SM 126 Atherosclerosis Pathogenesis Flashcards
Where do lesions grow and what is the significance?
Lesions grow and expand at the periphery as more cells are recruited towards older cells that necrose and apoptose at the center
What changes make an atherosclerotic plaque “complicated”?
Dystrophic calcifications, fissure formation, and plauque rupture
These changes can cause a mature plaque to rupture
Where are atherosclerotic plaque derived thrombi most dangerous?
Small arteries such as those supplying the heart, which are easily totally occluded
Additionally, small arteries are less effectively cleared of clots by the fibrinolytic system
If a person survives a clot, fibrinolysis can clear the clot naturally
What is Canakinumab?
mAb against IL-1Beta leads to significant decrease in atherosclerotic cardiovascular disease in the CANTOS trial
Why do macrophages become foam cells?
They accumulate oxidized LDL via scavenger receptors faster than they can clear it
Describe the pathology of a mature lesion?
Firm what plaques below the endothelium which project into the vascular lumen and cause stenosis
Calcification is present, hardening the walls of the artery
How do macrophages clear oxidized LDL?
Oxidized lipid induce transcription factors that stimulate metabolizing enzymes
Eventually overwhelmed by high amounts of LDL
Why does Atherosclerosis occur in areas of turbulent flow?
Leukocytes can’t attach in arterial areas due to extremely fast blood flow, so turbulent areas allow for Luekocytes to attach and begin an inflammatory response
Why is a mature plaque rupture dangerous?
Rupturing of the fibrous cap exposes blood in the lumen to the material in the plaque, leading to thrombi formation
Thrombi can block arteries, especially small ones, and lead to fatal injury
What are the complications of Atherosclerosis?
CAAF = reasons people die
Calcification
Atheroembolism
Aneurysm formation
Fissuring/plaque hemorrhage = heart attack and stroke
What are the effects of increased Cholesterol in cells?
Inhibits HMG CoA Reductase to decrease Cholesterol synthesis
Activats ACAT to stimulate Cholesterol Storage
Decreases LDLR expression
What is Atherosclerosis?
A lifelong disease characterized by chronic inflammation
What are the common late stage manifestations of Athersclerosis?
MGAC
Myocardial Infarction
Cerebral Infarction
Abdominal Aortic Aneurysm
Gangrene of Extremities
Why does the fibrous cap of a plaque thin?
Release of MMPs by dying foam cells
What are the inflammatory stimuli in chronic inflammation leading to atherosclerosis?
DAMPs from necrotic foam cells and ApoB lipoproteins from high amounts of LDL
How are macrophage scavenger receptors effected by the presence of DAMP’s and Oxidized LDL?
They are not effected by the presence of DAMPs and Oxidized LDL; unlike the LDLR, they are not downregulated in the presence of high intracellular ligand, and as a result continually uptake substrate to toxic levels
How and where does atherosclerosis cause aneurysms?
Aneurysms = thinning of an arterial wall
Atherosclerosis causes weakening of the media of an artery, leading to thinning of the wall, most commonly in the abdominal aorta
What is the relationship between DAMPs and Oxidized LDL?
Both are physically similar and induce a similar pro-inflammatory response, and can be taken up by Macrophage Scavenger receptors
How long does it take for LDL to become an inflammatory stimuli?
LDL is converted into oxidized LDL in subintima over the period of decades
What are the risk factors for atherosclerosis and why?
DHOC = inflammatory conditions promote atherosclerosis
Diabetes = glycation of proteins activates scavenger receptors on macrophages
Hypertension = activated T cells secrete proinflammatory cytokines
Obesity = more fat
Cigarette smoke = ROS buildup
What is “secondary necrosis”?
Macrophages that become foam cells must be cleared by other macrophages, but this rarely happens
Release Damage Associated Molecular Patterns (DAMPs) which recruit more inflammatory cells and the growth of the lesion
What is the pathological appearance of an atherosclerotic plaque?
Plaque extends above the vessel and occludes the lumen, with thrombi formation occuring and large stenosis
What is a fatty streak?
A fatty streak is the earlier recognized lesion in the progression of Atherosclerosis, and consists of foam cells
May regress or progress into mature lesions, found in young people
How are smooth muscle cells recruited to fatty streaks?
Macrophages secrete the pro-inflammatory VEGF, which recruits smooth muscle to the area
Why does angiogenesis occur in plaque formation?
Inflammatory cells secrete angiogenic factors to try and restore blood flow, but ultimately the new vessels only make the develop plaque grow even larger and fail to save the tissue
What histopathological feature distinguishes a mature lesion?
A fibrous cap derived from collagen produced by smooth muscle cells
What effect does infection and autoimmune disease have on atherosclerosis?
They accelerate the progression of atherosclerosis by creating an inflammatory environment
How do changes in LDL mediate progression of Atherosclerosis?
LDL invasion of subintima can result in LDL accumulating
LDL can be oxidized over time and become pro-inflammatory stimuli for endothelial cells and APC’s like Macrophages
What type of immune response is involved in atherosclerosis?
Both innate (macrophages) and adaptive (T cells) are involved in Atherosclerosis
Knockouts in mice of proteins in both systems lead to reduced Atherosclerotic plaque development
What are the 3 layers of arteries?
Innermost to outermost:
Intima = innermost layer Media = vascular smooth muscle cells Adventitia = contains vaso venosus which provides nutrients
What layers of the vessels does Atherosclerosis effect?
Atherosclerosis initially effects subintimal potential space, a single area
After it induces a chronic inflammatory response, it affects all 3 layers
Why do statins have disproportionate protection against atherosclerosis?
Statins have anti-inflammatory as well as anti-lipid effects
Statins are good against atherosclerosis due to anti-inflammatory effect mostly
Describe the pathology of a fatty streak?
Small patches of yellow below the endothelium in artery cross sections, mostly normal
H&E stains show cells with clear cytoplasm = foam cells
How do mature lesions develop?
Develop from fatty streaks as a chronic inflammatory response in a fatty streak continues
Buildup of foam cells promotes migration and proliferation of smooth muscle, which secrete collagen and form a fibrous cap
Recruitment of cells outgrows metabolic supply, leading to central necrosis which stimulates more inflammation and recruitment of immune cells
Where does Atherosclerosis tend to occur?
Atherosclerosis occurs in large muscular and elastic areas at branch points, where non-laminar flow occurs
Does not occur in small arterioles or veins
Where does Atherosclerosis manifest?
Initially begins when LDL passively enters the arterial subintima, between the intima and the media of the arteries, and binds ECM
What are foam cells?
Macrophages that have become oversaturated with oxidized lipids
