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Cardiovascular > Inflammation and Atherogenesis > Flashcards

Inflammation and Atherogenesis Flashcards

1
Q

How does LDL “activate” the endothelium and what happens?

A

LDL penetrates the endothelium and is retained in the intimate where it undergoes oxidative modification. This releases pro-inflammatory lipids which stimulate endothelial cells to express adhesion molecules and recruit the local inflammation cells. Adhesion molecules on the surface of the endothelium allow monocytes to marginate and eventually adhere to the endothelium and enter. The monocytes differentiate into macrophages when they are in the intimate and they engulf the LDL and turn into foam cells. At the same time, we have T cells, mast cells, and platelets which further release the further inflammatory mediators which promote plaque growth and eventual instability.

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2
Q

Why is inflammation implicated in atherogenesis? (theory)

A

It is thought to be an evolutionary response.

Pathogen-associated molecular patterns (PAMPs) and Danger-associated molecular patterns (DAMPs) trigger the inflammatory process and Oxidized LDL and cholesterol crystals seem to trigger the inflammatory process as well. It seems that the evolution of the host response to bacterial infection increased the risk of sterile inflammation.

From evolutionary perspective, a lot of what we see in atherosclerosis is the body’s natural response and protection system that is invoked to protect against microbial pathogens. Thousands of years ago, people didn’t live past 30 most of the time so there weren’t any evolutionary disadvantages from these responses. However, we live longer now and have problems like atherosclerosis from these pathways.

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3
Q

What are normal self and altered self cells?

A

Normal cells would be like LDL or any viable cell. Altered self is when LDL becomes oxidized (OxLDL) or if a viable cell became apoptotic.

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4
Q

What are PAMPs and DAMPs?

A

They are altered lipid membranes that signal pathogenicity or danger. PAMP = pathogen-associated molecular patterns. DAMP = Danger-associated molecular patterns.

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5
Q

What do altered self cells release? How is this the “intersection” between what your body considers “self” and what is considered “pathogen”?

A

Microbial pathogens also release PAMPs and DAMPs. Altered self cells release PAMPs and DAMPs. Thus, PAMPs and DAMPs are the intersection of altered cells and microbial pathogens so your body must decide what is what.

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6
Q

What are Pattern Recognition Receptors? Name 4 classes

A

These are receptors of our innate immune system.

  1. Natural antibodies
  2. Toll-like Receptors
  3. Scavenger receptors
  4. Soluble receptors
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7
Q

True or False: All type of innate immunity cells have been implicated in atherogenesis.

A

True

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8
Q

What is the most crucial player of the innate immune system for atherogenesis?

A

Monocytes (2-10% of all leukocytes). They turn into macrophages and turn into foam cells from eating LDL.

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9
Q

True or False: Studies have shown that monocyte accumulation is progressive and proportional to the extent of atherosclerotic disease.

A

TRUE

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10
Q

True or False: Monocyte adhesion to activated endothelium is an obligate step in atherogenesis.

A

TRUE. If you don’t have monocyte adhesion, you have significantly less plaque formation in experimental models.

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11
Q

What is VCAM-1 and what is its presence in activated endothelium?

A

VCAM-1 is vascular cell adhesion molecule-1. Its presence is unregulated in activated endothelium.

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12
Q

What are CD11c and VLA-4?

A

These are proteins on the monocyte which interface with VCAM-1 to allow for monocyte adhesion to endothelium.

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13
Q

True or False: Knockout of VLA-4 and CD11c on the endothelium limits atherogenesis significantly.

A

FALSE. Knocking out VLA-4 and CD11c does limit atherogenesis significantly BUT they are on the monocyte surface, not the endothelium. VCAM-1 is on the endothelium.

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14
Q

What happens to macrophage content in atherosclerotic lesions when VLA-4 and/or CD11c are knocked out?

A

Macrophage content decreases.

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15
Q

What is the role of dendritic cells in atherosclerosis?

A

Dendritic cell antigen presentation with subsequent T cell activation promotes clonal T cell expansion. The Th1 response promotes INF-gamma elaboration and atherosclerosis.

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16
Q

Does atherosclerosis have a Th1 response or Th2 response when talking about adaptive immunity?

A

Th1 (and also TH17).

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17
Q

What is the difference between the roles of Th1 response and Th17 response in atherosclerosis?

