Elsevier

Heart Rhythm

Volume 12, Issue 1, January 2015, Pages 3-10
Heart Rhythm

Plasma microRNAs are associated with atrial fibrillation and change after catheter ablation (the miRhythm study)

https://doi.org/10.1016/j.hrthm.2014.09.050Get rights and content

Background

MicroRNAs (miRNAs) are associated with cardiovascular disease and control gene expression and are detectable in the circulation.

Objective

The purpose of this study was to test the hypothesis that circulating miRNAs may be associated with atrial fibrillation (AF).

Methods

Using a prospective study design powered to detect subtle differences in miRNAs, we quantified plasma expression of 86 miRNAs by high-throughput quantitative reverse transcriptase–polymerase chain reaction in 112 participants with AF and 99 without AF. To examine parallels between cardiac and plasma miRNA profiles, we quantified atrial tissue and plasma miRNA expression using quantitative reverse transcriptase–polymerase chain reaction in 31 participants undergoing surgery. We also explored the hypothesis that lower AF burden after ablation would be reflected in the circulating blood pool by examining change in plasma miRNAs after AF ablation (n = 47).

Results

Mean age of the cohort was 59 years; 58% of participants were men. Plasma miRs-21 and 150 were 2-fold lower in participants with AF than in those without AF after adjustment (P ≤.0006). Plasma levels of miRs-21 and 150 also were lower in participants with paroxysmal AF than in those with persistent AF (P <.05). Expression of miR-21, but not of miR-150, was lower in atrial tissue from patients with AF than in those without AF (P <.05). Plasma levels of miRs-21 and 150 increased 3-fold after AF ablation (P ≤.0006).

Conclusion

Cardiac miRs-21 and 150 are known to regulate genes implicated in atrial remodeling. Our findings show associations between plasma miRs-21 and 150 and AF, suggesting that circulating miRNAs can provide insights into cardiac gene regulation.

Introduction

Atrial fibrillation (AF) is an important cardiovascular health problem with major adverse health consequences.1 The prevalence of AF is 5.2 million in the United States today and is predicted to rise to 12.1 million by 2030.2 Clinical risk scores show modest predictive ability at identifying individuals at risk for AF, but few robust AF biomarkers exist.3

MicroRNAs (miRNAs) are a class of RNA species with gene regulatory functions. Tissue levels of miRNAs have been associated with processes underlying cardiovascular diseases,4, 5, 6 including cardiac electrical remodeling (miR-328)7, 8, 9, 10 and structural remodeling (miR-21).11, 12, 13 miRNAs can be exported by cardiomyocytes14 and fibroblasts and are present in the circulation,15, 16 but little is known about the source and significance of circulating miRNAs, particularly as they relate to arrhythmias.17

Despite reports implicating miRNAs as determinants of susceptibility to AF under experimental conditions,18, 19, 20 few studies have examined the relationships between circulating miRNAs and AF in humans.9, 19 In a previous study, we showed that whole-blood levels of miR-328, an miRNA associated with L-type Ca2+ channel density and AF susceptibility,21 was associated with prevalent AF.9, 22, 23 We hypothesized that plasma miRNAs would provide a clear window into cardiac gene regulation in AF and after ablation. We sought to explore these hypotheses by profiling expression of 86 miRNAs in plasma and atrial tissue in a prospectively recruited cohort.

Section snippets

Study sample

The miRhythm study is an ongoing, prospective study of AF and its gene regulatory mechanisms. Study participants include individuals with and without AF who presented to the University of Massachusetts Medical Center (UMMC) for evaluation or treatment between April 2011 and January 2014. To date, investigators have enrolled 453 individuals presenting to the UMMC, including 227 presenting for an ablation procedure, 114 presenting for surgery, and 112 presenting for cardiovascular evaluation. For

Results

The characteristics of the miRhythm participants who composed the study sample are given in Table 1. The clinical and surgical characteristics of the subsample of miRhythm participants who donated atrial tissue and plasma are given in Table 2.

The overall sample included middle-aged and older adults with a modest burden of cardiovascular risk factors. Participants with AF were more likely to be men and have higher body mass as well as echocardiographic left atrial volume indices. Study

Discussion

In our prospective study of 211 participants (Table 1) powered to detect subtle differences in plasma miRNA expression, we observed that miRs-21 and 150 were differentially expressed in the plasma of patients with preexisting AF and that associations persisted after adjustment for factors known to influence circulating miRNA profiles and susceptibility to AF. We also observed that miR-21 expression was lower in atrial tissue isolated from participants with AF and that miRs-21 and 150 increased

Conclusion

We observed strong associations between plasma levels of miRs-21 and 150, 2 miRNAs expressed in cardiac tissue and linked to atrial remodeling, with AF. Our findings support the hypothesis that circulating miRNAs provide key insights into cardiac gene regulation and implicate miRs-21 and 150 as markers of susceptibility to AF.

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    This study was supported by Grants 1U01HL105268-01 and KL2RR031981 to Dr. McManus; N01-HC 25195, 6R01-NS 17950, RFA-HL-12-008, and 1R01 HL64753 to Dr. Freedman; R01 HL087201A to Drs. Freedman and Tanriverdi; and R01 HL076784 and 1 R01 AG028321 to Dr. Benjamin from the National Heart, Lung, Blood Institute, National Institutes of Health.

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