Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia

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, 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 and Svetlana Reilly ()
Additional contact information
Lucia M. Moreira: University of Oxford, John Radcliffe Hospital
Abhijit Takawale: Research Centre, Montreal Heart Institute and University of Montreal
Mohit Hulsurkar: Baylor College of Medicine
David A. Menassa: University of Oxford, John Radcliffe Hospital
Agne Antanaviciute: University of Oxford
Satadru K. Lahiri: Baylor College of Medicine
Neelam Mehta: University of Oxford, John Radcliffe Hospital
Neil Evans: University of Oxford, John Radcliffe Hospital
Constantinos Psarros: University of Oxford, John Radcliffe Hospital
Paul Robinson: University of Oxford, John Radcliffe Hospital
Alexander J. Sparrow: University of Oxford, John Radcliffe Hospital
Marc-Antoine Gillis: McGill University
Neil Ashley: University of Oxford
Patrice Naud: McGill University
Javier Barallobre-Barreiro: King’s College London
Konstantinos Theofilatos: King’s College London
Angela Lee: University of Oxford, John Radcliffe Hospital
Mary Norris: University of Oxford, John Radcliffe Hospital
Michele V. Clarke: The University of Melbourne
Patricia K. Russell: The University of Melbourne
Barbara Casadei: University of Oxford, John Radcliffe Hospital
Shoumo Bhattacharya: University of Oxford, John Radcliffe Hospital
Jeffrey D. Zajac: The University of Melbourne
Rachel A. Davey: The University of Melbourne
Martin Sirois: McGill University
Adam Mead: University of Oxford
Alison Simmons: University of Oxford
Manuel Mayr: King’s College London
Rana Sayeed: John Radcliffe Hospital
George Krasopoulos: John Radcliffe Hospital
Charles Redwood: University of Oxford, John Radcliffe Hospital
Keith M. Channon: University of Oxford, John Radcliffe Hospital
Jean-Claude Tardif: McGill University
Xander H. T. Wehrens: Baylor College of Medicine
Stanley Nattel: Research Centre, Montreal Heart Institute and University of Montreal
Svetlana Reilly: University of Oxford, John Radcliffe Hospital

Nature, 2020, vol. 587, issue 7834, 460-465

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2890-8

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