Atherosclerosis and Angina

Pathophysiology of Atherosclerosis

Tetiana Povshedna

Learning Objectives

By the end of this chapter, you will be able to:

  • identify and explain the main processes that occur during various stages of atherosclerotic plaque development
  • describe the biological rationale for the most common locations of atherosclerotic plaques
  • describe common clinical scenarios of atherosclerosis progression

 

Atherosclerosis develops as a result of a continuous process that involves endothelial activation, lipid accumulation, atheroma plaque formation, vascular remodeling, and ultimate narrowing of the blood vessel lumen. This blood flow restriction due to atherosclerosis can manifest a variety of clinical diagnoses, which are named based on the location of atherosclerotic plaque (heart attack, stroke, and peripheral artery disease )

Atherosclerosis progression is initiated by endothelial activation in response to cardiovascular risk factors, such as hypertension, high blood glucose, smoking, increased cholesterol levels, etc.

Common locations of atherosclerotic plaques

Even though the vascular tree is uniformly exposed to metabolic risk factors, some regions are more likely to form atherosclerotic plaques than others. This phenomenon can be partially explained by mechanical stress (wall shear stress, WSS) and type of blood flow (laminar vs turbulent), Figure 8.24.

Blood flow disturbance in branching points and bifurcations of the vascular tree results in a specific distribution of atherosclerotic plaques, with the majority of them forming in these common atheroma-prone regions.

This trend highlights the importance of arterial branches and bifurcations in the diagnosis of atherosclerotic lesions.

Some examples of such locations include the bifurcations of:

  • abdominal aorta into right and left iliac arteries
  • common carotid arteries into external and internal carotic arteries
  • left coronary artery into left anterior descending (LAD) and circumflex

 

 

image of aorta experiencing normal laminar flow vs turbulent flow. Turbulent flow starts the process of atherosclerotic plaque formation
Figure 8.24 Effects of blood flow and mechanical stress on atherosclerotic plaque formation.A) Endothelial cells appear flat in straight vessel segments with laminar flow and physiological (moderate) WSS;  High-curvature vessel segments (bifurcations and branch points) exhibit turbulent flow, reduced WSS, and cobblestone appearance of endothelial cells. B) Low shear stress promotes endothelial dysfunction and LDL accumulation, initiating atherosclerotic plaque formation in athero-prone regions.   Used under CC-BY license form Int. J. Mol. Sci. 2022, 23(6), 3346; https://doi.org/10.3390/ijms23063346
Atherosclerotic plaque formation starts with the fatty streak (accumulation of lipids within the intima) and progresses into the fibrous plaque with a necrotic core – a complex structure that can facilitate clot formation and/or detach and become an embolus.

Stages of atherosclerotic plaque formation

  1. Lesion initiationAtherosclerosis plaque formation begins with activation and/or damage to the endothelium, which disrupts the normal process of LDL intake and metabolism. As a result, LDL is modified and accumulated within the tunica intima of a vessel. Endothelial activation/damage affects its permeability, stimulates leukocyte adhesion to its surface, and diapedesis. The leukocytes recruited from the blood into the blood vessel wall are monocytes, that become macrophages once they leave the systemic blood circulation and migrate into tissues.Once within the intimal layer, LDL particles are oxidized by free radicals that are contained in the extracellular matrix and/or produced by recruited monocytes. Oxidized LDL (oxLDL) is a key inflammatory component that facilitates atherosclerosis progression. These initial processes create a “vicious circle” that results in further recruitment of monocytes, LDL retention, and oxLDL accumulation. Recruited monocytes and vascular smooth muscle cells (VSMCs) within the tunica intima engulf oxLDL and become “foam cells” – a name given to these cells because of a foamy appearance of the cytoplasm due to the oxLDL deposition.
the life cycle of a macrophage in the subendothelial space of a vessel. A newly recruited macrophage enters the subendothelial space and releases its free radicals as part of its inflammatory role. These radicals convert LDL to oxidized LDL. The macrophages then engulf the oxidized LDL transforming the macrophage into a fat-laden foam cell. The foam cell then sends inflammatory chemicals which recruit more macrophages to the site and the cycle continues.
Fig 8.25. Vicious circle of atherosclerosis initiation. Created by Tetiana Povshedna with Biorender.com under the creative commons license

 2. Fatty streak 

As the “vicious circle” progresses, LDL is deposited both inside cells and in the extracellular matrix, and cholesterol crystals form. The initial lesion increases in size and appears as a visible flat yellow streak on the luminal side of the vessel.

