Improvement in cardiac function after sarcoplasmic reticulum Ca2+-ATPase gene transfer in a beagle heart failure model.
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 x 10(12) microg) and rAAV1-SERCA2a (1 x 10(12) microg) 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/dt(max)), and the maximal rate of decline of left ventricular pressure (-dp/dt(max)) (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 HF. We expect further studies on SERCA2a's long-term safety, efficacy, dosage and the optimization before using it in humans with HF.
Mi
Ya-Fei
YF
Department of Cardiology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, Linhai, Zhejiang 317000, China.
Li
Xiao-Ying
XY
Tang
Li-Jiang
LJ
Lu
Xiao-Chun
XC
Fu
Zhi-Qing
ZQ
Ye
Wei-Hua
WH
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004285:Dogs; D004452:Echocardiography; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000628:therapy*; D006439:Hemodynamics; D007150:Immunohistochemistry; D009206:Myocardium / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000502:physiology*
C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases