTRODUCTION D espite their efficacy, recent advances in therapies for secondary prevention of atherosclerosis have failed to eliminate the ongoing risk of cardiovascular (CV) events. 1, 2, 3 Greater appreciation of how accumulation of free (unesterified) cholesterol in thevascularbed leads to the development, progression, and instability of atherosclerotic plaque should provide clearer rationale for the development of additional effective therapeutic strategies. It is recognized that as lipoproteins accumulate in the arterial wall they may coalesce and form into vesicles in the interstitial space 4,5 or be sequestered within macrophages that transform into foam cells and orchestrate a persistent low-grade cellular response.This eventually leads to the formation of simple fibrous atheroma, which contains extracellular cholesterol. At times, circulating leukocytes including neutrophils can be attracted into the atherosclerotic bed and if activated may cause inflammatory injury to the plaque. 6 In addition, rapid expansion of the plaque core by growing cholesterol crystals (CCs) can lead to traumatic injury and even rupture. 7,8 Although the injurious agents that initiate and sustain inflammatory and traumatic injury in the atherosclerotic bed are not fully characterized, there is growing evidence that these process are largely driven by CCs that form within resident macrophages, the interstitial space, and the lipid rich core. 7, 8, 9, 10 (Fig. 1). “Viewing atherosclerosis through a crystal lens” makes it possible to see how the evolving nature of cholesterol within atherosclerotic plaque changes the behavior of the disease. Specifically, it helps explain how free cholesterol in the intracellular and extracellular compartments within atherosclerotic plaque spontaneously self- assembles into metastable CCs, and why their transition into flat plate structures predisposes to the perpetual risk of inflammatory and traumatic injury. FORMATION AND GROWTH OF CHOLESTEROL CRYSTALS IN ATHEROSCLEROTIC PLAQUE CCs are the most abundant crystalline species in atherosclerotic plaque. Their formation and growth results from a process of spontaneous self-assembly of cholesterol molecules that is initiated in the presence of excess free cholesterol, and is sensitive to several physiochemical factors in their environment including