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.

Feed Forward Modeling: an efficient approach for mathematical modeling of the force frequency relationship in the rabbit isolated ventricular myocyte.

Background and Objective. This study addresses the Force-Frequency relationship, a fundamental characteristic of cardiac muscle influenced byß1-adrenergic stimulation. This relationship reveals that heart rate (HR) changes at the sinoatrial node lead to alterations in ventricular cell contractility, increasing the force and decreasing relaxation time for higher beat rates. Traditional models lacking this relationship offer an incomplete physiological depiction, impacting the interpretation of in silico experiment results. To improve this, we propose a new mathematical model for ventricular myocytes, named 'Feed Forward Modeling' (FFM).Methods. FFM adjusts model parameters like channel conductance and Ca2+pump affinity according to stimulation frequency, in contrast to fixed parameter values. An empirical sigmoid curve guided the adaptation of each parameter, integrated into a rabbit ventricular cell electromechanical model. Model validation was achieved by comparing simulated data with experimental current-voltage (I-V) curves for L-type Calcium and slow Potassium currents.Results. FFM-enhanced simulations align more closely with physiological behaviors, accurately reflecting inotropic and lusitropic responses. For instance, action potential duration at 90% repolarization (APD90) decreased from 206 ms at 1 Hz to 173 ms at 4 Hz using FFM, contrary to the conventional model, where APD90 increased, limiting high-frequency heartbeats. Peak force also showed an increase with FFM, from 8.5 mN mm-2at 1 Hz to 11.9 mN mm-2at 4 Hz, while it barely changed without FFM. Relaxation time at 50% of maximum force (t50) similarly improved, dropping from 114 ms at 1 Hz to 75.9 ms at 4 Hz with FFM, a change not observed without the model.Conclusion. The FFM approach offers computational efficiency, bypassing the need to model all beta-adrenergic pathways, thus facilitating large-scale simulations. The study recommends that frequency change experiments include fractional dosing of isoproterenol to better replicate heart conditionsin vivo.

Differentiation of Sinoatrial-like Cardiomyocytes as a Biological Pacemaker Model.

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.

Kv1.1 channels help set the pace.

JGP study (Si et al. https://doi.org/10.1085/jgp.202413578) reveals that, although they are present at low levels and only generate small currents in the sinoatrial node, Kv1.1 channels have a significant impact on cardiac pacemaking.

Transcriptional regulation of the postnatal cardiac conduction system heterogeneity.

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information. Integration of single-cell and spatial transcriptomics uncover region-specific markers and zonation patterns of expression. Network inference shows heterogeneous gene regulatory networks across the CCS. Notably, region-specific gene regulation is recapitulated in vitro using neonatal mouse atrial and ventricular myocytes overexpressing CCS-specific transcription factors, Tbx3 and/or Irx3. This finding is supported by ATAC-seq of different CCS regions, Tbx3 ChIP-seq, and Irx motifs. Overall, this study provides comprehensive molecular profiles of the postnatal CCS and elucidates gene regulatory mechanisms contributing to its heterogeneity.

Lifelong longitudinal assessment of the contribution of multi-fractal fluctuations to heart rate and heart rate variability in aging mice: role of the sinoatrial node and autonomic nervous system.

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.

Electrophysiological differences of randomized deep sedation with dexmedetomidine versus propofol.

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.

Epilepsy-associated Kv1.1 channel subunits regulate intrinsic cardiac pacemaking in mice.

The heartbeat originates from spontaneous action potentials in specialized pacemaker cells within the sinoatrial node (SAN) of the right atrium. Voltage-gated potassium channels in SAN myocytes mediate outward K+ currents that regulate cardiac pacemaking by controlling action potential repolarization, influencing the time between heartbeats. Gene expression studies have identified transcripts for many types of voltage-gated potassium channels in the SAN, but most remain of unknown functional significance. One such gene is Kcna1, which encodes epilepsy-associated voltage-gated Kv1.1 K+ channel α-subunits that are important for regulating action potential firing in neurons and cardiomyocytes. Here, we investigated the functional contribution of Kv1.1 to cardiac pacemaking at the whole heart, SAN, and SAN myocyte levels by performing Langendorff-perfused isolated heart preparations, multielectrode array recordings, patch clamp electrophysiology, and immunocytochemistry using Kcna1 knockout (KO) and wild-type (WT) mice. Our results showed that either genetic or pharmacological ablation of Kv1.1 significantly decreased the SAN firing rate, primarily by impairing SAN myocyte action potential repolarization. Voltage-clamp electrophysiology and immunocytochemistry revealed that Kv1.1 exerts its effects despite contributing only a small outward K+ current component, which we term IKv1.1, and despite apparently being present in low abundance at the protein level in SAN myocytes. These findings establish Kv1.1 as the first identified member of the Kv1 channel family to play a role in sinoatrial function, thereby rendering it a potential candidate and therapeutic targeting of sinus node dysfunction. Furthermore, our results demonstrate that small currents generated via low-abundance channels can still have significant impacts on cardiac pacemaking.

