title: Augmentation of left ventricular mechanics by recirculation-mediated AAV2/1-SERCA2a gene delivery in experimental heart failure.
abstract: OBJECTIVE
  Down-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.
  
  
  RESULTS
  Heart failure was induced in adult sheep by rapid pacing (180 b.p.m.) for 1 month, followed by delivery of adeno-associated virus (AAV) 2/1-SERCA, 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 AAV2/1-SERCA2a after a further 4 weeks of pacing in comparison with untreated HF controls. Left ventricular function was significantly improved in the AAV2/1-SERCA2a-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 AAV2/1-SERCA2a-treated animals, and an analysis of gene delivery showed no evidence of regional myocardial heterogeneity in the distribution of AAV2/1-SERCA.
  
  
  CONCLUSIONS
  In a large animal model, AAV2/1-mediated SERCA2a gene delivery using percutaneous, recirculating cardiac delivery leads to improved LV function.
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, PO Box 6492 St Kilda Rd Central, Melbourne, VIC 8008, Australia.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Mariani
authors.forename: Anka
authors.initials: A
authors.lastname: Smolic
authors.forename: Arthur
authors.initials: A
authors.lastname: Preovolos
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Byrne
authors.forename: John M
authors.initials: JM
authors.lastname: Power
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006333:Heart Failure / Q000628:therapy*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D012756:Sheep; D016277:Ventricular Function, Left / Q000187:drug effects* / Q000235:genetics
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases