cardiovascular pathology Flashcards
atherosclerosis: explain the pathology, pathophysiology, and clinical features of atherosclerosis
define atherosclerosis
outcome of a permanently activated endothelium, causing formation of plaques within walls of large arteries, potentially causing thrombosis or occlusion
modifiable risk factors of atherosclerosis
smoking, lipid intake, blood pressure, diabetes, obesity, sedentary lifestyle
non-modifiable risk factors of atherosclerosis
age, sex, genetic background
agents which activate endothelium in atherogenesis
smoking, viruses, toxins, mechanical stress (turbulent flow), inflammation, hypertension, OxLDL (carried to arteries), high glucose (diabetes), ageing, oxidative stress, hypercholesterolaemia, sex hormonal imbalance
epidemiology of atherosclerosis
statins and antihypertensives mean obesity is driving factor
LDL structure
lipid monolayer and docking apolipoproteins, with cargo fat (triglycerides and cholesterol esters)
location of atherosclerosis
branch points of arteries
why does atherosclerosis occur at branch points
turbulent, not laminar, flow is present, so speed changes magnitude and direction
why does laminar flow not normally cause atherosclerosis (3)
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
why can turbulent flow cause atherosclerosis (6)
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
what are the 6 protective effects of nitric oxide on vascular endothelium
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)
how does blood flow regulate gene expression
transcription factors selectively activated by laminar (e.g. eNOS for NO production) or turbulent (e.g. NF-KB) flow
blood flow regulation of endothelial epigenetic pathways
mechanosensors sense blood flow and cause changes in transcription by regulating chromatin (epigenetic)
3 stages of pathogenesis of atherosclerosis
endothelial dysfunction, fatty streak formation, advanced complicated lesion formation
summary of endothelial dysfunction
endothelium in large vessels receive chronic stimuli of inflammation increase, increasing permeability and causing leukocyte accumulation under activated endothelium
summary of fatty streak formation
lipids get stuck under more permeable endothelium, binding to proteoglycans and becoming oxidised, before engulfment by macrophages, forming foam cells (fatty streaks)
summary of advanced complicated lesion formation
other chronic processes such as macrophage accumulation, necrosis, senescence and angiogenesis cause an advanced complicated lesion to form
what blood vessels does leukocyte recruitment occur in normaly vs in atherosclerosis
normally affects post-capillary venules by contact inhibition, but in atherosclerosis it affects large arteries, as all stimuli activate endothelium in wrong place
define contact inhibition and how does this contribute to formation of endothelial junctions
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
what is the effect of increased endothelial permeability in major arteries
leakage of plasma proteins (including lipoproteins) through junctions into subendothelial space, as well as oedema
leukocyte recruitment in atherosclerosis: effect on monocytes
monocytes stuck between endothelium and smooth wall mature into macrophages
leukocyte recruitment in atherosclerosis: how do leukocytes pass through endothelium when there is an inflammatory trigger (captured by intra-vital microscopy)
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)
outcome and fate of lipoproteins entering endothelium
lipoprotein pass through endothelium and are oxidised; macrophages present in subendothelial space then consume the lipoproteins and become foam cells, forming a fatty streak
subtypes of macrophage scavenger receptors
A and B
macrophage scavenger receptor subtype A
CD204, bind oxLDL, dead cells and gram +ve bacteria to cause inflammation and destruction
macrophage scavenger receptor subtype B
CD36, bind oxLDL, malaria parasites and dead cells for safe clearance and reverse cholesterol transport
5 macrophage actions
generate free radicals to oxidise LDL, phagocytose modified lipoproteins, express cytokine mediators to recruit monocytes, express chemo-attractants and growth factors, express metalloproteinases
macrophages that express cytokine mediators to recruit monocytes
chemokines attract monocytes, cytokines activate endothelial cell adhesion molecules
macrophages that express chemo-attractants and growth factors
platelet-derived growth factor and transforming growth factor B for wound healing release complementary protein growth factors to recruit muscle cells and stimulate proliferation
fate of macrophages and effect of metalloproteinases
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
outcome of ruptured plaque
fibrous cap becomes so thin that will break and rupture, allowing necrotic core to contact blood and cause thrombus formation
characteristics of a vulnerable cap
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
define angiogenesis
formation of new vessels by sprouting from existing vessels
what 3 physiological functions is angiogenesis essential for
embyronic development, menstrual cycle, wound healing
what is the most powerful trigger for angiogenesis
hypoxia (e.g. caused by atheroclerosis)
how does angiogenesis contribute to atherosclerosis
promotes plaque growth
how does angiogenesis aid in atherosclerosis
prevents damage post-ischaemia
define cellular senescence and contribution to atherosclerosis
growth arrest that halts proliferation of ageing and/or damaged cells (e.g. protective defence against cancer); pro-inflammatory and so contribute to atherosclerosis
two main methods of protecting endothelium and preventing atherosclerosis
promote anti-pathways or prevent pro-pathways (e.g. anti-inflammatory)
what type of toxin is resveratol and what does this mean
hormetic toxin (in lower doses it has a protective effects on cardiovascular diseases, but at high doses it has cytotoxic effects)
what factors can influence atheroprotective genes
novel therapies, statins, diet, exercise, haemodynamics, hormonal balance, epigenetics, miRNAs
outcome of expression of atheroprotective genes
production of a vasoprotective endothelial phenotype which contributes to vascular homeostasis
atherosclerosis window of opportunity
lifestyle changes and risk factor management during intermediate/advanced lesion stage
clinical interventions of atherosclerosis
catheter based interventions, revascularisation surgery and treatment of heart failure/attacks
