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LSS Cadiovascular System > cardiovascular pathology > Flashcards

cardiovascular pathology Flashcards

atherosclerosis: explain the pathology, pathophysiology, and clinical features of atherosclerosis

1
Q

define atherosclerosis

A

outcome of a permanently activated endothelium, causing formation of plaques within walls of large arteries, potentially causing thrombosis or occlusion

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2
Q

modifiable risk factors of atherosclerosis

A

smoking, lipid intake, blood pressure, diabetes, obesity, sedentary lifestyle

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3
Q

non-modifiable risk factors of atherosclerosis

A

age, sex, genetic background

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4
Q

agents which activate endothelium in atherogenesis

A

smoking, viruses, toxins, mechanical stress (turbulent flow), inflammation, hypertension, OxLDL (carried to arteries), high glucose (diabetes), ageing, oxidative stress, hypercholesterolaemia, sex hormonal imbalance

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5
Q

epidemiology of atherosclerosis

A

statins and antihypertensives mean obesity is driving factor

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6
Q

LDL structure

A

lipid monolayer and docking apolipoproteins, with cargo fat (triglycerides and cholesterol esters)

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7
Q

location of atherosclerosis

A

branch points of arteries

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8
Q

why does atherosclerosis occur at branch points

A

turbulent, not laminar, flow is present, so speed changes magnitude and direction

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9
Q

why does laminar flow not normally cause atherosclerosis (3)

A

activates KLF2/4 transcription factors to upregulate eNOS and anti-thrombotic and anti-inflammatory factors; also promotes nitric oxide production and inhibition of smooth muscle cell proliferation; downregulates DNA methyltransferases to allow continued demethylation of anti-atherotic gene promoter regions

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10
Q

why can turbulent flow cause atherosclerosis (6)

A

activates NK-kappaB for pro-inflammatory effects; upregulates DNMT to hypermethalate which repress anti-therotic genes; promotes coagulation, leukocyte adhesion, smooth muscle cell proliferation, endothelial apoptosis and reduced nitric oxide production

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11
Q

what are the 6 protective effects of nitric oxide on vascular endothelium

A

dilates blood vessels, reduces platelet activation, inhibits monocyte adhesion, reduces proliferation of smooth muscle cells in vessel wall, reduces release of superoxide radicals, reduces oxidation of LDL cholesterol (plaque)

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12
Q

how does blood flow regulate gene expression

A

transcription factors selectively activated by laminar (e.g. eNOS for NO production) or turbulent (e.g. NF-KB) flow

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13
Q

blood flow regulation of endothelial epigenetic pathways

A

mechanosensors sense blood flow and cause changes in transcription by regulating chromatin (epigenetic)

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14
Q

3 stages of pathogenesis of atherosclerosis

A

endothelial dysfunction, fatty streak formation, advanced complicated lesion formation

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15
Q

summary of endothelial dysfunction

A

endothelium in large vessels receive chronic stimuli of inflammation increase, increasing permeability and causing leukocyte accumulation under activated endothelium

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16
Q

summary of fatty streak formation

A

lipids get stuck under more permeable endothelium, binding to proteoglycans and becoming oxidised, before engulfment by macrophages, forming foam cells (fatty streaks)

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17
Q

summary of advanced complicated lesion formation

A

other chronic processes such as macrophage accumulation, necrosis, senescence and angiogenesis cause an advanced complicated lesion to form

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18
Q

what blood vessels does leukocyte recruitment occur in normaly vs in atherosclerosis

A

normally affects post-capillary venules by contact inhibition, but in atherosclerosis it affects large arteries, as all stimuli activate endothelium in wrong place

19
Q

define contact inhibition and how does this contribute to formation of endothelial junctions

A

when cells in monolayer touch they stop proliferating and enter senescence; when leukocytes need to enter tissue they squeeze through these junctions in capillaries, but this is not possible in thick arteries due to layers of smooth muscle

20
Q

what is the effect of increased endothelial permeability in major arteries

A

leakage of plasma proteins (including lipoproteins) through junctions into subendothelial space, as well as oedema

