Cardiac Pacemaker Research Articles

Segregation of morphogenetic regulatory function of Shox2 from its cell fate guardian role in sinoatrial node development

Shox2 plays a vital role in the morphogenesis and physiological function of the sinoatrial node (SAN), the primary cardiac pacemaker, manifested by the formation of a hypoplastic SAN and failed differentiation of pacemaker cells in Shox2 mutants. Shox2 and Nkx2-5 are co-expressed in the developing SAN and regulate the fate of the pacemaker cells through a Shox2-Nkx2-5 antagonistic mechanism. Here we show that simultaneous inactivation of Nkx2-5 in the SAN of Shox2 mutants (dKO) rescued the pacemaking cell fate but not the hypoplastic defects, indicating uncoupling of SAN cell fate determination and morphogenesis. Single-cell RNA-seq revealed that the presumptive SAN cells of Shox2-/- mutants failed to activate pacemaking program but remained in a progenitor state preceding working myocardium, while both wildtype and dKO SAN cells displayed normal pacemaking cell fate with similar cellular state. Shox2 thus acts as a safeguard but not a determinant to ensure the pacemaking cell fate through the Shox2-Nkx2-5 antagonistic mechanism, which is segregated from its morphogenetic regulatory function in SAN development.

Comparison of modified Del Nido and Custodiol® cardioplegia in minimally invasive mitral valve surgery.

In this study, we evaluated if modified Del Nido cardioplegia delivers comparable cardiac protection in comparison to Custodiol® in patients undergoing isolated minimally invasive mitral valve repair. From January 2018 to October 2021, all patients undergoing non-emergent isolated minimally invasive mitral valve repair were included in this study. The cardioplegia was chosen at the surgeons' discretion. The primary end points of this study were peak postoperative cardiac enzyme levels. Secondary end points were in-hospital mortality, hospital stay, occurrence of cardiac arrhythmias, pacemaker implantations, postoperative lactate and sodium levels and postoperative incidence of renal failure requiring dialysis. A total of 355 patients were included in this study. The mean age of patients was 57. After propensity score matching, a total of 156 pairs were identified. There was no difference in cross-clamp time between both groups. Postoperative creatine kinase levels were higher in patients receiving Custodiol on the 1st and 2nd postoperative days. Creatine kinase isoenzyme MB levels were higher in patients receiving Custodiol on the 2nd postoperative day (0.5 ± 0.2 vs 0.4 ± 0.1 µmol/l s; P < 0.001). Postoperative Troponin T concentrations were similar between both groups. Maximum lactate concentrations were higher in patients receiving Custodiol on the day of surgery (2.4 ± 1.9 vs 2.0 ± 1.1 mmol/l; P = 0.04). The overall hospital stay was longer in patients receiving Del Nido cardioplegia (10.6 ± 3.2 vs 8 ± 4.1 days; P < 0.01). Modified Del Nido cardioplegia based on Ionosteril® solution offers equivalent protection compared to Custodiol for isolated minimally invasive mitral valve repair.

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.

Analysis of changes in the action potential morphology of the mouse sinoatrial node true pacemaker cells during ontogenetic development in vitro and in silico.

Maturation of the mouse is accompanied by the increase in heart rate. However, the mechanisms underlying this process remain unclear. We performed an action potentials (APs) recordings in mouse sinoatrial node (SAN) true pacemaker cells and in silico analysis to clarify the mechanisms underlying pre-postnatal period heart rate changes. The APs of true pacemaker cells at different stages had similar configurations and dV/dtmax values. The cycle length, action potential duration (APD90), maximal diastolic potential (MDP), and AP amplitude decreased, meanwhile the velocity of diastolic depolarization (DDR) increased from E12.5 stage to adult. Using a pharmacological approach we found that in SAN true pacemaker cells ivabradine reduces the DDR and the cycle length significantly stronger in E12.5 than in newborn and adult mice, whereas the effects of Ni2+ and nifedipine were significantly stronger in adult mice. Computer simulations further suggested that the density of the hyperpolarization-activated pacemaker сurrent (If) decreased during development, whereas transmembrane and intracellular Ca2+ flows increased. The ontogenetic decrease in IK1 density from E12.5 to adult leads to depolarization of MDP to the voltage range in which calcium currents are activated, thereby shifting the balance from the "membrane-clock" to the "calcium-clock."

