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Skeletal myoblasts after myocardial infarction and inducibility of ventricular arrhythmias

Skeletal myoblasts after myocardial infarction and inducibility of ventricular arrhythmias. Patricia Lemarchand. Siminiak. Amiodarone. (POZNAN trial). for some Pt. Ménasché. (MAGIC trial). Clinical trials with autologous myoblasts. Study. Year. LVEF. Patient number. Arrhythmia.

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Skeletal myoblasts after myocardial infarction and inducibility of ventricular arrhythmias

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

  2. Siminiak Amiodarone (POZNAN trial) for some Pt Ménasché (MAGIC trial) Clinical trials with autologous myoblasts Study Year LVEF Patient number Arrhythmia Ménasché 2003 24+/-4% 10 4 VT 4 VT (2 death) Smits 2003 36+/-11% 13 Pagani 2003 5 ? Herreros 2003 36+/-8% 12 Amiodarone 2004 25–40% 10 4 VT Chachques 2004 28+/-3% 20 Amiodarone Dib 2005 28% 24 2 VT ? 6 1 VT ? 2005 15 to 35 % 63 6 VT Amiodarone ICD

  3. Animal model to investigate arrhythmias related to myoblast transplantation Ventricular arrhythmias Life threatening adverse events Related to The history of the heart failure ? The injection procedure ? The myoblast itself ?

  4. Study design D 7 control vehicle autologous myoblasts autologous bone marrow cells D 14 21 28 35 Electrophysiological studies ECG recordings Programmed electrical stimulations D 0

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

  6. Telemetric recordings 250 msec D8 - D35 Vehicle (557 hrs) Myoblasts (573 hrs) Free moving animals Spontaneous arrhythmias No spontaneous sustained ventricular tachycardia Occurrence of extrasystoles - rare - similar in both groups

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

  8. Programmed electrical stimulation (2) p< 0.05 80 Control (n=17) p < 0.005 Vehicle (n=19) Myoblast (n=20) 60 BMC (n=9) 6 % rat with sustained VT 5 40 4 Rat with sustained VT 3 2 20 1 0 0 D14 D21 D28 D35 Control n=17 Vehicle n=19 Myoblast n=20 BMC n=9 Myoblasts increased ventricular electrical excitability +++

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

  10. 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 Electrical coupling and arrhythmias Why no electrical coupling?

  11. Cx 43 lentivirus vector * * * Skeletal muscle (tibialis) myoblasts 100 ms * * * * * * 14 days Myocardium from control group Myocardium from LV-Cx43 group Evaluation Intramural monophasic action potential (2) Cx43 promotes electrical coupling

  12. Myoblast transplantation induced a specific substrate for arrhythmias Arrhythmias did not result from injection Electrophysiological studies are feasible to identify potential arrhythmogeneic risk Telemetric recordings are not accurate to detect electrical instability after cell transplantation Cx43 overexpression increased electric coupling Summary

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