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M2 Cardio > 11/2 Atherosclerosis - Corbett > Flashcards

11/2 Atherosclerosis - Corbett Flashcards

1
Q

atherosclerosis as a systemic disease

explain

A

atherosclerosis in one place (ex. coronary arteries) makes it very likely that it’s also present in other places (peripheral vasc, renal arteries, carotids, etc)

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2
Q

layers of elastic arteries

A
  1. TUNICA INTIMA
  • endothelial cells
  • basal lamina
  • internal elastic membrane
  1. TUNICA MEDIA
  • smooth muscle cells
  • elastin and collagen
  1. TUNICA ADVENTITIA
  • nerve fibers
  • blood vessels and veins (vasa vasorum)
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3
Q

layers of muscular arteries

A
  1. TUNICA INTIMA
  • endothelial cells
  • basal lamina
  • internal elastic membrane
  1. TUNICA MEDIA
  • smooth muscle cells
  • much less elastin and collagen
  1. TUNICA ADVENTITIA
  • nerve fibers
  • blood vessels and veins (vasa vasorum)
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4
Q

role of endothelial cells

4 toles

A

participate in structural and fx integrity of vasc wall

  • dynamically respond to flow (align in direction of flow)
  1. CONSTRICTION: endothelium-dependent vasodilatation
    • nitric oxide
    • prostacyclin
    • endothelin
  2. INFLAMMATION: modulation of immune response
    • resist WBC adhesion and attachment
  3. PROLIFERATION: antihypertrophic properties
    • inhibition of VSMC
    • proliferation and migration
  4. HEMOSTASIS/THROMBOSIS: anticoagulant, antithrombotic, profibrinolytic function
    • heparan sulfate
    • thrombomodulin
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5
Q

why does atherosclerosis occur?

where?

how? 5 major steps

A

doesn’t occur randomly → occurs at v specific sites

  • L and M size muscular arteries, at bifurcations, branch points, high curvature regions
    1. endothelial dysfx and/or injury
    2. lipoprotein entry and modification in subendothelial space
    3. inflammation
    4. leukocyte and SMC recruitment
    5. SMC proliferation and ECM deposition
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6
Q

arterial endothelial injury

two types

pathogenesis within each

(long slide)

A
  1. MECHANICAL arterial endothelial injury
  • “atherogenic” aterial blood flow patterns at branch points/direction changes
    • creates patterns of low flow, gradients, flow reversal
    • disturbed shears modulates gene expression → alters EC phenotype and behaviors

high laminar shear

  • low EC turnover
  • EC alignment
  • anti-infl genes
  • low permeability
  • low oxidative stress

disturbed shear

  • high EC turnover
  • poor EC alignment
  • infl genes
  • high permeability
  • oxidative stress

consider how hypertension makes this worse

  1. CHEMICAL arterial endothelial injury
  • dyslipidemia (high lipid in blood)
  • cigarette smoking (nicotine, oxidizing chemicals)
  • diabetes (glycation of EC proteins and lipoproteins)

all result in endothelial cell activation

  1. release of infl cytokines
  2. incr cell surface adhesion molecules (leukocyte recruitment)
  3. altered release of vasoactive substances (prostacyclin and NO decreased)
  4. ROS production
  5. prothrombotic
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7
Q

mechanical endothelial injury

what is it

high vs disturbed shear

A
  1. MECHANICAL arterial endothelial injury
  • “atherogenic” aterial blood flow patterns at branch points/direction changes
    • creates patterns of low flow, gradients, flow reversal
    • disturbed shears modulates gene expression → alters EC phenotype and behaviors

high laminar shear

  • low EC turnover
  • EC alignment
  • anti-infl genes
  • low permeability
  • low oxidative stress

disturbed shear

  • high EC turnover
  • poor EC alignment
  • infl genes
  • high permeability
  • oxidative stress

consider how hypertension makes this worse

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8
Q

chemical injury

A
  1. CHEMICAL arterial endothelial injury
  • dyslipidemia (high lipid in blood)
  • cigarette smoking (nicotine, oxidizing chemicals)
  • diabetes (glycation of EC proteins and lipoproteins)

all result in endothelial cell activation

  1. release of infl cytokines
  2. incr cell surface adhesion molecules (leukocyte recruitment)
  3. altered release of vasoactive substances (prostacyclin and NO decreased)
  4. ROS production
  5. prothrombotic
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9
Q
  1. lipoprotein entry/modification in subendothelial space
A

endothelial dysfx allows entry and modification of lipids in subendothelial space

evidence of lipoprotein deposition occurs early

  • areas of yellow discoloration on artery inner surface (as early as age 20)

high plasma LDL-C is central to the process of atherogenesis

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10
Q

lipoproteins summary

A

proteins that carry fats in the blood

  • lipid core (triglycerides and cholesterol esters)
  • phospholipids
  • free chol
  • apolipoproteins

LDL is key for us - contain cholesterol esters

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11
Q

exogenous pathway

chylomicron synthesis

A

exogenous pathway mechanism:

chylomicrons are synthesized in epithelial cells of small intestine using the lipids picked up from products of digestion

  • combination of: chol esters, phospholipids, lots of triglyceride, apoB48
    • apoB48 : truncated form of apoB100, does not gind to LDL-R
    • if you cant synthesize apoB proteins → abetalipoproteinemia (cant absorb or utilize chylomicrons, cant absorb dietary lipids)
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12
Q

exogenous pathway

fate of chylomicrons

A

chylomicrons are secreted into lymph → hit bloodstream, pick up apoC-II (cofactor for LPL)

lipoprotein lipase is activated by ApoC-II on the chylomicron surface

  • removes 80-90% of TAG in muscle and adipose tissue → making particles increasingly dense

chylomicron remnant undergoes apoE-mediated uptake by hepatocytes via any of the following

  • LDL receptor (B/E receptor)
  • LDL receptor related protein
  • heparan sulfate proteoglycans
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13
Q

endogenous triglyceride supply

hepatic pathway

what happens to VLDL remnants?

