L5 cardiac arythmias

Question 1

how common is sudden cardiac death?

Answer 1

1,000,000 cases of syncope and sudden cardiac death a year in europe + america

Question 2

what are the subunits of a Ca2+ channel?

Answer 2

alpha1 subunit - forms channel

alpha 2, beta1-4 are regulatory subunits

Question 3

what are L type calcium channels?

Answer 3

• high voltage activated dependent calcium channels.
• Cav1.2
• CACNA1C gene
• found in heart, brain, lungs

(long lasting activation)

Question 4

what are the types on inactivation Ca2+ can undergo?

Answer 4

Calcium dependent and voltage dependent inactivation

• when + voltage - inactivated
• Ca2+ feeds back and inhibits own channel

Question 5

what is timothy syndrome?

Answer 5

A rare disorder which effects multiple organs such as the heart, skin, eye, teeth, and brain.

• congenital heat disease
• arythmias
• syndactyly
• round face, flat nasal bridge, thin upper lip
• immune deficiency
• autism
• prolonged QT interval

Question 6

what causes timothy syndrome?

Answer 6

• CACNA1C mutations

- associated with LQT

Question 7

what heart issues are there with timothy syndrome?

Answer 7

• congenital heart disease and arythmias
• prolongs QT interval
• 2:1 atrioventricular block (to P waves (Acontraction) for every QRS - as repolarisation is delayed - atrial contraction occurs (twice)as SA node triggers atrial contraction and no ventricular contraction occurs as not ready to contract as still hasnt fully repolarised. )
• ventrivels become out of time which increases risk of ventricular tachycardia and fibrillation and death
• small changes in ECG - e.g. alternating polarity of T wave (problems with repolarisation)

Question 8

how many children suffering with timothy syndrome died?

Answer 8

• 10/17 children died which is likely to be caused by ventricular tachycardia/fibrillation (due to 2:1 atrioventricular block)
• mean death 2.5 years old
• 12 of 17 experienced life threatening arythmias
• survivors had motor/cognitive impairment-brain damage

Question 9

what change in Cav1.2 was seen in all timothy patients who were examined ?

Answer 9

A NEW SPLICED VARIANT of Cav1.2 was observed in all timothy patients examined. (not the same as a mutation - not due to genetic changes?)

• glycine changed to arginine (G406R)
• glycine is conserved in other organisms at this position - represents its importance
• not all cav1.2 channels in the patients have this different variant

Question 10

what impact does G406R have? (new spliced variant)

Answer 10

It slows inactivation of the calcium channels (cav1.2)- so the channels stay open for longer (larger current) - this causes a longer plateau phase , which causes repolarisaiton to be delayed - therefore there is a longer QT interval

Question 11

what form of inactivation does the G460R effect?

Answer 11

• has little effect on calcium dependent inactivation

- has large effect on voltage dependent inactivation

Question 12

when does calcium dependent inactivation of Cav1.2 stop?

Answer 12

it is relieved at a more positive potential

Question 13

how can you be sure that only voltage dependent inactivation of Cav1.2 channels is being measured?

Answer 13

• need to block calcium dependent inactivation
• add barium (Ba2+) - generates same current as Ca2+ (same charge) but does not feedback to inhibit the channel.
• substitute calcium for barium?
• therefore only looking at voltage dependent inactivation.

Question 14

What happens when calcium dependent inactivation of the Cav1.2 channel is inhibited?

Answer 14

• there is slower inactivation - as only relying on voltage dependent inactivation

Question 15

what effect does the new spliced variant of Cav1.2 - G406R have on voltage dependent inactivation?

Answer 15

• has a big impact
• the channel barely inactivates
• hardly any decrease in current compared to WT - long delay in inactivation
• 17% longer heart AP - large impact - LQT

Question 16

what is the other name for short QT syndrome?

Answer 16

• Brugada syndrome - leads to ventricular arythmia

Question 17

what are the 5 forms of SQT syndrome caused by?

Answer 17

SQT1-3 - gain of function K channels
SQT4- loss of function CACNA1C
SQT5 - loss of function CACNB2B

Question 18

what are the symptoms of brugadas syndrome?

Answer 18

• arythmias, ectopic beats, ventricular tachycardia, fibrillation - sudden cardiac death
• accentuated J wave
• ST segment elevation
• short QTc interval

Question 19

what intervals are classed as short QT in males and females?

Answer 19

<360ms male

<370 ms female

Question 20

How is the QTc interval calculated?

Answer 20

by bazetts formula

Question 21

what are the mutations in calcium channels that cause brugadas syndrome?

Answer 21

CACNB2B - serine to leucine S481L
CACNA1C- glycine to arginine G490R (biggest effect)
CACNA1C- arginine to valine A39V

(all loss of function in calcium channels - reuction in Ca2+ currents- inactivation of channels happens sooner-shorter plateau phase - repolarisation happens sooner - SQT)

Question 22

What is the location of Cav1.2 when loss of function?

Answer 22

A36V-mostly in cells - little at PM - traffiking issues
G490R- little at membrane
S48L - Cav1.2 still traffiked to the membrane but there are issues in gating

Question 23

what can different mutations in Cav`1.2 channels cause?

Answer 23

• CACNA1A gain of function (G406R) new spliced variant- LQT
  (loss of inactivaiton - longer plateu phase)
  -CACNA1A loss of function (G490R, A36V) - SQT
  _CACNB2B loss of function (S481L) - SQT