skeletal myoblasts after myocardial infarction and inducibility of ventricular arrhythmias

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