Secondary mitral regurgitation-Insights from microRNA assessment

Abstract

Background: While secondary mitral regurgitation (sMR) is associated with adverse outcome in heart failure with reduced ejection fraction (HFrEF), key pathophysiologic mechanisms remain poorly understood and might be elucidated by microRNAs (miRNA/miR), that were recently related to cardiac remodelling. This study sought to assess (i) the differences of miRNA profiles in patients with severe sMR compared to matched disease controls, (ii) the correlation between circulating miRNAs and surrogates of sMR severity as well as (iii) the prognostic implications of miRNA levels in severe sMR.

Materials and methods: Sixty-six HFrEF patients were included, of these 44 patients with severe sMR 2:1 matched to HFrEF controls with no/mild sMR. A comprehensive set of miRNAs (miR-21, miR-29a, miR-122, miR-132, miR-133a, miR-let7i) were measured and correlated to echocardiographic sMR severity.

Results: miRNA patterns differed distinctly between patients with severe sMR and HFrEF controls (P < .05). Among the panel of assessed miRNAs, miR-133a correlated most strongly with surrogates of sMR severity (r = -0.41, P = .001 with sMR vena contracta width). Interestingly, elevated levels of miR-133 were associated with an increased risk for cardiovascular death and/or HF hospitalizations with and adjusted HR of 1.85 (95% CI 1.24-2.76, P = .003).

Conclusions: This study unveils distinct pathophysiologic maladaptions at a cellular level in patients with severe sMR compared to no/mild sMR by showing significant differences in miRNA profiles and correlations with sMR severity, supporting the concept that sMR drives cardiac remodelling in heart failure. Moreover, the increased risk for adverse outcome in HFrEF patients with severe sMR conveyed by miR-133a might indicate irreversible myocardial damage.

Keywords: fibrosis; heart failure with reduced ejection fraction; hypertrophy; miR-133a; microRNA; secondary mitral regurgitation.

Figure 1

miRNA profiles in HFrEF patients with either severe sMR or no/mild sMR (matched controls). MicroRNA profiles are displayed as Tukey boxplots, comparisons between patients with severe sMR and matched controls were analysed by an independent t test

Figure 2

Scatter plot displaying the association between quantified surrogates of sMR (ie sMR vena contracta width and sMR regurgitant jet area) and microRNA levels in patients with HFrEF and severe sMR or no/mild sMR (matched controls). The correlation between the aforementioned variables was assessed using Spearman's rho correlation analysis

Figure 3

Kaplan‐Meier estimates of the primary outcome comparing patients with severe sMR and miR‐133a levels below the median to patients with severe sMR and miR‐133a levels above the median (log‐rank P = .03)