Abstract
Abstract Background Anderson Fabry disease (AFD) is an X-linked lysosomal disorder, characterized by progressive sphingolipid storage and organ dysfunction. Cardiac involvement is characterized by left ventricular hypertrophy, inflammation and fibrosis and is leading cause of mortality. MicroRNAs (miRNAs) are emerging as promising biomarkers in medicine, as they are dysregulated in many human diseases, offering opportunities to improve our understanding of disorders and discover new therapeutic targets. However, so far, only a few studies have evaluated the role of miRNAs in Fabry disease, and cardiac tissue miRNAs have never been assessed. Purpose To determine the specific tissue miRNA profile analyzing myocardial tissue of AFD patients and to evaluate their relationship with the severity of cardiac involvement. Methods 19 AFD patients (10 females [53%]; median age 53 years [IQR 43-63]) undergoing right ventricular endomyocardial biopsy (n=15) or surgical septal myectomy (n=4), standard cardiac magnetic resonance (1.5T, cines for maximum wall thickness (MWT) and indexed LV mass (LVMi) calculation) and high-sensitivity Troponin I (TnI) dosage were included and compared to 7 endomyocardial biopsies of controls. Myocardial samples were fixed in formalin and embedded in paraffin. RNA was extracted from 3-5 slides of tissue and used to generate small RNA libraries (Qiagen) for Next Generation Sequencing analysis on Illumina sequencer. Raw data were normalized and analyzed using DEseq2 pipeline. Correlations were performed using Pearson r; a p < 0.05 was considered statistically significant. Results In AFD group median MWT was 13 mm [IQR 8-17], LVMi was 72 g/m2 [IQR 46-97]. TnI was increased in 9 patients (47%) and NT-proBNP in 8 (42%). 6 patients were on specific AFD treatment. We identified 9 miRNAs differentially expressed in AFD patients compared to controls; miRPath analysis revealed that these miRNAs are associated to pathways involved in AFD pathogenesis (autophagy and mTOR signalling, HIF-1, apoptosis, TGF-beta signalling and inflammation) (figure 1). Moreover, we found 10 miRNAs that were differentially expressed in maximal wall thickness (<10 mm, 10-15 mm, >15 mm) groups (figure 2), in particular 3 miRNAs that progressively increased at the increasing of thickness. Among these miRNAs, miR-21-5p showed the strongest correlation with myocardial hypertrophy (r=0.869, p value<0.001 for MWT; r=0.905, p<0.001 for LVMi) and with cardiac damage (r=0.831, p<0.001 for TnI). Additionally, miR-21-5p had a modest correlation with age (r=0.518, p=0.05) and did not differ between patients on specific AFD treatment and patients not treated (p=0.660). Conclusions This study for the first time evaluated the myocardial miRNA profile in AFD patients and identified miR-21-5p as a cardiac biomarker correlating with clinical heart involvement, both in terms of left ventricular hypertrophy (MWT, LVMi) and myocardium damage (troponin).Figure 1Figure 2
Published Version
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