Abstract 14520: Ultrasound-Mediated Anti-apoptotic Gene Therapy for Doxorubicin-Induced Cardiomyopathy
Background: Progressive apoptosis following the primary injury has been implicated in the progression to end-stage heart failure. Survivin, a member of the inhibitor of apoptosis protein, is one of the most potent suppressor of apoptosis. We hypothesized that preventing apoptosis by survivin gene therapy may prevent deterioration in left ventricular (LV) systolic dysfunction in a doxorubicin-induced cardiomyopathy model in rats.
Methods and Results: A reproducible model of doxorubicin (dox)-induced cardiomyopathy was established in male Fisher rats by 6 equal doses (2.5 mg/kg bw) of i.p. injection every other day for 2 weeks. Echocardiographic assessment was performed at week 0, 3, and 6. A subset of animals (DOX+SURV, n=8) was treated with the survivin gene using the ultrasound targeted microbubble destruction (UTMD) technique at week 3. Control animals (DOX, n=12) did not receive any treatment at week 3. At week 0 (pre-dox), LV% fractional shortening (FS) was comparable in DOX+SURV and DOX animals (46.6±2.9% vs 50.9±3.7%, p=ns). However by week 6, LV%FS in DOX animals declined significantly from baseline (37.5±6.7%, p<0.0001 vs week 0) whereas LV%FS was maintained in DOX+SURV animals (45.3±3.6%, p=ns vs week 0). At week 6, LV end-systolic dimension increased significantly in DOX group (0.329±0.042cm vs 0.408±0.045, P<0.05), compared to DOX+SURV (0.357±0.035 vs 0.348±0.036, p=ns), suggesting a primary role of systolic dysfunction in this model of heart failure. Increased survivin expression in treated myocardium was confirmed by PCR. By TUNEL staining, there was a trend towards a decrease in apoptosis in the DOX+SURV compared to DOX at week 6 (n=6, 299±37% vs n=4, 353±19% respectively).
Conclusion: We have shown that gene delivery of survivin using UTMD can prevent and/or delay the progression of LV systolic dysfunction in doxorubicin-induced cardiomyopathy. The mechanism may in part be related to a reduction in apoptosis by survivin therapy.
- © 2010 by American Heart Association, Inc.