Pathophysiology of CVD and CHF

Question 1

What is upstream inflammatory response and roles

Answer 1

WBC (monocytes & lymphocytes)

2nd line of defence in response to injury/damage/illness

Question 2

What is downstream inflammatory response TNF-a and roles

Answer 2

Multiple roles and effects (pro&anti)

In relation to atherosclerosis, it is produced by activated T-cells

Activates NF-kB

Stimulates acute phase response on the liver

Question 3

What is downstream inflammatory response IL-6 and roles

Answer 3

Multiple roles and effects like TNF-a

Regulates immune function (pro&anti)

In relation to atherosclerosis, released from smooth muscle cells in response to macrophage derived TNF-a

Messenger cytokine

Question 4

What is CRP (C reactive protein) and roles

Answer 4

Acute phase protein synthesised by hepatocytes (liver)

Released in response to IL-6

High sensitivity CRP

Stable biomarker

Question 5

Look at Jupiter study, Ridker, 2003!!

Answer 5

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Question 6

What were the HRs across all Cv endpoints 150mg

Answer 6

Primary - 0.85

Secondary - 0.83

Myocardial infarction - 0.76

Urgent revascularization - 0.64

Any coronary revascularization - 0.68

Stroke - 0.98

cardiac arrest - 0.63

CV death - 0.90

All cause morality - 0.92

Question 7

What were the HRs at 300mg

Answer 7

Primary - 0.86

Secondary - 0.83

Myocardial infarction - 0.84

Urgent revascularization - 0.58

Any coronary revascularization - 0.70

Stroke - 0.80

Cardiac arrest - 0.46

CV death - 0.94

All cause morality - 0.94

Question 8

What is the protective role of the healthy endothelium against plaque formation in arteries?

Answer 8

A variety of factors lead to
atherogenesis:
 Reduction in bio-availability of NO

 Increased oxidative stress
- e.g. oxidised LDL

 Vasoconstriction by endothelin-1
(ET1)

 Endothelium upregulates ET1 in
response to oxidised LDL etc.

Question 9

Define M-CSF and outline its role in the development of atherosclerotic plaque

Answer 9

1. Macrophages engulf oxLDL  foam cells
2. Foam cells multiply  fatty streak/atheroma
3. Secretion of inflammatory cytokines and
   growth factors
4. Smooth muscle cell proliferation
5. Collagen  plaque holding foam cells in
   • Macrophage Colony-Stimulating Factor (M-CSF)

Question 10

What is the role of TNFa and VCAM-1

Answer 10

1. *Change to endothelial function
2. *Infiltration of oxidised LDL into intimal
   layer
3. ^Adhesion molecules are expressed on
   endothelium to attract WBC’s
4. # WBC migrate into intima  macrophages• *Nuclear Factor Kappa Beta (NF-κβ)
   • ^Vascular Cell Adhesion Molecule 1 (VCAM-1)
   •
   # Monocyte Chemoattractant Protein 1 (MCP-1)

Question 11

What is a key player in the breakdown of
the fibrous cap and subsequent
thrombus release? Describe.

Answer 11

9. Continued inflammation increases enzymes
   that interfere with stability and strength of
   collagen matrix
    prevent new collagen*
    destructs existing collagen (enzymes)
10. Weakens plaque  rupture of atheroma
11. Thrombus released into blood and is most
    probable cause of MI
    * γ-Interferon

Question 12

How does CANTOS study (Ridker, 2017) support inflammatory hypothesis’ of heart disease

Answer 12

Look at Ridker 2017

Question 13

What does ventilation-perfusion mismatching represent in patients with heart failure - include the physiological
mechanism and the key symptom?

Answer 13

↑ CO2 & H+  Chemoreceptors (metabolic acidosis)

 ↑ Rate & depth of respiration in attempt o restore pH

Peripheral muscle receptors (metabo- or mechanoreceptors) produce an abnormal ergoreflex, resulting in an abnormal VE/VCO2 slope during exercise.
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