Role of myocardial microRNAs in the long-term ventricular remodelling of patients with aortic stenosis

Abstract

Aims: We hypothesize that miRs are key players in the dynamics of the hypertrophy phenotype in aortic stenosis (AS) patients. In our study, we aimed to identify the transcriptional patterns (protein-coding transcripts and miRs) from myocardial sample biopsies that could be associated with the absence of left ventricular (LV) mass regression after aortic valve replacement (AVR) in patients with severe AS and LV hypertrophy.

Methods and results: We prospectively included 40 patients with severe AS, LV hypertrophy, and preserved ejection fraction undergoing AVR. Myocardial biopsies obtained during surgery were analysed for transcriptomic analysis performed by next-generation sequencing. At a 1-year follow-up, no hypertrophy reversal was observed in about half of the patients in the absence of patient-prosthesis mismatch and prosthesis dysfunction of uncontrolled hypertension. Predictors of mass regression were assessed from clinical, echocardiographic, and biochemical variables as well as from 300 miRs obtained from myocardial specimens, allowing the identification 29 differentially expressed. miR-4709-3p was found as a positive independent predictor of hypertrophy regression together with high-sensitivity troponin T (cTNT-hs) as a negative predictor. Gene transcripts RFX1, SIX5, MAPK8IF3, and PKD1 were predicted as simultaneous targets of five upregulated miRs suggesting its importance in LV hypertrophy.

Conclusion: In our cohort, tissue miR-4709-3p and cTNT-hs were independent predictors of hypertrophy regression. The hypertrophy reversal process will likely depend from a complex network where miRNAs may have an important role, allowing a potential opportunity for therapy.

Keywords: Aortic stenosis; Cardiac remodelling; MicroRNA; Prognosis.

Graphical Abstract

Figure 1

Flowchart of the included cohort. AVR, aortic valve replacement.

Figure 2

Differential expression and functional analysis of coding mRNAs in the patients with reverse myocardial remodelling after aortic valve replacement, when compared with the persistent phenotype. (A) Volcano plot of the differentially expressed mRNAs. (B) Principal component analysis (PCA) analysis (Rev: patients with reverse myocardial remodelling after aortic valve replacement; Hyp: patients with persistent hypertrophic phenotype after aortic valve replacement). (C) Gene set enrichment analysis of the biochemical pathways integrated within the Reactome database, performed by WebGestalt application. (D) Gene set enrichment analysis of the gene ontology terms selected by biological processes, performed by WebGestalt application.

Figure 3

Functional analysis of the transcriptomic data from the selected patients. (A) mRNA–miR interaction networks established in patients with reverse myocardial remodelling and no detectable hypertrophy. Upregulated miRs, represented by triangles, are connected with lines to their cognate targets as predicted by the mirDIP algorithm. Depicted gene targets, represented by circles, are downregulated in the remodelled myocardium, suggesting a possible functional connection between them. The size of the gene circle symbols is proportional to the number of miRs targeting a particular mRNA. (B–E) The normalized gene expression values in both groups of patients of the gene transcripts predicted to be regulated by five upregulated miRNAs. (F and G) The normalized gene expression of gene transcripts targeted by miR-4709-3p. HYP, patients with hypertrophy after follow-up; REV, patients with reverse remodelling after follow-up. *P < 0.05.