Origin of Structural Biological Valve Prosthesis Deterioration: Role of Lipid-Mediated Factors – OriginSVD

With the population aging, the number of calcific aortic valve stenosis, the most frequent valvular heart disease, is expected to double in the next 20 years. So far, no pharmacological treatment is available, the only option is to perform an aortic valve replacement (AVR). A shift toward the use of biological instead of mechanical prosthetic valve is in progress. Their main limitation is the durability, with a structural valve deterioration (SVD) described as a progressive process starting early post-implantation. To date, little is known on the underlying pathophysiological mechanisms and no preventable actions or pharmacological targets have been identified. Nevertheless, it is worth noting that implanted bioprosthetic valves face the same environment as the native valves prone to exacerbate biological tissue degeneration, suggesting similar mechanisms are at work.
With OriginSVD, I will to bridge the gap between the observable deterioration of biological valves and the underlying targetable or modifiable mechanisms, with a specific focus on the role of lipid-mediated factors. I will address this unanswered question via the implementation of integrative and complementary approaches including state-of-the-art in vivo experimentations coupled with in vitro mechanistic approaches. Thanks to the already available models (i.e. PCSK9 KO mice and the model of orthotopic AVR on minipigs with PCSK9 gain of function mutation), I will dissect the specific role of hypercholesterolemia and PCSK9 on the nature and differentiation of recruited cells into the biological implanted valve, and their impact on biological valve structure and composition. I will unravel the precise cellular and molecular mechanisms in vitro, with experiments based on the modulation of flow and lipids. Understanding how biological prosthetic valve deteriorates early post-surgery, is the cornerstone to develop preventable and/or pharmacological approaches.