Challenges Experienced by Iranian Patients with Temporary Transvenous Cardiac Pacemakers: A Phenomenological Study

Background: One of the main causes of mortality in patients with heart disease is arrhythmia. A temporary pacemaker is inserted to control arrhythmias, particularly when an intervention is urgently needed. Since this procedure is not benign, patients might experience many challenges. As the first step in the development of nursing interventions, identifying these experiences can help reinforce evidence in this field and enhance the quality of nursing care. Objectives: The present study aimed to explore the challenges experienced by patients with temporary transvenous cardiac pacemakers (TTCPs). Methods: This qualitative, interpretive phenomenological study was conducted on 18 patients with pacemakers who were selected by purposive sampling. The data were collected through in-depth semi-structured interviews. All the interviews were recorded and simultaneously analyzed via van Manen’s analytical method. Results: The results of data analysis resulted in three major themes: "Disregard for patient’s dignity”, “dependent life”, and "physical and psychological problems”. Conclusions: This study showed the challenges of patients with TTCPs. This group of patients is facing challenges related to the care and hospitalization matter and facing an uncertain future. Therefore, there is a need to pay more attention to patients' needs during hospitalization, such as informing patients about the procedure, respecting patients’ dignity and rights, and controlling physical and psychological problems.

Wireless Power Supply Based on MNG-MNZ Metamaterial for Cardiac Pacemakers

Wireless Power Supply Based on MNG-MNZ Metamaterial for Cardiac Pacemakers

Safety and performance of a novel subxiphoidal pacemaker system.

Traditional cardiac pacemakers commonly have a range of complications related to the presence of intracardiac leads. A new class of extravascular and leadless pacemakers has recently emerged with the potential to mitigate these complications and expand access to cardiac pacing. The objective of this study is to evaluate the implantation, short-term chronic safety, and performance of a novel subxiphoidal extracardiac pacemaker. Normal Yorkshire Cross swine (n = 16) were implanted with the subxiphoidal pacemaker. The pacemaker was inserted through a midline chest incision and clipped to the underside of the sternum, with the stimulation electrode placed on the anterior pericardium. Animals were chronically paced and followed for 90days post-implant, with periodic measurement of pacing capture threshold (PCT) and electrode impedance. All 16 animals were successfully implanted with the study device. At implant, a consistent average PCT of 2.2 ± 0.4V at a pulse width of 1.0ms was observed in all animals, with an average implant impedance of 648 ± 44 Ω. Chronic pacing was programmed at a rate of 60bpm, an amplitude of 3.4 ± 0.7V, and a pulse width of 1.0ms. PCT rose to 4.6 ± 0.8V at 14days and stabilized; at 90days, PCT was 3.8 ± 1.2V and electrode impedance was 533 ± 105 Ω. All implanted animals completed the study with no clinically significant findings, no clinically significant abnormalities, and with no adverse events that affected animal welfare. This study demonstrated the safety and feasibility of a novel subxiphoidal extracardiac pacemaker to deliver short-term chronic extravascular therapy. Further studies are required to assess the safety, feasibility, and long-term chronic pacing performance in human subjects.

