State-of-the-Art Differentiation Protocols for Patient-Derived Cardiac Pacemaker Cells.

Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes raise the possibility of generating pluripotent stem cells from a wide range of human diseases. In the cardiology field, hiPSCs have been used to address the mechanistic bases of primary arrhythmias and in investigations of drug safety. These studies have been focused primarily on atrial and ventricular pathologies. Consequently, many hiPSC-based cardiac differentiation protocols have been developed to differentiate between atrial- or ventricular-like cardiomyocytes. Few protocols have successfully proposed ways to obtain hiPSC-derived cardiac pacemaker cells, despite the very limited availability of human tissues from the sinoatrial node. Providing an in vitro source of pacemaker-like cells would be of paramount importance in terms of furthering our understanding of the mechanisms underlying sinoatrial node pathophysiology and testing innovative clinical strategies against sinoatrial node dysfunction (i.e., biological pacemakers and genetic- and pharmacological- based therapy). Here, we summarize and detail the currently available protocols used to obtain patient-derived pacemaker-like cells.

Leadless cardiac ventricular pacing using helix fixation: Step-by-step guide to implantation.

INTRODUCTION: Leadless cardiac pacemakers are an alternative modality to traditional transvenous pacemaker systems. Recently receiving Food and Drug Administration approval, the AVEIR VR leadless pacemaker system provides a helix based active fixation leadless pacemaker system. This step-by-step review will cover patient selection, preprocedural planning, device implantation technique, implant site evaluation, troubleshooting, short- and long-term complications as well as future directions for leadless pacing. METHODS: We collected and reviewed cases from primary operators to provide a step-by-step review for implanters. RESULTS: Our paper provides a guide to patient selection, pre-procedural planning, device im plantation technique, implant site evaluation, troubleshooting, short- and long-term complications as well as future directions for leadless pacing. CONCLUSION: The helix based active fixation leadless pacemaker system is a safe and efficacious way to provide pacing support to patients and provides an alternative to transvenous pacing systems. Our review provides a step-by-step guide to implantation.

Advanced helix-fixation leadless cardiac pacemaker implantation techniques to improve success and reduce complications.

INTRODUCTION: Leadless cardiac pacemakers (LCPs) are becoming more commonly utilized because of their potential advantages (i.e., reduced short and long-term complications, improved patient comfort) and may be the preferred option for patients with venous access problems, high-risk for infection, previous lead fractures, or skin erosion. There are currently two types of LCP fixation mechanisms that have been FDA approved-Medtronic's Micra system has a tine-based fixation and Abbott's Aveir system has a helix-fixation design. This article highlights important tips and tricks for a successful implant of a helix-fixation LCP, particularly when difficulties are encountered, and provides precautions to avoid potential complications. METHODS: Cases of single chamber Aveir LCP implantation were reviewed to highlight examples of procedural pitfalls and suggested methods to circumnavigate them. RESULTS: There are unique procedural considerations regarding the Aveir LCP implant as well as challenges that that may be occasionally encountered. Techniques to address these-such as avoiding air embolism, maneuvering difficult entry into the right ventricle, handling complicated positioning/repositioning, evaluating proper fixation, and releasing difficult tethers-are illustrated in detail. Advice to reduce risks of perforation and to position optimally for potential retrieval and communication for dual chamber pacing are also described. CONCLUSIONS: The advanced teaching concepts described and emphasized in this article may help improve success and prevent procedural complications, especially when physicians are learning how implant these novel helix-fixation LCPs.

Safety and performance of MR-conditional pacing systems with automated MRI mode at 1.5 and 3 Tesla.

