atherosclerosis and coronary artery disease Flashcards
what is arteriosclerosis?
thickening of the arterial wall which then loses elasticity
what does sclerosis mean
hardening
what is the most common form of arteriosclerosis?
atherosclerosis
how does arteriosclerosis manifest clinically?
coronary artery disease
cerebrovascular disease
peripheral artery disease
what is atherosclerosis?
plaque builds up inside the arteries over many years –> narrows artery
what are the main functions of the endothelium?
- Vasomotor tone – vasodilators (NO/PGI2) and vasoconstrictors (angiotensin II/endothelin)
- Thrombosis – anticoagulant and procoagulant, platelet inhibitors/activators
- Inflammatory factors – leucocyte interactions
- Cellular adhesion molecules – receptors
explain the classic mechanism of atheroma formation?
o Endothelial damage
o Uptake of modified LDL particles
o Adhesion and infiltration of macrophages
o Smooth muscle proliferation and formation of a fibrous cap
why can endothelial damage occur?
bc of shear stress, toxic damage, hyperlipidemia, viral or bacterial infection (e.g. Chlamydia penumoiae)
why is damaged endothelium dysfunctional?
inappropriate vasoconstriction and reduced antithrombotic properties
how do macrophages infiltrate the endothelium?
- Endothelial damage and the oxidised LDLs attract monocytes
- Monocytes bind to/cross endothelium
- Monocytes macrophages which accumulate oxidised LDLs
name types of lipoprotein?
chylomicrons, VLDL (very low density), IDL (intermediate density), LDL (low density), HDL (high density)
how does the density of a lipoprotein relate to how much lipid it contains relative to protein?
The lower the density of a lipoprotein, the more lipid it contains relative to protein
how can LDLs be modified?
oxidation
glycation
what facilitates oxidation of LDL?
Oxidation – facilitated by reactive oxygen species (free radicals)
what facilitates glycation of LDL?
Glycation – facilitated by high glucose levels (diabetes mellitus)
in what conditions is higher glycated LDL present?
diabetes
what type of LDL is more likely to be oxidised?
glycated LDL
what does oxidised LDL stimulate?
expression of inflammatory mediators inc adhesion molecules for monocytes
what do LDL receptors recognise?
apolipoprotein B100
describe the negative feedback mechanism of the normal uptake of LDL?
internal accumulation of LDL by macrophages so decreased LDL surface receptors –> decreased LDL uptake
why is the uptake of modified LDL unlimited?
modified LDL not recognised by LDL-receptor
uptake is done via the scavenger receptor
no negative feedback –> uptake unlimited
what are foam cells?
when LDL accumulates in large droplets
what are fatty streaks?
fat laden foam cells
how do fatty streaks become mature plaques?
- endothelial cells and macrophages release growth factors to cause SMC proliferation in the intima + collagen production
- breakdown of IEL –> atrophy
- SMC become foam cells - uptake modified LDL
- formation of a plaque
- collagen forms a fibrous plaque
name complications of atherosclerosis
- Stroke
- Coronary artery disease – Angina, MI
- Aneurysm
- Renal artery stenosis
- Peripheral vascular disease (peripheral arterial occlusive disease) –> leads to ulcers, peripheral neuropathy and gangrene
what is the purpose of the coronary circulation?
- supplies oxygen rich and nutrient rich blood to the heart
- ensures adequate oxygenation of the myocardium
- oxygen requirements increase with increased cardiac output
what are the short term consequences of narrowing the coronary arteries?
reduces blood flow –> reduced oxygenation (ischaemia) –> pain
what are the long term consequences of narrowing the coronary arteries?
angina and myocardial infarction
what are the types of coronary artery lesions?
stenotic
non-stenotic
describe stenotic coronary artery lesions?
thick fibrotic cap
leads to ischaemia
angina
+ve exercise test
describe a non-stenotic coronary artery lesion
thin cap; susceptible to rupture; formation of thrombus; myocardial infarction
what are the two main clinical manifestations of CAD?
angina and myocardial infarction
what is the diagnostic challenge of CAD?
to determine whether or not the patient with chest pain has flow limiting coronary obstructions
what are methods of functional testin of evidence of ischaemia?
ETT, SPEC, stress echo, stress cMR
what are the methods of anatomical testing for evidence of obstructive disease?
CTCA
what are the clinical manifestations of myocardial infarction?
- rise and/or fall of troponin
one of the following;
o Symptoms of ischaemia
o New ST segment or T wave changes or new left bundle branch block on ECG
o Pathological Q wave on ECG
o Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality
o Identification of an intracoronary thrombus by angiography
why is troponin evidence of myocardial infarction?
only found in cardiomyocytes - evidence of cell death
summarise stable plaques
Increasing plaque volume causes stenosis of the lumen and limits flow
why do unstable plaques grow quickly?
bc of rapid lipid deposition
summarise how unstable plaques work?
