Selective blockade of microRNA-31-5p−calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia burden

Q: What are the key findings of this study?

Selective blockade of miR-31-5p-CALCR interaction with miR-31/CTR-TSB reversed established atrial fibrosis by 30% (p<0.0001) and reduced AF burden by 16% (p=0.033) in mice.

Q: What is the clinical evidence from this study?

Population: Atrial fibrillation and atrial fibrosis (n=136). Intervention: miR-31/CTR-TSB (locked nucleic acid target site blocker) vs. Negative control target site blocker (NC-TSB). Primary outcome: Reversal of established atrial fibrosis and reduction in atrial fibrillation burden in Lkb1-aKD mice (p=<0.0001).

Q: What does this research mean for the field?

Selective blockade of the microRNA-31-5p and calcitonin receptor interaction restores calcitonin receptor expression, reverses established atrial fibrosis, and reduces atrial fibrillation susceptibility. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To determine the role of microRNA-31-5p in atrial fibrosis and test whether disrupting its interaction with the calcitonin receptor can reverse atrial remodeling and arrhythmia susceptibility.

Jasha Trompf*; Kathryn Cox*; Mohit M. Hulsurkar; Lucia M. Moreira; Chi Him Kendrick Yiu; Aaron M. Johnston; Satadru K. Lahiri; Shuai Zhao; Paul J. Robinson; Roddy Hiram; Mozhdeh Mehdizadeh; Lorena Perez Carrillo; Rana A Sayeed; George Krasopoulos; Vivek Kumar Srivastava; Nicholas Walcot; Shakil Farid; Antonios Kourliouros; Priya Sastry; David A. Menassa; Benjamin Davies; Rita A. Schack; Robia G. Pautler; Keith M. Channon; Craig A. Lygate; Stanley Nattel; Xander H.T. Wehrens; Svetlana N. Reilly

doi:10.1038/s44161-026-00897-1

Key result

miR-31-CALCR blockade reverses established atrial fibrosis by ~30% and reduces AF burden in mice.

P<0.0001
n=136

Figures

Why the study?

Effective therapies for atrial fibrosis in AF are lacking, and although microRNA-31-5p has been linked to AF, its role in atrial fibrosis was unknown.

Does selective blockade of the microRNA-31-5p-calcitonin receptor interaction using a locked nucleic acid target site blocker prevent or reverse atrial fibrosis and reduce atrial fibrillation burden in preclinical mouse models and human atrial fibroblasts?

Key Points

To determine the role of microRNA-31-5p in atrial fibrosis and test whether disrupting its interaction with the calcitonin receptor can reverse atrial remodeling and arrhythmia susceptibility.
Analyzed atrial fibroblasts from patients with persistent atrial fibrillation and sinus rhythm controls using luciferase reporter assays, actinomycin D chase assays, and RNA immunoprecipitation.
Engineered tamoxifen-inducible, fibroblast-specific miR-31 transgenic mice to evaluate the effects of in vivo miR-31 overexpression on atrial fibrosis and atrial fibrillation inducibility.
Applied a locked nucleic acid target site blocker to selectively disrupt the miR-31-5p-CALCR interaction in human atrial fibroblasts and in mice with established atrial remodeling.
Atrial fibroblasts from patients with persistent atrial fibrillation showed a 2.7-fold increase in miR-31-5p in right atrial appendages (P=0.003) and a 2.5-fold increase in left atrial appendages (P=0.008), leading to enhanced degradation of CALCR mRNA (P=0.0114).
Fibroblast-specific miR-31 overexpression in mice doubled atrial fibrosis (P=0.0025) and collagen-1 and collagen-3 accumulation without altering ventricular fibrosis, leading to a 2-fold higher atrial fibrillation inducibility (P=0.0136).
Selective blockade of the miR-31-5p-CALCR interaction using a locked nucleic acid target site blocker decreased CALCR loading into the RNA-induced silencing complex by ~60% (P=0.0334), restored receptor expression, and promoted regression of established atrial fibrosis.

Structured PICO

Does selective blockade of the microRNA-31-5p-calcitonin receptor interaction using a locked nucleic acid target site blocker prevent or reverse atrial fibrosis and reduce atrial fibrillation burden in preclinical mouse models and human atrial fibroblasts?

