Hyperlipidaemia, atherosclerosis and angina

Question 1

What is cholesterol? (3)

Answer 1

• structural component of cell membrane
• precursor to steroid hormones
• precursor to bile acids

Question 2

What do bile acids do?

Answer 2

bile acids act as detergents in the GI tract emulsifying lipids so they can be digested and absorbed

Question 3

Where are bile acids synthesized?

Answer 3

bile acids are synthesised from cholesterol in the liver and secreted into the GI tract via the bile duct

95% of the bile acids are reabsorbed, returned to liver via the hepatic portal vein and recycled
remainder is excreted in the faeces

Question 4

When is cholesterol lost from body?

Answer 4

when cells lining the GI tract are shed into the faeces

this loss of cholesterol must be balanced by cholesterol synthesis in the liver and absorption from the diet

Question 5

Synthesis of cholesterol

Answer 5

HMG-CoA turned into mevalonate

this reaction is catalysed by HMG-CoA reductase and is the rate- limiting step in the pathway - the one that controls the overall rate of cholesterol synthesis

Hepatocyte cholesterol levels regulate the HMG-CoA reductase pathway through feedback mechanisms

Question 6

Absorption of dietary cholesterol

Answer 6

when your body loses cholesterol, it can make up for it by absorbing more from the food you eat

the cells lining your gut (called enterocytes) have a special “door” on their surface called NPC1L1 that lets cholesterol from food enter the cells.

once the cholesterol gets inside, it goes to a part of the cell called the endoplasmic reticulum (ER), where it gets changed slightly (this is called esterification).

then, other fats and proteins are added to the cholesterol in the ER and Golgi complex to make a package called a chylomicron.

these chylomicrons are like tiny delivery trucks that carry fats and cholesterol. They leave the cells, enter the lymphatic system (a kind of fluid highway in your body), and from there, they move into your bloodstream to be used by the body

Question 7

How are lipids transported around the body?

Answer 7

lipoprotein particles

Question 8

Lipoprotein structure

Answer 8

all lipoproteins have a similar structure

outer membrane consisting of a monolayer of phospholipids and cholesterol

core contains triglycerides and cholesterol esters- this structure is organised around proteins called apolipoproteins

each class of lipoprotein complex has a distinctive complement of apolipoproteins

Question 8

Polipoproteins in LDL and VLDL

Answer 8

ApoB-100

Question 9

Polipoproteins in HDL

Answer 9

ApoA-I and ApoA-II

Question 10

Function of apolipoproteins

Answer 10

addition to their structural role apolipoproteins enable the body to identify which class a particle belongs to- they are molecular adress labels

Question 11

What do “high” and “low” refer to in lipid composition?

Answer 11

refers to the physical density of the particles NOT than their cholesterol content

Question 12

What lipids have the lowest density?

Answer 12

chylomicrons
VLDL
IDL
LDL
HDL

Question 13

Framingham Heart Study

Answer 13

longitudinal study which followed the cardiovascular health of more than 5000 residents investigated the epidemiology of hypertension and heart disease and provided the first evidence for many of the risk factors for cardiovascular problems

the first clinical study of any kind to use “risk factor”

Question 13

One of the most important clinical studies ever conducted

Answer 13

the Framingham Heart Study (1948)

Question 14

Key findings of Framingham Heart Study

Answer 14

that high levels of serum cholesterol were linked with cardiovascular disease

then the study provided evidence that high levels of HDL cholesterol are actually protective against heart disease

coupled with evidence from other studies and increased understanding of the structure and function of lipoproteins this gave rise to the concepts of “good” and “bad” cholesterol

Question 15

“Good” cholesterol

Answer 15

HDL

Question 15

“Bad” cholesterol

Answer 15

LDL

IDL

VLDL

measured together as “non-HDL cholesterol” and this is the term that NICE use in the treatment guidelines

Question 16

What is done about “bad” cholesterol?

Answer 16

doctors routinely measure serum lipoprotein concentrations in patients aged 50+

Question 17

Total cholesterol serum concentration

Answer 17

below 5

Question 18

Non-HDL cholesterol

Answer 18

below 4

Question 19

LDL cholesterol

Answer 19

below 3

Question 19

HDL cholesterol

Answer 19

> 1(man), >1.2(women)

Question 20

What did the Framingham Heart study show?

Answer 20

the Framingham Heart study showed that if you take people who have the same LDL levels there is a 10-fold increase in risk going from high HDL to low HDL

on the other hand in people who have the same HDL level there is only a 3-fold increase in risk going from low LDL to high LDL

Having low HDL (good cholesterol) is more dangerous than having high LDL (bad cholesterol)

Question 20

Total cholesterol: HDL ratio

Answer 20

the lower the better a ratio of <4 is normal 6 is high risk

Question 21

Regulation of LDL receptor and PCSK9 expression process

Answer 21

1) cholesterol levels regulate the expression of LDL receptors and PCSK9 and the expression of both proteins increases when cholesterol levels fall 2) LDL receptors have a single transmembrane domain and their binding site for ApoB-100 faces into the extracellular fluid so PCSK9 is released into the extracellular fluid 3) the LDL receptor binds to the ApoB-100 found on LDL particles and once bound it is endocytosed in a clathrin coated vesicle 4) PCSK9 is also able to bind to the LDL receptor complex If PCSK9 is attached, the receptor can’t be reused and instead of going back to the surface it gets sent to the cell’s "trash system" (endosome then lysosome) 5) In the lysosome, the LDL receptor and ApoB-100 are degraded to amino acids and cholesterol released from the LDL particle is transported into the cytoplasm by two proteins called NPC1 and NPC2 6) LDL receptors that are not bound to PCSK9 can be recycled to the cell surface to bind more LDL

Question 22

What is hypercholesterolaemia?

