An innovative model is expected to advance the study of heart rhythm disorders by enabling both the study of the underlying mechanisms of such disorders and laboratory testing of the effects drugs have on them. Based on a cardiac tissue developed from human induced pluripotent stem cells, the model developed by Professor Lior Gepstein, Director of the Division of Cardiology at the Rambam Health Care Campus and a faculty member at the Technion’s Rappaport Faculty of Medicine, was described in Stem Cell Reports.

Heart rate disturbances (arrhythmias) are a family of life-threatening heart disorders. Arrhythmias arise from electrical or structural abnormalities of the heart muscle and are impacted by both genetic and environmental factors. Drugs are one of these environmental factors, and, in fact, some approved drugs have been withdrawn from the commercial market after being found to cause dangerous arrhythmias.

Current treatment of arrhythmias combines drugs, ablation of the defective tissue and implantation of electrical devices like a pacemaker and defibrillator. Innovative research models, such as the one developed by Prof. Gepstein, are necessary to develop more effective and less invasive arrhythmia treatments. The model he and his team developed mimics clinical conditions of heart rate disturbances in human heart tissue.

Prof. Gepstein’s lab was one of the first in the world to pioneer the development of human cardiac cells from embryonic and induced pluripotent stem cells. Induced pluripotent stem cells are generated by reprogramming adult cells taken from a patient (e.g., from the skin or blood) using a unique procedure that turns them into a specialized form of stem cells, capable of becoming any type of cell in the body. These unique stem cells are provided, in the Gepstein lab, with the appropriate signaling factors to convert them into beating heart cells. Previous works from his laboratory and others have demonstrated the broad applicability of such cardiac cells for the field of regenerative medicine — for myocardial repair and to treat cardiac insufficiency following a heart attack and for the generation of a biological pacemaker as an alternative to electrical pacemakers. Induced pluripotent stem cells may also serve as unique patient-specific models for the study of genetic diseases as well as a platform to develop and test drugs.

As in Prof. Gepstein’s earlier models, the cardiac cells comprising the present tissue rely on hiPSC technology (human induced pluripotent stem cells). This technology was developed by the 2012 Nobel Laureate in Medicine Professor Shinya Yamanaka of Japan. The technology has since been advanced thanks to the work of many researchers (including Professor Gepstein).

Prof. Gepstein’s previous works demonstrated the feasibility of generating cardiac cells from induced pluripotent stem cells collected from patients with a genetic-based cause of arrhythmias, and to demonstrate that the obtained cardiac cells, as in the patient’s heart, develop arrhythmias on a single-cell level. In the new study, his students Naim Shaheen and Assad Shiti, who conducted the experiments together with the lab staff, successfully generated arrhythmias on a tissue level. “This is a significant step,” says Prof. Gepstein, “as most arrhythmias in patients (e.g., ventricular and atrial arrhythmias) cannot develop on a single-cell level, rather on a tissue-level.”

The tissue developed by the Technion researchers, contains millions of cardiac cells and will enable characterization of the mechanisms underlying the development of arrhythmias, as well as the effects of various treatments on these disturbances.

“The tissue we developed,” said Prof. Gepstein, “is a two-dimensional sheet, but we hope to develop a 3D tissue in the future. The cardiac cell-sheet we developed spontaneously beats, as we have noted in models we’ve developed in the past, but here, we were able to induce clinically-relevant rotary (or spiral-wave) arrhythmias, which look much like a hurricane. This allows us to assess and to provide new insights into the mechanisms underlying cardiac arrhythmias and to evaluate effects of any treatment.”

The present work involved a number of stages: (1) the differentiation process, effective formation of human cardiac cells from induced stem cells (90% efficiency); (2) formation of a two-dimensional, uniform, electrically active tissue from these cells; (3) induction (formation) of arrhythmias; and (4) precise monitoring of the electrical activity throughout the tissue. This monitoring is based on combination of a sensitive and high-speed camera and a fluorescent biological sensor that reports on any changes in the electrical activity (voltage) of the tissue.

The result, as said, was an innovative research model that enables evaluation of the effects of different treatments — electrical treatment, pharmaceutical treatment, genetic treatment, etc. In addition, the model tissues are genetically identical to the tissues of the patient from whom the adult cells were collected. Therefore, the experiment reflects the true heart tissue function of that particular patients.

“In this work, we assessed the various mechanisms responsible for formation of arrhythmias, which, for example, shed light on mechanisms in which different drugs may cause side effects, including complex arrhythmias, as well as assess possible treatments for these disturbances,” said Prof. Gepstein. “This approach will enable drug companies to screen drugs at very early stages of development — which will avoid investment in drugs that will cause dangerous side effects, and thereby, will improve the safety of marketed drugs.”

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