4th lecture (cholersterol accumulation)

Question 1

where is cholesterol stored in cell?

Answer 1

intercellular vacuoles, mostly in macrophages. Also a major component of cell membranes.

Question 2

arteriosclerosis is a common term covering 3 different diseases.

Answer 2

• arteriosclerosis (thickening and hardening do to old age)
• arteriolosclerosis (hardening and loss of elasticity do to hypertension and diabetes mellitus)
• Monckeberg medial calcific sclerosis (MCS) is a ring-like calcification of the vascular media of small to medium sized vessels without associated intimal thickening

Question 3

morphological unit of atherosclerosis?

Answer 3

the atheroma plaque.
“Fibrous cap”
“LIPID core” made of cells

Question 4

what makes up the fibrous cap?

Answer 4

intimal change made of endothelial coverage under which fibroblasts, SM cells, ECM inflammatory cells (macrophages cholesterin) and lymphocytes can be found.
the above make up the fibrous cap.

Question 5

what makes up the lipid core of the atherosclerosis?

Answer 5

• cell debris
• cholesterin trispase?????!!!! (could not hear what you said during the lecture)
• calcified particles
• ECM

Question 6

what is the shoulder of the atherosclerosis plaque?

Answer 6

joint between the normal and the atherosclerosis plaque. It is the most fragile part of the plaque and it ruptures here during vasoconstriction.

Question 7

what are the circumstances that predisposes to atherosclerotic plaques?

Answer 7

RISK FACTORS: the correlation between risk factors vs atherosclerosis is exponential.
A. Major constitutional factors (cannot be changed)
B. major modifiable (can be changed)
C. additional factors

Question 8

what are the major constitutional factors (cannot be changed)?

Answer 8

• age (after 50-60 years old)
• sex (more prominent in men, women are more protected then men from atherosclerosis up until menopause, progesterone may play a role)
• genetics (gene sequencing showed that the secrete to long life showed that down-regulated genes for atherosclerosis)

Question 9

what are the major modifiable factors (can be changed)

drugs could potentially be used to change some of these

Answer 9

-hyperlipidemia/hypercholesterolemia
(high LDL, bad lipoprotein, transports from liver to cell)
(high HDL, good lipoprotien, transports from cell to liver)
(low level of alcohol consumption allows for higher HDL)
lipoprotein A, (Lip-A) a modified LDL with apo-b100, important for myocardial infraction)
-hypertension (RR is used as a shortening for hypertension) Both systolic and diastolic increase the risk for atherosclerosis, the hyper pressure causes physical injury of the endothelial cells
-smoking, (1 pack/year increases atherosclerosis risk 100x)
-diabetes, (peripheral resistance of glucose uptake causes LDL/fat mobilization).

Question 10

what are the additional factors for atherosclerosis risk?

Answer 10

• Inflammation (C-reactive proteins synthesis is the laboratory hallmark if inflammation is going on, this cytokine can produce increased platelet aggregation which could progress atherosclerosis)
• obesity (hyperlipidemia, hypertension)
• lack of exercise (activity reduces the LDL level)
• stress
• type A person (a competitive person)

Question 11

how is atherosclerosis related with bad breath?

Answer 11

in teeth the roots stick to the gums tightly. But if the person has bad oral hygiene, tooth stones developed at the gap between the tooth and the gums, and a gap forms between the gum and tooth. Bacteria accumulates in the gap. the bacteria generates inflammation which breaks down the food particles that end up in them causing bad breath.

Question 12

Theory of atherosclerosis called “Response to injury”.

Answer 12

there is an endothelial damage; non denuding cell injury. The endothelial cell are damaged but not removed (denuded) but the cells biochemistry is changed.

Question 13

the risk factors in the pathogenesis of the endothelial cells in line with the “response to injury”

Answer 13

• hemodynamic changes (hypertension).
• dyslipidemia (increase in LDL levels)
• (inflammation) dysfunction of the endothelium predisposes to platelet aggregation.

Question 14

what are the hemodynamic changes to endothelial cells during hypertension?

Answer 14

high pressure results in a non denuding cell injury, of the endothelial cell. The ROS increases in the endothelial cells. In laminar flow the endothelial cells produce superoxide dismutase, during turbulent they don’t produce superoxide dismutase and increase ROS. The areas where turbulent flow occurs in vessels, the cells are more frequently impacted and this forms atherosclerotic plaques. Endothelial dysfunction.

Question 15

what happens during dyslipidemia when LDL levels increase?

Answer 15

LDL levels increases with endothelial attraction, along with ROS increase results in oxidative LDL result. The oxidative LDL is removed by macrophages which have scavenger receptors. The macrophages that then take up the LDL will die and form the cell debris that forms the lipid core of the atherosclerotic plaque.

Question 16

the problems of platelet aggregation with atherosclerosis?

Answer 16

Dysfunctional endothelium predisposes the endothel to platelet aggregation. Platelet aggregation can also be increased in the presence of inflammation.
The platelets aggregation form PDGF (platelet derived growth factor) which increases the chemotaxis of macrophages to the area. The inflammation also increases the expression of adhesion molecules on the surface of the endothel.
expression of VCAM1 occurs (vascular adhesion molecule 1) increases which invites the macrophages to the area which ingrown into the area. Lymphocytes also have adhesion molecules.
cytokines of macrophages increases the proliferation of smooth muscles, fibroblasts, and ECM.

Question 17

the monoclonal theory of the atherosclerosis.

