Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis
Yijie Wang, Qihao Li, Bo Tao, Marina Angelini, Sivakumar Ramadoss, Baiming Sun, Ping Wang, Yuliya Krokhaleva, Feiyang Ma, Yiqian Gu, Alejandro Espinoza, Ken Yamauchi, Matteo Pellegrini, Bennett G. Novitch, Riccardo Olcese, Zhilin Qu, Zhen Song, Arjun Deb
Abstract
After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.