04.07 - Atherosclerosis 1 and 2 (Nichols) Flashcards
5 major modifiable risk factors for atherosclerosis
Smoking, HTN, Obesity, DM, Dyslipidemia
___ causes 20-25% of fatal acute MI’s
Superficial erosion of coronary atheromata
2 most important causes of endothelial dysfunction
hemodynamic disturbances; Hypercholesterolemia
3 Characteristics of Endothelial Dysfunction
Impaired endothelium-dependent vasodilation, Hypercoagulable states, increased oxygen free radical production
3 Factors that maintain SM cells in quiescent state
Heparan, NO, TGF-alpha
3 Major components of ECM in plaque
Collagen, Elastic Fibers, Proteoglycans
95% of HTN is
Idiopathic (Essential HTN)
Action of Lp-PLA2
Travels with circulating LDL and Hydrolyzes oxidized phospholipids in LDL
Action of Products of Lp-PLA2 reaction generated in atherosclerotic lesions
Upregulate MCP-1, ICAM-1, and VCAM-1 on endothelial cells
Actions of Myocardial Natriuretic Peptides
Inhibit Na resorption –> Diuresis; Also systemic Vasodilation
Arteries v Veins: Which are more prone to penetration by tumors or inflammatory processes?
Veins
Arteriosclerosis literally definition
Hardening of arteries
Atheroscerlosis is characterized by
Presence of intimal lesions called Atheromas
Canakinumab
IL-1beta mab
Cause of Homozygous Familial Hypercholesterolemia
Defective LDL receptors and inadequate LDL uptake
Cause of Hyaline Arteriolosclerosis
Leakage of plasma components across injured endothelial cells; Increased ECM production by SM cells in response to chronic stress
Causes of Artery Amyloidosis (3)
Plasma Cell Dyscrasia; Chronic Systemic Inflammation (esp RA); Genetic (esp TTR)
Causes of Fibrinoid Necrosis (2)
Malignant HTN; Autoimmune Vasculitis, esp. PAN
Causes of Hyaline Arteriolosclerosis (2)
Benign HTN, DM
Causes of Hyperplastic Arteriolosclerosis (2)
Malignant HTN; Autoimmune: Scleroderma, Lupus
Cholesterol crystals contribute to development of atherosclerosis by activating
Inflammasome in Mac’s –> IL-1 production
Color of young vs old fibrosis
Young is clear, Old is dark pink
Complication of Fibromuscular Dysplasia in Renal Arteries
Renovascular HTN
Complications of Fibromuscular Dysplasia
Luminal Stenosis, Abnormal Vessel Spasm that reduces vascular flow
CRP levels strongly and independently predict risk of
MI, Stroke, PVD, SCD
CRP secreted by cells within atherosclerotic plaque can
activate endothelial cells –> increase adhesiveness and pro-thrombotic state
Cutoff for Malignant HTN
200/120
Darapladib
Small molecule inhibitor of Lp-PLA2
Determinants of Plaque Vulnerability
Thinness of Fibrous Cap; Size of Lipid Core; Amount of Inflammation, Amount of Calcification
Dominant lipids in atheromatous plaques
Cholesterol and Cholesterol Esters
Earliest atherosclerotic lesion is called
Fatty streak
Early human atherosclerotic lesions begin at sites of
intact, but dysfunctional, endothelium
Effect of Kinins and Prostaglandins on TPR
Both Decrease thru Vasodilation
Effect of Lp-PLA2 bioactive lipid products on macrophages
Upregulated MCP-1 –> Secrete IL-1beta and undergo apoptosis
Effect of MCP-1 on macrophages
Secrete IL-1b and Apoptosis
Extensive AV fistulas can cause
high-output cardiac failure
First 3 steps of Atherosclerosis
Malfunction of injured endothelial cells; Accumulation of lipid in intima; Leukocyte recruitment
Focal irregular thickening of the walls of medium-sized and large muscular arteries due to combo of medial and intimal hyperplasia
What is Fibromuscular Dysplasia
How does Ang II raise BP
(1) Vascular SM contraction; (2) stim aldosterone secretion; (3) Increase tubular Na resorption
How does obesity contribute to atherosclerosis
Pro-inflammatory, Pro-thrombotic
How does Thrombin initiate Inflammation
Cleaves PARs on leukocytes, endothelium, and other cells
How is LDL modified in Tunica Intima
Oxidized and Glycated
How is LDL taken up by macrophages
Not by LDL-R, but by a Scavenger Receptor
Hyaline Arteriolosclerosis in kidney leads to
Nephrosclerosis (Glomerular Scarring)
IL-1beta mab
Canakinumab
In general, plaque inflammation increases
Collagen degradation and reduces collagen synthesis –> Destabilizing cap
In malignant HTN, Hyperplastic Arteriolosclerosis changes are accompanied by
Fibrinoid Deposits and Vessel Wall Necrosis (necrotizing arteriolitis)
Injured endothelial cells secrete
IL-1 and TNFalpha
Injured endothelial cells secrete less
Superoxide Dismutase, NO, Prostacyclin
Last step of Atherosclerosis
ECM (wavy collagen) deposition
Major clinical consequences of Atherosclerosis
MI, Stroke, PVD, AA’s
