PROJECT SUMMARY/ABSTRACT Transcatheter aortic valve replacement (TAVR) is an essential alternative to surgical aortic valve replacement (SAVR) in elderly patients with aortic valve stenosis. At the current pace, TAVR procedures are expected to increase twofold from ~163,000 in 2020 to ~289,000 in 2025, and the number of patients with severe aortic stenosis is anticipated to rise to 3.5M by 2050. Given the predominately older patients in the intermediate and high-risk TAVR groups, vascular injury with bleeding is still a major complication (6% to 8% incidence), and an unmet clinical need, which must be avoided by next-generation devices with lower profiles. However, lowering the profile of the current TAVR delivery systems with smaller sheath size comes at the cost of a more aggressive stent-crimp. Stent-induced traumatic injury to the leaflets after transcatheter valve implantation has been scientifically and clinically established. Considering that the stress exerted by each thin stent's strut is equal to the crimping force divided by strut's surface pressing over the leaflets, the magnitude of stent-crimping stress will be enormous since the strut surface is very small. Leaflet damage in TAVR due to current practice of stent crimping provokes a calcium influx that leads to calcium crystal nucleation and collagen fiber disruption, which predispose to leaflet degeneration, and early valve failure, as presented by leaflet thickening, stiffening and apparent calcification. FoldaValve™ Technology, a novel self-expandable 14-Fr transfemoral TAVR system which uses a fundamentally different concept to spare leaflets from stent-crimping, has been developed by Kheradvar Lab to address TAVR clinical unmet needs by reducing the delivery profile while avoiding aggressive stent-crimp of the leaflets. Due to its unique folding mechanism, FoldaValve™ attains the smallest delivery size at true 14-Fr, implantable using a 15-Fr sheath. In addition to its small delivery profile, given that aggressive stent-crimping is considered a triggering factor for early structural deterioration and subclinical leaflet thrombosis by many investigators, FoldaValve should contribute to TAVR durability. Moreover, FoldaValve™ is uniquely equipped with an intravascular ultrasound (IVUS)-guided delivery system (Ingenuity™), which reduces the need for Fluoroscopy during implantation and minimizes radiation to both patient and physician. Ingenuity™ uniquely allows repositioning in six degrees-of-freedom even when the valve is fully implanted and allows complete intraprocedural valve retrieval, which has not yet practiced in other TAVR systems. This Phase I project will first test the hypothesis that FoldaValve's inverse folding mechanism under the sheath protects the valve's structural integrity and improve its durability compared to the current TAVR generation's stent-crimping, and then will assess FoldaValve's chronic performance according to ISO 5840-3:2021: Specific Aim 1: Establish the protective effects of FoldaValve's inverse folding mechanism under the sheath in comparison with the traditional stent-crimping as practiced by other TAVR systems. Specific Aim 2: Assess FoldaValve's chronic performance (20 weeks) in standard ovine model considering paravalvular leakage, leaflet thrombosis, and calcification according to ISO 5840-3:2021.

PROJECT NARRATIVE Given the predominately older patients in the intermediate and high-risk TAVR groups, vascular injury with bleeding is still a major complication (6% to 8% incidence), and an unmet clinical need, which must be avoided by next-generation devices with lower profiles. However, lowering the profile of the current TAVR delivery systems with smaller sheath size comes at the cost of a more aggressive stent-crimp. Stent-induced traumatic injury to the leaflets after transcatheter valve implantation has been scientifically and clinically established. FoldaValve™ Technology, a novel self-expandable 14-Fr transfemoral TAVR system which uses a fundamentally different concept to spare leaflets from stent-crimping, aims to address TAVR clinical unmet needs by reducing the delivery profile while avoiding aggressive stent-crimp of the leaflets.