AIMS: The aim of this study was to investigate anti-apoptotic gene therapy using 
ultrasound-mediated plasmid delivery of survivin, an inhibitor of apoptosis 
protein, to prevent apoptosis and to attenuate left ventricular (LV) systolic 
dysfunction in a model of heart failure induced by doxorubicin.
METHODS AND RESULTS: Effect of survivin transduction was investigated in vitro 
in rat cardiomyoblasts. After survivin transduction, survivin protein was 
detected in cell culture supernate confirming secretion of extracellular 
survivin. Under doxorubicin stimulation, survivin-transduced cells had 
significantly reduced apoptosis; however, incubation with survivin-conditioned 
media also showed reduced apoptosis that was absent with null-conditioned media. 
Doxorubicin-induced cardiomyopathy was established in Fischer rats. Subsets of 
animals underwent ultrasound-mediated survivin gene delivery or empty vector 
gene delivery at Week 3. Control rats received doxorubicin alone. Animals were 
studied using PCR, immunohistochemistry, echocardiography, and invasive 
haemodynamic studies out to Week 6. By Week 6, LV % fractional shortening by 
echocardiography and systolic function by pressure-volume loops were greater in 
survivin treated when compared with control- and empty-treated animals. There 
was reduced apoptosis by TUNEL and caspase activity in survivin-treated animals 
compared with control and empty treated at Week 4, with reduced interstitial 
fibrosis at Week 6.
CONCLUSION: Survivin gene therapy can attenuate the progression of LV systolic 
dysfunction in doxorubicin cardiomyopathy. This effect can be attributed to 
decreased myocyte apoptosis and prevention of maladaptive LV remodelling, by 
both direct myocyte transfection and potentially by paracrine mechanisms.