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Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia

Research output: Contribution to journalArticlepeer-review

Lucia M. Moreira, Abhijit Takawale, Mohit Hulsurkar, David A. Menassa, Agne Antanaviciute, Satadru K. Lahiri, Neelam Mehta, Neil Evans, Constantinos Psarros, Paul Robinson, Alexander J. Sparrow, Marc Antoine Gillis, Neil Ashley, Patrice Naud, Javier Barallobre-Barreiro, Konstantinos Theofilatos, Angela Lee, Mary Norris, Michele V. Clarke, Patricia K. Russell & 16 more Barbara Casadei, Shoumo Bhattacharya, Jeffrey D. Zajac, Rachel A. Davey, Martin Sirois, Adam Mead, Alison Simmons, Manuel Mayr, Rana Sayeed, George Krasopoulos, Charles Redwood, Keith M. Channon, Jean Claude Tardif, Xander H.T. Wehrens, Stanley Nattel, Svetlana Reilly

Original languageEnglish
Pages (from-to)460-465
Number of pages6
JournalNature
Volume587
Issue number7834
DOIs
Accepted/In press2020
Published19 Nov 2020

King's Authors

Abstract

Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans1. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies2. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism3, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.

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