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Personal ESA 2 Mechanisms of Disease > Session 7 > Flashcards

Session 7 Flashcards

0
Q

Define Atherosclerosis

A

The thickening and hardening of arterial walls as a consequence of atheroma

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1
Q

Define Atheroma

A

The accumulation of intracellular and extracellular lipid in the intima and media of large and medium sized arteries.

NOTE: plaque contains other substances other than lipids

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2
Q

Define Arteriosclerosis

A

The thickening of the walls of arteries and arterioles usually as a result of hypertension or diabetes mellitus.

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3
Q

What are three 3 macroscopic features of an atheroma?

A

Fatty streak

Simple plaque

Complicated plaque

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4
Q

Describe the Fatty Streak of an Atheroma

A

Lipid deposits in the intima

Yellow, slightly raised

[Relationship to atheroma somewhat debatable (e.g.found in populations which are not prone to atheroma) but generally fatty streak is thought to be a precursor to atheroma]

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5
Q

Describe the Simple Plaque of an Atheroma

A

Raised yellow/white

Irregular outline

Widely distributed

Enlarge and coalesce (extensive atheroma)

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6
Q

Describe the Complicated Plaque of an Atheroma

A

Thrombosis

Haemorrhage into plaque

Calcification

Aneurysm formation (due to loss of elastic recoil as fibrosis occurs so as aorta expands, it remains fixed in balloon state -so wall is weaker and more prone to rupture)

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7
Q

What are the common sites of atheroma formation?

A

Aorta - especially abdominal

Coronary arteries

Carotid arteries

Cerebral arteries

Leg arteries

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8
Q

Describe the Normal Arterial Structure

A

Endothelium

Sub-endothelial connective tissue

Internal elastic lamina

Muscular media

External elastic lamina

Adventitia

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9
Q

How are the Microscopic Features of an Atheroma classified?

A

Early changes

Later changes

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10
Q

Describe the microscopic early changes of an Atheroma

A

Proliferation of smooth muscle cells

Accumulation of foam cells (containing lipid)

Extracellular lipid (within the wall of the artery)

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11
Q

Describe the microscopic later changes of an Atheroma

A

Fibrosis (include dense fibrous cap over plaque)

Necrosis

Cholesterol clefts (when cholesterol crystallises and forms deposition in the tissue, not the plaque)

+/- Inflammatory cells (very variable)

Disruption of internal elastic lamina

Ingrowth of new blood vessels (formation of new capillaries which are very leaky and therefore may contribute to haemorrhage into plaque)

Plaque fissuring (movement of blood produces shearing forces)

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12
Q

The effect of atheroma depends on site.

Describe the clinical effects of severe atherosclerosis in Ischaemic Heart Disease

A

Atheroma of the coronary arteries reduces the flow to the myocardium and coronary thrombosis commonly over atheromatous plaques.

They could lead to:

Sudden death (without any warning/ previous symptoms)

Myocardial infarction

Angina pectoris (chest pain upon exercise)

Arrhythmias (if it is ventricular fibrillation, it could lead to sudden deaths

Cardiac failure

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13
Q

The effect of atheroma depends on site. Describe the clinical effects of severe atherosclerosis in Cerebral Ischaemia

A

Transient Ischaemic Attack (‘mini-stroke’) - infarction of part of the brain.

Symptoms resolved within 24 hours - thrombus in carotid artery is dissolved by Fibrinolysis.

Cerebral infarction (stroke) Multi-infarct dementia (dementia due to multiple infarcts causing cognitive impairment)

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14
Q

The effect of atheroma depends on site. Describe the clinical effects of severe atherosclerosis in Mesenteric Ischaemia

A

Mesenteric artery can become blocked either due to atheroma or thrombus. This could lead to:

Ischaemic colitis

Malabsorption (because of impoverished blood supply)

Intestinal infarction

Aneurysm due to the high pressure, hardening and weakening.

