Inflammation and atherosclerosis

Question 1

What is the most important cause of cardiovascular diseases?

Answer 1

Atherosclerosis: the single most important cause for CVD

Question 2

What are the major risk factors of atherosclerosis?

Answer 2

• Hypercholesterolemia
• Elevated blood pressure
• Diabetes
• Smoking
• Sitting still

Question 3

What are the steps for LDL to infiltrate arteries into the sub-endothelial space and get retained?

Answer 3

Early steps of atherosclerosis starts with high doses of LDL moving in the body => they normally attache to their receptors (mainly in the liver)
But since the doses are too high, they won’t link to the receptors anymore (saturated receptors) and will push themselves through the endothelial of arteries and get stuck there (sub-endothelial space)
The LDL will change and get oxidized there, which expresses adhesion receptors form the endothelium => this is because the endothelium senses the oxidized LDL as an infection
This will recruit a lot of macrophages and leucocytes at the infiltrated part

Question 4

Which part of the endothelium does the atherosclerotic lesion happen?

Answer 4

In the inner part of the endothelium => the intima

Question 5

What are the consequences of LDL leakage (beginning of atherosclerosis)?

Answer 5

Atherosclerosis lesion (LDL leakage => beginning of atherosclerosis) leads to monocytes attaching to the adhesion receptors (expressed by the endothelium because of oxidized LDL) and attract T-cells
Macrophages will also attache to the adhesion receptors and uptake all the oxidized LDL (and start producing inflammatory cytokines to promote inflammation and recruit even more immune cells), by doing so macrophages will turn into foam cells and end-up in necrosis which accentuates the inflammation

Question 6

What are the differences between stable VS unstable plaques?

Answer 6

Stable (inactive and non-inflamed plaque):
• small lipid pool
• thick fibrous cap
• preserved lumen

Unstable (active and inflamed plaque):
• large lipid pool
• thin fibrous cap
• inflammatory cells

Question 7

What is the causes of strokes?

Answer 7

Thromboembolic: formation of thrombus moving with blood stream
Plaque debris (part of thrombosis) can move along the bloodstream and move to smaller arteries and get blocked there => this is mainly what happens in brain strokes
Different types of strokes causes different phenotypes

Question 8

Where in the blood stream does atherosclerosis happen the most?

Answer 8

Atherosclerosis happens a lot in arteries where there are bifurcations in the blood stream (where blood flow isn’t laminar anymore)

Question 9

How does the fiber plaque form and what happens if it explodes?

Answer 9

Smooth muscle cells in the outer part of the endothelium produce fibers that go to the inside of the endothelium (intima) to form a fiber plaque and retain the expanding necrotic core of the atherosclerotic lesion
Once that core explodes through the endothelium => it will coagulate the blood and form a thrombosis which will clog the artery

Question 10

What are the symptoms of carotid stenosis plaque rupture?

Answer 10

• Transitory ischemic attack: getting dizzy and short episode paralysis
• Temporary blindness and blind spots
• Stroke: minor and/or major

Question 11

How can carotid plaques be easily diagnosed?

Answer 11

Ultrasounds allow easy diagnostic of carotid plaques

Question 12

What is a carotid endarterectomy?

Answer 12

Removal of plaque by surgery

Patients have a much longer life expectancy

Question 13

What is the goal of BiKE: Biobank of Karolinska Carotid Endarterectomies?

Answer 13

Identification of novel genes and signaling pathways in atherosclerosis by gene expression profiling
Once the procedure is done (carotid endarterectomy), the lab takes different samples from the plaque (blood, leukocytes, DNA, RNA, etc.)
This is to create a gene library and tissue biobank.

Question 14

Did the BiKe study find a transcript correlating to Major Adverse Cardio Cerebrovascular Events (MACCE) outcomes for patients?

Answer 14

Yes, the found transcript is TLR7: when it is highly expressed => it is associated with little events, contrary to the transcript being lowly expressed
=> higher levels of TLR7 transcript correlate with better outcomes

Question 15

In which cells is the transcript TLR7 expressed?

Answer 15

It has been shown to be expressed by macrophages and T-cells

Question 16

What do carotid plaques produce in response to TLR7 ligand and what does that suggest?

Answer 16

Plaques produced cytokines (IL-10 and TNFa)
Secretion of pro- and anti-inflammatory cytokines after ex-vivo plaque stimulation with a synthetic TLR7 ligand suggest TLR7 as a modulator of inflammation

Question 17

What are the similarities and differences from man to mouse when studying atherosclerosis?

Answer 17

Similarities:
• lesions formation (plaque development)
• dependence on cholesterol levels
• inflammatory processes and immune cell infiltration

Differences:
• no plaque rupture 
• few fatal events
• time span
• type of cholesterol

Question 18

What type of KO-mice models could you use for atherosclerosis studies?

Answer 18

Apolipoprotein-E KO mouse (apoE-/-): spontanous atherosclerosis

LDL receptor-KO mouse (LDLr-/-): need western diet to develop disease

Question 19

What stimulation can treat and heal atherosclerosis (and how), what is the side effect and why?

Answer 19

Treatment of atherosclerosis and healing is possible with TLR7 stimulation because macrophages turn less into foam cells which reduces necrosis and they are better at up-taking apoptotic cells
Side effect: splenomegaly because there is a much bigger B-cell population producing antibodies specifically against oxidized LDL, also there is a bigger T-cell activation

Question 20

What are the protective effects of TLR7 activation against atherosclerosis on both systemic and local level?

Answer 20

Local response of TLR7 in plaque:
• increases efferocytosis (apoptotic cell clearance)
• decrease of necrotic core area leading to more stable plaque phenotype

Systemic effect to TLR7 activation in spleen:
• expansion of marginal zone B-cells and subsequent production
of IgM against oxidized LDL
• expansion of regulatory T-
cells

Question 21

What is the main cause for myocardial infarction and stroke?

Answer 21

Atherosclerosis is the main cause for myocardial infarction and stroke

Question 22

Is atherosclerosis multifactorial?

Answer 22

Yes, the disease is multifactorial

Main risk factor are hypercholesterolemia, hypertension and smoking

Question 23

What is the starting point of plaque formation and lesion?

Answer 23

LDL cholesterol leaking into sub-endothelial space is the starting point for the formation of plaque and lesions

Question 24

How fast does an atherosclerotic plaque form and what does it contain?

Answer 24

The plaque develops over decades

The lesions contain foam cells, infiltrating leukocytes, mainly macrophages and T-cells and a necrotic center

Question 25

What dangerous event leads to myocardial infarctions (heart attack)?

Answer 25

Plaque rupture in coronary or carotid artery is the dangerous event leading to MI or stroke

Question 26

Is atherosclerosis hereditary?

Answer 26

There are hereditary forms, such as ”Familial hypercholesterolemia” with mutations in the LDL receptor