Atherosclerosis 1 Flashcards
arteriosclerosis - defined
*hardening or stiffening of arteries
atherosclerosis - defined
*specific type of arteriosclerosis in which CHOLESTEROL deposits and build-up contributes significantly to the hardening and stiffening of arteries
*most common form of arteriosclerosis
normal arterial histology
*arteries possess 3 layers:
-intima = lower bordering the lumen; contains the endothelium (innermost layer)
-media = contains smooth muscle cells and extra-cellular matrix; provides the contractile & elastic functions to the artery
-adventitia = outermost layer; contains connective tissue to stabilize the structure of the artery
*internal elastic membrane separates the intima from the media
*external elastic membrane separates the media from the adventitia
*recall: endothelium may produce nitric oxide to induce vasorelaxation
endothelial cells of arteries
*form a tight barrier
*prevent clotting under normal circumstances (express heparin sulfate, thrombomodulin, and plasminogen activator on their surface)
*oppose local inflammation (prevent leukocyte adhesion)
*produce nitric oxide to promote vasorelaxation
arterial smooth muscle cells
*normal contractile function (responsible for vasoconstriction)
*produce and maintain extra-cellular matrix
*contained within the MEDIA layer (small amount may be found in the intima)
*may produce inflammatory mediators, such as IL-6 and TNF, to initiate/respond to inflammation
transcytosis of LDL across the endothelial cells into the intima
*LDL cholesterol traveling in the bloodstream encounters endothelial cells along the blood vessel
*transport of LDL across the endothelial cell may be by receptor (scavenger receptor, ALK-1, SRB1, etc) or fluid-phase transport with non-receptor mediated vesicles
*process occurs both ways
*DRIVEN BY CONCENTRATION DIFFERENCE BETWEEN BLOOD & INTERSTITIUM, not necessarily by need
*if the endothelial cell needs LDL for its OWN purposes, it uses the LDL receptor
endothelial injury/dysfunction and progression to atherosclerosis (part 1)
- endothelial injury can occur due to low shear stress, high glucose, high lipids, high blood pressure, and environmental factors (ex. tobacco smoke)
- injury causes endothelial cells and smooth muscle cells to produce inflammatory mediators (IL-1, TNF, etc), “activating” the endothelial cells & SMCs
3a. activated endothelial cells have:
-INCREASED permeability, inflammatory cytokines, and leukocyte adhesion molecules
-DECREASED vasodilator substances (NO) and antithrombotic molecules
3b. activated SMC have:
-INCREASED inflammatory cytokines & extracellular matrix synthesis
-migration to intima and proliferation
how does shear stress cause vascular endothelial injury?
*in straight arteries, the blood travels in a normal laminar fashion, which causes high shear stress that leads to production of nitric oxide (a vasodilator) & superoxide dismutase (protects against ROS)
*in branched arteries, there is less shear stress, and therefore less nitric oxide & superoxide dismutase are produced
endothelial injury/dysfunction and progression to atherosclerosis (part 2)
- increased permeability of activated endothelial cells allows LDL particles to directly enter the intima through spaces between the endothelial cells
- LDL particles become oxidized in the intima by activated intima and SMC
- oxidized LDL particles bind to proteoglycans in the extracellular matrix, becoming trapped & increasing their time in the intima
[factors that contribute to LDL trapping: HTN increases ECM content; activated SMC increase ECM deposition; both lead to increased LDL trapping]
how does leukocyte recruitment by activated endothelial cells contribute to atherosclerosis?
- activated endothelial cells release MCP-1, which attracts monocytes into the subintimal space, and LAM (VCAM-1 and ICAM-1)
- monocytes become macrophages, and oxidize LDL to help attack them
- vicious cycle: oxidized LDL cells irritate intima and activate more endothelial cells & SMCs, which oxidize more LDL, which activates more, etc
- macrophages eat LDL particles to become FOAM CELLS
how do macrophages become foam cells?
*using scavenger receptors, macrophages phagocytize oxidized LDL particles
*LDL particles are broken down by lysosomes and stored as esterified fat droplets
*macrophages become foam cells as they become full of lipid particles
how do foam cells cause fatty streaks/atherosclerotic plaques?
