Background Heart failure （HF） is a major cause of morbidity and mortality worldwide, but current treatment modalities cannot reverse the underlying pathological state of the heart. Gene-based therapies are emerging ...Background Heart failure （HF） is a major cause of morbidity and mortality worldwide, but current treatment modalities cannot reverse the underlying pathological state of the heart. Gene-based therapies are emerging as promising therapeutic modalities in HF patients. Our previous studies have shown that recombinant adeno-associated viral （rAAV） gene transfer of Sarco-endoplasmic reticulum calcium ATPase （SERCA2a） can be effective in treating rats with chronic heart failure （CHF）. The aim of this study was to examine the effects of SERCA2a gene transfer in a large HF animal model. Methods HF was induced in beagles by rapid right ventricular pacing （230 beats/min） for 30 days. A reduced rate ventricular pacing （180 beats/min） was continued for another 30 days. The beagles were assigned to four groups： （a） control group （n=4）; （b） HF group （n=4）; （c） enhanced green fluorescent protein group （n=4）; and （d） SERCA2a group （n=4）. rAAV1-EGFP （1×10^12 μg） and rAAV1-SERCA2a （1×10^12 μg） were delivered intramyocardially. SERCA2a expression was assessed by Western blotting and immunohistochemistry. Results Following 30 days of SERCA2a gene transfer in HF beagles its protein expression was significantly higher than in the HF group than in the control group （P 〈0.05）. Heart function improved along with the increase in SERCA2a expression. Left ventricular systolic function significantly improved, including the ejection fraction, left ventricular systolic pressure, maximal rate of rise of left ventricular pressure （＋dp/dtmax）, and the maximal rate of decline of left ventricular pressure （-dp/dtmax） （P 〈0.05）. Left ventricular end-diastole pressure significantly decreased （P 〈0.05）. The expression of SERCA2a in the myocardial tissue was higher in the SERCA2a group than in the HF group （P〈0.05）. Conclusions Intramyocardial injection of rAAV1-SERCA2a can improve the cardiac function in beagles induced with HE We expect further studies on SERCA2a＇s long-term safety, efficacy, dosage and the optimization before using it in humans with HF.展开更多
基金This work was supported by grants from the China ＂973＂ plan （No. 2006CB503806）, and the National Science Foundation of China （No. 30600236）.
文摘Background Heart failure （HF） is a major cause of morbidity and mortality worldwide, but current treatment modalities cannot reverse the underlying pathological state of the heart. Gene-based therapies are emerging as promising therapeutic modalities in HF patients. Our previous studies have shown that recombinant adeno-associated viral （rAAV） gene transfer of Sarco-endoplasmic reticulum calcium ATPase （SERCA2a） can be effective in treating rats with chronic heart failure （CHF）. The aim of this study was to examine the effects of SERCA2a gene transfer in a large HF animal model. Methods HF was induced in beagles by rapid right ventricular pacing （230 beats/min） for 30 days. A reduced rate ventricular pacing （180 beats/min） was continued for another 30 days. The beagles were assigned to four groups： （a） control group （n=4）; （b） HF group （n=4）; （c） enhanced green fluorescent protein group （n=4）; and （d） SERCA2a group （n=4）. rAAV1-EGFP （1×10^12 μg） and rAAV1-SERCA2a （1×10^12 μg） were delivered intramyocardially. SERCA2a expression was assessed by Western blotting and immunohistochemistry. Results Following 30 days of SERCA2a gene transfer in HF beagles its protein expression was significantly higher than in the HF group than in the control group （P 〈0.05）. Heart function improved along with the increase in SERCA2a expression. Left ventricular systolic function significantly improved, including the ejection fraction, left ventricular systolic pressure, maximal rate of rise of left ventricular pressure （＋dp/dtmax）, and the maximal rate of decline of left ventricular pressure （-dp/dtmax） （P 〈0.05）. Left ventricular end-diastole pressure significantly decreased （P 〈0.05）. The expression of SERCA2a in the myocardial tissue was higher in the SERCA2a group than in the HF group （P〈0.05）. Conclusions Intramyocardial injection of rAAV1-SERCA2a can improve the cardiac function in beagles induced with HE We expect further studies on SERCA2a＇s long-term safety, efficacy, dosage and the optimization before using it in humans with HF.
