How many sudden cardiac deaths per year in the UK
70000
What % of sudden cardiac deaths are caused by ischaemic heart disease
60%
What % of sudden cardiac deaths have no identifiable cause
40%
Long and Short QT syndromes are examples of __________ syndromes
Inherited
What is the main effect of long/short QT
Change to the action potentials of ventricular myocytes
P wave represents
Atrial depolarisation
QRS complex represents
Ventricular depolarisation
T wave represents
Ventricular repolarisation
Why is atrial repolasrisation not shown on an ECG
Because it is masked by the depolarisation of the ventricles
In long QT
Repolarisation is delayed
QT interval increases
In short QT
Repolarisation is accelerated
QT interval decreases
What is phase 0 of the ventricular AP
Depolarisation
What currents mediate depolarisation of the ventricles
Influx Ina
What is phase 1 of the ventricular AP
Partial repolarisation
What currents mediate the partial repolarisation of the ventricles
Ito influx
What is phase 2 of the ventricular AP
Plateau
What currents mediate the plateau phase
Influx Ina Ica
Efflux Iks Ikr Ikur
What is phase 3 of the ventricular AP
Repolarisation
What currents mediate repolarisation
Efflux: Iks Ikr Ikur IkATP IkACh
What is phase 4 of the ventricular AP
Resting
What currents mediate the resting state of the ventricular AP
Influx Ina Ica
Efflux Ik1 Ik2p
Normal QT interval is
0.36
Threshold for short QT is
0.34
Threshold for long QT is
0.45
Two main classes of implications of long and short QT, what can they lead to
Triggered activity
Re-entrant excitation
Lead to ventricular tachycardia and then to ventricular fibrilation
Describe triggered activity
Cells reach the threshold when they shouldn’t and fire action potentials
Leads to an additional beat - ectopic
Describe re-entrant excitation
Few layers of cells affected that include the extra beat
This can spread to other cells
Spatial and temporal distortion
AP propagation
When actual signal arrives cells are in refractory so can’t respond
What is spatial distortion
Electrical signals that can spread from one affected group of cells to another
What is temporal distortion
Where one cluster of cells fires an action potential - these then fire again at another point in time
Main symptom of Long QT
Syncope
What does syncope mean
Episodes of fainting
A twisting of the ECG trace is known as …
HINT: it is a form of VT
Torsade de pointes
LQT1 is caused by a muation in what gene
KCNQ1
LQT1 affects which ion channel
Kv7.1a
Kv7.1a is coded for by which gene
KCNQ1
LQT1 is caused by a _____ of function mutation in the gene ______ which codes for _______, affected the current _____
Loss
KCNQ1
Kv7.1a
Iks
Iks current is involved in
Repolarisation
What is the prevalence of LQT1
30-35%
LQT2 is caused by a mutation in what gene
KCNH2
Which ion channel is affected by LQT2
Kv11.1a
Kv11.1a is mutated in which form of LQT
2
Kv7.1a is mutated in which form of LQT
1
LQT2 is caused by a _____ of function mutation in the gene ______ which codes for _______, affected the current _____
Loss
KCNH2
Kv11.1a
Ikr
Ikr is involved in
Repolarisation
LQT3 is caused by a mutation in which gene
SCN5A
Prevalence of LQT2
25-30%
Prevalence of LQT3`
5-10%
What ion channel is mutated in LQT3
Nav1.5a
LQT3 is caused by a _____ of function mutation in the gene ______ which codes for _______, affected the current _____
Gain
SCN5A
Nav1.5
Ina
what is Ina involved in
Depolarisation and the plateau
LQT5 is caused by a _____ of function mutation in the gene ______ which codes for _______, affected the current _____
Loss
KCNE1
MinK (regulatory)
Iks
Iks current involved in
Repolarisation
Prevalence of LQT5
1%
What protein is mutated in LQT5
MinK
What gene is mutated in LQT5
KCNE1
What gene is mutated in LQT1
KCNQ1
What gene is mutated in LQT2
KCNH2
What gene is mutated in LQT3
SCN5A
What gene is mutated in LQT5
KCNE1
What type of mutation LQT1
Loss
What type of mutation LQT2
Loss
What type of mutation LQT3
Gain
What type of mutation LQT5
Loss
What protein mutated LQT1
Kv7.1a
What protein mutated LQT2
Kv11.1a
What protein mutated LQT3
Nav1.5a
What protein mutated LQT5
MinK
What current affected LQT1
Iks - repolarising
What current affected LQT2
Ikr - repolarising
What current affected LQT3
Ina - plateau
What current affected LQT4
Iks - repolarising
What type of channelopathy is LQT1
k channelopathy
How many subunits must come togehter to form the fucntional channel Kv7.1
4
Where are a few of the mutation sites found in Kir7.1
At the carboxy terminus
Intracelluar loops
Where are the majority of mutations found in Kir7.1
Tm spannig omains
Why does the loss of function in Kv7.1 cause the long QT
repolarisation is delayed as you can’t get the K+ into the cell as quickly
Explain why LQT1 also causes deafness
Kv7.1 (Q1/E1) also found in the stria vascualris (pump K+ to form the endolymph) of the ear. When mutated endolymph doesnt form so where hair cells move and K+ channels open there is no K+ to move in and depolarise
Explain how a gain of function in a Ca channel would lead to long QT syndrome
Open normally but stay open for longer, would delay the start of the repolarisation
Explain how a gain of function mutation in a Na channel would lead to long QT syndrome
Na channels don’t close as quickly so plateau is delayed which would delay the start of repolarisation
What class of beta blockers would be used to treat long QT
Class two antidysrhythmic drugs
What would an example of a beta blocker be
What is it linked to
What actions would it have on the heart
Atenolol
cAMP linked
Negative chrondotropic and ionotropic actions
What group of patients may not be suitable for treatment with atenolol, why?
People with an obstructive lung disease
Atenolol may cause bronchoconstrcition
What is atenolo
B1 adrenoreceptor antagonist
Short QT syndrome calssified by
A shortened QT interval
What other symptoms of SQT syndrome
Arrhymthmias, palpitations, syncope
How many forms of Lqt
12
How many forms of SQT
5
What is syncope
Fainting episodes
What percentage of males are effected by SQT
75%
What other aspects of an ECG trace are characteristic of SQT
Short/absent ST
Tall/peaked T wave
QT interval fixed - doesn’t move
A mutatation in what gene causes SQT1
Is this a gain or loss of function mutation
KCNH2
GAIN
KCNH2 codes for what ion channel and is mutated in which form of SQT
Kv11.1a (gain of function)
1
What current is Kv11.1a involved in
Ikr
Explain how a loss of function mutation in a Ca channel may cause SQt
Dont open normally or close early
Less Ca influx into the cell - reduced plateau and repolarisation would be initiated earlier
Explain how a gain of function mutation in a K Ch would cause SQT
More channels in membrane//may open sooner
More K+ efflux from the cell
Repolarisation would occur soon
Two treatments for SQT
Implant defib
Quinidine
What is the mechanism for quinidine action
Block K channels and delay repolarisation
What is the issue with using quinine for the treatment of SQT
Blocks other K channels throughout the body
