What is the role of plaque growth in the pathophysiology of coronary artery atherosclerosis?

Updated: Apr 09, 2021
  • Author: Sandy N Shah, DO, MBA, FACC, FACP, FACOI; Chief Editor: Yasmine S Ali, MD, MSCI, FACC, FACP  more...
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The lesions of atherosclerosis do not occur in a random fashion. Hemodynamic factors interact with the activated vascular endothelium. Fluid shear stresses generated by blood flow influence the phenotype of the endothelial cells by modulation of gene expression and regulation of the activity of flow-sensitive proteins.

Atherosclerotic plaques (or atheromas), which may require 10-15 years for full development, characteristically occur in regions of branching and marked curvature at areas of geometric irregularity and where blood undergoes sudden changes in velocity and direction of flow. Decreased shear stress and turbulence may promote atherogenesis at these important sites within the coronary arteries, the major branches of the thoracic and abdominal aorta, and the large conduit vessels of the lower extremities.

A study by Samady et al suggests low shear segments in the coronary arteries develop greater plaque and necrotic core progression and constrictive remodeling, whereas high shear segments develop greater necrotic core and calcium progression, regression of fibrous and fibrofatty tissue, and excessive expansive remodeling. [5] This suggests a transformation to a more vulnerable phenotype.

The earliest pathologic lesion of atherosclerosis is the fatty streak, which is observed in the aorta and coronary arteries of most individuals by age 20 years. The fatty streak is the result of focal accumulation of serum lipoproteins within the intima of the vessel wall. Microscopy reveals lipid-laden macrophages, T lymphocytes, and smooth muscle cells in varying proportions. The fatty streak may progress to form a fibrous plaque, the result of progressive lipid accumulation and the migration and proliferation of SMCs.

Platelet-derived growth factor, insulinlike growth factor, transforming growth factors alpha and beta, thrombin, and angiotensin II (A-II) are potent mitogens that are produced by activated platelets, macrophages, and dysfunctional endothelial cells that characterize early atherogenesis, vascular inflammation, and platelet-rich thrombosis at sites of endothelial disruption. The relative deficiency of endothelium-derived nitric oxide further potentiates this proliferative stage of plaque maturation.

The SMCs are responsible for the deposition of extracellular connective tissue matrix and form a fibrous cap that overlies a core of lipid-laden foam cells, extracellular lipid, and necrotic cellular debris. Growth of the fibrous plaque results in vascular remodeling, progressive luminal narrowing, blood-flow abnormalities, and compromised oxygen supply to the target organ. Human coronary arteries enlarge in response to plaque formation, and luminal stenosis may occur only when the plaque occupies more than 40% of the area bounded by the internal elastic lamina. Developing atherosclerotic plaques acquire their own microvascular network, the vasa vasorum, which are prone to hemorrhage and contribute to progression of atherosclerosis. [6]

As endothelial injury and inflammation progress, fibroatheromas grow and form the plaque. As the plaque grows, two types of remodeling, positive remodeling and negative remodeling, occur, as illustrated in the image below.

Coronary Artery Atherosclerosis. Positive and nega Coronary Artery Atherosclerosis. Positive and negative arterial remodeling are illustrated.

Positive remodeling is an outward compensatory remodeling (the Glagov phenomenon) in which the arterial wall bulges outward and the lumen remains uncompromised. Such plaques grow further; however, they usually do not cause angina, because they do not become hemodynamically significant for a long time. In fact, the plaque does not begin to encroach on the lumen until it occupies 40% of the cross-sectional area. The encroachment must be at least 50-70% to cause flow limitation. Such positively remodeled lesions thus form the bulk of the vulnerable plaques, grow for years, and are more prone to result in plaque rupture and ACS than stable angina, as documented by intravascular ultrasonography (IVUS) studies.

Many fewer lesions exhibit almost no compensatory vascular dilation, and the atheroma steadily grows inward, causing gradual luminal narrowing. Many of the plaques with initial positive remodeling eventually progress to the negative remodeling stage, causing narrowing of the vascular lumen. Such plaques usually lead to the development of stable angina. They are also vulnerable to plaque rupture and thrombosis.

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