Unit 2 Day 5 (Mon 4/13) Flashcards
CVD Prevalence
- inc. with age
- initially most common in men, but as age inc. it becomes more common in women
Steps in Atherosclerotic Process
- LDL infiltrates into sub endothelial space
- LDL is oxidized
- release of inflammatory cytokines and inc. expression of adhesion molecules
- monocytes recruited to clean up oxidized LDL
- phagocytosis of LDL leads to foam cell formation
- foam cells and T lymphocytes within plaque secrete MMP
- secretion and activation of tissue factors
- plaque rupture occurs in unstable lesions, leading to vessel thrombosis and acute coronary events
Lipid Metabolism- Exogenous
- dietary
- processed into chylomicrons (E, C2, B48)
- LPL removes triglycerides from chylomicrons = remnant
- remnant binds to remnant receptor on liver
- taken up by liver and cleared from body
Lipid Metabolism- Endogenous
- VLDL particles made by liver (proteins E, C2, B100)
- LPL removes triglycerids from VLDL to form smaller IDL
- IDL exposed to more LPL eventually forms LDL with only B100 protein
- LDL binds LDL receptor on liver
Statins
-upregulate LDL receptor on liver to dec. LDL in bloodstream
HDL
- removes cholesterol and replace with triglycerides
- CTP protein lowers HDL levels
- tries to remove cholesterol from body
- HDL is good
- under chronic inflammatory state, HDL may be no longer effective
Current Guidelines for Treating Blood Cholesterol
- 4 major statin benefit groups
- individuals with known clinical ASCVD
- individuals with LDL >190 mg/dl
- individuals with diabetes (>40 yo and LDL >70)
- individuals (>40, LDL>70) w/o ASCVD or diabetes who have est. 10 yr ASCVD risk >7.5%
Hypertiglyceridemia
- associated with acute pancreatitis
- unclear whether lowering TG is beneficial
Why is inflammation implicated in atherogenesis?
- evolution of host response to bacterial infection inc. risk of sterile inflammation
- PAMPs
- DAMPs (oxidized LDL, cholesterol crystals)
- innate immune cell interaction with endothelium drives initial plaque formation
Monocyte Adhesion
- VCAM1 on endothelium binds to CD11c and VLA4 on monocyte (oxidized LDL promotes expression of VCAM)
- adhesion is obligate step in atherosclerosis
- knocking out VLA-4 and CD 11c inhibits monocyte adhesion and limits atherosclerosis
Adaptive Immunity in Atherogenesis
- dendritic cell presentation and subsequent T cell activation promotes T cell expansion
- Th1 response promotes IFNg elaboration and atherosclerosis
- Th17 may promote plaque instability
- T cells promote lesions expansion and plaque vulnerability
Major Drivers of Plaque Instability
- Macrophage apoptosis and necrosis promotes a “necrotic core”
- Matrix metalloproteinases degrade the fibrous cap (secreted by macrophages)
- Intra-plaque hemorrhage further weakens core
C Reactive Protein
- possibly expressed by macrophages and smooth muscle cells
- activates classical complement pathway
- high CRP-high LDL combined leads to dec. probability of event-free survival
- predicts excess risk of CV events after accounting for standard risk factors
Role of Inflammation and Atherosclerosis
- impaired HDL efflux capacity associated with more psoriasis
- also related to RA
- inc. monocyte/macrophage activation: common mechanism underlying many autoimmune diseases
- tx of autoimmune disease may be associated with lower risk of CV events
Prevalence of Peripheral Vascular Disease and Risk Factors
- adult prevalence = 10-20%
- risk factors: diabetes, smoking, lipids, hypertension
- PAD has 6x inc. risk of CV death
Arterial Dynamics in PAD
- radius decreases
- flow rate inc. at stenosis and becomes turbulant
- however flow dec. relative to normal people in response to exercise
- blood viscosity inc.?
Risk Factors for Abdominal Aortic Aneurysm
4 Major Risk Factors
- age
- gender (worse in men)
- smoking
- family history
Risk of AAA Rupture in Relation to Size (diameter 5.0-
AAA diameter of 5-5.9 has a 25% 5 year rupture rate
Key Risk Factors that Initiate Aortic Dissection
- hypertension (drugs ex. cocaine)
- inherited disorders of connective tissues (marfan, ehlers danlos)
- bicuspid aortic valve
- coarctation
- pregnancy
- aortitis
- iatrogenic (surgery, arterial catheterization)
- trauma
Clinical Consequences of Aortic Dissection
- present with sever, tearing pain
- stroke (carotid)
- syncope (vertebral)
- myocardial infarction (coronary)
- intestinal ischemia (mesenteric vessels)
- renal failure (renal arteries)
Virchow’s Triad
- abnormal flow (stasis)
- injury
- coagulation factors
- all of these can lead to thrombus
Heparin
- parenteral
- directly binds antithrombin III, thus indirectly inhibiting factors II (thombin) and X
- factor Xa inhibitor
Warfarin
- oral
- inhibits vitamin K dependent cofactors (II, VII, IX, X)
Relationship between depression, cardiovascular disease (CVD) risk, and cardiovascular disease (CVD) outcomes.
- depression predicts incident of CV disease
- depression inc. risk of CAD by 1.5-2 times in otherwise physically healthy individuals
- depression predicts mortality after acute coronary syndrome
- “dose response relationship”
Biologic and Behavioral Relationship Between Depression and CVD
- autonomic dysfunction
- elevated cortisol
- platelet activation
- endothelial dysfunction
- inflammation
- defective serotonin signaling ultimately leads to inc. platelet activation (unifying hypothesis)
- behavioral mechanisms: physical inactivity, lack of med adherence, lack of lifestyle changes, lack of self-management, lack of recommended testing, lack of follow up
Screening and Treatment Strategies for Depression in CVD
- screening: two question screen, pt health questionnaire
- tx: SSRIs, bupropion, cognitive behavior therapy, exercise training
- tx must be coupled with education about expectations, structured follow up, dose adjustment, and additional health care if needed
ankle-brachial index
- BPs from these locations should have 1:1 ratio
- ratio
Critical Leg Ischemia
- severe PAD
- may have ulcers
- blanches if elevated
- dependent rubor
