Flashcards in Pathology of Atherosclerosis Deck (46):
What is the leading cause of death in our country?
coronary artery disease
What is arteriosclerosis?
"hardening of the arteries" due to thickening of the blood vessel wall.
What are the 3 pathologic patterns of arteriosclerosis?
3. Monckeberg medial calcific sclerosis
What is atherosclerosis?
dominant pattern causing intimal fibrofatty plaques that obstructs blood flow. Endothelium is key to the development, because when it becomes damaged due to smoking, hypertension, or any variety of disorders, it can cause atheromas (soft-yellow lesion).
What is vascular disease?
diseases that narrow the lumen and injure endothelium, weakening the walls of the vessels.
Does vascular disease lead to hypertension and diabetes, and vice versa?
YES. Good thing is hypertension and diabetes are 2 modifiable risk factors.
What are some important functions of the endothelium?
maintain a permeable barrier, anti-coagulant, pro-coagulant, modulate blood flow, regulates inflammation, and regulated cell growth.
What is Monckeberg's arteriosclerosis?
calcification of the media of muscular (medium-sized) arteries; nonobstructive (lumen is still preserved). Usually occurs after age 50. May falsely evelvate systolic BP.
Not clinically significant.
What is arteriolosclerosis?
narrowing of small arterioles; divided into hylaine and hyperplastic types.
**What are the NONMODIFIABLE risk factors for atherosclerosis?
- Sex (males, or post-menopausal women due to loss of protective estrogen)
- Genetics (familial predisposition)
What other some additional atherosclerosis risk factors?
- homocysteine= associated with stroke, CAD, PVD
- lipoprotein A= altered form of LDL associated with CAD and cerebrovascular risk, independent of LDL levels.
- c-reactive protein= acute phase reactant synthesized in the liver and used as a marker for inflammation. It takes endothelial cells from an anti-coagulant state to a pro-coagulant state.
What is important to remember about atherosclerosis risk factors?
the more you have, the more likely to have a cardiovascular event :(
What causes most cases of hypertension?
idiopathic (we don't know)
What are the 2 types of hypertension?
1. benign hypertension (most)
2. malignant hypertension
What is hypertension?
increased blood pressure due to increased blood volume, HR, sodium, and peripheral resistance (angiotensin II or catecholamines)
What are some of the ways hypertension can cause vascular pathology?
- hyaline arteriolosclerosis
- hyperplastic arteriolosclerosis
What is hyaline arteriolosclerosis?
pink hyaline thickening of the walls of arterioles with narrowing of the lumen. Consistent with benign hypertension.
What is hyperplastic arteriolosclerosis
malignant hypertension with onion skinning concentric narrowing of lumen.
**What are the MODIFIABLE risk factors for atherosclerosis?
- hypercholesterolemia (LDL increases risk; HDL decreases)
**What happens to a blood vessel when it begins to undergo atherosclerotic changes?
Damage to endothelium allows lipids to leak into the intima where they are oxidized and then consumed by macrophages via scavenger receptors, resulting in foam cells. Inflammation and healing leads to deposition of extracellular matrix and proliferation of smooth muscle, macrophages, endothelial cells, and collagen deposition.
What does V-CAM-1 have to do with the inflammation component of atherosclerosis?
it binds leukocytes, including monocytes and T cells (release proinflammatory molecules and fibrogenic growth factors). The monocytes then transform to macrophages, which engulf lipid and secrete cytokines (IL-1 and TNF), which increase adhesion of leukocytes.
Will loss of T cells help to reduce atherosclerosis?
What makes up the atheromatous plaques?
cholesterol and cholesterol esters
What may antioxidants help to do?
slow the development of plaques due to macrophages oxidizing lipids.
How can we slow the rate of progression of plaques?
lower serum cholesterol levels by diet, drugs, and exercise
How do oxygen free radicals cause impaired endothelial function in chronic lipidemia?
deactivate NO, which is a major endothelial relaxing factor.
Can smooth muscle cells syntesize ECM?
