This theory proposes that the primary event that triggers the development atherosclerosis is focal accumulation of lipids in the vessel wall. The lipids from these lesions are believed to be derived from plasma lipoproteins (i.e. low density lipoproteins, LDL), which is consistent with the role of hyperlipidemia being a risk factor for atherosclerosis and acute coronary syndrome. The LDL particle is too large to penetrate the tightly closed junctions between adjacent endothelial cells. However, endothelial cells have receptors for LDL and are able to transport these lipids across an intact endothelium by receptor-mediated uptake. Lipids may also be engulfed by monocytes while in the circulation and then transport into the intima as they transmigrate into the wall between dysfunctional endothelial cells. Lipids that are in the extracellular space within the intima become trapped within the extracellular matrix where they accumulate over time.

This theory initially proposed that material from the blood was deposited on the inner surface of arteries and lead to thickening of the inner lining creating a mural thrombus. It was thought that platelets and fibrin of thrombi initiated atherosclerosis. Although mural thrombosis is not the initial event in atherogenesis, it is likely to promote the later progression of the atherosclerotic lesion and is the major event leading to vascular occlusion, especially in coronary arteries.

The reaction to injury theory is the most widely excepted among scientific and medical scholars. This theory states that the initial event in the pathogenesis of atherosclerosis is injury to the endothelium that compromises the integrity of the endothelial barrier. The nature of the injury is likely to involve numerous factors and is different in different people depending on genetic and environmental conditions. Injured endothelium triggers an inflammatory response with migration of inflammatory cells (predominantly macrophages and lymphocyte). Inflammatory cell migration along with oxidized low-density lipoproteins within the lesion is thought to be the key player during the development of an atherosclerotic plaque [13, 15].

Endothelial injury and dysfunction is the cornerstone for the initiation of atherosclerosis. The specific mechanism contributing to endothelial dysfunction is not completely understood, although the most important culprits that trigger endothelial dysfunction include hypertension, hyperlipidemia, diabetes, and toxin from cigarette smoking. Regardless of the cause of endothelial dysfunction this lead to increased vascular permeability.

In the presence of a lipoprotein abnormality lipids begin to accumulate on the endothelial cells lining the endothelium. As the lipid particles accumulate they migrate into the intima and coalesce into the proteoglycan of the extracellular matrix (ECM) were they get “trapped” (Fig. 3.2). Lipoproteins that accumulate in the ECM are susceptible to oxidative stress. The oxidized lipoproteins produce free radicals that causes localize cellular injury and dysfunction. This stimulates the release of growth factors, cytokines, and chemokines by endothelial cells, and hinders the vessels vasodilator activity.

Accumulation of extracellular lipoprotein particles is one of the first morphologic changes to occur. Lipoprotein particles become trapped in the strands of proteoglycan within the subendothelial region of the intima where they begin to accumulate. Proteoglycan-associated lipoproteins appears particularly are susceptible to oxidative modification. In response to oxidized lipoproteins, cellular injury occurs and triggers an immune respond with the recruitment of monocytes that migrate into the intima of the artery wall (Fig. 3.3). Once monocytes have migrated into the intima they differentiate into macrophages and engulf the harmful oxidized lipoproteins form intracellular lipid filled vacuoles. These macrophages that are filled with vacuoles of lipoproteins are referred to as foam cells. Although, the foam cells serve a theoretically protective function the oxidized lipoproteins within these cells augments cellular activation and cytokine production resulting in additional recruitment of mononuclear cells. Activate macrophages also produce reactive oxygen species that further augments oxidation of lipoproteins within the cell. Over time the macrophages and foams cells die releasing the lipid content into the intercellular space. As a result of this cyclic chronic inflammatory state (with local tissue injury, endothelial dysfunction, and breakdown of the vessel wall endothelial barrier), T lymphocyte recruitment occurs resulting in additional release of cytokines that further stimulates macrophages, endothelial cells, smooth muscle cells, and proliferation of the extracellular matrix. With the accumulation of foam cells and the proliferation of intimal smooth muscle cells and extracellular matrix the earliest grossly visible lesion sign of an atherosclerotic lesion develops called a fatty streak. Over time the lesions further mature into an atheroma and will progressively grow with the development of a lipid core. During the lesion maturation process the smooth muscle cells synthesizing extracellular matrix (notably collagen) in an attempt to stabilize the atherosclerotic plaques. Many times this is unsuccessful resulting in an unstable plaque that is prone to rupture [2].