P

Population

136 patients with persistent atrial fibrillation or sinus rhythm undergoing cardiac surgery providing atrial biopsies, alongside 175 experimental mice in in vivo studies.

I

Intervention

Selective blockade of the miR-31-5p/CALCR interaction using antisense locked nucleic acid (LNA) miRNA Power Target Site Blocker (miR-31/CTR-TSB): in vitro transfection of hACFs with 25 or 50 nM miR-31/CTR-TSB (or miR-31-5p mimic/inhibitor); in vivo administration in 8-week-old Lkb1-aKD mice for 4 weeks (preventive strategy) or in 20.5-week-old Lkb1-aKD mice with established atrial fibrosis at 25 mg/kg intraperitoneally thrice per week for 3.5 weeks (therapeutic strategy).

C

Comparator

Non-targeting negative control target site blocker (NC-TSB), negative control mimic (NC-mimic), negative control inhibitor (NC-inhibitor), and control mouse genotypes (WT/Cre, WT/WT, miR31/WT, Lkb1 FL/FL).

O

Outcome

Atrial fibrosis (assessed by Masson's trichrome staining, hydroxyproline assay, and collagen-1 binding Gadolinium-DTPA dye EP3533 cardiac MRI) and atrial fibrillation (AF) burden, duration, and inducibility (assessed by surface ECG, telemetry, and transesophageal burst pacing).surrogate

Main Result

Absolute Event Rate: -30% vs 46%

p-value: p=<0.0001

Selective disruption of the miR-31-5p-calcitonin receptor interaction using a locked nucleic acid target site blocker restores calcitonin receptor expression, reverses established atrial fibrosis, and reduces atrial fibrillation burden in mice, identifying a novel therapeutic target for structural remodeling in atrial fibrillation.

Limitations

In vivo therapeutic efficacy was evaluated in murine models and requires validation in human clinical trials.
Relatively short (3.5 weeks) target site blocker treatment period in older mice.
Progressive suppression of endogenous calcitonin ligand in Lkb1-aKD mice may have limited the reduction in AF burden.
In vitro studies utilized supra-physiological miR-31-5p levels which may not fully reflect the complex endogenous myocardial environment.

Implication

Preclinical miR-31 blockade may regress atrial fibrosis; hypothesis-generating for human AF reversal, requiring clinical trials before adoption.

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is promoted by atrial fibrosis, a form of structural remodelling for which effective therapies are lacking. MicroRNA-31-5p (miR-31-5p), an aging-associated, atrial-enriched microRNA, has been linked to AF, but its role in atrial fibrosis is unknown. Here we show that atrial fibroblasts from patients with persistent AF exhibit increased miR-31-5p expression and reduced expression of the calcitonin receptor (CTR, encoded by CALCR). MiR-31-5p directly represses CTR and promotes pro-fibrotic fibroblast responses, whereas its inhibition restores CTR expression. Fibroblast-specific overexpression of miR-31 in mice reduces atrial CTR expression, increases atrial fibrosis and enhances arrhythmia susceptibility. Selective disruption of miR-31-5p-CALCR binding using a locked nucleic acid target site blocker restores atrial CTR expression, prevents fibrosis progression and reduces arrhythmia burden. In mice with established atrial remodeling, this strategy promotes fibrosis regression, identifying the miR-31-5p-CTR axis as a potential therapeutic target in AF.

Discussion

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Cite This Study

Trompf* et al. (2026) studied Atrial fibrillation and atrial fibrosis (n=136). miR-31/CTR-TSB (locked nucleic acid target site blocker) vs. Negative control target site blocker (NC-TSB) was evaluated on Reversal of established atrial fibrosis and reduction in atrial fibrillation burden in Lkb1-aKD mice (p=<0.0001). Selective blockade of miR-31-5p-CALCR interaction with miR-31/CTR-TSB reversed established atrial fibrosis by 30% (p<0.0001) and reduced AF burden by 16% (p=0.033) in mice.

synapsesocial.com/papers/6ae92596a8a6b2adf62f5fb2 https://doi.org/10.1038/s44161-026-00897-1

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Selective blockade of microRNA-31-5p−calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia burden

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Selective blockade of microRNA-31-5p−calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia burden

Figures

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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