Cardiac Pacemaker Research Articles

Transitioning from 0.5 to 0.9 mT: Protecting against inadvertent activation of magnet mode in active implants.

The "5 gauss line" is a phrase that is likely to be familiar to everyone working with MRI, but what is its significance, how was it defined, and what changes are currently in progress? This review explores the history of 5 gauss (0.5 mT) as a threshold for protecting against inadvertently putting cardiac pacemakers, implantable cardioverter defibrillators, and other active implantable medical devices into a "magnet mode." Additionally, it describes the background to the recent change of this threshold to 9 gauss (0.9 mT) in the International Standard IEC 60601-2-33 edition 4.0 that defines basic safety requirements for MRI. Practical implications of this change and some ongoing and emerging issues are also discussed.

Elderly patients with decompensated heart failure: prospective analysis from the LECRA-HF registry

Abstract Background/Introduction Heart failure (HF) presents as a clinical syndrome associated with an adverse prognosis, increased mortality risk, and recurrent hospitalizations for HF (HHF). In Poland, there has been a persistent increase in the overall prevalence and hospitalizations of HF among patients. Each subsequent HHF is associated with progressively worsening prognosis. In Europe, HF is most prevalent in elderly individuals, rendering this patient group particularly susceptible to HF exacerbations. Purpose The aim of this study was to conduct a comprehensive analysis of the oldest patients (≥80 years) hospitalized due to HF decompensation, compared to the rest of the evaluated cohort, including overall mortality after median 46 months of observation. Methods The prospective registry of patients with HF decompensation (LECRA-HF) is an ongoing registry conducted at a tertiary cardiology center specializing in HF treatment. Patients enrolled in the registry (n=1394) were evaluated for the presence of cardiovascular risk factors, HF phenotype, laboratory, and echocardiographic findings, as well as overall mortality. Due to the frequent occurrence of HF in elderly patients, we arbitrarily chose to compare two cohorts of patients: those above (n=306) vs. below 80 years of age (n=1088). Results Median age of elderly patients was 84 [82-86] years, of which only 7.8% were >90 years of age. HFrEF was the most common HF phenotype, which, occurred less frequently in the elderly (54.4 vs 74.4%, P<0.001). In turn, HFpEF was more prevalent in elderly group (39.2 vs 17.7%, P<0.001). Elderly patients were more often female (45.1 vs 30.2%, P<0.001) and had more comorbidities: arterial hypertension (85.6 vs 78.6%, P=0.007), atrial fibrillation (61.1 vs 45.7%, P<0.001), renal failure (49.7 vs 28.5%, P<0.001) as well as peripheral arterial disease (17 vs 9.8%, P=0.005). Those patients had more frequently implanted cardiac pacemakers (28.6 vs 12.6%, P<0.001), but less often implantable cardioverter-defibrillators (7.9 vs 14.3%, P=0.003). During HHF they were less often qualified to elective coronary angiography (24.2 vs 31.5%, P=0.039). At discharge mineralocorticoid receptor antagonist were less often prescribed in that group (42.4 vs 50.3%, P=0.010). During long-term observation patients ≥80 years had a higher all-cause mortality (81 vs 67.4%, P<0.001, Panel A). Moreover, it was also higher elderly with NT-proBNP>4497 pg/mL (P<0.001) and LVEF<41% (P=0.014) (Panel B). Conclusion(s) Patients aged ≥80 years were characterized by a higher burden of comorbidities. They were more often qualified to cardiac pacemakers, but less often to implantable cardioverter-defibrillators and invasive coronary procedures. The most common HF phenotype was HFrEF, however with a significant increase in HFpEF. They exhibited significantly higher overall mortality compared to those <80 years old, which was associated with both LVEF and NT-proBNP levels.

Comparative safety outcomes of leadless versus transvenous cardiac pacemaker: a systematic review and meta-analysis

