Abstract 2668: Downregulation of Myocardial Connexin43 and Arrythmogenesis After Injection of Skeletal Myoblasts but not Bone Marrow Cells into the Failing Heart
Background: Arrhythmia occurrence is a serious concern of cell therapy for treating heart failure. We have previously shown persistent arrhythmias after skeletal myoblast (SMB) injection into a post-infarction chronic heart failure model which is free of anti-arrhythmia drugs. In this study, using the same model, we compared injection of bone marrow cell (BMC) with SMB to highlight donor cell-specific arrhythmogenesis.
Methods and Results: Primary SMB, BMC or PBS were injected intramyocardially into rat hearts 3 weeks after coronary artery occlusion. At 28 days post cell injection, the left ventricular ejection fraction was significantly (p<0.01) improved in both the SMB (45.2±1.0%, n=10) and BMC (44.8±1.0%, n=10) groups, compared to PBS control (33.7±0.9%, n=10). Continuous ECG monitoring detected a very low occurrence of ventricular premature contractions in the BMC (2.8±2.7/h) and PBS (0.1±0.0/h) groups compared to the SMB group (26.6±19.8/h). The susceptibility of the BMC- or PBS-injected hearts to isopreterenol-induced ventricular tachycardia was also significantly lower than in the SMB-injected hearts. A significant elongation of the QRS complex was also detected in the SMB group (27.8±1.8 ms, n=8) compared to the BMC group (21.7±1.2 ms, n=7) and PBS control (22.5±1.2 ms, n=7). Western blot analysis showed that the main cardiac gap junction protein, connexin43 (Cx43), was decreased by 25% in the SMB group compared to the other groups. Immunolabelling confirmed that there was less intense staining for Cx43 throughout the ventricular myocardium in the SMB group. We have previously shown that IL-1β was significantly upregulated in SMB-injected hearts but not BMC-injected hearts. In vitro experiments demonstrated that exposure to IL-1β (20 ng/ml) caused a 38% decrease in the expression of Cx43 in cultured cardiac myocytes.
Conclusions: The injection of SMB into chronic failing hearts resulted in a reduction in the ventricular expression of Cx43. Such an effect was not observed after BMC injection, indicating that this was a cell-specific effect. The reduction in Cx43 after SMB injection is likely to be a factor in the observed arrhythmias and the QRS elongation. The reduction in Cx43 could be related to the elevated level of IL-1β after SMB injection.