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Every year, cardiovascular diseases cause millions of deaths worldwide. These diseases involve complex mechanisms that are difficult to study. To remedy this problem, we propose to develop a heart–brain platform capable of reproducing the mechanisms involved in generating the heartbeat. The platform will be designed to operate in real time, with the most economical and integrated design possible. To achieve this, we are implementing highly biologically coherent cellular models on FPGA, which we interconnect with in vitro cell cultures. In our case, we are using the Maltsev–Lakatta cell model, which describes the behavior of the pacemaker cells responsible for the heart rhythm, to stimulate a cardiomyocyte culture. [ABSTRACT FROM AUTHOR]

Introduction: Sepsis, a life-threatening syndrome, is often accompanied by tachycardia in spite of hypovolemia and hypotension have been corrected. Recently, relevant studies have shown that sustained tachycardia in sepsis was related to high mortality, and appropriate control of heart rate (HR) could improve prognosis. Ivabradine reduces HR directly without a negative inotropic effect through inhibition of the If ionic current, which is different from the traditional rate control drug (beta-blockers). Methods and analysis: This is a prospective, multicenter, randomized, open label study designed to investigate the effect of heart rate control with ivabradine on hemodynamic in patients with sepsis. Our study will enroll 172 patients with sepsis as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria with sinus rate of 95 bpm or higher despite a hemodynamic optimization. Patients will be randomly assigned to standard treatment group (GS) or ivabradine group (GI, standard treatment for sepsis plus enteral ivabradine). Patients in GI will receive ivabradine to maintain HR between 70 and 94 bpm. The primary outcome is the difference of a reduction in HR below 95 bpm and the effect of ivabradine on hemodynamics between GI and GS group within the first 96 h after randomization. The secondary outcomes include organ function measures, the difference in SOFA score, incidence of adverse events, need for organ support, length of ICU stay, and 28-day overall mortality. Discussion: There are limited studies on ivabradine to control heart rate in patients with sepsis. Our study aims to evaluate whether direct sinus node inhibition can improve hemodynamics, as well as its impact on organ function and prognosis in patients with sepsis, so as to provide evidence for the safe usage in clinical practice. Trial registration: ClinicalTrials.gov NCT05882708. Registered on May 11, 2023, https://clinicaltrials.gov/ct2/show/NCT05882708. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Data from the literature suggest a slight increase in cardiovascular risk for people with non-O blood types. The purpose of the study was to evaluate if there is an association between advanced cardiac conduction disorders and blood groups. In this retrospective study, a group of patients with atrio-ventricular conduction disorders or sinus node disease, having an indication for permanent cardiostimulation, was analyzed and compared with a control group consisting of patients who underwent coronary angiography or elective peripheral angiography. The blood group was determined in all patients. Univariate and multivariate statistical methods were used. Six hundred forty patients, mean age 72±11y, 55.3% men, were included: 320 patients with advanced atrio-ventricular conduction disorders or sinus node dysfunction in the study group and 320 patients in the control group. Blood type A had the highest prevalence (46.8%), followed by blood types O (28.95%), B (16.74%) and AB (7.51%). In the group with heart rhythm disorders, patients with blood type A had an increased risk of atrio-ventricular block (OR 1.38, p= 0.02), but not with sinus node disease (OR 1.02, p= 0.98). Blood type O had a protective role both for atrio-ventricular block and for sinus node dysfunction (OR 0.65, p= 0.01). Blood type A proved to be an independent predictor for atrio-ventricular conduction disorders in patients with severe heart rhythm disorders with indication for permanent cardiostimulation. [ABSTRACT FROM AUTHOR]

(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. [ABSTRACT FROM AUTHOR]

Background and Aims: Antipsychotic drugs are critical in managing psychosis but they also carry risks when misused, leading to toxicity. Case Presentation: A patient overdosed on olanzapine, resulting in anticholinergic toxidrome with symptoms like tachycardia and altered mental status. Immediate recognition and management of antipsychotic toxicity-induced toxidromes in emergency settings are crucial. Treatment strategy includes maintaining airway, breathing and circulation along with decontamination. There is no specific antidote. Conclusion: This case underscores the need for emergency physicians to remain vigilant and proactive in identifying and addressing such toxicity by identification of toxidromes to prevent complications and missed diagnosis in emergency department. [ABSTRACT FROM AUTHOR]

Introduction: We report a case of accelerated idioventricular rhythm (AIVR) identified by Emergency Medical Services (EMS) monitoring of an infant presenting with lethargy and respiratory distress. Accelerated idioventricular rhythms are rare ventricular rhythms originating from the His-Purkinje system or ventricular myocytes, consisting of >3 monomorphic beats with gradual onset and termination.1 An AIVR is usually well-tolerated and does not require treatment, though sustained arrythmia may induce syncope, and the rhythm has been seen in newborn infants with congenital heart diseases.1 Monitoring ill children with ECG can identify such dysrhythmias in the prehospital setting. Case Report: An 18-month-old male presented to their pediatrician with lethargy and respiratory distress, prompting activation of EMS. The patient was placed on a 4-lead ECG initially revealing monomorphic QRS complexes at a rate of 170 beats per minute (BPM). A 12-lead ECG was interpreted as sinus tachycardia by the paramedics who noted the QRS complexes were "getting taller and shorter" with a stable rapid heart rate. The clinician then noted a consistently wide tachycardia which spontaneously converted to a narrow complex tachycardia. The QRS pattern remained variable, with notation of variable R-wave height. After arrival to the emergency department, pediatric cardiology was consulted and interpreted the prehospital ECG findings as accelerated idioventricular rhythm. The patient experienced multiple occurrences of accelerated idioventricular rhythm during hospitalization without associated hypoxia or decreased perfusion. Discussion: Accelerated idioventricular rhythm is relatively rare entity without underlying cardiac disease and most cases are asymptomatic or benign. In the pediatric population, AIVR is generally related to congenital heart defects, cardiac tumors, and cardiomyopathies. In the prehospital setting, continuous ECG monitoring should be a part of care by Advanced Life Support personnel in children with altered mental status, respiratory distress, unexplained syncope, or suspected arrhythmias and 12 lead ECG should be considered if there is any abnormality noted. While this patient did not experience persisting morbidity from AIVR, the potentially hazardous rhythm would not have been recognized without the astute observation, clinical management and persistent follow up of the prehospital clinicians. [ABSTRACT FROM AUTHOR]

Background: 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. Results: 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. Conclusions: 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." Key Findings: ontogenesis, ionic mechanisms, electrophysiological properties, action potential, sinoatrial node cell. [ABSTRACT FROM AUTHOR]

