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Long QT Syndrome Type 3: Lessons from mouse models
Dr Glyn Thomas MRCP PhDConsultant Electrophysiologist
Bristol Heart Institute
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Inherited Long QT Syndrome
• Prolonged QT interval
• Syncope & Sudden Cardiac Death
• Ventricular Arrhythmias (TdP)
From: “Ion Channels and Disease” F.M. Ashcroft. Academic Press 2000
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Inherited Channel MutationsLQTS Chromosome Gene Protein Ion Current Trigger
1 11p15.5 KCNQ1 KvLQT1 IKS Exercise, emotion
2 7q35‐36 KCNH2 HERG IKr Rest, emotion, exercise
3 3p24‐21 SCN5A Nav1.5 INa Rest, emotion, sleep
4 4q24‐27 ANK2 Ankyrin‐B INa‐Kr, INa‐Ca, Ina Exercise
5 21q22 KCNE1 MinK IKS Exercise, emotion
6 21q22 KCNE2 MiRP1 IKr Rest, exercise
7 17q23 KCNJ2 Kir2.1 IK1 Rest, exercise
8 12p13.3 CACNA1C Cav1.2 Ica Exercise, emotion
9 3p25.3 CAV3 Caveolin‐3 Ina Non‐exertional, sleep
10 11q23.3 SCN4B Navβ4 Ina Exercise, post‐partum
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Long QT syndrome type 3
• 1.7‐8% genotyped patients
• Gain of function mutation in the Scn5a gene
• Encodes the α‐(pore‐forming) subunit of the cardiac Na+ channel
• Increased late Na+current (INa)
Roden D. N Engl J Med 2008;358:169‐176
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0
‐100
mV
EAD
L‐type Ca2+ channel ‘window’
‘Conditioned’ AP
Normal AP
‘Window’ current hypothesis
INa
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Genotype‐specific triggers for cardiac events
Schwartz, P. J. et al. Circulation 2001;103:89‐95
QTc = 498, 497, 506 ms p = NS
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Lethal cardiac events according to 3 classified triggers in 3 genotypes
Schwartz, P. J. et al. Circulation 2001;103:89‐95
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Zareba W et al. N Engl J Med 1998;339:960‐965
Cumulative Probability of a Cardiac EventIn LQT1, LQT2, and LQT3 Groups
LQT1 53%, LQT2 29%, LQT3 6%
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Zareba W et al. N Engl J Med 1998;339:960‐965
Cumulative Probability of Death in LQT1, LQT2, and LQT3 Groups
20% of events fatal in LQT3 vs 4% in LQT1 & LQT2 (P<0.001)
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Priori, S. G. et al. JAMA 2004;292:1341‐1344.
Event‐Free Survival in β‐blocker treatedpatients
Cardiac events: 32% in LQT3 vs 10% in LQT1 & 23% in LQT2
(P<0.001)
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Etheridge, S. P. et al. J Am Coll Cardiol 2007;50:1335‐1340
Indications for Device Implantation
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Schwartz, P. J., C. Spazzolini, et al. (2009). All LQT3 patients need an ICD: true or false? Heart Rhythm 6(1): 113‐20
LQT3 patients need ICDs:True or False?
3 Died despite β‐blockers
3 Died Aged 14, 16, 26 years
2 syncopal episodes9 ± 6 years
QTc: 650, 648, 550, 525ms
QTc: 540 ± 29ms450 ± 42ms
QTc: 497 ± 25ms
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Poor prognosis in patients with events in the first year of life
2 months QTc 648 ms
1 week QTc 650 ms
2 months QTc 550 & 700 ms
Schwartz, P. J., C. Spazzolini, et al. (2009). All LQT3 patients need an ICD: true or false? Heart Rhythm 6(1): 113‐20
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Rare Genetic Variants in LQTS Genes Identified in 26 SIDS Cases
Arnestad, M., L. Crotti, et al. (2007). Prevalence of long‐QT syndrome gene variants in sudden infant death syndrome. Circulation 115(3): 361‐7.
