It remains unclear to what extent interactions between different types of heart cells influence normal heart rhythm and can trigger life-threatening arrhythmias. A new measurement method developed at the University of Bern combines for the first time the optical and electrical recording of cardiac ventricular activation which, in conjunction with optogenetics, will provide comprehensive answers to these questions.
The heart’s normal function relies on a pacemaker that generates electrical impulses (“action potentials”) that travel rapidly throughout the heart muscle where they trigger the contraction leading to the heartbeat. In the past, it was assumed that the propagation of action potentials was controlled exclusively by heart muscle cells. However, recent findings suggest that other cell types in the heart, such as connective tissue cells (“fibroblasts”) and macrophages, may also affect the propagation of the action potential and, thus, play an important role in determination of cardiac function. These results were obtained using a new method called optogenetics which uses light to monitor the electrical behavior of defined cell types such as fibroblasts, thus making it possible to assess their involvement in the process of cardiac activation.
To enable comprehensive optogenetic studies with hearts, researchers led by Stephan Rohr from the Department of Physiology at the University of Bern have developed a new experimental system called the “Panoramic Opto-Electric Stimulation and Measurement System (POEMS)”. The POEMS system is the first to allow simultaneous optical and electrical measurements and stimulation spanning the entire ventricular surface of mouse hearts. The results obtained with the system should open new perspectives in the study of normal cardiac function and the investigation of the mechanisms causing cardiac arrhythmias. The study describing the system was published in the journal Nature Communication.
Are connective tissue cells the cause of heart arrhythmias?
Cell culture experiments have already shown that cardiac muscle cells communicate with activated cardiac fibroblasts by means of electrical signals and that this interaction leads to cardiac arrhythmias. However, it is still not known whether this mechanism is also operational in intact hearts because conventional electrophysiological methods are not suitable to study this question.
The lack of suitable experimental approaches is today filled by optogenetics, which makes it possible to directly question the presence and the functional consequences of cellular interactions between muscle and non-muscle cells of the heart. The presence of direct electrical communication can be assessed by allowing specific cell types such as fibroblasts to express so-called “optogenetic voltage reporters”. On the other hand, the functional consequences of such a coupling can be studied by expressing “optogenetic voltage actuators” in these cells and by observing the effects of light activation on the electrophysiology of the whole heart. Currently, performing optogenetic experiments is complex and requires a lot of equipment. In addition, it is not possible to combine electrode-based experiments with optical studies, which greatly limits the range of possible experiments.
POEMS system creates new possibilities
“With our POEMS system, all these drawbacks have been overcome, because the entire surface of the ventricles is covered with a combination of optical and electrical measurement and stimulation sites, which allows free combinations of the two modalities ”, explains Professor Stephan Rohr, author principal of the study The Heart of the New POEMS The system consists of a cup the size of a mouse heart, its internal surface lined with 294 optical fibers and 64 electrodes. All optical fibers and electrodes can be individually configured as measurement and stimulation sites, allowing precise tailoring of individual experiments to the specific requirements of the optogenetic reporter and actuator used in a given experiment.
Simultaneous optical and electrical panoramic measurements of cardiac activation using stimulated mouse hearts expressing optogenetic stress reporters demonstrated that the POEMS The system provides, whatever the measurement modality, congruent and very precise measurements of the propagation of the ventricular action potential with differences between optically and electrically determined activation times less than one millisecond. Beyond that, the POEMS The system was designed with the aim of allowing simple and efficient experimentation. “With our ‘drop & go’ approach, experiments can be started immediately after the isolated mouse has been placed in the measurement container,” says study co-author Michael Rieger, who developed the system with others. members of the physiology department. The gentle treatment of hearts increasing the success rate of the experiments as well as the increased informative content provided by the POEMS This system is also relevant with regard to the principles of 3Rs (replace, reduce, refine) because the number of animal experiments required to answer a given question can be considerably reduced.
“With the POEMS system in place, we are currently investigating the burning question of whether cardiac arrhythmias can also be caused by non-muscle cells such as activated connective tissue cells, ”says Stephan Rohr. If this were to be the case, it would open up new avenues for the treatment of cardiac arrhythmias as different cell types of muscle cells may become targets for antiarrhythmic therapies.
The study was supported by the Swiss National Science Foundation SNSF.
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