Selective blockade of microRNA-31-5p/calcitonin receptor interaction reverses established atrial fibrosis and atrial arrhythmia substrate.

Atrial fibrillation (AF), the commonest cardiac arrhythmia, is a major contributor to mortality and morbidity. Atrial tissue fibrosis, a hallmark of structural remodelling in AF, is currently incurable and significantly hinders AF-treatment. MicroRNA(miR)-31 is linked to ageing (a key risk factor for AF). Here, we show that AF-patients are characterised by upregulation of miR-31-5p in atrial cardiofibroblasts that negatively regulates the calcitonin receptor (CTR), thereby promoting atrial fibrogenesis and arrhythmia. Specific blockade of miR-31-5p/CTR-mRNA binding with LNA-miRNA-Target-Site-Blocker selectively increases atrial CTR expression and reverses advanced atrial fibrosis and arrhythmogenesis in vivo. These findings suggest a key role for miR-31-5p/CTR binding in promoting atrial fibrosis and arrhythmogenesis, and represents a first example of an RNA-based therapeutic capable of reversing established fibrosis that forms an AF substrate.