Upon damage, the cardiac tissue is replaced by a fibrotic scar. The cardiac scar has long been considered a dead fibrotic tissue, acting as a barrier to normal electrical propagation in the heart. Studies in the past decade have shown that the scar is embedded with non-excitable cells even at late stages of remodeling, and these cells can electrically couple with cardiomyocytes. However, the in vivo physiological relevance of this coupling between non-excitable fibroblasts in the scar and cardiomyocytes was unclear.
In a recent study, Wang et al. provide evidence that depolarization of cardiac fibroblasts in scar tissue can directly drive cardiac excitability. The authors genetically engineered a mouse in which cardiac fibroblasts, buy not myocytes, expressed the blue light-sensitive optogenetic cationic channel channelrhodopsin-2 (ChR2) under the control of Tcf21 promoter. In vivo and ex vivo analyses showed that upon optical stimulation of the scar tissue, heart rate increased in exact concordance with the frequency of stimulation. The regular sinus rhythm was replaced by a ventricular rhythm, which indicates that fibroblast depolarization in these conditions was sufficient to affect organ-wide excitation both in the acute (10 days) and chronic (~80 days) phases of repair after myocardial infarction. A subset of hearts did not return to normal sinus rhythm after cessation of the optical stimulation, suggesting that fibroblast depolarization in the scar tissue can lead to sustained arrhythmias in vivo.
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