title: 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: Myocardial 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.
  
  
  
  Thirty-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 micrometers(2). 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.
  
  
  
  Despite 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: R(2) = 0.30; p = 0.02; SSL: R(2) = 0.36; p = 0.01; SL-Sr: R(2) = 0.39; p < 0.001; SL-SrE: R(2) = 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 R(2) = 0.50; p = 0.0005) and functional (SSL R(2) = 0.35; p = 0.006) remodeling, was found.
  
  
  
  In 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.
authors: Department of Surgical, Medical, Molecular Pathology and Critical Area, Cisanello Hospital, University of Pisa/A.O.U.P, Via Paradisa, 2, 56100, Pisa, PI, Italy. iacopofabiani@gmail.com.
authors: Iacopo
authors: I
authors: Fabiani
authors: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56100, Pisa, Italy.
authors: Cristian
authors: C
authors: Scatena
authors: Fondazione Pisana per la Scienza, 56100, Pisa, Italy.
authors: Chiara Maria
authors: CM
authors: Mazzanti
authors: Department of Surgical, Medical, Molecular Pathology and Critical Area, Cisanello Hospital, University of Pisa/A.O.U.P, Via Paradisa, 2, 56100, Pisa, PI, Italy.
authors: Lorenzo
authors: L
authors: Conte
authors: Department of Surgical, Medical, Molecular Pathology and Critical Area, Cisanello Hospital, University of Pisa/A.O.U.P, Via Paradisa, 2, 56100, Pisa, PI, Italy.
authors: Nicola Riccardo
authors: NR
authors: Pugliese
authors: Fondazione Pisana per la Scienza, 56100, Pisa, Italy.
authors: Sara
authors: S
authors: Franceschi
authors: Fondazione Pisana per la Scienza, 56100, Pisa, Italy.
authors: Francesca
authors: F
authors: Lessi
authors: Fondazione Pisana per la Scienza, 56100, Pisa, Italy.
authors: Michele
authors: M
authors: Menicagli
authors: Division of Cardiac Surgery, Department of Surgical, Medical, Molecular Pathology and Critical Area, Cisanello Hospital, University of Pisa/A.O.U.P, 56100, Pisa, Italy.
authors: Andrea
authors: A
authors: De Martino
authors: Division of Cardiac Surgery, Department of Surgical, Medical, Molecular Pathology and Critical Area, Cisanello Hospital, University of Pisa/A.O.U.P, 56100, Pisa, Italy.
authors: Stefano
authors: S
authors: Pratali
authors: Division of Cardiac Surgery, Department of Surgical, Medical, Molecular Pathology and Critical Area, Cisanello Hospital, University of Pisa/A.O.U.P, 56100, Pisa, Italy.
authors: Uberto
authors: U
authors: Bortolotti
authors: Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56100, Pisa, Italy.
authors: Antonio Giuseppe
authors: AG
authors: Naccarato
authors: Division of Internal Medicine, Villa Sofia Hospital, 90100, Palermo, Italy.
authors: Salvatore
authors: S
authors: La Carrubba
authors: Department of Surgical, Medical, Molecular Pathology and Critical Area, Cisanello Hospital, University of Pisa/A.O.U.P, Via Paradisa, 2, 56100, Pisa, PI, Italy.
authors: Vitantonio
authors: V
authors: Di Bello
mesh_terms: D000368:Aged; D001024:Aortic Valve Stenosis / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D015415:Biomarkers; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D010865:Pilot Projects; D012044:Regression Analysis; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; C524940:MIRN21 microRNA, human; D035683:MicroRNAs
keywords: Aortic stenosis; Aortic valve; Aortic valve replacement; Myocardial strain; Tissue and strain Doppler echocardiography; Tissue characterization