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Circulating microRNA Profiling Needs Further Refinement Before Clinical Use in Patients With Aortic Stenosis.

ABSTRACT: Aortic stenosis (AS) is a progressive condition leading to heart failure and death without treatment. No medical therapy currently exists for AS, and a major management challenge is deciding on the correct timing of aortic valve replacement. MicroRNAs (miRNAs) are short noncoding RNAs that are stable in the circulation. We wished to use miRNAs as biomarkers of disease in AS.We performed microarray-based whole miRNome profiling of 24 participants with AS and 27 control participants. After adjustment for age and multiple testing, we identified 4 miRNAs significantly different between groups. These findings were then examined using quantitative polymerase chain reaction in a larger validation cohort of 101 controls and 94 participants with AS, stratified in a prespecified analysis by presence of coexisting coronary artery disease (CAD). We obtained mixed results for miR-22-3p, miR-24-3p, miR-382-5p, and miR-451a in the validation cohort, with differing associations according to CAD status. miR-21-5p was increased in AS patients without CAD, but there was no difference between groups with CAD.Despite holding great promise, circulating miRNA profiling requires further refinement before translation into clinical use as a biomarker in aortic stenosis.

SUBMITTER: Coffey S

PROVIDER: S-EPMC4599470 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Circulating microRNA Profiling Needs Further Refinement Before Clinical Use in Patients With Aortic Stenosis.

Coffey Sean S Williams Michael J A MJ Phillips L Vicky LV Jones Gregory T GT

Journal of the American Heart Association 20150824 8

<h4>Background</h4>Aortic stenosis (AS) is a progressive condition leading to heart failure and death without treatment. No medical therapy currently exists for AS, and a major management challenge is deciding on the correct timing of aortic valve replacement. MicroRNAs (miRNAs) are short noncoding RNAs that are stable in the circulation. We wished to use miRNAs as biomarkers of disease in AS.<h4>Methods and results</h4>We performed microarray-based whole miRNome profiling of 24 participants wit ...[more]

PMID: 26304936

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Project description:BackgroundCirculating micro-RNAs have been proposed as a novel class of cardiovascular (CV) biomarkers, but whether they meet analytical requirements and provide additional information to establish risk indices have not been established. miR-210 levels are increased in subjects with low VO2 max, which is a recognized risk factor in patients with aortic stenosis (AS), and we hypothesized that circulating miR-210 levels may be increased in patients with AS and associated with a poor prognosis.MethodsWe measured circulating miR-210 levels by real-time PCR in 57 patients with moderate to severe AS and in 10 age- and gender-matched healthy controls. The merit of miR-210 as a biomarker was assessed according to established criteria, including by comparing miR-210 levels with NT-proBNP and miR-22 levels, which is another miRNA biomarker candidate.ResultsAll patients and control subjects had miR-210 levels within the range of detection (Cq<35) and the analytical variability was low. Circulating miR-210 levels were 2.0±0.2 [mean±SEM] fold increased in AS patients compared to controls (p?=?0.002), whereas miR-22 levels were not differently expressed in the AS patients (0.12±0.06 fold increase, p?=?0.45). The increase in miR-210 levels in AS patients was comparable to the increment in NT-proBNP levels: [AUC] 0.82 (95% CI 0.70-0.90) vs. 0.85 (0.75-0.93), respectively, p?=?0.71. During a median follow-up of 1287 days, 15 patients (26%) died. There was a significant association between higher circulating levels of miR-210 and increased mortality during follow-up: hazard ratio [supra- vs. inframedian levels] 3.3 (95% CI 1.1-10.5), p?=?0.039. Adjusting for other risk indices in multivariate analysis did not attenuate the prognostic merit of circulating miR-210 levels.ConclusionCirculating miR-210 levels are increased in patients with AS and provide independent prognostic information to established risk indices. Analytical characteristics were also excellent supporting the potential of micro-RNAs as novel CV biomarkers.