A

Th17 has downstream effects. Th1 promoties IFN-gamma elaboration and atherosclerosis while Th17 cells promote plaque instability and neoangiogenesis through IL17, IL22, and IL21.

Blocking IL17A may reduce atherosclerosis.

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18
Q

True or false: Th1 cells increase lesion formation and plaque vulnerability

A

True

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19
Q

True or False: Th2 cells increase lesion formation and plaque vulnerability.

A

False. It is unclear as to whether or not Th2 cells participate in atherogenesis.

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20
Q

What is the role of Treg in atherosclerosis?

A

Treg (T regulatory cells) have an anti-inflammatory response by activating TGFB and IL-10. Decrease in lesion formation and decrease in plaque vulnerability.

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21
Q

True or False: Immune response to injury initiates atherogenesis

A

True

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22
Q

True or False: Innate immune cell interaction with endothelium drives initial plaque formation.

A

True

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23
Q

True or False: T cells counteract further lesion expansion and plaque vulnerability.

A

False. T cells promote further lesion expansion and plaque vulnerability.

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24
Q

True or False: Sheer forces can activate endothelium

A

True

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25
Q

What happens after establishment of fatty streak? (progression of atherosclerosis)

A

Inflammatory mediators drive additional plaque expansion. T1 mediated process in conjunction with macrophage apoptosis. Plaque growth transitions from stable plaque to unstable/ruptured plaque. Interplay of atherosclerosis and thrombosis.

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26
Q

There are thought to be 5 steps in the progression of atherosclerosis to MI. What are they and what are the components of the steps? (Lilly)

A
  1. Basal inflammation (cytokines, acute phase reactants)
  2. Endothelial activation (monocyte adhesion and leukocyte diapedesis)
  3. Oxidative Stress (LDL oxidation, foam cells)
  4. Neoangiogenesis (blood vessel formation, intraplaque hemorrhage, activation of MMPs)
  5. Plaque instability (rupture/erosion, platelet activation)
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27
Q

What are the major drivers of plaque instability? (3 things)

A
  1. Macrophage apoptosis and necrosis promotes a “necrotic core”
  2. MMPs degrade the fibrous cap
  3. Intra-plaque hemorrhage further weakens the core.
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28
Q

In atherosclerosis, what does MMP do and how does it do this?

A

MMP destabilizes plaque by breaking down Type 1 collagen

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29
Q

Comparing normal endothelium to a vulnerable plaque, which has more MMP-8?

A

Vulnerable plack has more MMP-8. It’s very high in MMPs

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30
Q

Comparing normal endothelium to vulnerable plaque, which has more smooth muscle cells?

A

Normal endothelium has more smooth muscle cells. Vulnerable plaques have way fewer smooth muscle cells. With less smooth muscle cells, a plaque is more likely to rupture. Stable plaques have more smooth muscle cells than vulnerable plaques.

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31
Q

Comparing normal endothelium to vulnerable plaque, which has more macrophages?

A

Vulnerable plaques have a much stronger macrophage presence compared to normal endothelium.

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32
Q

Red blood cell remnants, iron, and disrupted intraplaque vessels are signs of _____.

A

Intraplaque hemorrhage

33
Q

True or False: Progression from atherosclerotic plaque to MI involves…
Lesion expansion => Weakening of fibrotic cap => macrophage apoptosis and necrosis => eventual plaque rupture

A

FALSE. The correct sequence of events is:

Lesion expansion => macrophage apoptosis and necrosis => weakening of fibrotic cap => eventual plaque rupture

34
Q

True or False: When patients present with an MI, there is evidence of old plaque ruptures.

A

True. It is thought that plaques are rupturing and clotting over time but doesn’t cause an MI until it causes significant obstruction.

35
Q

The old theory of plaque progression to MI was that plaques grew bigger and bigger until they obstructed the vessels. What is the current understanding of what causes MI’s?

A

Ruptures cause MI. E.g. A 30-40% lesion ruptures and causes MI.

36
Q

Can a biomarker of inflammation predict cardiovascular risk?

A

Maybe. The role of inflammation in atherogenesis suggests that inflammatory markers may predict residual risk. Inflammatory markers are used as additional prognostic information on top of known “standard” risk factors.

37
Q

Biomarkers have 5 clinical uses. What are they?

