Atherosclerosis and arteriosclerosis: Pathology review

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Case Study0:00–1:03

Mikhail is a 60 year old man with a history of hypertension, diabetes and dyslipidemia who presents to your clinic complaining of sudden-onset retrosternal chest pain associated with shortness of breath.
He has a 35-pack-a-year smoking history, and he mentions that he also develops lower limb pain when walking for more than 15 minutes.
His father underwent a below the knee amputation of his right lower extremity and died from a stroke. On physical examination, his BMI is 32.
On further workup, his ECG and high troponin levels suggest a myocardial infarction. Mikhail goes to the cath lab to undergo per-cutaneous coronary intervention, which showed a clot occluding the left anterior descending coronary artery.
After the procedure, his chest pain resolved. However, he started developing a web-like skin rash.
Mikhail suffers from arteriosclerosis, which is a hardening and thickening of the arterial wall, causing it to lose its elasticity.

Pathology1:03–5:23

A specific type of arteriosclerosis is atherosclerosis, which is a chronic inflammatory disorder that affects the endothelium of medium and large arteries, and is characterized by the buildup of cholesterol plaques within the arterial lumen.
In a descending order, the most common arteries affected by atherosclerosis are the abdominal aorta, coronary artery, popliteal artery and then the carotid artery.
Risk factors for atherosclerosis can be divided into modifiable and nonmodifiable risk factors. Modifiable risk factors include hypertension, diabetes mellitus, smoking and dyslipidemia, particularly an increase in LDL levels or a decrease in HDL levels.
Non-modifiable risk factors include age, family history, and being of African-American descent. The pathogenesis of atherosclerosis is essentially an inflammatory response to endothelial cell injury.
The endothelium is injured by stress against the arterial wall, like in hypertension. This is especially more prominent at arterial bifurcations, such as the carotid artery bifurcation.
Other causes of endothelial injury include tobacco smoking and homocysteinemia, which is elevated levels of the amino acid, homocysteine.
Regardless of the cause, when the endothelium is injured, LDL particles are allowed to leak into the intimal layer, where it gets oxidized.
When LDL is oxidized, it becomes a pro-inflammatory antigen that induces an immune response in which inflammatory cells like macrophages come to fight this antigen.
These macrophages will enter the arterial walls and eat up the oxidized LDL particles, creating what’s known as foam cells.
Accumulation of foam cells underneath the endothelium creates the first marker of atherosclerosis, a fatty streak. Fatty streaks might as well be called “flatty” streaks, because they are not raised, meaning they don’t obstruct the lumen so they don’t produce clinical symptoms like angina.
Damage to the endothelium calls upon platelets to join the party. Platelet and endothelial cells release factors like platelet derived growth factor, or PDGF and fibroblast growth factor, or FGF, and transforming growth factor beta, or TGF-beta.
These factors stimulate smooth muscle cell proliferation and migration from the tunica media to the tunica intima. Smooth muscle cells then proliferate and stimulate the production of extracellular matrix.
This results in the formation of a fibrous cap overlying a lipid core in the center, and this structure is called a plaque.
The lipid core is made of cholesterol crystals that under the microscope look like white slit-like spaces. The fibrous cap is what separates the lipid core from the blood vessel lumen.
Unlike the fatty streak, an ath-erosclerotic plaque could obstruct the lumen and produce symptoms. Keep in mind that although fatty streaks can form as early as adolescence, they don’t always develop into plaques.
Now over time, foam cells within the lipid core undergo necrosis, and release matrix metallo-proteinases, or MMPs. These enzymes begin chewing away at the fibrous cap, making it thinner and thinner, until one day, it ruptures.
When this happens, the atheroma is now exposed to the blood vessel lumen. Platelets react as they should, by forming a fibrin clot at the site of rupture.
Unfortunately, these clots can occlude the lumen of the artery even more, or they may detach and move to obstruct other blood vessels like the arteries in the brain.
Okay, complications of atherosclerosis include ischemia to the supplied organs. Typically, at least 70% of the lumen must be occluded prior to the onset of the symptoms.