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Life‐threatening neonatal arrhythmia
Kehl, H.‐G. et al. Circulation 2004;109:e205‐e206
Preterm female infant 35 weeks gestational age
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Mice as Models for Investigating Cardiac Arrhythmias
Advantages
• Ease of molecular manipulation
• Common physiological structures
• Action potential heterogeneity
• Similar ionic currents
• Demonstrable atrial and ventricular arrhythmias
Disadvantages
• Mouse heart rate 600‐700/min
• Shorter action potential duration without plateau
• Ito is predominant repolarizing current (cf IKr & IKs)
• Markedly different ECG appearance
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Mouse Models of LQT3
• Mechanism of arrhythmogenesis
• Effect of β‐blocker therapy
• Other therapeutic options
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Mechanism of Arrhythmogenesis
• ΔKPQ 1505‐1507 deletion in channel inactivation domain by homologous recombination in ES cells
Head, C. E., Balasubramaniam, R., Thomas, G., Goddard, C. A., Lei, M., Colledge, W. H., Grace, A. A. & Huang, C. L.‐H. (2005). Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in KPQ Scn5a Mice. Journal of Cardiovascular Electrophysiology 16, 1329‐1340.
Current Clamp (‐ 80mV)
Head, C. E., R. Balasubramaniam, Thomas G et al. (2005). "Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in KPQ Scn5a Mice." Journal of Cardiovascular Electrophysiology 16(12): 1329‐1340.
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1. Triggered Activity
Thomas, G., I. S. Gurung, et al. (2007). "Effects of L‐type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3." J Physiol 578(Pt 1): 85‐97.
Scn5a+/Δ VT* *
100ms
100ms
WT alone
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ENDOM‐cell
EPI
BASE
APEX
LA
LV
RA
RV
2. Re‐entry facilitated by transmural dispersion of repolarization (spatial)
EPI
ENDO
S1 S1 S2Orthodrom
ic impulse
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Optical Mapping of Mouse re‐entrant VT
Salama, G. and B. London (2007). "Mouse models of long QT syndrome." J Physiol 578(Pt 1): 43‐53
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Time
Record
Pace
S1 S1 S2 S1 S1 S2
S1S2 reduced on eachoccasion by 1 millisecond
Paced Electrogram Fractionation Analysis of LQT3 Mouse
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Increased Electrogram Fractionation in LQT3 Mice
Head, C. E., R. Balasubramaniam, Thomas G et al. (2005). "Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in KPQ Scn5a Mice." Journal of Cardiovascular Electrophysiology 16(12): 1329‐1340.
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Transmural dispersion of repolarization
Anumonwo, J. M., Y. N. Tallini, et al. (2001). "Action potential characteristics and arrhythmogenic properties of the cardiac conduction system of the murine heart." Circ Res
Wild Type Mouse
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Increased TDR in LQT3 Mice
Thomas, G., M. J. Killeen, et al. (2008). "Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome." Acta Physiol (Oxf) 192(4): 505‐17.
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Increased TDR in LQT3 Mice
Thomas, G., M. J. Killeen, et al. (2008). "Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome." Acta Physiol (Oxf) 192(4): 505‐17.
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Proposed Arrhythmogenesis in LQTS
Early After Depolarizations
Prolonged QT Interval
Dispersion of repolarization (Spatial and temporal)
Re‐entrant excitation
Triggered ActivityFunctional conduction block
pVT (TdP)
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Effect of β‐blocker therapy
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Protective effect of β‐adrenoreceptor agonist isoproterenol
Nuyens, D., M. Stengl, et al. (2001). "Abrupt rate accelerations or premature beats cause life‐threatening arrhythmias in mice with long‐QT3 syndrome." Nat Med 7(9): 1021‐7.