*foam cells become engorged with LDL and get stuck in the emerging plaque
*the influx of new macrophages and proliferation of those already there means the emerging plaque continues to grow
*as numbers of foam cells increase, some undergo APOPTOSIS
*when they dies, they release cholesterol and proinflammatory mediators that further drive atherosclerotic plaque development
*clearance of dead foam cells becomes inefficient, promoting the accumulation of cellular debris and extracellular lipids, forming the lipid-rich center of the plaque (NECROTIC CORE)
fatty streaks and development into atheromas
*grossly, the first visual indication of atherosclerosis
*as long as the deposition remains in the intima, it constitutes a fatty streak
*initially, the fatty streak deposits in the wall and grows outward
*as it progresses, the fatty streak and subsequent atheroma will grow inward and start REDUCING INTIMAL SIZE
smooth muscle cell migration into the intima & progression of atheromas
- platelets translocate into the intimal space in response to inflammation
- foam cells, activated endothelium, and activated platelets produce platelet-derived growth factor that draws SMCs into the intima
- foam cells and other belligerents release cytokines that induce SMC proliferation, stimulating SMC to deposit ECM into the intima
- SMC in the intima deposit can phagocytize LDL particles and become QUASI-FOAM CELLS
fibrous cap formation
*migration of SMC into the intima form the fibrous cap (a collagen-rich barrier that helps to contain the necrotic core of the plaque) by EXTRACELLULAR MATRIX DEPOSITION
*recall: necrotic core contains contents of dead foam cells; necrotic core continues to release proinflammatory mediators and esterified cholesterols
stress in the emerging atheroma
*with increasing size and protrusion of the atheroma into the arterial lumen, mechanical stress focuses on the plaque border, abutting normal tissue (called the shoulder regions)
fibrous cap synthesis & degradation
*matrix metalloproteinases (MMP) break down the fibrous cap!!
*interferon inhibits production of collagen from SMC
*the BALANCE BETWEEN SYNTHESIS & DEGRADATION of the fibrous cap determines the nature of the cap (which can determine if and how someone presents with CAD)
“stable” plaques
*lesions with a THICK fibrous cap
*less likely to rupture!
*still can narrow the arterial lumen
“vulnerable” plaques
*lesions with THIN fibrous caps tend to be fragile
*MORE LIKELY TO RUPTURE & CAUSE THROMBOSIS
*less obstructive to blood flow
spectrum of fibrous caps
*in general, vulnerable plaques (thin cap) are more likely to rupture relative to stable plaques (thick cap)
*however, it is important to note that vulnerable plaques may never cause a clinical problem, and that some stable plaques may cause significant problems
plaque ruptures & progression
*when a plaque ruptures, blood and passing platelets are exposed to a significant amount of proinflammatory mediators
*when a plaque ruptures with limited thrombus formation, it leads to SMC proliferation to produce more ECM to plug up the rupture and reabsorb the thrombus
*results in a rapid, short-term PROGRESSION of plaque
*therefore, plaque rupture leads to stepwise progression of atherosclerosis
clinical events that may be associated with plaque rupture
- plaque rupture with thrombus, leading to complete occlusions (ex. STEMI)
- plaque rupture with thrombus, leading to significant partial occlusion (ex. non-ST elevation MI)
- plaque rupture with fixed obstruction from reabsorption of prior plaque ruptures
- plaque rupture with overlying thrombus that embolizes downstream (ex. stroke)
clinical event associated with plaque rupture: COMPLETE OCCLUSION (INFARCTION)
*complete occlusion from plaque rupture with thrombus which fills the lumen
*clinical examples:
1. acute myocardial infarction (STEMI)
2. thrombotic stroke
*note - only 2 vascular beds have plaque ruptures that completely occlude vessel with thrombus (CORONARY ARTERIES & INTRACRANIAL VESSELS)
clinical event associated with plaque rupture: PARTIAL OCCLUSION (infarction/ischemia)
*partial occlusion from plaque rupture with thrombus leading to either ischemia, infarction, or both depending on extent of flow limitation
*clinical examples:
1. acute myocardial infarction (non-ST segment elevation MI)
2. unstable angina (ischemia without infarction)
clinical event associated with plaque rupture: ISCHEMIA
*prior plaque rupture with thrombus that has been reabsorbed into a fixed plaque
*clinical examples:
1. stable angina
2. carotid artery disease
clinical event associated with plaque rupture: EMBOLISM
*plaque rupture with thrombus that embolizes
*clinical examples:
1. aorta (thrombus embolism to brain, kidney, intestines, legs)
2. carotid artery (embolizes to brain)
3. coronary artery (proximal thrombus can embolize to distal vessel)
*note - if you see an acute 100% occlusion in a non-coronary or a non-intracranial artery, it might be an embolism
risk of atherosclerosis - 2 determining factors
- LDL level
- CRP inflammation
*high LDL combined with high inflammation makes at high risk for atherosclerosis
plaque rupture vs. plaque erosion
*plaque rupture: thin, collagen-poor fibrous cap; large lipid core; many macrophages; fibrin-rich thrombus; causes vast majority of clinical events; RED thrombus
*plaque erosion: proteoglycan-rich atheroma; little or no lipid core; neutrophils; many SMCs; platelet-rich thrombus; less likely to lead to a complete occlusion (more likely a non-STEMI); causes vast minority of clinical events (more common in women & young people); WHITE thrombus
