Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Research Centre, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
Nature. 2020 Nov;587(7834):460-465. doi: 10.1038/s41586-020-2890-8. Epub 2020 Nov 4.
Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans. 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 therapies. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism, 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.
心房颤动是最常见的心律失常，是导致死亡率和发病率的重要因素，特别是对人类中风风险的重要因素。心房组织纤维化是心房颤动的一个核心病理生理特征，也阻碍了其治疗；其潜在的分子机制尚未得到充分理解，鉴于目前治疗方法的不足，值得进一步研究。在这里，我们发现降钙素是甲状腺产生的一种参与骨代谢的激素产物，它也由心房心肌细胞大量产生，并作为旁分泌信号，影响邻近的胶原产生成纤维细胞，以控制其增殖和细胞外基质蛋白的分泌。在小鼠中，全身性破坏降钙素受体信号会导致心房纤维化，并增加心房颤动的易感性。在肝脏激酶 B1 在心房中特异性敲除的小鼠中，心房特异性敲降降钙素会促进心房纤维化，并增加和延长自发性心房颤动发作，而心房特异性过表达降钙素则可预防心房纤维化和颤动。持续性心房颤动患者的心肌降钙素水平比正常心律的对照组个体低 6 倍，并且纤维母细胞膜上的降钙素受体丢失。尽管对人类心房成纤维细胞进行转录组分析后发现，降钙素暴露后几乎没有变化，但蛋白质组分析显示细胞外基质蛋白和与纤维生成、感染和免疫反应以及转录调控相关的途径发生广泛改变。因此，恢复心肌降钙素信号中断的策略可能为心房颤动患者提供治疗途径。
