1
Q
What is atherosclerosis?
A
- The most common form of arteriosclerosis.
- A narrowing and hardening of arteries due to intimal atheromas
- Atherosclerotic plaque
2
Q
What vessels are most affected by atherosclerosis?
A
- Abdominal aorta
- Coronary arteries
- Popliteal arteries
- Carotid arteries
- Vessels of the circle of Willis
3
Q
What are the contents of a plaque in atherosclerosis?
A
- Fibrous cap
- Lipid Core/Necrotic center
- Cell debris, cholesterol or foam cells, Ca2+) - Media
4
Q
What factors can induce chronic endothelial “injury” that leads to atherosclerosis progression?
A
- Hypertension
- Hyperlipidemia
- Smoking
- Toxins
- Viruses
- Immune reactions
Doesn’t have to be a tearing of the endothelium
5
Q
What are the steps of atherosclerosis progression?
A
- Chronic endothelial “injury”
- Endothelial dysfunction. Monocyte adhesion and emigration.
- Macrophage activation. SM recruitment. Cytokines recruit other lymphocytes.
- Leukocytes and SM cells engulf lipid.
* Hyperlipidemia is likely a primary player in etiology* - SM proliferation. Collagen and EC lipid deposition (complicated plaque)
6
Q
How are atherosclerosis and BP related?
A
High BP damaged the endothelium and activates inflammation.
- Promotes turbulent flow in a BV
- Turbulent flow is evident in areas of branching or constriction of the BV
- Turbulent flow damages the endothelium
- Endothelial damage increaseslikelihood of cholesterol invasion/clot formation
7
Q
What are the two categories of major risk factors of atherosclerosis?
A
Non-modifiable
- Age
- Gender
- Genetics
Modifiable
- Lifestyle
- Smoking
- Diabetes
- Inflammation
8
Q
What are complications of atherosclerosis?
A
- Stenosis
- Thrombosis/embolus
- Aneurysm
- Calcification
9
Q
What modification is necessary for cholesterol to be pathogenic?
A
Oxidation
10
Q
Does cholesterol have any impact on heart disease or mortality?
A
Very little
11
Q
Two LDL cholesterol patterns/types?
A
A type
- Large, less dense
B type
- Small, more dense
12
Q
Which LDL cholesterol type penetrates endothelium more easily?
A
B type
13
Q
What are risk factors for pattern B cholesterol?
A
Genetics
Oral contraceptives
Diet
14
Q
What kind of diet can induce LDL type B expression?
A
Low fat, high carb
-Can therefore increase heart disease
15
Q
How can we measure LDL-B cholesterol?
A
LDL-S3 GGE test to measure the diameter of the LDL
16
Q
What is a good surrogate to measure LDL-B in the absence of LDL-B measurements? What should the ideal value be?
A
TG:HDL ratio (
17
Q
Do low fat diets increase or decrease heart disease risk for some?
A
Increase; increased dietary fat improved every lipid blood marker
18
Q
Does promoting a high fat diet affect LDL particle size? And if so, how?
A
Increases diameter of LDL particle
19
Q
Does sugar affect LDL size? And if so, how?
A
Decreases diameter
Sugar also impairs glucose and lipid metabolism
20
Q
What enzyme mediates the conversion of O2 to H2O2?
A
Superoxide dismutase
21
Q
What enzymes convert H2O2 into H2O? Which is most important?
A
Glutathione (GSH)
Catalase
GSH is most important
22
Q
What happens if you don’t have enough GSH?
A
If you don’t have enough GSH due to excess oxidative stress, you have HO- free radicals floating around that can oxidize LDLs, making them pathogenic
23
Q
T/F? Antioxidant therapy reduces atherosclerosis development?
A
True.
People with CAD have reduced antioxidant capacity
24
Q
What is one way that we can increase antioxidant mechanisms?
A
Exercising
Keto diet increases GSH
25
What enzyme is a key regulator of cholesterol production?
HMG CoA Reductase
26
What two hormones affect cholesterol absorption?
Glucagon
| Insulin
27
What is the effect on cholesterol absorption when insulin is high?
Increased absorption
| Insulin activates HMG CoA Reductase, increasing cholesterol
28
What is the effect on cholesterol absorption when glucagon is high?
Decreased absorption
29
What are statins? What do they do?
HMG CoA Reductase Inhibitors
Prolong life in those with a h/o CV event, but they provide very little primary protection
30
What are some adverse side effects of statins?