OBJECTIVES: To evaluate at 1.5 and 3 T MRI the safety and performance of trademarked ENO®, TEO®, or OTO® pacing systems with automated MRI Mode and the image quality of non-enhanced MR examinations. METHODS: A total of 267 implanted patients underwent MRI examination (brain, cardiac, shoulder, cervical spine) at 1.5 (n = 126) or 3 T (n = 141). MRI-related device complications, lead electrical performances stability at 1-month post-MRI, proper functioning of the automated MRI mode and image quality were evaluated. RESULTS: Freedom from MRI-related complications at 1 month post-MRI was 100% in both 1.5 and 3 T arms (both p < 0.0001). The stability of pacing capture threshold was respectively at 1.5 and 3 T (atrial:: 98.9% (p = 0.001) and 100% (p < 0.0001); ventricular: both 100% (p < 0001)). The stability of sensing was respectively at 1.5 and 3 T (atrial: 100% (p = 0.0001) and 96.9% (p = 0.01); ventricular: 100% (p < 0.0001) and 99.1% (p = 0.0001)). All devices switched automatically to the programmed asynchronous mode in the MRI environment and to initially programmed mode after the MRI exam. While all MR examinations were assessed as interpretable, artifacts deteriorated a subset of examinations including mostly cardiac and shoulder ones. CONCLUSION: This study demonstrates the safety and electrical stability of ENO®, TEO®, or OTO® pacing systems at 1 month post-MRI at 1.5 and 3 T. Even if artifacts were noticed in a subset of examinations, overall interpretability was preserved. CLINICAL RELEVANCE STATEMENT: ENO®, TEO®, and OTO® pacing systems switch to MR-mode when detecting magnetic field and switch back on conventional mode after MRI. Their safety and electrical stability at 1 month post MRI were shown at 1.5 and 3 T. Overall interpretability was preserved. KEY POINTS: • Patients implanted with an MRI conditional cardiac pacemaker can be safely scanned under 1.5 or 3 Tesla MRI with preserved interpretability. • Electrical parameters of the MRI conditional pacing system remain stable after a 1.5 or 3 Tesla MRI scan. • The automated MRI mode enabled the automatic switch to asynchronous mode in the MRI environment and to initial settings after the MRI scan in all patients.

Syncope and Cannabis: hypervagotonia from chronic abuse? A case report and literature review.

BACKGROUND: Cannabis is the most consumed drug worldwide and number of users is increasing, particularly among youth. Moreover, cannabis potential therapeutic properties have renewed interest to make it available as a treatment for a variety of conditions. Albeit rarely, cannabis consumption has been associated with cardiovascular diseases such as arrhythmias, myocardial infarction (MI) and potentially sudden death. CASE PRESENTATION: A 24-year-old woman presented to the emergency department sent by her cardiologist because of a recent finding of a 16 seconds asystole on the implantable loop recorder (ILR) she implanted 7 months before for recurrent syncopes. She declared that she is a heavy cannabis user (at least 5 cannabis-cigarette per day, not mixed up with tobacco, for no less than 12 years) and all syncopes occurred shortly after cannabis consumption. After a collective discussion with the heart team, syncope unit, electrophysiologists and toxicologist, we decided to implant a dual chamber pacemaker with a rate response algorithm due to the high risk of trauma of the syncopal episodes. 24 months follow-up period was uneventful. CONCLUSIONS: Cannabis cardiovascular effects are not well known and, although rare, among these we find ischemic episodes, tachyarrhythmias, symptomatic sinus bradycardia, sinus arrest, ventricular asystole and possibly death. Because of cannabis growing consumption both for medical and recreational purpose, cardiovascular diseases associated with cannabis use may become more and more frequent. In the light of the poor literature, we believe that cannabis may produce opposite adverse effects depending on the duration of the habit. Acute administration increases sympathetic tone and reduces parasympathetic tone; conversely, with chronic intake an opposite effect is observed: repetitive dosing decreases sympathetic activity and increases parasympathetic activity. Clinicians should be aware of the increased risk of cardiovascular complications associated with cannabis use and should investigate its consumption especially in young patients presenting with cardiac dysrhythmias.

Use of Spinal Cord Stimulators in Patients With Pacemakers or Implantable Cardiac Defibrillators: A Review of Documented Accounts of Interference.

OBJECTIVES: To assess the currently available evidence regarding associations between spinal cord stimulator (SCS) lead type, clinical indications for device placement, and interference between SCSs and cardiac pacemakers (CPMs)/implantable cardioverter-defibrillators (ICDs). STUDY DESIGN: Review of case reports and original research studies assessing the interference between SCS and CPM/ICD. MATERIALS AND METHODS: PubMed and Cochrane databases were searched for articles commenting on the interference between SCS and CPM/ICD. The search criteria which generated the greatest number of relevant studies was (spinal cord stimulator AND [pacemaker OR implantable cardioverter defibrillator]). Additional, empiric review was conducted using JSTOR, ScienceDirect, and EBSCOhost databases; however, no additional eligible studies were identified. Data were extracted, summarized into tables, and quantitatively analyzed using LibreTexts and MedCalc software. RESULTS: There was no statistically significant interference observed between SCS and CPM/ICD devices in patients regardless of indication for SCS placement and SCS lead polarity. LIMITATIONS: Limited by variability of patient cases and variability in maximum frequency and amplitude of SCS devices tried in individual cases. Also limited by small sample size and the absence of a standard definition for device interference across studies. CONCLUSIONS: Interference between cardiac devices and SCSs is a rare occurrence. As there are currently no published guidelines, devices should be interrogated on a case-by-case basis in the SCS trial period (if implanted after cardiac device), during permanent implantation, and during scheduled follow-up visits. Peri-operative testing should include increasing the SCS settings to maximally tolerated levels with cardiac device set at its maximum sensitivity.

