7Cardio - Heart Disease and Atherosclerosis Flashcards
What is coronary heart disease?
Coronary heart disease = occlusion of coronary artery = can’t supply blood (with glucose & oxygen) = heart can’t contract
Heart pumps at 5-20ltr/min
Pumping ability depends on oxygenated blood supply via coronary arteries to cardiac muscle
If coronary arteries “fur up” and harden = heart attacks and possibly death
What is the prevalence of coronary heart disease?
Coronary heart disease = major cause of death in the UK
It caused 1 death every 3 mins in 1990 and 1 death every 4 mins in 2000
Evidence to suggest it is linked to environmental/lifestyle causes:
In the UK it accounts for 180 deaths per 1000 births
In Japan it accounts for 25 deaths per 1000 births
But in Japanese Americans it accounts for 130 deaths per 1000 births
What is atherosclerosis?
Disease of the medium to large arteries = causes thickening of the intima region - which narrows the lumen
Coronary arteries are very susceptible to developing atherosclerotic lesions
Eventually this can block the vessel = resulting in tissue death
Thickening is due to: Lipid (cholesterol ester (CE), some free cholesterol), collagen, macrophages and smooth muscle cells containing CE = “foam cells”
What are the initiating events in atherosclerosis?
Development of Fatty Streak = Localised accumulation of LIPID in vessel wall with some fibrous thickening of the wall
Lipid = CHOLESTEROL + CHOLESTEROL ESTER
Lipid laden, fibrous plaques reduce size of lumen
The average age for US soldiers killed in the Korean War was 22 y/o. At post mortem, 77% of them had fatty streaks or plaques but no clinical symptoms of CHD
This indicates that ATHEROSCLEROSIS IS A SLOW PROCESS
What are the three hypotheses for initiating events in atherosclerosis?
1) Response to Injury
Initial event is injury to endothelial and smooth muscle cells (Ross, 1993)
2) Oxidation
Emphasises importance of oxidative modification of the (accumulating) low density lipoprotein in recruiting macrophages (form foam cells) to lesion areas (Steinberg, 1999)
3) Response to Retention
Initiating event is the retention of the (accumulating) low density lipoprotein in arteries (LDL concentration correlated with probability of developing CHD) (Williams & Tabas, 1995) [LDL influx vs HDL efflux]
In reality, these events are not mutually exclusive = all contribute to some extent to initiation of this pathology
What is required for the formation of an atherosclerotic lesion?
1) Formation of Fatty Streak
2) Development of Lesion
3) Plaque Rupture and Thrombosis
Involves interaction of: Modified lipoproteins Monocyte/macrophages T cells Cells of vessel walls: endothelium, smooth muscle cells
(Inflammatory response required in order for atherosclerosis to occur)
What are the initiating events in the development of a fatty streak?
Cholesterol bound to LDL enters intima through endothelial cells (damages endothelium may aid this process)
Monocyte enters intima via endothelial cells = develop into macrophages
LDL is oxidised in the intima = can be oxidised into 2 forms
mmLDL
oxLDL
Non-selective uptake of LDL by macrophages (via Scavenger receptors)
Development of macrophages into foam cells = swollen macrophages full of vacuoles of oxidised cholesterol
If HDL is high, cholesterol is taken back to the liver
If LDL overburdens HDL = fatty steak develops
How are mmLDL and oxLDL processed by the LDL receptor?
Minimally Modified LDL (mmLDL)
Recognises LDL receptor (LDLR)
Lipid component oxidised (15-LO)
Fully Oxidised LDL (oxLDL)
Not recognised by LDLR = cannot be taken up by its specific receptor = cannot be taken back into liver
ApoB100 = lysine residues covalently modified by reactive species (produced by oxidised lipids)
What are the steps involved in the progression of an atherosclerotic lesion?
If LDL concentration overburdens HDL, lesions start to progress
Interactions between macrophage/foam cells and T helper cells
Cytokines released = causing smooth muscle cells to migrate from media to intima = form fibrous cap over macrophage foam cells = (fibrous cap also contains collagen, fibrin and proteoglycans)
Occlusion starts to occur = artery wall starts to swell = diameter of lumen of artery decreases
What are the steps involved in plaque rupture and thrombosis? (This is often fatal)
Necrosis of macrophage occurs = forming lipid gruel
Macrophages excrete metalloproteinases = weakening endothelial wall
Weakening of endothelial wall caused platelets to be recruited = formation of thrombus = occludes artery = myocardial infarction
Atherosclerosis involves a balance between LDL uptake and HDL efflux - what is this balance?
If LDL influx outweighs HDL efflux, will develop atherosclerotic lesions with foam cells
What are some of the major risk factors for atherosclerosis that have been identified by epidemiological studies?
Age - but if under 50 only for male gender
Hypertension
Diabetes
Smoking
High (saturated) fat diet and lack of exercise
Elevated blood total cholesterol concentration particularly associated with apoB-containing lipoprotein
(Reducing LDL cholesterol by eating diet high in polyunsaturated fat and low in saturated fat)
Why does oestrogen offer some protection against atherosclerosis in women who have not reached menopause?
Oestrogen increases amount of LDLR synthesised
What is the lipid hypothesis (response to retention) of atherosclerosis?
Increased plasma total cholesterol, particularly low density lipoprotein (LDL) cholesterol, is a major cause of atherosclerosis in the general population.
Therefore, any treatments that reduce plasma total cholesterol, particularly low density lipoprotein (LDL) cholesterol, will decrease death and incapacitation (CHD etc.) from atherosclerosis.
[cholesterol = free plus esterified cholesterol - most is esterified]
C/CE carried on lipoproteins, thus raised C/CE = raised lipoproteins
What is the link between cholesterol and atherosclerosis?
In experimental animals, atherosclerosis is produced on feeding diets high in cholesterol [NOTE: there is a significant variation in how different species respond to dietary cholesterol].
In experimental animals, thickening of artery walls (produced by physical trauma = endothelial damage) does not result in atherosclerosis unless blood cholesterol is raised.
In human populations, atherosclerosis does not develop unless the population mean plasma cholesterol exceeds 160mg/100ml (4mmol/L).
In human populations (eating a “Western” high calorie diet), the probability of an individual developing a myocardial infarction increases with their plasma cholesterol concentration.
Single gene disorders which elevate plasma (or tissue) cholesterol content produce atherosclerosis in childhood or prematurely without needing contributing risk factors.
Cholesterol = free plus esterified cholesterol - most is esterified