Project description:BackgroundCirculatory efficiency reflects the ratio between total left ventricular work and the work required for maintaining cardiovascular circulation. The effect of severe aortic valve stenosis (AS) and aortic valve replacement (AVR) on left ventricular/circulatory mechanical power and efficiency is not yet fully understood. We aimed to quantify left ventricular (LV) efficiency in patients with severe AS before and after surgical AVR.MethodsCirculatory efficiency was computed from cardiovascular magnetic resonance (CMR) imaging derived volumetric data, echocardiographic and clinical data in patients with severe AS (n?=?41) before and 4 months after AVR and in age and sex-matched healthy subjects (n?=?10).ResultsIn patients with AS circulatory efficiency was significantly decreased compared to healthy subjects (9?±?3% vs 12?±?2%; p?=?0.004). There were significant negative correlations between circulatory efficiency and LV myocardial mass (r?=?-?0.591, p?<?0.001), myocardial fibrosis volume (r?=?-?0.427, p?=?0.015), end systolic volume (r?=?-?0.609, p?<?0.001) and NT-proBNP (r?=?-?0.444, p?=?0.009) and significant positive correlation between circulatory efficiency and LV ejection fraction (r?=?0.704, p?<?0.001). After AVR, circulatory efficiency increased significantly in the total cohort (9?±?3 vs 13?±?5%; p?<?0.001). However, in 10/41 (24%) patients, circulatory efficiency remained below 10% after AVR and, thus, did not restore to normal values. These patients also showed less reduction in myocardial fibrosis volume compared to patients with restored circulatory efficiency after AVR.ConclusionIn our cohort, circulatory efficiency is reduced in patients with severe AS. In 76% of cases, AVR leads to normalization of circulatory efficiency. However, in 24% of patients, circulatory efficiency remained below normal values even after successful AVR. In these patients also less regression of myocardial fibrosis volume was seen. Trial Registration clinicaltrials.gov NCT03172338, June 1, 2017, retrospectively registered.

Project description:BackgroundThe 2016 guidelines of the American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) for evaluation of left ventricular (LV) diastolic dysfunction by Doppler flow and tissue Doppler- echocardiography do not adjust assessment of high filling pressures for patients with aortic stenosis (AS). However, most of the studies on this patient group indicate age independent specific diastolic features in AS. The aim of this study is to identify disease-specific range and distribution of diastolic functional parameters and their ability to identify high N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels as a marker for high filling pressures.MethodsIn this study, 169 patients who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) were prospectively enrolled. Resting echocardiography was performed including Doppler of the mitral inflow, pulmonary venous flow, tricuspid regurgitant flow and tissue Doppler in the mitral ring and indexed volume-estimates of the left atrium (LAVI). Echocardiography, and NT-proBNP levels were assessed before TAVR/SAVR and at two postoperative visits at 6 and 12 months.ResultsPre- and postoperative values were septal e'; 5.1 ± 3.9, 5.2 ± 1.6 cm/s; lateral e' 6.3 ± 2.1; 7.7 ± 2.7 cm/s; E/e'19 ± 8; 16 ± 7 cm/s; E velocity 96 ± 32; 95 ± 32 cm/s; LAVI 39 ± 8; 36 ± 8 ml/m2, pulmonary artery pressure (PAP) 39 ± 8; 36 ± 8 mmHg, respectively. The scoring recommended by ASE/EACVI detected elevated NT pro-BNP with a specificity of 25%. Adjusting thresholds towards PAP ≥ 40 mmHg, E velocity ≥ 100 cm/s, E deceleration time < 220 ms, and E/septal e' ≥ 20 or septal e' < 5.0 cm/s increased prediction of NT-proBNP levels ≥500 ng/L with substantially improved specificity (> 85%).ConclusionDiastolic echocardiographic parameters in AS indicate persistent impaired relaxation and NT-proBNP indicate elevated filling pressures in most of the patients, improving only modestly 6-12 months after TAVR and SAVR. Applying the 2016 ASE/EACVI recommendations for detection of elevated filling pressures to patients with AS, elevated NT pro-BNP levels could not be reliably detected. However, adjusting thresholds of the echocardiographic parameters increased specificities to useful diagnostic levels.Trial registrationThe study was prospectively approved by the regional ethical committee, REK North with the registration number: REK 2010/397-10 .

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Circulating microRNA Profiling Needs Further Refinement Before Clinical Use in Patients With Aortic Stenosis.

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Circulating microRNA Profiling Needs Further Refinement Before Clinical Use in Patients With Aortic Stenosis.

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