Post-Cardiac Injury Syndrome Following Permanent Pacemaker Implantation Presenting Exclusively As Massive Pleural Effusion: A Rare Occurrence.

Post-Cardiac Injury Syndrome (PCIS) akin to Dressler's syndrome is late-onset pericarditis that is triggered by the body's immune system and presents commonly as pleuro- pericardial symptoms and raised inflammatory markers. Its occurrence following the insertion of a pacemaker has been reported infrequently and varies in different studies with an estimated prevalence of 1-2%. Our case reports a unique incidence of isolated pleural effusion following the implantation of a pacemaker in a 62-year-old female with complete heart block with no evidence of pericardial effusion on imaging. She developed dyspnoea, pleuritic chest pain, and lethargy. She successfully responded to treatment with NSAIDs and colchicine with no recurrence. This report demonstrates the uncommon course of the disease and highlights the need to consider PCIS as a possible diagnosis in patients presenting with predominant pulmonary findings and suspect it early so that timely treatment can be started, thereby preventing complications.

Placement of permanent pacemaker in a low-birth-weight infant with congenital heart block: a case report.

One of the rare diseases with a high mortality rate in infants is congenital heart block (CHB) with neonatal lupus erythematosus (NLE) as the most common cause. A permanent pacemaker (PPM) is indicated for symptomatic bradycardia. The choice of PPM in the paediatric population is different from that in the adult population because of several reasons like small size, account of somatic growth, and difference in physiological changes. Here, we present a case in which a 2.6 kg and 45 days old baby with CHB secondary to NLE was successfully treated with a single-chambered adult-sized PPM with epicardial lead. According to our knowledge, this is the smallest baby in Pakistan in which PPM has been implanted.

Safety Review of Radiotherapy for Tumor Patients with Implantable Cardiac Pacemaker.

Permanent pacemaker implantation is one of the most effective treatments for chronic arrhythmia. However, there is a certain risk associated with radiation therapy in cancer patients with implantable cardiac pacemakers. To prevent radiotherapy-induced pacemaker failure, there are established medical guidelines for the use of pacemakers in patients undergoing radiotherapy. With advancements in science and technology, the variety of available pacemakers has considerably increased, and radiotherapy equipment has also been updated. Given the variations in irradiation methods and the types of radiation used in clinical practice, there is a pressing need for international consensus on the regulations governing the use of cardiac pacemakers in cancer patients. Currently, many countries lack clinical guidelines for radiotherapy in cancer patients with cardiac pacemakers. This review summarizes recent reports and studies from PubMed (National Center for Biotechnology Information) regarding the safety of radiotherapy in cancer patients with implanted cardiac pacemakers, and provides valuable insights for clinical practice.

Hemodynamic response and safety of vasodilator stress cardiovascular magnetic resonance in patients with permanent pacemakers or implantable cardioverter-defibrillators.

INTRODUCTION: Vasodilator stress cardiovascular magnetic resonance (CMR) is a powerful diagnostic modality, but data toward its use in patients with permanent pacemakers (PPMs) or implantable cardioverter-defibrillators (ICDs) is limited. METHODS AND RESULTS: Patients with ICDs (>1% pacing) or PPMs who underwent regadenoson single photon emission computed tomography (SPECT) and all patients with ICDs or PPMs who underwent stress CMR were retrospectively identified. SPECT tests were analyzed for hemodynamic responses and new pacing requirements; CMR studies were examined for safety, device characteristics and programming, hemodynamic responses, and image quality. Changes from baseline were evaluated with the Related-Samples Wilcoxon Signed Rank Test. Of 67 patients (median age 65 [IQR 58-72] years, 31 [46%] female, 31 [46%] Black), 47 underwent SPECT and 20 CMR. With regadenoson SPECT, 89% of patients experienced tachycardic responses above resting heart rates (+19 [13-32] beats per minute, p < .01). During stress CMR, 10 (50%) devices were asynchronously paced approximately 10 beats per minute above resting rates, and the remaining were temporarily deactivated. Those with asynchronous pacing had no changes in heart rates, whereas patients with deactivated devices had near uniform heart rate accelerations. Image quality was diagnostic in the majority of stress CMR sequences, with nonconditional ICDs contributing 40 of 57 (70%) of nondiagnostic segments. CONCLUSION: This data supports the safety of vasodilator stress CMR with promising diagnostic quality images in patients with CMR conditional ICDs and PPMs. Despite a near uniform tachycardic response to regadenoson in the SPECT environment, high rates of asynchronous pacing during vasodilator stress CMR did not result in competitive pacing or adverse arrhythmic events. Further studies are needed to validate these findings and confirm the diagnostic and prognostic performance of stress CMR in these individuals.

