Abstract 371: Long-term Cardioselective S100A1 Gene Therapy Improves Cardiac Function in Heart Failure
Background- Heart failure (HF) continues to represents an enormous clinical challenge, since the mortality of patients with end stage heart failure is similar to patients suffering from neoplastic diseases and projections are that the incidence of HF in the coming years will rise. Cardiac S100A1 expression is decreased in HF and normalization of S100A1 protein expression in vivo rescues failing myocardium via a significant gain in sarcoplasmic reticulum Ca2+-cycling. In the current study we address the effects of cardioselective long-term S100A1 gene therapy in a rat HF model and we compare therapeutic effects with β-blocker treatment.
Methods and Results- 10 weeks after myocardial infarction left ventricular ejection fraction (EF) was measured echocardiographically and rats with HF were randomized for intracoronary delivery of PBS (n=12), AAV6-GFP (n=20) and AAV6-S100A1 (n=21). Non-infarcted rats (Sham; n=14) also received PBS. AAV6-GFP (n=10) and AAV6-S100A1 (n=10) subgroups were additionally treated with β-blockers (metoprolol 2g/1L drinking water). A cardioselective promoter was used for overexpression of S100A1. 8 weeks after AAV6-S100A1 (4x1011 tvp) gene therapy in HF echocardiography and left ventricular catheterization demonstrated significantly increased EF, +dP/dt and -dP/dt while EDP was significantly reduced compared to PBS and AAV6-GFP treatment (EF: Sham 60.8±1.8 %; HF/PBS 32.4±1.9 %, HF/AAV6-GFP 30.9±2.8 %; HF/AAV6-S100A1 51.1±1.2 %, p<0.05 HF/AAV6-S100A1 vs. all groups). The improved contractile function of S100A1 treated hearts was preserved under β-blocker treatment but β-blocker treatment by itself did not affect impaired myocardial function in HF during the 8 week observation period. Both, S100A1 gene therapy and β-blocker treatment significantly reduced cardiac remodeling and reversed characteristics of HF such as fetal gene expression and up-regulation of the G-protein-coupled receptor kinase 2 (GRK2).
Conclusions-S100A1 gene therapy provides a potential novel treatment strategy in HF which might be additive to pharmacological β-blocker treatment.