Block A Lecture 3 - Atherosclerosis and Myocardial Infarction Flashcards
What is dyslipidaemia?
Abnormal levels of lipids in the blood
(Slide 10)
What are the 4 main classes of lipoproteins and what do they do?
Chylomicrons - transport dietary cholesterol and triglycerides to capillaries in tissue / fat
VLDL - transports cholesterol and newly synthesised triglycerides to capillaries in tissue / fat
LDL - transports cholesterol to tissues for membrane synthesis / steroid production
HDL - returns cholesterol from tissue to the liver
(Slide 10)
What is hyperlipoproteinemia?
When poor diet and genetic factors disrupt lipid metabolism, leading to elevated levels of LDL and VLDL
(Slide 10)
What do high levels of LDL and VLDL lead to?
Atherosclerosis development
(Slide 10)
What is atherosclerosis?
A slowly worsening disease which is characterised by a progressive narrowing of the blood vessel lumen caused by plaque build up
(Slide 11)
What are the 9 steps of lipid accumulation and inflammation?
- Endothelial cell injury occurs
- Increased endothelial permeability to lipids leads to lipid deposition
- Oxidation of trapped LDL occurs by endothelial cells
- Expression of endothelial adhesion molecules and chemokines occurs
- Adhesion / migration of monocytes, T cells, platelets and smooth muscle cells, macrophages are also activated
- Fatty streaks form due to macrophages and smooth muscle cells engulf oxidised lipids
- Plaque growth results due to continued uptake of lipids, lipid oxidation and inflammation response. A “necrotic core” (a core of dead cells) forms
- Formation of a fibrous cap composed of extracellular matrix proteins secreted by smooth muscle cells over the foam cell layer occurs
- Growth, stiffening and calcification of atheroma (a fatty deposit on vessel walls) occurs. Plaques become brittle and may rupture, leading to thrombosis (blood clot formation)
(Slides 12 and 13)
How does the formation of the fibrous cap which is a step of lipid accumulation occur?
- Platelets release platelet-derived growth factor
- This activates smooth muscle cells
- Smooth muscle cells migrate into the plaque and form the fibrous cap together with matrix proteins which are secreted by foam cells
(Slide 14)
Why does the location of plaque formation matter?
As it determines its effect on blood flow. If blood vessels are branched, plaque may only block one “branch” while the rest are normally following, blockage in something like the Aorta is devastating and will likely lead to death
(Slide 15)
What is the best target for the stabilisation and regression of atherosclerotic plaques?
Plasma cholesterol concentration
(Slide 16)
What are 4 drugs / drug classes which can be used to prevent cardiovascular disease?
Answers Include:
Statins
Ezetimibe
Bempedoic Acid
PCSK9 Inhibitors (such as alirocumab or evolocumab)
(Slides 20 to 23)
What do statins do?
They block HMG-CoA reductase, which is the rate-limiting enzyme in cholesterol synthesis and also upregulate hepatic LDL receptors (reducing LDL levels)
(Slide 20)
How do statins effect lipid levels?
They reduce circulating LDL and triglyceride levels while increasing HDL levels
(Slide 20)
What enzyme are statins metabolised by?
CYP450
(Slide 20)
When are statins taken and why?
In the evening, as it aligns with cholesterol synthesis times
(Slide 20)
When should you not give a patient statins and what should you avoid eating while on statins?
Pregnant patients should not be given statins, and grapefruit juice should be avoided in CYP3A4 metabolised statins as it inhibits the activity of these enzymes
(Slide 20)
What is the mechanism of action of ezetimibe?
It inhibits the NPC1L1 transporter, which results in the inhibition of the absorption of cholesterol in the gut, resulting in less delivery to the liver.
This results in the liver compensating by increasing expressing of LDL receptors, reducing LDL levels
(Slide 21)
What are the pharmacodynamics of ezetimibe and bempedoic acid?
Prodrugs which are metabolised to an active metabolite in the liver (bempedoic acid and ezetimibe) and intestines (ezetimibe only)
(Slides 21 and 22)
When is ezetimibe prescribed?
When statins fail to achieve lipid target (used in combination with statins here) or when statins are not tolerated or contraindicated (used on its own here)
(Slide 21)
When should ezetimibe not be given to a patient?
If they are breastfeeding (it may be secreted in breast milk) or if the patient experiences hepatic impairment.
(Slide 21)
What can the combination of ezetimibe and statins cause in rare cases?
Rhabdomyolysis (severe muscle breakdown)
(Slide 21)
What is the mechanism of action of bempedoic acid?
It is a ATP citrate lyase inhibitor - resulting in reduced cholesterol synthesis via blocking reactions upstream of HMG-CoA reductase, resulting in a reduced circulating LDL level
(Slide 22)
When is bempedoic acid prescribed?
When ezetimibe alone fails to achieve lipid target (used in co-therapy)
(Slide 22)
What patients should bempedoic acid not be given to?
Pregnant / breastfeeding women (due to possible reproductive toxicity + possible secretion into breast milk) and patients with hepatic impairment
(Slide 22)
What are some adverse effects of bempedoic acid?