- grow quickly
- thin fibrin cap
- cap ruptures and releases platelet tissue factor - collagen exposed causing platelet aggregation
- thrombus formation
- reduces lumen diameter
- may occlude lumen completely (MI)
what method of imaging can be used to observe plaques?
ultrasound
what are risk factors for cvd?
smoking, weight, high BP, physical activity, diabetes, dyslipidemia
what are non-modifiable risk factors for CVD?
age, sex, ethnicity, family history
what are the normal desirable levels of blood cholesterol?
- Total cholesterol should be <200mg/dL
- LDL cholesterol should be <130mg/dL
- HDL cholesterol should be >60mg/dL
what is the aim of primary prevention?
aims to prevent the disease or injury before it ever occurs for people with no history of angina
what are methods of primary prevention?
•Lifestyle modification; smoking, weight loss, salt intake, hypertension, exercise
Drug treatments
o Statins – uncertainty in the data for low risk individuals
o Aspirin
what is the aim of secondary prevention?
- Tries to intervene and hopefully put an end to the disease before it fully develops
- Trying to reduce the number of new/severe cases
name methods of secondary prevention for angina
o Lifestyle modification
o Beta blocker + CCB, sublingual GTN, aspirin, statin, ACE inhibitor
o Possible revascularisation (PCI, CABG)
name methods of secondary prevention for acute myocardial infarction
defibrillator and reperfusion (aspirin, ticagrelor, heparin, PPCI)
oPCI immediately for STEMI, within 24-96 NSTEMI
name methods of secondary prevention for chronic myocardial infarction
aspirin, statin, beta blocker, GTN, ticagrelor/prasugrel/clopidogrel, ACE inhibitor
what drug is given acutely after a myocardial infarction?
tissue plasminogen activator
what is tissue plasminogen activator?
- Endogenous fibrinolytic agent found in endothelial cells
* Facilitates conversion of plasminogen to plasmin and dissolves the clot
what is streptokinase used to treat?
thrombolytic medication
how does streptokinase work?
directly lyses fibrin in the thrombus
what does a low does of aspirin inhibit?
COX-1
what does a high dose of aspirin inhibit?
COX2
what does COX-1 do?
converts arachidonic acid into PGH2 (precursor for other prostaglandins)
• PGH2 converted to thromboxane A2 – strong stimulator of platelet aggregation
what type of COX inhibitor is aspirin?
irreversible
where does aspirin bind to platelets?
in portal system following absorption
what effects do beta blockers have?
- Decrease heart rate, contractility and systemic vascular resistance
- Decrease myocardial O2 demand
what is propanolol?
beta blocker
non-selective B adrenoceptor antagonist
what is propanolol contraindicated in?
asthmatics and COPD
what should you use instead of propanolol in asthmatics and COPD?
B1 preferring antagonist (atenolol)
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 are ACE inhibitors?
RAAS system preventing conversion of inactive angiotensin I to active angiotensin II
how do ace inhibitors decrease blood pressure?
due to prevention of AngII vasoconstriction
what type of drug is ramipril?
ace inhibitor
what effect do calcium channel blockers have?
- Decrease heart rate + contractility
- Increase coronary artery vasodilation
- Decrease total peripheral resistance
- Decrease myocardial O2 demand
where are calcium channels expressed?
o the SAN and cardiomyocytes (L and T type)- mediate the cardiac action potential
o Cardiac arteries and peripheral arteries
o Involved in smooth muscle contraction
name L type calcium channel blockers
amplodopine
nifedipine
what is the rate limiting step in cholesterol synthesis?
HMG-CoA reductase
what drugs are competitive inhibitors of HMG-CoA?
statins
what effects do statins have?
- Decreased hepatic cholesterol synthesis upregulates LDL receptor synthesis –> increases clearance from blood
- Decreases plasma triglycerides and increase HDL
why are statins considered more effective than stents?
o Statins affect all of the cholesterol deposition in coronary arteries
o Stents/CABG only affect treated artery
how does nitric oxide have a vasodilation effect?
- NO activates guanylate cyclase to form cGMP
- cGMP stimulates dephosphorylation of myosin light chain
- Causes vascular smooth muscle relaxation and consequent vasodilation
what effect does nitroglycerin have?
• Increase O2 supply, decrease preload (venous blood pressure) so decrease O2 demand
name p2y12 antagonists
Clopidogrel/Ticagrelor
how do p2y12 antagonists work?
• P2Y12 receptors found on platelets
o Inhibition of P2Y12 has anti-platelet aggregation properties
o Prevents thrombus formation
what is PCI?
Percutaneous Coronary Intervention
what is CABG?
Coronary Artery Bypass Graft
