Module 4 Section 3 (Atherosclerosis) Flashcards
What is atherosclerosis?
Atherosclerosis is one of the leading causes of death for both men and women in Western countries.
It is characterised by a buildup of plaque inside the arteries, narrowing the blood vessel lumen and limiting blood flow.
Atherosclerosis is the main cause of coronary artery disease. It can lead to carotid artery disease, peripheral artery disease, and chronic kidney disease.
How is atherosclerosis treated?
In the last four decades, drugs in conjunction with behavioural changes have been successfully utilized to reduce blood cholesterol, triglycerides, and their related lipoproteins
How does atherosclerosis lead to coronary artery disease (CAD)?
1) The coronary arteries in the heart are responsible for supplying oxygen-carrying blood to the heartmuscle. In atherosclerosis, a fatty sludge infiltrates the inner coronary artery walls so that the narrowed coronary artery will carry less blood.
2) The fatty infiltrate is made up of an accumulation of white blood cells (both living and dead), as well as cholesterol and triglycerides.
- Eventually, calcium will deposit in these plaques and cause stiffness of the artery.
3) As a result, the heart receives too little oxygen to function at maximum capacity. The heart is able to cope at rest, but when the heart rate increases, such as during exercise, the narrowed coronary arteries cannot supply sufficient oxygen to the tissues and the individual experiences angina pectoris.
What are some behavioural risk factors for coronary heart disease (CHD)
- Obesity (20% or more overweight)
- Lack of exercise
- Cigarette smoking
- Hypertension
These risk factors can be controlled and decreased with behavioural changes.
Atherosclerotic plaque is made up primarily of white blood cells and lipids. What are the 3 major types of lipids?
Cholesterol (C): cholesterol is a waxy, fat-like, ring-structured chemical present in all cells in the body.
- It is a component of cell membranes and it is used for the synthesis of sex hormones, bile salts, and vitamin D.
- The body synthesises cholesterol on a daily basis in the liver and intestines, and even if the diet is very low in cholesterol, cholesterol is not lowered, as the body makes up the difference.
= Cholesterol only endangers health if the concentration in the blood is elevated, and if it infiltrates arterial walls, narrowing the lumen, decreasing blood flow, and hence decreasing the amount of oxygen available.
- Cholesterol is essential to life, as an energy source and as providers of essential fatty acids (CE and TG).
Cholesterol esters (CE): cholesterol esters are organic compounds containing cholesterol and fatty acids.
Triglycerides (TG): triglycerides are esters of glycerol and fatty acids.
- They comprise about 90% of total lipids in the human body.
- Triglycerides serve as a source of energy, and are stored in the body. Some dietary carbohydrates are converted to triglycerides.
Are lipids soluble in water?
Lipids, including cholesterol, cholesterol esters, and triglycerides, are insoluble in water and are therefore packaged for transport in the body in combination with proteins.
What are lipoproteins?
Any group of proteins that combine with and transport fats are called lipoproteins.
Lipoproteins have a surface coat and a lipid core, which consists of cholesterol esters and triglycerides.
What are the 4 main types of lipoprotein?
Chylomicrons: these are the largest of the lipoproteins.
- They are formed in the intestine and carry triglycerides of dietary origin and some cholesterol and cholesterol esters for absorption.
Very low density lipoproteins (VLDL): these lipoproteins are secreted by the liver and carry triglycerides to peripheral tissues for utilization or storage.
- VLDL triglyceride is at least in part derived from dietary carbohydrate.
Low density lipoproteins (LDL): LDL is referred to as the “bad” lipoprotein or “bad” cholesterol because it is taken up by macrophages (large white blood cells) and plays a role in increasing fatty deposits inside the arteries and thickening the inside of blood vessels.
High density lipoproteins (HDL): HDL is referred to as the “good” lipoprotein because it transports cholesterol away from the arteries to the liver, where cholesterol is biotransformed into bile acids and excreted.
- In this way, HDL helps to protect against heart disease.
What are hyperlipoproteinemias?
They are blood disorders characterized by an inability to break down lipids or fats in your body, specifically cholesterol and triglycerides.
What are the 2 conditions that hyperlipoproteinemias exist in?
Primary: this type arises from a gene defect inherited in a predictable Mendelian fashion. It may also be caused by a combination of subtle genetic factors acting together with environmental factors.
Secondary: these arise as complications of more generalized metabolic disturbances, such as diabetes mellitus, hypothyroidism, or chronic ingestion of large amounts of alcohol.
True or false: an accurate heart-risk assessment requires a detailed blood lipid analysis and a calculation of the HDL/LDL ratio.
True
Population studies have shown that an elevation of blood total cholesterol or of LDL-cholesterol is a major risk factor for atherosclerotic events. What readings indicate an elecated cholesterol level?
Individuals with blood cholesterol greater than 220-250 mg/dL, there will be a three-fold greater risk of heart attack than in individuals with blood cholesterol levels less than 195 mg/dL.
Does lowering of plasma concentration of LDL-cholesterol diminish the risk of coronary heart disease?
