Abstract 3034: Ramipril Retards Development Of Aortic Valve Stenosis In a Rabbit Model: Role of thioredoxin interacting protein

Background: The prevalence of aortic stenosis (AS) has steadily increased over the past 10 years with little improvement in development of therapeutic interventions. We have previously demonstrated that AS develops within 8 weeks in rabbits treated with vitamin D 2 (vit D 2 25,000IU/4 days weekly), and is associated with biochemical and physiological evidence of induction of endothelial dysfunction. We now conduct an investigation in this model of the effects of the ACE inhibitor ramipril on development of AS, extent of endothelial dysfunction and valvular thioredoxin-interacting protein (Txnip), an important regulator of cellular redox balance. Methods: Male New Zealand White rabbits were treated with vit D 2 alone (n=10) or vit D 2 /ramipril (ramipril about 0.5 mg/kg/day; n=12). Six untreated rabbits served as a normal comparator group. AS development was assessed by echocardiography with measurement of transvalvular velocity ratio (AVv/LVOTv), aortic valve area (AVA), and aortic valve backscatter scores (AV BS ). The extent of endothelial dysfunction, was assessed by plasma asymmetric dimethylarginine (ADMA) concentrations and responsiveness to acetylcholine (ACh) in phenylephrine pre-contracted aortic rings. Positive immunostaining for Txnip was quantified by computer-assisted image analysis. . Results: ( mean ±SEM) Echocardiographic data indicated increased AVv/LVOTv, decreased AVA and increased AV BS in the vit D 2 treated rabbits over 8 weeks .Vit D 2 /ramipril attenuated AVv/LVOTv (p<0.05) and AVA (p<0.05, 2-way ANOVA for both); with borderline decreases in AV BS (17.8 ± 2.1dB vs 11.9 ± 2.4 dB, p=0.08). ADMA concentrations were decreased (p<0.01, 2-way ANOVA) in the Vit D 2 /ramipril group and vascular response to ACh and AV BS were inversely correlated (r 2 = 0.9, p<0.0001). Valve Txnip was diminished for vit D 2 /ramipril (0.44±0.03 % total area,) vs vit D 2 (0.89±0.18 %), p=0.03. Conclusion: In this model of AS, ramipril significantly retarded progression of AS and ameliorated endothelial dysfunction. Furthermore, ramipril reversed vit D 2 -induced increases in valvular Txnip, implying an improvement of intracellular antioxidant status. These data add to the rationale for formal clinical evaluation of ACE inhibitor effects in AS.