A major public health concern in recent years has been increasing reports of adverse cardiac events, including sudden cardiac death (SCD) that have been associated with the use of non-cardiac drugs. Multiple non- cardiac drugs had to be withdrawn from the market after being linked to SCD due to abnormal heart rhythm (arrhythmia), resulting in the loss of significant developmental costs. Therefore, it is critically important tha cardiac liability of therapeutic compounds be recognized early on. Unfortunately, there is currently no reliable, high throughput screening (HTS) method to test such compounds because most safety tests are performed either in non-cardiac cells, non-human cardiac myocytes, or complex and costly animal preparations. Recent advances utilizing induced pluripotent stem cells to derive human cardiac myocytes (hCM) have revolutionized the investigation of cardiac arrhythmia mechanisms. Moreover, fluorescent indicators of cellular function provide for a wide array of electrophysiological metrics to assess arrhythmia liability. These developments provide a very unique opportunity to develop a novel HTS platform for testing drug induced arrhythmia. However, limitations associated with electrical stimulation of excitable cells significantly hamper such development. Recently, we have made it possible to use pulsed infrared (IR) light to stimulate excitable tissue. There are numerous features of IR light stimulation that are very advantageous for HTS, especially when combined with fluorescent measurements of cardiac myocyte function. Such a fully optical HTS platform does not currently exist and, thus, this proposal represents a significant innovation. However, it is unknown if IR light stimulation in hCM monolayers is robust enough for an HTS platform. Technical issues associated stimulation efficiency, interference with fluorescent measurements, spatial specificity to perform accurate measurements in small wells (for HTS capabilities) remain a question. In addition, the physiological and pathophysiological response of hCM monolayers to IR light stimulation is unknown. Our objective is to create a contactless, fully optical, HTS platform for testing drug induced arrhythmias.
The specific aims of this proposal are to: 1) Develop, optimize, and determine the robustness of IR light stimulation in hCM monolayers, with specific regard to stimulation and damage metrics, and 2) Determine the physiological response of hCM monolayers with IR light stimulation compared to electrical stimulation (gold standard) and compared to the whole heart. Our ultimate goal is to develop a new approach that is desperately needed for cardiac safety screening. This would have a significant impact on the pharmaceutical industry, FDA, and the research community.
A major public health concern in recent years has been increasing reports of adverse cardiac events, including arrhythmias and sudden cardiac death that have been associated with the use of non-cardiac drugs. To reduce the incidence of adverse events, we will develop a novel, fully optical platform that leverages recent advances in infrared light stimulation with fluorescent indicators of cellular function that is suitable for a igh throughput screening format. Our long term goal to advance the safe use of effective therapeutic drug compounds.
