TY - JOUR
T1 - Augmentation of left ventricular mechanics by recirculation-mediated AAV2/1SERCA2a gene delivery in experimental heart failure
AU - Mariani, Justin A.
AU - Smolic, Anka
AU - Preovolos, Arthur
AU - Byrne, Melissa J.
AU - Power, John M.
AU - Kaye, David M.
PY - 2011/3
Y1 - 2011/3
N2 - AimsDown-regulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) is a key molecular abnormality in heart failure (HF), which is not currently addressed by specific pharmacotherapy. We sought to evaluate, in detail, the impact of augmented SERCA2a expression on left ventricular (LV) mechanics in a large animal model of HF.Methods and resultsHeart failure was induced in adult sheep by rapid pacing (180 b.p.m.) for 1 month, followed by delivery of adeno-associated virus (AAV) 2/1SERCA, using a percutaneous, recirculating system for gene delivery over a 10 min period. Left ventricular mechanics was investigated by echocardiography and conductance catheter measurements in sheep receiving AAV2/1SERCA2a after a further 4 weeks of pacing in comparison with untreated HF controls. Left ventricular function was significantly improved in the AAV2/1SERCA2a-treated group, despite continued pacing, as measured by fractional shortening (delta absolute FS, control -4.2 ± 1.5 vs. treatment 4.4 ± 1.5; P < 0.01) and conductance catheterization (delta Ees, control -1.22 ± 0.60 vs. treatment 0.65 ± 0.51; P < 0.05). Western blots showed an increase in SERCA protein in AAV2/1SERCA2a-treated animals, and an analysis of gene delivery showed no evidence of regional myocardial heterogeneity in the distribution of AAV2/1SERCA.ConclusionIn a large animal model, AAV2/1-mediated SERCA2a gene delivery using percutaneous, recirculating cardiac delivery leads to improved LV function.
AB - AimsDown-regulation of sarcoplasmic reticulum calcium ATPase (SERCA2a) is a key molecular abnormality in heart failure (HF), which is not currently addressed by specific pharmacotherapy. We sought to evaluate, in detail, the impact of augmented SERCA2a expression on left ventricular (LV) mechanics in a large animal model of HF.Methods and resultsHeart failure was induced in adult sheep by rapid pacing (180 b.p.m.) for 1 month, followed by delivery of adeno-associated virus (AAV) 2/1SERCA, using a percutaneous, recirculating system for gene delivery over a 10 min period. Left ventricular mechanics was investigated by echocardiography and conductance catheter measurements in sheep receiving AAV2/1SERCA2a after a further 4 weeks of pacing in comparison with untreated HF controls. Left ventricular function was significantly improved in the AAV2/1SERCA2a-treated group, despite continued pacing, as measured by fractional shortening (delta absolute FS, control -4.2 ± 1.5 vs. treatment 4.4 ± 1.5; P < 0.01) and conductance catheterization (delta Ees, control -1.22 ± 0.60 vs. treatment 0.65 ± 0.51; P < 0.05). Western blots showed an increase in SERCA protein in AAV2/1SERCA2a-treated animals, and an analysis of gene delivery showed no evidence of regional myocardial heterogeneity in the distribution of AAV2/1SERCA.ConclusionIn a large animal model, AAV2/1-mediated SERCA2a gene delivery using percutaneous, recirculating cardiac delivery leads to improved LV function.
KW - Adeno-associated virus
KW - Animal model
KW - Gene delivery
KW - Gene therapy
UR - http://www.scopus.com/inward/record.url?scp=79951824228&partnerID=8YFLogxK
U2 - 10.1093/eurjhf/hfq234
DO - 10.1093/eurjhf/hfq234
M3 - Article
C2 - 21289077
AN - SCOPUS:79951824228
VL - 13
SP - 247
EP - 253
JO - European Journal of Heart Failure
JF - European Journal of Heart Failure
SN - 1388-9842
IS - 3
ER -