The Role of Adaptive and Innate Immunity for the Development of Aortic Valve Stenosis

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Heart valve disorders are prevalent and affect approximately 10% of people 75 years and older. The most frequent disorder is aortic stenosis, caused by a multifactorial process. Next to genetic predispositions and metabolic alterations, immune cells and inflammatory processes drive the onset and progression of aortic valve degeneration. Interestingly, up to 15% of all valve cells are leukocytes. This proposal explores how and which leukocytes contribute to aortic valve degeneration during aging. We will explore numerical and qualitative alterations of the valve’s leukocyte pool using state-of-the-art technology, including high-dimensional flow cytometry, sequencing methods, and recently developed mouse models that eliminate distinct cell subsets. A significant focus will be set on the interplay of T-lymphocytes and myeloid leukocytes. The application of a recently developed spatial transcriptomics approach will allow us to examine cell-cell interaction in diseased valve tissue. In a translational approach using human tissue, we will assess cellular diversity and activation states by combining single-cell RNA sequencing and single-cell chromatin accessibility assays. The proposed experiments will help refine our understanding of inflammatory processes occurring during aortic valve degeneration and potentially open up new and precise therapeutic avenues.