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Brief Report
September 2018

Associations of Circulating Extracellular RNAs With Myocardial Remodeling and Heart Failure

Author Affiliations
  • 1Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Boston University School of Public Health, Boston University, Boston, Massachusetts
  • 3University of Massachusetts, Worcester
  • 4Department of Medicine, University of Michigan at Ann Arbor, Ann Arbor
  • 5Gladstone Institute for Bioinformatics, University of California, San Francisco
  • 6Framingham Heart Study, Framingham, Massachusetts
JAMA Cardiol. 2018;3(9):871-876. doi:10.1001/jamacardio.2018.2371
Key Points

Question  Can investigating circulating, noncoding, extracellular RNAs (ex-RNAs) associated with heart failure (HF) and myocardial disease in a community-based sample offer insights into pathways of myocardial remodeling?

Findings  In this large epidemiologic cohort with a broad array of ex-RNAs, we found several micro RNAs associated with prevalent left ventricular remodeling. Three of these RNAs were associated with incident HF during long-term follow-up and with regulating genes implicated in hypertension.

Meaning  Circulating ex-RNAs associated with myocardial remodeling and incident HF in this community-based sample regulate biological pathways relevant to cardiomyocyte pathobiology. Further studies integrating the molecular epidemiology of HF with mechanistic studies to inform disease detection and therapy are warranted.


Importance  Mortality 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.

Objective  To measure the association of highly expressed circulating ex-RNAs with left ventricular remodeling and incident HF in a community-based cohort.

Design, Setting, and Participants  This 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.

Exposures  A 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 Measures  Echocardiographic indices of left ventricular (LV) remodeling and incident heart failure.

Results  A 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 Relevance  This 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.