History of cardiac pacemaker therapy in Germany

Cardiac pacemaker therapy began with successful stimulation of human hearts already in the first half of the 20thcentury. Complete implantation of apacemaker by the cardiac surgeon Åke Senning on October 8, 1958 at the Karolinska Hospital in Stockholm is considered the actual birth of today's pacemaker therapy. The first pacemaker implantation in Germany was performed by Hans-Joachim Sykosch on October 6, 1961 at the Surgical Clinic of the University of Düsseldorf. Two years later, the first implantation in East Germany (GDR) was carried out by Friedrich Flemming on September 2, 1963 at the Charité in East Berlin. The first pacemaker manufactured in West Germany arrived on the market 1963; East Germany started device production in 1978. In 1974, pacemaker therapy in West Germany showed a50% survival rate after 6.3years compared to < 1year with drug therapy. After initially using bare metal wires, pacemaker leads have significantly improved in both quality and reliability. Development culminated in the leadless pacemaker. Battery development led to avariety of inventions: rechargeable pacemakers, biogalvanic cells, bioenergy sources, nuclear generators and lithium batteries, the latter ultimately prevailed. In the beginning, only fixed-rate ventricular pacemakers were available. Subsequently, systems adapted to physiological requirements were developed: on-demand pacemakers, atrial-based pacing and rate-adaptive systems. However, it was not until the return to direct stimulation of the conduction system that truly physiological stimulation of the heart became possible.

Challenges facing paroxysmal supraventricular tachycardia in early infancy

The heart generates its own electrical signal. The sinoatrial node is considered the natural pacemaker of the heart and generates an electrical stimulus regularly, 60 to 100 times per minute under normal conditions. Supraventricular tachycardia is the most common rhythm disturbance in children. The majority of the clinically important Supraventricular tachycardia in healthy children is caused by the presence of an accessory electrical connection between the atrium and the ventricle or within the atrioventricular node. Here is reported the case of a 3-months old infant who was presented with pallor, lethargy, poor feeding and was diagnosed with Supraventricular tachycardia. In infants it presents with nonspecific symptoms. Supraventricular tachycardia is typically not life threating but can become if left undiagnosed and untreated, so a high index of suspicion should be maintained while evaluating a child even in early infancy.

Circadian regulation of sinoatrial nodal cell pacemaking function: Dissecting the roles of autonomic control, body temperature, and local circadian rhythmicity.

Strong circadian (~24h) rhythms in heart rate (HR) are critical for flexible regulation of cardiac pacemaking function throughout the day. While this circadian flexibility in HR is sustained in diverse conditions, it declines with age, accompanied by reduced maximal HR performance. The intricate regulation of circadian HR involves the orchestration of the autonomic nervous system (ANS), circadian rhythms of body temperature (CRBT), and local circadian rhythmicity (LCR), which has not been fully understood. Here, we developed a mathematical model describing ANS, CRBT, and LCR in sinoatrial nodal cells (SANC) that accurately captures distinct circadian patterns in adult and aged mice. Our model underscores how the alliance among ANS, CRBT, and LCR achieves circadian flexibility to cover a wide range of firing rates in SANC, performance to achieve maximal firing rates, while preserving robustness to generate rhythmic firing patterns irrespective of external conditions. Specifically, while ANS dominates in promoting SANC flexibility and performance, CRBT and LCR act as primary and secondary boosters, respectively, to further enhance SANC flexibility and performance. Disruption of this alliance with age results in impaired SANC flexibility and performance, but not robustness. This unexpected outcome is primarily attributed to the age-related reduction in parasympathetic activities, which maintains SANC robustness while compromising flexibility. Our work sheds light on the critical alliance of ANS, CRBT, and LCR in regulating time-of-day cardiac pacemaking function and dysfunction, offering insights into novel therapeutic targets for the prevention and treatment of cardiac arrhythmias.

Enhancing Power Generation for Solar-Based Cardiac Pacemakers: A Novel Approach with FOPID and HCMKH-BS2

Biomedical implants, such as implantable cardioverter heart monitors, rely on limited battery life, which necessitates costly replacements and patient discomfort. To address these challenges, a novel solar-based pacemaker model is proposed that is integrated with a fractional-order proportional integral derivative (FOPID) controller and a Hybridized Chaotic multiverse Krill Herd-based Backtracking Search Strategy (HCMKH-BS2) to enhance power generation for pacemaker operation. Our approach considers the impact of partial shading conditions on solar power. To mitigate these conditions, a FOPID controller with an HCMKH-BS2 model is developed which also addresses environmental issues through the adoption of a DC-DC converter. The gain parameters of the FOPID controller are determined using the proposed HCMKH-BS2 algorithm. The proposed technique is implemented to evaluate its performance using various measures in terms of duty cycle, convergence analysis, and power. The performance validation is performed based on the analyses of constant irradiance and changed irradiance. The proposed method achieved a fitness value of 0.01 from the convergence analysis and the duty cycle of 0.48D. These results demonstrate the superiority of our proposed technique over previous methods, highlighting its potential for enhancing the performance of solar-based cardiac pacemakers.

