Vascular Diseases

Question 1

Describe method of LDL reduction by hepatocytes

Answer 1

Hepatocytes express LDLR, which works to remove LDL by its uptake into hepatocytes and subsequent breakdown (with the help of Apo B100)

Question 2

Describe method of LDL removal by HDL

Answer 2

HDL removes excess LDL from cells; incorporated into Apo A1

Question 3

What is Lp(a)?

Answer 3

Lp(a) forms from LDL (+Apo B100) - competes with plasminogen (precursor to plasmin - plasmin removes blood clots)

Question 4

How does inflammation contribute to atherosclerosis?

Answer 4

Circulating leukocytes will stick to and enter tissue

Question 5

Describe 3 steps of vessel wall inflammation caused by LDL

Answer 5

1. excess LDL enters vessel wall, becomes oxidised. Oxidised LDL induces expression of adhesion molecules. Oxidised LDL phagocytosed by macrophages (become foam cells).
2. Adhesion molecules facilitate entry of monocytes, which differentiate into macrophages, releasing inflammatory factors.
3. T cells infiltrate; activated T cells produce Th1 cytokines, such as IFN-gamma, IL-6, IL-1beta and TNF.
   This further increases inflammation in the area.

Question 6

What enzyme do statins inhibit and why is this used as a treatment for atherosclerosis?

Answer 6

Statins inhibit HMG-CoA reductase, a rate-limiting enzyme in the cholesterol-synthesis pathway. Decreases cholesterol synthesis in the liver.
The reduction of endogenous cholesterol in hepatocytes also increases # of LDLR, which leads to increased LDL clearance.

Question 7

Apart from statins, what is a second class of drugs used to treat hyperlipidaemia (hypercholesterolaemia)?

Answer 7

PCSK9 inhibitors
PCSK9 enzymes bind to LDLR and mark it for lysosomal degradation. Inhibition of PCSK9 using antibodies increases number of LDLR and decreases levels of LDL.

Question 8

ACS guidelines differentiate 2 types of patients based on ECG - what are they?

Answer 8

STEMI - persistent (>20m) elevation of ST segment - usually indicates total coronary occlusion. Immediate treatment required.

NSTEMI (partial occlusion, partial thickness infarct)/ normal

Question 9

ACS universal definition of MI is a combination of a “funny ECG” with:

Answer 9

Increase in biomarker troponin (cTn) - gold standard.
cTn detected 4-10h after AMI, peak at 12-48h, abnormal for 4-10d
Would do at least 2 tests to see changes in cTn levels

Question 10

What other biomarkers can be tested for AMI?

Answer 10

Myoglobin and creatine kinase (CK-MB Relatively-heart specific)

Question 11

What is an inflammatory biomarker used to inform on statin therapy?

Answer 11

C-reactive protein; stimulated by IL-6, binds to surface of dying cells and promotes phagocytosis.

Question 12

How does a fibrous cap form? How does it rupture?

Answer 12

The fibrous cap is formed by SM cells that migrate towards site of inflammation and produce collagen, which forms the cap.
The cap is subsequently ruptured by factors of inflammatory signalling, including reduction in collagen production (T cell driven), degradation using MMP (macrophages) and degradation using tissue factor (macrophages)

Question 13

What are 2 acute coronary syndromes?

Answer 13

• acute angina

- acute myocardial infarction

Question 14

What are 2 chronic coronary syndromes?

Answer 14

• stable angina

- heart failure

Question 15

Where does the AMI usually occur?

Answer 15

Left ventricle - thicker muscle

Question 16

What are 2 possible causes of angina pectoris (chronic)?

Answer 16

CHD; coronary vasospasm due to lack of oxygen

Question 17

What symptoms require urgent medical attention for angina pectoris (chronic) sufferers?

Answer 17

• chest pain lasting for more than a few minutes

- worsening/ unstable angina

Question 18

Name 3 types of angina.

Answer 18

• Chronic/ stable angina (caused by demand e.g. exercise)
• Unstable angina (classic ACS) - unpredictable; thrombus formation
• Variant (vasospastic) angina (no atherosclerosis) - spasm of coronary artery

Question 19

What are some drug and non-drug treatments for angina?

Answer 19

Acutely relieved by rest and nitrovasodilators

Question 20

Explain heart failure/ congestive heart failure/ cardiac failure and some causes.

Answer 20

Decreased CO not being able to meet up with the demand.

Caused by AMI/ CHD, arrhythmias, hypertension, diabetes, etc.

Question 21

Name 2 types of chronic heart failure.

Answer 21

• systolic dysfunction (HF with reduced ejection fraction) - dilated LV
• diastolic dysfunction (HF with preserved ejection fraction) - contraction OK, but impaired filling due to hypertrophy of LV

Question 22

Name 4 types of drugs used to treat hypertension - which ones can also be used to treat HF?

Answer 22

• ACE inhibitors
• beta blockers
• calcium channel blockers
• diuretics
  A,B and D can be used for HF as well.

Question 23

ACE-inhibitor drug name suffix

Answer 23

-pril

Question 24

angiotensin receptor blocker drug name suffix

Answer 24

-sartan

Question 25

When would you give a patient losartan instead of captopril?

Answer 25

If patient is intolerant of ACE inhibitors, e.g. has a persisent cough due to increase in bradykinin

Question 26

Treatment of pulmonary arterial hypertension (drug)

Answer 26

O2
anti-coagulants/ blood thinners
diuretics
endothelin-1 antagonists (stops reduction of lumen)
vasodilators
inotropic agents (increases heart’s pumping ability)
sildenafil (relaxes pulmonary SM cells

Question 27

What pathway mediates Ca2+ sensitivity in vascular smooth muscle? What new treatment is now being trialled?

Answer 27

The RhoA/ ROK pathway, which acts to decrease the myosin light chain phosphatase activity, increasing the amount of phosphorylated MLC at a constant Ca2+ concentration, which is called Ca2+ sensitivity.
[If the phosphatase cannot remove the phosphate from the MLC, the increased levels of phosphorylated MLC cause contraction in the tissue.]
Drugs being tested are Fasudil and y27632, both of which are RhoA/ ROK inhibitors. Successful so far.