Abstract Introduction Leadless Cardiac Pacemakers (LCP) have emerged as a promising alternative to Transvenous Pacemakers (TVP) for managing bradyarrhythmias, especially in cases where TVP options are limited, such as venous access issues in haemodialysis patients or high infection risk individuals. However, long-term safety data, including mortality and hospitalisation rates, are lacking, hindering informed clinical adoption decisions. Purpose This systematic review and meta-analysis compares safety endpoints of LCP with TVP. Methods A systematic search of PubMed, Medline, Embase, Scopus, Web of Sciences, and gray literature was conducted following PRISMA guidelines from release of the Micra LCP to market until May 15, 2023. Meta-analysis was performed using RevMan 5.4. Results Twenty-four studies including data from 33,450 patients (12,802 LCP, 20,648 TVP) were evaluated. The mean age of the population was 77.5 ± 10.6 years, with a mean left ventricular ejection fraction (LVEF) of 58.6 % ± 6.7. Follow-up durations ranged from 6 to 36 months. Compared to TVP, the LCP was associated with significantly fewer overall complications, major complications, acute, mid-term complications, hospitalisations, re-interventions, and device dislodgements (p<0.05). Mortality, tricuspid regurgitation, pacemaker-induced cardiomyopathy, and heart failure hospitalisation rates did not significantly differ. Although LCP showed higher cardiac injury risk, no significant difference in cardiac tamponade rates was observed (Figure 2). LCP exhibited increased vascular-related complications but decreased lung injury, endocarditis, device, and pocket-related issues. Conclusion In the largest review of LCPs, we report that LCP is associated with significantly lower rates of overall complications compared to conventional TVP. This knowledge is critically important as more LCPs enter clinical practice and serves as a baseline against which future data can be evaluated. Nevertheless, proper skill training may help to mitigate the risk of vascular and cardiac injury. These findings underscore the importance of conducting randomized controlled trials to comprehensively evaluate the safety of LCP compared to TVP.Cardiac complication

Assessing the impact of implantable loop recorder placement on anxiety level

Abstract Background Anxiety is a prolonged state of apprehension or worry that can be an independent predictor of cardiovascular events, associated with a 48% increased risk of cardiac death. About one-third of patients with arrhythmias present with high anxiety levels, and subsequently worse quality of life. In our experience of patient care, many patients feel anxious about the possibility of an arrhythmia that could lead to their demise, especially if their symptoms are undiagnosed. Purpose Our project aims to explore the change in patients’ anxiety levels following implantable loop recorder (ILR) placement. Methods This is a survey-based observational study that was performed in an outpatient clinic and hospital using validated General Anxiety Disorder-7 (GAD-7) questionnaires. Individuals who met indications to undergo ILR implantation including palpitations, syncope, subclinical atrial fibrillation, and cryptogenic stroke underwent baseline assessment of anxiety prior to implantation. Individuals had repeat assessments at 6 weeks and 12 weeks post-implantation to evaluate the effect of ILR placement. Results Our study included 50 individuals. Out of the initial subjects, 10/25 females and 11/25 males were lost to follow-up. The average initial GAD-7 score was 3.3 (Range 0, 15), average 6-week score was 1.6 (Range 0, 14), and average 12-week score was 0.9 (Range 0, 10). Total decrease in GAD-7 score after 6 weeks of having ILR was 50%. Total decrease in GAD-7 score after 12 weeks of ILR was statistically significant at 73% (P=0.03). Females showed greater improvement of GAD-7 scores in comparison to males at 6 weeks (67% vs 36%) and 12 weeks (81% vs 66%). Conclusion Studies have suggested an overall decreased level of anxiety in patients receiving implantable devices that have the potential to treat arrhythmias such as implantable cardiac defibrillators and pacemakers. Our results suggest that the benefit may extend to implantable devices that seek to provide further diagnostic information and aid in the prognostication of disease burden. As seen in our study population, GAD-7 scores showed dramatic improvement with greater percentage in female than male population. After the placement of loop recorders, many patients experience a sense of security with having a device that monitors them. Our study is the first to address the association between ILR and anxiety. Future studies evaluating this association would help increase the power of the study.Figure 1:Bar graph of GAD-7 Scores

Acute myocarditis presentation and intra-hospital prognosis: results of the multicenter prospective MYOCARDITIRM study

