Abstract 1827: Myocardium-Targeted Delivery of Endothelial Progenitor Cells By Ultrasound-Mediated Microbubble Destruction Improves Cardiac Function via an Angiogenic Response
Background: Application of ultrasound-mediated destruction of microbubbles (US+Bubble) to skeletal muscle creates capillary ruptures leading to leakage of the cell components. We studied whether US+Bubble combined with bone marrow-derived mononuclear cells (BM-MNCs) infusion enables the targeted delivery of endothelial-lineage cells into the myocardium and improves cardiac function of the cardiomyopathy model due to the paucity of neocapillary formation.
Methods and Results: Pulsed US was applied to the anterior chest of BIOTO2 cardiomyopathy hamsters for 90 seconds after the intravenous injection of microbubble (OptisonR), followed by infusion of BM-MNCs. Cardiac samples from US+microbubble+BM-MNCs (US+Bubble+BM), US+Bubble, US+BM without Bubble, and saline infusion control groups were analyzed 12 weeks after treatment. Labeled BM-MNCs transplanted by US+Bubble were found to be mainly localized in the microvessels; but not by US stimulation without microbubble (121.2±24.5 vs. 2.80±1.30 cells/mm2, p<0.001). Capillary densities in US+Bubble+BM group were increased 1.7 fold (p < 0.05) over the control and neither US+Bubble nor US+BM enhanced neocapillary formation. 99mTc-Tetrofosmin scintigraphy revealed that blood perfusion area in the US+Bubble+BM group was 48% greater than the control (p<0.01). US+Bubble stimulation induces the expression of adhesion molecules (VCAM-1 and ICAM-1) in capillaries and the US+Bubble-mediated supply of BM-MNCs increased the myocardial content of VEGF and bFGF. The left ventricular wt/body wt, area of cardiac fibrosis and apoptotic cell numbers in the US+Bubble+BM group significantly (p < 0.05) decreased by 82%, 73% and 64% relative to the control, respectively. The cardiac function in myopathic hamsters (assessed by fractional shortening) was markedly improved 36% (p< 0.05) by US+Bubble+BM treatment.
Conclusions: Targeted-delivery of BM-MNCs by US+Bubble to the myocardium of the cardiomyopathic hamster increased the capillary densities and regional blood flow and inhibited cardiac remodeling, resulting in the prevention of heart failure. This non-invasive cell delivery system may be useful as a novel efficient approach for angiogenic cell therapy to the myocardium.