Week 3: Cardiovascular Disease Learning Outcomes: 1. Define the difference forms of CVD 2. Describe the various risk factors of CVD 3. Describe atherosclerosis and its stages 4. Describe the role of oxidation, inflammation, cholesterol and lipoproteins in CVD Part 1 Risk Factors and Atherosclerosis LO1. Define the Different Forms of CVD Cardiovascular Disease (CVD): Collective term for diseases of the heart and blood vessels. Includes diseases such as CHD, heart failure, cardiomyopathy, congenital heart disease, peripheral vascular disease and stroke. Coronary Heart Disease/Ischemic Heart Disease: Deficient supply of blood to heart due to obstruction of the inflow of arterial blood (as by the narrowing of arties by spasm or disease), partial blockage. Infraction (aka heart attack) Irreversible necrosis (death) or tissue or organ resulting from obstruction of the local circulation by a thrombus or embolus (formed in different artery, dislodged then travelled to another artery); complete blockage. NOTE: myocardinal infraction just means an infraction relating to the muscle of the heart! Cerebrovascular Disease: The narrowing and/or blockage of vessels that flow to the brain
Stroke: Clinical manifestation of cerealvascular disease. Two types: 1. Haemorrhagic stroke (bleeding) 2. Ischaemic stroke (blockage) Peripheral Vascular Disease: Affecting blood vessels in the limbs Congestive heart failure: Due to weak and damaged heart. It happens to older over (75+) due to the weakening of chambers inside the heart and fluid retention! ONLY TYPE THAT HAPPENS DUE TO OLD AGE AND NOT IN PARTICULAR ATHEROSCLREOSIS! NOTE: underpinning all these problems is Atherosclerosis (except for congestive heart failure which is due to many years of hypertension!)
Note: Aneurysm is when the capillaries burst LO2. Describe the Various Risk Factors of CVD Unmodifiable Risk Factors: Age: the older you get, the greater chance! Sex: males have a greater rate even after women pass menopause (note: may be different for different populations) estrogen is thought to be protective! Race: minorities have a greater chance Family History: if family members have had CHD, there is a greater chance Modifiable Risk Factors: Hypertension Blood cholesterol Obesity Diabetes Mellitus Physical inactivity Cigarette smoking Alcohol intake Depression LO3. Describe Atherosclerosis and its Stages low grade inflammatory state of inner lining of arteries There are 4 stages of progressive development of atherosclerosis! 1. Epithelial Damage site of injury 2. Fatty streak 3. Plaque Growth immune cells, smooth muscle cells, development of plaque
4. Complicated lesion (rupture, thromboembolism, myocardial infraction) Stage 1: Epithelial Damage Injury to and inflammation of the epithelium as a result of hypertension, diabetes, smoking etc. Stage 2: Fatty Streak First deposition of fat (fatty streak). Attraction of defence cells, which take up LDL particles, die and become deposited. Basically, LDL enters the damaged site of the endothelial and start depositing. Stage 3: Plaque growth/unstable LDL cells attract immune cells which attract smooth muscle cells. Under the influence of growth factors, smooth muscle cells migrate into the vascular endothelium (they make a fibrous cap known as plaque made up of connective tissue). NOTE: The amount of risk if not necessarily the size of the plaque but the stability of its cap!
Stage 4A: The Rapture The deposit may suddenly rupture due to mechanical efforts (e.g. increased BP) or the processes in the vascular wall. Stage 4B: The Thrombus Blood platelets immediately migrate to the site of the event in order to steal the leak. Stage 4C: The Occlusion By clumping together, the platelets form a blood clot (i.e. thrombus). The vessel is blocked!
LO4. Describe the Role of Oxidation, Inflammation, Cholesterol and Lipoproteins in CVD Atherosclerosis begins when there is damage to the endothelial cells. This damage may be a result of high blood pressure, diabetes, smoking etc. Endothelial Dysfunction: once there is damage to the endothelial cells (as above), LDL cholesterol is attracted to the site of injury! The LDL molecules then become oxidised. This oxidation initiates inflammatory responses which stimulates the cytokine release. The release of these cytokines promotes the release of macrophages (conversion from monocytes). The macrophages digest the LDL cholesterol which form foam cells (first development of plaque). Foam cells attract smooth muscle cells which forms the cap of the plaque! Oxidation and CVD: As mentioned above, LDL cholesterol is oxidised, which promotes the release of cytokines. Remember, oxidation is the process by which free radicals (i.e. oxidants) attack and damage target molecules. Target molecules: DNA COH PUFAS, MUFAS, SFAs Proteins
Risk Factors to Oxidative Stress: Hypercholesterolemia Hypertension Diabetes Smoking Heart failure Inflammation: Inflammation is involved in all stages of atherosclerosis and is a response to endothelial damage! One marker of inflammation is CRP! C-Reactive Protein (CRP) Critical component of the immune system! It is a complex set of protein that our bodies make when we are faced with a major infection or trauma! NOTE: Everyone makes CRP, but in different amounts depending on a variety of factors, including genetics, exercise and smoking It is also a strong predictor of CHD risk! Use of CRP as a marker of inflammation: Positive: Stable over long time Inexpensively measured Directly proportional to degree of inflammation Less variable by race or gender Limitations: Has individual variation Increased by infection/asymptomatic inflammation NOTE: CRP levels change over time so it needs to be measured twice in the same patient over a period of time Cholesterol and Lipoproteins and CVD: CHD can occur in people with totally normal cholesterol! So, what else is contributing to CHD?? To understand this, we need to understand lipid metabolism! Lipid Digestion and Absorption:
NOTE: most food in our diet is in the form of triglycerides! 1. Consume fat 2. Enters the intestine and is mixed with bile salts 3. Triglycerides broken down into FFA (monoglycerides) 4. FFA enter the epithelial lining of the intestine with the help of micelles 5. FFA gets converted back into triglycerides and travel into the lymph system in the form of chylomicrons Chylomicrons: This is a lipoprotein (i.e. protein + lipid) that transport dietary lipids! Contains cholesterol, triacylglycerols and phospholipids Lipid Metabolism: Once the chylomicron enters the blood stream, it reacts with LDL (lipoprotein lipase) where FFA and chylomicron remnant is released.
NOTE: the FFA enter the tissues (i.e. adipose and muscle), whereas the chylomicron remnant goes to the liver. BUT HOLD ON! WTF ARE LIPOPROTEINS? Lipoproteins: Biological mediators of cholesterol and triglyceride transport There are different subclasses of lipoproteins depending on the lipoprotein s core lipid size and density! Chylomicrons VLDL LDL ILD (intermediate-density lipoprotein) HDL LDL is responsible for the transport of cholesterol to tissue and has long been considered to be the most significant atherogenic lipoprotein! Why!? The smallest and dense particles are the most atherogenic because of their ability to easily penetrate the sub-endothelial space! HDL is responsible for mobilizing cholesterol from peripheral tissues and return to the liver for excretion. HDL has thus been termed good cholesterol!
NOTICE that the LDL in the larger person is much smaller! The small LDL molecules easily penetrate the sub-endothelial space and they also have a larger SA:V! the more SA, the more oxidative damage!! It is important to note that total cholesterol isn t the only factor contributing to disease risk! The ratio of LDL and HDL is also important to consider! We can use a coronary angiogram! How to Detect a Blockage? This is a special x-ray of your heart using an ingested contrast dye It basically looks for heart muscle or heart valve abnormalities and also see if the coronary arteries are narrowed or blocked!