atherosclerosis Flashcards
does the risk for atherosclerosis increase or decrease with age?
risk increases with age
is atherosclerosis more prevalent in males or females?
why?
more prevalent in males bc estrogen protects against atherosclerosis (usually catch up after menopause)
what are genetic risk factors for atherosclerosis?
- inherited mutations can lead to increased predisposition
- e.g. mutation in LDL receptors leads to accumulation in cholesterol
what are risk factors for atherosclerosis associated with family history?
can be multifactorial - based on inherited genes or other factors
how does smoking effect the risk of atherosclerosis?
- can initate or accelerate the disease
- effects endothelial cells resulting in poor vascualr tone, increased vasoconstriction, oxidation and prothrombotic products
what is the effect of diabetes mellitus on atherosclerosis?
associated with increased endothelial dysfunction and lipid levels
what is the effect of hypertension on atherosclerosis?
accelerates development of atheromas
what is the effect of hyperlipidemia on atherosclerosis?
increases lipid level in blood increasing likelihood of plaque buildup
what is coronary artery disease and what is it caused by?
what can it lead to?
- most common cardiovascular disease
- casued by atherosclerosis
- can lead to chest pain, heart attack or death
what are the 3 characteristics of atherosclerosis?
- endothelial dysfunction
- vascular inflammation
- build-up of lipids, cholesterol, Ca and other cellular debris
define atherosclerosis
when build up of plaque clogs the arteries
what is the contemporary theory for the pathology of atherosclerosis?
give a general explanation for this theory.
- response-to-injury hypothesis
- states: atherosclerosis develops as healing response to endothelial injury
- thus, endo dysfuntion is the critical triggering event
what can cause endothelial dysfunction?
hemodynamic forces, hyperlipidemia,
hypertension, smoking, toxins, viruses, etc.
what happens once vascular endothelial cells are damaged? (explain altherosclerosis in detail)
- blood contents enter intima of bv
- LDLs and VDLs are oxidized, monocytes are transformed into macrophages
- sm cells in tunica media migrate to intima and (w macrophages) engulf LDLs of foam cells
- engulfing progresses forming an atherosclerotic cap
- fatty streaks form and progress
- eventually the complete plaque is formed (now called atheromatus plaque)
- there’s progressive accumulation of lipids within the tunica intima and plaque grows
what is the first visual manifestation of atheroscleoris?
formation of fatty acid streaks
is an atheromatus plaque stable? can it progress?
- clinically stable (not thrombus prone)
- can progress to structurally unstable (thrombus prone)
progression of atherosclerosis (when do symptoms start)?
- earliest event = plaque grows and begins closing off vessel (still symptomless)
- if builds slowly - once occlusion = 75% now critical and symptoms show (usually chest pain)
- if acute change in plaque (usually thrombus superimposed on plaque) - symptoms show
- once the plaque is severe the patient is subject to major complications (heart attack, aneurism)
fully formed plaque will be composed of:
necrotic tissue at the center and a fibrous cap
compare healthy vs atherosclerotic cardiac muscle cells
- healthy = striated with nuceli and intercalated discs
- atherosclerotic = dying (coloured spots through the muscle shown as result of imflammatory cells recruited to contain the necrotic tissue)
what is the clinical presentation of atherosclerotic plaque development leading to blood clot formation?
(1) early lesion (endo damage) - no symptoms
(2) plaque growth (damages inner wall of bv, fatty deposits accumulate narrowing arteries) - mild symptoms
(3) plaque ruptutes - spills cholesterol, etc. into bloodstream
(4) causes clot to form and block blood flow to specific part of body
hyperlidemia increases the risk of what stage of atherosclerotic development?
plaque growth
define cardiac tamponade.
is it considered a medical emergency?