Aging is a major risk factor for sinoatrial node (SAN) dysfunction, which can impair heart rate (HR) control and heart rate variability (HRV). HR and HRV are determined by intrinsic SAN function and its regulation by the autonomic nervous system (ANS). The purpose of this study was to use multi-scale multi-fractal detrended fluctuation analysis (MSMFDFA; a complexity-based approach to analyze multi-fractal dynamics) to longitudinally assess changes in multi-fractal HRV properties and SAN function in ECG time series recorded repeatedly across the full adult lifespan in mice. ECGs were recorded in anesthetized mice in baseline conditions and after autonomic nervous system blockade every three months beginning at 6 months of age until the end of life. MSMFDFA was used to assess HRV and SAN function every three months between 6 and 27 months of age. Intrinsic HR (i.e. HR during ANS blockade) remained relatively stable until 15 months of age, and then progressively declined until study endpoint at 27 months of age. MSMFDFA revealed sudden and rapid changes in multi-fractal properties of the ECG RR interval time series in aging mice. In particular, multi-fractal spectrum width (MFSW, a measure of multi-fractality) was relatively stable between 6 months and 15 months of age and then progressively increased at 27 months of age. These changes in MFSW were evident in baseline conditions and during ANS blockade. Thus, intrinsic SAN function declines progressively during aging and is manifested by age-associated changes in multi-fractal HRV across the lifespan in mice, which can be accurately quantified by MSMFDFA. [ABSTRACT FROM AUTHOR]

Background: Individuals living with HIV are at increased risk of developing cardiovascular diseases. This heightened vulnerability is influenced by various factors, including the direct impact of HIV infection, the side effects of HIV medications, and a higher presence of traditional cardiovascular risk factors. Detecting and managing cardiovascular diseases early in HIV-infected individuals is crucial for their overall health and well-being. Electrocardiography, a simple and non-invasive test, can provide valuable information in this regard. However, there is currently no published data on the prevalence of electrocardiographic abnormalities and the associated factors among HIV-infected adults in Ethiopia. Objectives: This study was aimed at assessing the prevalence of ECG abnormalities and associated factors among HIV-infected adults on antiretroviral therapy. Methodology: A hospital-based comparative cross-sectional study was conducted at Mettu Karl Specialized Hospital (MKSH), southwest Ethiopia, among 96 HIV-infected patients and 96 HIV-negative control groups. A systematic random sampling technique was used to select HIV-infected respondents, and HIV-negative respondents were purposively recruited from caregivers. A face-to-face interview with a semi-structured and pretested questionnaire was conducted to collect the socio-demographic and behavioral characteristics of the study participants. Electrocardiography was done for all study participants using a 12-lead electrocardiograph, interpreted by a cardiologist, and classified according to the Minnesota Code classification system. The data were entered into Epi-Data version 4.6 and exported to SPSS version 25 for analysis. Finally, descriptive statistics, chi-square, independent t-test, bivariable, and multivariable logistic regression analyses were done at a 5% significance level. Results: The study found that 49% of HIV-infected and 19.8% of HIV-negative participants had at least one ECG abnormality. The proportion of coded ST-segment abnormalities, T-wave abnormalities, longer QT interval, and sinus tachycardia was significantly higher in HIV-infected respondents than in HIV-negatives. Being a smoker [AOR = 3.7, 95%CI: 1.03-13.6], being on Protease inhibitors [AOR = 3.6, 95%CI: 1.02-13.1] and having CD4 less than 350 cells/mm3 [AOR = 3.2, 95%CI: 1.22-8.49] were significantly associated with ECG abnormalities among HIV-infected respondents. Conclusion: Compared to HIV-negative participants, HIV-infected patients had a significantly higher prevalence of ECG abnormalities. Screening for ECG abnormalities is needed for the early detection of cardiac abnormalities and the reduction of future complications. [ABSTRACT FROM AUTHOR]

Introduction: Major ABO-incompatible allogeneic hematopoietic stem cell transplantation (allo-HCT) is a common practice and represents a challenging transfusion scenario. Prolonged thrombocytopenia with increased platelet transfusion needs is one of its reported adverse effects, and this has been linked to the persistence of recipient anti-donor isoagglutinins. Case Presentation: A 55-year-old male patient, O Rh(D)-positive, with chronic myelomonocytic leukemia underwent major incompatible allo-HCT from a A Rh(D)-negative donor. He presented with prolonged thrombocytopenia and multiple transfusion reactions after A Rh(D)-negative platelet transfusions. Considering the outcomes of numerous examinations, we tested the anti-A1 titers, finding a significant persistence of anti-donor isoagglutinins. We limited platelet transfusions to blood group O Rh(D)-negative donors, which significantly decreased the requirement for platelet transfusions. In addition, the transfusion reactions ceased. Conclusion: In case of transfusion reactions against platelet products in major ABO-incompatible allo-HCT patients, isoagglutinin monitoring should be considered and a change in the platelet transfusion protocol may be beneficial in patients presenting high isotiters against recipient's blood type. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are widely used for disease modeling and pharmacological screening. However, their application has mainly focused on inherited cardiopathies affecting ventricular cardiomyocytes, leading to extensive knowledge on generating ventricular-like hiPSC-CMs. Electronic pacemakers, despite their utility, have significant disadvantages, including lack of hormonal responsiveness, infection risk, limited battery life, and inability to adapt to changes in heart size. Therefore, developing an in vitro multiscale model of the human sinoatrial node (SAN) pacemaker using hiPSC-CM and SAN-like cardiomyocyte differentiation protocols is essential. This would enhance the understanding of SAN-related pathologies and support targeted therapies. Generating SAN-like cardiomyocytes offers the potential for biological pacemakers and specialized conduction tissues, promising significant benefits for patients with conduction system defects. This review focuses on arrythmias related to pacemaker dysfunction, examining protocols' advantages and drawbacks for generating SAN-like cardiomyocytes from hESCs/hiPSCs, and discussing therapeutic approaches involving their engraftment in animal models. [ABSTRACT FROM AUTHOR]

The atrioventricular node (AVN) is a key component of the cardiac conduction system and takes over pacemaking of the ventricles if the sinoatrial node fails. IP3 (inositol 1,4,5 trisphosphate) can modulate excitability of myocytes from other regions of the heart, but it is not known whether IP3 receptor (IP3-R) activation modulates AVN cell pacemaking. Consequently, this study investigated effects of IP3 on spontaneous action potentials (APs) from AVN cells isolated from rabbit hearts. Immunohistochemistry and confocal imaging demonstrated the presence of IP3-R2 in isolated AVN cells, with partial overlap with RyR2 ryanodine receptors seen in co-labelling experiments. In whole-cell recordings at physiological temperature, application of 10 µM membrane-permeant Bt3-(1,4,5)IP3-AM accelerated spontaneous AP rate and increased diastolic depolarization rate, without direct effects on ICa,L, IKr, If or INCX. By contrast, application via the patch pipette of 5 µM of the IP3-R inhibitor xestospongin C led to a slowing in spontaneous AP rate and prevented 10 µM Bt3-(1,4,5)IP3-AM application from increasing the AP rate. UV excitation of AVN cells loaded with caged-IP3 led to an acceleration in AP rate, the magnitude of which increased with the extent of UV excitation. 2-APB slowed spontaneous AP rate, consistent with a role for constitutive IP3-R activity; however, it was also found to inhibit ICa,L and IKr, confounding its use for studying IP3-R. Under AP voltage clamp, UV excitation of AVN cells loaded with caged IP3 activated an inward current during diastolic depolarization. Collectively, these results demonstrate that IP3 can modulate AVN cell pacemaking rate. [ABSTRACT FROM AUTHOR]