Increased risk of adverse events - 40%
- Increased risk of diabetes
- -- T2DM increased by 50%
- Kidney failure
- Liver failure
- Muscle pain
- -- Rhabdomyolysis may be b/c of reduced ubiquinone (Coenzyme Q10)
31
What effects does reduced ubiquinone (Coenzyme Q10) manifest? How can you tx this?
- Rhabomyolysis
- Myopathy (muscle weakness and pain)
- Reduced mitochondrial function
- Cataracts
CoQ10 supplementation
32
What is the effect of oxidative stress on the ETC?
Reduced ubiquinone (CoQ10) and superoxide stress blocks the flux of electrons to Complex III because CoQ10 shuttles electrons from Complex I to III
33
What is IMT? Can it indicate plaque size?
Intima Media Thickness; Yes
Statins have no effect on IMT
34
What is the effect of statins on atherosclerotic plaques and LDL diameter?
No effect
35
What is the most cost
| effective preventative tx for coronary heart disease?
Aspirin
- 1/5 the cost
- Better potential tx for atherosclerosis than statin or just as good
- Helps keep the platelets "slippery"
36
Why is cholesterol important?
- Cell membranes
- Steroid synthesis
- Bile salts
- Vitamin D
- Ubiquinone
37
What does data suggest about statins and cholesterol?
- Statins reduce risk of a re-occurring CV event
- Statins are not effective at primary prevention
- Statins do not reduce overall mortality
- Stains may elicit significant side effects
38
Atherosclerosis development steps
1. LDL-B enters through the endothelium
2. LDL-B is oxidized (from ROS)
3. Oxidized LDL-B attracts macrophages
4. Macrophages become lipid laden and turn into "foam cells"
5. Foam cells accumulate and induce inflammation
6. Plaque consists of foam cells and WBCs
39
What are the different types and causes of hypertension?
Benign
- Essential (95% of cases)
- Secondary
Malignant
40
What are the two types of benign hypertension and the causes of each?
1. Essential
- AKA Primary HTN
- Idiopathic
- Mix of genetic and environmental factors
- Erroneously assumed to result from weight gain
2. Secondary - if you know the cause
- Results from structural (aortic coarctation), renal (renal artery stenosis), endocrine defect (adrenocortical hyperfunction)
41
What does benign HTN increase the risk of?
- Atherogenesis
- Aortic dissection
- Stroke
42
What type of hypertension can cause small blood vessel disease?
Benign
43
Types of small BV diseases?
Hyaline arteriosclerosis
- Hyaline = glassy, pink appearance
- Usually an acellular, protenaceous material
Hyperplastic arteriosclerosis
- Concentric arteries
44
Malignant HTN. What does it usually accompany?
Lethal i n 1-2 years if untx'd
>200/120mmHg
- Renal failure
- Retinal hemorrhages
- Papilledema
45
What diseases can primary hypertension: insulin resistance give rise to?
1. RAAS dysfunction
2. Enhanced GF activity/Endothelial hypertrophy
3. SNS dysfunction
4. Dyslipidemia
5. Reduced nitric oxide
46
What is RAAS dysfunction, induced by primary HTN: insulin resistance?
Insulin increases kidney Na+ reabsorption
- Insulin increases aldosterone secretion
Slight increase in plasma insulin is capable of eliciting an antidiuretic effect
*If insulin is high, you'll have water retention
47
What is endothelial hypertrophy/enhanced GF activity, induced by primary HTN: insulin resistance?
Receptors for IGF-1 and insulin in capillary endothelial cells
- Vascular cells are responsive to insulin
- Hypertrophy of vascular wall = narrowing of vascular lumen
48
What is SNS dysfunction, induced by primary HTN: insulin resistance?
Insulin causes dose-related increase in NE release
| - Increase in pulse and BP
49
What is dyslipidemia, induced by primary HTN: insulin resistance?
- Reduced HDL
- Increased VLDL
- Increased LDL - pattern B
- Increased TG
50
What is decreased NO, induced by primary HTN: insulin resistance?
NO reduces BP
- Potent vasodilator
Insulin inhibits NO production
- Insulin resistant endothelial cells fail to release NO
- Insulin resistance, insulin can't induce NO-mediated vasodilation
51
What is the major pathogenic defect initiating the hypertensive process?
Insulin resistance
52
Salt sensitive HTN
Insulin resistance MIGHT explain salt sensitivity, but there may exist a distinct genetic component
53
What is DASH diet and what are its effects on HTN?
Diet low in refined carbs, high fruit/veg, low sodium
Decreases BP
54
What is an aneurysm?
Localized abnormal BV dilation
55
What are the two types of aneurysms?