Heart Rhythm New Zealand consensus statement on the practical management of cardiac implanted electronic devices in the peri-operative environment.

Electrosurgery is commonly used during a range of operations in order to maintain effective haemostasis. This can cause electromagnetic interference (EMI) with cardiac implanted electronic devices (CIEDs), which prevents normal device function. CIEDs include pacemakers (PPM), implantable cardiac defibrillators (ICD), cardiac resynchronisation therapy devices-both pacemakers and defibrillators (CRT-P/CRT-D)-and implantable loop recorders (ILRs). Damage to the generator, inhibition of pacing, activation of asynchronous pacing and ventricular fibrillation can all be induced by electrocautery. An active management plan for CIEDs during electrosurgery is critical to minimise these adverse effects of EMI. Purpose: To facilitate the safe and effective peri-operative management of CIED patients during electrosurgery.

Heart rhythm in vitro: measuring stem cell-derived pacemaker cells on microelectrode arrays.

Cardiac arrhythmias have markedly increased in recent decades, highlighting the urgent need for appropriate test systems to evaluate the efficacy and safety of new pharmaceuticals and the potential side effects of established drugs. The Microelectrode Array (MEA) system may be a suitable option, as it provides both real-time and non-invasive monitoring of cellular networks of spontaneously active cells. However, there is currently no commercially available cell source to apply this technology in the context of the cardiac conduction system (CCS). In response to this problem, our group has previously developed a protocol for the generation of pure functional cardiac pacemaker cells from mouse embryonic stem cells (ESCs). In addition, we compared the hanging drop method, which was previously utilized, with spherical plate-derived embryoid bodies (EBs) and the pacemaker cells that are differentiated from these. We described the application of these pacemaker cells on the MEA platform, which required a number of crucial optimization steps in terms of coating, dissociation, and cell density. As a result, we were able to generate a monolayer of pure pacemaker cells on an MEA surface that is viable and electromechanically active for weeks. Furthermore, we introduced spherical plates as a convenient and scalable method to be applied for the production of induced sinoatrial bodies. We provide a tool to transfer modeling and analysis of cardiac rhythm diseases to the cell culture dish. Our system allows answering CCS-related queries within a cellular network, both under baseline conditions and post-drug exposure in a reliable and affordable manner. Ultimately, our approach may provide valuable guidance not only for cardiac pacemaker cells but also for the generation of an MEA test platform using other sensitive non-proliferating cell types.

The pancreas does not contribute to the non-adrenergic-non-cholinergic stimulation of heart rate in digesting pythons

Vertebrates elevate heart rate when metabolism increases during digestion. Part of this tachycardia is due to a non-adrenergic-non-cholinergic (NANC) stimulation of the cardiac pacemaker, and it has been suggested these NANC factors are circulating hormones that are released from either gastrointestinal or endocrine glands. The NANC stimulation is particularly pronounced in species with large metabolic responses to digestion, such as reptiles. To investigate the possibility that the pancreas may release hormones that exert positive chronotropic effects on the digesting Burmese python heart, a species with very large postprandial changes in heart rate and oxygen uptake, we evaluate how pancreatectomy affects postprandial heart rate before and after autonomic blockade of the muscarinic and the beta-adrenergic receptors. We also measured the rates of oxygen consumption and evaluated the short-term control of the heart using the spectral analysis of heart rate variability and the baroreflex sequence method. Digestion caused the ubiquitous tachycardia, but the intrinsic heart rate (revealed after the combination of atropine and propranolol) was not affected by pancreatectomy and therefore hormones, such as glucagon and insulin, do not appear to contribute to the regulation of heart rate during digestion in Burmese pythons.

Accelerating neurotechnology development using an Agile methodology.

