Atherosclerosis Flashcards
What is atherosclerosis?
Disease of the arteries, it involves the narrowing of arteries caused by the deposition of cholesterol (plaques).
How does thrombosis occur?
Erosion of the fibrous cap causes contents of plaque to leak and come into contact with the bloodstream causing platelet aggregation, thus a thrombus forms.
What can thrombosis cause?
Sudden death, unstable angina and myocardial infarction.
What is myocardial infarction?
It is caused by a thrombotic event which cuts off blood flow downstream of the clot, nutrients and oxygen are unable to be delivered to cells which are non-regenerative, thus die.
What is the cause endothelial dysfunction?
It is the first stage of atherogenesis, it is caused by reduced NO synthesis and high concentrations of atherogenic lipoproteins (LDL).
What is the role of NO in the artery?
NO is responsible for smooth muscle relaxation, thus is a vasodilator.
What is sterile inflammation?
Caused by Damaged-associated Molecular Patterns (DAMPs) which are danger molecules released from our damaged/dying cells. Does not involve pathogens or infection.
What is the contribution of leukocytes in atherosclerosis?
Monocytes have receptors which detect DAMPs, tissue debris attract immune cells. Macrophages and lymphocytes are recruited but produce cytotoxic components when taking up debris thus cause more damage. This amplifies the inflammatory response and thus causes more damage to tissues.
What is the process of anti-inflammation caused by PAMPs?
PAMPs cause an acute inflammatory response which causes neutrophils to ingest bacteria and recruit monocytes. Monocytes differentiate into macrophages which ingest bacteria. When neutrophils die, M1 macrophages engulf them (efferocytosis) which drives anti-inflammatory processes and repair (resolvins, TGFs etc.) These stimulate stromal cells to divide and restore tissue.
What are foam cells?
Macrophages that have ingested cholesterol and recruit inflammatory cytokines, this drives endothelial cells to become activated which recruit more.
Why does the number of foam cells continue increase?
They are unable to egress after ingesting cholesterol and unable to undergo efferocytosis.
What is the fate of foam cells?
They undergo secondary necrosis due to defective efferocytosis; macrophages eat the apoptotic bodies.
What causes the thinning of the fibrous cap?
Matrix metellaproteinase eats away at the fibrous cap which causes the cap to rupture and leak plaque contents.
What is the difference between stable vs vulnerable plaques?
Stabilised: small lipid pool, thick fibrous cap, preserved lumen
Vulnerable: large lipid pool, thin fibrous cap, many inflammatory cells
What are the features of a healed ruptured plaque?
Narrow lumen and fibrous intima.
What are the major non-modifiable risk factors for atherosclerosis?
Age, male gender, family history of CHD, menopause
What are the major modifiable risk factors for atherosclerosis?
Biomedical: dyslipidaemia (high LDL/low HDL), hypertension, diabetes, abdominal obesity
Behavioural: smoking, physical activity, diet
What are the components of a chylomicron?
Cholesterol, phospholipids, cholesterol ester, triglycerides, proteins.
What is the mechanism of action of statins?
Statins inhibit HMG-CoA reductase which is a rate-limiting enzyme in hepatic cholesterol biosynthesis which leads to:
- up-regulation of LDL receptors in liver
- increased removal of Apo B-containing lipoproteins from the circulation
- reduction in synthesis and secretion of lipoproteins from liver
- anti-inflammatory action
- enhanced DNA repair and reduced senescence in vascular smooth muscle cells
What are the adverse effects of statins?
Headache, fatigue, GI intolerance, flu-like symptoms; increase in liver enzymes; myopathy.
What other drugs are used in combination with statins?
Anti-platelet medications (aspirin) to reduce thrombosis; beta-blocker medications which reduce heart rate and blood pressure; ACE inhibitors which lower blood pressure; calcium channel blockers which lower blood pressure; diuretics which also lower blood pressure.
How do statins effect leukocytes entering tissues?
They can reduce the expression of all adhesion molecules so fewer leukocytes enter tissue.
What is the role of RHO GTPase in leukocytes and endothelial cells?
Found to have a positive impact on increasing NO production which blocks some pro-inflammatory effects.
How can PCSK9 inhibitors be used to treat atherosclerosis?
PCSK9 proteins prevent LDL being taken up and broken down in the liver as they prevent binding. PCSK9 inhibitor prevents LDL receptors from being degraded thus allowing more LDL receptors to be available for LDL to be broken down.