Detailed heart rate (HR) response patterns during exercise in patients with heart failure (HF) and sinus rhythm remain uncertain. We screened consecutive patients with HF who underwent cardiopulmonary exercise tests at a large academic center from November 2013 to July 2023. HR response during exercise was statistically classified using logistic differential equation models. A total of 99 patients were included. Of them, 75 patients were assigned to "sigmoidal pattern" and the other 24 to "exponential pattern." Patients with the sigmoidal pattern were older and exhibited higher plasma B-type natriuretic peptide levels. Increases in HR and oxygen consumption (V̇ o 2)/kg up to the anaerobic threshold level were not different between both patterns. However, beyond the threshold, the sigmoidal pattern group showed no further increase in HR and significantly lower V̇ o 2/kg than their counterparts (interactions for P < 0.001). HR response during exercise in patients with heart failure and sinus rhythm was categorized into two unique groups: sigmoidal and exponential patterns. More detailed clarification of the sigmoidal pattern, potentially indicating sinus node dysfunction, should offer new clinical insights for chronotropic incompetence. NEW & NOTEWORTHY: Heart rate response patterns can be classified into two groups among patients with chronic heart failure reaching maximal exertion: sigmoidal and exponential. [ABSTRACT FROM AUTHOR]

Background: The growing participation of women in competitive sports necessitates a comprehensive understanding of sex‐specific cardiovascular adaptations and risks. Historically, research has predominantly focused on male athletes, leaving a gap in knowledge about the unique cardiovascular dynamics of female peers. Hypothesis: we hypothesized that female athletes exhibit distinct cardiovascular adaptations and face different risks, influenced by physiological, hormonal, and structural differences. Methods: A systematic review of the literature was conducted, analyzing studies on cardiovascular responses and adaptations in athletes. Data were extracted on hemodynamic changes, autonomic and neural reflex regulation, cardiac remodeling, and arrhythmias. Comparative analyses were performed to identify sex‐specific patterns and discrepancies in cardiovascular health outcomes. Results: We revealed considerable sex differences in cardiovascular adaptations to athletic training. Female athletes generally have longer QT intervals, greater sinoatrial node automaticity, and enhanced atrioventricular node function compared to males. They also exhibit lower sympathetic activity, lower maximal stroke volumes, and a tendency toward eccentric cardiac remodeling. Conversely, male athletes are more prone to concentric hypertrophy and higher incidences of bradyarrhythmia and accessory pathway arrhythmias. Female athletes are more likely to experience symptomatic atrial fibrillation and face higher procedural complications during catheter ablation. Conclusions: Our findings underscore the necessity for sex‐specific approaches in sports cardiology. Recognizing and addressing these differences could enhance performance and reduce adverse cardiac events in athletes. Future research should focus on developing tailored screening, prevention, and treatment strategies to bridge the knowledge gap and promote cardiovascular health in both male and female athletes. [ABSTRACT FROM AUTHOR]

Ivabradine is a pharmacologic agent that inhibits the funny current responsible for determining heart rate in the sinoatrial node. Ivabradine's clinical potential has been investigated in the context of heart failure since it is associated with reduced myocardial oxygen demand, enhanced diastolic filling, stroke volume, and coronary perfusion time; however, it is yet to demonstrate definitive mortality benefit. Alternative effects of ivabradine include modulation of the renin-angiotensin-aldosterone system, sympathetic activation, and endothelial function. Here, we review key clinical trials informing the clinical use of ivabradine and explore opportunities for leveraging its potential pleiotropic effects in other diseases, including treatment of hyperadrenergic states and mitigating complications of COVID-19 infection. [ABSTRACT FROM AUTHOR]

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The composite material-like extracellular matrix (ECM) in the sinoatrial node (SAN) supports the native pacemaking cardiomyocytes (PCMs). To test the roles of SAN ECM in the PCM phenotype and function, we engineered reconstructed-SAN heart tissues (rSANHTs) by recellularizing porcine SAN ECMs with hiPSC-derived PCMs. The hiPSC-PCMs in rSANHTs self-organized into clusters resembling the native SAN and displayed higher expression of pacemaker-specific genes and a faster automaticity compared with PCMs in reconstructed-left ventricular heart tissues (rLVHTs). To test the protective nature of SAN ECMs under strain, rSANHTs and rLVHTs were transplanted onto the murine thoracic diaphragm to undergo constant cyclic strain. All strained-rSANHTs preserved automaticity, whereas 66% of strained-rLVHTs lost their automaticity. In contrast to the strained-rLVHTs, PCMs in strained-rSANHTs maintained high expression of key pacemaker genes (HCN4, TBX3, and TBX18). These findings highlight the promotive and protective roles of the composite SAN ECM and provide valuable insights for pacemaking tissue engineering.

Cardiac function is tightly regulated by the autonomic nervous system (ANS). Activation of the sympathetic nervous system increases cardiac output by increasing heart rate and stroke volume, while parasympathetic nerve stimulation instantly slows heart rate. Importantly, imbalance in autonomic control of the heart has been implicated in the development of arrhythmias and heart failure. Understanding of the mechanisms and effects of autonomic stimulation is a major challenge because synapses in different regions of the heart result in multiple changes to heart function. For example, nerve synapses on the sinoatrial node (SAN) impact pacemaking, while synapses on contractile cells alter contraction and arrhythmia vulnerability. Here, we present a multiscale neurocardiac modelling and simulator tool that predicts the effect of efferent stimulation of the sympathetic and parasympathetic branches of the ANS on the cardiac SAN and ventricular myocardium. The model includes a layered representation of the ANS and reproduces firing properties measured experimentally. Model parameters are derived from experiments and atomistic simulations. The model is a first prototype of a digital twin that is applied to make predictions across all system scales, from subcellular signalling to pacemaker frequency to tissue level responses. We predict conditions under which autonomic imbalance induces proarrhythmia and can be modified to prevent or inhibit arrhythmia. In summary, the multiscale model constitutes a predictive digital twin framework to test and guide high-throughput prediction of novel neuromodulatory therapy. KEY POINTS: A multi-layered model representation of the autonomic nervous system that includes sympathetic and parasympathetic branches, each with sparse random intralayer connectivity, synaptic dynamics and conductance based integrate-and-fire neurons generates firing patterns in close agreement with experiment. A key feature of the neurocardiac computational model is the connection between the autonomic nervous system and both pacemaker and contractile cells, where modification to pacemaker frequency drives initiation of electrical signals in the contractile cells. We utilized atomic-scale molecular dynamics simulations to predict the association and dissociation rates of noradrenaline with the β-adrenergic receptor. Multiscale predictions demonstrate how autonomic imbalance may increase proclivity to arrhythmias or be used to terminate arrhythmias. The model serves as a first step towards a digital twin for predicting neuromodulation to prevent or reduce disease.