Novel bioelectronic medical devices that target neural control of visceral organs (e.g., liver, gut, spleen) or inflammatory reflex pathways are innovative class III medical devices like implantable cardiac pacemakers that are lifesaving and life-sustaining medical devices. Bringing innovative neurotechnologies early into the market and the hands of treatment providers would benefit a large population of patients inflicted with autonomic and chronic immune disorders. Medical device manufacturers and software developers widely use the Waterfall methodology to implement design controls through verification and validation. In the Waterfall methodology, after identifying user needs, a functional unit is fabricated following the verification loop (design, build, and verify) and then validated against user needs. Considerable time can lapse in building, verifying, and validating the product because this methodology has limitations for adjusting to unanticipated changes. The time lost in device development can cause significant delays in final production, increase costs, and may even result in the abandonment of the device development. Software developers have successfully implemented an Agile methodology that overcomes these limitations in developing medical software. However, Agile methodology is not routinely used to develop medical devices with implantable hardware because of the increased regulatory burden of the need to conduct animal and human studies. Here, we provide the pros and cons of the Waterfall methodology and make a case for adopting the Agile methodology in developing medical devices with physical components. We utilize a peripheral nerve interface as an example device to illustrate the use of the Agile approach to develop neurotechnologies.

Frequency of Anterior Inferior Cerebellar Artery Vascular Loops Using CISS Sequence on 3.0T MRI in the Otologic Symptomized Patients

Aim: To estimate the frequency of vascular loops in the anterior inferior cerebellar artery in the otologic symptomized patients using CISS sequence on 3.0 Tesla MRI” in Pakistani populations. Methodology: Cross sectional descriptive study was conducted in Armed Forces Institute of Radiology and Imaging, Military Hospital Rawalpindi from 12th April 2019 to 11th October 2019. One hundred patients of both genders between age of 20-60 years were presented with otologic symptoms i.e. tinnitus, dizziness and hearing loss (unilateral/bilateral) and advised MRI brain. Patients with any diagnosed arterial, venous and arterio-venous cause of otologic symptoms, severe claustrophobia and with internal cardiac pacemakers or any other metallic foreign body were excluded. Patients were undergone MRI brain on 3.0 Tesla. TIWS, T2WS and CISS sequences were taken along with post-contrast T1WS images. Results: There was 20 to 60 years of patients range of age having mean age of 38.38±12.05 years and majority of patients 65% between 20-40 years. There were 53(53%) males and 47(47%) females and having 1.2:1 ratio of male to female. Frequency of anterior inferior cerebellar artery vascular loops in the otologic symptomized patients using CISS sequence on 3.0 Tesla MRI was seen in 59(59%) patients. Conclusion: The frequency of anterior inferior cerebellar artery vascular loops in the otologic symptomized patients using CISS sequence on 3.0 Tesla MRI is very high. Keywords: Anterior inferior cerebellar artery vascular loops, Magnetic resonance imaging, Otologic symptoms

It’s not just the heart: respiratory limitations to constant-load exercise in adult Fontan patients and potential implications for rehabilitation

