Cell based arrhythmias

Question 1

What does thapsigargin do?

Answer 1

Inhibits SERCA

Question 2

What are the 3 arrhythmogenic mechanisms?

Answer 2

1. Bradyarrhythmias
2. Tachyarrhymias
3. Abnormal focal activites

Question 3

How do braddyarrhythmias occur?

Answer 3

• Slowed pacemaking - increased vagal tone - vasovagal syncope/beta blockade
• Depressed impulse conduction - conduction block- AV node and bundle branch block

Question 4

How do Tachyarrhymias occur?

Answer 4

• Accelerated pacemaker activity - sinus tachy

- Re-entry

Question 5

How does abnormal focal activity occur?

Answer 5

Triggered depolarizations (afterdepolarizations) If threshold is reached spontaneous action potentials result producing ectopic beats in tissues outside the sinus node

Question 6

What is automaticity?

Answer 6

Basis of cardiac pacemaker function. Various areas of the conduction system can show automaticity and are potentially arrhythmogenic

Question 7

What is a channelopathy

Answer 7

diseases caused by disturbed function of ion channel subunits or the proteins that regulate them

Question 8

What are the categories of channelopathies

Answer 8

1. Heritable – resulting from a mutation or mutations in the encoding genes
2. Acquired
   ® drug-induced
   ® remodelled

Question 9

Heritable channelopathy that increases function of channel

Answer 9

Mutations in SCN5A encoding Na channel - hannels that incompletely inactivate leading to increased Na influx

Question 10

Heritable channelopathy that decreases function of channel

Answer 10

Mutations of genes encoding K channels (IKr and IKs)

- Produce channels that have loss of function so decrease K efflux

Question 11

Which channel K or Na is more susceptible to mutation and why?

Answer 11

Na channel is 4 domains lumped together to produce the channel so the single protein forms the pore.
In K channels like Ikr and Iks they are single monomers and 4 of them are put together to form the channel.
Means there is an increased probability of a mutation in one of these monomers crippling the channel

Question 12

Is late Na current changed in HF?

Answer 12

Increased

Question 13

How is increased Na influx proarrhythymic?

Answer 13

Small change in Na will alter NCX system (associated charge because 3:1 stoichiometry)
- Provoked depolarization/repolarization depending on Na concentration

Question 14

How is reduced K efflux proarrhythmic?

Answer 14

Repolarization slowed - voltage range overcomes refractory period and Ca channels to be reactivated - can get depolarization - Na channels activated - upstroke

Question 15

Which current is HERG channel?

Answer 15

Ikr

Question 16

2 different structural features of HERG vs other voltage gated K channels

Answer 16

• Lack of proline residues in the S6 transmembrane domain

- Presence of two aromatic residues (Y, F) (actually tyrosine and phenylalanine) in same domain form drug binding site

Question 17

What do structural differences of HERG make it useful for

Answer 17

Lackck of proline residues increases the size of the HERG inner cavity creating large space for channel–drug interactions.

• Often tested upon for safety
• Not a good idea to have a drug that binds to this channel because repolarisation in the heart will be affected

Question 18

What happens to ITO in HF

Answer 18

Downregulation

Question 19

What happens to NCX in HF?

Answer 19

Upregulation

Question 20

What does 4AP do?

Answer 20

Inhibits ITO (the notch) - prolongation of AP

Question 21

When do EADs occur?

Answer 21

during the plateau or late phase of repolarization

Question 22

When do DADs occur?

Answer 22

when Em has returned to normal resting potential

Question 23

Characteristic of AP with EAD

Answer 23

Prolonged

Question 24

3 causes of EADs

Answer 24

1. Hypokalaemia (decreased gIk1)
2. Pharmacology (K blockade)
3. Congenital channel defects (Long QT)

Question 25

Cause of EAD related to channels

Answer 25

• reactivation of Ca channels when AP is long and Ca transient is declining
• As Em is in range of “window” Ca current, a proportion of Ca channels recover and can be opened again
• EADs that occur later in repolarization unlikely to result from ICa reactivation

Question 26

Which currents is plateau of AP based on

Answer 26

balance between Ca influx and K efflux

Question 27

Cause of DAD

Answer 27

1. Cellular (diastolic) Ca raised

2. SR Ca raised

Question 28

Drug that causes DADs

Answer 28

beta agonists

Cardiotonic steroids

Question 29

Mechanism of Ca release events from SR causing depolarization (DAD)

Answer 29

1.Increased SR load and/or increased cytoplasmic [Ca] increase open probability of RYR
2. Increased Ca spark activity
3. Increased Na/Ca exchange-mediated efflux of Ca from cell
Inward current produces depolarization
4. Inward current produces depolarization

Question 30

What does caffeine do?

Answer 30

Releases all Ca from SR - get an inward current

Question 31

Which current responsible for DAD

Answer 31

NCX