Remdesivir (RDV) is the first drug approved by the FDA for clinical treatment of hospitalized patients infected with COVID-19 because it has been shown to have good antiviral activity against a variety of viruses, including Arenaviridae and Coronaviridae viral families. However, it has been reported that its clinical treatment leads to the symptoms of sick sinus syndrome such as sinus bradycardia, conduction block, and sinus arrest, but the electrophysiological mechanism of its specific cardiac adverse events is still unclear. We report complementary, experimental, studies of its electrophysiological effects. In wireless cardiac telemetry experiments in vivo and electrocardiographic studies in ex vivo cardiac preparations, RDV significantly caused sinus bradycardia, sinus atrial block, and prolongation of the QT interval in guinea pigs. Dose-dependent effects of RDV on the electrical activities of sinoatrial node (SA node) preparations of guinea pigs were characterised by multielectrode, optical RH237 voltage mapping. These revealed reversibly reduced sinoatrial conduction time (SACT), increased AP durations (APDs), and decreased the pacemaking rate of the SA node. Patch-clamp experiments showed that RDV significantly inhibited the If current of HCN4 channels, resulting in a significant decrease in the spontaneous firing rate of SA node cells, which may underlie the development of sick sinus node syndrome. In addition, RDV significantly inhibits IKr currents in hERG channels, leading to prolongation of the QT interval and playing a role in bradycardia. Therefore, these findings provide insights into the understanding the bradycardia effect of RDV, which may be used as basic theoretical guidance for the intervention of its adverse events, and prompt safety investigations of RDV's cardiac safety in the future. [ABSTRACT FROM AUTHOR]

Background: Cardiac pacemaking remains an unsolved matter from many perspectives. Extensive experimental and computational studies have been performed to describe the sinoatrial physiology across different scales, from the molecular to clinical levels. Nevertheless, the mechanism by which a heartbeat is generated inside the sinoatrial node and propagated to the working myocardium is not fully understood at present. This work aims to provide quantitative information about this fascinating phenomenon, especially regarding the contributions of cellular heterogeneity and fibroblasts to sinoatrial node automaticity and atrial driving. Methods: We developed a bidimensional computational model of the human right atrial tissue, including the sinoatrial node. State-of-the-art knowledge of the anatomical and physiological aspects was adopted during the design of the baseline tissue model. The novelty of this study is the consideration of cellular heterogeneity and fibroblasts inside the sinoatrial node for investigating the manner by which they tune the robustness of stimulus formation and conduction under different conditions (baseline, ionic current blocks, autonomic modulation, and external high-frequency pacing). Results: The simulations show that both heterogeneity and fibroblasts significantly increase the safety factor for conduction by more than 10% in almost all the conditions tested and shorten the sinus node recovery time after overdrive suppression by up to 60%. In the human model, especially under challenging conditions, the fibroblasts help the heterogeneous myocytes to synchronise their rate (e.g. -82% in sCL under 25 nM of acetylcholine administration) and capture the atrium (with 25% L-type calcium current block). However, the anatomical and gap junctional coupling aspects remain the most important model parameters that allow effective atrial excitations. Conclusion: Despite the limitations to the proposed model, this work suggests a quantitative explanation to the astonishing overall heterogeneity shown by the sinoatrial node. [ABSTRACT FROM AUTHOR]

Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used to treat type 2 diabetes and obesity. Albeit cardiovascular outcomes generally improve, treatment with GLP-1 RAs is associated with increased heart rate, the mechanism of which is unclear. Methods and results We employed a large animal model, the female landrace pig, and used multiple in vivo and ex vivo approaches including pharmacological challenges, electrophysiology, and high-resolution mass spectrometry to explore how GLP-1 elicits an increase in heart rate. In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta, or combined alpha-beta blockade), ganglionic blockade (hexamethonium), nor inhibition of hyperpolarization-activated cyclic nucleotide–gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1. GLP-1 administration to isolated perfused pig hearts also increased heart rate, which was abolished by GLP-1 receptor blockade. Electrophysiological characterization of GLP-1 effects in vivo and in isolated perfused hearts localized electrical modulation to the atria and conduction system. In isolated sinus nodes, GLP-1 administration shortened the action potential cycle length of pacemaker cells and shifted the site of earliest activation. The effect was independent of HCN blockade. Collectively, these data support a direct effect of GLP-1 on GLP-1 receptors within the heart. Consistently, single nucleus RNA sequencing showed GLP-1 receptor expression in porcine pacemaker cells. Quantitative phosphoproteomics analyses of sinus node samples revealed that GLP-1 administration leads to phosphorylation changes of calcium cycling proteins of the sarcoplasmic reticulum, known to regulate heart rate. Conclusion GLP-1 has direct chronotropic effects on the heart mediated by GLP-1 receptors in pacemaker cells of the sinus node, inducing changes in action potential morphology and the leading pacemaker site through a calcium signalling response characterized by PKA-dependent phosphorylation of Ca2+ cycling proteins involved in pacemaking. Targeting the pacemaker calcium clock may be a strategy to lower heart rate in people treated with GLP-1 RAs. [ABSTRACT FROM AUTHOR]

Background: New antithrombotic medications and improved stent designs have reduced branch occlusion, although the sino‐atrial nodal artery (SANA) may still be occluded after a percutaneous coronary intervention (PCI), causing sinus node dysfunction (SND). Ischemic sinus nodes are usually asymptomatic but can cause sinus arrest sometimes requiring pacemaker placement. In rare cases, junctional escape rhythms, a manifestation of sinus exit blocks after PCI, can predict cardiogenic shock. Methods: We present a case study of a patient who underwent bifurcation PCI to the LMCA to the LCX but subsequently developed cardiogenic shock as a result of SND, a junctional escape rhythm required substantial inotropic support. This case offers an exemplification of a sparsely documented, yet infrequent manifestation of iatrogenic ischemic SND at an unorthodox site, the confluence of the LMCA‐LCX. In addition, we conducted a comprehensive analysis of 22 scholarly works pertaining to the subject of sinus node dysfunction (SND) subsequent to PCI resulting from ischemia caused by stenosis or occlusion of the SANA. Results: RCA was responsible for 96.1% of SND cases, whereas LCX was responsible for 3.9%. SND was asymptomatic in 49.3% of cases and junctional escape rhythm in 37.6% of symptomatic cases. 28% needed a temporary transvenous pacemaker, while 7.8% needed a permanent one. Interventional management recanalized the SANA in 5.2% of patients, restoring flow. Conclusion: Transient sino‐atrial node ischemia after PCI can cause acute SND. Before stent implantation, doctors should consider SND. Complete plaque evaluation around the SANA is needed before choosing the best PCI procedure. [ABSTRACT FROM AUTHOR]