Abstract Background Acute myocarditis (AM) usually presents as chest pain with rising troponin and normal coronary arteries. Despite frequent favorable evolution at the acute phase, it is associated with heart failure and ventricular rhythm disorders and is considered the leading cause of sudden cardiac death in young apparently healthy adults. There is no recommendation for AM, only expert consensus, given the lack of important databases for a strong level of confidence. Methods We performed a multicenter prospective observational study of patients admitted for AM acknowledged by cardiac MRI to describe baseline characteristics, management, in-hospital and long-term outcomes of AM patients in France. Secondary objectives were to investigate determinants of prognosis, modalities of treatment and follow-up, and to identify gaps between expert consensus and real-life management. Results We enrolled 805 consecutive patients hospitalized for AM in 49 participating centers between May 2016 and February 2019. Median age was 31 (IQR 23-41) with 19% of female. Chest pain was the most frequent symptom (93%) and 112 (14%) had severity criteria upon admission (LVEF<50% or severe ventricular arrythmia or high-grade AV block or cardiogenic shock). ST elevation was observed in 49% of patients. One 26-years old patient died during initial hospital stay. Overall, 62 patients (8%) experienced intra-hospital complication of their AM, defined as a combined endpoint of death, LVEF<40% (MRI), sustained ventricular or supraventricular arrythmia, acute renal failure, cardiogenic shock, need for ventricular assistance device, need for inotropic drugs, temporary cardiac pacing, pace-maker or cardiac defibrillator implantation. Patients with initial severity criteria were 10 times more likely to present intra-hospital complication (33% vs 3.6%, p<0.001). Conclusion This prospective cohort represents the largest database on AM worldwide. Here we report baseline characteristics and in hospital events. Most patients had typical presentation with favorable outcomes but as much as 8% of patients did exhibit intra-hospital complication. The prospective follow up will provide valuable data to better identify subset of patients with poor prognosis that may be of interest to develop new therapeutic strategies.Acute myocarditis on cardiac MRI

Cells of the adult mouse cardiac conduction system in wild type and Nkx2-5 heterozygous loss-of-function mutation

Abstract Background Specialised cardiomyocytes in the cardiac conduction system (CCS) generate and spread the electrical impulse that initiates synchronised heartbeats. Disrupted signal transduction in the atrioventricular (AV) node, a key electrical connection between atria and ventricles, causes AV block. AV block potentially leads to electromechanical uncoupling and sudden cardiac death. Nkx2-5 encodes a cardiac transcription factor that is critical for embryonic CCS formation. Heterozygous loss-of-function mutation of Nkx2-5 (Nkx2-5+/–) results in a hypoplastic CCS in humans and mice and progressive AV block. Purpose We aimed to create a cell atlas of the adult mouse CCS and define the consequences of Nkx2-5 haploinsufficiency on the structural organisation and transcript expression of CCS cells. Methods We performed single-nucleus RNA sequencing on the sinoatrial nodes, AV nodes, His bundles, right bundle branches (RBB) and moderator bands of 17 wild type and 14 Nkx2-5+/– mice (aged 13 to 35 weeks, 5159 CCS cells). Employing single-molecule fluorescent RNA in situ hybridisation (smFISH), we validated selected transcripts and examined the spatial organisation of identified cell populations. Results In the AV node, we identified two subpopulations of pacemaker cells that were spatially separated in the proximal and distal pacemaker region (Fig1). Within these subpopulations, expressed transcripts indicated an atrial-to-ventricular gradient of electrical activity, corresponding to their respective topography. We determined two subpopulations in the His bundle and RBB that were enriched for either slow or fast conduction markers. Spatially, the slow-conducting populations seemed to surround the fast-conducting ones and might act as electrical isolation (Fig1). In Nkx2-5+/- cells of the pacemaker AV node, His bundle, RBB and Purkinje fibres, genes involved in Slit-Robo signalling were dysregulated. Slit-Robo signalling was previously reported in neuronal differentiation and embryonic heart lumen formation. Slit ligand 3 was downregulated in Nkx2-5+/- pacemaker AV node cells (Slit3, log2FC = -2.22, p = 7.0e-42), as was the roundabout guidance receptor 1 (Robo1, log2FC = -0.96, p = 1.6e-4). By contrast, there was upregulation of neural EGF-like 1 (Nell1, log2FC = 3.18, p = 5.3e-6), an alternative ligand of roundabout guidance receptors. Altered Nell1 and Slit3 expressions were confirmed by smFISH (Fig2). Conclusions Our cell atlas defines new CCS cell populations with informative transcriptomic profiles and spatial organisation, providing insights into subpopulations in the AV junction where electrical signals switch from slow to fast conduction. We identified disrupted Slit-Robo signalling in Nkx2-5+/-, possibly impairing differentiation and maturation of the CCS and altering electrophysiologic functions. Our normative anatomical and transcription data on the CCS can inform future studies of cardiac electrophysiology and arrhythmias.Fig1 - Subpopulations in AV junctionFig2 - Nell1 smFISH in pacemaker AV node