True
- Involves all three layers
False
- Hole covered with hematoma because of tear in innermost layers
56
What is the most common aneurysm?
Abdominal aortic aneurysm.
| Males <50
57
What can cause aneurysms?
```
Atherosclerosis
Wall degeneration
Trauma
Congenital defects (ie Marfans)
Infection
Hypertension
```
58
What is aortic dissection?
Aortic wall tears and blood pours into wall
- HTN men, 40-60yo
- Sudden onset, severe pain
- Can rupture causing massive hemorrhage`
59
Three different types of aortic dissection
I. Originates in ascending aorta, propagates at least to the aortic arch and beyond it distally
II. Originates in ascending aorta and confined to ascending aorta
III. Originates in descending, rarely extends proximally, but does distally
60
What are two vasculitis diseases affecting large vessels?
Giant cell arteritis
| Takayasu arteritis
61
Giant-cell arteritis
Large vessel vasculitis.
*MOST COMMON*
Feature
- Chronic granulomatous inflammation of arteries in the head
- Accompanied by vague (fever) and/or localized (headache, vision loss) symptoms
Tx: Corticosteroids
Related diseases
- None
Summary
- >50
- Arteries in head
62
Takayasu arteritis
Large vessel vasculitis.
Feature
- Granulomatous inflammation of aortic arch
- Severe narrowing of major branches
- Ocular disturbances
Related diseases
- None
Summary
- F<40
- "Pulseless disease" - weakening of pulse in upper extremities
63
What are the two vasculitis diseases affecting medium vessels?
Polyarteritis nodosa
| Kawasaki disease
64
Polyarteritis nodosa
Medium vessel vasculitis.
Feature
- Necrotizing vasculitis throughout the body
- Fatal if untx'd, but steroids are curative
Related diseases
- Hep B Ag-Ab complexes
Summary
- Young adults
- Widespread - different stages can coexist in the same artery
65
Kawasaki disease
Medium vessel vasculitis.
Feature
- Possibly necrotizing
Related diseases
- None
Summary
- <4
- Coronary disease
- Lymph nodes
66
What are the three vasculitis diseases affecting small vessels?
Wegener granulomatosis
Churg-Strauss syndrome
Microscopic polyangitis
67
Wegener granulomatosis
Small vessel vasculitis.
Feature
- Lung granulomas and renal disease
- *Strawberry gingivitis*
- Palatal ulcerations
Related diseases
- Churg-Strauss - typically relates to allergies and asthma
Summary
- Lung, kidney
- c-ANCA
68
Churg-Strauss syndrome
Small vessel vasculitis.
Feature
- Vasculitis in lung
- Triad:
- -- Lung granulomas
- -- Renal disease
- -- Vasculitis
- Fatal if untx'd (within a year)
- Similar, but related to allergies and asthma without renal disease
- T-cell mediated hypersensitivity
Related diseases
- Wegener
Summary
- Lung
- Eosinophils
- Asthma
- p-ANCA, c-ANCA positive
69
Microscopic polyangitis
Small vessel vasculitis.
Feature
- Vasculitis in lung and kidney
- Widespread necrotizing vasculitis in smaller vessels
- Ab response to drug or bug
- Neutrophils heavily present in vessels
- Possble Type III hypersensitivity
- Removed offending agent usually resolves problem
Related diseases
- None
Summary
- Lung, kidney
- p-ANCA
70
Tumors
Hemangioma
Glomus tumor
Kaposi sarcoma
Angiosarcoma
71
Hemangioma
Common benign tumor of BV
72
What are the three types of hemangioma?
1. Capillary
- Skin, oral mucosa, sometimes organs
- "Strawberry" type present at birth, regresses
2. Cavernous
- Organs, sometimes skin
- Cosmetic problem, unless brain
3. Pyogenic
- Rapidly growing red nodule on skin, in mouth
- Microscopically resembles granulation tissue
73
Glomus tumor
- Benign but painful
- Arise from glomus body cells
- Distal digits, especially under fingernails
- Excise
74
Kaposi sarcoma
- Low grade malignancy of endothelial cells
- Four forms
1. Chronic
2. African
3. Transplant associated
4. AIDS associated
- Clinical course varies (chronic is best prognosis)
- Excise
75
Angiosarcoma
- High grade malignancy of endothelial cells
- Often in skin, soft tissue, breast, liver
- Arsenic and PVC increase risk
- Covers a spectrum from well-differentiated to anaplalstic
- Metastasize rapidly: 30% survival at 5 years
DMD 5247
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