Postural Orthostatic Tachycardia Syndrome (POTS) affects up to 1% of the US population, predominantly women, and is characterized by a complex, elusive etiology and heterogeneous phenotypes. This review delves into the intricate physiology and etiology of POTS, decoding the roles of the sinoatrial node, the autonomic nervous system, fluid dynamics, and the interplay between the immune and endocrine systems. It further examines key contributing factors such as dysautonomia, thoracic hypovolemia, autonomic neuropathies, sympathetic denervation, autoimmune responses, and associations with conditions such as small-fiber neuropathy and mast cell activation syndrome. Given the numerous mysteries surrounding POTS, we also cautiously bring attention to sinoatrial node and myocardial function, particularly in how the heart responds to stress despite exhibiting a normal cardiac phenotype at rest. The potential of genomic research in elucidating the underlying mechanisms of POTS is emphasized, suggesting this as a valuable approach that is likely to improve our understanding of the genetic underpinnings of POTS. The review introduces a tentative classification system for the etiological factors in POTS, which seeks to capture the condition's diverse aspects by categorizing various etiological factors and acknowledging co-occurring conditions. This classification, while aiming to enhance understanding and optimize treatment targets, is presented as a preliminary model needing further study and refinement. This review underscores the ongoing need for research to unravel the complexities of POTS and to develop targeted therapies that can improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Dexmedetomidine and propofol are common sedatives in intensive care units and for interventional procedures. Both may compromise sinus node function and atrioventricular conduction. The objective of this prospective, randomized study is to compare the effect of dexmedetomidine with propofol on sinus node function and atrioventricular conduction. Methods: In a tertiary care center in Switzerland we included from September 2019 to October 2020 160 patients (65 ± 11 years old; 32% female) undergoing first ablation for atrial fibrillation by cryoballoon ablation or by radiofrequency ablation. Patients were randomly assigned to deep sedation with dexmedetomidine (DEX group) versus propofol (PRO group). A standard electrophysiological study was performed after pulmonary vein isolation with the patients still deeply sedated and hemodynamically stable. Results: Eighty patients each were randomized to the DEX and PRO group. DEX group patients had higher baseline sinus cycle length (1022 vs. 1138 ms; p = 0.003) and longer sinus node recovery time (SNRT400; 1597 vs. 1412 ms; p = 0.042). However, both corrected SNRT and normalized SNRT did not differ. DEX group patients had longer PR interval (207 vs. 186 ms; p = 0.002) and AH interval (111 vs. 95 ms, p = 0.008), longer Wenckebach cycle length of the atrioventricular node (512 vs. 456 ms; p = 0.005), and longer atrioventricular node effective refractory period (390 vs. 344 ms; p = 0.009). QRS width and HV interval were not different. An arrhythmia, mainly atrial fibrillation, was induced in 33 patients during the electrophysiological study, without differences among groups (20% vs. 15%, p = 0.533). Conclusions: Dexmedetomidine has a more pronounced slowing effect on sinus rate and suprahissian AV conduction than propofol, but not on infrahissian AV conduction and ventricular repolarization. These differences need to be taken into account when using these sedatives. Trial registration: ClinicalTrials.gov number NCT03844841, 19/02/2019 [ABSTRACT FROM AUTHOR]

Introducere. Datele din literatură sugerează o creștere ușoară a riscului cardiovascular pentru persoanele care au grupe sangvine non-O. Scopul studiului este de a evalua existența unei asocieri între tulburările de conducere cardiace șl grupele sangvine. Material and methods. In this retrospective study, a group of patients with atrio-ventricular conduction disorders or sinus node disease, having an indication for permanent cardiostimulation, was analyzed and compared with a control group consisting of patients who underwent coronary angiography or elective peripheral angiography. The blood group was determined in all patients. Univariate and multivariate statistical methods were used. Results. Six hundred forty patients, mean age 72±lly, 55.3% men, were included: 320 patients with advanced atrio-ventricular conduction disorders or sinus node dysfunction in the study group and 320 patients in the control group. Blood type A had the highest prevalence (46.8%), followed by blood types O (28.95%), B (16.74%) and AB (7.51%). In the group with heart rhythm disorders, patients with blood type A had an increased risk of atrio-ventricular block (OR 1.38, p= 0.02), but not with sinus node disease (OR 1.02, p= 0.98). Blood type O had a protective role both for atrio-ventricular block and for sinus node dysfunction (OR 0.65, p= 0.01). Conclusion: Blood type A proved to be an independent predictor for atrio-ventricular conduction disorders in patients with severe heart rhythm disorders with indication for permanent cardiostimulation. [ABSTRACT FROM AUTHOR]

Beta-blockers exert cardioprotective effects against heart failure. However, variability in therapeutic responses is associated with ADRB1 variants. ADRB1 variants contribute to rate control and autonomic dysfunction. Persistent hyperadrenergic stimulation contributes to the impairment of the pacemaker (SA node). HCN4 significantly influenced the regulation of heart rate in the pacemaker. Exploring the effect of beta-blockers on pacemaker cells is expanding the view of their cardioprotective effects in heart failure. The objectives of this review were to identify ADRB1 variants affecting heart rate response in heart failure patients receiving beta-blocker treatment and to explore the effect of beta-blockers on HCN4/SA node. A systematic review was performed using three databases (Scopus, PubMed, and Science Direct). The inclusion criteria were English language and original manuscripts with relevant topics. The exclusion criteria were duplication and inaccessibility to the full text. Quality assessment tools were classified based on the use of research subjects and study designs, including NOS (cohort), SYRCLE (animal studies), and SciRAP (in vitro studies). Eight of 668 manuscripts were selected. This review found that ADRB1 variants (A145G(Ser49Gly) and C1165G(Arg389Gly)) can affect heart rate response in beta-blocker-treated heart failure. The percentage of patients with Ser49Ser- Gly389X (67%) who achieved the heart rate target was higher than that of the other haplotypes (48-52%). Among the responders, Arg389Arg required larger carvedilol equivalent daily doses of beta-blockers to reach the identical heart rate target than those with Gly389X (>50% (>25mg) versus ≤50% of the guideline-directed medical therapy (GDMT) target dose (≤25mg), respectively). In addition, this review found that beta-blockers demonstrated beneficial effects in regulating heart rate by inhibiting HCN-gated channels and improving channel regulation in the SA node. In general, this review provides important insights into beta-blockers in treating heart failure, specifically concerning the genetic variability of ADRB1 and the effect of betablockers on SA node/HCN4. [ABSTRACT FROM AUTHOR]

The epididymal duct exhibits spontaneous phasic contractions (SPCs) to store and transport sperm. Here, we explored molecular identification of pacemaker cells driving SPCs in the caudal epididymal duct and also investigated properties of pacemaker currents underlying SPCs focusing on ANO1 Ca2+-activated Cl− channels (CaCCs). Immunohistochemistry was performed to visualise the distribution of platelet-derived growth factor receptor α (PDGFRα)- or ANO1-positive cells in the rat caudal epididymal duct. Perforated whole-cell patch clamp technique was applied to enzymatically isolated epididymal cells, while SPCs were recorded with video edge-tracking technique. Immunohistochemistry revealed the distribution of α-smooth muscle actin (α-SMA)-positive cells co-expressing both PDGFRα and ANO1 in the innermost smooth muscle layer. Approximately one-third of isolated epididymis cells exhibited spontaneous transient inward currents (STICs) at the holding potential −60 mV. The reversal potential for STICs was close to the calculated chloride equivalent potential depending on intracellular Cl− concentrations. Ani9 (3 µM), the ANO1 specific inhibitor, decreased both amplitude and frequency of STICs, while cyclopiazonic acid (CPA, 30 µM), a sarco-/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor, abolished STICs. Ani9 (3 or 10 µM) reduced the frequency of SPCs without changing their amplitude. Thus, PDGFRα+, ANO1+ specialised smooth muscle cells (SMCs) appear to function as pacemaker cells to electrically drive epididymal SPCs by generating ANO1-dependnet STICs. STICs arising from spontaneous Ca2+ release from intracellular Ca2+ store and subsequent opening of ANO1 result in depolarisations that spread into adjacent SMCs where L-type voltage-dependent Ca2+ channels are activated to develop SPCs. [ABSTRACT FROM AUTHOR]