Impact of atrial high-rate episodes on new onset of atrial fibrillation and all-cause mortality in elderly patients over 90 years old with dual-chamber pacemaker implantation

Objective: To investigate the impacts of atrial high-rate episodes (AHRE) on the risks of new onset of atrial fibrillation and all-cause mortality in elderly patients over 90 years old after cardiac dual-chamber pacemaker implantation. Methods: This study was a retrospective study. Patients aged 90 years and above who were implanted with cardiac dual-chamber pacemakers and followed up in the People's Liberation Army General Hospital from January 2017 to June 2022 were enrolled and divided into AHRE≥6 h group and AHRE<6 h group according to the onset time of AHRE. The primary endpoint was new onset of atrial fibrillation, and the secondary endpoints were all-cause mortality and cardiovascular mortality. Kaplan-Meier survival curve was poltted, and log-rank test was used to compare the differences in the incidence of new onset of atrial fibrillation, all-cause death and cardiovascular death between AHRE≥6 h and AHRE<6 h groups. Multivariate Cox survival analysis was used to investigate the factors affecting new onset of atrial fibrillation, all-cause death and cardiovascular death in elderly patients aged 90 years and above with dual-chamber pacemaker implantation. Results: A total of 169 patients were enrolled, aged (93.95±3.28) years, including 18 females (11%). The median follow-up time was 28.9 months. There were 87 and 82 patients in AHRE≥6 h group and AHRE<6 h group, respectively. Kaplan-Meier survival curve analysis showed that the incidence of new onset of atrial fibrillation (log-rank P<0.001), all-cause death (log-rank P=0.004) and cardiovascular death (log-rank P=0.026) in AHRE≥6 h group was significantly higher than that in AHRE<6 h group.After adjusting for traditional risk factors, multivariate Cox survival analysis showed that AHRE≥6 h was an independent risk factor for new onset of atrial fibrillation (HR=4.046, 95%CI 2.402-6.814, P<0.001) and all-cause mortality (HR=1.668, 95%CI 1.119-2.487, P=0.012) in elderly patients over 90 years old with cardiac dual-chamber pacemaker implantation. However, AHRE≥6 h had no effect on cardiovascular mortality (P>0.05). Anemia (HR=3.098, 95%CI 1.342-7.153, P=0.008) and heart failure with reduced ejection fraction (HR=3.028, 95%CI 1.181-7.763, P=0.021) were both independently associated with cardiovascular mortality. Conclusions: AHRE is common in cardiac dual-chamber pacemakers recipients aged 90 years and above, and AHRE≥6 h can be used as a predictor of new onset of atrial fibrillation or all-cause mortality in these patients.

Simultaneous versus staged approach in transcatheter aortic valve implantation for severe stenosis and endovascular aortic repair for thoracic and abdominal aortic aneurysm.

Thoracic/abdominal aortic aneurysms(T/AAAs) and aortic stenosis(AS) may be concomitant diseases requiring both transcatheter aortic valve implantation(TAVI) and endovascular aneurysm repair(T/EVAR) in high risk patients for surgical approaches, but temporal management is not clearly defined, yet. Aim of the study was to analyze outcomes of simultaneous vs staged TAVI and T/EVAR. Retrospective observational multicentre study on patients requiring TAVI and T/EVAR from 2016 to 2022. Patients were divided into 2 groups: "Simultaneous group" if T/EVAR+TAVI were performed in the same procedure and "Staged group" if T/EVAR and TAVI were performed in two steps, but within 3 months. Primary outcomes were: technical success, 30-day mortality/major adverse events and follow-up survival. Secondary outcomes were procedural metrics and length of stay (LOS). Forty-four cases were collected; 8(18%) had TEVAR and 36(82%) EVAR, respectively. Upon temporal determination 25(57%) and 19(43%) were clustered in simultaneous and staged groups, respectively. In staged group, median time between procedures was 72(interquartile-range-IQR : 57-87) days. Preoperative and intraoperative figures were similar. There was no difference in 30-day mortality(Simultanoeus : 0/25 vs Staged : 1/19; p = 0.43). Pulmonary events(Simultaneous : 0/25 vs Staged : 5/19; p = 0.01) and need of postoperative cardiac pacemaker(Simultaneous : 2/25 vs Staged : 7/19; p = 0.02) were more frequent in Staged patients. The overall LOS was lower in Simultaneous group[Simultaneous : 7(IQR : 6-8) vs Staged : 19(IQR : 15-23)days; p = 0.001]. The median follow-up was 25(IQR : 8-42) months and estimated 3-year survival was 73% with no difference between groups(Simultanoeus : 82% vs Staged : 74%; p = 0.90). Both simultaneous or staged T/EVAR and TAVI procedures are effective with satisfactory outcomes. Despite the small numbers, simultaneous repair seems to reduce length-of-stay and pulmonary complications, maintaining similar follow-up survival.

