Dataset Information

Myocardial microRNAs associated with reverse remodeling in human heart failure.

ABSTRACT:

Background

In dilated cardiomyopathies (DCMs) changes in expression of protein-coding genes are associated with reverse remodeling, and these changes can be regulated by microRNAs (miRs). We tested the general hypothesis that dynamic changes in myocardial miR expression are predictive of β-blocker-associated reverse remodeling.

Methods

Forty-three idiopathic DCM patients (mean left ventricular ejection fraction 0.24 ± 0.09) were treated with β-blockers. Serial ventriculography and endomyocardial biopsies were performed at baseline, and after 3 and 12 months of treatment. Changes in RT-PCR (candidate miRs) or array-measured miRs were compared based on the presence (R) or absence (NR) of a reverse-remodeling response, and a miR-mRNA-function pathway analysis (PA) was performed.

Results

At 3 months, 2 candidate miRs were selectively changed in Rs, decreases in miR-208a-3p and miR-591. PA revealed changes in miR-mRNA interactions predictive of decreased apoptosis and myocardial cell death. At 12 months, 5 miRs exhibited selective changes in Rs (decreases in miR-208a-3p, -208b-3p, 21-5p, and 199a-5p; increase in miR-1-3p). PA predicted decreases in apoptosis, cardiac myocyte cell death, hypertrophy, and heart failure, with increases in contractile and overall cardiac functions.

Conclusions

In DCMs, myocardial miRs predict the time-dependent reverse-remodeling response to β-blocker treatment, and likely regulate the expression of remodeling-associated miRs.

Trial registration

ClinicalTrials.gov NCT01798992.

Funding

NIH 2R01 HL48013, 1R01 HL71118 (Bristow, PI); sponsored research agreements from Glaxo-SmithKline and AstraZeneca (Bristow, PI); NIH P20 HL101435 (Lowes, Port multi-PD/PI); sponsored research agreement from Miragen Therapeutics (Port, PI).

SUBMITTER: Sucharov CC

PROVIDER: S-EPMC5256135 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Myocardial microRNAs associated with reverse remodeling in human heart failure.

Sucharov Carmen C CC Kao David P DP Port J David JD Karimpour-Fard Anis A Quaife Robert A RA Minobe Wayne W Nunley Karin K Lowes Brian D BD Gilbert Edward M EM Bristow Michael R MR

JCI insight 20170126 2

<h4>Background</h4>In dilated cardiomyopathies (DCMs) changes in expression of protein-coding genes are associated with reverse remodeling, and these changes can be regulated by microRNAs (miRs). We tested the general hypothesis that dynamic changes in myocardial miR expression are predictive of β-blocker-associated reverse remodeling.<h4>Methods</h4>Forty-three idiopathic DCM patients (mean left ventricular ejection fraction 0.24 ± 0.09) were treated with β-blockers. Serial ventriculography and ...[more]

