Abstract 3180: Mobilization of Cardiac Progenitor Cells by Hepatocyte Growth Factor (HGF) and Insulin-Like Growth Factor-1 (IGF-1) for Repairing Chronic Myocardial Infarction (MI) is Not Proarrhythmic
Resident Cardiac Progenitor Cells (CPCs) appear best suited for reconstituting lost tissue and preventing arrhythmias. HGF+IGF-1 administration promotes homing, differentiation and proliferation of CPCs. The hypothesis was advanced that activating the lineage commitment of CPCs for heart repair via HGF/IGF-1-receptor systems ameliorates cardiac mechanical and electrical function. Adult male Wistar rats with one month old MI (n=110) were either treated with growth factors (GF n=59) or vehicle (V, n=51) or sham operated (SO, n=15). In selected groups of rats we determined: (i) stress-induced ventricular arrhythmias (VAs) by telemetry ECG, (ii) cardiac function by echocardiography, and (iii) epicardial excitability, refractoriness and conduction velocity by high resolution multiple lead recording. Measurements were carried out prior and two weeks after GF/V injection. BrdU was infused by osmotic pump for the detection cell proliferation. After invasive hemodynamic measurements, hearts were: (i) perfusion fixed for anatomical, morphometric and immuno-histochemical studies or (ii) frozen for immunoblot and quantitative RT-PCR analyses. In MI+GF rats compared with MI+V, VAs were reduced (−58%*) and effective refractory period prolonged (+29%*) with no change in QTc duration and mRNA levels for K-channel β-subunits Kv1.4, Kv4.2 and Kv4.3. By contrast, lower mRNA levels for β-subunit KChIP2 were detected in remote left ventricles (−22%*) in association with positive LV remodelling (chamber volume: −20%*, mass/chamber volume: +27%*; myocyte hypertrophy: −17%*; myocardial fibrosis: −52%*). Echocardiograpy and invasive hemodynamics indicated that GF treatment abolished the positive correlation of infarct size with deterioration of mechanical function found in MI+V. GF promoted the formation of 12.5±5 mm3 of new myocardium and the generation of 5.1±0.1×106, electro-mechanically connected, developing myocytes as determined by BrdU incorporation and distribution of connexin 43 and N-cadherin. In conclusion, locally delivered GF in scarred infarcts increases liminal length for impulse formation by improved intercellular coupling and reduces unfavourable LV remodelling thus ameliorating cardiac electrical stability. *=p<.05.