Atherosclerosis and lipid metabolism Flashcards

1
Q

What is important to remember about fats

A

They are insoluble in water and therefore need to be packaged into proteins (lipoproteins).

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2
Q

Summarise the basic structure of lipoproteins

A

These consist of a central core of hydrophobic lipid (including triglycerides and cholesteryl esters) encased in a hydrophilic coat of polar phospholipid, free cholesterol and apoprotein.

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3
Q

What are apoproteins

A

Apoproteins bind to specific receptors that mediate uptake of lipoprotein particles into liver, blood or other tissues.

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4
Q

Describe how the different lipoproteins differ

A

There are four main classes of lipoprotein, differing in the relative proportion of the core lipids and in the type of apoprotein (various kinds of apoA and apoB)

Lipoproteins differ in size and density, and this latter property, measured originally by ultracentrifugation but now commonly estimated by simpler methods, is the basis for their classification

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5
Q

Name the different lipoproteins

A

HDL particles (contain apoA1 and apoA2), diameter 7–20 nm

LDL particles (contain apoB-100), diameter 20–30 nm

very-low-density lipoprotein (VLDL) particles (contain apoB-100), diameter 30–80 nm

chylomicrons (contain apoB-48), diameter 100–1000 nm

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6
Q

Describe the exogenous pathway of lipid metabolism

A

The exogenous metabolic pathway is concerned with the transport and utilisation of dietary fats. Dietary fat is broken down in the gastrointestinal tract into cholesterol, fatty acids and mono- and diglycerides. These molecules, together with bile acids, form water-soluble micelles that carry the lipid to absorptive sites in the duodenum.1
Normally, virtually all triglyceride (TG) is absorbed, compared with only 50% of cholesterol. Following absorption in the duodenum, chylomicrons are formed which enter the bloodstream via intestinal lymphatics and the thoracic duct. On entering the plasma, rapid changes take place in the chylomicron. It is hydrolysed by the enzyme lipoprotein (LP) lipase releasing the triglyceride core, free fatty acids and mono- and diglycerides for energy production or storage. The residual chylomicron undergoes further delipidation, resulting in the formation of chylomicron remnants. These are taken up by a number of tissues. In the liver they undergo lysomal degradation, and are either used for a variety of purposes including remanufacture into new lipoproteins, production of cell membranes or excretion as bile salts.1

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7
Q

Where is lipoprotein lipase found

A

On the vascular endothelium of capillaries

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8
Q

Which two tissues can the FFAs released by lipoprotein lipase enter

A
Skeletal muscle (minority)
Adipose  tissue (majority)
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9
Q

What else can happen to the chylomicron remnants

A

They are very good at getting into the tunica intima and so can cause atheroma (normally cleared an hour after a fatty mea l)

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10
Q

What do the chylomicron remnants contain

A

Cholesterol esters.

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11
Q

Describe what happens to the chylomicron remnants upon entering the liver

A

pass to the liver, bind to receptors (remnant receptors) on hepatocytes and undergo endocytosis. Cholesterol liberated in hepatocytes is stored, oxidised to bile acids, secreted unaltered in bile, or can enter the endogenous pathway.

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12
Q

Describe the endogenous pathway of lipid metabolism

A

Whilst chylomicrons transport triglyceride from the gut to the liver, VLDL is the analogous particle that transports triglycerides from the liver to the rest of the body. Triglycerides together with cholesterol, cholesterol ester and other lipoprotein particles are transported in VLDL in the bloodstream, where VLDL undergoes delipidation with the enzyme lipoprotein lipase in a similar way to chylomicrons; this is the endogenous pathway of lipid metabolism. During this process, triglyceride is removed from the core and exchanged for cholesterol esters, principally from HDL. Whilst most VLDL is transformed into LDL, the larger VLDL particles are lipolysed to IDL, which is then removed from the plasma directly. Lipoprotein lipase is the main enzyme used in the lipolysis of large VLDL particles, whereas hepatic lipase reacts with the small VLDL and IDL particles.1 IDL is highly atherogenic.
The product of this metabolic cascade, LDL, exists in the plasma in the form of a number of subfractions; LDL I–IV. It has been shown that small dense LDL particles are the most atherogenic. They are absorbed by macrophages within the arterial wall to form lipid-rich foam cells, the initial stage in the pathogenesis of atherosclerotic plaques.1
The enterohepatic circulation provides a route for the excretion of cholesterol and bile acids.1

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13
Q

What is the purpose of delivering LDL to cells

A

LDL provides the source of cholesterol for incorporation into cell membranes and for synthesis of steroids

