https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Angiologie Tübingen, Deutschland; 2Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Kreislauferkrankungen Tübingen, Deutschland
Background:
Aortic stenosis (AS) is driven by progressive inflammatory and fibro-calcific processes regulated by circulating inflammatory cells, as well as valve resident endothelial (VEC) and interstitial cells (VIC) and their mediators. The formation and accumulation of calcium nodules are driven by VIC. Cyclophilin A (CyPA) is an ubiquitously distributed protein and the most important immunophilin that is a key player in several detrimental cardiovascular processes, such as calcification. To date, there are only limited data on the role of valvular CyPA expression during calcification processes of AS. Here, we aimed to identify the role of CyPA in AS by studying a patient cohort with severe aortic stenosis undergoing surgical aortic valve (AV) replacement.
Methods:
We prospectively enrolled 96 consecutive patients with severe symptomatic AS and analyzed explanted valvular tissue after AV replacement. Patients were stratified by their valvular CyPA expression into two groups with either low (CyPAlow) or high CyPA expression (CyPAhigh). Cardiac workup included physical examination, echocardiography, blood sampling for laboratory parameters as well as collection of explanted valve tissue for further analysis of protein, gene and metabolite expression or abundance.
We prospectively enrolled 96 consecutive patients with severe symptomatic AS and analyzed explanted valvular tissue after AV replacement. Patients were stratified by their valvular CyPA expression into two groups with either low (CyPAlow) or high CyPA expression (CyPAhigh). Cardiac workup included physical examination, echocardiography, blood sampling for laboratory parameters as well as collection of explanted valve tissue for further analysis of protein, gene and metabolite expression or abundance.
Results:
Macroscopic and immuno-histological analysis of AVs revealed that CyPA expression is significantly associated with the degree and patterns of local AV calcification. We further stratified calcifying patterns of the explanted AVs into four different phenotypes due to their gross pathology including calcification area, formation and accumulation of calcium nodules and their distribution within the leaflets. CyPAhigh patients showed significantly more severe calcification patterns as illustrated in Figure 1 A and B compared to CyPAlow patients. Associations of CyPA expression and gross calcifying pathology could be confirmed in histological and immunohistochemical analysis as shown in Figure 1 C. Furthermore, CyPA-associated valvular gene expression was significantly different among patients with high and low degree of AV calcification.
Conclusion:
Our findings suggest an association of valvular CyPA expression in severe aortic stenosis with specific calcification patterns and degrees of calcification. Therefore, CyPA may serve as novel therapeutic target in calcifying AS development and progression, especially CyPA inhibition may provide a novel pharmacological approach for AS treatment.