Lipids and CVD

Question 1

what are lipids

Answer 1

organic compounds
poorly soluble in water but miscible in organic solvents

Question 2

what are the important lipids in human physiology

Answer 2

steroids - cholesterol, steroid hormones
fat-soluble vitamins - A, D, E, K
phospholipids
sphingolipids
triglycerides

Question 3

important lipids in CVD

Answer 3

cholesterol and triglycerides
they are components of lipoproteins, this is how they are transported around the blood stream
cholesterol provides flexibility and strength to the phospholipid bilayer
triglycerides acts as an energy source

Question 4

what is a lipoprotein

Answer 4

particle that has a phospholipid monolayer rather then bilayer
the hydrophobic tail points towards the cell centre, in the centre there is lots of hydrophobic contents

Question 5

what are the types of lipoproteins

Answer 5

chylomicrons - high triglyceride, low cholesterol, biggest
very low density lipoprotein - slightly lower triglyceride, slightly higher cholesterol
intermediate density lipoprotein - higher cholesterol, lower triglyceride, very short-lived
low density lipoprotein - higher cholesterol, lower triglyceride, long-lived
high density lipoprotein - highest cholesterol, lowest triglyceride, smallest, long-lived
LDL and HDL play the biggest roles

Question 6

where are lipoproteins created

Answer 6

small intestine - dietary lipids
liver - endogenous lipids

Question 7

transport pathways of lipids

Answer 7

stored within hepatocytes or absorbed from gut and secreted into the circulation to deliver cholesterol and/or triglycerides
reverse cholesterol transport - hdl plays a key role, delivers lipids back to the liver

Question 8

describe exogenous lipid pathways

Answer 8

delivers lipids from the gut to the peripheral tissues
dietary lipids from the small intestine are packaged into chylomicrons
these are secreted into the lymphatic system and then to the circulation
one they are in the circulation they’re broken down by lipoprotein lipase, which breaks down the triglycerides, these become fatty acids which can be taken up and stored in muscle or adipose tissue and used as an energy source
as they are progressively broken down they lose more triglyceride content until they become a micro remnant and return to the liver and stored in the hepatocytes

Question 9

describe endogenous lipid pathways

Answer 9

originates in the liver
VLDL - triglyceride rich, low cholesterol content
delivers triglyceride to peripheral tissues and is progressively broken down and form IDL, most of these are taken up by the liver
if they are not taken up by the liver they are further broken down by hepatic lipoprotein lipase and become LDL, which is primarily cholesterol rich

Question 10

what is the main function of LDL

Answer 10

deliver cholesterol to the peripheral tissues
has a protein that latches onto the LDL receptor, this enables LDL to be taken up by cells, and for cholesterol to be delivered to the cells
any remaining LDL is taken up by the liver using the same mechanism

Question 11

function of HDL

Answer 11

created in the liver and the gut
collects cholesterol from the peripheral tissues
cholesterol can be secreted from cells via the ABC1-A1 transporter, via LCAT (enzyme) which esterifies it and makes it hydrophobic so it can be taken up by hdl
it is then taken up by the liver where it is stored
alternatively VLDL can take cholesterol from HDL via the enzyme CETP, this can disrupt the pathway and has implications for the levels of HDL

Question 12

what do apolipoproteins do

Answer 12

determine lipoprotein behaviour

Question 13

lipids and their connection to CVD

Answer 13

elevated HDL decreases rates of CVD
elevated LDL increases rates of CVD

Question 14

mechanism of atherosclerosis and lipoproteins

Answer 14

if not cleared by the liver LDL can be taken up into arterial walls
LDL accumulation in arterial wall can be maximised by high concentration of LDL and damage to arterial wall (hypertension, oxidation or glycation)
leads to the formation of fatty streaks

Question 15

how do fatty streaks from

Answer 15

LDLs oxidised by oxygen free radicals and are consumed by macrophages
macrophages laden with LDL are known as foam cells
fatty streak is a collection of foam cells within the arterial wall

Question 16

how do oxygen free radicals from

Answer 16

glycation reactions (diabetes)
toxins from cigarette smoke
macrophages

Question 17

atheromatous plaque formation

Answer 17

smooth muscles cells are stimulated by macrophages to migrate, proliferate and differentiates
SMCs differentiate into fibroblasts which produce a fibrous collagen cap
foam cells undergo necrosis or apoptosis to leave a pool of extracellular cholesterol
atheroma is a cholesterol pool beneath a fibrous cap within arterial wall

Question 18

mechanism of plaque rupture

Answer 18

cholesterol rich lesions (area of abnormal tissue) are more likely to rupture and cause thrombosis (formation of a blood clot) this causes total lumen obstruction and causes tissue ischaemia (leads to MI if in coronary arteries)
fibrous lesions have less cholesterol and are less likely to rupture, this created reduced blood flow (stable angina if in coronary arteries)

Question 19

what is familial hypercholesterolaemia

Answer 19

inherited disorder of lipoprotein metabolism (form of lipid-driven CV disease)
autosomal dominant
mutation in LDL receptor leads to high LDL levels
if left untreated it can lead to premature CHD onset
be suspicious if there is a family history of hyperlipidaemia or premature CVD, unusually high levels of LDL despite v healthy lifestyle, history of hyper lipidaemia from a young age

Question 20

what is a stigmata of hyperlipidaemia

Answer 20

cholesterol can deposit in other parts of the body
most commonly found on the surface of tendons (tendon xanthoma), in the cornea of the eye (corneal arcus)

Question 21

how is cholesterol measured

Answer 21

measure the total cholesterol in the bloodstream
measure the amount of HDL and triglycerides in the bloodstream
LDL is calculated , not measured using the freidewald equation, relies on being able to measure the total cholesterol, the total HDL, and there being a fixed relationship between triglycerides and LDL
specialist labs can measure concentrations of lipoproteins and apolipoproteins

Question 22

types of prevention of CVD

Answer 22

primary - individuals without disease
secondary - individuals with disease

Question 23

describe secondary prevention

Answer 23

crucial as there is a >20% risk of any CV event over 10 yrs
lifestyle changes
drugs - ace inhibitor or beta-blocker (reduce post MI mortality), aspirin or clopidogrel (reduce CVD recurrence and mortality), statins (reduce CVD recurrence and mortality)

Question 24

describe primary prevention

Answer 24

lifestyle change - diet (reduce saturated fats, simple carbs, salt), aerobic exercise, aim for BMI of 20-25, reducing alcohol intake, quit smoking
can offer drugs like statins or blood pressure lowering meds but is controversial as these individuals don’t have a disease yet

Question 25

who do we treat in primary prevention

Answer 25

based on potential benefit vs side effect - risk of serious side effect must be small, must produce a reasonable reduction in risk
treat those at the highest absolute risk (risk of CV event over 10 yrs), use a risk calculator such as QRISK
if high risk treatment is lifestyle advice and statin

Question 26

effects of lipid-lowering drugs

Answer 26

statins - reduce LDL, lower risk of CHD, 1st choice for CVD prevention
ezetimibe - reduce LDL, lower risk of CHD, usually an adjunct (supplementary)
fibrates - reduce LDL and triglycerides, increase HDL, only beneficial where low HDL and high trigs, used as an adjunct

Question 27

mechanism of action of statins

Answer 27

HMG-CoA reductase inhibitors (enzyme that makes cholesterol), inhibit rate limiting step of cholesterol synthesis, intracellular cholesterol depletion which leads to increased LDL uptake

Question 28

mechanism of action of ezetimibe

Answer 28

inhibits cholesterol absorption at small intestine, binds to Nieman-pick C1 like 1 protein which is a critical mediator of cholesterol absorption in GI epithelial cells