1. Skeletal myoblasts after myocardial infarction and inducibility of ventricular arrhythmias Patricia Lemarchand

2. Ménasché200324+/-4%104 VT Smits200336+/-11%13 4 VT (2 death) Pagani20035? Herreros200336+/-8%12Amiodarone Siminiak (POZNAN trial) 200425–40%104 VT Amiodarone for some Pt Chachques200428+/-3%20Amiodarone Dib200528%242 VT? 61 VT? Ménasché (MAGIC trial) 200515 to 35 %636 VTAmiodarone ICD StudyYearLVEFPatient numberArrhythmia Clinical trials with autologous myoblasts

3. 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

4. Study design D 0 D 14 21 28 35 Electrophysiological studies ECG recordings Programmed electrical stimulations controlvehicleautologous myoblasts D7D7 autologous bone marrow cells

5. Myoblasts 24h after injection Cell injection Bone marrow cells

6. 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

7. Non-sustained ventricular tachycardia -Sustained ventricular tachycardia - Fibrillation No arrhythmia Programmed electrical stimulation (1)

8. Myoblasts increased ventricular electrical excitability +++ Control (n=17) Vehicle (n=19) Myoblast (n=20) BMC (n=9) % rat with sustained VT Control n=17 Vehicle n=19 Myoblast n=20 BMC n=9 0 20 40 60 80 p< 0.05 p < 0.005 Programmed electrical stimulation (2) 0 1 2 3 4 5 6 D14D21D35 Rat with sustained VT D28

9. Intramural monophasic action potential (1) myoblasts 100 ms * * * Skeletal muscle (tibialis) * * Myocardium 14 days Evaluation No electrical coupling

10. 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?

11. 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

12. 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