Micro-RNA-21 (biomarker) and global longitudinal strain (functional marker) in detection of myocardial fibrotic burden in severe aortic valve stenosis: a pilot study

Abstract

AimsMyocardial fibrosis (MF) is a deleterious consequence of aortic valve stenosis (AVS). Global longitudinal strain (GLS) is a novel left ventricular (LV) functional parameter potentially useful to non-invasively estimate MF. MicroRNAs (miRNAs) are non-coding small ribonucleic acids (RNA) modulating genes function, mainly through RNA degradation. miRNA-21 is a biomarker associated with MF in pressure overload. The aim of the present study was to find an integrated algorithm for detection of MF using a combined approach with both bio- and functional markers.MethodsThirty-six patients (75.2 ± 8 y.o.; 63 % Female) with severe AVS and preserved LV ejection fraction (EF), candidate to surgical aortic valve replacement (sAVR) were enrolled. Clinical, bio-humoral evaluation (including plasmatic miRNA-21 collected using specific tubes, PAXgene, for stabilization of peripheral RNA) and a complete echocardiographic study, including GLS and septal strain, were performed before sAVR. Twenty-eight of those patients underwent sAVR and, in 23 of them, an inter-ventricular septum biopsy was performed. Tissues were fixed in formalin and embedded in paraffin. Sections were stained with Hematoxylin and Eosin for histological evaluation and with histochemical Masson trichrome for collagen fibers. The different components were calculated and expressed as micrometers2. To evaluate tissue miRNA components, sections 2-μm thick were cut using a microtome blade for each slide. Regression analysis was performed to test association between dependent variable and various predictors included in the model.ResultsDespite a preserved EF (66 ± 11 %), patients presented altered myocardial deformation parameters (GLS −14,02 ± 3.8 %; septal longitudinal strain, SSL −9.63 ± 2.9 %; septal longitudinal strain rate, SL-Sr −0.58 ± 0.17 1/s; Septal Longitudinal early-diastolic strain rate, SL-SrE 0.62 ± 0.32 1/s). The extent of MF showed an inverse association with both GLS and septal longitudinal deformation indices (GLS: R2 = 0.30; p = 0.02; SSL: R2 = 0.36; p = 0.01; SL-Sr: R2 = 0.39; p < 0.001; SL-SrE: R2 = 0.35; p = 0.001). miRNA-21 was mainly expressed in fibrous tissue (p < 0.0001). A significant association between MF and plasmatic miRNA-21, alone and weighted for measures of structural (LVMi R2 = 0.50; p = 0.0005) and functional (SSL R2 = 0.35; p = 0.006) remodeling, was found.ConclusionsIn AVS, MF is associated with alterations of regional and global strain. Plasmatic miRNA-21 is directly related to MF and associated with LV structural and functional impairment.

MicroRNAs distribution in different phenotypes of Aortic Stenosis

“…miRNA21 is up-regulated in cardiomyocytes during the fibrotic process; indeed, both myocardial and circulating levels of miRNA21 are significantly higher in patients with AVS compared to controls, correlating with MG and fibrosis. Previous data from our group also showed how miRNA21 manifested both in interstitial tissueand myocytes, with the fibrous tissue representing the site of major expression 25 – 27 . In this study, miRNA21 levels are associated with an impaired myocardial deformation, evaluated by GLS, and a reduced SVi, together with altered diastolic function and increased non-invasively-estimated filling pressure.…”

Review in translational cardiology: Micrornas and myocardial fibrosis in aortic valve stenosis, a deep insight on left ventricular remodeling

“…Furthermore, this integrated approach could help in better stratifying those patients that currently fall in a diagnostic “gray zone” of AVS severity. [29]…”

Imaging of Myocardial Fibrosis and Its Functional Correlates in Aortic Stenosis: A Review and Clinical Potential

“…We recently reported the high accuracy of both native T1 relaxation time with a cut-off value ≥1,010 ms (Ss = 90%, Sp = 73%, AUC = 0.82) and ECV with a cut-off value ≥0.315 (Ss = 80%, Sp = 90%, AUC = 0.85) to identify extensive (> 30%) DMF at histology [24]. Moreover, correlations between both native T1 and ECV with prognostic markers such as NT-pro-BNP or troponin have been reported [28, 29]. CMR-T1 has therefore been proposed as a promising technique to identify early structural changes in patients with AS.…”

“…First of all, GLS was found to be related to biomarkers of myocardial fibrosis such as those expressing calcification, collagen formation, or breakdown and inflammation [42, 43]. Several studies have also reported significant associations between LV systolic function and both FMF and DMF at CMR or myocardial histology [3, 14, 15, 18, 19, 24, 29, 44-46] (Table 2). Former studies have investigated the relationship between FMF and LV contractile function [14, 44, 45].…”