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(Circulation. 2008;118:S138-S144.)
© 2008 American Heart Association, Inc.

Cell Transplantation and Tissue Regeneration

A Factor Underlying Late-Phase Arrhythmogenicity After Cell Therapy to the Heart

Global Downregulation of Connexin43 in the Host Myocardium After Skeletal Myoblast Transplantation

Steven R. Coppen, PhD; Satsuki Fukushima, MD; Yasunori Shintani, MD, PhD; Kunihiko Takahashi, MD, PhD; Anabel Varela-Carver, PhD; Husein Salem, PhD; Kenta Yashiro, MD, PhD; Magdi H. Yacoub, FRS; Ken Suzuki, MD, PhD

From Translational Cardiovascular Therapeutics (S.R.C., Y.S., K.T., H.S., K.Y., K.S.), William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry; and the Harefield Heart Science Centre (S.F., A.V.-C., M.H.Y., K.S.), National Heart & Lung Institute, Imperial College London, Harefield, Middlesex, UK.

Correspondence to Ken Suzuki, Translational Cardiovascular Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK. E-mail ken.suzuki{at}qmul.ac.uk

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.

Methods and 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-1β was shown to be upregulated in hearts after SMB injection, and in vitro experiments demonstrated that exposure to IL-1β 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.

Key Words: cell therapy • skeletal myoblast • arrhythmia • connexins

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