A factor underlying late-phase arrhythmogenicity after cell therapy to the heart: global downregulation of connexin43 in the host myocardium after skeletal myoblast transplantation.
BACKGROUND
Arrhythmia occurrence is a variable but serious concern of cell therapy for treating heart failure. Using a rat postinfarction chronic heart failure model, we compared skeletal myoblast (SMB) with bone marrow cell (BMC) injection to highlight donor cell-specific, late-phase arrhythmogenesis and the underlying factors.


RESULTS
SMBs or BMCs derived from male GFP-transgenic rats, or PBS were injected intramyocardially into female rat hearts 3 weeks after coronary artery occlusion. At 28 days after injection, echocardiography showed that the left ventricular ejection fraction was significantly improved in both the SMB and BMC groups, compared to PBS control despite poor graft survival as assessed by PCR for the male-specific gene. Radio-telemetry analysis revealed that the SMB group displayed a higher occurrence of ventricular premature contractions with an elongation of the QRS complex and the hearts were more susceptible to isopreterenol-induced ventricular tachycardia compared to the BMC and PBS groups. Western blot and immunoconfocal analysis showed that the gap junction protein, connexin43, was widely and persistently decreased in the SMB group compared to the other groups. IL-1beta was shown to be upregulated in hearts after SMB injection, and in vitro experiments demonstrated that exposure to IL-1beta caused a decrease in connexin43 and intercellular communication in cultured cardiomyocytes.


CONCLUSIONS
Although cell therapy was capable of improving function of the postinfarction chronically failing heart, there was late-phase arrhythmogenicity specific to donor cell type. Global downregulation of connexin43 in the host myocardium was indicated to be an important factor underlying late-phase arrhythmogenicity after SMB transplantation.
Coppen
Steven R
SR
Translational Cardiovascular Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK.
Fukushima
Satsuki
S
Shintani
Yasunori
Y
Takahashi
Kunihiko
K
Varela-Carver
Anabel
A
Salem
Husein
H
Yashiro
Kenta
K
Yacoub
Magdi H
MH
Suzuki
Ken
K
D000818:Animals; D030801:Animals, Genetically Modified; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D016026:Bone Marrow Transplantation / Q000379:methods; D002450:Cell Communication; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D054059:Coronary Occlusion / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000601:surgery*; D015536:Down-Regulation; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D006085:Graft Survival; D007267:Injections; D053583:Interleukin-1beta / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D032448:Myoblasts, Skeletal / Q000637:transplantation*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011183:Postoperative Complications; D051381:Rats; D017207:Rats, Sprague-Dawley; D013318:Stroke Volume; D015854:Up-Regulation; D018879:Ventricular Premature Complexes / Q000209:etiology
D018031:Connexin 43; D053583:Interleukin-1beta