“Scn5aΔ/+ are mice are sensitive to rate accelerations or premature beats… β‐blockers would suppress these triggers during sudden sympathetic surges “
“ However, β‐receptor activation was anti‐arrhythmic , possibly shortens the action potential, reduces transmural dispersion”
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Propranolol increases electrogram fractionation
Head, C. E., R. Balasubramaniam, Thomas G et al. (2005). "Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in KPQ Scn5a Mice." Journal of Cardiovascular Electrophysiology 16(12): 1329‐1340.
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Propranolol suppresses EADs in LQT3 Mice
Thomas, G., M. J. Killeen, et al. (2008). "Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome." Acta Physiol (Oxf) 192(4): 505‐17
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Propranolol increases TDR in LQT3 Mice
Thomas, G., M. J. Killeen, et al. (2008). "Pharmacological separation of early afterdepolarizations from arrhythmogenic substrate in DeltaKPQ Scn5a murine hearts modelling human long QT 3 syndrome." Acta Physiol (Oxf) 192(4): 505‐17
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Propranolol causes AV block in Ambulant LQT3 Mice
Fabritz, L., M. Emmerich, et al. (2005). "Aggravation of bradycardia by propranolol in deltaKPQ SCN5A (Long QT3) mice." European Heart Journal 26 (Abstract Supplement): S299
100 ms
SCn5a Δ/+ KPQ Mouse
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What other potential drugs?
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Therapeutic Targets
0
‐100
mV
Normal AP
INaIK
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Mexiletine
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Effect of Mexiletine on QTc in LQT3 Patients
Schwartz, P. J., S. G. Priori, et al. (1995). "Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene‐specific therapy." Circulation 92(12): 3381‐6.
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Mexiletine shortens APD during bradycardia in LQT3 Mouse Model
Fabritz, L., P. Kirchhof, et al. (2003). "Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice." Cardiovasc Res 57(4): 1085‐93.
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Mexiletine prevents inducible pVT in LQT3 Mouse Model
Head, C. E., R. Balasubramaniam, Thomas G et al. (2005). "Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in KPQ Scn5a Mice." Journal of Cardiovascular Electrophysiology 16(12): 1329‐1340.
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Nifedipine
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Scn5a+/Δ + 1 µM nifedipine
C
Scn5a+/Δ VT
A
* *
100ms
100ms
WT alone WT + 1 µM nifedipine
B
D
100ms
100ms
Results
Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in ΔKPQ Scn5a (long QT 3) murine hearts (2006). Thomas, G, Killeen, MJ, Gurung IS, Hakim, P, Goddard, CA, Colledge WH, Grace, AA, Huang, C L-H. J Physiol (In press)
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Perc
enta
ge o
f MA
Ps d
ispl
ayin
g EA
Ds
Scn5a+/Δ
alone
Scn5a+/Δ
+ 1 nM Nifed
Scn5a+/Δ
+ 10 nM Nifed
Scn5a+/Δ
+ 100 nM Nifed
Scn5a+/Δ
+ 1 µM Nifed
0
10
20
30
40
50
60
70
80
90
100
Scn5a+/Δ
+ 300 nM Nifed
Results
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Perc
enta
ge o
f MA
Ps d
ispl
ayin
g EA
Ds
-10 -9 -8 -7 -6 -50
20
40
60
80
100
log [nifedipine] M
Results• IC50 = 79 nM
• Nifedipine exerts IC50block of ICa-L at 50nM at holding potential of -40 mV in isolated guinea pig myocytes1
1. Shen, J. B., Jiang, B. & Pappano, A. J. (2000). Comparison of L-type calcium channel blockade by nifedipine and/or cadmium in guinea pig ventricular myocytes. J Pharmacol Exp Ther 294, 562-570.
