WEEK 2: Atherosclerosis and thrombosis

Question 1

What is atherosclerosis?

Answer 1

Simply put; it is the build up of fats, cholesterol and other substances in and on your artery walls.

It is a process of progressive thickening and hardening of the walls of medium- sized and large arteries as a result of atheroma.

Question 2

What is an atheroma?

Answer 2

Are formed from the accumulation of intracellular and extracellular lipid in the intima of large and medium-sized arteries.

May begin as fatty streaks.

Question 3

What is Arteriosclerosis?

Answer 3

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

Question 4

What is thrombosis?

What is a thrombus?

What is an embolus?

What is thromboembolism?

Answer 4

1. The formation or presence of a blood clot in a blood vessel.

The vessel may be any vein or artery as, for example, in a deep vein thrombosis or a coronary (artery) thrombosis.

2. A thrombus is a blood clot that forms inside the circulatory system and can impede blood flow. It is large and stationary.
3. Embolus is a piece of a blood clot that is unattached and can travel along the bloodstream into a considerable distance from its point of origin.

4.. If the clot breaks loose and travels through the bloodstream, this phenomenon is thromboembolism.

Question 5

Compare atherosclerosis and arteriosclerosis.

Answer 5

1. MEANING
   Atherosclerosis
   The buildup of plaque in artery walls causes the arteries to narrow

Arteriosclerosis
The hardening or thickening of artery walls, restricting blood flow to organs and tissues

2. SCOPE
   *A type of arteriosclerosis
   *A broader term for a group of conditions

3.Type of deposits
*Fatty deposits
*Calcium deposits

4.Occurrence of symptoms
*Mild atherosclerosis shows no symptoms. Symptoms are usually experienced in moderate to severe atherosclerosis.

*It causes no symptoms, especially in the early stages.

5.Causes
*Damage to endothelial cells
*Damage to elastin fibers

Question 6

What is the leading cause of death resulting from vascular disease worldwide?

Answer 6

Atherosclerosis is the leading cause of death resulting from vascular disease worldwide.

Question 7

Outline the 3 major clinical manifestations of atherosclerosis.

Answer 7

• Ischemic heart disease (IHD),
• Ischemic stroke,
• Peripheral arterial disease.

Question 8

The epidemiology of cardiovascular diseases in sub-Saharan Africa is unique as compared to other world regions.

Describe the epidemiology of atherosclerosis in Sub-Saharan Africa.

Answer 8

Half of cardiovascular diseases (CVDs) due to other causes other than atherosclerosis.

CVDs contributed only 8.8 % of deaths.

However, in affluent societies, the incidence is raising.

Stroke, atrial fibrillation and peripheral arterial disease where leading causes of death and disability from CVD in 2010.

Question 9

Describe the endothelium of an artery wall.
Namee the substance found in the endothelial cell.

Answer 9

Normally arterial endothelium repels cells (RBCs, WBCs and platelets) and inhibits blood clotting.

The lumen of healthy arterial wall is lined by a single-cell thick confluent layer of endothelial cells.

Endothelial cell (EC) integrity is critical for normal vessel wall hemostasis and circulatory function.

ECs contain Weibel-Palade bodies that contain von Willebrand factor (vWF).

Question 10

The arterial wall has 3 layers. Name and describe them.

Answer 10

1. Intima (subendothelial layer)
2. Media (middle layer) with smooth muscle cells (VSMC)
3. Adventitia (outer layer) with connective tissue and nerves

Question 11

State the functions of the endothelium.

Answer 11

*Controls important functions: vasodilatation and vasoconstriction.

*Regulates tissue and organ blood flow and plays a role in the maintenance of a non-thrombogenic blood-tissue interface.

*Metabolism of hormones and

*Regulation of immune and inflammatory reactions as well as

*Growth regulation of other cell types especially SMCs.

Question 12

Endothelial activation occurs when the ECs respond to various pathophysiological stimuli by adjusting their usual functions and expressing new properties.

Outline some of the inducers of endothelial activation.

Answer 12

Inducers of endothelial activation are:

*Cytokines,
*Bacterial products which induce inflammation and septic shock
*Hemodynamic stresses
*Lipid products critical to the pathogenesis of atherosclerosis
*Advanced glycosylation end products, viruses, complement and hypoxia.

Question 13

The endothelium releases a variety substance in order to control vasomotor tone:
State an example of the following.

