Skeletal myoblasts after myocardial infarction and inducibility of ventricular arrhythmias Patricia...
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Transcript of Skeletal myoblasts after myocardial infarction and inducibility of ventricular arrhythmias Patricia...
Skeletal myoblasts after myocardial
infarction and inducibility
of ventricular arrhythmias
Patricia Lemarchand
Ménasché 2003 24+/-4% 10 4 VT
Smits 2003 36+/-11% 13 4 VT (2 death)
Pagani 2003 5 ?
Herreros 2003 36+/-8% 12 Amiodarone
Siminiak (POZNAN trial) 2004 25–40% 10 4 VT Amiodarone
for some Pt
Chachques 2004 28+/-3% 20 Amiodarone
Dib 2005 28% 24 2 VT ?6 1 VT ?
Ménasché (MAGIC trial) 2005 15 to 35 % 63 6 VT Amiodarone
ICD
Study Year LVEF Patient numberArrhythmia
Clinical trials with autologous myoblasts
Related to
The history of the heart failure ?
The injection procedure ?
The myoblast itself ?
Ventricular arrhythmias
Life threatening adverse events
Animal model to investigate arrhythmias related to myoblast transplantation
Study design
D 0
D 14 212835
Electrophysiological Electrophysiological studiesstudies
ECG recordings
Programmed electrical stimulations
control vehicle autologous myoblasts
D7
autologous bone marrow cells
Myoblasts
24h after injection
Cell injection
Bone marrow cells
No spontaneous sustained ventricular tachycardia
Occurrence of extrasystoles - rare
- similar in both
groups
250 msec
D8 - D35
Vehicle (557 hrs) Myoblasts (573 hrs)
Telemetric recordings
Free moving animals
Spontaneous arrhythmias
Non-sustained ventricular tachycardia
-Sustained ventricular tachycardia
- Fibrillation
No arrhythmia
Programmed electrical stimulation (1)
Myoblasts increased ventricular electrical excitability +++
Control (n=17)Vehicle (n=19)Myoblast (n=20)BMC (n=9)
% r
at
wit
h s
us
tain
ed V
T
Control
n=17 Veh
icle
n=19
Myo
blast
n=20 BM
C
n=9
0
20
40
60
80p< 0.05
p < 0.005
Programmed electrical stimulation (2)
0
1
2
3
4
5
6
D14 D21 D35
Rat with sustained VT
D28
Intramural monophasic action potential (1)
myoblasts
100 ms* * *Skeletal muscle
(tibialis)
* *Myocardium
14 days
Evaluation
No electrical coupling
Electrical coupling and arrhythmias
Muscle cells do not form gap junctions with cardiomyocytes
The absence of electrical coupling favors reentry and may explain ventricular excitability
Muscle cells do not express Cx43
Cx43 overexpression in myoblasts will increase electrical coupling
Why no electrical coupling?
Intramural monophasic action potential (2)
Cx43 promotes electrical coupling
14 days
Evaluation
myoblasts
Myocardium from
LV-Cx43 group
* * * *
* * *Skeletal muscle
(tibialis) 100 ms
* *Myocardium from
control group
Cx 43 lentivirus vector
Summary
Myoblast transplantation induced a specific substrate for arrhythmias
Arrhythmias did not result from injection
Electrophysiological studies are feasible to identify potential arrhythmogeneic risk
Cx43 overexpression increased electric coupling
Telemetric recordings are not accurate to detect electrical instability after cell transplantation