Empowering artificial intelligence in characterizing the human primary pacemaker of the heart at single cell resolution.

The sinus node (SN) serves as the primary pacemaker of the heart and is the first component of the cardiac conduction system. Due to its anatomical properties and sample scarcity, the cellular composition of the human SN has been historically challenging to study. Here, we employed a novel deep learning deconvolution method, namely Bulk2space, to characterise the cellular heterogeneity of the human SN using existing single-cell datasets of non-human species. As a proof of principle, we used Bulk2Space to profile the cells of the bulk human right atrium using publicly available mouse scRNA-Seq data as a reference. 18 human cell populations were identified, with cardiac myocytes being the most abundant. Each identified cell population correlated to its published experimental counterpart. Subsequently, we applied the deconvolution to the bulk transcriptome of the human SN and identified 11 cell populations, including a population of pacemaker cardiomyocytes expressing pacemaking ion channels (HCN1, HCN4, CACNA1D) and transcription factors (SHOX2 and TBX3). The connective tissue of the SN was characterised by adipocyte and fibroblast populations, as well as key immune cells. Our work unravelled the unique single cell composition of the human SN by leveraging the power of a novel machine learning method.

Development of the Cardiac Conduction System.

The electrical impulses that coordinate the sequential, rhythmic contractions of the atria and ventricles are initiated and tightly regulated by the specialized tissues of the cardiac conduction system. In the mature heart, these impulses are generated by the pacemaker cardiomyocytes of the sinoatrial node, propagated through the atria to the atrioventricular node where they are delayed and then rapidly propagated to the atrioventricular bundle, right and left bundle branches, and finally, the peripheral ventricular conduction system. Each of these specialized components arise by complex patterning events during embryonic development. This chapter addresses the origins and transcriptional networks and signaling pathways that drive the development and maintain the function of the cardiac conduction system.

A modified method for isolating sinoatrial node myocytes from adult mice.

Sinoatrial node (SAN) is the pacemaker of the heart in charge of initiating spontaneous electronical activity and controlling heart rate. Myocytes from SAN can generate spontaneous rhythmic action potentials, which propagate through the myocardium, thereby triggering cardiac myocyte contraction. Acutely, the method for isolating sinoatrial node myocytes (SAMs) is critical in studying the protein expression and function of myocytes in SAN. Currently, the SAMs were isolated by transferring SAN tissue directly into the digestion solution, but it is difficult to judge the degree of digestion, and the system was unstable. Here, we present a modified protocol for the isolation of SAMs in mice, based on the collagenase II and protease perfusion of the heart using a Langendorff apparatus and subsequent dissociation of SAMs. The appearance and droplet flow rate of the heart could be significantly changed during enzymatic digestion via perfusion, which allowed us to easily judge the degree of digestion and avoid incomplete or excessive digestion. The SAMs with stable yield and viability achieved from our optimized approach would facilitate the follow-up experiments.

miR-1 as a Key Epigenetic Regulator in Early Differentiation of Cardiac Sinoatrial Region.

A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development. In this study, miR-1 potential role in early cardiac chamber differentiation was analyzed through specific signaling pathways. For this, we performed in chick embryos functional experiments by means of miR-1 microinjections into the posterior cardiac precursors-of both primitive endocardial tubes-committed to sinoatrial region fates. Subsequently, embryos were subjected to whole mount in situ hybridization, immunohistochemistry and RT-qPCR analysis. As a relevant novelty, our results revealed that miR-1 increased Amhc1, Tbx5 and Gata4, while this microRNA diminished Mef2c and Cripto expressions during early differentiation of the cardiac sinoatrial region. Furthermore, we observed in this developmental context that miR-1 upregulated CrabpII and Rarß and downregulated CrabpI, which are three crucial factors in the retinoic acid signaling pathway. Interestingly, we also noticed that miR-1 directly interacted with Hdac4 and Calm1/Calmodulin, as well as with Erk2/Mapk1, which are three key factors actively involved in Mef2c regulation. Our study shows, for the first time, a key role of miR-1 as an epigenetic regulator in the early differentiation of the cardiac sinoatrial region through orchestrating opposite actions between retinoic acid and Mef2c, fundamental to properly assign cardiac cells to their respective heart chambers. A better understanding of those molecular mechanisms modulated by miR-1 will definitely help in fields applied to therapy and cardiac regeneration and repair.

