Abstract 518: Factors Contributing to Ventricular Arrhythmias After Skeletal Myoblast Transplantation
Background: A serious complication arising after skeletal myoblast (SkM) transplantation is the occurrence of ventricular arrhythmias but the precise cause is unknown. It has been reported that the ability of grafted SkM to form adequate gap junctions with host cardiomyocytes in vivo is limited, suggesting alternative mechanisms are responsible. Hence, the aim of this study was to determine the arrhythmogenic factors present after SkM transplantation
Methods and Results: Primary SkM (5x106) or PBS were injected intramyocardially into female rat hearts 3 weeks after coronary artery occlusion. A high frequency of ventricular premature beats (VPB), including multiform, consecutive VPB and VT, were observed by continuous ECG monitoring 3 days after SkM injection (124.4±74.7/hour, n=8) compared to PBS control (0.3±0.1/hour, n=7). At this time, immunolabelling showed islet-like clusters, consisting of grafted GFP+ SkM and accumulated inflammatory cells in the border zone. Also, quantitative RT-PCR demonstrated that pro-inflammatory cytokines including IL-1β and IL-6 were markedly upregulated in SkM injected hearts. While the frequency of VPBs in the SkM injected hearts decreased by 28 days, their occurrence was still significantly higher (26/hour) than in the PBS control (<0.2/hour). Furthermore, VT could be induced by administration of isopreterenol into SMB injected hearts at this stage but not in control hearts. The inflammatory response had largely receded by this time but western blot analysis indicated that there was a significant decrease (25%) in the expression of the gap junction protein connexin43 (Cx43) at 28 days compared to earlier time points and control hearts. There was no evidence of gap junction formation between grafted cells and native cardiomyocytes
Conclusion: There are at least two different arrhythmogenic changes caused by SkM transplantation. One is an initial local heterogeneity involving intense inflammation, disturbing the myocardial structure and electrical conductance. The other is a later reduction in the expression of Cx43, particularly in the border zones. Such a decrease in Cx43 will enhance underlying heterogeneities in the pattern of impulse propagation increasing the susceptibility to arrhythmias.