Arterial Thrombosis (1)

Key Risk Factors: Changes in blood lipids

- high plasma cholesterol levels, particularly LDL levels, - high plasma triglyceride levels - low HDL levels all increase risk of atheroma.

Metabolic Causes of Secondary Hyperlipidaemia - Excessive alcohol consumption

- high trig's and fatty acids

Metabolic Causes of Secondary Hyperlipidaemia Type 2 diabetes

- high trig's and fatty acids

Metabolic Causes of Secondary Hyperlipidaemia Metabolic syndrome

- high trig's, small dense LDL

Metabolic Causes of Secondary Hyperlipidaemia Lipodystrophy

- inability to store fat in adipose tissue- VLDL & LDL

Metabolic Causes of Secondary Hyperlipidaemia - Anorexia nervosa

- increased VLDL and LDL

Metabolic Causes of Secondary Hyperlipidaemia - Cholestatic liver disease

- increased cholesterol & Lp-X (no apoB) Lipoprotein X (LP-X) is an abnormal lipoprotein that appears in the sera of patients with obstructive jaundice and is thus a marker for cholestasis.

Consequences of Atherosclerosis: Thrombotic complications

- Angina - Myocardial infarction - Transient ischaemic attacks - Thrombotic stroke - Claudication - Amputation - Renal failure - Cardiac Failure

Key Risk Factors

- Changes in blood lipids - Hypertension - Diabetes Mellitus

Claudication

- Claudication is a common condition in which pain occurs in the legs with exercise. - The pain is the result of a reduction in the bloodflow to the muscles of the legs

Ischaemic Heart Disease

- Coronary heart disease (CHD) is the largest single cause of death in the Ukin humans. - Caused by the formation of fibro-fatty plaques in the artery called atheroma (process of atherosclerosis). - Number of risk factors for development of atherosclerosis and CHD. - Prevention tends to focus on the identification and reduction of these risk factors.

Key mechanisms are?

- Hyperlipidaemia - activation of endothelial cells - activation of platelets

Thrombotic stroke

- In a thrombotic stroke, a blood clot (thrombus) forms inside one of the brain's arteries. - The clot blocks blood flow to a part of the brain. - This causes brain cells in that area to stop functioning and die quickly.

Metabolic Causes of Secondary Hyperlipidaemia Renal disease (especially with proteinuria)

- TRL's Patients with chronic kidney disease (CKD) frequently display: - abnormalities of plasma lipids and lipoproteins. - include hypertriglyceridemia associated with elevated levels of very low-density lipoproteins (VLDLs) and chylomicrons.

What is Atherosclerosis

- arteries become clogged with fatty substances called plaques, or atheroma. - plaques cause the arteries to harden and narrow, restricting the blood flow and oxygen supply to vital organs, and increasing the risk of blood clots that could potentially block the flow of blood to the heart or brain

Metabolic Causes of Secondary Hyperlipidaemia Paraproteinaemia (excessive quantities of paraprotein are present in the blood)

- can cause high IDL & xanthomas Xanthomas are lesions characterized by accumulations of lipid-laden macrophages. Xanthomas can develop in the setting of altered systemic lipid metabolism or as a result of local cell dysfunction.

Angina

- chest pain caused by reduced blood flow to the heart muscles

Lipoproteins may be classified according to their density, as follows:

- chylomicrons (lipoprotein rich in triglyceride and common in the blood during fat digestion and assimilation) - very-low-density lipoproteins (VLDL) - intermediate-density lipoproteins (IDL), - low-density lipoproteins (LDL) - high-density lipoproteins (HDL).

Metabolic Causes of Secondary Hyperlipidaemia - Hypothyroidism

- decreased breakdown especially of LDL

Cardiac Failure

- heart is unable to pump blood around the body properly. - It usually occurs because the heart has become too weak or stiff (due to plaques)

Hypertension

- high blood pressure is considered to be 140/90mmHg or higher

As a general guide, LDL levels should be:

3mmol/L or less for healthy adults 2mmol/L or less for those at high risk

total cholesterol levels should be:

5mmol/L or less for healthy adults 4mmol/L or less for those at high risk

Myocardial infarction

A heart attack (myocardial infarction or MI) is a serious medical emergency in which the supply of blood to the heart is suddenly blocked, usually by a blood clot

Interaction between risk factors and key mechanisms: Diet

A high fat diet, familial defects in lipid metabolism, diabetes mellitus can all contribute to increased LDL levels. A diet low in antioxidants, increased oxidative stress (due to infection, inflammation, diabetes mellitus, smoking) will accelerate the deposition of LDL in the artery.