Introduction: Inappropriate sinus tachycardia (IST) is a common condition with frequently not tolerated beta‐blockers or ivabradine and a high rate of complication in ablation strategy; we describe an alternative anatomical approach of sinus node (SN) modulation. Methods: This retrospective study describes a case series of 6 patients from two centers diagnosed with symptomatic IST undergoing SN ablation. Results: The mean age was 40.6 ± 13.9 years; five of the six patients were female, 100% of patients reported heart palpitations, and 66% reported dizziness, the average heart rate (HR) on a 24‐h Holter was 93.2 ± 7.9 bpm. HR during the first stage of a stress test using a standard Bruce protocol was 150 ± 70 bpm, The average HR on 24‐h Holter postablation was 75 ± 5.6 bpm, the sinus rate HR during stage 1 of a Bruce protocol exercise stress test was 120 ± 10 bpm. Conclusion: This is the first case series reporting the acute and long‐term results of a novel anatomical approach for SN modulation to treat IST targeting the arcuate ridge (AR) under intracardiac echography (ICE) guidance. The novel anatomic ICE‐guided catheter ablation approach aimed to identify the earliest activation at the AR with an extension of RF lesions toward its septal region seems effective and safe to modulate the SN in symptomatic patients with IST refractory to medical treatment. [ABSTRACT FROM AUTHOR]

Background: To preserve the benefit of atrial sensing without the implantation of an additional lead, a single‐lead ICD system with a floating atrial dipole (DX ICD) has been developed. The purpose of this nationwide survey was to provide an overview of the current key influences of device selection focusing on DX ICD and to test the applicability of a previously published decision‐making flowchart of ICD‐type selection. Methods: An online questionnaire was sent to all implanting centers in Hungary. Eleven centers reported data from 361 DX ICD and 10 CRT‐DX systems implantations between February 2021 and May 2023. Results: The most important influencing clinical factors indicated by the participating doctors were elevated risk of atrial fibrillation (AF)/stroke (56%), risk of sinus/supraventricular tachycardias (SVT) (42%), and a potential need for CRT upgrade in the future (36%). The DX ICD was considered in the majority of cases instead of the VVI system (87%), and only in a small proportion instead of a DDD ICD (13%). 60% of the patients with DX ICDs were also included into remote monitoring‐based follow‐up. In 83% of the cases, good (>2 mV) or excellent (>5) atrial signal amplitude was recorded within 6 weeks after the implantation. Conclusion: In the current national survey, the most important influencing factors indicated by the implanters for selecting a DX ICD were the elevated risk of stroke or sinus/SVT and a potential need for CRT upgrade in the future. These findings support the use of a previously published decision‐making flowchart. [ABSTRACT FROM AUTHOR]

Acute intermitttent porphyria belongs to a rare group of diseases hallmarked by deficient biosynthesis of heme. It carries a significant symptom burden, both physical and emotional,and therefore palliative care has emerged as an essential tool in the armamentarium of porphyria management. It takes care of the patient as a whole and caters to all aspects that the disease process demands. There are many lacunae in the literature regarding the palliative management of porphyria. We are reporting a case of a 16-year-old female who presented with severe abdominal pain, lower backache and symmetrical bilateral lower limb pain to the palliative ward referred by the neurology department for supportive care. This case describes the palliative care aspects of porphyria management which was successfully provided in the palliative care unit right from referral till the last. A multidisciplinary palliative care team managed the patient, and the necessary interventions were provided to the patient and family. Palliative acre in AIP needs to be emphasized, and palliative care services need to be utilized in these cases. The unavailability of specific treatment measure, heme, in countries like India further emphasizes the need for long-term supportive care for the patient and family. The case shows the importance of palliative care throughout the disease course as it is a chronic disease with significant morbidity and carries a heavy symptom burden. This case provides the insight that rather than conventional management alone for such chronic diseases, palliative care should be incorportated. Early integration with palliative care helps in exploring all the domains of disease. This is one of the first cases reported highlighting palliative care in porphyria , bridging the gap in the literature. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: Compression of the vagus nerve by a pharyngeal mass is a well-documented condition that can result in sinus node dysfunction (SND). However, there is scarce literature on extrinsic vagal nerve compression from a tonsillar abscess. Case Report: A 59-year-old woman with a history of asthma and chronic throat discomfort presented to the Emergency Department with bradycardia, palpitations, and voice changes. Following a shellfish allergy hospitalization, an otolaryngology evaluation revealed an enlarged right tonsil, recommending tonsillectomy, but scheduling challenges persisted. The patient reported mild throat pain, dysphagia, hoarseness, rhinorrhea, and exertional dyspnea and was admitted for the evaluation of peritonsillar mass. She was found to be bradycardic with a heart rate of 47, with an electrocardiogram revealing SND. Albuterol and ipratropium nebulizers, as well as dexamethasone and pantoprazole, were initiated. With this treatment, the patient symptomatically improved with a new heart rate of 68. She was discharged with outpatient appointments, but was unfortunately lost to follow-up. Conclusions: This case reveals sinus node dysfunction resulting from extrinsic vagal nerve compression by a tonsillar abscess. Pressure on the vagus nerve can trigger bradycardia and low blood pressure, possibly due to compensatory overfiring of afferent vagal nerve signals from local mass effect. Early recognition and antibiotic treatment are essential to prevent cardiac complications. Clinicians must remain vigilant for such extrinsic causes, particularly in patients with chronic sore throat and cardiac symptoms. Further research and case reports are needed to deepen our understanding of this rare yet significant association. [ABSTRACT FROM AUTHOR]

Introduction: This study was undertaken to explore the potential therapeutic effects of Tongyang Huoxue Granules (TYHX) on sinoatrial node (SAN) dysfunction, a cardiac disorder characterized by impaired impulse generation or conduction. The research question addressed whether TYHX could positively influence SAN ion channel function, specifically targeting the sodium-calcium exchanger (INCX) and L-type calcium channel (ICaL) of the SAN. Methods: Sinoatrial node cells (SANCs) were isolated and cultured from neonatal Japanese big-eared white rabbits within 24 h of birth. The study encompassed five groups: Control, H/R (hypoxia/reoxygenation), H/R+100 μg/mL TYHX, H/R+200 μg/mL TYHX, and H/R+400 μg/mL TYHX. The H/R model, simulating hypoxia/reoxygenation stress, was induced within 5 days of culture. Whole-cell patch clamp technique was employed to record currents following a 3-min perfusion and stabilization period with TYHX. Results: TYHX administration demonstrated improvements in the ignition phase of impaired SANCs. The half-maximal effective dose of TYHX, as determined by SANC beating frequency, was found to be 323.63 μg/mL. Inward current density of INCX increased in response to TYHX (200 and 400 μg/mL), while TYHX enhanced ICaL current density in H/R SANCs, with 400 μg/mL exhibiting greater efficacy. Additionally, TYHX regulated the gating mechanisms of ICaL by right-shifting the steady-state inactivation curve and accelerating recovery from inactivation. Notably, TYHX increased the activation time constant under 200 and 400 μg/mL, prolonged the fast inactivation time constant t1 with 400 μg/mL, and extended the slow inactivation time constant t2 with 100 and 400 μg/mL. Discussion and conclusion: The findings suggest that TYHX may hold promise as a therapeutic intervention for sinus node dysfunction, offering potential avenues for drug development aimed at safeguarding SAN function. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to analyze the diagnosis, treatment, and follow-up of six cases of complex arrhythmias associated with RYR2 gene mutations in children. Method: A retrospective analysis was conducted on six children diagnosed with complex arrhythmias associated with RYR2 gene mutations. The study included an analysis of the age of onset, initial symptoms, electrocardiographic characteristics, genetic results, treatment course, and follow-up outcomes. Results: Among the six cases included in the study, there were four males and two females, with an average age of 3.5 ± 0.5 years. The average time from initial symptoms to diagnosis was 2.7 ± 1.3 years. The most common clinical manifestation was syncope, with exercise and emotions being the main triggers. All six children had de novo missense mutations in the RYR2 gene identified through whole-exome sequencing. In Holter electrocardiogram, atrial arrhythmias and sinoatrial node dysfunction were commonly observed in younger children. Four patients underwent exercise stress testing, with two experiencing bidirectional ventricular premature contractions and two experiencing bidirectional ventricular tachycardia and polymorphic ventricular tachycardia. Initial treatment involved oral propranolol or metoprolol. If arrhythmias persisted, flecainide or propafenone was added as adjunctive therapy. Two patients received permanent cardiac pacemaker treatment (single chamber ventricular pacemaker, VVI). All patients survived, with three experiencing occasional syncope during treatment. The follow-up period ranged from 12 to 37 months, with an average follow-up time of 24.3 ± 3.7 months. Conclusion: Complex arrhythmias associated with RYR2 gene mutations in children can present with various clinical manifestations. Atrial arrhythmias combined with sinoatrial node dysfunction are commonly observed in younger children, and the combination of pharmacological therapy and cardiac pacemaker treatment yields favourable treatment outcomes. [ABSTRACT FROM AUTHOR]

