ICL 3.7: Pathology of Atherosclerosis Flashcards
what are the 3 components of normal arteries?
- endothelial cells
- smooth muscle cells
- extracellular matrixes = elastin, collagen, glycosoaminoglycans
what are the 3 concentric laters of arteries?
- intima
single layer of endothelial cells, minimal subendothelial connective tissue
- media
smooth muscles (concentric layers), external elastic lamina, vasa vasorum
- adventitia
nerve fibers, vaso vasorum
what is the vascular wall’s response to injury?
intimal thickening!
trying to protect itself from further injury
what are some of the major risk factors for atherosclerosis?
- age
- male gender
- family history
- genetic abnormalities
how does gender effect atherosclerosis?
premenopausal, men are more likely
post-menopausal the women are at higher risk because they lose estrogen
in their 70s and 80s it’s the same risk
how does genetics effect atherosclerosis?
- diabets
- HTN
- familial hyperlipidemia
which hyperlipidemia are familial?
type 2 and 3
which factors can we control to limit atherosclerosis?
- HTN
- hyperlipidemia
- smoking
- DM
- CRP**
BUT 20% of cardiovascular events occur without HTN, smoking, hyperlipidemia or DM so what does that leave? CRP!! It’s a devil
what is hypercholesterolemia?
high serum cholesterol
high LDL delivers choleric to peripheral tissues!
HDL mobilizes cholesterol from the tissue and trsports it to the liver to be secreted in the bile
what is CRP?
it’s an acute phase reactant synthesized in the liver and is downstream of a number of inflammatory triggers
it plays a role in inflammation and inflammation is present in all stages of atherosclerosis
assessment of systemic inflammation has become an important factor in risk stratification
CRP is a great marker of inflammation and has become the most simple and most sensitive to assess the risk of ischemic heart disease
how does CRP play a role in the innate immune response?
- opsonizes bacteria
2. activates complement
what happens when CRP is secreted from cells within the intima?
- activates local endothelial cells –> inflammatory cascade starts and then when the leucocytes (specifically monocytes) they start to produce cytokines which again enhance the inflammatory cascade
- induces a prothrombotic state ):
- increases the adhesiveness of the endothelium to leucocytes
what does high sensitivity CRP predict the risk of?
- MI
- stroke
- sudden cardiac death
high sensitivity CRP is the same as CRP but it’s our technological ability to detect minute amounts of CRP – so even tiny amouts of CRP means they’re at a higher risk for these adverse effects!
what is hyperhomocystinemia?
elevated homocysteine
familial hyperhomocystinemia is associated with premature cardiovascular disease in teens and 20s
what can cause hyperhomocystinemia?
- low folate
2. low B12
what is metabolic syndrome?
- obesity
- HTN
- hyperlipdemia
- DM
what is lipoprotein a?
it’s an altered form of LDL
increased levels of it is associated with increased risk of coronary artery diseases and cerebrovascular diseases INDEPENDENT of total cholesterol and LDL levels!!!
what are the hidden evil spirits that can cause atherosclerosis?
- CRP
- hyperhomocystinemia
- obesity
- lipoprotein a
what levels of HTN put you at a higher risk of atherosclerosis?
BP higher than 160/95
BP lower than 140/90 has a lower incidence of atherosclerosis
how does DM put you at a higher risk of atherosclerosis?
DM induces hypercholesterolemia which increases the incidence of atherosclerosis
what happens when there’s endothelium injury?
increased adhesion molecule (VCAM1) is produced
VCAM1 attracts monocytes and they adhere to the endothelial
then monocytes migrate to the intimate and transform into macrophages and foam cells
macrophages start phagocytosis the lipids that we’ve been putting into our system and when they eat the lipids, the macrophages become foam cells
then platelets adhere and chemkines/cytokines are released from the macrophages, platelets and vascular cells which triggers inflammation
this leads to smooth muscle recruitment from the media to the intima and the smooth muscle proliferations and produced extracellular matrix!
what do macrophages do?
monocytes are initially protective via phagocytosis but then they generate chemokines and also produce growth factor which leads to smooth muscle proliferation
they also produce toxic oxygen spices leading to oxidation of LDL in the lesions
what is the initial cell in atherosclerotic lesions?
the foam cell that used to be a monocyte!!! aka macrophages
what is the initial trigger in atherosclerosis?
endothelial cell activation
what is the composition of the lesion seen in atherosclerosis?
it’s called an atheroma or fibrofatty plaque in the intima
it consists of:
1. cells including macrophages
- core of lipid intracellular and extracellular choelsterol
- fibrous cap of ECM including collagen elastic fibers
what happens to the smooth muscle in the arteries during atherosclerosis?
it migrates from the media to the intima and proliferates!
it also deposits ECM components and converts the fatty streaks to mature fibrofatty atheromas
this is initiated by PDGF released from the platelets adheres to the endothelial cells
how do atheromas evolve?
- early intimal plaque foam cells of macrophage and SMC origin
- advanced atheroma modified by SMCs synthesized collagen producing the fibrous cap –> fibrous caps are very dangerous because if the cap breaks off, it can become an embolism
- disruption of the fibrous CAP with superimposed thrombus –> serious clinical events
what is the big point in the pathology of atherosclerosis?
inflammation is the foundation of atherosclerosis!
what is the morphology of atherosclerosis?
atherosclerosis starts as fatty lipid streaks filled with foamy macrophages
the initial lesion is foam cells which are lipid filled macrophages
then there is intracellular lipid accumulation in other cells, not just macrophages
then there is formation of the fibrous cap
what are the plaques in atherosclerosis composed of?
- cells including smooth muscle cells, macrophages and T cells
- ECM
- intra and extracellular lipids
what is a fibroatheroma?
an atheroma with a fibrotic core and calcification
what are the complications that can be seen with atheromas?
- ulcerated atheromas
- thrombus formation
- hemorrhage
- aneurysmal dilation –> abdominal aorta! not the ascending aorta like with syphilis aortic regurgitation
Marfans or severe HTN will have dissecting aortic aneurism
a 55 year old baker is found to have a high sensitivity CRP on his routine annual checkup
blood glucose, lipid profile is normal, not a smoker, very active and exercise regularly
what is the meaning of the high sensitivity CRP and what else should be checked?
he’s at a higher risk of CVD and cerebrovascular disease
you need to check lipoprotein a levels!
fibrous CAP
made of ECM
LDL oxidation
CRP oxidizes LDL and triggers inflammatory cascade
what maintains the vascular permeability barrier?
endothelium
