Myocardial Fibrosis and Steatosis in Patients with Aortic Stenosis: Roles of Myostatin and Ceramides

Aortic stenosis (AS) involves progressive valve obstruction and a remodeling response of the left ventriculum (LV) with systolic and diastolic dysfunction. The roles of interstitial fibrosis and myocardial steatosis in LV dysfunction in AS have not been completely characterized. We enrolled 31 patients (19 women and 12 men) with severe AS undergoing elective aortic valve replacement. The subjects were clinically evaluated, and transthoracic echocardiography was performed pre-surgery. LV septal biopsies were obtained to assess fibrosis and apoptosis and fat deposition in myocytes (perilipin 5 (PLIN5)), or in the form of adipocytes within the heart (perilipin 1 (PLIN1)), the presence of ceramides and myostatin were assessed via immunohistochemistry. After BMI adjustment, we found a positive association between fibrosis and apoptotic cardiomyocytes, as well as fibrosis and the area covered by PLIN5. Apoptosis and PLIN5 were also significantly interrelated. LV fibrosis increased with a higher medium gradient (MG) and peak gradient (PG). Ceramides and myostatin levels were higher in patients within the higher MG and PG tertiles. In the linear regression analysis, increased fibrosis correlated with increased apoptosis and myostatin, independent from confounding factors. After adjustment for age and BMI, we found a positive relationship between PLIN5 and E/A and a negative correlation between septal S’, global longitudinal strain (GLS), and fibrosis. Myostatin was inversely correlated with GLS and ejection fraction. Fibrosis and myocardial steatosis altogether contribute to ventricular dysfunction in severe AS. The association of myostatin and fibrosis with systolic dysfunction, as well as between myocardial steatosis and diastolic dysfunction, highlights potential therapeutic targets.