The Story of a Plaque- from Cholesterol to a heart attack

Created on : #march2025 #april2025

Author: Dr. Om J Lakhani

If you find this useful, please use the link to see the various ways in which you can Support us →
For online consultation with Dr. Om J Lakhani please use the following link Online Consultation →

Introduction

The story of atherosclerotic plaque begins with subtle changes in the arterial walls and can culminate in a life-threatening myocardial infarction. Let me walk you through this journey and explain how medications like ezetimibe and statins can intervene to prevent this dangerous progression.

The Birth and Growth of Atherosclerotic Plaque

Initial Arterial Damage

In a healthy person, arterial walls are smooth and uniform in thickness, allowing blood to flow freely to the heart and other parts of the body[2]. However, the story of plaque begins when the inner lining of an artery (endothelium) becomes damaged. This damage can be caused by several factors:

Lipid Accumulation and Inflammation

Once the arterial wall is damaged, lipids—particularly low-density lipoprotein (LDL) cholesterol—begin to accumulate at the site of injury. This accumulation triggers an inflammatory response, where inflammatory cells, especially macrophages, move into the affected arterial walls[1]. Over time, these macrophages engulf cholesterol products and transform into "foam cells"[1].

Plaque Formation

As foam cells die, they release their contents, forming a cholesterol core within the arterial wall. In response to growth factors secreted by macrophages, smooth muscle cells and other cells migrate into the developing plaque and produce fibrous tissue that acts to stabilize it[1]. This process creates what we call atherosclerotic plaque—deposits made up of cholesterol, fatty substances, cellular waste products, calcium, and fibrin (a clotting material)[6].

Plaque Progression

As plaque builds up, the arterial wall thickens, narrowing the channel within the artery and reducing blood flow[6]. This narrowing decreases the amount of oxygen and nutrients reaching the heart muscle. If atherosclerosis develops in the coronary arteries, the condition is called coronary artery disease (CAD)[2].

The Path to Myocardial Infarction

Stable vs. Unstable Plaque

Plaques can be categorized as stable or unstable:

Plaque Rupture

The dangerous turning point occurs when an unstable plaque ruptures. When exposed to the pressure of blood flow, plaques with thin linings may break open, releasing their cholesterol-rich contents into the bloodstream[1][3]. This rupture triggers the body's clotting mechanism.

Thrombus Formation

When plaque ruptures, blood platelets rush to the site and begin to form a blood clot (thrombus). This clot can grow in size until it completely blocks the coronary artery[2][3]. Alternatively, a piece of plaque can break off and be carried by the bloodstream until it gets stuck elsewhere[6].

Myocardial Infarction

When a coronary artery becomes completely blocked, blood flow to part of the heart muscle is cut off. Without oxygen, heart cells in the affected area begin to die within 15-30 minutes—a process called infarction[1]. This tissue death is what we call a myocardial infarction or heart attack.

The damage spreads from the subendocardial region (just below the inner surface of the heart) outward, potentially becoming a full-thickness transmural infarct. The initial "wave" of infarction can take place over 3-4 hours[1]. The extent of damage depends on:

How Ezetimibe and Statins Intervene

Statins: Multi-faceted Protection

Statins are powerful medications that work through several mechanisms to prevent plaque formation and rupture:

  1. Cholesterol Reduction: Statins block an enzyme in the liver (HMG-CoA reductase) that helps make cholesterol, thereby lowering LDL cholesterol production[7]. By reducing circulating LDL, statins decrease the amount of cholesterol available to build up in arterial walls.

  2. Anti-inflammatory Effects: Statins possess anti-inflammatory properties that help combat the inflammatory processes contributing to plaque buildup[7].

  3. Plaque Stabilization: Rather than simply reducing plaque volume, statins appear to promote plaque healing and stabilization. They modify plaque composition by:

    • Reducing fibrous plaque volume
    • Increasing dense calcium volume, which helps stabilize the plaque[8]
    • Preventing plaques from breaking open and releasing chemicals that stimulate blood clot formation[7]

  4. Plaque Regression: With high-dose statin therapy, especially with potent statins like atorvastatin (Lipitor) and rosuvastatin (Crestor), studies have shown that plaque can actually regress. When LDL cholesterol is lowered below 70 mg/dL, regression of plaque by up to 24% has been observed[5].

Ezetimibe: Complementary Approach

Ezetimibe works differently but complementarily to statins:

  1. Cholesterol Absorption Inhibition: Ezetimibe inhibits the absorption of cholesterol from the intestine by blocking the Niemann-Pick-like 1 receptor[4]. This reduces the amount of dietary and biliary cholesterol entering the bloodstream.

  2. Enhanced LDL Reduction: When combined with statins, ezetimibe provides additional LDL-C reduction beyond what statins alone can achieve[4].