Significance: Damage to the cardiac conduction system remains one of the most significant risks associated with surgical interventions to correct congenital heart disease. This work demonstrates how light-scattering spectroscopy (LSS) can be used to non-destructively characterize cardiac tissue regions. Aim: To present an approach for associating tissue composition information with location-specific LSS data and further evaluate an LSS and machine learning system as a method for non-destructive tissue characterization. Approach: A custom LSS probe was used to gather spectral data from locations across 14 excised human pediatric nodal tissue samples (8 sinus nodes, 6 atrioventricular nodes). The LSS spectra were used to train linear and neural-network-based regressor models to predict tissue composition characteristics derived from the 3D models. Results: Nodal tissue region nuclear densities were reported. A linear model trained to regress nuclear density from spectra achieved a prediction r-squared of 0.64 and a concordance correlation coefficient of 0.78. Conclusions: These methods build on previous studies suggesting that LSS measurements combined with machine learning signal processing can provide clinically relevant cardiac tissue composition. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD), the main non-psychotropic phytocannabinoid produced by the Cannabis sativa plant, blocks a variety of cardiac ion channels. We aimed to identify whether CBD regulated the cardiac pacemaker channel or the hyperpolarizationactivated cyclic nucleotide-gated channel (HCN4). HCN4 channels are important for the generation of the action potential in the sinoatrial node of the heart and increased heart rate in response to β-adrenergic stimulation. HCN4 channels were expressed in HEK 293T cells, and the effect of CBD application was examined using a whole-cell patch clamp. We found that CBD depolarized the V1/2 of activation in holo-HCN4 channels, with an EC50 of 1.6 μM, without changing the current density. CBD also sped activation kinetics by approximately threefold. CBD potentiation of HCN4 channels occurred via binding to the closed state of the channel. We found that CBD's mechanism of action was distinct from cAMP, as CBD also potentiated apo-HCN4 channels. The addition of an exogenous PIP2 analog did not alter the ability of CBD to potentiate HCN4 channels, suggesting that CBD also acts using a unique mechanism from the known HCN4 potentiator PIP2. Lastly, to gain insight into CBD's mechanism of action, computational modeling and targeted mutagenesis were used to predict that CBD binds to a lipidbinding pocket at the C-terminus of the voltage sensor. CBD represents the first FDA-approved drug to potentiate HCN4 channels, and our findings suggest a novel starting point for drug development targeting HCN4 channels. [ABSTRACT FROM AUTHOR]

Background Double-wave macrore-entry is a rare mechanism of atrial tachycardia with limited documentation in the literature. We present a three-dimensional documentation of a double-wave 'typical' atrial flutter in a patient with extensive atrial cardiomyopathy. Case summary A 78-year-old female with a history of atrial cardiomyopathy and dual-chamber pacemaker for sinus node disease presented with palpitations and incessant atrial flutter. Electrophysiological study revealed a regular tachycardia with a cycle length (TCL) of 230 ms, with proximal to distal coronary sinus (CS) activation. Three-dimensional mapping identified two independent wavefronts circulating the cavotricuspid isthmus (CTI), each with a TCL of 460 ms. Cavotricuspid isthmus ablation resulted in conversion into a distinct tachycardia with left atrial roof origin. Linear ablation in this location slowed the TCL to 435 ms with concentric CS activation and another CTI dependent atrial flutter was mapped, this time with only one wavefront of activation. Further ablation with a second, more lateral, line in the CTI led to tachycardia interruption. Given the extensive atrial scarring and high arrhythmic recurrence risk, atrioventricular node ablation was performed. Discussion Double-wave re-entrant tachycardias were primarily observed in experimental models, precipitating acceleration of ventricular and supraventricular tachycardias via extrastimulation. In our case, there is documentation of a spontaneous double-wave of activation around the CTI, representing the first documented double-wave 'typical' atrial flutter. Unlike other cases in the literature, the two wavefronts were equidistant, which resulted in a regular tachycardia with TCL that was half of the single-wave cycle length. Three-dimensional propagation mapping was essential to visualize the two distinct wavefronts. [ABSTRACT FROM AUTHOR]

IntroductionThe heart rate variability (HRV) continually evolves throughout life, reflecting modifications in the architecture of the sinoatrial node (SAN) and in the regulation of heart rate by the autonomic nervous system (ANS). Both can be considerably affected by Chagas disease, causing important changes in the complex nature of HRV. We aim to evaluate the ability of an index based on the false nearest neighbors method (FN10) to reflect these changes during disease progression.MethodsWe perform a retrospective, descriptive, and cross-sectional study analyzing HRV time series of participants with Chagas disease. We determine the dependence of FN10 on age and sex in a healthy population, and then evaluate FN10 in individuals with Chagas disease.Results and discussionIn the healthy population, FN10 has a scaling behavior with age, which is independent of sex. In Chagas disease, some individuals show FN10 values significantly above those seen in the healthy population. We relate the findings to the pathophysiological mechanisms that determine the progression of the disease. The results indicate that FN10 may be a candidate prognostic biomarker for heart disease.

