Researchers in Chao Zhou’s lab used cardiac optogenetics to study arrhythmia and its impact on the brain noninvasively. Using highly sensitive imaging in a mouse model, they found that arrhythmia in a mouse heart alters oxygen concentration in the brain during and after arrhythmia.
Image Credit: Zhou lab using Manus AI
Scientific Frontline: Extended "At a Glance" Summary: Cardiac Optogenetics and Arrhythmia
The Core Concept: Cardiac optogenetics is an advanced technique combining genetic engineering and light to noninvasively induce and study arrhythmias. Researchers utilize this method to observe how irregular heartbeats disrupt hemodynamics and alter oxygen concentration in the brain.
Key Distinction/Mechanism: Unlike traditional heart pacing methods that require invasive electrical leads or high-power stimulation, this approach uses red light applied broadly to the skin to activate light-sensitive ion channels (opsins) in cardiac cells. This safely and temporarily alters the pacing of the heartbeat to create on-demand arrhythmias without risking tissue damage.
Major Frameworks/Components:
- Opsin Engineering: The genetic modification of cardiomyocytes and neurons to express light-sensitive ion channels.
- Red Light Stimulation: The utilization of longer light wavelengths that penetrate deeper into tissue to trigger cardiac responses safely.
- Hemodynamic Monitoring: The use of highly sensitive imaging to measure systemic disruptions, specifically tracking decreases in oxygenated hemoglobin and increases in deoxygenated hemoglobin in the brain.
Branch of Science: Biomedical Engineering, Cardiology, Genetics, and Neuroscience.
Future Application: The methodology can be extended to other cardiac optogenetic models for translational medicine, and combined with other measurement techniques to provide a broader perspective on how arrhythmia-induced blood flow changes impact various highly perfused organs.
Why It Matters: By providing a highly targeted, wire-free tool to control heart rhythms, this research allows scientists to accurately track short-timescale disruptions to blood and oxygen flow, offering critical insights into the mechanisms linking irregular heartbeats to heightened risks of stroke and cognitive decline.
An irregular heartbeat, or arrhythmia, leads to the inefficient pumping of blood by the heart, which then prevents blood and oxygen from getting to the body’s other organs. When blood and oxygen flow poorly to the brain, the risk of stroke and cognitive decline increases.
A team of researchers based at Washington University in St. Louis used cardiac optogenetics to study arrhythmia and its impact on the brain noninvasively. Using highly sensitive imaging in a mouse (Mus musculus) model, they found that arrhythmia in a mouse heart alters oxygen concentration in the brain during and after arrhythmia.
Chao Zhou, a professor of biomedical engineering in the McKelvey School of Engineering, Abby Matt, a graduate student in his lab, and Marcello Magri Amaral, a former visiting researcher from Universidade Brasil, led a team using optogenetics—the combination of genetic engineering and light to control neurons or cardiac cells—to produce this stimulation in mice genetically modified with opsins, or light-sensitive ion channels that turn neurons or cardiomyocytes on and off. By shining a red light over a broad surface area of the skin over the mouse heart, which is about the size of a human pinky fingernail, they could safely change the pacing of the heartbeat up to 175% of the resting heart rate to create arrhythmia on demand. After the stimulation was removed, the heart rate returned to its initial resting baseline.
Matt said the challenge to this research was that mice have naturally fast heart rates. In their experiments, they used several frequencies ranging from a below-resting heart rate of 6 Hz to 14 Hz, a rate well above the resting heart rate, while recording the electrocardiogram signal during rest, light pacing, and recovery periods. The largest changes in the brain took place at 6 Hz and 14 Hz. Across the range of pacing frequencies, changes in blood and oxygen concentration were in proportion to the discrepancy between the resting heart rate and the pacing frequency.
“With this model, we showed that we reduced the cardiac output, which is the volume of blood per second coming out from the heart, and then from this, we extended it to study a very highly perfused organ, the brain,” Matt said. “In collaboration with Dr. Adam Bauer's group [associate professor of radiology at WashU Medicine Mallinckrodt Institute of Radiology (MIR) and of biomedical engineering in McKelvey Engineering], we showed that on a global scale, we can disrupt hemodynamics, meaning we can decrease the concentration of oxygenated hemoglobin and increase the amount of deoxygenated hemoglobin in the brain. So, starting from a heart scale, we're able to override rhythm. And we can use that to study highly perfused organs and how these are disrupted on a very short timescale.”
Optogenetics was started at Stanford University in 2005, focusing primarily on neuroscience. Zhou first published his work in cardiac optogenetics in Science Advances in 2015 while at Lehigh University, where he used the method to change the heartbeat in the fruit fly (Drosophila melanogaster). His team later made additional fruit fly models that are responsive to different colors of light—red stops the heartbeat, and blue enhances the heartbeat.
“Red light opsins respond to light of longer wavelengths that penetrate deeper in tissue,” Zhou said.
Traditional methods of heart pacing are invasive and technically complex, requiring the direct implantation of LED sources on the heart surface or high power, which risks burning the skin.
“Our advantage with using light is that it's noninvasive and doesn’t require a wire or an electrical lead to do pacing,” Matt said. “Instead, the effect is only confined to where our light-sensitive proteins are expressed, so cardiac optogenetics is more targeted and gives us more control.”
Future work may combine optical intrinsic signal imaging with other methods that measure blood flow and oxygen saturation to give a wider perspective of how arrhythmia-induced blood flow changes affect the brain and other organs. While the team showed the method is effective in mice, they state it could be extended to other cardiac optogenetic models that may have greater potential for translational medicine.
Funding: Support for this research was provided by Washington University in St. Louis; the National Institutes of Health (R01-EB025209, R21-EB032684, R01-HL156265, R01NS10287005, R01NS12632601, and RF1AG07950301); the National Science Foundation Graduate Research Fellowship Program (GRFP); and the American Heart Association (25PRE1365124).
Published in journal: Science Advances
Title: Noninvasive optogenetic induction of cardiac arrhythmias alters systemic hemodynamics in mice
Authors: Marcello Magri Amaral, Abigail Matt, Kaelyn H. Schloss, Fei Wang, Elena Gracheva, Yuxuan Wang, Hongwu Liang, Annie Bice, Jimin Ding, Attila Kovacs, Carla Weinheimer, Abhinav Diwan, Jianmin Cui, Stacey L. Rentschler, Jeanne Nerbonne, Christian W. Zemlin, Adam Q. Bauer, and Chao Zhou
Source/Credit: McKelvey School of Engineering | Beth Miller
Edited by: Scientific Frontline
Reference Number: eng060426_01
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