Lecture 3: Atherosclerosis Flashcards
Define atherosclerosis
What size arteries does it affect?
Atherosclerosis is :
- disease of elastic arteries, and large and medium size muscular arteries
- characterized by fibrous thickening of the arterial wall associated with lipid-infiltrated plaques that may calcify
- affects mid to large size arteries
Explain the origin and progression of atherosclerosis
Progression of Atherosclerosis:
pneumonic: “Even Manny Forgets Farting Saturday’s Finnish Class”
1. Endothelial Cell Dysfunction
2. Macrophage and LDL accumulation
3. Foam Cell formation
4. Fatty streaks
5. SMC migration
6. Fibrous Plaque
7. Complex Atheroma
Explain the changes that happen in endothelial cells and SMCs during inflammation
Normally, endothelial cells are impermeable to large molecules, anti-inflammatory, resist thrombosis and promote vasodilation
When activated by inflamation endothelial cells: Increase Permeability, Increase inflamatory cytokines, Increase leukocyte adhesion, Decrease vasodilators, Decrease antithrombitic
SMCs normally: contract and contain in medial layer
Upon activation by inflamation, SMCs increase inflammatory cytokines, increase extracellular matrix synthesis and increase migration and proliferation
What factors cause endothelial dysfunction?
Endothelial dysfunction intitiates foam cell formation by invading _____
Lipoprotein oxidation plays a major role in ______ recruitment
Chemical forces and hemodynamic stress cause endothelial dysfunction
Endothelial dysfunction initiates foam cell formation by invading macrophages
Lipoprotein oxidation plays a major role in leukocyte recruitment
Macrophage and LDL accumulation:
The site of the lesion is determined by ________, shear stress at artery branches increase the likelihood of ______ formation, where LDLs infiltrate into the ______ region.
Endothelial cells increase their permeability due to shear stress, LDL cholesterol starts to migrate inside and gets trapped, it then binds to ______
The site of the lesion is determined by hemodynamic forces. Shear stress at artery branches increase the likelihood of plaque formation, where LDLs infiltrate into the sub-endothelial region.
Endothelial cells increase their permeability due to shear stress, LDL cholesterol mirgration starts to migrate inside and gets trapped, it then binds to ApoB
What are the following prodisease mechanisms:
_____ permeability
_____ leukocyte adhesion
_______ NO production
Pro-disease mechanisms:
INCREASED permeability
INCREASED leukocyte adhesion
Decreased NO production
Explain why LDL is “bad cholesterol” whereas HDL is “good cholesterol”
LDL is bad because in atherosclerosis it is the carrier of cholesterol inside the plaque
HDL, however, is acting as a positive factor, it actually binds to cholesterol and transports it outside
Stages of plaque development:
Foam Cells——> Fatty Streaks
How do fatty streaks (which are not necessarily pathological) become plaques?
Fatty streaks become fatty streaks due to foam cell recruitment
Plaque progression happens due to smooth muscle cell migration and altered matrix synthesis and degradation
Fatty Streaks:
- Fatty streaks are early lesions, consist of (location) accumulation of foam cells
- Foam cells are…..
- Fatty streaks are found in the aorta in the ___ decade of life, in the coronary artery in the ___ decade and in the cerebral artery in ___
Fatty Streaks:
- fatty streaks are early lesions, consist of sub-endothelial accumulation of foam cells
Foam cells are LDL and cholesterol engorged macrophages
- Fatty streaks are found in the aorta in first decade of life, found in the coronaries in second decade of life and found in the cerebral arteries in 3 and 4th decades of life
Fatty Streaks are forecasts of _______
Fatty streaks cause _____ permeability, ______ leukocyte filtration, ______ NO, _____ vasodilation
Fatty streaks are forecasts of fibrous lesions
Fatty streaks cause increased permeability, increased leukocyte filtration, decreased NO, and defective vasodilation
SMC Migration:
Foam cells start accumulating to form a necrotic core
PDGF and FGF-Beta attract proliferation and migration of SMCS to the necrotic core
Which two molecules play a role in attraction of SMC to the lesion?
Antiotensin and homocystine
play a role in attraction of smooth muscle cells to the necrotic lesion
Fibrous legions:
Fibrous legions are characterized by accumulation of lipid rich _____ and ______.
The fibrous cap consists of ____ and ______ enclosing the necrotic core
Fibrous legions may eventually _____
Fibrous legions:
Fibrous legions are characterized by accumulation of lipid rich necrotic debris and SMCs
The fibrous cap consists of SMCs and extracellular matrix enclosing the necrotic core
Fibrous legions may eventually calcify
Explain why females are protected from atherosclerosis until after menopause:
Estrogren promotes ____ NO and ____ prostocyclins, causing ______ vasodilation
Females are protected from atherosclerosis until after menopause because
Estrogen promotes INCREASED NO and increased prostacyclins….. causing increased vasodilation
Complex atheroma and thrombosis:
Complex plaques with superimposed thrombi and THICK
Risk factor for ___ and ____ embolization
Result in vascular insufficiency, abnormal renal circulation.. aneursym… clots
“Big two” places to get clots are?
Complex atheroma and thrombis:
Complex plaques with superimposed thrombi and are thick
Risk factor for cerebral and peripheral embolization
Big two places to get clots: heart and brain
Stable vs unstable plaque
Explain stable vs unstable plaques
Plaques will begin to grow and obstruct blood flow
Stabilized plaques: growth of fibrous cap and decreased lipid layer/foam cells
Vunerable plaque: lipid layer/foam cell layer keeps growing, with a thin fibrous cap
Vunerable plaques are at risk for rupturing and releasing a thrombus
What are the pro-coagulants?
