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					Atherosclerosis
  and Statins

Dr Usama AlAlami


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                  Atherosclerosis

The coronary arteries are especially susceptible to the
formation of atheroma (plaques)
The reason for this is not fully understood.
The following risk factors contribute to the disease…

• Poor diet – high fat and low fruit & vegetables
• Obesity
• Smoking
• Lack of exercise
• Hypertension and diabetes
Coronary Arteries
Atherosclerosis in the Coronary Arteries




     A severely occluded coronary artery
                Atherosclerosis

There are various processes that cause the development
   of an atheroma. The key ones are…
1. Accumulation of lipids
2. Inflammation
3. Damage by free radicals

Leucocytes are key players (transport lipids)
Diabetes and hypertension also exacerbate problem
                     Cholesterol

• Cholesterol has been implicated in the development
and progression of cardiovascular disease.

• Ideally, cholesterol levels should be controlled by diet,
exercise and abstinence from harmful habits e.g.
smoking

• In reality, we often have to use statins
         What do you remember about
                Cholesterol?

• Cholesterol is a steroid lipid from animal fats in the
  diet and can also be made in the liver.

• It is important for the structural stability of cell
  membranes and also forms the raw material for the
  manufacture of steroid hormones and vitamin D.

• It is also an important constituent of bile
                    Lipoproteins

• Cholesterol is transported in small spheres called
  lipoproteins.

• There are two key types of lipoprotein…
• High density lipoprotein (HDL) that transports
  cholesterol from the tissues to the liver
• Low density lipoprotein (LDL) that transports
  cholesterol from the liver to tissue cells

(There are other types but these are the ones generally
 encountered in blood tests)
  How is cholesterol transported?


liver


                            HDL


  LDL
                   tissue
                    cells
                     Cholesterol

• The ratio between HDL and LDL is important,
  generally, HDL should be high and LDL should be low.
• However, dietary cholesterol consumption is not the
  sole determinant of serum lipid levels.
• Other lifestyle factors such as lack of exercise and
  smoking can adversely affect the HDL : LDL ratio
• Sometimes a fall in blood cholesterol may provoke an
   increase in hepatic cholesterol synthesis.
• This can result in elevated blood cholesterol despite a
   reduction in dietary intake.
    Recommended levels of cholesterol

Total cholesterol        5.2 mmol/L or lower
LDL (bad) cholesterol     3.5 mmol/L or lower
HDL (good) cholesterol   1.3 mmol/L or higher

*NHS Direct 2005
                             Statins

• Statins inhibit HMG CoA reductase* in the hepatocytes

• A key enzyme in the pathway that synthesises of cholesterol

• Inhibiting HMG CoA reductase reduces cholesterol production

• Low levels of cholesterol increase the expression of LDL
  receptors

• This increases the uptake of LDL into the hepatocytes

• Cholesterol levels in the blood fall

*3-hydroxy-3-methylglutaryl coenzyme-A reductase
 Cholesterol synthesis pathway
acetyl CoA + acetoacetyl CoA


 3-hydroxy-3-methylglutaryl CoA
          (HMG CoA)                           Reaction
                                            catalysed by
                                            HMG CoA        You do not need
                                                            to learn this
                                             reductase


mevalonate                     5-phosphomevalonate
                                                            pathway for
                                                              the test
 isopentenyl             5-pyrophosphomevalonate
pyrophosphate


 dimethyallyl                  geranyl pyrophosphate
pyrophosphate


  squalene                farnesyl pyrophosphate


squalene epoxide                    lanesterol


                                   cholesterol
Summary of action of statins
                                              HMG CoA
                                              reductase
                        HEPATOCYTE             enzyme


                       HMG CoA


Upregulation of LDL    mevalonate
receptors pulls LDL
                                     reaction inhibited by
into hepatocytes and
                                     HMG CoA reductase
lowers serum LDL
                       cholesterol   inhibitor (statin)




                                low cholesterol
                                upregulates LDL
                                receptors
                        Statins

Examples - atorvastatin, fluvastatin, pravastatin,
rosuvastatin and simvastatin.

Contra-indicated in patients with liver disease,
pregnancy and breast feeding

Side effects – myositis (inflammation of muscles),
headache, GI disturbance etc.

Administered before bed as most cholesterol is
synthesised at night time
End of Presentation


               That’s all
                folks

				
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posted:1/26/2011
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