- accumulation of fluid in the pericardial sac
- compresses heart muscle and blood flow
- medical emergency
state the 2 hemodynamic forces and explain how they can influence atherosclerosis
(mechanical forces exerted by blood flow)
(1) pressure: acts perpendicular to vessel wall & affects vascular sm cells
(2) shear stress: acts parallel to vessel walls (exherted longitudinally in direction of bf) & affects endo cells
- influenced by type of blood flow
- both forces can damage artery walls leading to atherosclerosis
explain laminar blood flow and how it is related to atherosclerosis
- normal condition of blood flow
- research has shown laminar slow induces endo cells to express genes that protect against atherosclerosis
explain turbulent blood flow and how it is related to atherosclerosis
- laminar blood flow can become turbulent in aterial curves or at branches
- now have incresed shear stress
- blood can swirl around and cause dysfunction in the endo cells or contribute to the accumulation of fats - leading to atherosclerosis
explain observable changes in endothelial cell morphology when exposed to physiological shear stress (>15 dynes/cm^2)
- cells are elongated and aligned to the direction of blood flow
- do this to increase the aerodynamics of their shape
- minimizes interference with vessel components
explain observable changes in endothelial cell morphology when exposed to low arterial l shear stress (0-1 dynes/cm^2)
-cells have a cobblestone appearance
explain the regulatory features of laminar sheer stress
- endothelial cells express genes like KFL2 or Nrf2
- act in a protective manner & help inhibit the expression of NFkB (pro-inflammatory transcription factor)
- blocks oxidative stress/inflammatory pathways
- limits thrombosis
explain the regulatory features of turbulent sheer stress
- expression of protective genes is lost
- NFkB is upregulated to create a pro-inflammatory environment in bvs
- allows recruitment of monocytes & macrophages to initate plaque formation
- also enables sm cells to proliferate
compare quiescent phenotypes (laminar) to activated phenotypes (turbulent) of coagulation factors
- quiescent: increased PGL2, NO, tPA and decreased platelet aggregation
- activated: decreased PGL2, NO, tPA and increased platelet aggregation
compare quiescent phenotypes (laminar) to activated phenotypes (turbulent) of endothelium
- quiescent: decreased proliferation, apoptosis and increased alignment
- activated: increase proliferation, apoptosis and decreased alignment
compare quiescent phenotypes (laminar) to activated phenotypes (turbulent) of the inflammatory state
- quiescent: decreased sm proliferation and leukocyte adhesion (anti-inflamm)
- activated: increased sm proliferation and leukocyte adhesion (pro-inflamm)
what are xanthomas? where are they found?
- cholesterol deposits under the skin
- found in joints, eyelids & ankle tendons
what are lipoproteins used for?
the trandport of lipids in the blood plasma
what are 4 lipoproteins and what do they do?
(1) CMs (least dense) carry triglycerides from intestine to tissues
(2) VLDLs deliver triglycerides to cells
- converted into intermediary IDL
(3) LDLs main transporter of cholesterol to tissues
- synthesized from VLDL/IDLs
(4) HDLs (most dense) mediator of reverse cholesterol transport
explain the process of reverse cholesterol transport
- diet absorbed and transformed into triglycerides & cholesterol
- CM/VLDLs transport to fat cells
- synthesized into LDLs - used for bodily functions
- HDL associates with cholesterol released by LDL and transports it back to the liver
how does HDL mediate reverse cholesterol transport (2)
(1) direclty binds and deposits cholesterol into liver
(2) interacts with VLDL/LDL causing them to deposit their cholesterol in the liver
how do lipids influence atherosclerosis?
- dysfunctional endo cells mediate adhesion/migration of leukocytes with VCAM-1 receptor
- increased lipids promotes increased expression of VCAM-1
- suggests hyperlipidemia promotes atherosclerosis through leukocyte adhesion
- also excess lipids in blood reduces blood flow (more viscous)
define primary hyperlipidemia
- result of a genetic disorder
- e.g. gene mutation or receptor protein defects
define secondary hyperlipidemia
- acquired - usually as a result of environmental influences or existing health condition
- e.g. diabetes, hyperthyroidism, pancreatitis
- diet rich in sugar/fat increases risk
explain treatment approaches for hyperlipidemia
- life-style changes (exercise)
- modified diet
- statins (drug)
explain how statins work (2 fronts)
- lower cholesterol levels by inhibiting cholesterol biosyntesis at the liver by increasing expression of LDL receptors
- also increase KLF2 expression
