L9 - Cardiac Channelopathies

Question 1

What are long or short QT syndromes caused by?

Answer 1

Changes to ventricular myocyte APs

Many ion channel mutations identified that lead to QT syndromes

Question 2

How many people does sudden cardiac death affect?

Answer 2

70,000 UK
60% ischaemic heart disease
40% no detectable cause
Some of these are inherited syndromes

Question 3

Ventricular action potential overview

Answer 3

Depolarisation phase – mediated by voltage gated Na channels
Plateau phase – mediated by voltage gated Ca channel
Repolarisation – mediated by voltage gated K channels

Question 4

What are the time differences of the ventricular action potential between people with long or short QT syndrome?

Answer 4

Normal - 0.36 s
Long - 0.45 s
Short - 0.34 s

Question 5

What are the two implications or short or long QT syndrome?

Answer 5

Triggered activity
Re-entrant excitation
Both increase risk of ventricular tachycardia (increase in firing rate of the ventricles)
- This is a risk factor for ventricular fibrillation (myocytes contract in an uncontrolled manor)

Question 6

What is the effect of triggered activity?

Answer 6

After depolarisations threshold reached when you wouldn’t expect 
Additional beat (ectopic)

Question 7

What is the effect of re-entrant excitation?

Answer 7

Different layers of myocyte cells impacted by having an additional beat
This action potential then spreads to neighbouring cells
Spatial (space) and temporal (time) dispersion refractory period
Re-entry of additional action potentials into other cells and AP propagation

Question 8

What are long QT syndrome patients at risk of?

Answer 8

Sudden death – torsades de pointes (form of ventricular tachycardia) + ventricular fibrillation
Syncope (fainting)
Symptoms do not appear until teenage years

Question 9

Long QT syndrome overview

Answer 9

Prolonged QT interval
Self limiting episode – stops itself and myocytes go back to normal activity
1:10,000 to 1:15,000

Question 10

How many different form of long QT syndrome are there?

Answer 10

12
Dominant and recessive forms
Gain and loss of function

Question 11

What does the long QT syndrome affecting Q1 and its regulator E1 affect?

Answer 11

The ear
Stria vascularis secretes K into endolymph
- Q1 is regulated by E1 inside the stria vascularis
Bending of hair cells when noise hits the cochlea
- This opens K channels allowing K to enter hair cells
- This depolarisation leads to neurotransmitter release
In patients with loss of function
- Mutation to E1
- Endolymph does not form so hair cells cannot depolarise

Question 12

What are the characteristics the LQT3 mutation causes?

Answer 12

Associated with mutation in Na channel NAv1.5α
Gain of function mutation
Associated with INa current
5-10%

Question 13

What are the characteristics the LQT1 mutation causes?

Answer 13

Associated with mutations in K channel Kv7.1α
Loss of function mutation
Associated with Iks¬ current
30-35% of individuals
Cluster of mutations in transmembrane spanning domains
If K channel lost, cannot get as much K channel out the cell as quickly – slows repolarisation

Question 14

What are the characteristics the LQT5 mutation causes?

Answer 14

Associated with mutation in K channel MinK
Loss of function
Associated with Iks current
1%

Question 15

Gain of function mutations in Na and Ca channels in long QT syndrome cause?

Answer 15

Channel opens normally but close too slowly
This prolongs plateau phase
Delays the start of repolarisation – extends QT interval

Question 16

What are two examples of treatment for long QT syndrome?

Answer 16

Beta blockers – class 2 antidysrhythmic drugs
Atenolol - 1 selective antagonist
- cAMP linked receptor
- Negative cronotrophic and ionotrophic actions
- Reduces the heart rate to reduce ventricular tachycardia
- Contraindications
- Anyone with obstructive lung disease have a risk of bronchoconstriction

Question 17

What are people with short QT syndrome at risk of?

Answer 17

Arrhythmias and palpitations
Syncope (fainting)
Sudden death – ventricular tachycardia and ventricular fibrillation
Symptoms do not appear until teenage years

Question 18

How many forms of short QT syndrome are there?

Answer 18

5

Gain and loss of function

Question 19

What % of short QT syndrome cases are male?

Answer 19

75%

Question 20

What does the ECG of a short QT syndrome patient show?

Answer 20

Short or absent ST segment
Tall T wave
QT interval fixed (on exercise it doesn’t change)

Question 21

What is an example of a short QT syndrome mutation?

Answer 21

SQT2
- Associated with mutations in K channel Kv7.1α
- Gain of function
- Associated with IKs current
Mirror image to mutations for long QT syndrome

Question 22

Loss of function mutations in Ca channels in short QT syndrome causes?

Answer 22

Channels don’t open normally reducing activity
Channels open normally but close to quickly
Repolrarisation starts earlier - shortens plateau phase
Shortens QT interval

Question 23

Gain of function mutations in K channels in short QT syndrome causes?

Answer 23

More channels in the membrane or channels open earlier than they should
Repolrarisation starts earlier - shortens plateau phase
Shortens QT interval

Question 24

How is short QT syndrome treated?

Answer 24

Implant defibrillator

Research suggests quinidine (K+ channel blocker)