Plaque Lifecycle

There are 4 key areas of Plaque lifecycle:

• Initiation
• Vascular remodelling
• Plaque progression
• Plaque rupture

Initiation

The mechanisms of initiation remain unclear but are generally considered to be due to injury of the endothelium, followed by an inflammatory response¹. Causes of endothelial injury include oxidised low-density lipoprotein cholesterol (LDL-C), infectious agents, toxins, hyperglycemia and hyperhomocystinemia. Monocytes and T-cells migrate towards the site of injury, where monocytes adhere in response to signals within the early plaque. LDLs enter the intima, are modified by oxidation or enzyme activity and aggregate in the extracellular matrix, increasing their phagocytosis by monocytes. The uncontrolled uptake of LDLs into macrophages leads to the development of foam cells that are less mobile and thereby accumulate to form fatty streaks, which is the beginning of the atherosclerotic lesion. Oxidised LDL results in excess free radical production causing inactivation of nitric oxide. The decreased availability of nitric oxide is associated with increased platelet adhesion, increased plasminogen activator inhibitor, decreased plasminogen activator, increased tissue factor, decreased thrombomodulin and alterations in heparin sulphate proteoglycans, all of which have a procoagulant effect and enhance platelet thrombus formation.

The earliest pathological lesion of atherosclerosis is the fatty streak, the result of serum lipoproteins within the intima, which can be observed in the arteries of most individuals by the age of 20. The fatty streak may progress to form a fibrous plaque. Vascular smooth muscle cells migrate and proliferate in the intima and deposit large quantities of extracellular connective tissue matrix increasing retention and aggregation of atherogenic lipoproteins. T cells are also recruited to the lesion, propagating inflammation.

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Vascular remodelling

In the early stages as the plaque grows, the arterial wall expands outward, known as remodelling. The lumen size therefore remains the same despite plaque accumulation. It was initially thought that this was a compensatory process to maintain blood flow, and that stenosis occurred when further expansion became impossible. However, recent studies have demonstrated a link between outward remodelling and unstable coronary syndromes². In the light of these findings, it is recommended that the term outward remodelling rather than positive remodelling is used. Outward remodelling has been associated with an inflammatory response at the lesion site, which may explain the link with unstable coronary syndromes.

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Plaque progression

As the lesion develops, foam cells undergo necrosis, releasing cellular debris and crystalline cholesterol, and increasing the free cholesterol content of the plaque. Smooth muscle cells form a fibrous cap underneath the endothelium separating the lumen of the vessel from the plaque. This promotes the recruitment of inflammatory cells and adds to the formation of the necrotic core. The developing atherosclerotic plaque acquires its own microvascular blood supply, known as the vasa vasorum. Interplaque haemorrhage caused by immature blood vessels has been identified as a key factor in plaque growth and destabilisation³. The rapid accumulation of erythrocyte membranes causes raises free cholesterol in the lipid core and infiltration by macrophages.

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Plaque rupture

Atherosclerosis can remain asymptomatic for decades until plaque rupture occurs. The majority of the plaques that cause ACS occlude the arteries by less than 50%. These plaques, which have a greater proportion of soft lipid core and thinner fibrous caps with chemoactive cellular infiltration near the shoulder region, are called vulnerable plaques. Most plaque ruptures occur because of disruption of the fibrous cap, exposing the thrombogenic lipid core of the plaque to the blood. This occurs most often where the cap is thinnest and most heavily infiltrated by macrophages and therefore weakest, namely at the cap’s shoulders. Following rupture, the fatty core of the plaque and its high content of tissue factor provide a powerful substrate for the activation of the coagulation cascade. Plaque rupture can be clinically silent or cause symptoms of ischemia depending on thrombus burden and the degree of vessel occlusion. In addition, plaque rupture and subsequent healing is recognized to be a major cause of further rapid plaque progression⁴.

After rupture the plaque may stabilize, eventually causing inward remodelling (vessel shrinkage) of the arterial segment and calcification of the associated plaque. The resulting lesions limit arterial blood flow causing clinical symptoms, but are stable.