Innovations in Drug Delivery: From Microtechnology to Targeted Therapeutics

Drug delivery systems are developed to maximize drug efficacy and minimize side effects. As drug delivery technologies improve, the drug becomes safer and more comfortable for patients to use. The study on advanced drug delivery systems aims to increase patient compliance, decrease adverse effects, and improve treatment efficacy. Furthermore, the goal of these systems is to deliver drugs to particular body tissues or cells in a targeted manner, which should enhance treatment outcomes. During the last seven decades, extraordinary progress has been made in drug delivery technologies, such as systems for long-term delivery for months and years, localized delivery, and targeted delivery. In this review, we explain the general principles of several advanced drug delivery systems, their introduction objective, components, mechanism, functioning principle, and application. The implantable polymeric drug delivery system, cardiac pacemaker, prefilled dual chamber device, closed-loop insulin delivery system, hepatic infusion pumps, MEMS devices, inhaled insulin devices, and hydrogel-forming microneedles are among the medical devices that are being discussed in this article as being at the forefront of technological innovation in medicine. For a variety of medical diseases, these devices provide minimally invasive procedures, real-time monitoring, and more accurate drug delivery. The scope of medical treatment and monitoring procedures is changing due to the integration of cutting-edge materials and technology. By increasing convenience, decreasing adverse effects, and increasing efficacy, these cutting-edge solutions directly help patients. Furthermore, the adoption of advanced drug delivery systems has demonstrated promising results in enhancing patient compliance and treatment outcomes. By increasing the bioavailability and pharmacokinetics of pharmaceuticals, these systems have the potential to transform the fields of drug delivery and personalized medicine. However, the field also faces challenges in overcoming physicochemical barriers and biological unknowns. Challenges facing the advanced drug delivery systems industry include complicated formulation requirements, regulatory obstacles, and the need for new technologies to enhance patient outcomes and therapeutic efficacy. Strict intellectual property rules and competition from generic drug manufacturers can also directly hinder the expansion and financial success of businesses in this field. To progress, the field should focus on translatable research ideas, develop realistic goals, and most importantly, diversify technologies. This emphasis on diversity will inspire new ideas and approaches, leading to the development of more effective, patient-friendly drug delivery systems.

Treatment of malignant primary cardiac tumors requires attention to cardiovascular complications: a single-center, retrospective study.

Malignant primary cardiac tumors require multimodal approaches including surgery, chemotherapy and radiotherapy, but these treatments can be associated with cardiovascular complications. However, few reports have described the cardiovascular complications related to primary cardiac tumor treatment because of their rarity. Clinical records of patients with primary cardiac tumors treated at Kyushu University Hospital from January 2010 to August 2021 were retrospectively examined. Of the 47 primary cardiac tumor patients, 13 (28%) were diagnosed with malignancy, including 5 angiosarcomas, 3 intimal sarcomas, 3 diffuse large B-cell lymphomas, 1 Ewing's sarcoma and 1 fibrosarcoma. Cardiovascular events were observed in 10 patients (77%), including cardiac dysfunction in 6 patients, arrhythmias in 5 patients, right heart failure in 2 patients, and excessively prolonged prothrombin time due to the combination of warfarin and chemotherapy in 1 patient. Two patients who showed notable cardiac complications are described. Case A involved a 69-year-old woman who underwent surgery for a left atrial intimal sarcoma, followed by postoperative chemotherapy with doxorubicin plus ifosfamide and radiotherapy. After three cycles of chemotherapy and sequential radiotherapy, her left ventricular ejection fraction decreased to 34%, and ongoing heart failure therapy was required. Case B involved a 66-year-old man who received chemotherapy for primary cardiac lymphoma, resulting in tumor shrinkage. However, due to tumor involvement of the intraventricular septum, atrioventricular block developed, requiring cardiac pacemaker implantation. High incidences of cardiac failure and arrhythmias were observed during multimodal treatments for malignant primary cardiac tumors. Proper management of complications may lead to a favorable prognosis in patients with malignant primary cardiac tumors.