Answer 22

elevated serum levels of lipoprotein cholesterol

Question 22

Causes of hypercholesterolaemia (8)

Answer 22

- smoking - obesity - liver disease especially NAFLD - genetics - diabetes - diet - medication - physical inactivity

Question 23

Familial hypercholesterolaemia

Answer 23

Some genetic factors have a small influence on serum lipoprotein levels but can have an additive effect if someone inherits more than one (polygenic disease) Other genetic differences have a stronger impact and act in a monogenic manner, usually following an autosomal dominant inheritance pattern familial hypercholesterolaemias is relatively common, with a prevalence of around 1 in 500 (some studies suggest 1 in 250)

Question 24

What mutation causes familial hypercholesterolaemia?

Answer 24

the most common mutations that cause familial hypercholesterolaemia are in the LDL receptor, apoB-100 or PCSK9

Question 25

Mutations in LDL

Answer 25

mutations in the LDL receptor can stop it from recognising apoB-100 which prevents uptake of LDL by the liver causing it to accumulate in the circulation

Question 26

Mutations in apoB-100

Answer 26

mutations in apoB-100 can alter its structure, preventing it from binding efficiently to LDL receptors which reduces the ability of the liver to clear LDL from the circulation

Question 27

Mutations in PCSK9

Answer 27

when PCSK9 binds to the LDL receptor it directs the receptor to the lysosome, leading to it being broken down this reduces the number of LDL receptors on the surface of the hepatocytes and reduces clearance of LDL from the bloodstream gain of function mutations in PCSK9 (which increase its stability or activity) result in fewer LDL receptors being available this increases LDL levels in the blood and so increases cardiovascular risk conversely, loss of function mutations in PCSK9 are associated with reduced cardiovascular risk

Question 28

Familial hypercholesterolaemia risk

Answer 28

increased risk of the cardiovascular problems associated with excess LDL cholesterol and develop them at a much earlier age than the general population they may also show other signs such as xanthelasma (yellow deposits of cholesterol around the eyes) and xanthomas (nodules of cholesterol deposited in the skin or on tendons)

Question 29

What happens in atherosclerosis?

Answer 29

plaques obstruct blood flow and can result in tissue becoming temporarily ischaemic (deprived of oxygen) If the ischaemic tissue is in the heart it results in chest pain known as angina a similar situation can occur in the brain which results in a transient ischaemic attack (TIA) this is a form of stroke (sometimes called a "mini stroke") that lasts a few minutes as time passes the plaque can become fibrous Atherosclerosis can also occur in other tissues- peripheral arterial (or artery) disease is a common condition where atherosclerosis restricts blood flow to the legs and symptoms include cold feet and pain from ischaemia in the leg muscles (known as claudication)

Question 29

Atherosclerosis

Answer 29

form of arteriosclerosis- "hardening of the arteries" progressive condition characterised by the deposition of fatty atherosclerotic plaques (also known as atheromas) in the blood vessels only start to show symptoms after about 30 years and at this point an atheroma has formed

Question 30

What causes atherosclerosis?

Answer 30

hypercholesterolaemia is a major risk factor for atherosclerosis because LDL cholesterol is the source of the lipids that are deposited in the arteries atherosclerosis is a chronic inflammatory condition that occurs in response to injury to the endothelium lining blood vessels which means that factors such as hypertension, smoking and diabetes, which can damage blood vessels, all increase the risk of atherosclerosis occurring

Question 31

Foam cells

Answer 31

Foam cells started off as immune system cells (macrophages) Previously atherosclerosis was thought of as being a lipid storage disease but the involvement of macrophages shows it is a chronic inflammatory condition

Question 32

Ischaemic heart disease

Answer 32

the largest single cause of death worldwide UK it accounted for nearly 70000 deaths in 2022 and 2.3 million people are currently living with it due to better treatments and better awareness of modifiable factors such as smoking and diet, the number of annual deaths from ischaemic heart disease has halved in the last 60 years

Question 33

Symptoms of cardiac ischaemia

Answer 33

left-sided chest pain or discomfort that can radiate to the arm, back, neck and jaw (referred pain) and can in some cases be severe breathlessness dizziness sweating

Question 34

Why does ischaemia cause pain?

Answer 34

because when cardiac muscle is deprived of oxygen, it releases pain signals such as adenosine, protons, bradykinin and potassium ions

Question 35

Conditions that involve cardiac ischaemia (2)

Answer 35

stable angina and acute coronary syndromes (ACS) both involve similar types of chest pain but can be more severe in ACS

Question 36

What causes stable angina?

Answer 36

stable angina usually occurs paroxysmally (in attacks) but in a predictable way stable angina attacks occur when a cardiac artery is partially blocked and cannot supply the muscle with enough oxygenated blood to meet its demands normally resolves within a few minutes if the person rests or takes a dose of one of the main angina medications, glyceryltrinitrate (GTN)

Question 37

Acute coronary syndromes

Answer 37

ACS are more serious than stable angina and occur when a blood clot forms on an atherosclerotic plaque. There are three main types: Unstable angina: rarer but more serious form of angina than stable angina. It occurs less predictably and is not relieved by rest or GTN. It has a high risk of progression to a heart attack. Non-ST elevated myocardial infarction (NSTEMI) and ST elevated myocardial infarction- heart attack