European Society of Cardiology Quality Indicators for the care and outcomes of cardiac pacing: developed by the Working Group for Cardiac Pacing Quality Indicators in collaboration with the European Heart Rhythm Association of the European Society of Cardiology.

AIMS: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults undergoing cardiac pacing. METHODS AND RESULTS: Under the auspice of the Clinical Practice Guideline Quality Indicator Committee of the European Society of Cardiology (ESC), the Working Group for cardiac pacing QIs was formed. The Group comprised Task Force members of the 2021 ESC Clinical Practice Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy, members of the European Heart Rhythm Association, international cardiac device experts, and patient representatives. We followed the ESC methodology for QI development, which involved (i) the identification of the key domains of care by constructing a conceptual framework of the management of patients receiving cardiac pacing, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified-Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. Four domains of care were identified: (i) structural framework, (ii) patient assessment, (iii) pacing strategy, and (iv) clinical outcomes. In total, seven main and four secondary QIs were selected across these domains and were embedded within the 2021 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization therapy. CONCLUSION: By way of a standardized process, 11 QIs for cardiac pacing were developed. These indicators may be used to quantify adherence to guideline-recommended clinical practice and have the potential to improve the care and outcomes of patients receiving cardiac pacemakers.

Genomic and physiological analyses of the zebrafish atrioventricular canal reveal molecular building blocks of the secondary pacemaker region.

The atrioventricular canal (AVC) is the site where key structures responsible for functional division between heart regions are established, most importantly, the atrioventricular (AV) conduction system and cardiac valves. To elucidate the mechanism underlying AVC development and function, we utilized transgenic zebrafish line sqet31Et expressing EGFP in the AVC to isolate this cell population and profile its transcriptome at 48 and 72 hpf. The zebrafish AVC transcriptome exhibits hallmarks of mammalian AV node, including the expression of genes implicated in its development and those encoding connexins forming low conductance gap junctions. Transcriptome analysis uncovered protein-coding and noncoding transcripts enriched in AVC, which have not been previously associated with this structure, as well as dynamic expression of epithelial-to-mesenchymal transition markers and components of TGF-ß, Notch, and Wnt signaling pathways likely reflecting ongoing AVC and valve development. Using transgenic line Tg(myl7:mermaid) encoding voltage-sensitive fluorescent protein, we show that abolishing the pacemaker-containing sinoatrial ring (SAR) through Isl1 loss of function resulted in spontaneous activation in the AVC region, suggesting that it possesses inherent automaticity although insufficient to replace the SAR. The SAR and AVC transcriptomes express partially overlapping species of ion channels and gap junction proteins, reflecting their distinct roles. Besides identifying conserved aspects between zebrafish and mammalian conduction systems, our results established molecular hallmarks of the developing AVC which underlies its role in structural and electrophysiological separation between heart chambers. This data constitutes a valuable resource for studying AVC development and function, and identification of novel candidate genes implicated in these processes.

[ESC guidelines 2021 on cardiac pacing and cardiac resynchronization therapy : What's new?] / ESC-Leitlinien 2021 zur Schrittmacher- und Resynchronisationstherapie : Was gibt es Neues?

The new European Society of Cardiology (ESC) guidelines on cardiac pacing and cardiac resynchronization therapy were presented together with the new ESC heart failure guidelines at the ESC congress in September. The new document includes detailed sections on patient evaluation and clinical assessment, implantation, minimizing complications and patient follow-up. The guidelines have been updated and expanded particularly on the approach to reflex syncope, the indications after transcatheter aortic valve implantation (TAVI) and the perioperative management. The indications for cardiac resynchronization therapy (CRT) are now in line with the simultaneously published ESC heart failure guidelines. New physiological forms of stimulation and leadless pacing are now included in the guidelines.

