The treatment of arrhythmias today combines drug treatment, cauterization of the center of the arrhythmia and the implantation of electrical devices such as a pacemaker and an implanted defibrillator. To develop more effective and less invasive treatments for arrhythmias, innovative research models are needed. Such is the model developed by Prof. Gepstein - a model of arrhythmias in human heart tissue that simulates the clinical situation
An innovative model is expected to advance the study of heart disorders and allow the laboratory to test the effect of drugs on these disorders. The model developed by Prof. Lior Gepstein, director of the cardiology department at the Rambam Medical College and a faculty member at the Rappaport Faculty of Medicine, was recently published in the journal Stem Cell Reports.
Arrhythmia is a family of life-threatening heart disorders. Arrhythmias result from a disruption in the electrical or structural function of the heart muscle and are influenced by both genetic and environmental factors. Medicines are one such environmental factor and indeed, certain drugs that were already approved were withdrawn after they were found to cause dangerous arrhythmias.
The treatment of arrhythmias today combines drug treatment, cauterization of the center of the arrhythmia and the implantation of electrical devices such as a pacemaker and an implanted defibrillator. To develop more effective and less invasive treatments for arrhythmias, innovative research models are needed. Such is the model developed by Prof. Gepstein - a model of arrhythmias in human heart tissue that simulates the clinical situation.
Prof. Gepstein's laboratory was one of the pioneers in the world in the production of human heart cells from a source of embryonic stem cells and induced stem cells. Induced stem cells are cells taken from the patient (for example from the skin), have undergone a laboratory process that turns them into unique stem cells - heart cells, bone cells, etc. Prof. Gepstein's research demonstrated the applicability of heart cells produced in this way for a variety of purposes, including regenerative medicine - restoring heart tissue as a treatment for heart failure and creating a biological pacemaker as an alternative to electrical pacemakers. Induced stem cells may also be used as unique models for the study of genetic diseases and as a platform for drug development and testing.
As in previous models developed by Prof. Gepstein, the heart cells that make up the current tissue are also based on the use of hiPSC technology (induced pluripotent stem cells). The development of this technology earned the Japanese Prof. Shinya Yamanaka the Nobel Prize in Medicine for 2012. Since then, hiPSC technology has been perfected thanks to the work of many researchers, including Prof. Gepstein.
In the hiPSC process, mature cells such as skin cells or blood cells are taken from the patient, undergo reprogramming in a sort of "cellular time tunnel" and are returned to the state of progenitor cells that resemble a fertilized egg (or embryonic stem cells). Later, the stem cells that are infused back into the desired tissue are sorted - the heart muscle, in this case. The tissues produced by this method have a significant advantage in the context of transplantation: they are not rejected by the patient's immune system since they originate from the patient's own cells (and not from the cells of a donor).
Previous works by Prof. Gepstein demonstrated the ability to create heart cells from a source of induced stem cells from patients with arrhythmias on a genetic background and to demonstrate that the resulting heart cells, similar to the patient's heart, develop arrhythmias at the single cell level. The students Naim Shahin and Asad Shiti, who conducted the experiment under the guidance of Prof. Gepstein together with the laboratory team, have now succeeded in creating arrhythmias at the tissue level. According to Prof. Gepstein "this is a significant step, since most of the arrhythmias in patients (such as atrial fibrillation or ventricular arrhythmias) cannot develop at the individual cell level but only at the tissue level."
The tissue that the Technion researchers developed in the laboratory contains millions of heart cells, and it will make it possible to test in the laboratory the mechanisms underlying the development of cardiac arrhythmias, as well as the effects of various treatments on these disorders.
According to Prof. Gepstein, "The embroidery we developed here is a two-dimensional sheet, but we hope that in the near future we will also develop a three-dimensional embroidery. The sheet we have developed begins to beat spontaneously, as we have seen in previous models we have developed, but here we create an initiated rhythm disturbance in it in the form of a rotor (or spiral wave), reminiscent of a hurricane. This way we can test the effects of any treatment on her."
Video 1 – Dynamic mapping of an arrhythmia in the form of a spiral wave. The intervention taken by the researchers (defibrillation, i.e. an electric shock) corrects the disorder and returns the heart to normal function
Video 2 – Again, spiral wave arrhythmia correction. Another type of intervention (fast electrical pacing) alleviates the disturbance and finally eliminates it completely
Video 3 - Demonstration of a dangerous side effect of a drug. The drug dofetilide, which is intended to treat arrhythmias, actually develops a life-threatening arrhythmia here. The disturbance starts after the second beat
The current research combines three components: a directed differentiation process of the induced stem cells to create human heart cells with high efficiency (creating tens of millions of heart cells with an efficiency of over 90%); Creating a uniform two-dimensional tissue, electrically active, from these cells; Soaking (creation) of the arrhythmia; and precise monitoring of the electrical activity throughout the tissue. This monitoring is based on the combined use of a sensitive and fast camera and a biological fluorescent sensor that reports tension changes in the tissue.
The result, as mentioned, is an innovative research model that makes it possible to test the effect of various treatments - electrical therapy, drug therapy, genetic therapy, and more. Furthermore, the model tissues are identical in their genetic properties to the patient's tissues from which the mature cells were taken at the beginning of the process, so the experiment reflects the function of the patient's real heart tissue. According to Prof. Gepstein, "In the current work we examined different mechanisms responsible for creating heart arrhythmias. Thus, for example, we were able to shed light on the mechanisms by which various drugs may cause side effects, including complex arrhythmias, as well as examine possible treatments for these disorders. This approach will allow pharmaceutical companies to scan drugs at a very early stage of the development process - a possibility that will prevent investment in the development of drugs with dangerous side effects and will improve the safety of drugs entering the market."
Prof. Lior Gepstein is a faculty member at the Rappaport Faculty of Medicine and since 2015 has been the head of the cardiology department at the Rambam Medical College. After completing his medical studies at the Faculty of Medicine at the Technion, he went on to obtain a Doctor of Science degree. As part of this, he developed a new system for electrical mapping of the heart - a system that to this day provides the best solution for the treatment of heart rhythm disorders through electrical cauterization. After specializing in internal medicine and cardiology at the Rambam Medical College, he went on to do a post-doctorate at the University of California Hospital in San Francisco. From there he returned to the Faculty of Medicine at the Technion, this time as a faculty member and head of the laboratory for electrophysiological research and cardiac function reconstruction. His research focuses on the electrophysiology of the heart, the study of genetic diseases of the heart and the use of stem cell technologies, tissue engineering, and genetic engineering in the development of innovative treatment methods for heart diseases. He won many important awards including the Zeips Award from the American Cardiology Association and the Outstanding Researcher Award from the European Cardiology Association and was elected a member of the Young National Academy of Sciences.
For the article in Stem Cell Reports
More of the topic in Hayadan:
- Israeli-Canadian development: a new biological pacemaker
- The illuminated heart - researchers have demonstrated the possibility of timing and resynchronizing the disrupted heart rhythm using a beam of light as a replacement for an electric pacemaker
- The Technion researchers for the first time turned patients' skin cells into heart muscle cells in order to repair a damaged heart
