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Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation.

ABSTRACT: Mitral valve prolapse (MVP) associated with severe mitral regurgitation is a debilitating disease with no pharmacological therapies available. MicroRNAs (miRNA) represent an emerging class of circulating biomarkers that have never been evaluated in MVP human plasma. Our aim was to identify a possible miRNA signature that is able to discriminate MVP patients from healthy subjects (CTRL) and to shed light on the putative altered molecular pathways in MVP. We evaluated a plasma miRNA profile using Human MicroRNA Card A followed by real-time PCR validations. In addition, to assess the discriminative power of selected miRNAs, we implemented a machine learning analysis. MiRNA profiling and validations revealed that miR-140-3p, 150-5p, 210-3p, 451a, and 487a-3p were significantly upregulated in MVP, while miR-223-3p, 323a-3p, 340-5p, and 361-5p were significantly downregulated in MVP compared to CTRL (p ? 0.01). Functional analysis identified several biological processes possible linked to MVP. In addition, machine learning analysis correctly classified MVP patients from CTRL with high accuracy (0.93) and an area under the receiving operator characteristic curve (AUC) of 0.97. To the best of our knowledge, this is the first study performed on human plasma, showing a strong association between miRNAs and MVP. Thus, a circulating molecular signature could be used as a first-line, fast, and cheap screening tool for MVP identification.

SUBMITTER: Songia P

PROVIDER: S-EPMC7924183 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation.

Songia Paola P Chiesa Mattia M Alfieri Valentina V Massaiu Ilaria I Moschetta Donato D Myasoedova Veronika V Valerio Vincenza V Fusini Laura L Gripari Paola P Zanobini Marco M Poggio Paolo P

International journal of molecular sciences 20210220 4

Mitral valve prolapse (MVP) associated with severe mitral regurgitation is a debilitating disease with no pharmacological therapies available. MicroRNAs (miRNA) represent an emerging class of circulating biomarkers that have never been evaluated in MVP human plasma. Our aim was to identify a possible miRNA signature that is able to discriminate MVP patients from healthy subjects (CTRL) and to shed light on the putative altered molecular pathways in MVP. We evaluated a plasma miRNA profile using ...[more]

PMID: 33672625

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Project description:Mitral annular disjunction (MAD) is routinely diagnosed by cardiac imaging, mostly by echocardiography, and shown to be a risk factor for ventricular arrhythmias. While MAD is associated with mitral valve (MV) prolapse (MVP), it is unknown which patients with MAD are at higher risk and which additional imaging features may help identify them. The value of cardiac computed tomography (CCT) for the diagnosis of MAD is unknown. Accordingly, we aimed to: (1) develop a standardized CCT approach to identify MAD in patients with MVP and severe mitral regurgitation (MR); (2) determine its prevalence and identify features that are associated with MAD in this population. We retrospectively studied 90 patients (age 63 ± 12 years) with MVP and severe MR, who had pre-operative CCT (256-slice scanner) of sufficient quality for analysis. The presence and degree of MAD was assessed by rotating the view plane around the MV center to visualize disjunction along the annulus. Additionally, detailed measurements of MV apparatus and left heart chambers were performed. Univariate logistic regression analysis was performed to determine which parameters were associated with MAD. MAD was identified in 18 patients (20%), and it was typically located adjacent to a prolapsed or flail mitral leaflet scallop. Of these patients, 75% had maximum MAD distance > 4.8 mm and 90% > 3.8 mm. Female gender was most strongly associated with MAD (p = 0.04). Additionally, smaller end-diastolic mitral annulus area (p = 0.045) and longer posterior leaflet (p = 0.03) were associated with greater MAD. No association was seen between MAD and left ventricular size and function, left atrial size, and papillary muscle geometry. CCT can be used to readily detect MAD, by taking advantage of the 3D nature of this modality. A significant portion of MVP patients referred for mitral valve repair have MAD. The presence of MAD is associated with female gender, smaller annulus size and greater posterior leaflet length.

Project description:BackgroundInitial studies have suggested the familial clustering of mitral valve prolapse, but most of them were either community based among unselected individuals or applied non-specific diagnostic criteria. Therefore little is known about the familial distribution of mitral regurgitation in a referral-type population with a more severe mitral valve prolapse phenotype. The objective of this study was to evaluate the presence of familial mitral regurgitation in patients undergoing surgery for mitral valve prolapse, differentiating patients with Barlow's disease, Barlow forme fruste and fibro-elastic deficiency.MethodsA total of 385 patients (62 ± 12 years, 63% men) who underwent surgery for mitral valve prolapse were contacted to assess cardiac family history systematically. Only the documented presence of mitral regurgitation was considered to define 'familial mitral regurgitation'. In the probands, the aetiology of mitral valve prolapse was defined by surgical observations.ResultsA total of 107 (28%) probands were classified as having Barlow's disease, 85 (22%) as Barlow forme fruste and 193 (50%) patients as fibro-elastic deficiency. In total, 51 patients (13%) reported a clear family history for mitral regurgitation; these patients were significantly younger, more often diagnosed with Barlow's disease and also reported more sudden death in their family as compared with 'sporadic mitral regurgitation'. In particular, 'familial mitral regurgitation' was reported in 28 patients with Barlow's disease (26%), 15 patients (8%) with fibro-elastic deficiency and eight (9%) with Barlow forme fruste (P < 0.001).ConclusionsIn a large cohort of patients operated for mitral valve prolapse, the self-reported prevalence of familial mitral regurgitation was 26% in patients with Barlow's disease and still 8% in patients with fibro-elastic deficiency, highlighting the importance of familial anamnesis and echocardiographic screening in all mitral valve prolapse patients.