Introduction Congenital heart defects may require surgical intervention such as the Fontan procedure that connects the systemic venous return to the pulmonary arteries. Although this procedure has increased survival, it results in reduced exercise capacity; which is reduced not only due to cardiovascular factors, but respiratory limitations as well. However, there is a lack of evidence outlining ventilatory limitations during constant-load exercise, which better represents exercise in cardiac rehabilitation programs and non-laboratory based exercise. Therefore, the aim of the present study was to compare responses to constant-load exercise in adult Fontan patients with those of healthy well-matched controls. Methods 14 adult Fontan patients (5F, 27 ± 6yrs) were recruited with 14 healthy matched controls. Participants performed forced vital capacity (FVC), as well as maximal inspiratory and and expiratory pressure assessments (MIP and MEP, respectively). Patients performed an incremental cycling test (ICT) to exhaustion to determine peak work rate. Following a period of recovery, patients performed a constant-load cycling test (CLCT) at 70% of peak ICT work rate until exhaustion. Healthy subjects reproduced the exercise of their matched patient. Cardiorespiratory variables and heart rate (HR) were measured using a metabolic cart and a 12-lead electrocardiogram, respectively. Participants were asked to rate their perception of breathlessness and respiratory exertion via a visual analogue scale every 2 min and at peak exercise. Patients without cardiac pacemakers underwent involuntary assessments of respiratory muscle contractility via phrenic (n = 8) nerve magnetic stimulation before and following exercise to quantify respiratory muscle fatigue. Results Patients showed significantly reduced FVC, MIP and MEP compared to controls (all p &lt; 0.025). Patients’ time-to-exhaustion during the CLCT was 7.1 ± 3.3 min. During CLCT vs. the ICT, patients reached maximal HR, respiratory rate (fR), breathlessness, respiratory exertion, and leg exertion. End-exercise V̇O2 during the CLCT did not reach ICT values, with a mean difference of 1.5 ml/kg/min (p = 0.017). Controls did not reach peak ICT responses during the CLCT. During the CLCT, patients displayed significantly elevated minute ventilation (V̇E; mean difference = 21.5 L/min), fR (mean difference = 13.8 breaths-per-minute), breathlessness (mean difference = 3.4 points), and respiratory exertion (mean difference = 2.3 points), along with significantly decreased ventilatory reserve (V̇E/maximal voluntary ventilation; mean difference = 27.5%; all p &lt; 0.002). Following the CLCT, Fontan patients showed a larger decrease in involuntary respiratory muscle contractility (15 ± 12% vs. 2 ± 11%). Finally, a decreased ventilatory reserve was significantly correlated with decreased MIP (r = 0.723, p = 0.003) and MEP (r = 0.623, p = 0.042). Discussion/Conclusion Fontan patients had a lower-than-expected time-to-exhausiton, in part due to their abnormal ventilatory response. First, the increased pulmonary restriction in the Fontan patients likely led to increased V̇E driven by a high fR during exercise. Second, Fontan patients showed decreased ventilatory reserve - which was significantly associated with respiratory muscle weakness. Third, patients showed significantly increased respiratory muscle fatigue following exercise. Collectively, these factors likely contributed to the increased breathlessness and respiratory exertion in patients, leading to increased exercise limitation. Given this, and the fact that patients reached near maximal physiological responses during the CLCT, it’s possible that patients may benefit more from aerobic training at less than 70% of peak word rate, or from interval-training with significant recovery time.

Expression, distribution, and role of Piezo channels in the cardiac pacemaker

Expression, distribution, and role of Piezo channels in the cardiac pacemaker

Stochastic resonance ensures fail-safe operation of cardiac pacemaker at low rates

Stochastic resonance ensures fail-safe operation of cardiac pacemaker at low rates

Bipolar, high-voltage, long-duration pulsed radiofrequency ablation of the Gasserian ganglion for the treatment of trigeminal neuralgia in a patient with a cardiac implantable electronic device: illustrative case.

One of the common methods of treating trigeminal neuralgia (TN) nowadays is radiofrequency therapy. However, it has serious limitations in patients with a cardiac pacemaker because of electromagnetic interference. Therefore, it is crucial to select optimal radiofrequency ablation parameters to make this procedure safe with favorable outcomes for such patients. In this study, the authors present a case of a 70-year-old man with a history of cardiac pacemaker dependency and previous microvascular decompression with complaints of severe, constant facial pain. After reprogramming the cardiac implantable electronic device (CIED), the authors performed bipolar, high-voltage, long-duration pulsed radiofrequency therapy (PRFT) of the Gasserian ganglion under electrocardiography and pulse rate control in the pre-, intra-, and postoperative periods. There were no cardiovascular or neurological complications after PRFT. The patient reported relief of pain after the procedure, and at the 9-month follow-up, he was pain-free. This clinical case demonstrates that the use of bipolar, high-voltage PRFT for TN treatment in patients with a CIED can be safe and effective, provided that the rules and pacemaker instructions are followed. It is necessary to use ablative treatment with caution and to guide the patient in collaboration with a cardiac surgeon and an anesthesiologist resuscitator.