Progression of Atherosclerosis and Plaque Vulnerability

In a normal artery, the intima is a monolayer of smooth muscle cells
(SMCs), endothelial cells, and matrix proteins such as collagen. The
intima is located between the media and the arterial endothelium.¹

1. Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

At the start of atherosclerosis, low-density lipoproteins (LDLs) accumulate in the intima, triggering a proinflammatory response that promotes increased intimal SMC growth
and replication. This pathological response is known as adaptive intimal thickening.^1-4

SMC, smooth muscle cells.

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

Disease progresses to pathological intimal thickening with the infiltration and proliferation of smooth muscle cells. These cells generate extracellular matrix network.^1-4

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

Extracellular lipids, degraded SMCs, and infiltrating matrix proteins also begin to accumulate and form lipid pools, or fatty streaks.^1-4

SMC, smooth muscle cell.

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

Proinflammatory molecules also attract macrophage foam cells. These cells infiltrate the intima during pathological intimal thickening and contribute to plaque development.^1-4

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

Cholesterol clefts, comprised of free cholesterol, also start to form in the lipid pool.^1-3

The lipid pool continues to grow as more foam cells take up LDLs, degrade, and add to existing lipid deposits.^1-3

As SMCs and foam cells die and degrade, they form small calcified plaques within the lipid pool.^1-3

LDL, low-density lipoprotein; SMC, smooth muscle cell.

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
3. 3.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27 2021.

Pathological intimal thickening progresses into an early-stage fibroatheroma. At this stage, the fibroatheroma is characterized by a fibrous cap that is comprised of SMCs and collagen fibers.^1-4

SMC, smooth muscle cell.

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

As atherosclerosis progresses, a late-stage fibroatheroma forms. Its hallmark feature is a necrotic core comprised of dead SMCs and foam cells, and cholesterol clefts.^1-4

Calcified plaques also accumulate in the lipid pool to form calcified sheets.^1,3,4

SMC, smooth muscle cell.

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

Exposure to increased LDL-C, continued inflammation, and cell death make the fibrous
cap vulnerable to thinning and rupture.^1-4

Thin-cap fibroatheromas, or vulnerable plaques, emerge in advanced atherosclerosis. They have a large necrotic core with a thinning but intact fibrous cap (<65 µm thickness) and a lipid arc greater than 90 degrees as measured by optical coherence tomography.^1-4

LDL-C, low-density lipoprotein - cholesterol

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

At this stage, some plaques remain asymptomatic, while some become obstructive causing stable angina, yet others elicit acute thrombosis which may lead to acute coronary syndrome.^1-4

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

Sustained inflammation, necrotic core growth, and fibrous cap thinning lead to a plaque rupture and the release of lipid debris into the lumen.^1-4

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

At the site of the rupture, platelets and red blood cells aggregate with the lipid debris to form a thrombus.^1-4

The thrombus, in combination with plaque, further restrict luminal blood flow and may result in acute coronary syndrome.^1-4

1. 1.Bentzon JF, Otsuka F, Virmani R, et al. Circ Res. 2014;114:1852-66
2. 2.Stefandis C, Antonious C-K, Tsiachris D, et al. J Am Heart Assoc, 2017;6:e05543. doi:101161/JAHA.117.005543
3. 3.Yahagi K, Kolodgie FD, Otsuka F, et al. Nat Rev Cardio. 2016;13(1):79-98. doi.org/10.1038/nrcardio.2015.164
4. 4.Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
   Available from: https://www.ncbi.nlm.nih.gov/books/NBK534260/. Accessed September 27, 2021.

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