Systematic review of the study of biological pacemakers through cell therapy as a possible treatment for the replacement of the function of the Sinoatrial node. Protocol
Creators: name: Magallanes Marrufo, Julia Aidee
Publisher: name: Zenodo
Year: 2021
Subjects: subject: Systematic review
subject: Protocol
subject: Biomedical Engineering
subject: FOS: Medical engineering
subject: Biological pacemakers
subject: cell therapy
subject: Sinoatrial node
subject: myocardial

description: <strong>Background</strong><br> One of the main causes of mortality in the world is heart disease, which causes 17.3 million deaths per year among men and women. In 2021, these cardiovascular diseases ranked second among the ten main causes of mortality in Mexico, presenting a rate of 23.81% of the population [1], where it is stated that ischemic heart disease is one of the major public health problems, mainly affecting elderly men [2]. This is why there is interest from various researchers in designing or improving current treatments, as well as developing new therapeutic alternatives based on bioengineering, with the aim of reducing heart disease [3].<br> In recent years, various treatment alternatives have been developed for heart disease, the pacemaker being one of them. Pacemaker devices have the main function of detecting abnormal rhythms due to certain pathologies such as bradycardia, sinus dysfunction, atrioventricular block or atrial fibrillation. Once an unusual rhythm is detected due to these diseases, it stimulates the heart through electrical impulses with sufficient intensity. so that the activation and contraction of the heart is carried out correctly [4].<br> The development of pacemakers and the evolution of cardiac electrical stimulation over the years is quite extensive. In the first decades, efforts were directed at finding an efficient treatment capable of treating atrioventricular block. late in the 30s they were mostly devoted to introducing new frequency modulation modalities by scanning the sinoatrial node [5] however, over the last 15 years it has been shown through experimental evidence that both gene-based and cells may be capable of creating biological pacemakers [6].<br> The main biological pacemaker of the heart is the sinoatrial node or NSA, which is in charge of generating an electrical impulse that travels through conduction channels allowing the atria and ventricles to contract correctly so that the pumping is carried out of blood in the heart [7]. However, there are many cellular and molecular mechanisms that allow the electrical activity of the NSA pacemaker to be carried out, the current I_f(funny current) being one of them, this is expressed in highly active cardiac regions and can be defined as a mixture of sodium-potassium channels that allow slow depolarization of pacemaker cells in the diastolic phase [8].<br> The main objective of creating biological pacemakers in recent years is to develop cells capable of generating an action potential that replace the dysfunctional pacemaker cells of the sinoatrial node, thus allowing the heart to maintain its proper rhythm. A clear example of these new methodologies is the clinical trial conducted by A. Futakuchi et al. [9] where cardiomyocytes derived from embryonic stem cells (hESC-CMs) were transplanted into primate monkeys with myocardial problems, which had successful results, improving left ventricular ejection by 10.6 ± 0.9% against 2.5 ± 0.8%. However, the challenge to develop new ways of obtaining cells for the treatment of heart disease persisted. In 2011 H. Zhang et al. [10] tested the expression of NSA pacemaker cell activity autologously in the right ventricle in adult canine models. These were monitored for 2 weeks in which they presented a rhythm of 90 ± 17 bpm and it was estimated that more than 80% of the isolated cells were viable. In addition, a sample of 18 cells was taken where it was obsearved that they presented a dependent input current If, and the hyperpolarization point was activated at -105mV and at +15mV for its deactivation.<br> In 2017, a different process was carried out to obtain adult pluripotent stem cells, where S. Chauveau et al. [11] created induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from human hair follicle keratinocytes, which were implanted into canine models of atrioventricular block. The action potentials were recorded from the concentration of the cells where approximately 25% presented a spontaneous contraction, likewise the behavior of the pacemaker current I_f was studied where it was determined that the automaticity of the cardiomyocytes depends on said current to carry out stimulation of the heart. <strong>Research Question</strong>:<br> During the last years, cell therapy has prevailed as an alternative to create new treatments for the reduction of heart diseases, for which there is a commitment to use the best suitable cell differentiation pathways that allow replacing dysfunctional cells in the sinoatrial node, paying attention to the control of electrophysiological parameters, which is why we have asked ourselves the following research question: What values of action potential and I_f current determine whether cardiomyocytes derived from embryonic or pluripotent cells fulfill the function of pacemaker cells in the sinoatrial node in preclinical models? <strong>Inclusion criteria:</strong> The record is a study about cell differentiation of induced pluripotent stem cells or embryonic stem cells. The record reports at least one result of the electrical potential or current I_f, or derived from measurements of the cell studied. The record is a preclinical trial in animals. <strong>Exclusion criteria:</strong> Records with a publication date prior to 2012 The record does not have an approval by an ethics committee. The record is a publication other than a research article, such as a systematic review, meta-analysis, editorial comment or conference proceedings. Records without full access. <strong>General objective:</strong><br> To identify which action potential and I_f current values determine whether cardiomyocytes derived from embryonic or pluripotent cells fulfill the function of pacemaker cells in the sinoatrial node in preclinical models.<br> <strong>Specific objectives:</strong> To analyze studies on the experimentation of embryonic or pluripotent stem cells for the creation of biological pacemakers. To highlight the importance of the electrophysiological properties of pacemaker cells. To identify action potential values based on depolarization and hyperpolarization of implanted cells. <strong>Justification:</strong><br> Nowadays, new ideas about the functioning of pacemakers continue to be designed, since, despite their effectiveness, these medical devices present certain deficiencies such as the risk of infections, generation of thrombi, lack in response to stimuli derived from the system nervous, as well as its limited battery life [12]. This is why today there is the challenge of designing biological pacemakers capable of carrying out cardiac stimulation through excitable cells, which present adequate electrophysiological parameters allowing the heart to maintain a normal rhythm.<br> This systematic review arises from the need to evaluate the electrophysiological properties such as: the action potential and I_f current of cardiomyocytes derived from pluripotent stem cells or embryonic stem cells in preclinical records, to finally determine in the future if they present mechanisms similar to pacemaker cells and may be capable of creating cardiac impulses that allow myocardial contraction to be carried out in the sinoatrial node. <strong>Proposed methodology:</strong> Selection of records based on the implementation of stem cells according to the following databases: Science direct, Pubmed, Web of science, NCBI. Declaration of search terms with booleans: ("Biological Pacemaker" OR Pacemaker) AND (“Stem Cell” OR “Embryonic stem cell” OR Myocyte OR “Cell Therapy”) Selection of articles according to the established inclusion criteria. Data extraction of electrophysiological properties (Action Potential and I_f Current) recorded in preclinical trials. Analysis and interpretation of the data obtained in accordance with the methodologies proposed in clinical trials. Comparison of the behavior of the extracted data against the physiological behavior of a pacemaker cell.
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