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Selective blockade of microRNA-31-5p−calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia burden
Jasha Trompf*Kathryn W. Aguilar‐AgonMohit HulsurkarLucia M. MoreiraChi Him Kendrick YiuAaron JohnstonSatadru K. LahiriShuai ZhaoPaul D. RobinsonRoddy HiramMozhdeh MehdizadehLorena Perez CarrilloRana SayeedGeorge KrasopoulosVivek SrivastavaNicholas WalcotShakil FaridAntonios KourliourosPriya SastryDavid A. MenassaBenjamin DaviesRita A. SchackRobia G. PautlerKeith M. ChannonCraig A. LygateStanley NattelXander H.T. WehrensSvetlana Reilly
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Key result
miR-31-5p target site blocker reverses established atrial fibrosis by ~30% in mice.
- P<0.0001
Why the study?
Effective therapies for atrial fibrosis in AF are lacking, and although miR-31-5p has been linked to AF, its specific role in atrial fibrosis remained unknown.
Does selective blockade of the miR-31-5p–calcitonin receptor interaction using a locked nucleic acid target site blocker reverse established atrial fibrosis and reduce atrial fibrillation burden in preclinical mouse models of atrial fibrillation and human atrial fibroblasts?
Key Points
- To investigate whether microRNA-31-5p regulates calcitonin receptor expression in atrial fibroblasts and whether disrupting this interaction can reverse atrial fibrosis and arrhythmia burden.
- Examined human atrial cardiofibroblasts from the right and left atrial appendages of patients with persistent atrial fibrillation versus sinus rhythm controls.
- Performed dual-luciferase reporter assays in HEK293 cells and transfected human atrial cardiofibroblasts with miR-31-5p mimics or inhibitors.
- Assessed cardiac remodeling in mice with fibroblast-specific miR-31 overexpression and evaluated the effects of a locked nucleic acid target site blocker that disrupts miR-31-5p–CALCR binding.
- Atrial cardiofibroblasts from patients with persistent atrial fibrillation showed 2.7-fold increased miR-31-5p expression in the right atrial appendage (P=0.0038) and 2.5-fold in the left (P=0.0080), which negatively correlated with CALCR expression (RAA: P=0.0299; LAA: P=0.0495).
- In human atrial cardiofibroblasts, miR-31-5p mimic halved calcitonin receptor mRNA (P=0.0028) and protein (P=0.0312), whereas miR-31-5p inhibition increased calcitonin receptor mRNA by approximately 30% (P=0.0183) and nearly doubled calcitonin receptor protein (P=0.0112).
- Disrupting the miR-31-5p–CALCR interaction with a locked nucleic acid target site blocker restored atrial calcitonin receptor expression, prevented fibrosis progression, promoted fibrosis regression, and reduced arrhythmia burden in mice.
Structured PICO
Does selective blockade of the miR-31-5p–calcitonin receptor interaction using a locked nucleic acid target site blocker reverse established atrial fibrosis and reduce atrial fibrillation burden in preclinical mouse models of atrial fibrillation and human atrial fibroblasts?
P
Population
Human atrial cardiofibroblasts from patients with persistent AF or sinus rhythm controls, alongside transgenic (miR-31/Cre) and spontaneous AF (Lkb1-aKD) mouse models evaluated over 3 to 4 weeks of target site blocker treatment.
I
Intervention
Selective blockade of miR-31-5p–Calcr interaction using locked nucleic acid target site blocker (miRCURY LNA miRNA Power Target Site Blocker, miR-31/CTR-TSB), administered in vivo at 25 mg/kg intraperitoneally three times per week for 3 weeks (in 20.5-week-old Lkb1-aKD mice) or for 4 weeks (in 8-week-old Lkb1-aKD mice); also in vitro transfection of hACFs with miR-31-5p mimic, miR-31-5p inhibitor, or miR-31/CTR-TSB.
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, miR-31/WT, Lkb1fl/fl).
O
Outcome
Atrial fibrosis (assessed via Masson's trichrome staining and collagen-1-binding gadolinium-DTPA dye EP3533 MRI) and atrial fibrillation burden and duration (assessed via electrocardiogram) in Lkb1-aKD mice after 3 to 4 weeks of treatment.surrogate
Main Result
p-value: p=<0.0001
Selective blockade of the miR-31-5p–calcitonin receptor interaction restores calcitonin receptor expression, reverses established atrial fibrosis, and reduces atrial arrhythmia burden in vivo, identifying a novel therapeutic target for persistent atrial fibrillation.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Atrial fibrosis is a major unmet clinical problem in atrial fibrillation, and currently we have no therapies that directly target the scarring process itself. Our findings identify a promising therapeutic pathway and suggest that targeted interventions may offer a new strategy for preventing or reversing the structural remodeling that underlies disease progression.”
“We have worked on this line of research for some time and anticipated the outcomes; however, we were surprised to see this treatment led to a reversal of some of the damage. More work is needed to understand how this treatment would work in humans, but our findings suggest that targeting this molecular interaction will help prevent further scarring and reduce tissue damage.”
Implication
Reverses established atrial fibrosis in mice; hypothesis-generating for miR-31-5p blockade in human AF pending prospective validation.
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 Persistent atrial fibrillation and atrial fibrosis. miRCURY LNA miRNA Power Target Site Blocker (miR-31/CTR-TSB) vs. Negative control target site blocker (NC-TSB) was evaluated on Reversal of established atrial fibrosis and reduction in atrial fibrillation burden in 20.5-week-old Lkb1-aKD mice (p=<0.0001). Selective blockade of miR-31-5p-Calcr binding 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 with spontaneous AF.
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