List the anti-coagulants?
tPA is _______
Procoagulants: tissue factor and PAI-1
Anticoagulants: thrombomodulin, protein S, protein C, heparin
tPA is pro-fibrolytic (prevents/treats blood clots)
List the two factors that are PRO-coagulation
Tissue factor and PAI-1 are pro-coagulation
Use of ______ modify the risks of complications from atherosclerosis
Example of a _____ is aspirin
Aspirin inhibits ________ (which enzyme)?
Use of anti-coagulants modify the risk of complications from atherosclerosis
Example of an anti-coagulant is aspirin
(other examples include thrombomodulin, protein S and C and heparin like substances)
Aspirin inhibits thromboxane
The risk factors of Atherosclerosis (hemodynamic stress, hypertension, smoking, fatty foods, diabetes)
all lead to the _______ of LDLs
Then those altered LDLs are recognized by “______”
That then _____
The risk factors of atherosclerosis (hemodynamic stress, fatty foods, high cholesterol, diabetes, etc)
all lead to OXIDATION of LDLs
Then those altered LDLs are recognized by “scavenger receptors” that then bind and stimulate inflammation, further driving atherogenesis
Explain the risk factors for atherosclerosis:
Modifiable Risk Factors
Non-modifiable risk factors
Modifiable Risk Factors: dyslipedemia (high LDL, low HDL), tobacco smoking, hypertension, diabetes, lack of physical activity
Non-modifiable risk factors: Age, Male gender, Heretibility/genetics
Explain why obesity, HTN and diabetes are a bad combo for atherosclerosis
Obesity, HTN and diabetes all promote the same things that are PRO-atherosclerosis
Hyperlipedemia, HTN, glucose intolerance, impaired thrombolysis, inflammation, endothelial dysfunction
ALL of those things promote atherosclerosis
Prevalence of Atherosclerosis:
- Begins early in life, Accelerated by genetics and enviornmental factors
- Common in societies where cholesterol rich diet is prevalent
- In the US it is the underlying cause of _____ deaths
- Almost all patients who die of ____ (and _____ resulting from cerebral thrombosis) have atherosclerosis
Prevalence:
- begins early in life, accelerated by genetic and enviornmental factors
- Common in societies where cholesterol rich diet is prevalent
- In the US it is the underlying cause of roughly 50% of all deaths
- Almost all patients who die of MI’s (and strokes resulting from cerebral thrombosis) have atherosclerosis
Explain each complication of atherosclerosis:
1. Calcification
- Rupture or ulceration
- Hemorrhage
- Embolization
- Aneursyms
- Calcification: lipid core accumulates calcium, creating rigid vessels and decreasing compliance, making it more fragile
- Rupture or ulceration of plaque causes thrombosis (clot)
- Hemorrhage into the plaque producing a hematoma in the vessel wall further reduces lamimal diamter
- Embolization of fragments to peripheral sites
- Weakning of vessel wall causing aneursyms
What is the gold standard to diagnose atherosclerosis?
What are some other methods?
Gold standard is catheterization (but angiograms are expensive and risky)
Other methods: look at markers like C protein, LDL, HDL HTN
List some of the complications for atherosclerosis:
- Heart problems/vasculature problems?
- Cerebrovascular Diseases?
- Kidney issues?
Clinical sequale for atherosclerosis:
- Coronary Artery Disease, Peripheral Vascular Disease
- Cerebrovascular Diseases: TIA’s, strokes
- Renal Artery Disease: renal hypertension
Treatment for atherosclerosis:
Explain lifestyle changes
What do the medications that you put the pt on do?
Types of surgical procedures?
Treatment for atherosclerosis:
- Lifestyle changes (diet and exercise, reduce blood sugar)
- Medications: anti-hypertension meds, control LDL levels, lower blood sugar
Procedures: coronary angioplasty, bypass grafting
Explain what coronary angioplasty is
Coronary angioplasty is a procedure where you basically baloon the artery around the plaque to allow more blood to flow
Explain the following lipid modifying drugs:
Statins
Niacin
Fibric Acid Inhibitors
Statins inhibit HMG-CoA Reductase
Niacin is a lipase inhibitor
Fibric Acid Inhibitors (reduce LDL levels and increase HDL levels)
Explain the mechanism of the following therapies for atherosclerosis:
- Statins
- Niacin
- Aspirin
- Beta-blockers
- Renin-angiotensin inhibitors
Statins: inhibit cholesterol synthesis (inhibit HMG-CoA Reductase)
Niacin: inhibits fat breakdown and increases HDL, anti-inflammatory
Aspirin: anticoagulant (inhibts thromboxane)
Beta-blockers: antihypertensive
-Renin-angiotensin inhbitors: anti-hypertensive
Which drug is a primary drug for atherosclerosis
Statins are primary prevention
Fill in the blank for the following lipid levels:
Total Cholesterol:
Desirable level
Borderline Level
High
TOTAL CHOLESTEROL
Desirable is less than 200
Borderline is 200-230
High is > 240
Fill in the blank for the following lipid levels:
LDL:
Optimal level
Borderline
High
LDL:
Optimal LDL is < 100
Borderline LDL is 130-159
High LDL is 160 and up
List the following lipid levels for HDL
HDL:
Risk for heart disease
Borderline
Cardioprotective
HDL:
Risk for heart disease < 40
Borderline: 40-59
Cardioprotective is > 240
What is the desirable level of total cholesterol?
What is the desirable level of LDL cholesterol?
At what level of HDL does it become cardioprotective?
Desirable level of total cholesterol < 200
Desirable level of LDL cholesterol < 100
At levels greater than 240 of HDL becomes cardioprotective
