Abstract 2040: Regardless of Cell-Delivery Route, Skeletal Myoblast Transplantation into Chronic Heart Failure Induces Transient Therapeutic Effects with Persistent Arrhythmogenesis
Long-term therapeutic effects and arrhythmogenicity of direct intramyocardial injection of skeletal myoblasts (Mb) into post-infarction chronic heart failure remains disputable. We hypothesized that retrograde intracoronary injection might enable homogenous Mb dissemination with less myocardial damage, resulting in enhanced therapeutic efficacy and reduced arrhythmogenesis.
Methods & Results: Three weeks after left coronary artery occlusion, female rats underwent injection of 5×106 male GFP+ rat primary Mb via either intramyocardial (IM) or retrograde intracoronary route (IC; injection into the left cardiac vein). For controls, PBS was injected via either route. Immunolabeling showed that grafted GFP+ Mb formed islet-like cell clusters which also contained many inflammatory cells in IM group, while IC group showed dissemination of Mb in both infarct and border zones with little inflammation. Graft survival analyzed with real-time PCR for male specific Sry gene was similar between the groups throughout the period. At 7, 14 and 28 days, echocardiography demonstrated that LVEF was similarly improved in IM and IC groups compared to pre-treatment (41.4±1.6 vs 33.7±0.6% in IM, 43.9±0.8 vs 33.9±0.7% in IC at day 28, n=18, p0.01). However, this effect disappeared in both IM (35.5±1.7%) and IC (35.8±2.3%) groups by 84 days. Radio-telemetry detected frequent ventricular premature contractions (VPC) including multiforms and ventricular tachycardia with a peak at 3 days (124±75/h) in IM group. The frequency of VPC decreased to 26.6±19.8/h by 28 days, but 5~10/h VPC lasted thereafter. In contrast, IC group showed rare (<1/h) VPC until 7 days, followed by 5~20/h VPC by 84 days. Both PBS controls showed rare VPC throughout the period. Noticeably, two-thirds of 84-day samples from both IM and IC, but none from controls, developed ventricular tachycardia in response to isopreterenol-stimulation.
Conclusion: Retrograde intracoronary infusion enabled Mb-delivery in a different pattern from intramyocardial injection, which would explain the prevented arrhythmia in the early phase. However, both methods achieved only transient functional improvement in post-infarction chronic heart failure with persistent arrhythmogenesis in the later phase.