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.

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)

An interesting electrocardiogram caused by lead reversal.

BACKGROUND: During normal sinus rhythm, atrial depolarization is conducted from right atrium to left atrium through Bachmann's bundle, and a normal P wave axis which is measured on the frontal plane is between 0º and + 75º. The change of P wave polarity is helpful for the analysis of origin point. CASE PRESENTATION: We report a patient with negative P wave in lead I. The characteristics of QRS complex in leads V1 to V6 are helpful to preliminarily differential diagnosis. The 12-lead electrocardiogram (ECG) with correct limb leads (right arm-left arm) placement shows sinus rhythm with complete right bundle branch block (RBBB). CONCLUSIONS: The change of P wave polarity as well as characteristics of QRS complex can help identify limb-lead reversals.

Decreased connexin 40 expression of the sinoatrial node mediates ischemic stroke-induced arrhythmia in mice.

BACKGROUND: Arrhythmia is the most common cardiac complication after ischemic stroke. Connexin 40 is the staple component of gap junctions, which influences the propagation of cardiac electrical signals in the sinoatrial node. However, the role of connexin 40 in post-stroke arrhythmia remains unclear. METHODS: In this study, a permanent middle cerebral artery occlusion model was used to simulate the occurrence of an ischemic stroke. Subsequently, an electrocardiogram was utilized to record and assess variations in electrocardiogram measures. In addition, optical tissue clearing and whole-mount immunofluorescence staining were used to confirm the anatomical localization of the sinoatrial node, and the sinoatrial node tissue was collected for RNA sequencing to screen for potential pathological mechanisms. Lastly, the rAAV9-Gja5 virus was injected with ultrasound guidance into the heart to increase Cx40 expression in the sinoatrial node. RESULTS: We demonstrated that the mice suffering from a permanent middle cerebral artery occlusion displayed significant arrhythmia, including atrial fibrillation, premature ventricular contractions, atrioventricular block, and abnormal electrocardiogram parameters. Of note, we observed a decrease in connexin 40 expression within the sinoatrial node after the ischemic stroke via RNA sequencing and western blot. Furthermore, rAAV9-Gja5 treatment ameliorated the occurrence of arrhythmia following stroke. CONCLUSIONS: In conclusion, decreased connexin 40 expression in the sinoatrial node contributed to the ischemic stroke-induced cardiac arrhythmia. Therefore, enhancing connexin 40 expression holds promise as a potential therapeutic approach for ischemic stroke-induced arrhythmia.

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

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

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

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

3D models of the cardiac conduction system in healthy neonatal human hearts.

Iatrogenic damage to the cardiac conduction system (CCS) remains a significant risk during congenital heart surgery. Current surgical best practice involves using superficial anatomical landmarks to locate and avoid damaging the CCS. Prior work indicates inherent variability in the anatomy of the CCS and supporting tissues. This study introduces high-resolution, 3D models of the CCS in normal pediatric human hearts to evaluate variability in the nodes and surrounding structures. Human pediatric hearts were obtained with an average donor age of 2.7 days. A pipeline was developed to excise, section, stain, and image atrioventricular (AVN) and sinus nodal (SN) tissue regions. A convolutional neural network was trained to enable precise multi-class segmentation of whole-slide images, which were subsequently used to generate high- resolution 3D tissue models. Nodal tissue region models were created. All models (10 AVN, 8 SN) contain tissue composition of neural tissue, vasculature, and nodal tissues at micrometer resolution. We describe novel nodal anatomical variations. We found that the depth of the His bundle in females was on average 304 µm shallower than those of male patients. These models provide surgeons with insight into the heterogeneity of the nodal regions and the intricate relationships between the CCS and surrounding structures.

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

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

A rare case of modified superior vena cava isolation by using the ultra-high-resolution mapping system.

We report a case of atrial fibrillation (AF) recurrence after pulmonary vein isolation, which patient had AF trigger in the superior vena cava (SVC) near the sinus node (SN). The ultra-high-resolution mapping revealed that SN located within the SVC and the atrial activation from the SN to SVC propagated in both septal and lateral direction, then upward with circumventing the spontaneous conduction block identified just above and lateral SN (upper hemisphere). We successfully isolated SVC including the ectopic origin at the same level as the SN by utilizing the spontaneous conduction block line around the SN without any complication.

Tachy-brady syndrome: Electrophysiology and evolving principles of management.

Sudden alterations in the heart rate may be associated with diverse symptoms. Sinus node dysfunction (SND), also known as sick sinus syndrome, is a sinoatrial (SA) node disorder. SND is primarily caused by the dysfunction of the pacemaker, as well as impaired impulse transmission resulting in a multitude of abnormalities in the heart rhythms, such as bradycardia-tachycardia, atrial bradyarrhythmias, and atrial tachyarrhythmias. The transition from bradycardia to tachycardia is generally referred to as "tachy-brady syndrome" (TBS). Although TBS is etiologically variable, the manifestations remain consistent throughout. Abnormal heart rhythms have the propensity to limit tissue perfusion resulting in palpitations, fatigue, lightheadedness, presyncope, and syncope. In this review, we examine the physiology of tachy-brady syndrome, the practical approach to its diagnosis and management, and the role of adenosine in treating SND.