*Black bowel due to lack of blood supply

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15
Q

The effect of atheroma depends on site. Describe the clinical effects of severe atherosclerosis in Peripheral Vascular Disease

A

Intermittent claudication (deep muscle/calf pain upon exercise - goes away after rest but may come back after walking a shorter distance progressively until there is pain at rest)

Leriche Syndrome (often associated with impotence, pain in the buttocks as the iliac artery is affected)

Ischaemic rest pain

Gangrene

Note: after an amputation, blood supply may still not be adequate for the metabolic demands of new tissue growth which results in a necessity for a second amputation.

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16
Q

Describe the Cellular events of Atheroma

A

Endothelial damage –> Platelets –> PDGF –> Smooth Muscle Proliferation

Proliferation and migration of smooth muscle takes the lipid with it.

Macrophages arrive and phagocytose the fat, becoming foam cells.

17
Q

Discuss the Risk Factors for Atheroma

A

Age: slowly progressive throughput adult life, risk factors operate over years (although onset can seem sudden).

Gender: women protected relatively before menopause (presumed hormonal - oestrogen - basis)

Hyperlipidaemia: high plasma cholesterol associated with atheroma (LDL most significant, HDL is protective)

Cigarette smoking: powerful risk factor for IHD, risk decreases gradually after giving up, mode of action is uncertain (in the coagulation system, there is reduced PG12 which increases platelet aggregation)

Hypertension: strong link between IHD and high BP, mechanism uncertain?

Diabetes Mellitus: doubles IHD risk, protective effect in premenopausal women lost, DM also associated with high risk of cerebrovascular and peripheral vascular disease

Alcohol

Infection

Lack of exercise

Obesity

Soft water

Oral contraceptives

Stress/personality type

18
Q

Explain why the mechanism linking hypertension and IHD is uncertain

A

Endothelial damage can be caused by raised pressure but some sites are more prone to developing atheroma than others but pressure is the same across the body, so if hypertension caused atheroma, shouldn’t atheroma have a uniform distribution?

19
Q

Explain how alcohol is a risk factor for atheroma

A

>5 units / day associated with increased risk of IHD.

Alcohol consumption is often associated with other risk factors e.g. Smoking and high BP but still an independent risk factor.

Small amounts of alcohol may be protective (studies looked at Mediterranean diet)

20
Q

What types of Infections have been linked to Atheroma?

A

E.g. Chalamydia pneumoniae, Helicobacter pylori, Cytomegalovirus

Note: no firm conclusive evidence - atherosclerosis is clearly multi-factorial.

21
Q

Describe Lipid Metabolism

A

Lipid is transported around the body via lipoproteins.

Lipoproteins have a hydrophobic lipid core (cholesterol esters and TAGs) and hydrophilic coat of (phospholipids and apoproteins (A-E)).

Chylomicrons transport lipid from intestine to liver.

VLDL carry cholesterol and TAGs from liver

TAGs are removed leaving LDL. LDL is rich in cholesterol and carry cholesterol to non-liver cells.

HDL carry cholesterol from periphery back to metabolism.

Genetic variations in ApoE are associated with changes in LDL levels. Polymorphisms of the genes involved lead to at least 6 ApoE phenotypes. Polymorphisms can be used as risk markers for atheroma

Genetically determined abnormalities of lipoproteins lead to early development of atheroma (Familial Hyperlipidaemia).

22
Q

What are the associated physical signs of Familial Hyperlipidaemia?

A

Associated physical signs include arcus (yellow ring around cornea), tendon xanthomas and xanthelasma (lipid nodules on corner of eyes or on eyelid)

23
Q

Explain about the Genetic Predisposition to atheroma

A

Familial predisposition is well known but actual family tree/ pattern of inheritance is unclear.

Possibly due to variations in apolipoprotein metabolism or in apolipoprotein receptors - lipoprotein abnormality.

24
Q

What is the Thrombogenic Theory?

A

Multiple mini thrombi associated with lipid causing an overlying fibrous cap to form.

25
Q

What is the Insudation Theory?

A

1856 Rudolf Virchow

Endothelial injury –> Inflammation –> Increased permeability to lipid from plasma

26
Q

What is the Reaction to Injury Hypothesis?

A

1872 Ross and Glomsef

Plaques form in response to endothelial injury.

Hypercholesterolaemia leads to endothelial damage in experiential animals.

Injury increases permeability and allows platelet adhesion.