Medial attenuation between focal segments of thickened wall prone to rupture
Fibromuscular Dysplasia
Monckeberg Medial Sclerosis is characterized by
Calcific deposits in muscular arteries (>50, do not encroach on lumen)
Morphology of Fatty Streaks
Yellow, flat, elongated, minimally raised
Most important determinant of stroke volume
Filling Pressure (regulated by sodium homeostasis)
Most important independent risk factor for atherosclerosis
Family History
Mutations in ENaC lead to
Increased distal tubular resorption of Na induced by Aldosterone
Neointimal vs Medial SM cells
Neointimal can’t contract; Do have capacity to divide and have great synthetic capacity
On its own, HTN can increase risk of IHD by __
60%
Plaques in individuals taking statins have
more fibrous character (resistant to rupture)
Problem with modified LDL being taken up by Scavenger Receptor
No feedback inhibition –> Take up too much
Result of upregulation of MCP-1, ICAM-1, and VCAM-1 on endothelial cells
Vasodilate less in response to NO and undergo apoptosis
Role of IFN gamma in plaques
Strongly inhibits SM cell production of collagen required to repair and maintain integrity of fibrous cap
Ruptured plaques tend to have (3 things)
Thin Cap, Large Lipid Core, Abundant Inflammatory Cells
Stereotypical response of vessel wall to any insult
Intimal thickening
Superficial erosion causes what percent of fatal acute MI
20-25%
T/F: Anti-Gout drugs can help atherosclerosis patients
True: Colchicine, 60% reduction of 3 year period
T/F: Intimal thickening is always pathologic
False, part of normal aging
T/F: Statins decrease the degree of stenosis as assessed on angiography
FALSE
T/F: Statins result in significant reductions in atheroma volume
FALSE
The pro-inflammatory role of Lp-PLA2 is mediated by
products of Lp-PLA2 reaction generated in athersclerotic lesions
Thin-walled arterial outpouchings in cerebral vessels
Berry Aneurysms
Top 3 most affected arteries with atherosclerosis
Infrareneal AA, Coronaries, Popliteals (Internal Carotids)
Triggering the inflammasome results in activation of enzyme called
Caspace-1 –> Cleaves Pro-IL1b to IL-1b
Two forms of small blood vessel disease that are HTN-related:
Hyaline Artiolosclerosis, Hyperplastic Arteriolosclerosis
Type of HTN associated with Hyaline Arteriolosclerosis
Benign/Mild
Up to ___ % of events due to atherosclerosis are from plaque rupture
75
What activates inflammasome in mac’s
Cholesterol Chrystals
What boosts production of interstitial collagenases in macrophages?
CD 40 ligand on T cells
What BP threshold is associated with increased risk of atherosclerosis
140/90
What causes renin release besides low pressure
Circulating Catecholamines, Low Sodium in Distal Convoluted Tubules
What does Aldosterone resorp and secrete
Resorb Na, Secrete K
What else beside IL-1 do Mac’s release
ROS –> LDL oxidation and growth factors that stimulate SM cell proliferation
What is Fibromuscular Dysplasia
Focal irregular thickening of the walls of medium-sized and large muscular arteries due to combo of medial and intimal hyperplasia
What is important about vasa vasorum formed in arteries that don’t normally have
Prone to rupture
What leads to conversion of Fatty Streak to Atheroma
Intimal SM cell proliferation and ECM deposition
What mediates pro-inflammatory role of Lp-PLA2
Bioactive lipid products of Lp-PLA2 rxn generated in athersclerotic lesions
What produces the MMPs implicating in degradating plaque collagen
Macrophages: MMP-1, MMP-8, MMP-13
What regulates Filling Pressure
Sodium Homeostasis
What T cell product is implicated in inhibiting the ability of SM cells to make new collage
Interferon Gamma
What upregulates expression of MCP-1, ICAM-1, and VCAM-1 on endothelial cells
Bioactive lipid products of Lp-PLA2 rxn generated in athersclerotic lesions
What women are protected against Atherosclerosis
Premenopausal
When can Hyaline Arteriolosclerosis be seen in absence of HTN
Old People; Diabetic Microangiopathy
When does Fibromuscular Dysplasia typically occur
Young women
When is there low sodium levels in distal convoluted renal tubules
When GFR falls (when CO low) –> Increased Na resorption by proximal tubules, lower levels more distally
Which come first in SHODDY
Smoking, then Obesity, then HTN
Why is inhibiting collagen production by SM cells bad in plaque
Collagen needed to maintain integrity of fibrous cap
With chronic hyperlipidemia, lipoproteins accumulate within intima, where they generate 2 pathogenic derivatives:
Oxidized LDL, Cholesterol Crystals
Without appropriate tx, 50% of HTN pts die of
IHD or CHF (another 1/3 of stroke)
