Study On The Protective Mechanism Of New Transcatheter Implantation Of Aortic Valve In Preclinical Study And Mitochondrial Autophagy On Atherosclerosis

Background:Aortic stenosis is one of the most common valvular diseases throughout the world. Transcatheter aortic valve implantation (TAVI) has gain worldwide recognition in treating inoperable or high-risk patients with severe aortic stenosis. The feasibility and effectiveness of this novel technique have already been confirmed by many large multicenter registries and the prospective, randomized Placement of Aortic Transcatheter Valves (PARTNER) trial. Nevertheless, TAVI still faces severe challenges. The incidence of paraprosthetic regurgitation is much higher than traditional surgery, and its related periprocedural complications can be severe. Therefore, accurate placement of the prosthetic valve remains a major problem to be solved. China started relatively late in research and development of transcatheter valves. But in recent years, domestic valves have made big breakthroughs in positioning technology innovation. J-Valve for the first time introduced a separated positioning element and its stepwise positioning mechanism. The new positioning element is desighed to help the valve obtaining easy and accurate positioning.Objectives:Preclinical study of a new, domestic transcatheter valve (J-Valve transapical system). Preclinical animal study and pathological examination are indispensable parts during development of new valves, which can provide reliable evidences for their entering clinical trials.Methods and materials:Self-expandable aortic valve prosthesis with a specially designed, annulus-like positioning element was implanted through a transapical approach in 12 Chinese miniature pigs. The positioning element was separated and can be released independent of the valve prosthesis. During valve implantation, firstly, the positioning element was unsheathed and fixed into the aortic sinus. Then, the prosthetic valve was guided to an anatomically oriented position and deployed. Six animals were followed up to 180 days to evaluate the chronic hemodynamic performance and durability of the valve.Results:With the help of the positioning element, all 12 J-Valve prosthetic valves were successfully deployed at the anticipated site. The valve release procedure (all steps between the delivery catheter entering and exiting the ventricle) took an average of 7.3 ± 2.5 minutes. The mean transvalvular pressure gradient was 2.8 ±1.1 mmHg at valve deployment. Of the six chronic animals, the mean transvalvular pressure gradient was 3.0 ±1.0 mmHg on day 7, and 2.9 ±1.6 mmHg on day 180 (P= 0.91). No migration, embolization, or coronary obstruction was observed during surgery and at necropsy. No conduction block or other type of arrhythmia was recorded during the follow-up. Pathological examination showed anatomically correct positioning of the prosthetic valve without signs of thrombosis or calcification.Conclusions:In this study, we confirmed the feasibility of the J-Valve transapical system for transapical implantation through a stepwise process. Satisfactory hemodynamic and pathological performance during a follow-up of 180 days was demonstrated. Both surgery and pathology observations established that the positioning elements of the J-Valve device are capable of providing anatomically correct positioning and alignment for the prosthetic valve and simplify the implantation procedures. Results of the present study also provide evidences supporting the J-Valve system entering the next stage of clinical trials.Atherosclerosis (AS) is the leading cause of mortality worldwide. Macrophage plays an important role in development of AS. Death of macrophage, the predominant cell type in the atherosclerotic lesion, has been demonstrated to be closely associated with the instability of the plaque in advanced AS. Clinical studies and animal experiments have reported that mitochondrial injury due to oxidative stress drives lesional macrophage death and atherosclerosis progression. Once damaged, mitochondria can activate diverse cellular pathways, which finally lead to macrophage apoptosis. Furthermore, overproduction of mitochondrial derived reactive oxygen species (mtROS) is strongly linked with lesional inflammation through activating the diverse signal pathway. Effective removal of damaged mitochondria may therefore be crucial.In the present study, we explored the mitophagy activity and its role in AS development both in oxidative low-density lipoproteins (ox-LDL) treated THP-1 macrophages and high-cholesterol fed ApoE-/- mice. Here, for the first time we demonstrated that mitophagy, the autophagic degradation of impaired or dysfunctional mitochondria, was promptly activated during the pathogenesis of atherosclerosis. Mitophagy activation played an anti-atherogenic role both in cultured THP-1 macrophages and lesional macrophages from high-cholesterol fed ApoE-/- mice. What’s more, the E3 ubiquitin ligase Parkin is a key mediator for mitophagy activation. During mitophagy activation, both the expression and mitochondrial translocation of Parkin were promoted. Moreover, silencing Parkin led to impaired macrophage mitophagy and intracellular accumulation of mitochondrial-derived ROS, which exacerbated inflammation activation and macrophage apoptosis. In advanced AS lesion, we found a decreasing in mitophagy activity accompanied by elevated ROS and apoptosis levels, indicating deficient mitophagy is likely to be one of the causes of plaque progression which representing a novel potential therapeutic strategy to prevent AS progression.