P405 IS THE IMPAIREMENT OF MITOCHONDRIAL QUALITY CONTROL MECHANISM INVOLVED IN THE ONSET AND PROGRESSION OF AORTIC VALVE STENOSIS?

Abstract

Abstract Background and aim Calcific aortic valve stenosis (CAVS) is the most common valvular disease and its pathogenesis is poorly understood. Despite the standards in cardiovascular surgery have improved, the establishment of new therapies is an ambitious goal. In the last 15 years, some studies tried to shed light on the dysregulation of the cellular self–digestion process in CAVS, but the results obtained remained controversial. This work aims to definitively establish the role of autophagy in CAVS, to analyze the involvement of other determinants that impact on the mitochondrial quality control mechanisms and to explore possible paths for pharmacological interventions in the treatment of this disease. Methods This study has been performed on 104 patients in which biological samples (cells and serum) have been analyzed using biochemical approaches and then have been correlated to clinical data. AV cusps were obtained from 59 patients unfergoing surgical aortic valve replacement from march 2018 to July 2019. Of them, 44 suffered from aortic stenosis and 15 from aortic regurgitation (control group). Results The two population didn‘t differ for baseline pre operative characteristics, except for male sex that was more represented in the AR group (73% vs 43% p=0.05). In CAVS patients, we unveiled a significant deficiency in mitochondrial respiration and in ATP production coupled to increase production of lactates. Moreover, mitochondrial population in the pathologic group was older, with significant alterations in biogenesis and mitophagy pathways. We are also reporting an update about the role of autophagy accompanying the calcification process and the advanced stages of the disease. In fact, we provided evidence for a rapamycin–based therapeutic strategy to eventually revert the process and to report the calcified phenotype back to the wild type one. Conclusions Our data suggest that the CAVS phenotype is featured by defects in mitochondrial quality control mechanisms and that autophagy is not activated enough to counteract cell death and sustain cell functions. Boosting autophagy and mitophagy from short– to long–term reverts quite all pathological phenotypes.