Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis

In healthy myocardium, cardiac fibroblasts critically contribute to the extracellular matrix, ensuring an optimal environment for maintaining the myocyte syncytium integrity and myocardial function. Upon myocardial stress, such as ischemic insult or pressure overload, cardiac fibroblast proliferation increases and their activation to myofibroblast results in fibrotic infiltration favoring tissue anisotropy and arrhythmogenesis. In addition, in vitro evidence suggests a proarrhythmogenic electrotonic coupling between myofibroblasts and cardiomyocytes. However, in vivo proof-of-concept has been missing, mainly because of technical limitations.

In this manuscript, published in Science, Wang Y. and collaborators took advantage of recent advances in mouse model generation and optogenetic tools. Combining both with classic electrophysiological approaches allowed them to obtain the first functional evidence of a proarrhythmogenic coupling in the ventricles. In this study, they generated a conditional mouse line expressing an optogenetic actuator (ChR2) exclusively within resident fibroblasts (TCF21 positive). After myocardial infarction, optical stimulation of the scar tissue elicited cardiac excitation at the organ level, thus demonstrating the electrotonic coupling between fibroblasts in the scar and ventricular cardiomyocytes. Interestingly, illumination outside the scar area did not affect the uninjured myocardium. Ablation of connexins did not fully abolish the observed effect, suggesting that electrical coupling does not only occurs through gap junctions. Computer modeling indicated in addition an ephaptic coupling between both cell types. This work significantly contributes to our understanding of the role of fibroblasts in arrhythmia. Further studies are needed to translate the findings obtained in mice to patients.