A gene desert required for regulatory control of pleiotropic Shox2 expression and embryonic survival

Approximately a quarter of the human genome consists of gene deserts, large regions devoid of genes often located adjacent to developmental genes and thought to contribute to their regulation. However, defining the regulatory functions embedded within these deserts is challenging due to their large size. Here, we explore the cis-regulatory architecture of a gene desert flanking the Shox2 gene, which encodes a transcription factor indispensable for proximal limb, craniofacial, and cardiac pacemaker development. We identify the gene desert as a regulatory hub containing more than 15 distinct enhancers recapitulating anatomical subdomains of Shox2 expression. Ablation of the gene desert leads to embryonic lethality due to Shox2 depletion in the cardiac sinus venosus, caused in part by the loss of a specific distal enhancer. The gene desert is also required for stylopod morphogenesis, mediated via distributed proximal limb enhancers. In summary, our study establishes a multi-layered role of the Shox2 gene desert in orchestrating pleiotropic developmental expression through modular arrangement and coordinated dynamics of tissue-specific enhancers.

Injection of carbon dioxide instead of iodinated contrast to display the common bile duct during endoscopic retrograde cholangiopancreatography.

Common bile duct (CBD) stones are usually caused by biliary tract infection, biliary stricture, duodenal peripapillary diverticulum, Oddis sphincter dysfunction, and so on. Treatment is preferably with endoscopic retrograde cholangiopancreatography (ERCP), where an iodine-containing contrast agent is injected into the CBD to display the stone under fluoroscopy and then to confirm complete removal of the stone(s). We described a 65-year-old woman with CBD stones who had undergone cardiac pacemaker implantation and was allergic to iodinated contrast media. We performed ERCP + lithotomy + stent implantation under local anesthesia, with injection of carbon dioxide instead of iodinated contrast into the CBD, and successfully visualized the stones under fluoroscopy and then confirmed complete removal of them. The patient was generally in good condition without complications. Thus, we have demonstrated in this case report that carbon dioxide can be used as a safe, economical, and effective alternative to iodinated contrast agent during ERCP.

People with cardiac pacemakers require multidisciplinary care.

People with cardiac pacemakers require multidisciplinary care.

Adaptive control of cardiac rhythms

Cardiac rhythms are related to heart electrical activity, being the essential aspect of the cardiovascular physiology. Usually, these rhythms are represented by electrocardiograms (ECGs) that are useful to detect cardiac pathologies. Essentially, the heart activity starts in the sinoatrial node (SA) node, the natural pacemaker, propagating to the atrioventricular node (AV), and finally reaching the His-Purkinje complex (HP). This paper investigates the control of cardiac rhythms in order to induce normal rhythms from pathological responses. A mathematical model that presents close agreement with experimental measurements is employed to represent the heart functioning. The adopted model comprises a network of three nonlinear oscillators that represent each one of the cardiac nodes, connected by delayed couplings. The pathological behavior is induced by an external stimulus in the SA node. An adaptive controller is proposed acting in the SA node considering an strategy based on the signal obtained by the natural pacemaker and its regularization. The incorporation of adaptive compensation in a Lyapunov-based control scheme allows the compensation for the unknown dynamics. The controller ability to deal with interpatient variability is evaluated by assuming that the heart model is not available to the controller design, being used only in the simulator to assess the control performance. Results show that the adaptive term can reduce the control effort by around 3% while reducing the tracking error by 20%, when compared to the conventional feedback approach. Additionally, the controller can avoid abnormal rhythms, turning the ECG closer to the expected normal behavior and preventing critical cardiac responses. Therefore, this work demonstrates that an adaptive controller can be used to regulate the ECG signal without prior information about the system and disregarding inter- and intrapatient variability.

Characterization of the cellular components of mouse collecting lymphatic vessels reveals that lymphatic muscle cells are the innate pacemaker cells regulating lymphatic contractions.