21
Q

leukocyte recruitment in atherosclerosis: effect on monocytes

A

monocytes stuck between endothelium and smooth wall mature into macrophages

22
Q

leukocyte recruitment in atherosclerosis: how do leukocytes pass through endothelium when there is an inflammatory trigger (captured by intra-vital microscopy)

A

leukocytes roll, but when inflammatory trigger become activated; adhesion molecules on surface bind to leukocytes and adhesion strengthens; leukocyte flattens and spreads out, then migrates through tight junctions in endothelium (para or transcellular)

23
Q

outcome and fate of lipoproteins entering endothelium

A

lipoprotein pass through endothelium and are oxidised; macrophages present in subendothelial space then consume the lipoproteins and become foam cells, forming a fatty streak

24
Q

subtypes of macrophage scavenger receptors

A

A and B

25
Q

macrophage scavenger receptor subtype A

A

CD204, bind oxLDL, dead cells and gram +ve bacteria to cause inflammation and destruction

26
Q

macrophage scavenger receptor subtype B

A

CD36, bind oxLDL, malaria parasites and dead cells for safe clearance and reverse cholesterol transport

27
Q

5 macrophage actions

A

generate free radicals to oxidise LDL, phagocytose modified lipoproteins, express cytokine mediators to recruit monocytes, express chemo-attractants and growth factors, express metalloproteinases

28
Q

macrophages that express cytokine mediators to recruit monocytes

A

chemokines attract monocytes, cytokines activate endothelial cell adhesion molecules

29
Q

macrophages that express chemo-attractants and growth factors

A

platelet-derived growth factor and transforming growth factor B for wound healing release complementary protein growth factors to recruit muscle cells and stimulate proliferation

30
Q

fate of macrophages and effect of metalloproteinases

A

die and release pools of fat, forming necrotic core which causes fibrous thickening - if insufficient, family of enzymes that activate each other by proteolysis to degrade collagen (need zinc), degrading wall of plaque

31
Q

outcome of ruptured plaque

A

fibrous cap becomes so thin that will break and rupture, allowing necrotic core to contact blood and cause thrombus formation

32
Q

characteristics of a vulnerable cap

A

large, soft, eccentric lipid-rich necrotic core with increased smooth muscle cell apoptosis, reduced muscle/collagen content, thin fibrous cap, infiltrate of activate macrophages expressing metalloproteinases

33
Q

define angiogenesis

A

formation of new vessels by sprouting from existing vessels

34
Q

what 3 physiological functions is angiogenesis essential for

A

embyronic development, menstrual cycle, wound healing

35
Q

what is the most powerful trigger for angiogenesis

A

hypoxia (e.g. caused by atheroclerosis)

36
Q

how does angiogenesis contribute to atherosclerosis

A

promotes plaque growth

37
Q

how does angiogenesis aid in atherosclerosis

A

prevents damage post-ischaemia

38
Q

define cellular senescence and contribution to atherosclerosis

A

growth arrest that halts proliferation of ageing and/or damaged cells (e.g. protective defence against cancer); pro-inflammatory and so contribute to atherosclerosis

39
Q

two main methods of protecting endothelium and preventing atherosclerosis

A

promote anti-pathways or prevent pro-pathways (e.g. anti-inflammatory)

40
Q

what type of toxin is resveratol and what does this mean

A

hormetic toxin (in lower doses it has a protective effects on cardiovascular diseases, but at high doses it has cytotoxic effects)

41
Q

what factors can influence atheroprotective genes

A

novel therapies, statins, diet, exercise, haemodynamics, hormonal balance, epigenetics, miRNAs

42
Q

outcome of expression of atheroprotective genes

A

production of a vasoprotective endothelial phenotype which contributes to vascular homeostasis

43
Q

atherosclerosis window of opportunity

A

lifestyle changes and risk factor management during intermediate/advanced lesion stage

44
Q

clinical interventions of atherosclerosis

A

catheter based interventions, revascularisation surgery and treatment of heart failure/attacks

LSS Cadiovascular System (40 decks)

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