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0
1
2
3
4
5
Scn5a+/Δ
alone
Scn5a+/Δ
+ 1nM Nifed
Scn5a+/Δ
+ 10 nM Nifed
Scn5a+/Δ
+ 100 nM Nifed
Scn5a+/Δ
+ 300 nM Nifed
Scn5a+/Δ
+ 1 µM Nifed
Num
ber o
f hea
rts
VT
No VT
CResults
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-40
-20
0
20
40
60
80
Scn5a+/Δ
alone
Scn5a+/Δ
+ 1nM Nifed
Scn5a+/Δ
+ 10 nM Nifed
Scn5a+/Δ
+ 100 nM Nifed
Scn5a+/Δ
+ 300 nM Nifed
Scn5a+/Δ
+ 1 µM Nifed
time
(ms)
Epi APD90
Endo APD90
ΔAPD90
ResultsP>0.05
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B
-40
-20
0
20
40
60
80tim
e (m
s)
WT
alone
WT
+ 1nM Nifed
WT
+ 10 nM Nifed
WT
+ 100 nM Nifed
WT
+ 300 nM Nifed
WT
+ 1 µM Nifed
Epi APD90
Endo APD90
ΔAPD90
ResultsP>0.05
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Figure 5
Scn5a+/Δ
WT
WTScn5a+/Δ Scn5a+/Δ+ 1 µM nifedepine
WT+ 1 µM nifedepine
VER
P (m
s)
0
10
20
30
40
50
60
70
80
ResultsP>0.05
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Results
25000 25200 25400
-400
0
400
Ca2+
cur
rent
[p
A]
T im e [m s]
Control 0.3 μM Nif
-40 mV
10 mV
300 nM Nifedipine inhibits L-type Ca2+ current in ΔKPQ Scn5a KPQ mice
Control
Nifed (300nM)
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Results
0 20 40 60 80 100-60
-30
0
30
Na+
Cur
rent
Den
sity
[pA
/pF]
Time [ms]
Control300nM Nifed
-100 mV
-40 mV
300 nM Nifedipine does not inhibit Na+ current in ΔKPQ Scn5a KPQ mice
Control
Nifed (300nM)
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Nicorandil
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Effect of Nicorandil on Clinical TWA26 year old Female with nocturnal TdPQTc 620 ms
Fujimoto, Y., H. Morita, et al. (1999). "Nicorandil abolished repolarisation alternans in a patient with idiopathic long QT syndrome." Heart 82(5): e8.
6 mg IV (182 ng/ml)
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Effect of Nicorandil on Human MAPs
Fujimoto, Y., H. Morita, et al. (1999). "Nicorandil abolished repolarisation alternans in a patient with idiopathic long QT syndrome." Heart 82(5): e8.
MAPs recorded from inferoseptal LV
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Anti‐arrhythmic effects of Nicorandil in LQT3 Mouse Model
Hothi, S. S., S. W. Booth, et al. (2008). "Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome." Prog Biophys Mol Biol 98(2‐3): 267‐80.
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Nicorandil reduces spatial TDR
Hothi, S. S., S. W. Booth, et al. (2008). "Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome." Prog Biophys Mol Biol 98(2‐3): 267‐80.
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Nicorandil reduces temporal TDR
Hothi, S. S., S. W. Booth, et al. (2008). "Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome." Prog Biophys Mol Biol 98(2‐3): 267‐80.
Untreated SCN5a +/Δ SCN5a +/Δ & Nicorandil 20 µM
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Hothi, S. S., S. W. Booth, et al. (2008). "Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome." Prog Biophys Mol Biol 98(2‐3): 267‐80.
Nicorandil reduces temporal TDR
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Summary
• LQT3 remains lethal in high risk groups
• Identifiable lower risk groups
• Triggered initiation maintained via re‐entry (spatial/temporal heterogeneity of repolarization)
• Anti‐adrenergic strategy reduces ‘triggers’
• Mexiletine/nifedipine/nicorandil offer anti‐arrhythmic effects
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Acknowledgements
• Dr Andrew Grace
• Prof Chris Huang
• Dr Matthew Killeen
• Dr Sandeep Hothi
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ECG Characteristics
Roden D. N Engl J Med 2008;358:169‐176
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Roden D. N Engl J Med 2008;358:169‐176
LQTS Management Guidelines