Atherosclerosis and Coronary Artery Disease Flashcards
what is atherosclerosis
• Thickening of arterial wall which then loses elasticity, the wall becomes hardened
what is atherosclerosis primary due to
formation of fatty plaques in the arterial wall which cause it to narrow
what diseases does atherosclerosis cause
- Coronary artery disease
- Cerebrovascular disease- Peripheral artery disease
what is the basic formation of atheroma
- Endothelial damage
- Uptake of modified LDL particles adhesion and infiltration of macrophages
- Small muscle proliferation and formation of a fibrous cap
what is function of the endothelium
- contains vasodilators
- responds to vasoconstrictors
- involved in thrombosis as it has anticoagulant and procoagulant
- inflammatory factors - interacts with leucocytes
- has receptors
what does endothelium dysfunction mean
this is an imbalance between vasodilating and vasoconstricting substances
what causes endothelial damage
- Shear stress
- Toxic damage
- High levels of lipids (Hyperlipidemia)
- Viral or bacterial infection (Chlamydia pneumoniae)
How do fatty streaks form
- Endothelial damage/oxidised LDLs - attract monocytes
- Monocytes bind to/cross endothelium
- Transformed into macrophages which accumulate oxidised LDLs
- Fat-laden cells foam cells appear as fatty streaks
name the 5 types of lipoprotein
- Chylomicrons
- VLDL (very low-density lipoprotein)
- IDL (intermediate-density lipoprotein)
- LDL (low-density lipoprotein)
- HDL (high-density lipoprotein)
the lower the density of the lipoprotein…
The lower the density of a lipoprotein the more lipid it contains relative to the amount of protein
name the ways in which LDLs are modified
- oxidation
- glycation
how does oxidation modify LDL
- facilitated by reactive oxygen species (free radicals)
* Oxidised LDL stimulates expression of inflammatory mediators including adhesion molecules for monocytes
how does glycation modified LDL
- facilitated by high glucose levels (diabetes mellitus)
- higher [glycated LDL] present in diabetes
- glycated LDL more likely to be oxidised
how are LDL normally uptakes
• LDL-receptor recognises apolipoprotein B100
• Negative feedback
- internal accumulation of LDL by macrophages
- decreasing LDL surface receptors
- decreasing LDL uptake
how is LDL taken up by scavenge receptors
- But modified LDL uptake via scavenger receptor
- No negative feedback - uptake unlimited
- LDL accumulates in large droplets - foam cells
how does the fatty streak convert to a mature plaque
- Endothelial cells and macrophages release growth factors (esp. platelet derived growth factor)
- Cause proliferation of Smooth Muscle Cells in intima & collagen production
- Breakdown of internal elastic lamina - atrophy
- Smooth muscle Cells also become foam cells - uptake of modified LDL
- Formation of a plaque
- Collagen forms fibrous cap (fragile)
name some complications of atherosclerosis
- Stroke
- Coronary artery disease – angina and MI
- Aneurysm
- Renal artery stenosis
- Peripheral vascular disease (peripheral arterial occlusive disease) – ulcers, peripheral neuropathy, gangrene
what is the purpose of coronary circulation
- Ensure adequate oxygenation of myocardium at all levels of cardiac activity
- Oxygenation requirements increase with increased cardiac output (exercise)
if the coronary arteries narrow what are the two main outcomes
- angina
* - myocardial infarction
what are the types of coronary artery lesion
stenotic
non stenotic
what does a stenotic coronary artery lesion lead to
- thick fibrotic cap
- Leads to ischemia
- Angina
- Positive exercise test
what does a non stenotic coronary artery lesion lead to