It can increase uric acid levels and increase risk of gout
(Slide 22)
What is the mechanism of action of PCSK9 inhibitors?
They are monoclonal antibodies which bind to and inhibit PCSK9, which prevents LDL receptor degradation, resulting in a decreased LDL circulating level
(Slide 23)
Why are PCSK9 inhibitors taken every 2-4 weeks?
Due to their long half lives
(Slide 23)
When are PCSK9 inhibitors prescribed?
When LDL concentrations are persistent despite maximal tolerated lipid-lowering treatments
(Slide 23)
What is a limitation of PCSK9 inhibitors?
Very high cost
(Slide 23)
What is a possible risk of PCSK9 inhibitors?
Foreign proteins can sometimes trigger immune-mediated hypersensitivity reactions, such as angioedema and vasculitis (inflammation of the blood vessels)
(Slide 23)
What is the mechanism of action of bile acid sequestrants?
They are resins which bind bile acids in the intestine, preventing their reabsorption and forcing the liver to use cholesterol to produce more bile acids, reduces circulating LDL levels but may increase triglyceride levels
(Slide 24)
Why are bile acid sequestrants not prescribed for cardiovascular disease?
As there is limited evidence of them reducing cardiovascular events, and they also have a high rate of gastrointestinal side effects
(Slide 23)
What is the mechanism of action of fibrates?
They are PPAR-α agonists which activate PPAR-α, increasing lipoprotein lipase activity which enhances triglyceride clearance, and reduces triglyceride levels while increasing HDL levels
(Slide 24)
Why are fibrates not used to treat cardiovascular disease?
As they have a modest effect on LDL and there is limited evidence of reduction in cardiovascular events
(Slide 24)
What are 5 possible risk factors for atherosclerosis?
Answers Include:
BMI
Age
Diabetes
Hypertension
Excess fat (aka obesity)
Alcohol
Relatives with cardiovascular disease (genetic?)
Tobacco
Mnemonic - first letter of each spells out “bad heart”
(Slide 26)
Atherosclerosis causes reduced blood vessel lumen diameter, what does this result in?
It results in a lower blood flow at rest, and a reduced oxygen and nutrient supply to important organs and tissues
(Slide 26)
Atherosclerosis leads to vascular cell dysfunction, what does this result in?
Impaired vasodilation and faulty blood flow control
(Slide 26)
What disease class can atherosclerosis lead to?
Cardiovascular disease
(Slide 27)
What is angina pectoris?
Chest pain or discomfort that occurs when the heart muscle doesn’t receive enough oxygen and blood
(Slide 28)
Outline the 3 different types of angina.
Stable angina - brought on by exercise and is short lived (~ 2-3 mins)
Unstable angina - can occur at rest and is an unpredictable, sudden increase in pain
Variant angina - is uncommon and is caused by artery spasm
(Slide 28)
What is coronary heart disease?
Progressive narrowing or blockage of blood vessels (by plaques or thrombosis formation) causing increasing severity of coronary heart disease and ischaemia
(Slide 29)
What is the difference between stable and unstable plaque?
The occlusion percentage: over 70% in stable plaque and over 90% in unstable plaque
(Slide 29)
What can stable plaque lead to?
Stable angina
(Slide 30)
What can unstable plaque lead to?
Transient (temporary) ischaemia and unstable angina or sustained (prolonged) ischaemia and myocardial infarction, which combined can lead to necrosis
(Slide 30)
What is an infarct?
Ischaemic (due to lack of blood) necrosis of a tissue
(Slide 31)
What 2 things can prolonged reduction or cessation of blood flow to the heart lead to?
Subendocardial infarct (NSTEMI) - when the innermost layer is injured first
Transmural infarct (STEMI) - when cell death extends throughout the whole thickness of the heart muscle
(Slide 31)
What 3 things can cell death in the heart muscle lead to?
Arrhythmia, heart failure or cardiogenic shock (when the heart can’t pump enough blood to the body)
(Slide 31)
What are used to treat stable angina attacks and how do they do this?
Nitrates (such as nitro-glycerine) are used as they increase blood flow via increased the diameter of blood vessels (promoting vasodilation)
(Slide 34)
What is a non-drug treatment for atherosclerosis?
Lifestyle changes such as healthy eating and exercise
(Slide 35)
What medications are used to treat atherosclerosis and how do they do this?
Lipid lowering drugs - used for stabilisation / regression, they lower plasma cholesterol and its transport
Anti-hypersensitive drugs - used to decrease heart rate, force and relax arteries to increase blood flow
Anti-clotting drugs - used to prevent thrombosis
Both of the above are used to prevent attacks and are taken every day
(Slide 35)
What are 2 classes of drugs which can be used as anti-clotting drugs, and how do they work?
COX-1 inhibitors (such as aspirin)- inhibit enzyme responsible for synthesis of thromboxane precursors, reduces thromboxane which is needed for platelet aggregation
ADP receptor inhibitors (such as clopidogrel) - its metabolites interfere with platelet function
(Slide 37)
What is the last hope treatment for angina?
Surgical intervention - coronary angioplasty and stenting or a coronary artery bypass graft
(Slide 40)
