What question did this study set out to answer?

The aim is to understand the molecular mechanisms related to poor cardiac remodelling in aortic stenosis patients.

May 16, 2026

Integrative omics to reveal endothelial mesenchymal transition as critical biological function associated with poor reverse cardiac remodelling in aortic stenosis patients

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Aortic valve stenosis (n=134). Intervention: Valve replacement surgery vs. Good reverse remodelling (LV mass index ≤51 g/m2.7) vs Poor reverse remodelling (>51 g/m2.7). Primary outcome: Differential expression of miRNAs and mRNAs associated with poor reverse remodelling.

Resultado clave

Epithelial-mesenchymal transition, linked to downregulated miR-26a and upregulated RGS4 and POSTN, is associated with poor reverse cardiac remodelling after valve replacement in aortic stenosis.

Puntos clave

The aim is to understand the molecular mechanisms related to poor cardiac remodelling in aortic stenosis patients.
RNA-seq and miRNA-seq on preoperative left ventricular biopsies from aortic stenosis (n=24) and control patients (n=12).
Patients were stratified into good and poor reverse remodelling groups one year post-surgery based on left ventricular mass index.
Gene set enrichment analysis was performed to identify pathways associated with differentially expressed genes.
Identified endothelial mesenchymal transition as critical for poor reverse remodelling in aortic stenosis patients.
Found deregulation of RGS4 and POSTN, and upregulation of miR-26 associated with poor remodelling outcomes.
Demonstrated that overexpression of miR-26a inhibits migration and endothelial mesenchymal transition in vitro.

Diseño del estudio

Tipo

Observational (n=134)

PICO estructurado

Población

24 aortic valve stenosis (AS) patients and 12 age- and sex-matched control patients, with a validation cohort of 98 AS patients; additionally, a transverse aortic constriction (TAC) mouse model and an in vitro cytokine-based EndTM model.

Intervención

Valve replacement surgery (human cohort); Transverse aortic constriction (TAC) and release (de-TAC) (mouse model); miR-26a overexpression (in vitro model).

Comparador

Good reverse remodelling (LV mass index ≤51 g/m2.7) vs poor reverse remodelling (LV mass index >51 g/m2.7) at one year; control patients; baseline/control models.

Resultado

Differential expression of miRNA/mRNA in left ventricular biopsies associated with poor reverse remodelling at one year.surrogate

Integrative omics identifies endothelial-mesenchymal transition, specifically involving miR-26a, RGS4, and POSTN, as a key mechanism underlying poor reverse cardiac remodelling after aortic valve replacement.

Resumen

Abstract Background Aortic valve stenosis (AS), a major cause of heart failure, is driven by chronic pressure overload that induces left ventricular (LV) hypertrophy and fibrosis. Surgical or transcatheter aortic valve replacement relieves the hemodynamic stress and initiates a reverse remodelling, a process characterized by gradual structural and functional recovery of the myocardium. Although regression of hypertrophy and fibrosis begins shortly after surgery, complete normalization of LV mass is not achieved in a substantial proportion of patients. Understanding the molecular mechanisms underlying poor reverse remodelling is therefore essential to identify novel therapeutic targets for mitigating adverse cardiac remodelling and promoting myocardial recovery. Purpose Co-profiling miRNA/mRNA in preoperative LV biopsies from AS patients to identify potential targets determinant of favourable reverse remodelling one year after valve replacement surgery. Methods and results The study was performed in AS (n=24) and control patients (n=12) (age and sex matched) followed up for one year after surgery. RNA-seq and miRNA-seq were performed on LV biopsies obtained during surgery. AS patients were stratified according to the quality of the reverse remodelling at one year in good (LV mass index ≤51 g/m2.7, n=12) or poor (LV mass index 51 g/m2.7, n=12) performers. Potential interactions between differentially expressed (DE) miRNAs and DEmRNAs were explored using the mirTarRnaSeq R package, based on expression correlations and cross-referenced with predicted interactions from the miRanda database. Gene set enrichment analysis performed on DE mRNAs targeted by DE miRNAs revealed enrichment in pathways associated with epithelial-mesenchymal transition (EMT) (NES=1.97). DEgenes related with EMT (RGS4 and POSTN) and their validated miRNA, miR-26a, were also found to be inversely deregulated in LV from AS patients with poor reverse remodelling (validation by qPCR; n=98). Overexpression of POSTN (2.96±0.33) and RGS4 (1.41±0.082 in males) along with an inverse correlation with miR-26a values (vs POSTN r=-0.46*; vs RGS4 r=-0.44* in males), were also observed in the LV of our animal model of transverse aortic constriction (TAC) after 4 weeks. In addition, reverse remodelling in mice LV after pressure overload release (de-TAC) was accompanied by a decrease in the expression of POSTN and RGS4. Interestingly, overexpression of miR-26a inhibited migration and EndTM in our cytokine-based EndTM in vitro model, accompanied by a decrease of RGS4 expression. Conclusions Performing integrative miRNA/mRNA co-profiling in LV from AS patients, were able to (1) establish EMT as a critical function associated with poor reverse remodelling in AS patients; (2) identify downregulation of RGS4 and POSTN, and upregulation of miR-26 as a shared process in the LV of our TAC and de-TAC animal model; (3) establish the anti-migration and anti-EndMT properties of miR-26 in our in vitro model.

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