Sinoatrial Node Dose Is Associated With Worse Survival in Patients Undergoing Definitive Stereotactic Body Radiation Therapy for Central Lung Cancers.

PURPOSE: Our purpose was to evaluate the clinical consequences of sinoatrial node (SAN) and atrioventricular node (AVN) irradiation in patients undergoing stereotactic body radiation therapy (SBRT) for central non-small cell lung cancer (NSCLC) tumors. METHODS AND MATERIALS: A single-institutional retrospective review of patients with primary NSCLC undergoing definitive SBRT for centrally located thoracic tumors from February 2007 to December 2021 was performed. The SAN and AVN were contoured in accordance with a published contouring atlas, and the maximum dose (Dmax) and mean dose (Dmean) for each structure were calculated. Sequential log rank testing between the 50th and 90th percentiles was used to identify potential cutoff values for the corresponding dosimetric parameters and overall survival. RESULTS: Among 93 eligible patients, the median age was 72.5 years (IQR, 66.6-78.3), and median follow-up was 32.4 months (IQR, 13.0-49.6). The median SAN Dmax and Dmean were 95 cGy (range, 9-5394) and 58 cGy (range, 7-3168), respectively. The median AVN Dmax and Dmean were 45 cGy (range, 4-2121) and 34 cGy (range, 3-1667), respectively. Candidate cutoff values for SAN Dmax and Dmean were 1309 and 836 cGy, respectively. No associations between AVN parameters and survival outcomes were identified. Upon multivariate Cox regression, the SAN Dmax cutoff (hazard ratio [HR], 2.03 [1.09-3.79]; P = .026) and SAN Dmean cutoff (HR, 2.22 [1.20-4.12]; P = .011) were significantly associated with overall survival. For noncancer-associated survival, the SAN Dmax cutoff trended toward significance (HR, 2.02 [0.89-4.57]; P = .092), and the SAN Dmean cutoff remained significantly associated (HR, 2.34 [1.05-5.18]; P = .037). CONCLUSIONS: For patients undergoing SBRT for NSCLC, SAN Dmax and Dmean were significantly associated with worse overall survival using cut-off values of 1309 and 836 cGy, respectively. Further studies examining the effect of SAN irradiation during SBRT are warranted.

Cadherin-5 facilitated the differentiation of human induced pluripotent stem cells into sinoatrial node-like pacemaker cells by regulating ß-catenin.

Our study was conducted to investigate whether cadherin-5 (CDH5), a vascular endothelial cell adhesion glycoprotein, could facilitate the differentiation of human induced pluripotent stem cells (hiPSCs) into sinoatrial node-like pacemaker cells (SANLPCs), following previous findings of silk-fibroin hydrogel-induced direct conversion of quiescent cardiomyocytes into pacemaker cells in rats through the activation of CDH5. In this study, the differentiating hiPSCs were treated with CDH5 (40 ng/mL) between Day 5 and 7 during cardiomyocytes differentiation. The findings in the present study demonstrated that CDH5 stimulated the expression of pacemaker-specific markers while suppressing markers associated with working cardiomyocytes, resulting in an increased proportion of SANLPCs among hiPSCs-derived cardiomyocytes (hiPSC-CMs) population. Moreover, CDH5 induced typical electrophysiological characteristics resembling cardiac pacemaker cells in hiPSC-CMs. Further mechanistic investigations revealed that the enriched differentiation of hiPSCs into SANLPCs induced by CDH5 was partially reversed by iCRT14, an inhibitor of ß-catenin. Therefore, based on the aforementioned findings, it could be inferred that the regulation of ß-catenin by CDH5 played a crucial role in promoting the enriched differentiation of hiPSCs into SANLPCs, which presents a novel avenue for the construction of biological pacemakers in forthcoming research.

Detailed study of collagen, vasculature, and innervation in the human cardiac conduction system.

