Dyslipidemia Patho

Question 1

Dyslipidemia

Answer 1

• Increase LDL-C, VLDL-C, Triglycerides

- Decrease in HDL-C

Question 2

Dyslipidemia Primary Prevention

Answer 2

Prevention of atherosclerotic cardiovascular disease (ASCVD) in a person without a known history of disease

Question 3

Dyslipidemia Secondary Prevention

Answer 3

Prevention of ASCVD in a person with a history of ASCVD

Question 4

Modifiable CVD Risks

Answer 4

• Physical inactivity
• High blood pressure
• Smoking
• High cholesterol/lipids
• Obesity
• Diabetes mellitus
• Metabolic syndrome

Risk factors are additive

Question 5

Non-Modifiable CVD Risks

Answer 5

• Age
• Family history
• Not being female

Risk factors are additive

Question 6

Lipoproteins

Answer 6

• High MW and water-soluble, responsible for cholesterol and TG transport
• Chylomicrons, VLDL, IDL, LDL, HDL, and Lp(a)
• Surface is made up of polar, hydrophilic constituents integrated between phospholipid monolayer
• Inner core contains nonpolar hydrophobic lipids, CEs, and TGs

Question 7

Cholesterol

Answer 7

• Necessary component of cell membranes, steroid hormones, and bile acid
• Regulated by absorption (extrinsic) and hepatic production/hepatic and bile acid excretion (intrinsic)
• Synthesis accounts for the majority of cholesterol in the body (greatest in liver and intestinal mucosal cells)

Question 8

Major Plasma Lipids

Answer 8

• Cholesterol
• Triglycerides
• Phospholipids

Question 9

Phospholipids

Answer 9

• Essential for cell function and lipid transport
• Do not directly contribute to atherosclerosis
• Lecithin is the major phospholipid
• Amphophilic and essential in transport of hydrophobic cholesterol esters (CE) and TGs through the plasma

Question 10

Triglycerides

Answer 10

• Dietary TGs absorbed as monoglycerides and FFAs
• TGs are formed in liver and transported to adipose tissue for storage
• TG lipolysis releases FFAs allowing for utilization by tissues

Question 11

Exogenous Pathway

Answer 11

• Dietary fats are incorporated into chylomicrons from the intestine into circulation to move the fats to adipose tissue
• CMs contain ApoCII that activates lipoprotein lipase which releases TG
• TGs then form FFAs which deposit in muscle and adipose tissue for use
• CM fragments are removed by the liver and recycled
• Cholesterol bile acids promotes lipid emulsification and intestinal absorption

Question 12

Endogenous Pathway (VLDL)

Answer 12

• Liver transports TGs (from FAs via the liver or adipose) and some cholesterol
• VLDLs contain ApoCII which performs the same function as in the exogenous pathway
• IDL lose more TG and become LDL

Question 13

LDL

Answer 13

• Major cholesterol carrier
• Major lipoprotein: ApoB-100
• CHD risk increases exponentially with increases total and LDL cholesterol
• LDL enters cells by receptor-mediated endocytosis, their hydrolysis in lysosomes releases the free cholesterol
• Number of LDL receptors adjusts cholesterol concentrations for cells (new, developing cells require more)

Question 14

Formation of LDL

Answer 14

• Liver produces VLDL
• VLDL then interacts with lipoprotein lipase and becomes a VLDL remnant
• VLDL remnant then interacts with hepatic lipase and becomes LDL

Question 15

Cholesterol Metabolism

Answer 15

• LDLs are taken up by endocytosis
• Lysosomes release free cholesterol
• Cholesterol is then esterified by ACAT and stored

Question 16

HDL

Answer 16

• Major lipoprotein: ApoA
• HDL subclasses are based on size and lipid content (HDL 1-4)
• HDL2 (larger, lipid-rich) and HDL3 (small, dense) are predominant in human plasma
• Subclasses contribute differently to reverse cholesterol transport

Question 17

HDL Synthesis

Answer 17

• ApoA becomes a pre-HDL that then interacts with macrophages to receive cholesterol efflux
• Pre-HDLs then become HDLs
• LDLs can also be converted to HDL

Question 18

Drugs that Induce Lipid Changes

Answer 18

• Thiazide diuretics (increase total cholesterol and TGs)
• Beta-blockers (increases TGs and decreases HDL)
• Alpha-antagonist (decreases in total cholesterol and TGs and increases HDL)

Question 19

Artherosclerosis

Answer 19

• INFLAMMATORY DISEASE
• Initiating event = endothelial injury
• Leads to endothelial activation and oxidation of LDLs
• Foam cells form and muscle cells differentiate
• Cells become hypoxic and the fibrous cap things, risking rupture

Question 20

Early Stages of Atheroma

Answer 20

• Endothelial activation - increases permeability of cell wall (lets in more LDL), increases adherence, and loss of NO
• Leukocyte recruitment/chemotaxis/adhesion occurs as well

Question 21

Middle Stages of Atheroma

Answer 21

• Oxidation of LDL
• Macrophage uptake of oxLDLand differentiates to Foam cells
• Foam cells are pro-inflammatory and oxidative which creates a feed-forward chronic inflammation pathway
• Smooth muscle differentiates from contractile to synthetic and growths
• T cell/adaptive immunity mechanisms

Question 22

Late Stages of Atheroma

Answer 22

• Lesion cells become hypoxic internally causes necrosis of internal cells and expression of VEGF and angiogenesis
• Proteolytic degradation of the extracellular fibers of the fibrous cap occurs
• Rupture can then occur which exposes procoagulant basement membrane proteins to the circulating factors

Question 23

Rupture Events

Answer 23

• Macrophages and T-cells release proteolytic enzymes that degrade the fibrotic layer
• Proteolysis in combination with mechanical stress can cause a rupture
• The rupture then exposes tissue and other procoagulant factors and proteins into their circulation
• Thrombus can form and completely occlude vessels
• Can also heal over, but larger lesion leading to progression of occlusion can also occur

Question 24

Principle Interventions/Objective for Atherosclerosis

Answer 24

Interventions

• Diet
• Exercise
• Pharmaceuticals

Objectives

• Lower LDL
• Lower TGs
• Increase HDL