PMID: 28138556

Similar Datasets

Project description:Background123Iodine-meta-iodobenzylguanidine scintigraphy is useful for assessing cardiac autonomic dysfunction and predict outcomes in heart failure (HF). The relationship of cardiac sympathetic function with myocardial remodeling and diffuse fibrosis remains largely unknown. We aimed to evaluate the cardiac sympathetic function of patients with HF and its relation with myocardial remodeling and exercise capacity.Methods and resultsProspectively enrolled patients with HF (New York Heart Association class II-III) were stratified into HF with preserved left ventricular ejection fraction [LVEF] ≥45%) and reduced LVEF. Ventricular morphology/function and myocardial extracellular volume (ECV) fraction were quantified by cardiovascular magnetic resonance, global longitudinal strain by echocardiography, cardiac sympathetic function by heart-to-mediastinum ratio from 123iodine-meta-iodobenzylguanidine scintigraphy. All participants underwent cardiopulmonary exercise testing. The cohort included 33 patients with HF with preserved LVEF (LVEF, 60±10%; NT-proBNP [N-terminal pro-B-type natriuretic peptide], 248 [interquartile range, 79-574] pg/dL), 28 with HF with reduced LVEF (LVEF, 30±9%; NT-proBNP, 743 [interquartile range, 250-2054] pg/dL) and 20 controls (LVEF, 65±5%; NT-proBNP, 40 [interquartile range, 19-50] pg/dL). Delayed (4 hours) 123iodine-meta-iodobenzylguanidine heart-to-mediastinum ratio was lower in HF with preserved LVEF (1.59±0.25) and HF with reduced LVEF (1.45±0.16) versus controls (1.92±0.24; P<0.001), and correlated negatively with diffuse fibrosis assessed by ECV (R=-0.34, P<0.01). ECV in segments without LGE was increased in HF with preserved ejection fraction (0.32±0.05%) and HF with reduced left ventricular ejection fraction (0.31±0.04%) versus controls (0.28±0.04, P<0.05) and was associated with the age- and sex-adjusted maximum oxygen consumption (peak oxygen consumption); (R=-0.41, P<0.01). Preliminary analysis indicates that cardiac sympathetic function might potentially act as a mediator in the association between ECV and NT-proBNP levels.ConclusionsAbnormally low cardiac sympathetic function in patients with HF with reduced and preserved LVEF is associated with extracellular volume expansion and decreased cardiopulmonary functional capacity.

Project description:ImportanceMortality is high among patients heart failure (HF) who are receiving treatment, and therefore identifying new pathways rooted in preclinical cardiac remodeling phenotypes may afford novel biomarkers and therapeutic avenues. Circulating extracellular RNAs (ex-RNAs) are an emerging class of biomarkers with target-organ epigenetic effects relevant to myocardial biology, although large human investigations remain limited.ObjectiveTo measure the association of highly expressed circulating ex-RNAs with left ventricular remodeling and incident HF in a community-based cohort.Design, setting, and participantsThis is a prospective observational cohort study of individuals who were included in the eighth examination of the Framingham Offspring Cohort (2005-2008). Collected data include measurements of the left ventricle via electrocardiography, determination of circulating ex-RNAs in plasma, and incidence of heart failure. Data analysis was completed from December 2016 to June 2018.ExposuresA total of 398 circulating ex-RNA molecules in plasma were measured by reverse transcription polymerase chain reaction; disease ontology analysis was also performed.Main outcomes and measuresEchocardiographic indices of left ventricular (LV) remodeling and incident heart failure.ResultsA total of 2763 participants of the Framingham Heart Study with measured ex-RNAs (mean [SD] age, 66.3 [9.0] years; 1499 [54.3%] female) were included in this study. Of this sample, 2429 to 2432 individuals had echocardiographic measures recorded (depending on the measurement). A total of 2681 individuals had HF status determined, of whom 116 (4.3%) experienced HF (median [interquartile range] follow-up, 7.7 [6.6-8.6] years). We identified 12 ex-RNAs associated with LV mass and at least 1 other echocardiographic phenotype (LV end-diastolic volume or left atrial dimension). Of these 12 ex-RNAs, 3 micro RNAs (miR-17, miR-20a, and miR-106b) were associated with a 15% reduction in long-term incident HF per 2-fold increase in circulating level during the follow-up period, after adjustments for age, sex, established HF risk factors, and prevalent or interim myocardial infarction. These 3 RNAs shared sequence homology and targeted a shared group of messenger RNAs that specified pathways relevant to HF (eg, transforming growth factor-β signaling, growth/cell cycle, and apoptosis), and shared a disease association with hypertension in disease ontology analysis.Conclusions and relevanceThis study identifies a group of circulating, noncoding RNAs associated with echocardiographic phenotypes, long-term incident HF, and pathways relevant to myocardial remodeling in a large community-based sample. Further investigations into the functional biology of these ex-RNAs are warranted for surveillance for HF prevention.

Dataset Information

Myocardial microRNAs associated with reverse remodeling in human heart failure.

Background

Methods

Results

Conclusions

Trial registration

Funding

Publications

Myocardial microRNAs associated with reverse remodeling in human heart failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets