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.

All-trans-Retinal (ATR) is a photosensitizer, serving as the chromophore for depolarizing and hyperpolarizing light-sensitive ion channels and pumps (opsins), recently employed as fast optical actuators. In mammalian optogenetic applications (in brain and heart), endogenous ATR availability is not considered a limiting factor, yet it is unclear how ATR modulation may affect the response to optical stimulation. We hypothesized that exogenous ATR may improve light responsiveness of cardiac cells modified by Channelrhodopsin2 (ChR2), hence lowering the optical pacing energy. In virally-transduced (Ad-ChR2(H134R)-eYFP) light-sensitive cardiac syncytium in vitro, ATR supplements ≤2 μM improved cardiomyocyte viability and augmented ChR2 membrane expression several-fold, while >4 μM was toxic. Employing integrated optical actuation (470 nm) and optical mapping, we found that 1–2 μM ATR dramatically reduced optical pacing energy (over 30 times) to several μW/mm2, lowest values reported to date, but also caused action potential prolongation, minor changes in calcium transients and no change in conduction. Theoretical analysis helped explain ATR-caused reduction of optical excitation threshold in cardiomyocytes. We conclude that cardiomyocytes operate at non-saturating retinal levels, and carefully-dosed exogenous ATR can enhance the performance of ChR2 in cardiac cells and yield energy benefits over orders of magnitude for optogenetic stimulation.

While noteworthy progress has been made on organic solid‐state lasers with low amplified spontaneous emission (ASE) thresholds and high optical gains in blue and green colors, the same advancement has not been achieved for red laser dyes. This is mainly due to their low photoluminescence quantum yields (PLQYs) because of “energy bandgap law.” Here, a new family of solution‐processable organic semiconductor laser dyes based on a bay‐annulated indigo derivative (Cibalackrot) with deep‐red emission is reported. They exhibit excellent PLQYs and low ASE thresholds (9.6 µJ cm−2) with deep‐red emission when blended in a mixed host of 1,3‐bis(N‐carbazolyl)benzene (mCP) and 2‐hydroxyphenylbenzothiazole (HBT). In contrast to a single blend in mCP, the co‐blend films are found to significantly enhance the photostability by retaining 90% of initial ASE intensity even after continuous pumping with over 9000 pulses at a pump input energy twice that of the ASE threshold, which can be attributed to efficient cascade energy transfer from mCP to HBT and then to the Cibalackrot chromophore. Low lasing threshold of 6 µJ cm−2 is further achieved at 641 nm by using distributed feedback gratings. Transient absorption spectroscopy measurements indicate that the dye has extremely low yield of triplet excited‐state under optical excitation. The results show Cibalackrot derivatives to be a promising new family of organic deep‐red laser dyes.

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