Increased valve thickness is a requisite finding in AS, caused by the combined effect of increased cellularity, lipid accumulation, and extracellular matrix deposition (9,12). Calcification is also a dominant feature, particularly when AS is severe (1,9). Recent studies have provided insights into the cellular and subcellular mechanisms underlying these macroscopic changes. (Figure 1) illustrates the multiple pathways in the genesis of valvular AS, with lipoproteins being a key component in many of these pathways (19- 20). The initiating event appears to be endothelial injury at areas of mechanical stress, predisposing to infiltration by plasma lipoproteins similar to what is known to happen in the development of atherosclerosis in susceptible arterial walls (17- 18). Another intriguing possibility is that the sequence of events may be triggered by an infective organism such as Chlamydia pneumoniae, which can be detected in half of the AS valves, but the role of infective agents in AS requires further studies (27- 28). Stenotic “degenerative” aortic valves have a much larger amount of lipids than non-stenotic valves (12). Lipid deposition tends to be localized to the aortic surface of the flexion areas, which are under high mechanical strain and lower shear stress. The abnormal mechanical forces are likely to be more prominent in BAV, leading to a greater degree of lipid deposition at an earlier age. Co-localization of components of atherogenic apolipoproteins (apo-B, apo-[a], and apo-E) has been demonstrated in close proximity to the extracellular lipids, strongly suggesting that the lipid deposits are derived from plasma lipoproteins (20,23). This is followed by oxidative modification, and after more extensive modification the oxidized particles are taken up by macrophages to form foam cells (12,23). Oxidized low-density lipoprotein (LDL) has been shown to have prothrombotic effects, as well as to be highly cytotoxic for many cells, including endothelial cells and valve fibroblasts. It is suggested that fibroblasts, upon exposure to oxidized LDL, release matrix vesicles which form the nidus for calcification (24- 25,30). Apolipoprotein deposition in early AS lesions resembles closely the process in early lesions of atherosclerosis (12). It has a predilection for areas of low shear stress and is associated with accumulation of macrophages, T-lymphocytes, and matrix proteins such as proteoglycans (12,20).