Cardiac Channelopathies

Question 1

What are the main groupings of sudden cardiac death?

What are the causes of this?

Answer 1

Long or short QT syndrome

Changes to ventricular myocyte action potentials and ion channel mutations in the ventricles

Question 2

What are the parts of the normal ECG?

What do these represent?

Answer 2

P wave - atrial depolarisation

QRS - ventricular depolarisation

T - ventricular REpolarisation

Question 3

What is the QT interval?

Answer 3

From the START of the QRS to the END of the T

Question 4

Why is atrial REpolarisation not shown on the ECG?

Answer 4

Happens at the SAME TIME as ventricular deoplarisation

So is MASKED by the QRS wave

Question 5

What is long QT?

Answer 5

DELAY of the T wave
Defect in the ventricle REPOLARISATION

Prolonged QT interval

Question 6

What is short QT?

Answer 6

SPEEDING up of the START of the T wave (happens too early)

Question 7

What channels are involved in the QT interval?

Answer 7

Voltage gated Ca2+ channels
Na+ channels
K+ channels

Question 8

What are the implications of altered QT intervals?

Answer 8

Increase risk of VENTRICULAR TACHYCARDIA

Question 9

What is ventricular tachycardia?

What does increase the risk of?

Answer 9

• Increase in the firing rate of action potentials
• Increase in the number of CONTRACTIONS of the ventricles

Risk factor of going into VENTRICULAR FIBRILLATION

Question 10

What is ventricular fibrillation?

Answer 10

Contraction of the ventricles in an UNCONTROLLED manner

Question 11

What is triggered activity?

Answer 11

Changes in the electrical signals in the cells:
- Depolarisation in the cells reach threshold at a time point in the cardiac cycle that are NOT normally expected

• EXTRA beat
• VENTRICULAR TACHYCARDIA if the cells have many extra beats
• At risk of VF

Question 12

What is re-entrant excitation?

Why is it called ‘re-entrant’?

Answer 12

Seen in clusters of of myocytes (not all of them):

• Electrical activity from the extra beat SPREADS from the effected cells to adjoining cells
• Different LAYERS impacted
• Causes FURTHER spread of contraction (effecting the normal spread)

Called re-entrant because the AP fired from the abnormal cells FEEDBACK onto the other cells, causing them to contract

Question 13

What impacts does re-entrant excitation have?

Answer 13

• Spatial (in space)

- Temporal (in time)

Question 14

What happens after the abnormal cells fire what happens to them?

What does this mean?

Answer 14

They become REFRACTORY

Unable to respond to a NORMAL signal coming down from the node

Question 15

What are the symptoms of long QT syndrome?

Answer 15

• Syncope (fainting)

- Sudden death (Torsades de pointes - forms VT)

Question 16

What is the inheritance of long-QT?

Answer 16

• 12 different forms of gene changes

- Gain of function/loss of function

Question 17

What are the different types of long-QT?

How are they different?

Answer 17

1) Self-limiting episode
- ECG goes back to NORMAL
2) Episode leading to ventricular fibrillation
- ECG doesn’t go back to normal

Question 18

How many different mutations leading to LQT?

Answer 18

12 types

Question 19

What causes LQT1?

Answer 19

LOSS OF FUNCTION mutation in Kv7.1alpha channel (KCNQ1 gene):

• K+ channel
• In the alpha subunit

Question 20

What is LQT1?

Answer 20

Long QT type 1

Question 21

What is the Kv7.1 alpha channel associated with?

Answer 21

The Iks current

Question 22

What cause LQT3?

Answer 22

GAIN OF FUNCTION mutation in Nav1.5alpha channel (SCN5A gene):

Question 23

What is the Nav1.5alpha channel associated with?

Answer 23

Ina current

Question 24

What causes LQT5?

Answer 24

Mutation in MinK protein (KCNE1 gene)

Question 25

What is MinK protein?

Answer 25

Regulator of K+ Kv7.1alpha

Question 26

What causes LQT8?

Answer 26

GAIN OF FUNCTION mutation in Cav1.2alpha channel (CACNA1C)

Question 27

What is Cav1.2aplha involved with?

Answer 27

Ica current

Question 28

Why is it not a massive impact if there is a mutation in K+ channel?

Answer 28

Not a massive impact as there are many K+ channels

If a mutation in one channel, other channels can subserve the function

Question 29

What is the structure of the KVLQ1 channel?

Answer 29

4 subunits come together to form a functional K+ channel

Question 30

Why are the mutations that could be present in the KVLQ1 channel?

Answer 30

• SOME are autosomal dominant and SOME are autosomal recessive
• SOME mutations in the C terminus
• MOST mutations in the membrane spanning domains
• Loss of function in Q1 potassium channel or its regulator

Question 31

What is the Q1 potassium channel important in?

What happens if there is a mutation in this channel?

Answer 31

Repolarisation

• Slows repolarisation
• QT interval extends

Question 32

How are forms of LQT syndromes are associated with deafness?

Answer 32

K+ channels in the stria vascularis - concentrate endolymph

Through the Q1/E1 complex

Question 33

What mutations occur to Na+ and Ca2+ channels in LQT?

What does this cause?

Why?

Answer 33

Gain of function mutations

Causes:

• Prolongation of the plateau phase
• Delay of the repolarisation phase

As these channels are normally open and cause depolarisation - but stay open for LONGER

Question 34

What are the treatments for LQT?

Example?

Answer 34

Beta blockers

Example: atenolol