Collecting lymphatic vessels (cLVs) exhibit spontaneous contractions with a pressure-dependent frequency, but the identity of the lymphatic pacemaker cell is still debated. By analogy to pacemakers in the GI and lower urinary tracts, proposed cLV pacemaker cells include interstitial cells of Cajal like cells (ICLC) or the lymphatic muscle (LMCs) cells themselves. Here we combined immunofluorescence and scRNAseq analyses with electrophysiological methods to examine the cellular constituents of the mouse cLV wall and assess whether any cell type exhibited morphological and functional processes characteristic of pacemaker cells: a continuous if not contiguous network integrated into the electrical syncytium; spontaneous Ca2+ transients; and depolarization-induced propagated contractions. We employed inducible Cre (iCre) mouse models routinely used to target these specific cell populations including: c-kitCreER T2 to target ICLC; PdgfrβCreER T2 to target pericyte-like cells; PdgfrαCreER ™ to target CD34+ adventitial cells and ICLC; and Myh11CreER T2 to target LMCs directly. These specific inducible Cre lines were crossed to the fluorescent reporter ROSA26mT/mG, the genetically encoded Ca2+ sensor GCaMP6f, and the light-activated cation channel rhodopsin2 (ChR2). c-KitCreER T2 labeled both a sparse population of LECs and round adventitial cells that responded to the mast cell activator compound 48-80. PdgfrβCreER T2 drove recombination in both adventitial cells and LMCs, limiting its power to discriminate a pericyte-specific population. PdgfrαCreER ™ labeled a large population of interconnected, oak leaf-shaped cells primarily along the adventitial surface of the vessel. Of these cells, only LMCs consistently, but heterogeneously, displayed spontaneous Ca2+ events during the diastolic period of the contraction cycle, and whose frequency was modulated in a pressure-dependent manner. Optogenetic depolarization through the expression of ChR2 under control of Myh11CreER T2 , but not PdgfrαCreER ™ or c-KitCreER T2 , resulted in propagated contractions upon photo-stimulation. Membrane potential recordings in LMCs demonstrated that the rate of diastolic depolarization significantly correlated with contraction frequency. These findings support the conclusion that LMCs, or a subset of LMCs, are responsible for mouse cLV pacemaking.

Creative and accurate method for optimal hardware implementation of neurons and biological cells: Application in FPGA-based implementation of cardiac pacemaker cell

The sinoatrial (SA) node cells play a vital role as the principal pacemaker in mammalian hearts, generating regular and spontaneous action potentials to regulate the heart’s rhythm. Comprehending the intricate activity of the SA node’s operation necessitates a collection of differential formulas that tackle non-linear functions. The study presents a new technique to improve the digital representation of the SA node cell model, offering benefits such as decreased hardware needs, enhanced processing speed and accuracy, and reduced implementation expenses by transforming the original model’s differential equations into a unified trigonometric function. This transformation significantly simplifies the computational complexity by eliminating the need for multipliers, resulting in a streamlined set of mathematical expressions. The digital implementation of this novel method can be efficiently realized using the Coordinate Rotation Digital Computer (CORDIC) algorithm, which circumvents the necessity for cumbersome mathematical operations. To demonstrate the viability of this approach, the proposed model is successfully synthesized and implemented on a Field-Programmable Gate Array (FPGA). The results of the implementation demonstrate a significant rise in the operating frequency, which is approximately 6.14 times greater than that of the original model. Furthermore, there is a notable 45 percent decrease in power usage. The lowered hardware needs make significant scalability possible, thus allowing for the inclusion of approximately 12 times as many SA node cells on a sole FPGA board in comparison to the original design.

Role of Piezoelectricity in Disease Diagnosis and Treatment: A Review.

Because of their unique electromechanical coupling response, piezoelectric smart biomaterials demonstrated distinctive capability toward effective, efficient, and quick diagnosis and treatment of a wide range of diseases. Such materials have potentiality to be utilized as wireless therapeutic methods with ultrasonic stimulation, which can be used as self-powered biomedical devices. An emerging advancement in the realm of personalized healthcare involves the utilization of piezoelectric biosensors for a range of therapeutic diagnosis such as diverse physiological signals in the human body, viruses, pathogens, and diseases like neurodegenerative ones, cancer, etc. The combination of piezoelectric nanoparticles with ultrasound has been established as a promising approach in sonodynamic therapy and piezocatalytic therapeutics and provides appealing alternatives for noninvasive treatments for cancer, chronic wounds, neurological diseases, etc. Innovations in implantable medical devices (IMDs), such as implantable piezoelectric energy generator (iPEG), offer significant advantages in improving physiological functioning and ability to power a cardiac pacemaker and restore the heart function. This comprehensive review critically evaluates the role of piezoelectricity in disease diagnosis and treatment, highlighting the implication of piezoelectric smart biomaterials for biomedical devices. It also discusses the potential of piezoelectric materials in healthcare monitoring, tissue engineering, and other medical applications while emphasizing future trends and challenges in the field.