BACKGROUND: The cardiac conduction system (CCS) creates and propagates electrical signals generating the heartbeat. This study aimed to assess the collagen content, vasculature, and innervation in the human sinoatrial and atrioventricular CCS, and surrounding tissue. MATERIALS AND METHODS: Ten sinoatrial and 17 atrioventricular CCS samples were collected from 17 adult human autopsied hearts. Masson trichrome stain was used to examine collagen, cardiomyocytes, and fat proportions. Immunohistochemically, vessels and lymphatics were studied by CD31 (pan-endothelial marker) and D2-40 (lymphatic endothelium marker) antibodies. General nerve densities were assessed by S100, while sympathetic nerves were studied using tyrosine hydroxylase, parasympathetic nerves with choline acetyltransferase, and GAP43 (neural growth marker) antibodies looked at these components. All components were quantified with QuPath software (Queens University, Belfast, Northern Ireland). RESULTS: Interstitial collagen was more than two times higher in the sinoatrial vs. atrioventricular CCS (55% vs. 22%). The fat content was 6.3% in the sinoatrial CCS and 6.5% in the atrioventricular CCS. The lymphatic vessel density was increased in the sinoatrial and atrioventricular CCS compared to the surrounding tissue and was lower in the sinoatrial vs. atrioventricular CCS (P=.043). The overall vasculature density did not differ between the SA and AV CCS. The overall innervation and neural growth densities were significantly increased in the CCS compared to the surrounding tissue. The overall innervation was higher in the atrial vs. ventricular CCS (P=.018). The neural growth was higher in the atrial vs. ventricular CCS (P=.018). The sympathetic neural supply was dominant in all the studied regions with the highest density in the sinoatrial CCS. CONCLUSIONS: Our results provide new insights into the unique morphology of the human CCS collagen, fat, vasculature, and innervation. A deeper understanding of the CCS anatomical components and morphologic substrates' role will help in elucidating the causes of cardiac arrhythmias and provide a basis for further therapeutic interventions.

The sinoatrial node extracellular matrix promotes pacemaker phenotype and protects automaticity in engineered heart tissues from cyclic strain.

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.

Redo procedures after sinus node sparing hybrid ablation for inappropriate sinus tachycardia/postural orthostatic sinus tachycardia.

AIMS: A novel sinus node (SN) sparing hybrid ablation for inappropriate sinus node tachycardia (IST)/postural orthostatic tachycardia syndrome (POTS) has been demonstrated to be an effective and safe therapeutic option in patients with symptomatic drug-resistant IST/POTS. The aim of this study was to evaluate the long-term rate of redo procedures after hybrid IST ablation and procedural strategy, outcomes and safety of redo procedures. METHODS AND RESULTS: All consecutive patients from 2015 to 2023 were prospectively enrolled in the UZ Brussel monocentric IST/POTS registry. They were analysed if the following inclusion criteria were fulfilled: 1) diagnosis of IST or POTS, 2) symptomatic IST/POTS refractory or intolerant to drugs, and 3) hybrid SN sparing ablation performed. The primary endpoint was redo procedure. The primary safety endpoint was pacemaker (PM) implantation. A total of 220 patients undergone to hybrid IST ablation were included, 185 patients (84.1%) were treated for IST and 61 patients (27.7%) for POTS.After a follow-up of 73.3 ± 16.2 months, 34 patients (15.4%) underwent a redo. A total of 23 patients (67.6%) had a redo for IST recurrence and 11 patients (32.4%) for other arrhythmias. Pacemaker implantation was performed in 21 patients (9.5%). Nine patients (4.1%) had no redo procedure and experienced sick sinus syndrome requiring a PM. Twelve patients (5.4%) received a PM as a shared therapeutic choice combined with SN ablation procedure. CONCLUSION: In a large cohort of patients the long-term free survival from redo procedure after hybrid IST ablation was 84.6% with a low PM implantation rate.

Mechanistic insight into the functional role of human sinoatrial node conduction pathways and pacemaker compartments heterogeneity: A computer model analysis.

The sinoatrial node (SAN), the primary pacemaker of the heart, is responsible for the initiation and robust regulation of sinus rhythm. 3D mapping studies of the ex-vivo human heart suggested that the robust regulation of sinus rhythm relies on specialized fibrotically-insulated pacemaker compartments (head, center and tail) with heterogeneous expressions of key ion channels and receptors. They also revealed up to five sinoatrial conduction pathways (SACPs), which electrically connect the SAN with neighboring right atrium (RA). To elucidate the role of these structural-molecular factors in the functional robustness of human SAN, we developed comprehensive biophysical computer models of the SAN based on 3D structural, functional and molecular mapping of ex-vivo human hearts. Our key finding is that the electrical insulation of the SAN except SACPs, the heterogeneous expression of If, INa currents and adenosine A1 receptors (A1R) across SAN pacemaker-conduction compartments are required to experimentally reproduce observed SAN activation patterns and important phenomena such as shifts of the leading pacemaker and preferential SACP. In particular, we found that the insulating border between the SAN and RA, is required for robust SAN function and protection from SAN arrest during adenosine challenge. The heterogeneity in the expression of A1R within the human SAN compartments underlies the direction of pacemaker shift and preferential SACPs in the presence of adenosine. Alterations of INa current and fibrotic remodelling in SACPs can significantly modulate SAN conduction and shift the preferential SACP/exit from SAN. Finally, we show that disease-induced fibrotic remodeling, INa suppression or increased adenosine make the human SAN vulnerable to pacing-induced exit blocks and reentrant arrhythmia. In summary, our computer model recapitulates the structural and functional features of the human SAN and can be a valuable tool for investigating mechanisms of SAN automaticity and conduction as well as SAN arrhythmia mechanisms under different pathophysiological conditions.

