Fibroblast Density is a Risk Factor for Drug-induced Arrhythmias

Abstract A recent study by Kawatou et al . has shown that the local heterogeneity of ion channel conductance is a critical substrate for focal or reentrant arrhythmias. However, the role of fibroblasts with repolarization heterogeneity in the initiation and maintenance of arrhythmias remains unknown. In this study, we investigated how diffuse fibrosis contributes to the formation of focal and reentrant arrhythmias under drug-induced heterogeneity using physiologically detailed mathematical models of the human heart. To simulate drug-induced heterogeneity, we varied the maximum conductance of transmembrane potassium and calcium currents, leading to heterogeneity in action potential duration (APD). Then, we assessed the effects of different fibrosis densities (FD) on the occurrence of premature ventricular complexes (PVCs). Fibroblasts were randomly and evenly inserted into the tissue, and various FD levels ranging from 0 to 35% were examined. We found a biphasic relationship between FD and drug-induced PVCs. Within a certain range of FD, FD positively correlated with PVC susceptibility. However, excessively high fibrosis levels were associated with reduced susceptibility to PVCs. In addition, the self-sustainability of arrhythmias exhibited a positive correlation with FD. This study demonstrates the interplay between the diffuse fibrosis and the drug-induced heterogeneity of APD in the genesis of ventricular arrhythmias. Author summary Sudden cardiac death remains a leading cause of death worldwide. Understanding the mechanisms underlying arrhythmia and its precursors is critical for the development of effective therapies and drugs. Repolarization heterogeneity plays a crucial role in both the initiation and maintenance of arrhythmias. Fibroblasts constitute a vital component of cardiac structure, originating from the remodeling of ventricular wall cells or the transformation of injured myocardial cells. Fibroblasts are known to couple with and alter the electrical properties of myocardial cells. However, our understanding of the role of fibroblasts in the development of arrhythmia remains limited. In this study, we employed a physiologically detailed mathematical model of cardiac tissue to investigate the roles of drug-induced heterogeneity and diffuse fibrosis in the initiation and maintenance of arrhythmias. We used 2D and 3D computational models to simulate various levels of drug-induced heterogeneity conditions with normal to pathological levels of fibroblast density (FD). We found that within a certain range of FD, fibroblasts promote PVCs under drug-induced heterogeneity. However, if FD exceeds 30%, the occurrence of PVCs decreases (biphasic relationship). On the other hand, the self-sustainability of VF (ventricular fibrillation) consistently increases with FD. This study implies that fibroblasts in cardiac tissue may play different roles in the initiation and maintenance of arrhythmia.