YES and stable the plaques :(
What does the prominent connective tissue of the intima do?
forms a fibrous cap around the atheroma (which can be good) unless it is disrupted, it can form a pro-thrombotic state, which can lead to fatal MI.
**How does atherosclerosis progress in the pre-clinical phase?
Begins as FATTY STREAKS (flat yellow lesions of the intima consisting of lipid-laden macrophages); present in most teenagers. This will then progress to a FIBROFATTY plaque, that will advance to an ATHEROMATOUS plaque (often eccentric). This is the pre-clinical phase.
**How does atherosclerosis progress in the clinical phase?
In the elderly, you can then see weakening of the vessel wall leading to an aneurysm that can rupture, or progress to occlusion of the already narrowed lumen via thrombus, and finally clinical stenosis.
Where do plaques commonly develop?
abdominal or thoracic aorta, coronary arteries, carotid arteries, and circle of willis
** What are the 3 major components to atherosclerotic plaques?
1. smooth muscles cells, T cells, and macrophages
2. ECM (proteoglycans, collagen and elastic fibers)
3. intracellular and extracellular lipid
What are complicated plaques?
more advanced plaques that have calcification, ulceration, thrombosis, and hemorrhage
Can smooth muscle cells also engulf lipids?
What are the 2 different ways diabetes can present?
1. MACROvascular disease= large arteries leading to atherosclerosis, hyaline arteriolosclerosis, increased myocardial infarcts, strokes, and gangrene.
2. MICROvascular disease= retina (retinopathy), kidney (nephropathy), and peripheral nerves (neuropathy).
**What are the 3 metabolic pathways that account for diabetic pathology?
1. formation of advanced glycation end products (AGEs)
2. activation of protein kinase C
3. disturbance in polyol pathways
How are AGEs formed?
from reaction between intracellular glucose derived dicarbonyl precursors with amino group of intracellular and extracellular proteins forming cross-links of collagen I molecules (decreasing elasticity) and collagen IV of the basement membrane (increasing fluid filtration; leakiness). So an increased glucose level will stimulate this interaction.
Are AGE cross-linked proteins resistant to proteolytic degradation?
What do the matrix components, modified by AGEs, trap?
nonglycated or interstitial materal such as LDL, contributing to atherosclerosis. This is why diabetics really need to control their LDL levels, because they are more prone to the adverse effects of LDL.
How may albumin lead to basement membrane thickening, in diabetics?
by binding to glycated basement membrane. Seen in microangiopathy.
What will AGEs do to circulating plasma proteins?
modify them causing them to bind to AGE receptors of macrophages, endothelial cells and mesangial cells (kidney), resulting in generation of proinflammatory cytokines and growth factors.
*Remember in diabetics due to high glucose levels.
**How does activation of protein kinase C (PKC) lead to diabetic pathology?
- intracellular hyperglycemia causes synthesis of diacylglycerol and activation of PKC= VEGF production leading to neovascularization in diabetic retinopathy.
- More importantly, PKC activates vasoconstrictor endothelin 1 (constricting the lumen) and decreases activity of eNOS (reducing vasodilation) :(
- produces transforming GF beta= more ECM deposition causing basement membrane thickening.
- produces plasminogen activator INHIBITOR-1= procoagulant by decreased fibrinolysis
- produces proinflammatory cytokines
**Summary: So why is diabetes such a problem?
its hitting the blood vessels from all different sides: prothrombotic, vasoconstriction, and damage to endothelial cells making you more prone to damage of LDLs.
**How does intracellular hyperglycemia (polyol pathway) lead to diabetic pathology?
- increases cell response to oxidative injury.
- increased glucose leads to more conversion to fructose (which requires NADPH as a cofactor). Because NADPH is being taken away from its other role in the production of glutathione (important antioxidant) we have more ROS! :(
What is the morphology of diabetes?
change in pancreas is not too dramatic, but will see amyloid replacements of islets in DM2. These occur around blood vessels and between cells!