Atherosclerosis Pathology & Drugs Flashcards
Describe the pathophysiology of atherosclerosis.
- Endothelial Damage due to Hypertension, Smoking, Hyperglycemia, Hypercholesterolemia
- Increased permeability of arterial wall, allowing LDL particles to enter the tunica intima
- Lipids and cholesterol in LDL particles undergo oxidation, producing oxLDL
*Oxidising agents are superoxide, NO, Hydrogen Peroxide
*Anti-oxidants are compounds that inhibit oxidation of LDL and these include Vitamin E, Ascorbic Acid, beta-carotene - oxLDL is taken up by macrophages (scavanger cells) via low-affinity, non-specific and non-regulated scavenger receptors (SR-A), forming foam cells
5, Foam cells accumulate, releasing growth factors and cytokines – abnormal proliferation of fibroblasts, smooth muscle cells, induce inflammatory responses, and produce collagen; foam cells eventually die (causing pro-inflammatory streaks) and release lipid content which are engulfed by neighbouring WBCs and smooth muscle cells
- Eventually the lipid content and dead cell fragments accumulate in the damaged site, forming a plaque with a lipid core.
- Endothelial cells grow to cover the plaque. The plaque accumulates calcium salts and more dead cells and hardens over time. This plaque is atherosclerosis
- Plaque can rupture, exposing necrotic core components to blood, causing thrombus formation. Blood clot can occlude blood vessel locally or break off as an embolus and occlude blood vessels at other sites.
How does damaged endothelium further promote blood clots, other than the pathophysiology of atherosclerosis?
Damaged endothelium produces less prostacyclin (anti-platelet effect) and does not produce TPA (breaks down clots), and even produces thromboplastin (enhances extrinsic clotting pathway) - hence thrombus formation is more likely
How does size of LDL particles affect atherosclerosis?
Small dense LDLs are more atherogenic than larger ones
- Bind poorly to LDL receptors on hepatocytes: not taken up by liver, likely to travel to coronary arteries
- higher permeability through endothelial wall barrier, pass through endothelial walls of coronary arteries
- increased retention in subendothelial matrix, allowing oxidation to oxLDL
When do small dense LDL particles occur? How?
Diabetes. Insulin resistance = High insulin = High de novo fatty acid synthesis (formation of TG-rich LDL particles, hepatic lipase at liver hydrolyses TGs to give FFAs & Glycerol, converting LDLs to small dense LDLs)
State 6 types of anti-hyperlipidemic drugs and explain their action.
- Statins - inhibits HMG-CoA reductase, so increases LDL receptors in all tissues to take up more LDL cholesterol because de novo cholesterol is inhibited
- PCSK9 Inhibitors - antibody vs PCSK9
which tags LDL receptors for degradation, thus Inhibits degradation of LDL receptors - Bile-Acid Resins (Cholestyramine) - Binds to bile salts and increases loss in feces; forces liver to convert cholesterol to bile acids; increases LDL receptors in all tissues to take up more LDL cholesterol; may increase VLDL, but has little effect on HDL
- Ezetimibe - Inhibits intestinal sterol resorption (NPC1L1 transporter)
- Niacin - decrease VLDL production, increase HDL synthesis by promoting synthesis of apolipoprotein precursors that produce HDL particles, decrease lipolysis in adipose tissue; decreases circulating fibrinogen & increases TPA
- Fibrates - Increase LPL activity (ligands for PPAR-alpha protein), thus clearing Chylomicrons and VLDL, increase HDL by increasing ApoA1 & ApoA2
Useful combinations of anti-lipid drugs?
- Statin & Bile-Salt binding resin
- Statin & Ezetimibe
Explain the different types of hyperlipidemias.
- Type 1: Defective LPL or ApoC2
- Type 2a: LDL Receptor Deficiency (Autosomal Dominant Mutation)
- Type 2b: Defects in Apo-B-100 on VLDL, LDL, IDL which is needed to bind to LDL receptors to be taken up into liver; overproduction of VLDL
- Type 3: Abnormal ApoE prevents clearance of IDL
- Type 4: Increased VLDL production and decreased clearance
- Type 5: Increased VLDL production and decreased LPL
What is atherosclerosis?
A degenerative and inflammatory disease resulting in thickening and loss of elasticity of medium and large arteries.
What is an atheroma?
A plaque consisting of a raised lesion with a soft yellow core of lipid covered by a white fibrous cap
What do early atherosclerosis lesions looks like?
Early – Fatty Streaks
Established – Atheromatous Plaques (patchy, on areas of vascular turbulence, easily ruptured)
What are common sites of atherosclerotic plaque formation?
Coronary Arteries, Popliteal, Internal Carotid, Circle of Willis
What are the modifiable and non-modifiable risk factors for atherosclerosis?
Non-modifiable:
1. Age
2. Male
3. Family History
4. Genetics
Modifiable
1. Hyperlipidemia
2. Hypertension
3. Diabetes
4. Smoking
What are the consequences of atherosclerosis?
- Vessel thickening = narrowed lumen = poor tissue perfusion = ischemia
- loss of elasticity = predisposition to aneursym, rupture & hemorrhage
- true aneurysm: vascular wall intact
- false aneurysm: vascular wall rupture
- dissection: break open intimal layer, forms clot in intimal & media layer - Endothelial Changes: Predisposition to thrombosis
What are clinical consequences of atherosclerosis?
Acute:
1. MI
2. Cerebral Infarct
3. Aortic Aneurysm
4. Peripheral Vascular Disease (intermittent claudication, ischemic atrophy or skin, gangrene, amputation)
Chronic:
1. Angina
2. Chronic Ischemic Heart Disease
3. Bowel Ischemia (mesenteric vessel atherosclerosis) (abdominal pain)
4. Ischemic Encephalopathy
5. Intermittent Claudication
What are the clinical uses of niacin?
Type 2b and Type 4 Hyperlipidemia, bit of Type 1 (not so focused treatment because Type 1 has low atherosclerotic role); NOT useful for Type 2a