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14
Q

Describe how cells take up LDL

A

Cells take up LDL by endocytosis via LDL receptors that recognise apoB-100. LDL receptors are critically important in determining the concentration of circulating LDL, and hence the development and progression of atheromatous disease; the most widely used drugs for the prevention of such disease, the statins, act by blocking the synthesis of cholesterol within hepatocytes which respond by increasing LDL receptor expression on their surface membranes

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15
Q

Where can IDL and LDLs be deposited

A

o IDL and LDLs are deposited in vessels to form atheroma

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16
Q

What happens to the size of the lipoprotein during endogenous lipid metabolism

A

During this process, the lipoprotein particles become smaller but retain a full complement of cholesteryl esters and become LDL particles.
They lose fat- but retain cholesterol esters- and thus increase in density

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17
Q

Describe reverse cholesterol transport

A

As cholesterol cannot be broken down within the body, it is eliminated intact. It 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.1
The observation that HDL acts as a vehicle for the transport of cholesterol for elimination has led to the identification of HDL as a protective factor against the development of atherosclerosis.

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18
Q

What is the purpose of reverse cholesterol transport

A

§ Reverse cholesterol transport – the removal of cholesterol from vessel walls back to the liver by HDL.

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19
Q

What else can happen to the HDL molecules in reverse cholesterol transport

A

Cholesterol can return to plasma from the tissues in HDL particles (reverse cholesterol transport). Cholesterol is esterified with long-chain fatty acids in HDL particles, and the resulting cholesteryl esters are transferred to VLDL or LDL particles by a transfer protein present in the plasma and known as cholesteryl ester transfer protein (CETP)

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20
Q

What type of disease can atherosclerosis be described as

A

“ Atherosclerosis is an inflammatory fibroproliferative disorder

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21
Q

Essentially, what is the issue in atherosclerosis

A

The endothelium of the tunica intima of large and medium sized arteries is damaged- making it leaky and allowing macrophages to enter.

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22
Q

Summarise the pathophysiology of atherosclerosis

A
  1. LDL enters endothelium (into tunica intima (media is VSMCs)).
  2. LDLs are oxidised by macrophages and VSMCs.
  3. Release of growth factors and cytokines.
  4. Additional monocytes/macrophages recruited.
  5. Foam cell accumulation.
  6. VSMC migration.
  7. VSMC proliferation.
  8. Plaque growth.
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23
Q

Describe endothelial dysfunction in atherosclerosis

A

Endothelial dysfunction in atherosclerosis is characterised by a series of early changes that precede lesion formation. The changes include greater permeability of the endothelium, up-regulation of leucocyte and endothelial adhesion molecules and migration of leucocytes into the artery wall.1

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24
Q

Summarise fatty streak formation

A

§ Migration of VSMCs.
§ Activation of T-cells.
§ Adherence & activation of platelets.
§ Formation of foam cells.

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25
Q

Describe the properties of fatty streaks

A

The ‘fatty streak’ is the earliest recognisable lesion of atherosclerosis and is caused by the aggregation of lipid-rich foam cells, derived from macrophages and T lymphocytes, within the intima, the inner most part of the artery wall
Fatty streaks are common; they may increase in size, remain static or even disappear.1

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26
Q

Explain the formation of fatty streaks

A

Monocytes adhere to the endothelium, migrate into the intima and differentiate into macrophages. Local oxidation of LDL (bound to proteoglycans) and once in the intima, macrophages take up the oxLDL and become foam cells.
Platelets adhere to the endothelial cells or areas of denuded matrix and become activated. Activated platelets, activated endothelial cells and macrophages release platelet-derived growth factor stimulating smooth muscle cell migration from the media to the intima.

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27
Q

Describe the uptake of oxLDL by macrophages

A

oxLDL uptake by macrophages via ‘scavenger’ receptors.

Uptake of oxLDL activates macrophages which release proinflammatory cytokines.

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28
Q

Summarise complicated plaque formation

A

§ Formation of fibrous cap.
§ Accumulation of macrophages.
§ Formation of necrotic core.

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29
Q

Describe the development of a lipid plaque

A

Smooth muscle proliferation and an increase in ECM occur in the intima. Additional cytokines and growth factors produced by activated macrophages and platelets promote additional monocyte and smooth muscle infilatration. Lipid may also be released from dying foam cells, contributing to extracellular free lipid pools.
This extracellular free lipid core is prone to calcification

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30
Q

Describe the formation of advanced plaques

A

An advanced atherosclerotic plaque consists of a lipid rich core and a fibrous cap.
The core of the lesion which can become necrotic consists of free lipid, macrophages, smooth muscle and other cellular debris.
The fibrous cap is composed of both collagen and lies over the core, beneath the endothelium. .