*Relaxing factors
*Contracting factors

Answer 13

The endothelium releases a variety of substances in order to control vasomotor tone: relaxing factors (Nitric oxide (NO) and contracting factors (endothelin).

Question 14

Exercise is an important mechanical stimulus mediated by shear stress to increase blood flow.

What is shear stress?

Answer 14

Exercise is an important mechanical stimulus mediated by shear stress to increase blood flow.

Shear stress is the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall.

Question 15

State at least 5 modifiable risk factors of atherosclerosis.

State the 3 main non-modifiable risk factors of atherosclerosis.

Answer 15

1. Modifiable
   High levels of low-density lipoproteins (bad cholesterol)
   High blood pressure (hypertension)
   Diabetes
   Lack of exercise
   Smoking
   Alcohol
   Obesity
   Soft water
   Oral contraceptives
   Stress

2.Non modifiable
A genetic family history of arteriosclerotic disease.
Gender
Age

Question 16

State the function of the following in Atheroma-lipid metabolism.

1.Chylomicrons
2.VLDL
3.LDL
4.HDL

Answer 16

1.Chylomicrons
transport lipid from intestine to liver

2.VLDL
carry cholesterol and TG from liver.
TG removed leaving LDL.

3.LDL
rich in cholesterol
carry cholesterol to non-liver cells.

4.HDL
carry cholesterol from periphery back to liver.

Question 17

State the 4 atheroma proposed theories.

Answer 17

1. Thrombogenic theory
   1852 Karl Rokitansky
   plaques formed by repeated thrombi.
   lipid derived from thrombi.
   overlying fibrous cap
2. Insudation theory:
   1856 Rudolf Virchow
   endothelial injury
   inflammation
   increased permeability to lipid from plasma
3. Monoclonal hypothesis

Benditt and Benditt
crucial role for smooth muscle proliferation
each plaque is monoclonal.
might represent abnormal growth control.
is each plaque a benign tumor?
could atheroma have a viral etiology?

4. Reaction to injury hypothesis

1972 Ross and Glomset
plaques form in response to endothelial injury
hypercholesterolaemia leads to endothelial damage in experimental animals
injury increases permeability and allows platelet adhesion
monocytes penetrate endothelium
smooth muscle cells proliferate and migrate

Question 18

Outline some of the causes of endothelial injury.

Answer 18

Raised LDL
‘Toxins’ e.g., cigarette smoke
Hypertension
Hemodynamic stress
Diabetes

Question 19

Describe the consequences of endothelial injury.

Answer 19

1. Endothelium becomes more permeable to lipoproteins.
2. Lipoproteins move below the endothelial layer (to intima).
3. Endothelium loses its cell-repellent quality.
4. Inflammatory cells move into the vascular wall.

Question 20

Name the substance expressed by dysfunctional endothelium to mediate rolling interaction with cells.

What is the key molecule that promote monocyte adhesion?

What are the adhering cells stimulated by monocyte which helps them cross the endothelium, settle into the intima?

Answer 20

1. Dysfunctional endothelium express adhesion molecules – selectins, mediate the “rolling” interaction of cells.

The key molecule - vascular cell adhesion molecule-1 (VCAM-1) promotes monocytes adhesion (precursors of macrophages).

Adhering cells are stimulated by monocyte chemoattractant protein-1 (MCP-1).

Monocytes cross the endothelium, settle down in the intima.

Question 21

Describe lipids contribution to atherosclerosis.

Answer 21

LIPIDS
Lipid entry into the arterial wall is a key process in atherogenesis.

Hypercholesterolemia – factor for VCAM-1 and MCP-1 induction.

LDL and VLDL are the most atherogenic and enter vascular wall more easily.

LDL – in plasma are protected against oxidation by vit. E, ubiquinon, plasma antioxidants (β-carotene, vit. C).

Out of plasma, LDL phospholipids and fatty acids oxidize.

Question 22

Review the atheroma formation from slides.

Answer 22

Macrophages and foam cells

*Foam cells ruptured (apoptosis).
*Lipid release to intima and their accumulation becomes the center of atherosclerotic plaques.

*The lipid center and fibrous cap are the main parts of a mature atherosclerotic plaque.
*Plaque emerges from the structurally changed vascular wall.
*So-called vulnerable plaque ruptures easily.
*The thrombus forms at the rupture site

Answer 23

Atheroma- lymphocytes and neutrophils

*Lymphocytes releases tumor necrosis factor (TNF) may affect lipoprotein metabolism.
*Stimulate proliferation and migration of smooth muscle cells.
*Neutrophils secrete proteases leading to continued local damage and inflammation.

Answer 24

Smooth muscle cells:

*Stimulated smooth muscle cells (SMCs) produce matrix material.
*Foam cells secrete cytokines causing

-further SMC stimulation
-recruitment of other inflammatory cells

Question 25

Outline ways of reducing atherosclerotic event.

Answer 25

The risk of atherosclerotic event can be decreased by:
-Eating diets low in cholesterol
-Exercise
-Stopping Smoking
-Control of high blood pressure
-Drugs statins, fibrates (fibric acid), ezetimibe, antioxidants

Question 26

Describe the MOA of the following drugs in preventing atherosclerosis.

1.Statins
2.Fibrates
3.Ezetimbe

Answer 26

1.Statins – inhibit intracellular cholesterol synthase (HMG-CoA reductase).

2.Fibrates
- lower plasma cholesterol by stimulating endothelial LPL (lipoprotein lipase) decreasing TAG concentration, less LDL and VLDL synthesis.
-It enhances synthesis of apoproteins AI and AII which result in enhancement of HDL synthesis.

3.Ezetimibe – inhibitor of intestinal cholesterol transporter.
β−carotene, α-tocoferol, vitamin C (such as these contained in fruits or their combinations) have preventive benefit, protect LDL against oxidation.

Question 27

State the 3 major macroscopic features of atheroma.

Answer 27

Fatty streak:
*Lipid deposits in intima
*Yellow slightly raised.

2. Simple plaque:
   *Raised yellow/white
   *Irregular outline
   *Widely distributed
   *Enlarge and coalesce
3. Complicated plaque
   *Thrombosis
   *Hemorrhage into plaque
   *Calcification
   *Aneurysm formation: An abnormal bulge or ballooning in the wall of a blood vessel.

Question 28

State the common sites for atheroma formation.

Answer 28

Aorta - especially abdominal

Coronary arteries

Carotid arteries

Cerebral arteries

Leg arteries

Question 29

Outline the early microscopic changes in atheroma formation.

Answer 29

Early changes
proliferation of smooth muscle cells
accumulation of foam cells
extracellular lipid

Answer 30

Later changes
fibrosis
necrosis
cholesterol clefts
+/- inflammatory cells
disruption of internal elastic lamina
damage extends into media.
ingrowth of blood vessels
plaque fissuring

Question 31

Describe the characteristics of the following clinical effects of atheroma.

1. ischemic heart disease
   2.Cerebral ischemia
   3.Mesentric ischemia
2. Peripheral vascular disease

Answer 31

1. ischemic heart disease (IHD)
   *Sudden death
   *Myocardial infarction
   *Angina pectoris
   *Arrhythmias
   *Cardiac failure
2. Cerebral ischemia
   transient ischemic attack
   cerebral infarction (stroke)
   multi-infarct dementia
3. Mesenteric ischaemia
   ischaemic colitis
   malabsorption
   intestinal infarction
4. Peripheral vascular disease
   intermittent claudication
   Leriche syndrome
   ischemic rest pain
   gangrene

Question 32

Outline the preventative measures for atherosclerosis.

Answer 32

1. Lifestyle changes:
   Control weight
   More regular exercises
   More vegetable/ high fiber diet
   Less red meat
   Omega 3 fatty acids in fish
   Early diagnosis and management of cardiovascular disease e.g., hypertension.

Question 33

Describe the relationship between atheroma and apolipoprotein E.

Answer 33

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

Question 34

Familial hyperlipidemia genetically determined abnormalities of lipoproteins
Lead to early development of atheroma

Answer 34

Associated physical signs:

*Corneal arcus (a ring round the cornea)

*Tendon xanthomas (cholesterol deposits in tendons)

*Xanthelasma (yellowish- white lumps of fatty material accumulated under the skin or on inner parts of the upper and lower eyelids).

Question 35

Infections can also result in atheroma formation.

State 3 examples.

Answer 35

1. Chlamydia pneumoniae: is a species of Chlamydia, an obligate intracellular bacterium that infects humans and is a major cause of pneumonia.
2. Helicobacter pylori (H. pylori): is a spiral-shaped bacterium that lives in the mucus lining of the stomach and duodenum.
3. Cytomegalovirus: A common viral infection that is mostly harmless, and only rarely causes illness. This causes body pain, fever, tiredness and sore throat.