Realization of fully biological restoration of cardiac rhythm: a computational translational exploration

Abstract

Abstract 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 human ventricular virtual cardiac monolayers. For the systemic delivery group, BioICD-expressing cells were homogeneously distributed (10 random variations) over the tissue with fixed total expression percentage (14 percentages). For the local delivery group, circular areas (7 radii) were given BioICD-expressing cells randomly patterned (10 variations) in a Gaussian distribution with 3 fixed total expression percentages. For both groups, spiral waves were initiated (9 locations) and studied for the following 10 seconds for each test condition, thereby equaling 1260 and 1890 conditions, respectively. Results For systemic delivery, normal rhythm was restored in all cases for >50% BioICD expressing cells, with time till termination being 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. Local delivery, on the other hand, resulted in islands of ionic heterogeneity, causing attraction and anchoring of the spiral waves in a size and distance-dependent manner. Hence, BioICD-based self-termination was not observed in any of the investigated conditions, leaving spiral waves to persist. 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 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. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council (Starting grant 716509) to D.A. Pijnappels.