Transient ischaemic attacks

A transient ischaemic attack (TIA) or "mini stroke" is caused by a temporary disruption in the blood supply to part of the brain

Key Risk Factors: Hypertension

An important risk factor that is easy to identify and treat. Thresholds for treatment vary depending on age and co-existing pathologies.

Pathogenic Events in Atherosclerosis:

Branch points in the arterial tree Changes in endothelial cell function-activation Formation of foam cells Proliferation of smooth muscle cells Formation of necrotic core Mural thrombosis Plaque rupture

Key Risk Factors: Diabetes Mellitus

Confers increased risk in men and women. Often 10year gap between onset and diagnosis.

Amputation

Due to tissue death from lack of blood supply to area

Mural thrombosis

Formation of a thrombus in contact with the endocardial lining of a cardiac chamber or, if not occlusive, with a wall of a large blood vessel.

Your ratio of total cholesterol to HDL may also be calculated. This is your total cholesterol level divided by your HDL level.

Generally, this ratio should be below four, as a higher ratio increases your risk of heart disease.

Hyperlipidaemia

Having an excessively high level of lipids in your blood Two types: - high-density lipoprotein (HDL) - (good) - low-density lipoprotein (LDL) - (bad)

Interaction between risk factors and key mechanisms: endothelial cell activation

Hypertension, smoking, diabetes mellitus oxidative stress all lead to endothelial cell activation.

Metabolic Causes of Secondary Hyperlipidaemia

Hypothyroidism Excessive alcohol consumption Obesity High energy diet Type 2 diabetes Metabolic syndrome Renal disease (especially with proteinuria) Lipodystrophy Anorexia nervosa Paraproteinaemia Cholestatic liver disease

Risk Reuction:

Identification and treatment of diabetes mellitus and other secondary causes of hyperlipidaemia May be metabolic or drug induced Review medication

Interaction between risk factors and key mechanisms: platelet activation

Psychological stress, infection, smoking, diabetes mellitus all lead to increased platelet activation.

Risk factors Lots, some modifiable, others not (e.g. age, family history, gender). The most important modifiable risk factors are:

Smoking Hypertension Sedentary lifestyle (lack of excercise) Hyperlipidaemia Fruit and vegetable intake Diabetes mellitus

Changes in endothelial cell function-activation Proliferation of smooth muscle cells Formation of necrotic core Mural thrombosis

The endothelial cells begin to produce cell surface adhesion molecules such as VCAM-1, causing monocytes and T-lymphocytes to adhere to the endothelium and then migrate beneath it by squeezing between the endothelial cells. Circulating monocytes and T-lymphocytes are attracted to the sites of injury by chemoattractant cytokines (chemokines). The endothelial cells also change shape, and the tight junctions between endothelial cells loosen, increasing the permeability to fluid, lipids, and leukocytes. Lipoprotein particles, and especially low-density lipoprotein (LDL), enter the arterial wall and undergo oxidation. Oxidation of LDL in the arterial wall occurs as a result of its exposure to nitric oxide, macrophages, and some enzymes such as lipoxygenase. Once they have migrated into the intima, monocytes differentiate into macrophages and begin to take up oxidized LDL that has gotten into the intima. Macrophages retain the lipid they take up, and as they become more lipid-laden, they are referred to as "foam cells." Eventually, the foam cell will undergo apoptosis and die, but the lipid will accumulate in the intima (mural thrombosis).

Activation of endothelial cells (slide 7)

can lead to recruitment of monocytes into the subendothelial space to form foam cells, it also leads to vasoconstriction (narrowing of the artery) and secretion of procoagulants, triggering thrombosis.

high-density lipoprotein (HDL) -

carries cholesterol away from the cells and back to the liver, where it's either broken down or passed out of the body as a waste product; for this reason, HDL is referred to as "good cholesterol", and higher levels are better

low-density lipoprotein (LDL) -

carries cholesterol to the cells that need it, but if there's too much cholesterol for the cells to use, it can build up in the artery walls, leading to disease of the arteries; for this reason, LDL is known as "bad cholesterol"

Metabolic Causes of Secondary Hyperlipidaemia High energy diet (especially in saturated fat)

high VLDL and LDL (Very-low-density lipoprotein (VLDL)

Metabolic Causes of Secondary Hyperlipidaemia - Obesity

high trig's and fatty acids

Activated platelets

secrete vasoconstrictors, growth factors (affect fibroblasts and smooth muscle cells) and are key in the formation of emboli and thrombi.

Hyperlipidaemia (slide 7)

specifically high plasma levels of low density lipoprotein (LDL) accelerate the production of foam cells and fatty streaks. This is further accelerated if the LDL has been modified by processes such as oxidation.