48. The Long-Term Effects of SERCA2a Overexpression in Large Animal Model of Heart Failure

Abstract

Top of pageAbstract Background: The acute overexpression of sarcoplasmic reticulum calcium ATPase (SERCA2a) by gene transfer has been shown to restore normal contractile function in rodent models of heart failure and is a promising therapy for chronic heart failure. However the long-term efficacy has not been cleared yet in a large animal model. Objectives: The aim of this study is to examine the long-term efficacy of SERCA2a gene expression in a porcine model of heart failure. Methods: A total 13 animals underwent rupture of posterior mitral valve chordae to create severe mitral valve regurgitation (MR) using a percutaneous approach. Four pigs died after MR creation. Nine pigs with MR were then divided into two groups: Group 1 (n=5): Treated with adeno-associated virus type 6 (AAV6) encoding SERCA2a under the control of a CMV promoter and Group 2 (n=4): Treated with AAV6 encoding for b-galactosidase (bgal). Viral solution containing 5|[times]|1013 genomes/ml was injected through coronary artery with coronary vein occlusion 1 month after MR creation. Left ventricular (LV) function was examined 1 month and 3 month after MR creation by echo and hemodynamics data. Results: The comparison of echo data between 1 month and 3 month after MR creation showed significant dilatation of left ventricular end-diastolic dimension (LVEDD) (51.8|[plusmn]|3.7 vs 56.9|[plusmn]|6.8; p<0.05), left ventricular end-systolic dimension (LVESD) (31.7|[plusmn]|3.0 vs 36.2|[plusmn]|3.1; p<0.05) but left ventricular ejection fraction (LVEF) (62.5|[plusmn]|2.7 vs 58.6|[plusmn]|7.5; p=ns) was well preserved in Group 1 despite severe MR. There was also no significant hemodynamics change between 1 month and 3 month after MR creation in Group 1: heart rate (HR) (88.0|[plusmn]|11.6, 89.2|[plusmn]|17.3; p=ns), end-systolic blood pressure (BP) (79.8|[plusmn]|5.5, 82.6|[plusmn]|12.3; p=ns), left ventricular end-diastolic pressure (LVEDP) (14.4|[plusmn]|6.3, 12.8|[plusmn]|3.4; p=ns), maximal rate of LV pressure rise (+dp/dt) (815.2|[plusmn]|152.9, 1198.6|[plusmn]|543.6; p=ns). Conclusions: SERCA2a gene transfer prevented the progression of congestive hear failure in swine with severe MR. (See Tables 1 and 2)