A
  1. Early detection of sub-clinical disease
  2. Diagnosis of acute or chronic syndrome
  3. Risk stratification
  4. Monitoring disease progression or response to therapy
  5. Selection of therapy
38
Q

Give an example of biomarkers being used for early detection of sub-clinical disease

A

Looking for fasting glucose levels to detect pre-diabetes.

39
Q

Give an example of biomarkers being used for diagnosis of acute or chronic syndrome

A

Troponin. It’s released from the heart when there is myocardial injury. Can use this to tell if someone is having an MI

40
Q

Give an example of biomarkers being used for selection of therapy.

A

If a certain biomarker is elevated, you may choose one drug over another.

41
Q

What is C Reactive Protein?

A

C Reactive Protein is either a bystander or mediator for inflammation.

42
Q

What produces C Reactive Protein?

A

Hepatocytes (liver) and possibly also expressed by macrophages and smooth muscle cells.

43
Q

Name a pentraxin acute phase reactant

A

C Reactive Protein. What does this mean? No idea… it wasn’t explained

44
Q

What does C Reactive Protein bind to?

A

Modified membranes, apoptotic cells, lipoproteins

45
Q

What does C Reactive Protein activate?

A

Classical complement pathway

46
Q

Where does CRP localize in atherosclerosis?

A

Typically localizes with the macrophages. (co-localize)

47
Q

True or False: CRP has been shown to be associated with adverse outcomes in CAD and MI

A

True. Shown in many studies

48
Q

True or False: CRP and cholesterol are NOT significant predictors for cardiovascular risk.

A

False. They are significant.

49
Q

Are CRP and cholesterol independent risk factors?

A

Yes

50
Q

True or False: Statins lower both cholesterol and CRP

A

True. Statins are mainly thought to reduce LDL but they are also shown to lower CRP which leads to increased plaque stability.

51
Q

What did the JUPITER trail test?

A

Huge trial (17800 patients) with LDL 2.0 mg/l. This CRP cutoff determined by other studies to be the amount of CRP circulating in the blood that is associated with a higher cardiovascular risk over time.

Tested if patients with normal cholesterol but elevated CRP would benefit from statin therapy.

Patients were given placebo or rosuvastatin (20mg). Primary endpoint of this study: MI, stroke, CV death, revascularization, unstable angina. Followed for 2 years.

52
Q

What was the result of JUPITER trial?

A

There was a statistically significant (50% reduction) reduction of cardiovascular risk over time taking rosuvastatin in patients with high CRP but low LDL.

53
Q

There have been hundreds of other biomarkers, other than CRP, that have been studied for their effects on cardiovascular disease. However, nothing has been found. Why?

A

The other biomarkers are not reliably measured as amounts can change throughout the day, impacted by common cold, etc. However, CRP tends to be very stable and is easy to reproduce in experiment. This makes it a more reliable biomarker in clinical situations.

54
Q

Patients with ____ (category of diseases) are shown to have accelerated atherogenesis.

A

Autoimmune diseases

55
Q

What are 4 potential reasons for the accelerated atherogenesis seen in patients with autoimmune diseases?

A
  1. Increased monocyte/macrophage activation (potential common mechanism underlying all autoimmune diseases)
  2. Impaired endothelial vasodilator function (seen in rheumatoid arthritis)
  3. Proatherogenic lipoproteins (pro-inflammatory HDL => increased LDL oxidation. This is observed in RA, psoriasis)
  4. Plaque instability (RA associated with similar extent of CAD, but increased plaque vulnerability)
56
Q

HDL is typically thought of as the good cholesterol. However, the measurement of HDL in the blood doesn’t tell you its functional capacity. How can HDL be pro atherogenic?

A

HDL can become pro-inflammatory if it’s not able to promote the reverse cholesterol transport for cholesterol efflux.

57
Q

What does endotoxin do to HDL?

A

Endotoxemia can alter HDL size and decrease reverse cholesterol transport capacity.

58
Q

In chronic inflammation, what can happen to HDL?

A

HDL may lose its anti-atherogenic functions and become pro-atherogenic

59
Q

True or False: HDL cholesterol efflux capacity is shown to improve risk of coronary artery disease

A

True/Falseish. Currently being studied. Association is possible and drugs may be able to increase cholesterol efflux to improve risk of coronary artery disease.

60
Q

How does psoriasis affect cardiovascular disease?

