Atherosclerosis, lipoproteins and lipid-lowering drugs Flashcards
What is endothelial dysfunction in atherosclerosis characterised by?
A series of early changes that precede lesion formation.
Changes include greater permeability of the endothelium, up-regulation of leukocyte and endothelial adhesion molecules, and migration of leukocytes into the artery wall.
What is the earliest recognisable lesion of atherosclerosis?
Fatty streak formation
What is fatty streak formation caused by?
Aggregation of lipid-rich foam cells, derived from macrophages and T-lymphocytes, within the intima (innermost part of artery wall).
What is the series of steps in fatty streak formation in atherosclerosis?
Smooth muscle cell migration T-cell activation Adherence and entry of leukocytes Foam cell formation Platelet adherence and aggregation
What does development of an atherosclerotic plaque indicate?
Advanced stage in the atherosclerotic process.
What does development of an atherosclerotic plaque result from?
Death and rupture of the lipid-laden foam cells in the fatty streak.
What is the role of the fibrous cap?
Crucial component of the mature atherosclerotic plaque as it separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors.
Protective.
What results in the formation of a fibrous cap over the lipid core?
Migration of vascular smooth muscle cells to the intimacy
Laying down of collagen fibres
What are stable atherosclerotic plaques characterised by?
Necrotic lipid core covered by a thick vascular smooth muscle-rich fibrous cap.
What is involved in the exogenous pathway of lipid metabolism?
Absorption of fats from the diet.
Transport and utilisation of dietary fats.
Where is dietary fat broken down, and into what?
In the GI tract, into cholesterol, fatty acids and mono- and diglycerides.
What are water-soluble micelles formed from?
Products of dietary fat breakdown (cholesterol, fatty acids and mono- and diglycerides) and bile acids.
What is the role of water-soluble micelles in the exogenous pathway of lipid metabolism?
Carry the lipid to absorptive sites in the duodenum.
What happens following absorption of triglycerides and cholesterol in the duodenum?
Chylomicrons are formed, which enter the bloodstream via intestinal lymphatics and the thoracic duct.
What happens to chylomicrons when they enter plasma?
Hydrolysed by lipoprotein lipase, releasing the triglyceride core, free fatty acids and mono- and diglycerides for energy production or storage
What happens to the residual chylomicron after hydrolysis?
Undergoes further delipidation, resulting in the formation of chylomicron remnants.
What happens to chylomicron remnants?
Taken up by a number of tissues.
In the liver they undergo lysosomal degradation, and are either used for remanufacture into new lipoproteins, production of cell membranes, or excretion as bile salts.
What is the role of VLDL in the endogenous pathway of lipid metabolism?
Transports triglycerides (together with cholesterol, cholesterol ester and other lipoprotein particles) from the liver to the rest of the body via the bloodstream.
What happens to VLDL in the bloodstream?
It undergoes delipidation with lipoprotein lipase, in a similar way to chylomicrons. Triglycerides are removed from the core and exchanged for cholesterol esters, principally from HDL.
What is the main enzyme used in the lipolysis of large VLDL particles?
Lipoprotein lipase
What is most VLDL transformed into in the endogenous pathway of lipid metabolism?
LDL
What are larger VLDL particles converted to?
They are lipolysed to IDL, which is then removed from the plasma directly.
What is the role of hepatic lipase?
Reacts with small VLDL and IDL particles in the endogenous pathway of lipid metabolism.
What is the role of the enterohepatic circulation in the endogenous pathway of lipid metabolism?
Provides a route for excretion of cholesterol and bile acids.
What is a feature of IDL?
Highly atherogenic.
What is the product of the metabolic cascade in the endogenous pathway of lipid metabolism?
LDL, which exists in the plasma in a number of sub-fractions: LDL I-IV.
What are the most atherogenic particles?
Small dense LDL particles
What happens to small dense LDL particles in the endogenous pathway of lipid metabolism?
Absorbed by macrophages within the arterial wall to form lipid-rich foam cells, the initial stage in the pathogenesis of atherosclerotic plaques.
Why is cholesterol eliminated from the body intact?
Cannot be broken down within the body.
What is the role of HDL in reverse cholesterol transport?
Cholesterol is transported via HDL from the peripheral tissues to be excreted by the liver.
HDL begins as a lipid-deficient precursor which transforms into lipid-rich lipoprotein. In this form it transfers cholesterol either directly to the liver or to other circulating lipoproteins to be transported to the liver for elimination.
HDL is a protective factor against the development of atherosclerosis.
What are elevated levels of LDL cholesterol associated with?
Ischaemic heart disease and atherosclerosis (without a major inflammatory component).
What is an inflammatory component of atherosclerosis driven by?
Elevated remnant cholesterol levels
What are vulnerable atherosclerotic plaques characterised by?
Thin fibrous cap
Core rich in lipid and macrophages
Less evidence of smooth muscle proliferation
Vulnerable plaques are prone to rupture and ulceration, followed by rapid development of thrombi.
Where does a plaque rupture usually occur?
At sites of thinning, particularly at the shoulder area of the plaque.
Associated with regions with relatively few smooth muscle cells but abundant macrophages and T-cells.
What is plaque rupture associated with?
Greater influx and activation of macrophages
Release of matrix metalloproteinases involved with the breakdown of collagen
What risk factors is LDL cholesterol modified by?
Low HDL cholesterol
Smoking
Hypertension
Diabetes
What percentage increase in CHD risk would a 10% increase in LDL cholesterol result in?
20%
What is a lower HDL cholesterol level associated with?
Higher risk of atherosclerosis and CHD
What is HDL lowered by?
Smoking
Obesity
Physical inactivity
List lipid-lowering therapies.
Bile acid sequestrants (resins) Nicotinic acid and its derivatives Fibrates (e.g. gemfibrozil) Statins (inhibit HMG CoA reductase) Ezetimibe
What are the first-line drugs in the treatment of dyslipidaemias?
Statins
What do bile acid sequestrants do?
Lower cholesterol (potent) Compliance is a problem (taste and texture) Adverse events: GI bloating, nausea, constipation
What does nicotinic acid do?
Increases HDL cholesterol levels
B-complex vitamin
Indicated for all dyslipidaemias except congenital lipoprotein lipase deficiency
Adverse events: flushing, skin problems, GI distress, liver toxicity, hyperglycaemia, hyperuricaemia
What do fibrates do?
Lower triglycerides-effect for patients with type III hyperlipoproteinaemia
Moderately successful in reducing LDL cholesterol in most patients
What do statins do?
Lower LDL cholesterol
Good tolerability profile
What is the mechanism of action of statins?
Inhibit HMG-CoA reductase (rate-limiting step of cholesterol formation, usually responsible for 2/3 of body cholesterol).
Hepatocytes up-regulate and increase the number of LDL receptors in response, increasing binding and removal of LDL cholesterol and LDL precursors from the plasma.
Increase in HDL levels.
What is the mechanism of action of fibrates?
Activation of PPAR (peroxisome proliferator activated receptors) alpha receptors.
What does ezetimibe do?
Inhibits cholesterol absorption.
Absorbed then activated as glucuronide.
