L9 - Cardiac Channelopathies Flashcards
What are long or short QT syndromes caused by?
Changes to ventricular myocyte APs
Many ion channel mutations identified that lead to QT syndromes
How many people does sudden cardiac death affect?
70,000 UK
60% ischaemic heart disease
40% no detectable cause
Some of these are inherited syndromes
Ventricular action potential overview
Depolarisation phase – mediated by voltage gated Na channels
Plateau phase – mediated by voltage gated Ca channel
Repolarisation – mediated by voltage gated K channels
What are the time differences of the ventricular action potential between people with long or short QT syndrome?
Normal - 0.36 s
Long - 0.45 s
Short - 0.34 s
What are the two implications or short or long QT syndrome?
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)
What is the effect of triggered activity?
After depolarisations threshold reached when you wouldn’t expect Additional beat (ectopic)
What is the effect of re-entrant excitation?
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
What are long QT syndrome patients at risk of?
Sudden death – torsades de pointes (form of ventricular tachycardia) + ventricular fibrillation
Syncope (fainting)
Symptoms do not appear until teenage years
Long QT syndrome overview
Prolonged QT interval
Self limiting episode – stops itself and myocytes go back to normal activity
1:10,000 to 1:15,000
How many different form of long QT syndrome are there?
12
Dominant and recessive forms
Gain and loss of function
What does the long QT syndrome affecting Q1 and its regulator E1 affect?
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
What are the characteristics the LQT3 mutation causes?
Associated with mutation in Na channel NAv1.5α
Gain of function mutation
Associated with INa current
5-10%
What are the characteristics the LQT1 mutation causes?
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
What are the characteristics the LQT5 mutation causes?
Associated with mutation in K channel MinK
Loss of function
Associated with Iks current
1%
Gain of function mutations in Na and Ca channels in long QT syndrome cause?
Channel opens normally but close too slowly
This prolongs plateau phase
Delays the start of repolarisation – extends QT interval
What are two examples of treatment for long QT syndrome?
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
What are people with short QT syndrome at risk of?
Arrhythmias and palpitations
Syncope (fainting)
Sudden death – ventricular tachycardia and ventricular fibrillation
Symptoms do not appear until teenage years
How many forms of short QT syndrome are there?
5
Gain and loss of function
What % of short QT syndrome cases are male?
75%
What does the ECG of a short QT syndrome patient show?
Short or absent ST segment
Tall T wave
QT interval fixed (on exercise it doesn’t change)
What is an example of a short QT syndrome mutation?
SQT2
- Associated with mutations in K channel Kv7.1α
- Gain of function
- Associated with IKs current
Mirror image to mutations for long QT syndrome
Loss of function mutations in Ca channels in short QT syndrome causes?
Channels don’t open normally reducing activity
Channels open normally but close to quickly
Repolrarisation starts earlier - shortens plateau phase
Shortens QT interval
Gain of function mutations in K channels in short QT syndrome causes?
More channels in the membrane or channels open earlier than they should
Repolrarisation starts earlier - shortens plateau phase
Shortens QT interval
How is short QT syndrome treated?
Implant defibrillator
Research suggests quinidine (K+ channel blocker)