- Thin cap
- Susceptible to rupture
- Formation of thrombus
- Myocardial infarction
what are the ECG changes of MI
- STEMI
- pathological Q waves
- T waves become elevated
what cardiomyocytes is troponin found in
Troponin only found in cardiomyocytes (cardiac I and T): evidence of cell death
what is troponin used as
evidence of cell death
Very specific biomarker for cardiomyocyte death
describe what stable plaques lead to
- Slow growing
- Fibrin cap matures (not prone to rupture)
- Reduced blood flow
- Stable angina (exertional)
- when a stable plaque increases in volume it causes stenosis of the lumen and limits flow causing stable angian
what happens in unstable plaques
- Grow quickly as result of rapid lipid deposition
- Thin fibrin cap
- Fragile cap ruptures
- haemorrhage from plaque
- release of platelet tissue factor (clotting cascade)
- collagen exposed causing platelet aggregation
- Thrombus formation
- Reduces lumen diameter
- May occlude lumen completely (MI)
what is the difference between stable and unstable plaques
Stable
- Slow growing
- Fibrin cap matures (not prone to rupture)
- Reduced blood flow
- Stable angina (exertional)
- when a stable plaque increases in volume it causes stenosis of the lumen and limits flow causing stable angian
Unstable
• Grow quickly as result of rapid lipid deposition
• Thin fibrin cap
• Fragile cap ruptures
• haemorrhage from plaque
• release of platelet tissue factor (clotting cascade)
• collagen exposed causing platelet aggregation
• Thrombus formation
• Reduces lumen diameter
• May occlude lumen completely (MI)
what is a difference between NSTEMI and a STEMI
NSTEMI
- ECG is non diagnostic
- rupture coronary plaque with subocculsive thrombus
STEMI
- ECG diagnostic
- ruptured coronary plaque with occlusvie thormbus
what are the modifiable risk factors for CVD
- Smoking - Regular smokers are twice as likely to have a heart attack.
- Weight - Overweight or obese people are more likely to have high cholesterol, a major factor in heart disease.
- High Blood Pressure - Can often show no symptoms but puts strain on the cardiovascular system.
- Physical activity - Lack of exercise can double the risk of heart attacks.
- Diabetes - Over time this can damage the heart and blood vessels.
- Dyslipidaemia
what is the normal range for blood cholesterol for adults
- Normally the triglycerides are in the range of 10-190mg/dl
- TC (total cholesterol) under 200 mg/dl
- LDL under 130 mg/dl
- HDL over 40 mg/d
how can you reduce blood cholesterol
- exercise
- diet
- drugs
what are emerging risk factors for atherosclerosis
- Increased Homocysteine (B6, B12 & folic acid deficiencies)
- Increase oxidant stress
- Lipoprotein (a) - (LDL + extra apolipoprotein)- more firmly retained in arterial wall
- Infection (Chlamydia pneumoniae)- inflammation of endothelium
How are B-vitamins used for reducing risk factors for atherosclerosis
- Methionine transformed to homocysteine in bloodstream
- Homocysteine converted to cysteine (B6) - cell folding/antioxidant
- Homocysteine converted back to methionine (B12 enzymes)
what is primary prevention
- This aims to prevent disease or injury before it ever occurs – for people with no history of angina
name some lifestyle modifications you can make to prevent atherosclerosis
- Smoking
- Weight loss
- Salt intake
- Hypertension
- Exercise
what drug treatments can you use to prevent atherosclerosis
- Statins – uncertainty in the data for low risk individuals
- Aspirin – heterogeneity in the data
what is secondary prevention
• Secondary prevention tries to intervene and hopefully put an end to the disease before it fully develops.
