Inflammation And CAD Flashcards
Inflammation contributes to what heart disease
Atherosclerosis (Coronary, cerebral, Peripheral vascular disease)
5x higher risk when you reach 40yo-60yo
Atherosclerosis risk factors that are non changeable
- XY
- Genetics
- Age
- FH
Atherosclerosis risk factors that are changeable
- Hyperlipidemia
- HTN
- Diabetes
- Obesity
- Chronic inflammation
- Smoking
- VIT deficiency (B6)*
- Sedentary lifestyle
5 stages of Atherosclerosis happening
- Chronic endothelial injury (from any risk factor, toxins, virus)
- Endothelial Dysfunction: increased permeability of leukocytes
- Macrophages are activated (SM is recruited)
- M and SM trap lipids
- SM proliferates (ECM has lipids and grows)
What does the endothelial injury cause
Usually from risk factors
It causes chronic inflammation to repair the tissue
* most common from HTN and hyperlipidemia
Where does atherosclerosis happen most likely
Opening of exiting vessels, branch points, and posterior abd aorta
= these locations have flow disturbances (HEMODYNAMIC TURBULENCE)**
Endothelial Dysfunction is when
There is a chronic injury due to risk factor present
——> permanent permeability increased for leukocytes, monocytes
= inflammatory response
Stage 1 injury to endothelium causes what
Endothelium altered and expresses adhesion molecules, pro inflammatory cytokines, procoagulators
= initiates thrombus formation , atherosclerosis, vascular lesions
Basal endothelial cells
Non-thrombogenic, keeps blood fluid
Mediate SM to increase resistance
SM in vessels
Vascular repair and atherosclerosis
Can proliferate and make collagen, cytokines
Dilate and constrict vessels
What do IL-1 and TNF do
Increase P and E selectins on endothelium
Increase ligand on leukocytes
(Rolling of leukocytes)=slows them so they can attach, cluster and flatten to cross the endothelium
= large inflammation in ECM (IL-6 and IL1 and TNF, brings pro inflammatory)
Long term increase in IL 1 and TNF causes
Increased dilation = increased turbulence in the vessels
Brings proteins close to the damaged organs
Which proteins are brought to the sight of damaged organ
- Clotting protein
- Complement proteins
- Kinin cascade (dilation, increase permeability, pain receptors)
- Fibrinolytic protein (degrade clot when wound is healed)
What happens when the endothelium dysfunction has happened for a while
Macrophages enter the area causing SM thickening
Circulating lipids do what at these inflammed sites
They deposited in intima and phagocyted by M and modified
* modified to toxic LDL incident the M and SM cells
= stimulation of foam cells in these lesions ——> FATTY STREAK
Atheroma
Atheromatous ——> atherosclerotic plaques
What are CD36 scavenger receptors
M and monocytes have these to OXIDIZE LDL
Can also happen when binding to TLR4
Oxidization of LDL has what types of cells
M1, IL1, IL6, CRP, Fibrinogen, Serum Amyloid A, C protein, plasminogen
M2 is in the plaques
Inflammasome
Foam cells and cholesterol crystals form these when LDL is present and is oxidized
They make IL1, IL8 = INFLAMMATION
Neutrophils NETosis
They release their NETs that provide platelets scaffolding, RBC activation, thrombosis
Also stimulates the M
Inflammation at the foam cells and NETosis site causes what
SM cells recruitment and proliferation that make COLLAGEN (ECM)
What stimulates SM proliferation
PDGF
FGF
TGF-a
SM can also (lipids)
Phagocytosis LDL
T cells effect on atherosclerosis
T cells are presented to the modified LDL by M and DCs
——> vascular inflammation
INF-gamma does what
Activated Macrophages
Mediators for adaptive immune system activated by the modified LDL and inflammation in vasculature
TH1, TH17, B cells
IFN-g, TNF-a , IL-17
(Adhesion molecules, cytokines, macrophage activation, uptake of oxLDL, HLAll presentation of Ag) = FATTY STREAKS
Fatty streaks happen how
Foam cells, ECM Lipids, inflammation, SM cells
Atherosclerotic plaque is what
Dense collagen (FIBROUS CAP) over the fatty streak Inside is SM and lipids, foam cells, thrombus, calcium = necrotic*
3 ways fatty streaks can become symptomatic
- Aneurysm and rupture of vessel
- Thrombus occlusion as plaque ruptures inside the vessel
- Plaque grows until critical stenosis of the vessel
What are some things that can cause plaque rupture
Increased inflammation can degrade the fibrous collagen cap
Calcification
Physical stress (vasoconstriction and BP change)
Low amount of SM
White thrombus
Erosion thrombosis
= goes away because BF
(thick fibrous cap, SM prominent, N NETs involved, high platelets)
Red Thrombus
Thrombosis form rupture
= has lipid core
= thin cap, many M, remodeled a lot
RISK FACTORS: Inflammatory markers
HSCRP (High sensitivity C-reactive Protein)
Serum Amyloid A
*not specific
RISK FACTORS: Pro-coagulant markers
Plasma Homocysteine
Tissue plasminogen
Plasminogen activator inhibitor
*not specific
RISK FACTORS: Process markers
Fibrinogen
TX that you should do for Atherosclerosis
Non-specific
Steroids (increase adverse events)
NSAIDS (destabilize plaques)
TX you should not fo for Atherosclerosis
Selective inhibitor
COX2 inhibitor (Vioxx)= increase in CVD mortality
TX of Atherosclerosis
AB against IL-1B
- IL-1B drives atherosclerosis (by making HSCRP)
- ACZ885 canakinumab blocks this pathway
STUDY on Canakinumab (anti-thrombosis)
Study showed that the drug in high and medium does decreased HSCRP, IL-6
No change in LDL
Decreases the mortality rate of each participant in these dosages
CIRT study
Looking at Low dose METHOTREXATE
= no reduction in HSCRP, IL1, IL6 or mortality form CV event
*CANTOS study on IL-1B inhibitor had more of a significance
Reason IL-1B inhibitor is not used
Not a significant difference in all mortality causes
And also expensive
Highly more risk of infection
Future plan to help CVD
Vaccination against B-cells and T-cells for oxLDL
CRISPR technology