Complications5:23–7:48

Ischemia may manifest as angina if the coronary arteries are involved, claudication in peripheral vascular disease, or chronic mesenteric ischemia if the mesenteric arteries are involved.
When the plaque ruptures, clot formation may potentially result in acute infarction of the supplied organ, such as myocardial infarction, ischemic stroke, acute limb ischemia or acute mesenteric ischemia.
Additionally, an atheroma may weaken the vessel wall, causing an aneurysm, especially at areas where the arterial wall is weaker.
For example, these can occur in the abdominal aorta below the level of L2 since it lacks the vasa vasorum, which are small blood vessels in the tunica adventitia supplying the aortic wall.
Without this vasa vasorum, the tunica media doesn’t get enough nutrients, causing it to weaken, which increases the risk of developing an abdominal aortic aneurysm that could rupture and cause hemorrhaging.
An interesting complication of atherosclerosis are cholesterol emboli. This occurs when an atherosclerotic plaque itself is dislodged and travels in the circulation as a cholesterol embolus.
A common exam question will have a person who underwent a cardiac procedure, such as percutaneous coronary intervention, present with this complication right afterwards.
This is caused by a plaque that was accidentally dislodged during the procedure. Symptoms depend on where the embolus ends up and include a web-like purplish rash called livedo reticularis, acute kidney injury, or even gangrene formation at the extremities.
Retinal emboli can be visualized on fundoscopy, and are called Hollenhorst plaques. A good clue is that laboratory investigations, interestingly, shows eosinophilia, and urinalysis shows eosinophil-uria.
Microscopically, cholesterol emboli are characterized by white needle-shaped cholesterol clefts within the occluded vessel lumen.
Okay, another subtype of arteriosclerosis is arterio-lo-sclerosis. A bit of a tongue twister.

Arteriolosclerosis7:48–8:05

From the name, this affects smaller arterioles, and there are two types; hyaline and hyperplastic arteriolosclerosis. Hyaline arteriolosclerosis results from deposition of protein within the vessel wall, which on microscopy, gives off a glassy, eosinophilic, pink appearance, hence the term hyaline.

Hyaline8:05–9:09

Accumulation of protein thickens the blood vessel wall and make it rigid, occluding the arteriolar lumen. Risk factors include chronic hypertension or diabetes.
In hypertension, the increased arterial wall stress literally pushes plasma proteins into the blood vessel wall. In diabetes, excess glucose combines with the proteins of the arteriolar basement membrane, a process called non-enzymatic glycation.
Having too much sugar in the basement membrane is not a good idea, because it can disrupt the structure and allow plasma proteins to leak in.
Clinical manifestations of hyaline arteriolosclerosis include hypertension and diabetic nephropathy, as well as small lacunar infarcts in the brain.

Hyperplastic9:09–9:42

Hyperplastic arteriolosclerosis on the other hand, typically happens as a reaction to severe, acute elevations in blood pressure.
This results in excessive growth of the basement membrane and proliferation of the arteriolar smooth muscle, which occludes the lumen, and gives the blood vessel the appearance of “onion-skin” on microscopy.
Hyperplastic arteriosclerosis most commonly affects the renal, retinal and intestinal arterioles. The final form of arteriosclerosis is an uncommon and benign form called medial calcific sclerosis, or Monckeberg sclerosis.

Medial calcific9:42–10:21

This form is characterized by calcification of the internal elastic lamina and tunica media, causing the vessel wall to become rigid.
But the thing is, although the blood vessel is rigid, the lumen is not occluded, so it’s not clinically significant and should be ruled out as an answer choice if the person suffers from symptoms of ischemia.
These calcifications may appear on x-ray, giving the bloodvessel a pipestem appearance. Okay to review, arteriosclerosis is hardening of the arteries, and has different subtypes, including atherosclerosis, hyaline and hyperplastic arteriolosclerosis, and medial calcific sclerosis.

Review10:21–12:21

Atherosclerosis results from endothelial injury secondary to risk factors like age, hypertension, diabetes and tobacco smoking.
When the endothelium is injured, LDL particles enter and are oxidized. Macrophages phagocytose LDL particles, forming foam cells, which forms the fatty streak.
Smooth muscle cells proliferate and migrate to the intimal layer, where they lay down extracellular matrix. Over time, an atherosclerotic plaque made of a fibrous cap and a lipid core is formed.
This plaque may occlude the lumen, causing ischemia to distal organs, which manifests as angina or claudication. When the plaque is disrupted, a thrombus is formed, which may produce acute infarction, such as myocardial infarction or stroke.
Atheromas can also weaken the vessel wall, resulting in the formation of aneurysms, like abdominal aortic aneurysm. Also, during cardiac procedures, atherosclerotic plaques can be dislodged, producing cholesterol emboli.
Hyaline arteriolosclerosis is associated with chronic hypertension and diabetes, and is characterized by protein deposition in the vessel wall.
Hyperplastic arteriolosclerosis is associated severe, acute hypertension, and is characterized by expansion of the basement membrane.
Finally, medial calcific sclerosis is a benign condition characterized by calcification of the tunica media, which can be visualized on x-rays.Back to our case.
Mikhail had multiple risk factors for atherosclerosis including old age, hypertension, diabetes, obesity, tobacco smoking and dyslipidemia.

Summary 12:21–13:09

He also has a family history of atherosclerosis, as his father likely had peripheral vascular disease, and died from a stroke.
He presents with chest pain characteristic of myocardial ischemia, which was confirmed by his ECG and troponin levels, and his lower limb pain on exertion is characteristic of claudication, which is most likely caused by peripheral vascular disease.
After his cardiac procedure, he developed a web-like rash that is likely livedo reticularis, indicating that his procedure was complicated