what is the secondary prevention for angina
- Lifestyle modification
- beta blocker ± CCB, Sublingual GTN, Aspirin, statin, ACE inhibitor
- Possible revascularisation (PCI, CABG)
what is the secondary prevention for acute myocardial infraction
- Acute: defibrillator and reperfusion (aspirin, ticagrelor, Heparin, PPCI)
- PCI immediately for STEMI, within 24 – 96 hours NSTEMI
- Chronic: aspirin, statin, beta blocker, GTN, ticagrelor/prasugrel/clopidogrel, ACE inhibitor
what is the immediate treatment for acute myocardial infarction in order to get rid of the clot
- Tissue plasminogen activator (tPA)
- Endogenous fibrinolytic agent found in endothelial cells
- facilitates the conversion of plasminogen to plasmin and dissolves the clot
- Given acutely after myocardial infarction
what does streptokinase do
- Thrombolytic medication
- Directly lysis fibrin in the thrombus
- Effective early trials to reduce death
what is streptokinase usually combined with
• Even better when combined with aspirin
what is the difference between a low dose and a high dose of aspirin
- Low dose inhibits COX-1
- high dose inhibits COX-2
what is the role of COX-1
COX-1 converts arachidonic acid into PGH2
how does COX-1 cause clots to form
COX-1 converts arachidonic acid into PGH2
• PGH2 is precursor for other prostaglandins
Importantly PGH2 converted to thromboxane A2
• Potent stimulator of platelet aggregation
how does aspirin prevent clot formation
- Irreversible inhibitor of COX in platelets
- Covalently binds to the enzyme
- Platelets can’t make new protein (no nucleus)
why do we use aspirin specifically when other NSAIDS bind to COX
- Aspirin binds to platelets in portal system following absorption
- Irreversible inhibition – for the lifetype of the platlet
- First pass metabolism reduces bioavailable aspirin
- Deacetylation
- Avoids systemic effects
- other NSAIDS increase cardiovascular mortality - this causes a rise in blood pressure
- thought to be due to inhibitor of COX-2 in the macular dense of the kidneys
what are the three things that beta blockers do
- Decrease heart rate
- Decrease contractility
- Decrease systemic vascular resistance
- These decrease myocardial oxygen demand
describe how beta blockers work
- Propanolol: non-selective β adrenoceptor antagonist
- Use β1 preferring antagonist (atenolol)
- It increases the end diastolic volume and increases the ejection time
who should not have beta blockers
- Propanolol: non-selective β adrenoceptor antagonist
- Contraindicated in asthmatics/COPD – causes bronchoconstriction
What is afterload
is the amount of resistance the heart must overcome to open the aortic valve and push the blood volume out into the systemic circulation
where are beta 1 adrenoreceptors expressed
- on the SAN- increase HR
- on cardiomyocytes- increase contractility
- in peripheral arteries- vasoconstriction
- Activated by noradrenaline in the SNS
What do ACE inhibitors do
- preventing conversion of (inactive) angiotensin I to (active) angiotensin II
- Decrease in BP due to prevention of AngII vasoconstriction
what do calcium channel blockers do
- Decrease heart rate
- Decrease contractility
- Increase coronary artery vasodilation
- Decrease total peripheral resistance
- These decrease myocardial oxygen demand
where are calcium channels expressed
- the SAN and cardiomyocytes (L and T type)- mediate the cardiac action potential
- Cardiac arteries and peripheral arteries
- Involved in smooth muscle contraction
name some L type calcium channel blockers
• Amplodipine, nifedipine are L type calcium channel blockers
what is the mechanism of action of statins
- HMG-CoA reductase is the rate limiting step in cholesterol synthesis
- Statins are competitive inhibitors of HMG-CoA
- Decreased hepatic cholesterol synthesis upregulates LDL receptor synthesis
what do statins do
• Increases clearance from blood
- Decrease plasma triglycerides and increase HDL
how does nitric oxide work in the cardiovascular system
- NO activates guanylate cyclase to form cGMP
- cGMP stimulates dephosphorylation of myosin light chain
- Causes vascular smooth muscle relaxation and consequent vasodilation
- Increase O2 supply, decrease preload (venous blood pressure) so decrease O2 demand
What happens when you inhibit P2Y12
- ADP found in platelets and stimulates platelet aggregation
- Positive feedback mechanism for platelet aggregation
- P2Y12 receptors found on platelets
- Inhibition of P2Y12 has anti-platelet aggregation properties
- Prevents thrombus formation
What is PCI
Percutaneous Coronary Intervention
What is CABG
Coronary Artery Bypass Graft