Cardiac conduction diseases: understanding the molecular mechanisms to uncover targets for future treatments.

INTRODUCTION: The cardiac conduction system (CCS) is crucial for maintaining adequate cardiac frequency at rest and modulation during exercise. Furthermore, the atrioventricular node and His-Purkinje system are essential for maintaining atrioventricular and interventricular synchrony and consequently maintaining an adequate cardiac output. AREAS COVERED: In this review article, we examine the anatomy, physiology, and pathophysiology of the CCS. We then discuss in detail the most common genetic mutations and the molecular mechanisms of cardiac conduction disease (CCD) and provide our perspectives on future research and therapeutic opportunities in this field. EXPERT OPINION: Significant advancement has been made in understanding the molecular mechanisms of CCD, including the recognition of the heterogeneous signaling at the subcellular levels of sinoatrial node, the involvement of inflammatory and autoimmune mechanisms, and the potential impact of epigenetic regulations on CCD. However, the current treatment of CCD manifested as bradycardia still relies primarily on cardiovascular implantable electronic devices (CIEDs). On the other hand, an If specific inhibitor was developed to treat inappropriate sinus tachycardia and sinus tachycardia in heart failure patients with reduced ejection fraction. More work is needed to translate current knowledge into pharmacologic or genetic interventions for the management of CCDs.

Pacemaker Channels and the Chronotropic Response in Health and Disease.

Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease-including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating ß-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate-sensitive hyperpolarization-activated current (If) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate-dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.

Intracardiac echocardiography guided anatomical ablation of the arcuate ridge for drug refractory inappropriate sinus tachycardia.

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.

Manejo quirúrgico del paciente con patología pseudoquística sinusal: a propósito de un caso / Surgical management of the patient with sinusal pseudocyst pathology: a case report

Introducción: la patología sinusal puede comprometer el éxito del tratamiento de implantes. Existe una elevada incidencia de patología sinusal. El tratamiento de esta patología puede implicar a otros profesionales, lo que supone un mayor coste sanitarios y demora en la realización de los tratamientos de implantes. El objetivo del presente artículo es presentar un caso clínico representativo de la patología pseudoquística del seno maxilar y una alternativa de su manejo quirúrgico simultáneo a la regeneración ósea requerida para su posterior rehabilitación mediante implantes, así como actualizar la evidencia científica disponible. Caso clínico: se presenta una paciente de 46 años con una lesión pseudoquística sinusal que es remitida para rehabilitar mediante implantes en 1.4 y 1.7, por movilidad y dolor en relación a prótesis fija dentosoportada en maxilar derecho. Se realiza el tratamiento quirúrgico de exodoncias, elevación de seno maxilar y eliminación de la lesión pseudoquística de manera simultánea. Discusión: existe controversia sobre el momento idóneo para realizar el tratamiento sinusal. Algunos estudios muestran éxito de la cirugía endoscópica simultáneamente a la eliminación de la fuente odontogénica. Otros han demostrado que realizar primero la cirugía sinusal tiene el mismo porcentaje de curación que realizar primero el tratamiento odontológico. Conclusión: el diagnóstico de la patología y la planificación quirúrgica deben tener en cuenta el tipo de patología, la extensión y las necesidades de tratamiento del paciente. El manejo quirúrgico de la patología sinusal de manera simultánea a la regeneración ósea es una alternativa segura y beneficiosa para el paciente. (AU)

Introduction: Sinus pathology can compromise the success of implant treatment. There is a high incidence of sinus pathology. The treatment of this pathology may involve other professionals, which means higher healthcare costs and delays in carrying out implant treatments. Besides updating available scientific evidence, the objective of this article is to present a representative clinical case of pseudocystic pathology of the maxillary sinus and an alternative to its simultaneous surgical management in the bone regeneration required for subsequent rehabilitation using implants. Clinical case: A 46-year-old patient with a pseudocystic sinus lesion, referred for rehabilitation using implants in 1.4 and 1.7, due to mobility and pain in relation to a tooth-supported fixed prosthesis in the right maxilla. The surgical treatment, consisting of extractions, maxillary sinus elevation and removal of the pseudocystic lesion, was performed simultaneously. Discussion: There is controversy about the ideal time to perform sinus treatment. Some studies show success of endoscopic surgery simultaneously with removal of the odontogenic source. Others have shown that performing sinus surgery first has the same cure rate as performing dental treatment first. Conclusion: Pathology diagnosis and surgical planning must take into account the type and extent of the pathology and the treatment needs of the patient. Surgical management of sinus pathology simultaneously with bone regeneration is a safe and beneficial alternative for the patient. (AU)

Use of machine learning and Poincaré density grid in the diagnosis of sinus node dysfunction caused by sinoatrial conduction block in dogs.

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.