Abstract
Multiple cardiac pathologies are accompanied by loss of tissue excitability, which leads to a range of heart rhythm disorders (arrhythmias). In addition to electronic device therapy (i.e. implantable pacemakers and cardioverter/defibrillators), biological approaches have recently been explored to restore pacemaking ability and to correct conduction slowing in the heart by delivering excitatory ion channels or ion channel agonists. Using optogenetics as a tool to selectively interrogate only cells transduced to produce an exogenous excitatory ion current, we experimentally and computationally quantify the efficiency of such biological approaches in rescuing cardiac excitability as a function of the mode of application (viral gene delivery or cell delivery) and the geometry of the transduced region (focal or spatially-distributed). We demonstrate that for each configuration (delivery mode and spatial pattern), the optical energy needed to excite can be used to predict therapeutic efficiency of excitability restoration. Taken directly, these results can help guide optogenetic interventions for light-based control of cardiac excitation. More generally, our findings can help optimize gene therapy for restoration of cardiac excitability.
Highlights
Been optogenetically transformed, the ability to functionally engage only transduced cells by light allows for quantitative assessment of the optimality of the spatial distribution of the transduced cells and their functional contribution, the efficiency of the “therapy”
We present here an optogenetics-based strategy to quantify the efficiency of gene and cell therapy, linking delivery mode (GD or CD) and spatial arrangements of a transgene to functional tissue response, represented by an increase in global excitability
Transgene distributions were designed to mimic the results of physiologically-realistic delivery modalities: 1) a consolidated, localized island of expression resulting from direct intra-myocardial injection2,3,26; 2) a spatially-disperse, low-density distribution produced by low-efficiency systemic or pericardial sac delivery[27]; and 3) a spatially-uniform, high-density expression pattern resulting from high-efficiency systemic transduction[5,6]
Summary
Been optogenetically transformed, the ability to functionally engage only transduced cells by light allows for quantitative assessment of the optimality of the spatial distribution of the transduced cells and their functional contribution, the efficiency of the “therapy”. We hypothesize that ChR2 expression can be used to abstract transduction with excitatory membrane proteins for the purpose of restoring excitability; that is, the threshold irradiance to achieve global excitation in optogenetically-transformed tissue can serve as a quantitative indicator of therapeutic efficiency of gene or cell therapy across delivery modes and geometric patterns. We validate the proposed framework by demonstrating that the performance of different transgene configurations (via addition of exogenous sodium channels to tissue with impaired excitability) is correctly predicted by our optogenetics-based analysis. These findings provide insights for the rational design of future biological interventions, including in vivo optogenetic manipulations, as well as more general non-optogenetic therapies for the restoration of cardiac excitability
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