31
Q

Describe the importance of the fibrous cap

A

The fibrous cap is a crucial component of the mature atherosclerotic plaque as it separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors. Stable atherosclerotic plaques are characterised by a necrotic lipid core covered by a thick VSM-rich fibrous cap. Lesions expand at the shoulders by continued leukocyte adhesion. 1

32
Q

Which cells are recruited in the process of atherosclerosis

A

Macrophages (which turn into foam cells)
Fibroblasts
Smooth muscle cells

33
Q

Which cells are responsible for producing a protective fibrous cap over the fat core

A

Smooth muscle cells lay down collagen fibres

34
Q

What are the types of atherosclerotic lesions

A
  1. Lesion-prone location – Adaptive thickening of smooth muscle cells.
  2. Type 2 lesion – foam cells.
  3. Type 3 lesion (preatheroma) – extracellular lipid.
  4. Type 4 lesion (atheroma) – bigger core of extracellular lipid.
  5. Type 5 lesion (fibroatheroma) – fibrous thickening.
  6. Type 6 lesion (complicated lesion) – fissure & haematoma.
35
Q

What are lipoprotein remnants and describe their importance

A

Formed as a result of the partial breakdown of large lipoproteins (chylomicrons, IDL, LDL) and are highly atherogenic

Lipoprotein remnants: engulfed by macrophages which become foam cells, and release cytokines to upregulate adhesion molecules - drives the inflammatory part of inflammation

36
Q

What is the key difference between LDL and lipoprotein remnants in terms of the atherogenesis that they cause

A

LDL associated with IHD but with low inflammatory activation- i.e they cause atherosclerosis but without activating the inflammatory and fibroproliferative pathways
The INFLAMMATORY part of atherosclerosis is NOT caused by LDL, but by lipid remnants!

37
Q

Compare vulnerable plaques to stable plaques

A

Vulnerable plaques are characterised by a thin fibrous caps, a core rich in lipid and macrophages, and less evidence of smooth muscle proliferation. In contrast, the stable plaque has a relatively thick fibrous cap protecting the lipid core from the contact with blood.

Vulnerable plaques are prone to rupture and ulceration, followed by rapid development of thrombi. The size of the plaque does not appear to predict whether a plaque is prone to rupture, indeed clinical data suggest that stable plaques more often show luminal narrowing detectable by angiography than do vulnerable plaques.

38
Q

Where does plaque rupture tend to occur

A

Rupture usually occurs at sites of thinning (particularly at the shoulder area of the plaque) and is associated with regions where there are relatively few smooth muscle cells but abundant macrophages and T cells. Rupture is associated with greater influx and activation of macrophages, accompanied by release of matrix metalloproteinases that are involved with the breakdown of collagen

39
Q

What are the consequences of an unstable plaque

A

The fibrous cap thins and eventually ruptures, exposing the thrombogenic lipid core to the platelets and coagulation factors
This causes THROMBOSIS
NOTE: plaque erosion is also associated with hardening of the arteries, leading to weakening and thickening of the vessel wall leading to aneurysm and possible haemorrhage

Damages by hypertension and trauma to fibrous cap (inflammation) - even in places away from the heart- periodontal disease (gum disease)

40
Q

Describe the key properties of an unstable plaque

A

§ Unstable plaque – thin fibrous cap, rich core of lipids & macrophages, less evidence of VSMC proliferation.

41
Q

What is LDL collated with

A

LDL cholesterol has been shown to be strongly associated with the development of atherosclerosis and the risk of CHD events in patients with established CHD (history of angina pectoris, MI etc.) and in those without CHD. This applies to women as well as men, but in women the general level of CHD risk is lower.1 A 10% increase in LDL cholesterol is associated with an approximate 20% increase in risk for CHD.1

42
Q

Describe how the association between LDL and CHD is modified

A

The association between LDL cholesterol and the risk of CHD events is considerably modified by other risk factors, such as low HDL cholesterol, smoking, hypertension and diabetes. This modification is apparent especially when total cholesterol and LDL cholesterol are only moderately elevated.1

43
Q

Describe the importance of HDL cholesterol

A

HDL cholesterol has a protective effect for risk of atherosclerosis and CHD
The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD

44
Q

When is HDL cholesterol lowered

A

HDL cholesterol tends to be low when triglycerides are high

HDL cholesterol is lowered by smoking, obesity and physical inactivity

45
Q

What is the range for normal HDL

A

The lower the HDL cholesterol level the higher the risk for CHD; a low level (<35 mg/dl, 0.9 mmol/l) increases risk and a higher level (³60 mg/dl, 1.6 mmol/l) can be considered a negative risk factor.1

46
Q

Describe the importance of a combination of plasma triglycerides and HDL cholesterol

A

A combination of plasma triglycerides >2 mmol/l (180 mg/dl) and HDL cholesterol <1 mmol/l (40 mg/dl, 1.0 mmol/L) predicts a high risk of CHD, in particular if the cholesterol to HDL cholesterol ratio is greater than 5.2

47
Q

Describe the relationship between total serum cholesterol and mortality in different countries

A

Twenty-five year follow-up data from the Seven Countries study1 show that serum total cholesterol levels are linearly related to CHD mortality across cultures. The relative increase in CHD mortality rates with a given increase in cholesterol are similar. However, the large between-country difference in CHD mortality rates at a given cholesterol level indicates that other factors, such as diet, also play a role in the development of CHD. The link between high cholesterol levels and increased incidence of CHD has also been shown in the prospective part of the Multiple Risk Intervention study.2

48
Q

What did the interheart study show

A

That the risk factors for CVD (smoking, HTN, obesity, LDL and diabetes) have an additive effect in terms of the mortality that they cause
A person with all the risk factors- 300 fold increased risk of death!

49
Q

Which step in cholesterol synthesis do statins block

A

Statins inhibit the HMG-CoA reductase, the enzyme involved in the rate-limiting step in the formation of cholesterol, which is usually responsible for two-thirds of the body’s cholesterol. In response to this the hepatocytes up-regulate and increase the number of LDL receptors, increasing binding and removal of LDL cholesterol and LDL precursors from the plasma. This results in an increase in HDL levels although the mechanism involved has not been fully established.3

50
Q

List some lipid-lowering therapies that can be used I the treatment of atherosclerosis

A

Lipid-lowering therapies include inhibitors of HMG CoA reductase (statins), fibrates, bile acid sequestrants (resins), nicotinic acid and its derivatives, and probucol.

Fibrates -
Gemfibrozil

Ezetimibe

51
Q

What is important to remember about the tolerability of bile acid sequestrants and nicotinic acid

A

Poor patient tolerability

52
Q

What is the normal range for triglycerides

A

< 200 mg/dL or 2.3 mmol/L

High plasma triglyceride levels is also linked with pancreatitis.

53
Q

Outline the synthesis of cholesterol

A

acetyl coA — HMG coA (HMG co A synthase)

HMG coA – mevalonic acid (HMG coA reductase)

mevalonic acid- mevalonate pyrophosphate

mevolanate pyrophosphate — isopentyl pyrophosphate

isopentyl pyrophosphate — geranyl pyrophosphate

geranyl pyrophosphate — farnesyl pyrophosphate

farnesyl pyrophosphate — squalene

squalene — cholesterol

54
Q

What are two important products of the cholesterol synthesis pathway

A

Geranyl pyrophosphate
Farnesyl pyrophosphate
They are involved in the modification and activation of proteins (Rho, ras) - migration and differentiation
They are not steroids

55
Q

Describe how statins reduce plasma LDL levels

A

Statins block the cholesterol synthesis pathway, which leads to the liver responding by producing more LDL receptors
Having more LDL receptors means that more LDL can be removed from the blood
Will also increase plasma HDL levels

Essentially, we starve the liver of its own de novo synthesis of cholesterol- therefore it needs to obtain it from the circulation

56
Q

What is meant by the selectivity ratio of the statin

A

§ Selectivity ratio – the higher the selectivity ratio, the greater the chance of it being concentrated in the hepatocyte.
o I.E. Simvastatin gets into many cells as it’s very lipid soluble. Pravastatin is mainly hepatocytes.

57
Q

What is meat by the potency of the statin

A

§ Potency – the lower the number, the more powerful the drug is as an inhibitor of the enzyme.