Improved Generation of Human Induced Pluripotent Stem Cell-Derived Cardiac Pacemaker Cells Using Novel Differentiation Protocols.

Current protocols for the differentiation of human-induced pluripotent stem cells (hiPSC) into cardiomyocytes only generate a small amount of cardiac pacemaker cells. In previous work, we reported the generation of high amounts of cardiac pacemaker cells by co-culturing hiPSC with mouse visceral endoderm-like (END2) cells. However, potential medical applications of cardiac pacemaker cells generated according to this protocol, comprise an incalculable xenogeneic risk. We thus aimed to establish novel protocols maintaining the differentiation efficiency of the END2 cell-based protocol, yet eliminating the use of END2 cells. Three protocols were based on the activation and inhibition of the Wingless/Integrated (Wnt) signaling pathway, supplemented either with retinoic acid and the Wnt activator CHIR99021 (protocol B) or with the NODAL inhibitor SB431542 (protocol C) or with a combination of all three components (protocol D). An additional fourth protocol (protocol E) was used, which was originally developed by the manufacturer STEMCELL Technologies for the differentiation of hiPSC or hESC into atrial cardiomyocytes. All protocols (B, C, D, E) were compared to the END2 cell-based protocol A, serving as reference, in terms of their ability to differentiate hiPSC into cardiac pacemaker cells. Our analysis revealed that protocol E induced upregulation of 12 out of 15 cardiac pacemaker-specific genes. For comparison, reference protocol A upregulated 11, while protocols B, C and D upregulated 9, 10 and 8 cardiac pacemaker-specific genes, respectively. Cells differentiated according to protocol E displayed intense fluorescence signals of cardiac pacemaker-specific markers and showed excellent rate responsiveness to adrenergic and cholinergic stimulation. In conclusion, we characterized four novel and END2 cell-independent protocols for the differentiation of hiPSC into cardiac pacemaker cells, of which protocol E was the most efficient.

New Method of Cardiac Lead Evaluation Using Chest Radiography.

Background and Objectives: There is currently no method that can be used for a precise evaluation of pacemaker leads using X-ray images, which could be a valuable add-on in the follow-up of patients. The aim of this paper was to create a simple method to measure selected points and lines using the chest radiography of patients with cardiac pacemakers. Materials and Methods: The study included 99 patients after permanent pacemaker implantation (72.0 ± 12.9 y; 58 W). The newly created method was used to evaluate the course of the leads based on an X-ray of the chest in an AP (posterior-anterior) projection (standing up) with optimization. The chest X-ray was applied to the original measurement grid, which was determined by specific anatomical points. For the purpose of this paper, a number of measurable parameters have been proposed. Results: The technical quality of the images was very good (4.50 ± 0.72). There were no gender-specific differences: women 4.46 ± 0.75/men 4.56 ± 0.67; p = 0.5183. The quality of the imaging of the leads was also good (3.72 ± 0.83), and no statistical differences were found between the genders. After verifying the technical quality of the X-ray images, the tract of the leads was measured. The only significant difference was found in parameter E-this value describing the so-called "death bend", which was significantly lower in women (3.98 ± 1.35) vs. men (4.58 ± 1.49): p = 0.039. Conclusions: The presented method permitted the leads of a cardiac pacemaker to be precisely described with good clinical validity using chest radiography.

An unusual 'bow tie' image in pacemaker implantation.

Upper venous system anatomic variations may cause difficulties during cardiac pacemaker implantation. Persistent left superior vena cava (PLSVC) and absent right superior vena cava could be an arrhythmogenic source of atrial arrhythmias and cardiac conduction disease. We represent dual-chamber pacemaker implantation in a patient with a very rare upper venous system anomaly, paroxysmal atrial fibrillation, sick sinus syndrome, that cause unusual fluoroscopic image.

[Study on Impedance of Implantable Cardiac Pacemaker in Unipolar/Bipolar Pacing Mode by in Vitro Experiment].

The unipolar/bipolar pacing mode of pacemaker is related to its circuit impedance, which affects the battery life. In this study, the in vitro experiment scheme of pacemaker circuit impedance test was constructed. The human blood environment was simulated by NaCl solution, and the experimental environment temperature was controlled by water bath. The results of in vitro experiments showed that under the experimental conditions similar to clinical human parameters, the difference between the circuit impedance of bipolar mode and unipolar mode is 120~200 Ω. The results of the in vitro experiment confirmed that the circuit impedance of bipolar circuit was larger than that of unipolar mode, which was found in clinical practice. The results of this study have reference value to the optimization of pacing mode and the reduction of pacemaker power consumption.