Severe hyperkalemia, or high potassium levels in the blood, can be life-threatening due to its effects on the heart. The resting membrane potential in cardiac cells is determined by potassium, and hyperkalemia can disrupt this potential, leading to increased myocardial excitability and abnormal electrical activity in the heart. Treatment for life-threatening hyperkalemia involves administering IV calcium to reverse acute membrane abnormalities, shifting potassium intracellularly, and removing potassium from the body through various methods. A recent study challenges the conventional wisdom that calcium restores membrane potential in hyperkalemia, but further research is needed to fully understand the mechanisms and improve clinical practice. [Extracted from the article]

Although vasovagal episodes are a common cause of syncope, vasovagal syncope can be cardioinhibitory in nature, resulting in a severe heart block or asystole. This case report focuses on a young man with a history of seizures and frequent syncopal episodes who required an extensive clinical workup and treatment for cardioinhibitory syncope. [ABSTRACT FROM AUTHOR]

BackgroundInappropriate sinus tachycardia (IST) is defined as resting heart rate >100 beats/min and average 24-hour heart rate >90 beats/min. It is associated with distressing symptoms and significant loss of quality of life. Drugs are not effective in symptom control of IST in up to 30% of patients. Catheter ablation of the sinus node has a high recurrence rate, and the complications are significant. Recently, a novel hybrid sinus node-sparing ablation approach for IST was described.ObjectiveThe objective of the Hybrid Epicardial and Endocardial Sinus Node Sparing Ablation Therapy for Inappropriate Sinus Tachycardia (HEAL-IST) investigational device exemption trial (NCT05280093) is to evaluate safety and effectiveness of the hybrid sinus node-sparing ablation procedure for the treatment of symptomatic, drug-refractory or drug-intolerant IST.MethodsThe HEAL-IST trial is a prospective, multicenter, pivotal, single-arm trial. Up to 142 subjects in up to 40 centers will be treated in the trial with a Bayesian adaptive design.ResultsSubjects will be assessed for primary safety through 30 days post-hybrid ablation procedure. The primary effectiveness endpoint will be freedom from IST at 12 months. Freedom from IST will be defined as mean heart rate of ≤90 beats/min or at least a 15% reduction in mean heart rate as compared with baseline, in the absence of new or higher dosage of previously failed medications at a 24-month follow-up assessment.ConclusionThe HEAL-IST trial is the first multicenter trial evaluating hybrid IST ablation in patients with symptomatic IST and refractory or intolerant to drugs. The results of this study will help guide decision making regarding the best management in this population.

The sympathetic nervous system fight-or-flight response is characterized by a rapid increase in heart rate, which is mediated by an increase in the spontaneous action potential (AP) firing rate of pacemaker cells in the sinoatrial node. Sympathetic neurons stimulate sinoatrial myocytes (SAMs) by activating β adrenergic receptors (βARs) and increasing cAMP. The funny current (If) is among the cAMP-sensitive currents in SAMs. If is critical for pacemaker activity, however, its role in the fight-or-flight response remains controversial. In this study, we used AP waveform analysis, machine learning, and dynamic clamp experiments in acutely isolated SAMs from mice to quantitatively define the AP waveform changes and role of If in the fight-or-flight increase in AP firing rate. We found that while βAR stimulation significantly altered nearly all AP waveform parameters, the increase in firing rate was only correlated with changes in a subset of parameters (diastolic duration, late AP duration, and diastolic depolarization rate). Dynamic clamp injection of the βAR-sensitive component of If showed that it accounts for ∼41% of the fight-or-flight increase in AP firing rate and 60% of the decrease in the interval between APs. Thus, If is an essential contributor to the fight-or-flight increase in heart rate.

Aims In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND. Methods and results We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND. Conclusion Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure. [ABSTRACT FROM AUTHOR]

Background: Prognosis of Chronic Chagasic Cardiomyopathy (CCC) patients depends on functional and clinical factors. Bradyarrhythmia requiring pacemaker is a common complication. Prognosis of these patients is poorly studied, and mortality risk factors are unknown. We aimed to identify predictors of death and to define a risk score for mortality in a large cohort of CCC patients with pacemaker. Methods: It was an observational, unicentric and prospective study. The endpoint was all-cause mortality. Cox regression was used to identify predictors of death and to define a risk score. Bootstrapping method was used to internal score validation. Results: We included 555 patients and after a mean follow-up of 3.7±1.5 years, 100 (18%) deaths occurred. Predictors of death were: right ventricular dysfunction (HR [hazard ratio] 2.24; 95%CI 1.41–3.53; P = 0.001); heart failure class III or IV (HR 2.16; 95% confidence interval [95%CI] 1.16–4.00; P = 0.014); renal disease (HR 2.14; 95%CI 1.24–3.68; P = 0.006); left ventricular end-systolic diameter > 44mm (HR 1.97; 95%CI 1.26–3.05; P = 0.003); atrial fibrillation (HR 1.94; 95%CI 1.25–2.99; P = 0.003) and cardiomegaly on X-ray (HR 1.87; 95%CI 1.10–3.17; P = 0.020). The score identified patients with: low (0–20 points), intermediate (21–30 points) and high risk (>31points). The optimism-corrected C-statistic of the predictive model was 0.751 (95% CI 0.696–0.806). Internal validation with bootstrapping revealed a calibration slope of 0.946 (95% CI 0.920–0.961), reflecting a small degree of over-optimism and C-statistic of 0.746 (95% CI 0.692–0.785). Conclusions: This study identified predictors of mortality in CCC patients with pacemaker defining a simple, validated and specific risk score. Author summary: Chronic Chagas Cardiomyopathy (CCC) is the most important clinical manifestation of chronic Chagas disease. Bradyarrhythmias caused by sinus node disease, atrio and intraventricular block occur in above 50% and requirement of permanent pacing is common. Prognosis of these patients is poorly studied, and mortality risk factors are unknown. Previous studies have identified predictors of death in CCC patients however CCC patients requiring pacemaker were underrepresented. We identified predictors of mortality in CCC patients with pacemaker defining a simple, validated and specific risk score. Predictors of death were: right ventricular dysfunction, heart failure class III or IV, renal disease, left ventricular end-systolic diameter > 44mm, atrial fibrillation and cardiomegaly on X-ray. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 46-year-old man with a history of ventricular tachycardia/ventricular fibrillation (VT/VF) on amiodarone therapy, chronic severe systolic heart failure, and Medtronic Claria CRT-D. It delves into the mechanisms behind the misclassification of ventricular tachyarrhythmia as sinus tachycardia, shedding light on the potential factors contributing to the failure of ICD therapy in this specific case.

Background: Sinus node dysfunction because of abnormal impulse generation or sinoatrial conduction block causes bradycardia that can be difficult to differentiate from high parasympathetic/low sympathetic modulation (HP/LSM). Hypothesis: Beat‐to‐beat relationships of sinus node dysfunction are quantifiably distinguishable by Poincaré plots, machine learning, and 3‐dimensional density grid analysis. Moreover, computer modeling establishes sinoatrial conduction block as a mechanism. Animals: Three groups of dogs were studied with a diagnosis of: (1) balanced autonomic modulation (n = 26), (2) HP/LSM (n = 26), and (3) sinus node dysfunction (n = 21). Methods: Heart rate parameters and Poincaré plot data were determined [median (25%‐75%)]. Recordings were randomly assigned to training or testing. Supervised machine learning of the training data was evaluated with the testing data. The computer model included impulse rate, exit block probability, and HP/LSM. Results: Confusion matrices illustrated the effectiveness in diagnosing by both machine learning and Poincaré density grid. Sinus pauses >2 s differentiated (P <.0001) HP/LSM (2340; 583‐3947 s) from sinus node dysfunction (8503; 7078‐10 050 s), but average heart rate did not. The shortest linear intervals were longer with sinus node dysfunction (315; 278‐323 ms) vs HP/LSM (260; 251‐292 ms; P =.008), but the longest linear intervals were shorter with sinus node dysfunction (620; 565‐698 ms) vs HP/LSM (843; 799‐888 ms; P <.0001). Conclusions: Number and duration of pauses, not heart rate, differentiated sinus node dysfunction from HP/LSM. Machine learning and Poincaré density grid can accurately identify sinus node dysfunction. Computer modeling supports sinoatrial conduction block as a mechanism of sinus node dysfunction. [ABSTRACT FROM AUTHOR]