Molecular aspects of cardiovascular & brain-related disorders Flashcards
what is the cardiovascular system responsible for?
transport of oxygen, nutrients,, hormones, waste
pulmonary circulation
deoxygenated blood to the lungs
systemic circulation
highly oxygenated blood to the tissue
arteries
high pressure, away from the heart
veins
low pressure, to the heart
capillaries
exchange of O2, nutrients to the tissue
cardiovascular disease (CD)
any disease that affects the cardiovascular system
cerebrovascular disease
disruption of blood supply to the brain
aortic aneurism & dissection
dilatation/rupture of the aorta
peripheral arterial disease
of arteries supplying arms/legs
deep venous thrombosis & pulmonary embolism
blood clots in the leg veins which can dislodge and move to heart/lungs
coronary heart disease
of blood vessel supplying the heart muscles
rheumatic heart disease
damage to heart muscle and valves from rheumatic fever (caused by streptococcal infection)
congenital heart disease
malformations of heart structures existing at birth
non-modifiable risk factors for developing CVDs
- advancing age
- genetic predisposition
- gender
modifiable risk factors for developing CVDs
- tobacco smoking, physical inactivity, poor diet, excessive alcohol
- high blood pressure/blood lipids (cholesterol), obesity
- diabetes
describe the stages of atherosclerosis
- fatty streak formation
- plaque progression (adaption)
- plaque disruption (clinical manifestation)
stage 1 of atherosclerosis (fatty streak formation)
- endothelial cell dysfunction
- lipoprotein entry & modification
- leukocyte recruitment & foam cell formation
- > impaired trafficking, local accumulation of macrophages, failure to resolve inflammation
endothelial cell dysfunction
vasoconstriction, lipoprotein oxidation, pro-inflammatory genes, NO-catabolism
lipoprotein entry
LDL binds to proteoglycans and accumulates (adds cholesterol)
how can HDL protect against atherosclerosis?
removes excess cholesterol
LDL / HDL
low/high density lipoprotein
oxidises LDL
LDL + free radical: introduces tissue damage, stimulates endothelial cells to produce pro-inflammatory molecules
(inhibits production of NO by endothelial cells, promotes recruitment of leukocytes)
leukocyte recruitment & foam cell formation
-phagocytic macrophages take up oxidized lipoproteins, forming foam cells
diaptesis
passage of blood cells through intact vessel walls
stage 2 of atherosclerosis (plaque progression /adaption)
- smooth muscle cell migration (foam cells release PDGF)
- extracellular matrix metabolism
- > fibrotic plaque generation
extracellular matrix metabolism
production of extracellular matrix molecules
stage 3 of atherosclerosis (plaque disruption)
clinical manifestation: integrity of plaques, thrombogenic potential
->thinning of fibrous cap, prone to rapture
how to inflammatory cells contribute to plaque disruption?
produce IFN-gamma (inibits matrix production), produce cytokines (stimulate foam cells to produce MMP)
MMP
metalloproteinases (degrade matrix)
integrity of plaques
- apoptosis of foam cells/SMCs
- release of cellular content, absorbed to lipid core (plaque instability)
factors for plaque rupture
- size of inflammation area
- size of lipid core
- thickness of fibrous cap
- disturbed balance of proteolytic enzymes
- plaque calcification (mineral disposition)
- hemorrhage in plaque (neovascularization)
thrombogenic potential
- components of necrotic core in direct contact with blood
- tissue factor produced by endothelial cells & macrophages
- initiates coagulation cascade by activation of platelet & clotting factors
- block of blood supply
how does advancing age contribute to CD?
- risk 3x with each life decade
- cardiac/vascular aging (dysregulated signaling, endothelial dysfunction..)
how does genetic predisposition contribute to CD?
-rare variants e.g. severe hypercholesterolemia, disturbed blood pressure
how does gender contribute to CD?
2-5x more common in men (young age), major differences in body weight/fat distribution, protective effect of estrogen on blood vessels
how does excessive alcohol consumption lead to disease?
high blood pressure, calories, increased triglyceride in blood
how can moderate drinking reduce risk of CD
beneficial effects on HDL cholesterol
how does inactivity influence CD?
-impairs endothelial function, blood pressure, lipid profile, weight gain
how does a poor diet contribute to CD?
undesirable lipid profile, insulin resistance, obesity, blood pressure
why is there a higher risk of cardiovascular event when having high blood pressure?
damage to endothelial cells, enlargement of heart, high levels of LDL accumulate and undergo oxidation
why does diabetes increase the risk of CD?
- increased blood glucose level -> uptake of cholesterol
- high prevalence of endothelial dysfunction among diabetes groups -> reduced NO, enhanced leukocyte adhesion
myocardial infarction (MI)
sudden ischemic death of myocardial tissue (imbalanced oxygen supply/demand)
what happens in the first seconds of MI?
aerobic metabolism & ATP production stop, lactic acid accumulates in toxic levels
-loss of myocardial contractility
when is the iscemic period reversible
if blood flow is restored before 15-20 mins
generally describe the cardiac repair after MI
very limited, lost cells replaced by fibrotic scar
- inflammatory phase
- reparative & proliferative phase
cerebral ischemic stroke
- mostly caused by compromised vascular supply to the brain
- brain tissue vulnerable to oxygen & glucose deprivation
global ischemia
entire brain
local ischemia
specific brain region
what follows vascular occlusion in cerebral ischemia?
cerebral blood flow goes down, metabolism interrupted (no oxygen/glucose), energy failure, loss of ion homeostasis, acidosis, toxicity, disruption of blood-brain barrier, activation of glia cells
panumbra
bordering region next to core region (immediate necrotic cell death), potential to recover
excitotoxicology
process of neuronal damage by overreaction of receptors for the excitatory neurotransmitter glutamate (ion fluxes, cell death)
neurogenesis
new neurons, birth of new cells, migration to injured sites
fats are not water soluble. How are they transported in the body?
complex with different proteins called lipoproteins
what is the major function of HDL?
transport cholesterol and triglycerides from peripheral tissues to liver
why are LDL receptor mutations associated with increased risk of coronary heart disease?
the mutations inhibit cellular uptake and processing of cholesterol