Monocytes penetrate endothelium

Smooth cells proliferate and migrate

Endothelial injury may be very subtle and be undetectable visually.

LDL, especially oxidised, may damage endothelium (may be toxic) but this hypothesis is difficult to prove in life.

27
Q

What is the Monoclonal Hypothesis (Benditt and Benditt)?

A

Crucial role for smooth muscle proliferation

Each plaque is monoclonal (derived from a single cell)

Might represent abnormal growth control

Is each plaque a mini benign tumour?

Could atheroma have a viral aetiology?

28
Q

What are the processes involved in Atheroma?

A

Thrombosis

Lipid accumulation

Production of intercellular matrix (abnormal composition such as different amounts of collage and polypeptide compared to normal)

Interactions between cell types.

29
Q

Describe how Endothelial Cells are involved in atheroma

A

Endothelial cells have a key role in Haemostasis:

Altered permeability to lipoproteins

Secretion of collagen

Stimulation of proliferation and migration of smooth muscle cells.

30
Q

Describe how platelets are involved in Atheroma

A

Stimulate proliferation and migration of smooth muscle cells (Platelet-Derived Growth Factor)

31
Q

Describe how Smooth Muscle cells are involved in Atheroma

A

Take up LDL and other lipids to become foam cells

Synthesise collagen and proteoglycans

32
Q

Describe how Macrophages are involved in Atheroma

A

Oxidise LDL

Take up lipids to become foam cells

Secrete proteases which modify intercellular matrix (this has an effect on plaque stability, risk of plaque rupturing and fissuring)

Stimulate proliferation and migration of smooth muscle cells

33
Q

Describe how Lymphocytes are involved in Atheroma

A

Tissue Necrosis Factor (TNF) may affect lipoprotein metabolism

Stimulate proliferation and migration of smooth muscle cells

34
Q

Describe how Neutrophils (present in some cases) are involved in Atheroma

A

Secrete proteases leading to continued local damage and inflammation

Can also modify intercellular matrix, affecting plaque stability which is important in the development of thrombi over plaque

35
Q

What is meant by the Unifying Hypothesis of Atherogenesis?

A

(Subtle) Endothelial injury due to: Raised LDL, Toxins e.g. Cigarette smoke, Hypertension, Haemodynamic Stress

Endothelial injury causes: Platelet adhesion, PDGF release, SMC proliferation and migration, Insudation of lipid, LDL oxidation, uptake of lipid by SMC and macrophages, migration of monocytes into intima

Stimulated smooth muscle cells produce matrix material.

Foam cells secrete cytokines causing further SMC stimulation and recruitment of other inflammatory cells (self-perpetuating development).

36
Q

Is atheroma reversible?

A

No, but progression may be slowed and complications may be reduced

37
Q

Discuss the prevention of atheroma

A

No smoking

Reduce fat intake

Treat hypertension

Not too much alcohol

Regular exercise/weight control

BUT some people will still develop atheroma (you can substantially reduce the risk but you cannot eliminate the risk - genetic predisposition is very important)

38
Q

What treatment do you need to do as an Intervention - e.g. After an MI?

A

Stop smoking

Modify diet

Treat risk factors

Treat diabetes

Lipid lowering drugs (statins, aspirin)

39
Q

Discuss Susceptibility to Coronary Heart Disease

A

Genetic - Disorders can increase risk e.g. Familial Hypercholesterolaemia

Geographical - Less common in the Mediterranean (diet)

Ethnicity - CHD common in Asians

40
Q

What are risk factors for Coronary Heart Disease?

A

Smoking

Gender - more common in men

Hypertension

Diabetes

Alcohol

Infection (helicobacter pylori - recent evidence unsure how, but there is an association)

41
Q

How does the normal endothelium prevent thrombosis by?

A
  • Prostacyclin production: prostacyclin is a prostaglandin which prevents adhesion and aggregation of platelets to endothelium.
  • Thrombomodulin production: binds to any locally formed thrombin and this complex initiates the anti-coagulant effects of Protein C and S
  • Prothrombin production: these molecules inhibit elements of the normal coagulation cascade.

Personal ESA 2 Mechanisms of Disease (11 decks)

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