A

hepatic pathway

  • TG (60%) and cholesterol (25%) are released as VLDL with apoB100 attached
  • acquire apoE, apoC, and cholesterol esters from HDL
    • chol, via CETP
  • VLDL interacts with LPL to hydrolyze its TGs → FFA in periphery

what happens to VLDL remnants? (aka IDLs)

  • cleared by hepatic receptors that recognize apoE (apoB/E receptors; LRP)
  • remaining VLDL remnants are processed by hepatic triglyceride lipase and LPL to form LDL
    • remaining TG removed
    • apoE and apoC removed
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14
Q

LDL characteristics

A

contain largely one apoprotein: apoB100

high proportions of:

  • free cholesterol
  • cholesterol ester

plasma halflife = 3 days

recognized by LDL receptor (apoB/E)

  • recognition requires apoB100
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15
Q

LDLs and overflow pathway

A

LDLs represent the overflow pathway of the fuel transport system

  • too much fat? LDLs are what you’re left with, what gets processed and what hangs around for a while
  • bad interactions with the endothelium
    • small dense LDL are highly atherogenic (v high in cholesterol)
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16
Q

good cholesterol

A

HDL is the “good” chol

  • involved in reverse chol transport
  • can pick up excess cholesterol from peripheral cells by action of LCAT (lecithin-cholesterol acyl transferase), after which…
    • transferred to VLDL/IDL/LDL for transport to liver (via CEPT)
    • picked up by liver and steroid-hormone-producing tissues (via SR-B1 receptor)
17
Q

link between LDL and atherosclerosis

A

inherited disorders assoc with severe elevations in total and LDL cholesterol →→→ accelerated atherosclerosis!!!

18
Q

familial hypercholesterolemia

what is it?

etiology

homozygous vs heterozygous FH

A

accelerated atherosclerosis

  • autosomal dominant disorder
  • severe elevations in total chol and LDL-C
  • usually mutations:

1. LDL receptor mutation (93%)

  • 300+ mutations identified
    2. ApoB100 mutation (5%)
  • single mutation: inhibits binding of LDL to LDL-r
    3. PCSK9 mutation (2%)
  • gain-of-fx mutation: enhanced LDL-r degradation
    4. LDL adaptor protein mutations (autosomal recessive)

homozygous FH : severely elevated chol levels (total chol and LDLc levels > 600mg/dL); TAG levels are within normal limits

heterozygous FH : elevated LDLc levels commonly > 250mg/dL

  • 1 per 500 people worldwide
19
Q
  1. inflammation
  2. leukocyte recruitment
A

consequences of lipoprotein entry into vessel wall:

  • LDL particles are altered by infl processes → become oxidized and/or glycated
  • oxidized/altered particles are recognized by leukocytes (monocytes that extravasate at site of injury, become macrophages) and phagocytized →→→ FOAM CELLS, which are super-pro-inflammatory

inflammation → T cell recruitment & cellular activation

  • activated T cells release cytokines
  • other cells in arterial wall begin to be affected as well
20
Q
  1. SMC and ECM proliferation
A

recall: below the endothelium smooth muscle cells are embedded in the matrix (in both elastic and muscular arteries)

inflammation results in activation of SMC → migration into intima from the media (and poss from bloodstream as well)

  • followed by proliferation and ECM synthesis, which helps stabilize plaques with fibrous cover
21
Q

timeline of plaque formation

A

persistent inflammation → plaque disruption → vessel thrombosis

22
Q

CV risk factors

5 modifiable risk factors

3 nonmod risk factors

A

risk factors are multiplicative

modifiable risk factors

  • dyslipidemia (elevated LDL, decr HDL)
    • atherogenic diet (high in satfat, transfat, cholesterol)
    • exacerbated by obesity, sedentary lifestyle, alcohol use
  • tobacco use (2x)
  • HTN (6x)
    • risk increases continuously with progressively higher pressures
    • mechanical events and infl are increased
  • DM (2x)
    • metabolic syndrome
  • lack of phys activity

nonmodifiable risk factors

  • older age: MI risk goes up 4x from 40-60
  • male sex: premenopausal women somewhat protected
  • genetics/FH
    • first degree relative with CAD at young age (<55M, <65F)
23
Q

prevention of atherosclerosis

A

PRIMARY PREVENTION : delaying or preventing onset of atherosclerosis

  • pts have no evidence of vasc disease
  • use risk assessment tool to predict 10yr risk

SECONDARY PREVENTION : reliant on early detection of disease process and application of interventions to prevent progression of disease

24
Q

20% of cardiac events occur in absence of identifiable risk factors

how can we predict these???

A

use novel biomarkers

  • inflammation assoc with atherogenesis → C-reactive protein??
  • lipoprotein(a) levels
  • homocysteine
  • small dense LDL
  • coronary artery calcification index
25
Q

C-reactive protein

A

highly conserved protein that is an acute phase reactant

  • released from liver in response to inflammatory signals (ex. IL-6)
  • marker of infl associated with CAD
26
Q

lipoprotein (a)

A
  • similar to LDL
    • apoprotein that is linked to apoB100 by a disulfide bond
  • structurally related to plasminogen
    • competes with plasminogen
    • thrombogenic
  • size and concentration is genetically determined
    • not affected by diet or other factors

1.5-2x risk for CAD

27
Q

homocysteine

A

independent risk factor for CVD

homoCys-lowering interventions (Bvit interventions, etc) DID NOT significantly affect non-fatal/fatal MI

M2 Cardio (22 decks)

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