Modeling Fibroblast–Cardiomyocyte Interactions: Unveiling the Role of Ion Currents in Action Potential Modulation

Fibrotic cardiomyopathy represents a significant pathological condition characterized by the interaction between cardiomyocytes and fibroblasts in the heart, and it currently lacks an effective cure. In vitro platforms, such as engineered heart tissue (EHT) developed through the co-culturing of cardiomyocytes and fibroblasts, are under investigation to elucidate and manipulate these cellular interactions. We present the first integration of mathematical electrophysiological models that encapsulate fibroblast-cardiomyocyte interactions with experimental EHT studies to identify and modulate the ion channels governing these dynamics. Our findings resolve a long-standing debate regarding the effect of fibroblast coupling on cardiomyocyte action potential duration (APD). We demonstrate that these seemingly contradictory outcomes are contingent upon the specific properties of the cardiomyocyte to which the fibroblast is coupled, particularly the relative magnitudes of the fast Na⁺ and transient outward K⁺ currents within the cardiomyocyte. Our results emphasize the critical importance of detailed ionic current representation in cardiomyocytes for accurately predicting the interactions between cardiomyocytes and fibroblasts in EHT. Surprisingly, complex ion channel-based models of fibroblast electrophysiology did not outperform simplified resistance-capacitance models in this analysis. Collectively, our findings highlight the promising potential of synergizing in vitro and in silico approaches to identify therapeutic targets for cardiomyopathies.