Computational translational exploration of fully biological restoration of cardiac rhythm via ion channel gene therapy

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study was supported by the European Research Council (Starting grant 716509) to D.A. Pijnappels. Background Recently it was demonstrated how the heart itself could be enabled to quickly restore its rhythm by realizing a biologically-integrated cardiac defibrillator (BioICD) through modification and subsequent expression of ion channels in cardiomyocytes [1]. By incorporating these frequency-dependent depolarizing ion channels, abnormal cardiac rhythm could be rapidly detected and terminated to restore sinus rhythm in a fully biological and shock-free manner. However, from a translational point of view, it remains unclear how such rhythm restoration can be realized via ion channel gene therapy. Purpose To explore and understand the importance of the distribution and number of BioICD-expressing cardiomyocytes in realizing fully biological restoration of cardiac rhythm. Methods To this purpose, two different realistic gene therapy configurations, i.e. those corresponding to systemic and local transgene delivery, were tested in a digital twin of human ventricular cardiac monolayers. For the systemic delivery group, BioICD-expressing cells were homogeneously distributed over the tissue with fixed total expression percentage. For the local delivery group, circular areas were given BioICD-expressing cells, randomly patterned in a Gaussian distribution. In both groups spiral waves were initiated and subsequently studied for 10 seconds. For systemic delivery, an additional set of simulations was performed for an adapted BioICD ion channel with a slower opening and faster closing rate. Results Upon comparing both gene therapy methods, the systemic approach showed a gradually increasing arrhythmia termination chance with increasing BioICD-expression percentage, while local delivery never resulted in termination. Instead, local delivery resulted in islands of ionic heterogeneity, causing attraction and anchoring of the spiral waves in a size and distance-dependent manner. Building on the results of the systemic approach, different ion channel parameters were tried, which resulted in normal rhythm being restored in all cases for >50% BioICD expressing cells. Time till termination was inversely related to the percentage, resulting in only 4.3s and 2.5s for 50% and 100%, respectively. Regarding termination, it was observed that conduction blocks appeared throughout the tissue and subsequently connected to force arrhythmic waves to terminate, while this process remained incomplete in the <50% groups. Conclusion This study reveals that wide-spread distribution of BioICD-expressing cardiomyocytes is required for the realization of fully biological self-restoration of cardiac rhythm, of which the efficiency is ion-channel-dynamics- and dosage-dependent. Local expression, however, results in stabilization of spiral wave activity. Further exploration of this emerging concept of biological cardioversion may not only expand our understanding of cardiac arrhythmias, but also pave the way to breakthrough advances in arrhythmia management.