Electric Pulp Test Threshold Responses in Healthy Mature Permanent Teeth

Electric pulp testers assess only the neural component of pulp sensibility in dental practice, while vascular status is evaluated with laser Doppler flowmeters and pulp oximeters, which are more reliable for determining vitality in traumatic teeth. Objective: To determine the accuracy of the electric pulp test in healthy mature permanent teeth. Methods: This cross-sectional study was conducted at the Liaquat University of Medical and Health Sciences Jamshoro by consecutive sampling on 220 participants aged 18-35, who had healthy, mature permanent central incisors, canines, first premolars, and first molars, with no history of cardiac pacemakers and metallic restorations. Teeth were isolated, dried, and tested with a COXO C-Pulse electric pulp tester using toothpaste as a conducting medium. Threshold responses were recorded at increasing currents, with each tooth tested twice to determine the mean value. Accuracy was assessed using additional metrics post-therapy. Chi-square tests were employed to compare accuracy across gender and age groups, with significance set at p&lt;0.05. Results: The mean age of the patients was 25.55 ± 5.41 years. 132 (60%) subjects were female, 88 (40%) subjects were male in this study. Accuracy of the electric pulp test in healthy mature permanent teeth was detected in 181 (82.3%) subjects in this study. Conclusion: It was concluded that the electric pulp tester method seems to be a reliable way to evaluate how sensitive the live nerve tissue inside a tooth is for healthy permanent teeth that have fully formed.

Fully Implantable Wireless Cardiac Pacing and Sensing System Integrated with Hydrogel Electrodes.

Cardiac pacemakers play a crucial role in arrhythmia treatment. Existing devices typically rely on rigid electrode components, leading to potential issues such as heart damage and detachment during prolonged cardiac motion due to the mechanical mismatch with cardiac tissue. Additionally, traditional pacemakers, with their batteries and percutaneous leads, introduce infection risks and limit freedom of movement. A wireless, battery-free multifunctional bioelectronic device for cardiac pacing is developed. This device integrates highly conductive (160Sm-1), flexible (Young's modulus of 80kPa is similar to that of mammalian heart tissue), and stretchable (270%) soft hydrogel electrodes, providing high signal-to-noise ratio (≈28dB) electrocardiogram (ECG)recordings and effective pacing of the beating heart. The versatile device detects physiological and biochemical signals in the cardiac environment and allows for adjustable pacing in vivo studies. Remarkably, it maintained recording and pacing capabilities 31 days post-implantation in rats. Additionally, the wireless bioelectronic device can be fully implanted in rabbits for pacing. By addressing a major shortcoming of conventional pacemakers, this device paves the way for implantable flexible bioelectronics, which offers promising opportunities for advanced cardiac therapies.

Profiling Reduced Expression of Contractile and Mitochondrial mRNAs in the Human Sinoatrial Node vs. Right Atrium and Predicting Their Suppressed Expression by Transcription Factors and/or microRNAs.

(1) Background: The sinus node (SN) is the main pacemaker of the heart. It is characterized by pacemaker cells that lack mitochondria and contractile elements. We investigated the possibility that transcription factors (TFs) and microRNAs (miRs) present in the SN can regulate gene expression that affects SN morphology and function. (2) Methods: From human next-generation sequencing data, a list of mRNAs that are expressed at lower levels in the SN compared with the right atrium (RA) was compiled. The mRNAs were then classified into contractile, mitochondrial or glycogen mRNAs using bioinformatic software, RStudio and Ingenuity Pathway Analysis. The mRNAs were combined with TFs and miRs to predict their interactions. (3) Results: From a compilation of the 1357 mRNAs, 280 contractile mRNAs and 198 mitochondrial mRNAs were identified to be expressed at lower levels in the SN compared with RA. TFs and miRs were shown to interact with contractile and mitochondrial function-related mRNAs. (4) Conclusions: In human SN, TFs (MYCN, SOX2, NUPR1 and PRDM16) mainly regulate mitochondrial mRNAs (COX5A, SLC25A11 and NDUFA8), while miRs (miR-153-3p, miR-654-5p, miR-10a-5p and miR-215-5p) mainly regulate contractile mRNAs (RYR2, CAMK2A and PRKAR1A). TF and miR-mRNA interactions provide a further understanding of the complex molecular makeup of the SN and potential therapeutic targets for cardiovascular treatments.