A

Psoriasis associated with systemic inflammation and impair HDL efflux capacity. If psoriasis patients are treated with anti-inflammation drugs, the level of HDL efflux improves over time. So, if you treat the immune disease, it may also increase prognosis for the CAD.

61
Q

It was once thought that patients with RA were more prone to CAD. This was shown to be untrue–patients with RA had similar overall prevalence of 3 vessel CAD. However, patients with RA do have what that causes worse prognosis?

A

RA patients had significantly more vulnerable plaque in LAD (48% vs 22%).

This shows that while RA patients developed CAD at same rates as non RA patients, perhaps the systemic inflammation from the RA caused significantly more vulnerable plaques which are more likely to rupture.

62
Q

Patients with RA have increased inflammatory components like… (name 4)

A
  1. TNF
  2. IL-1
  3. anti-CCP Abs
  4. Th17/Treg imbalance
63
Q

Patients with SLE (systemic lupus erythematous) have increased inflammatory components like… (name 3)

A
  1. IFNgamma
  2. FcyR
  3. anti-dsDNA Abs
64
Q

How does large vessel vasculitis affect atherogenesis?

A

Localized granulomatous arteritis. Anti-endothelial cell antibodies localize on the endothelium to cause damage and distortion of arterial anatomy which predisposes atherogenesis.

65
Q

A compilation of 14 RA studies with 42k patients shows that RA patients have an increased risk for CV disease, MI, and CVA (stroke). What is the % increase for each?

A

CV disease - 48% increase
MI - 68% increase
CVA - 41% increase

66
Q

What are the confounding factors when considering the connection between autoimmune diseases and CAD?

A

Autoimmune patients typically have a higher prevalence of obesity, HTN, smoking, diabetes, and metabolic syndromes.

67
Q

After controlling for confounding factors, severe psoriasis is shown to increase CV death and MI. What are the stats for CV death and MI? (meta analysis of of 4 studies)

A

CV Death - 39%

MI - 70%

68
Q

Is TNF-alpha inhibition associated with decreased CV risk?

A

Possibly.

Observational studies in RA have suggested a potential benefit of TNF alpha inhibition in reducing cardiovascular mortality and incident of MI.

Initial studies in psoriasis have also suggested a possible reduction in CV events among patients prescribed TNF alpha inhibitors

Potential residual confounding remains in all of these observational studies*

69
Q

What is the main shortcoming of observational studies?

A

Potential residual confounding

70
Q

Prednisone, a glucocorticoid, is a very common immunosuppressant and anti-inflammatory drug. Does it help CV risk?

A

No! Increased cardiovascular disease between 78%-162%. Shown in many studies. Prednisone affects many pathways and causes hypertension and weight cain so you’re adding other risk factors.

71
Q

Controlling confounding factors, how much did TNF-alpha Inhibitors improve CV risk?

A

61%

72
Q

True or False: Methotrexate was shown to reduce CV risk

A

TRUE. 21% reduction in CV events

73
Q

Many upstream inflammatory agents such as Canakinumab, Colchicine, Tocilizumab, low dose methotrexate, etc are being studied as potential new therapeutic targets in the inflammation-cardiovascular axis. Downstream from these, these all potentially effect what biomarker?

A

C Reactive Protein

74
Q

What is the CIRT Trial?

A

It’s an ongoing study that is investigating giving low dose methotrexate (10mg weekly) in patients with CAD (prior MI) and persistent elevation of hsCRP (>2 mg/L). 7,000 patients. These patients don’t have autoimmune disease but they are seeing if methotrexate helps the CAD.

75
Q

What is the CANTOS Trial?

A

It’s an ongoing study that is investigating giving canakinumab (IL-1B inhibitor) in patients with CAD (prior MI) and persistent elevation hsCRP (>2 mg/L). 10,000 patients.

76
Q

What is the ENTRACTE Trial?

A

Tocilizumab vs etanercept in patients with RA to see which one works better in CAD outcomes.

77
Q

True or false: There is interplay of innate and adaptive immunity in atherogenesis and disease progression.

A

True

78
Q

True or False: Biomarkers of inflammation are not a good predictor for future risk of CV events

A

FALSE. They are useful on top of the standard risk factors

79
Q

True or False: Inhibiting inflammation does not help inhibit CAD disease progression.

A

FALSE. Inhibiting inflammation helps inhibit CAD progression

Cardiovascular (22 decks)

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