Aernoud Fiolet

61 Viewing Atherosclerosis through a Crystal Lens CHOLESTEROL CRYSTAL EMBOLI CAUSE ISCHEMIC AND INFLAMMATORY INJURY Extracellular CCs that breach the vascular endothelium as a result of plaque rupture can travel downstream, “scrape” the intimal surface causing arterial vasospasm, 67 and if large enough, can obstruct medium to small size arteries and the microcirculation. Once lodged in tissues, there is evidence that CCs may induce inflammatory injury independent of ischemia. 68 (Fig. 5). In a rabbit model, CC emboli to muscle caused inflammatory injury in the absence of arterial obstruction, as evidenced by patent arteries by angiography and the presence of FDG-18 radioactive tracer reaching the site of macrophage infiltration. Muscle biopsy of these sites demonstrated severe myonecrosis and macrophages with crystalline materials, indicating a causal role for CCs in inducing inflammatory injury. 68 Similarly, macrophages from aspirates from culprit coronary arteries in patients during myocardial infarction have been found to contain crystalline material in their cytoplasm indicating that CCs were sensed as primary danger signals (Fig. 6). These were also associated with release of IL-1 β into the coronary circulation. 61 OTHER CRYSTALS SPECIES MAY PLAY A ROLE IN ATHEROSCLEROSIS Some advanced atherosclerotic plaques may contain monosodium urate and calciumphosphate crystals that accumulate as a result of apoptosis and necroptosis (Fig. 7). These crystal species have the potential to promote nucleation of free cholesterol and enhance inflammatory injury. 69,70 In addition, in rare genetic conditions, sterols and calcium oxalate crystals have also been associated with premature and highly aggressive atherosclerosis. 71, 72, 73 Aspirates from the infarct-related artery predominantly contain CCs, however, calcium phosphate crystals have also been frequently found (Fig. 7). Calcium phosphate crystals can contribute to inflammation via MAP kinase and protein kinaseCinflammatorypathways leading tosecretionof the inflammatorycytokines, TNF- α , IL-1 β , and IL-18 74 that can also promote dystrophic calcification. 75