  3. Plaque Composition Effects: Research suggests that ezetimibe combined with statins reduces fibro-fatty plaque more significantly than statins alone[4]. It can also:

    • Decrease levels of matrix metalloproteinase-9 (MMP-9), an enzyme that makes plaque rupture more likely[4]
    • Reduce cholesterol crystal accumulation and plaque inflammation[4]
    • Potentially increase plaque stability

  4. Cardiovascular Outcome Benefits: Studies have shown that adding ezetimibe to statin therapy further reduces cardiovascular events in patients with acute coronary syndrome compared to statins alone[4].

The Transformed Plaque

With effective statin and ezetimibe therapy, the nature of atherosclerotic plaques changes. Instead of regression (complete disappearance), what often occurs is a healing process:

This healing process explains why patients on optimal lipid-lowering therapy still have a "residual risk" of cardiovascular events. The mechanism of acute coronary syndromes may shift from plaque rupture to plaque erosion in these treated patients[8].

By understanding this complete story—from plaque formation to myocardial infarction and the mechanisms of intervention—we can better appreciate the importance of lipid-lowering therapies in preventing heart attacks and saving lives.

Citations:
[1] https://en.wikipedia.org/wiki/Myocardial_infarction
[2] https://www.msdmanuals.com/home/multimedia/video/myocardial-infarction
[3] https://cvrti.utah.edu/the-connection-between-atherosclerosis-and-heart-attacks/
[4] https://pmc.ncbi.nlm.nih.gov/articles/PMC10084938/
[5] https://health.clevelandclinic.org/can-statins-actually-reverse-plaque-buildup
[6] https://www.heart.org/en/health-topics/cholesterol/about-cholesterol/atherosclerosis
[7] https://www.health.harvard.edu/heart-health/dont-be-afraid-of-statins
[8] https://pmc.ncbi.nlm.nih.gov/articles/PMC4599025/
[9] https://www.ncbi.nlm.nih.gov/books/NBK534259/
[10] https://my.clevelandclinic.org/health/diseases/16753-atherosclerosis-arterial-disease
[11] https://www.sciencedirect.com/science/article/pii/S0735109707021286
[12] https://www.nhlbi.nih.gov/health/atherosclerosis
[13] https://www.ncbi.nlm.nih.gov/books/NBK537076/
[14] https://www.hopkinsmedicine.org/health/conditions-and-diseases/atherosclerosis
[15] https://www.mayoclinic.org/diseases-conditions/arteriosclerosis-atherosclerosis/symptoms-causes/syc-20350569
[16] https://my.clevelandclinic.org/health/diseases/16818-heart-attack-myocardial-infarction
[17] https://www.ncbi.nlm.nih.gov/books/NBK507799/
[18] https://www.mayoclinic.org/diseases-conditions/heart-attack/symptoms-causes/syc-20373106
[19] https://www.webmd.com/heart-disease/what-is-atherosclerosis
[20] https://www.phyathai.com/en/article/3304-plaque-accumulation-and-risk-of-heart-failure-pt2
[21] https://www.ahajournals.org/doi/10.1161/circulationaha.117.029095
[22] https://www.ahajournals.org/doi/10.1161/atvbaha.111.226167
[23] https://www.hopkinsmedicine.org/health/wellness-and-prevention/how-statin-drugs-protect-the-heart
[24] https://pmc.ncbi.nlm.nih.gov/articles/PMC5497285/
[25] https://pmc.ncbi.nlm.nih.gov/articles/PMC2697737/
[26] https://pubmed.ncbi.nlm.nih.gov/30642643/
[27] https://www.sciencedirect.com/science/article/pii/S2666667724000709
[28] https://www.ahajournals.org/doi/10.1161/ATVBAHA.117.310244
[29] https://www.health.harvard.edu/heart-health/can-we-reduce-vascular-plaque-buildup
[30] https://www.ecrjournal.com/articles/commencement-atorvastatin-and-ezetimibe-immediately-patients-presenting-acute-coronary?language_content_entity=en
[31] https://www.sciencedirect.com/science/article/pii/S2214762414000061
[32] https://www.sciencedirect.com/science/article/abs/pii/S1050173818302238
[33] https://www.ahajournals.org/doi/10.1161/ATVBAHA.119.312578
[34] https://www.ahajournals.org/doi/10.1161/circresaha.114.302721
[35] https://en.wikipedia.org/wiki/Atherosclerosis
[36] https://pmc.ncbi.nlm.nih.gov/articles/PMC11242737/
[37] https://academic.oup.com/eurjpc/article-abstract/31/10/1205/7614274
[38] https://www.jacc.org/doi/10.1016/j.jacc.2015.05.064
[39] https://pmc.ncbi.nlm.nih.gov/articles/PMC6516816/
[40] https://go.drugbank.com/drugs/DB00973