 3. Fibrous plaque

Foam cells (derived from macrophages and VSMCs ) undergo cellular death (apoptosis) and release their contents within the tunica intima. These contents are further engulfed by macrophages in an attempt to “clean” the lesion site. However, an overwhelming amount of oxLDL, dead cells, cholesterol crystals, and extracellular debris form a soft “necrotic” core of growing atherosclerotic plaque. As the lesion progresses, it can accumulate calcium salts and harden over time, impairing the elasticity of blood vessels and their ability to dilate and contract in response to blood pressure fluctuations.

In response to the atherosclerotic lesion progression, more VSMCs are recruited from the tunica media to the intima to form a fibrous cap – a protective layer that covers the necrotic core. Normally, VSMCs facilitate contraction/dilation of blood vessels, but once recruited to tunica intima, they switch towards synthetic activity. VSMCs within the fibrous cap produce a large amount of extracellular matrix (collagen and elastin fibers, proteoglycans) to “cover” the soft necrotic core and stabilize the plaque. The fibrous cap prevents plaque rupture and serves as a barrier between the lumen of the vessel and the necrotic core which, if exposed to the blood flow, can trigger the formation of a blood clot.

 4. Outcomes 

The thickness of the fibrous cap covering the soft necrotic core of an atherosclerotic lesion, as well as its composition (the amount of collagen/elastin fibers), affect the stability of the plaque and clinical outcomes. As atheroma increases in size, inflammation within the plaque (pro-inflammatory cytokines released by macrophages), as well as inflammatory cytokines in the bloodstream can affect the vulnerability of the plaque.

Atherosclerotic plaques can become more vulnerable if VSMCs within the fibrous cap respond to inflammation by producing enzymes that degrade components of the extracellular matrix, weakening the fibrous cap and making it more susceptible to rupture. A weaker fibrous cap increases the likelihood of the necrotic core getting exposed to the blood flow, which can result in clot formation on top of the plaque.

Segments of an artery in developing stages of atherosclerosis are shown, with a lower panel that focusses the tunica intima and tunica media layers. The health artery shows a negligible space in the intima between the endothelial and smooth muscle layers. As the artery progresses to atherosclerosis, more immune cells and lipoproteins begin to fill the intimal space. As the fatty streak develops into a plaque, foam cells form a large plaque with a necrotic core AND smooth muscle cells grow both above and below the plaque. The fibrous atherosclerotic plaque has a cap of smooth muscle cells between the endothelial layer and the necrotic core. When the plaque ruptures, the necrotic core has breached both the smooth muscle and endothelial layers, exposing it to the blood.
Figure 8.26 – Schematic representation of atheroma plaque formation from a healthy artery to (A) Lesion formation, (B) Fatty streak, (C) Fibrous plaque, and (D) Plaque rupture underlying the most important events that contribute to its development in each stage.

Key Takeaways

  1. Circulating monocytes (macrophages once outside of the bloodstream) play an important role in atherosclerosis initiation and progression and undergo morphological changes in the process
  2. Inflammation is relevant at all stages of atherosclerosis, from lesion initiation to its rupture
  3. Plaque stability determines the likelihood and severity of clinical complications

