Abstract 192: A Hypothesis on Initiation of Coronary Atherosclerosis: The Role of Intimal Neovascularization and Proliferation. Do Lipoproteins Invade Coronary Tunica Intima from the Opposite Site?

Objectives Tremendous success of statins in coronary atherosclerosis (CA) prevention offered great expectations for extended protection and effective therapeutics. However, stalled progress in pharmaceutical treatment gives a good reason to review whether the hypothesis underlining our efforts is consistent with undoubted facts on coronary artery in normal and diseased forms. Analysis An accepted hypothesis states that CA is initiated by endothelial dysfunction due to inflammation and high levels of LDL, followed by lipids and macrophage penetration into arterial intima and plaque formation. It is crucial to highlight that normal coronary intima is not a single-layer endothelium covering thin acellular compartment, as is commonly claimed in most publications, but always appears as a multi-layer cellular compartment, or diffuse intimal thickening (DIT), where cells are arranged in a few dozens layers. Since it is unanimously agreed that LDL invade DIT from lumen, the initial depositions ought to be most proximal to blood, i.e. in inner DIT layers. The facts show that the opposite is true, and lipids are deposited in the outer DIT. This contradiction is resolved by noting that normal DIT is always avascular, receiving oxygen and nutrients by diffusion from lumen, whereas in CA outer DIT is always neovascularized from adventitial vasa vasorum . Proteoglycan biglycan, confined to outer DIT of normal and diseased coronary, has high binding capacity for LDL. However, normal DIT is avascular, whereas in CA biglycan of outer DIT layers appears in direct contact with blood and extract lipoproteins. These facts explain patterns and mechanisms of CA initiation, which is not unique: normally avascular cornea accumulates lipoproteins after neovascularization, resulting in lipid keratopathy. The author offers a hypothesis on neovascularization. Cells in coronary DIT possess high proliferative capacity. Excessive cell replication increases DIT thickness, impairs diffusion, resulting in hypoxia of outer DIT. Hypoxia induces neovascularization of outer DIT layers, where biglycan extracts LDL from newly formed capillary bed, initiating CA. Conclusion Controls of cell proliferation and neovascularization in coronary DIT should be a priority of our research.