Quantification of artifacts during cardiac magnetic resonance in patients with leadless Micra pacemakers.

INTRODUCTION: When cardiac magnetic resonance (MR) is performed after previous leadless transcatheter pacemaker implantation, an image distortion has to be expected in the heart region and evaluation of myocardial tissue can be affected. In this clinical prospective study, we aim to assess the extent and impact of this artifact on individual ventricular segments and compare it to conventional pacing devices. METHODS: Total of 20 patients with leadless pacemaker placed in the right ventricle underwent cardiac MR imaging in a 1.5 Tesla scanner. A multiplanar segmentation was used to demarcate the left and right ventricular myocardium as well as the pacemaker-caused image artifact in systolic and diastolic time frames. Artifact size and its relative influence on myocardial segments were quantitatively assessed and expressed in AHA-17 model. RESULTS: Implanted leadless pacemaker caused an image artifact with a volume of 48 ± 5 ml. Most distorted were the apical septal (53 ± 23%), apical inferior (30 ± 18%), and midventricular inferoseptal (30 ± 20%) segments. The artifact intersection with basal and lateral segments was none or negligible (up to 2%). The portion of left ventricular (LV) myocardium affected by the artifact was significantly higher in systole (8 ± 4%) compared to diastole (10 ± 3%; p < .001). CONCLUSION: Implantation of leadless pacemaker represents no obstacle for cardiac MR imaging but causes an image artifact located mostly in septal, inferoseptal, and anteroseptal segments of apical and midventricular LV myocardium. With the exception of the apex, diastolic timing reduces the image distortion of all segments and improves global ventricular assessment.

[His bundle and left bundle branch pacing]. / His-Bündel- und Linksschenkelstimulation.

Cardiac pacemakers are an extremely effective treatment for bradycardia but can, however, cause desynchronization of ventricular contraction leading to cardiomyopathy. Pacing of the conduction system can prevent and even reverse desynchronization, which is impressively visible in echocardiography with speckle tracing. His' bundle and left bundle branch pacing requires a specific implantation technique, sheaths and leads which can achieve successful stimulation of the conduction system in up to 98% of cases. Data on conduction system pacing have been acquired in numerous studies but only a few randomized outcome studies. Therefore, in the current European guidelines His' bundle and left bundle branch pacing only have a low level recommendation. The guidelines recommend His' bundle pacing in patients in whom a coronary sinus lead cannot be implanted and in patients with permanent atrial fibrillation and planned atrioventricular (AV) node ablation for heart rate control. Additionally, conduction system pacing appears to be meaningful in patients with an AV block who require pacing of the ventricle for ≥20% of the time or who already show a slightly or moderately reduced left ventricular ejection fraction (36-50%). Even in patients scheduled for generator replacement who have developed a cardiac pacemaker-induced cardiomyopathy, the opportunity should not be missed to upgrade the system by implantation of a His' bundle electrode.

Application of Optogenetics for Muscle Cells and Stem Cells.

This chapter describes the current progress of basic research, and potential therapeutic applications primarily focused on the optical manipulation of muscle cells and neural stem cells using microbial rhodopsin as a light-sensitive molecule. Since the contractions of skeletal, cardiac, and smooth muscle cells are mainly regulated through their membrane potential, several studies have been demonstrated to up- or downregulate the muscle contraction directly or indirectly using optogenetic actuators or silencers with defined stimulation patterns and intensities. Light-dependent oscillation of membrane potential also facilitates the maturation of myocytes with the development of T tubules and sarcomere structures, tandem arrays of minimum contractile units consists of contractile proteins and cytoskeletal proteins. Optogenetics has been applied to various stem cells and multipotent/pluripotent cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to generate light-sensitive neurons and to facilitate neuroscience. The chronic optical stimulation of the channelrhodopsin-expressing neural stem cells facilitates their neural differentiation. There are potential therapeutic applications of optogenetics in cardiac pacemaking, muscle regeneration/maintenance, locomotion recovery for the treatment of muscle paralysis due to motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Optogenetics would also facilitate maturation, network integration of grafted neurons, and improve the microenvironment around them when applied to stem cells.