Yes
The results of the Lipid Research Clinic’s Primary Prevention Trial, reported in 1984, constituted a milestone in this therapeutic area. This major trial was a multicentre, randomized, double-blind study, and provided strong evidence that a decrease in plasma concentration of LDL-cholesterol was associated with a decrease in risk of coronary heart disease.
Analysis of this study showed that in patients with hyperlipoproteinemia, the incidence of coronary heart disease was decreased by approximately 50% for individuals with a drug-induced decrease of 25% in plasma total cholesterol, or a decrease of 35% in plasma LDL-cholesterol.
Elevated triglycerides (>150 mg/dl) are also associated with increased coronary heart disease.
What are some therapeutic measures for hyperlipoproteinemia?
Therapeutic measures consist of behavioural changes such as the elimination of aggravating factors and the institution of dietary measures.
- If behavioural changes alone fail to provide the desired changes in blood lipids, then drug therapy is instituted in conjunction with the behavioural changes.
- The choice of drug will be influenced by the type of lipid that is causing the problem.
Multiple aggravating factors increase the likelihood of hyperlipoproteinemia. Elimination of 6 factors reduce the risk of a patient developing the condion. What are those factors?
Elimination of aggravating factors:
1) Cessation of smoking.
2) Therapy of hypertension.
3) Institution of physical fitness program.
4) Control of blood glucose in diabetics.
5) Therapy of hypothyroidism.
6) Therapy of alcohol dependence.
What kind of diet should someone with hyperlipoproteinemia have?
It’s advisable to try to maintain a diet low in cholesterol and saturated fats.
The consumption of saturated fats results in an elevation of blood cholesterol.
- Reducing saturated fat intake is considered the most effective way to lower blood cholesterol, rather than exclusively cutting out cholesterol-rich foods such as eggs, cream, and liver.
- Saturated fats are mainly of animal origin (e.g. butter, bacon fat), but also include palm and coconut oils.
North Americans tend to eat too much saturated fat from meats, dairy products, baked goods, salad dressings, soups, and cheeses.
Polyunsaturated fats are found in fish, and in vegetable oils such as corn, sunflower, walnut, olive, and canola oil.
- The polyunsaturated fats assist in lowering blood cholesterol and improving the HDL/LDL ratio.
What are the 5 major drugs used to treat hyperlipoproteinemia?
Before choosing a particular drug or drug combination, the physician must take a careful patient history and have a lipid analysis done on a blood sample to be able to identify the nature of the lipid disorder.
1) Statins
2) Drugs that inhibit sterol absorption
3) Bile acid binding resins
4) Fibric acid derivatives
5) PCSK9 inhibitors
What are statins and how do they work?
In general, the first line treatment for hyperlipoproteinemia are the Statins.
Statins inhibit the enzyme β-Hydroxy β-methylglutaryl-CoA(HMG-CoA) in the liver, which catalyzes the rate-limiting step in cholesterol biosynthesis.
- By inhibiting cholesterol synthesis, statins ensure that more LDL is removed from the body than is being produced, thus decreasing blood levels of LDL.
True or false: statins are employed either alone or in combination with other drugs, where LDL levels are elevated in the blood.
True
Statins are the most effective drug class in lowering LDL and total cholesterol levels, especially when combined with appropriate diet and exercise.
What are some adverse effects of statins?
Adverse effects include myopathy and elevated liver enzymes.
The exact mechanism through which myopathy occurs is not fully known, but elevated liver enzymes is suspected to be a result of liver damage.
What are some commonly used statins?
- Lovastatin
- Simvastatin
- Fluvastatin
Is Simvastatin considered to be a “good” drug?
In this study, 4,400 patients were monitored for 5.4 years.
- Simvastatin reduced the incidence of non-fatal heart attacks by 30% and decreased the need for coronary bypass surgery by 37%.
- A 30% reduction in mortality was found in individuals receiving simvastatin compared to individuals receiving placebo.
This was the first study to demonstrate that lowering plasma cholesterol resulted in a reduction in mortality from cardiac causes.
How do drugs that inhibit sterol absorption work?
Ezetimibe is an example of a drug that inhibits sterol absorption.
- Ezetimibe inhibits a transporter in the GI tract that is responsible for the absorption of cholesterol and other sterols, thus decreasing plasma sterol levels in the body.
- It can also block the reabsorption of bile salts, which leads to the conversion of cholesterol to bile salts in the liver, causing a net reduction in cholesterol levels.
This class of drugs is usually used in combination with other drugs, such as the statins.
How do bile acid binding resins work?
Bile acid binding resins, also known as bile acid sequestrants, are a third class of drug that can lower cholesterol levels.
1) In the liver, cholesterol is metabolized to bile acids
2) These bile acids are then excreted into the small intestine to aid in the digestion of fats.
- Most of the bile acids are normally reabsorbed from the intestine
3) Bile acid binding resins, which are positively charged, can bind to the negatively charged bile acids in the intestine, thus inhibiting their reabsorption and greatly enhancing their excretion
4) The enhanced excretion of bile acids by these resins results in enhanced transformation of cholesterol to bile acids in the liver.