Main scenarios of the atheroma progression

  • growth of the plaque, progressive obstruction of the blood vessel lumen;
  • erosion/rupture of the fibrous cap with subsequent clot formation on its surface;
  • plaque/clot disruption and formation of the embolus in the bloodstream;
  • increased susceptibility to aneurysm formation ( Similarly to the process within the fibrous cap, extracellular matrix can be degraded within tunica media of the large vessels, weakening the muscular layer and making it more vulnerable to dilatation)
an artery is split into six segments, with a wall removed to demonstrate the development of an atherosclerotic plaque across the three tunics. The normal vessel demonstrates a smooth red surface. As the artery develops a fatty streak, the cells in the subendothelial layer gets thicker, narrowing the vessel lumen minimally. As the fatty streak develops into a fibrofatty plaque, a thick yellow plaque develops between the endothelial and smooth muscle layer, greatly reducing the vessel luminal opening. The advanced/vulnerable plaque is then split into three possible consequences: critical stenosis where the yellow fatty plaque takes up almost the entire luminal space; superimposed thrombus where the yellow plaque takes up most of the space, but a blood clot has formed in the luminal space; and Aneurysm and rupture where the blood vessel itself tears at the level of where the small luminal space was still open.
Figure 8.27. Late complications of atherosclerosis. Created by npatchett on Wikimedia, licensed under the Creative Commons Attribution-Share Alike 4.0 International license.

Clinical scenarios of atherosclerosis progression

As mentioned earlier, the distribution of atheromas within the vascular tree is non-random and most commonly occurs at the branching points and bifurcation of large arteries.
As a result, clinical complications of atherosclerosis present as a wide array of symptoms and diagnoses (Figure 8.28)

The major arteries of the body are visible with arrows pointing to common areas of atherosclerotic changes: brain, carotid (neck), thoracic (chest), heart, kidney, abdominal, and peripheral arteries (upper & lower limbs)
Figure 8.28. Clinical consequences of atherosclerosis. Created by Tetiana Povshedna with Biorender.com, under its creative commons license

Section summary

Microscopic and macroscopic changes that occur during the atherosclerosis progression are summarized in Fig 8.29.

Fig 8.29  Stages of the atherosclerotic plaque formation

 
Plaque formation stage
Microscopic changes in the blood vessel wall (histology)
Outcome
Macroscopic changes in the blood vessel wall (gross anatomy)
1. Lesion initiation Endothelial activation in response to risk factors (hypertension, lipid products, cigarette smoke, etc). Recruited monocytes and intimal VSMCs capture oxLDL and become foam cells Initial LDL oxidation and infiltration within the intimal layer –
2. Fatty streak Recruited monocytes and intimal VSMCs become foam cells; cholesterol crystals form within the intima Intracellular and extracellular LDL deposition Bright yellow lesions on the luminal surface of the vessel; minimally raised
3. Fibrous plaque Foam cells, recruited immune cells, and cholesterol crystals form a soft necrotic core. Impaired clearance of apoptotic cells, increased cellular death, and intraplaque hemorrhages facilitate its expansion.

VSMCs from media are recruited to the intimal layer, secrete collagen-rich extracellular matrix, and form a protective fibrous cap.

 Formation of the necrotic core and protective fibrous cap; thickness, composition, and collagen content of the fibrous cap determine stability of the plaque Firm, visible, raised, homogenous, well-marked white areas on the luminal surface of the vessel; sometimes areas of calcification are present
4.1 Plaque rupture/erosion Erosion (loss of endothelium) or rupture (disturbed fibrous cap) expose the thrombogenic core of the plaque and initiate coagulation Thrombus formation Heterogeneous raised lesions associated with surface thrombosis
4.2. Plaque growth Expansion of the necrotic core increases the size of the plaque Lumen obstruction Firm lesions that completely close the blood vessel lumen
4.3. Aneurysm formation and rupture Weakening of the tunica media might appear as fragmentation in the superficial layers (border between tunica media and tunica intima). Muscular layer of the blood vessel wall can appear condensed, the amount of elastic fibers is decreased Early stages – ballooning of the vessel wall, later stages – rupture Rupture of the blood vessel (often fatal)

References

Jebari-Benslaiman, S., Galicia-García, U., Larrea-Sebal, A., Olaetxea, J. R., Alloza, I., Vandenbroeck, K., Benito-Vicente, A., & Martín, C. (2022). Pathophysiology of Atherosclerosis. International journal of molecular sciences, 23(6), 3346. https://doi.org/10.3390/ijms23063346

https://www.statpearls.com/ArticleLibrary/viewarticle/17943

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Pathology Copyright © 2022 by Tetiana Povshedna is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, except where otherwise noted.

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