Abstract 17526: Dominant Negative TGF-β Receptor-2 Gene Therapy Improves Left Atrial Strain by Decreasing Left Atrial Fibrosis in Experimental Heart Failure
Introduction: Left atrial (LA) dilation and dysfunction are important risk factors for heart failure (HF), atrial fibrillation (AF), and stroke. Speckle-tracking echo (STE) can measure LA strain, including LA reservoir function (peak positive LA strain) and LA pump function (peak negative LA strain). Fibrosis is thought to contribute to LA dysfunction in HF. Since TGF-β signaling is implicated in atrial fibrosis, we hypothesized that gene therapy targeting the TGF-β pathway (by expressing a dominant-negative TGF-β Receptor-2 [TβdnRII]) will preserve LA strain during development of HF by decreasing LA fibrosis.
Methods: STE was performed in 12 dogs at baseline, and LA strain was analyzed. Dogs were then randomized to ∼15 mg of control (lacZ; N=5) or TβdnRII gene delivery (injected subepicardially in the posterior LA; N=7). HF was then induced in all dogs by RV pacing at 240 bpm for 19 days. LA TβdnRII protein expression was verified by Western blot in all active-treatment dogs. After 24 days, STE was repeated. Dogs were then sacrificed for quantitation of LA fibrosis.
Results: HF was induced by tachypacing in all dogs, and all dogs were successfully imaged using STE at baseline and with HF. Between baseline and development of overt HF, markers of LA mechanics (peak positive and peak negative LA strain) decreased significantly in all dogs (P<0.001 for all comparisons, even after adjusting for LA size and pressure). TβdnRII transgene delivery resulted in decreased LA fibrosis and improvements in peak positive LA strain (LA reservoir function, 9.6±0.5% [active treatment] vs. 7.6±0.4% [control]; P=0.002).
Conclusions: LA strain become markedly abnormal between baseline and HF, independent of LA size or pressure increases. TβdnRII transgene therapy decreases LA fibrosis and results in improved LA mechanics. Further optimization of this gene-based approach may translate into a new therapy to improve LA function and potentially decreased the risk of AF and stroke in HF.
- © 2012 by American Heart Association, Inc.