58
Q

List the statins in order of increasing ability to lower LDL

A
Fluvastatin (20mg)
Pravastatin (20mg)
Simvastatin (20mg)
atorvastatin (10mg)
rosuvastatin (10mg) -best
59
Q

What is the rule of 6

A

Doubling the dose of any statin will give a 6% reduction in the level of LDL cholesterol

60
Q

Summarise the statin trials and spectrum of risk

A

§ Different trials were designed to measure the effect of statins on different CHD risk groups of patients from low-risk à high-risk.
o 4S1 trial – CHD/high cholesterol group.
o WOSCOPS6 – No MI/high cholesterol.
§ Results showed that irrespective of risk group, all patients benefitted from a 30% reduction in risk.
§ Lowered LDLs too much resulted in problems in the CNS and memory

More likely to achieve lipid targets (lipid levels directly related to cardiovascular end points) in secondary prevention studies i,e those with CVD

61
Q

Summarise the pleiotropic effects of statins

A
Reduce platlet activation  
Reduce thrombotic effect
Increase plaque stability
Decrease vascular inflammation- why statins can be used in rheumatoid arthritis. 
Decrease SMC hypertrophy

Decrease endothelial dysfunction

Decrease SMC proliferation
Decrease vasoconstriction

Positive effects on atherosclerosis, CVD and HTN

62
Q

What are fibrates and how do they act

A

§ MoA – PPAR-alpha receptor agonist.
o PPAR – Peroxisome Proliferator Activated Receptors.
o Act on the liver.
§ Decrease FFAs and TGs. (by increasing cellular uptake of FFAs and increasing triglyceride metabolism)
§ Increases HDL very effectively but LDL doesn’t change a lot.

63
Q

What are the PPAR gamma activators

A

PPAR gamma activators are the thiazolidinediones (glitazones) used
in diabetes

They act on adipose tissue
They are often used in diabetics with high triglycerides

64
Q

What is nicotinic acid

A

Nicotinic acid, a B-complex vitamin whose lipid-lowering properties were first described in the 1950s, is very effective at increasing HDL cholesterol levels and is indicated for all dyslipidaemias except congenital lipoprotein lipase deficiency. The value of nicotinic acid has been limited by the incidence of adverse events, which include flushing, skin problems, gastrointestinal distress, liver toxicity, hyperglycaemia and hyperuricaemia.

65
Q

Why is nicotinic acid not routinely used

A

Should be very good (reduces blood viscosity, increases HDL, reduces LDL, causes vasodilation ,reduces inflammation and thrombosis)- not routinely used in clinical practice- because of side effect profile

66
Q

What is Ezetimibe

A

Inhibits cholesterol absorption

Absorbed then activated as glucuronide

§ Can be co-administered with statins to avoid the “rule of 6” with statins to have a more dramatic effect at lowering LDL.

67
Q

Describe why, in theory, CETP inhibitors would be useful

A

CETP Inhibitors – Cholesterol Ester Transfer Protein – Torcetrapib:
§ CETP converts HDL into LDL and so inhibiting it increases HDL levels

68
Q

Why are CETP inhibitors not used clinically

A

Adverse effects of torcetrapib “off target”

? due to activation of aldosterone synthesis leading to raised BP

Other “rapibs” do not have same effect

But are they any use clinically? no evidence on reducing CVD end points

69
Q

Describe Proprotein Convertase Subtilisin/Kexin Type-9 (PCSK9) Inhibitors

A

PCSK9 is synthesised in inactive form by many tissues, including brain and liver. It is activated autocatalytically by proteolytic cleavage, which removes a section of its peptide chain that blocks its activity. When activated, it binds to LDL receptors and promotes their lysosomal degradation following LDL uptake into hepatocyte cytoplasm (see Fig. 24.1), thereby preventing recycling of LDL receptors to the surface membrane and diminishing their ability to sequester LDL
Therefore diminish the effects of statins

70
Q

Describe the genetic variation in PCSK9

A

Family members who inherit a hyperactive form of the PCSK9 gene suffer from severe hypercholesterolaemia; conversely individuals with inactivating mutations in this gene have low circulating LDL and a low incidence of atheromatous disease.

71
Q

Which group of patients would benefit from PCSK9 inhibitors

A

§ PCSK9 is an inhibitor of the LDL receptor.
§ Monoclonal anti-PCSK9 antibodies have been made to inactivate PCSK9 and so more LDL can be absorbed by the liver.
§ One such group of patients that benefits from PCSK9 inhibition greatly are the people with Familial Hypercholesterolemia.

However, these drugs are very expensive

72
Q

What else could you do instead of giving PCSK9 inhibitors

A

VACCINE AGAINST PCSK9 - INCLISIRAN

Given sub-cutaneously twice a year

More convenient and maybe cheaper

73
Q

Outline the clinical manifestations of atherosclerosis

A

Coronary heart disease
Angina pectoris, myocardial infarction, sudden cardiac death

Cerebrovascular disease
Transient ischaemic attacks, stroke

Peripheral vascular disease
Intermittent claudication, gangrene