Answer 17

smooth muscle cell proliferation starts either from a single cell (monoclonal) or from few cells (oligoclonal)
This theory was supported by the fact that only one of the 2 G6PD enzymes are active in the plaque. The endothelial cells are a mixture of A and B isozymes.

Question 18

Types and morphology of atherosclerosis?

Answer 18

• fatty streak (white strips on the heart, made of endothelial cells and foam cells) Reversible state.
• artheromas plaque (shoulder, fibrous cap, etc.)
• complicated plaque/advanced plaque/secondary changes of plaque.

Question 19

describe the complicated plaque/advanced plaque/secondary changes of plaque.

(VERY IMPORTANT TO KNOW)

Answer 19

• calcification
• fissure/ulceration (rupture of plaque)
• cholesteral embolisim, plaque ruptures, cholesterin christals are liberated to the circulation, and may obliterate very tiny capillaries in heart or in the CNS. this is called Transient ischemic attack.
• thrombosus formed from the top of fissureing alceration.
• lipid core may erode the vasa-vasorum and cause bleeding into the plaque.
• lipid core growth may destroy, adventitia of the vessels causing dilation of the vessel (aneurysm)

Question 20

Primary prevention of atherosclerosis?

To prevent the development of atherosclerosis.

Answer 20

• stop smoking
• weight control
• RR (hypertension), blood pressure control with drugs if need be.

Question 21

Secondary prevention of atherosclerosis?
The patient already cerebral infraction or myocardial infraction and thrombosis of major artery in leg. etc.
prevent progression of disease.

Answer 21

• Aspirin (to preventing the platelet aggregation and anti-inflammatory drugs)
• Statin: drugs the control LDL production by the liver
• Control of the blood pressure (hypertension may progress symptoms)
• surgery (stent implantation, balloon catheter)

Question 22

Accumulation of proteins is caused by?

Answer 22

• increased secretion
• increase production
• cell injury,
• folding. (problem with chaperons)

Question 23

give an example of increased secretion of protein?

Answer 23

(tubular structure of the kidney, during protein-urea, tubular cells take up protein via endocytosis.

Question 24

give an example of increased production of protein?

Answer 24

(plasma cells makes immunoglobulin, during myeloma, excessive immunoglobulin is produced accumulating in the cell making “russel bodies”)

Question 25

give an example of cell injury that results in the protein accumulation?

Answer 25

Example: hepatocytes from alcohol damage cause aggregation of the cytoskeleton to occurs, called mallory body.

Question 26

alpha 1 antitripsin insufficiency disease?

Answer 26

alpha 1 antitripsin is produced by liver cells, and if there is a folding problem then secretion does not occur. Thus during inflammation the neurophils that produce proteases, which are clamped down by alpha 1 antitripsin, thus NO SECRETION causes over reactive inflammation.
In the lung infection, polymorphonuclear and inflammatory proteases are produced to stop the inflammation or remove the bacteria. But the proteases can destroy the alveoli due to no antitripsin, causing emphysema, loss of lung alveoli wall. The capillaries may be lost and thus pressure in the lungs will increase causing cor pulmonale, patient dies from right sided heart failure.

Question 27

define cor pulmonale chronic

Answer 27

High blood pressure in the pulmonary vessels do to increased resistance in the lungs circulation. This condition is often associated with right sided lung failure.

Question 28

amyloidosis description.

Answer 28

(amyloid is a chemical that has diverse forms, it got its name from the fact that it looks like starch) In medicine these are aggregates of misfolded proteins, always accumulating extracellular areas.
all tissues/cell the amyloid surrounds the cell causing pressure on the cells and atrophy of the cell.

Amyloid has a helical structure, inside this helix there are Beta-pleated sheets that stack on-top of one another, this forms the aggregates of mis-folded protein.
amyloid with congo-red staining can be revealed.

Question 29

4 important forms of amyloid structure?

Answer 29

• AL amyloid light chain come from the disease called plasma cell myloma. Plasma forms lots of kapa/lambda light chains that form AL amyloid.
• AA amyloid associate, related to long standing inflammatory diseases, the liver SAA (serium associated amyloid protein) acute phase protein, progenitor of amyloid synthesis.
• Amyloid beta chain (APP) amyloid precursor protein, occurs in brain during Alzheimer.
• transthyretin: misfolding of protein that is important in the transport of thyroxin.

Question 30

senile systemic amyloidosis definition?

Answer 30

disease that effects the heart and the tendons of elderly do to accumulation of misfolded transthyretin proteins.

Question 31

amyloidosis morphology?

Answer 31

Related to enlarged organs, the cut surface of the organ appears waxy. Amyloid is always extracellular accumulation of the protein.

Question 32

Amyloidosis in the kidney?

Answer 32

In the kidney glomerulus; amyloid deposited into the capillaries and the tubules and peritubular area, blocking the function of the tubules in the kidney, protein-urea is seen.

Question 33

Types of Amyloidosis in the spleen?

Answer 33

1. follicular

2. sinusoildal amyloidosis deposits (preserved follicles)

Question 34

Amyloidosis in the heart?

Answer 34

most of the amyloidosis deposits are in the subendocardial area. Drew drop (drops of water on the grass) pattern in the subendocardium, this fixes the heart making it unable to relax. Causes restricted cardio myopathy, diastolic insufficiency.

Question 35

Describe amyloidosis of the liver?

Answer 35

occurs mostly in the nissle spaces. The entire liver becomes move enlarged. Extracellular deposit around the liver cell causing the liver cells to shrink.