Project description:BackgroundMild physiologic mitral regurgitation (MR) is common in normal individuals. Patients with primary MR due to mitral valve prolapse (MVP) may also exhibit less than moderate MR. We sought to determine whether MVP patients with less than moderate MR displayed early cardiac chamber remodeling or factors related to early remodeling and whether early remodeling predicted MR progression.MethodsConsecutive MVP patients with less than moderate MR by proximal isovelocity surface area-derived effective regurgitant orifice < 20 mm2 and regurgitant volume < 30 mL, were matched for age and sex with non-MVP patients (controls) having less than moderate MR. Patients with moderate or greater dysfunctional left- or right-sided valves and left ventricular ejection fraction < 50% were excluded. We evaluated left ventricle (LV) and left atrium (LA) remodeling parameters (LV end-diastolic and end-systolic indexed diameters, LA volume-index, and LV mass-index) as well as determinants of remodeling. The last available transthoracic echocardiography was reviewed to identify progression to moderate-severe MR or more.ResultsA total of 253 MVP patients with less than moderate MR were matched to 344 controls (P for age and sex, ≥.18) with less than moderate MR. Patients with MVP (mean effective regurgitant orifice and regurgitant volume, 12 ± 4 mm2 and 18 ± 6 mL, respectively) had more premature ventricular contractions (PVCs), larger LV and LA remodeling parameters, and more mild-to-moderate MR (all P < .0001). Multivariate linear regression models showed that larger LV remodeling parameters were independently associated with MVP and female sex but not MR severity (all P < .0001). The LA volume index was independently associated with MVP, age, and E/e' (all P < .0001). The LV mass index was associated with MVP, age, and hypertension (all P ≤ .002). Presence of PVCs was associated with LV end-systolic diameter ≥ 40 mm and indexed ≥ 22 mm2 (P = .005). Among 323 (54%) patients having subsequent transthoracic echocardiography, 17 patients (all MVP) progressed to moderate-severe MR or more at a median of 4.3 (interquartile range, 1.7-6.4) years. Isolated posterior leaflet prolapse was the single factor associated with MR progression (adjusted hazard ratio, 2.70; 95% CI, 0.99-7.34; P = .048) after adjustment for MR severity. At a median of 5.9 (interquartile range, 4.6-7.2) years of follow-up, female sex and MVP (vs controls) were protective factors for mortality.ConclusionsPatients with less than moderate MR due to MVP exhibit early LV and LA remodeling, which does not predict MR progression or mortality. Left ventricle remodeling is associated with MVP, female sex, and presence of PVCs. Early chamber remodeling associated with MVP may be the phenotypical expression of a genetically mediated process and is at least partially related to PVCs.

Project description:OBJECTIVES:The Cardiothoracic Surgical Trials Network recently reported no difference in the primary end point of left ventricular end-systolic volume index at 1 year postsurgery in patients randomized to repair (n = 126) or replacement (n = 125) for severe ischemic mitral regurgitation. However, patients undergoing repair experienced significantly more recurrent mitral regurgitation than patients undergoing replacement (32.6% vs 2.3%). We examined whether baseline echocardiographic and clinical characteristics could identify those who will develop moderate/severe recurrent mitral regurgitation or die. METHODS:Our analysis includes 116 patients who were randomized to and received mitral valve repair. Logistic regression was used to estimate a model-based probability of recurrence or death from baseline factors. Receiver operating characteristic curves were constructed from these estimated probabilities to determine classification cut-points maximizing accuracy of prediction based on sensitivity and specificity. RESULTS:Of the 116 patients, 6 received a replacement before leaving the operating room; all other patients had mild or less mitral regurgitation on intraoperative echocardiogram after repair. During the 2-year follow-up period, 76 patients developed moderate/severe mitral regurgitation or died (53 mitral regurgitation recurrences, 13 mitral regurgitation recurrences and death, and 10 deaths). The mechanism for recurrent mitral regurgitation was largely mitral valve leaflet tethering. Our model (including age, body mass index, sex, race, effective regurgitant orifice area, basal aneurysm/dyskinesis, New York Heart Association class, history of coronary artery bypass grafting, percutaneous coronary intervention, or ventricular arrhythmias) yielded an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS:The model demonstrated good discrimination in identifying patients who will survive 2 years without recurrent mitral regurgitation after mitral valve repair. Although our results require validation, they offer a clinically relevant risk score for selection of surgical candidates for this procedure.

Project description:BackgroundIschemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited.MethodsWe randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank.ResultsAt 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, -6.6 and -6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P=0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P=0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months.ConclusionsWe observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes. (Funded by the National Institutes of Health and the Canadian Institutes of Health; ClinicalTrials.gov number, NCT00807040.).

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Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation.

Publications

Putative Circulating MicroRNAs Are Able to Identify Patients with Mitral Valve Prolapse and Severe Regurgitation.

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