D-galactose causes sinoatrial node dysfunction: from phenotype to mechanism.

With the population aging, age-related sinoatrial node dysfunction (SND) has been on the rise. Sinoatrial node (SAN) degeneration is an important factor for the age-related SND development. However, there is no suitable animal modeling method in this field. Here, we investigated whether D-galactose could induce SAN degeneration and explored the associated mechanism. In vivo, twelve C57BL/6 mice were divided into Control and D-galactose group to receive corresponding treatments. Senescence was confirmed by analyzing the hair and weight; cardiac function was evaluated through echocardiography, cerebral blood flux and serum-BNP; the SAN function was evaluated by electrocardiogram; fibrotic change was evaluated by Masson's trichrome staining and oxidative stress was assessed through DHE staining and serum indicators. Mechanism was verified through immunofluorescence-staining and Western blotting. In vitro, mouse-atrial-myocytes were treated with D-galactose, and edaravone was utilized as the ROS scavenger. Senescence, oxidative stress, proliferation ability and mechanism were verified through various methods, and intuitive evidence was obtained through electrophysiological assay. Finally, we concluded that D-galactose can be used to induce age-related SND, in which oxidative stress plays a key role, causing PITX2 ectopic expression and downregulates SHOX2 expression, then through the downstream GATA4/NKX2-5 axis, results in pacing-related ion channels dysfunction, and hence SND development.

Corrected sinus node recovery time as a screening test in patients with typical atrial flutter post-ablation to predict pacemaker implantation.

OBJECTIVE: The objective of the study was to establish the prognostic value of CSNRT regarding the necessity for pacemaker implantation in patients with atrial flutter (AFL) post-ablation. METHODS: This prospective cohort study, conducted at the National Institute of Cardiology "Ignacio Chavez" in Mexico City, assessed patients who had undergone ablation procedures to correct AFL, posterior to which an autonomic blockade was performed, and CSNRT was measured. RESULTS: The sample for this investigation was 40 patients. These were subdivided into two study groups depending on their requirement of pacemaker implant post-ablation (Pacemaker P, No Pacemaker NP). Sinus node (SN) dysfunction was diagnosed in 13 (32.5%) of the 40 participants, 10 (71.43%) of which required a pacemaker implant, while only 4 participants (28.57%) with normal SN function required pacemakers. Ten out of the 14 patients (71.43%) who required a pacemaker had an elevated CSNRT > 500 ms (p ≤ 0.01). Post-ablation CSNRT mean was 383.54 ms ± 67.96 ms in the NP group versus 1972.57 ms ± 3423.56 ms in the P group. Furthermore, SN pause in the P group had a mean of 1.86 s ± 0.96 s versus the NP group with 1.196 s ± 0.52 s. CONCLUSION: CSNRT has the potential to be a quantitative prognostic tool for the assessment of future pacemaker implants in patients with AFL post-ablation. This could aid in the timely diagnosis of sinus node dysfunction, which could, in the long run, result in the reduction of cardiac functional capacity loss due to cardiac remodeling.

OBJETIVO: Establecer el valor pronóstico del TRNSC basado en la necesidad de marcapasos en pacientes diagnosticados con aleteo atrial, pos-ablación. MÉTODOS: Este cohorte prospectivo, realizado en el Instituto Nacional de Cardiología "Ignacio Chávez" en la Ciudad de México, evaluó pacientes sometidos a ablación para corregir el aleteo atrial; se midió el TRNSC post bloqueo autonómico. RESULTADOS: La muestra de 40 pacientes se subdividió en 2 grupos según su requerimiento de marcapasos posterior a la ablación (P y NP). Se diagnosticó disfunción del nodo sinusal en 13 participantes (32.5%), de los cuales 10 (71.43%) requirieron marcapasos en comparación a 4 (28.57%) con función normal. En el grupo P la pausa del nodo sinusal post-ablación tuvo una media de 1.86 ± 0.96 s versus el grupo NP con 1.196 ± 0.52 s. En relación con el TRNSC, el grupo NP tuvo una media de 383.54 ± 67.96 ms vs. 1972.57 ± 3423.56 ms en el grupo P. 10 pacientes (25%) obtuvieron un TRNSC > 500 ms, de los cuales 100% requirieron marcapasos; de los 14 pacientes que requirieron marcapasos 10 (71.43%) tenían un TRNSC elevado (p ≤ 0.01). CONCLUSIONES: El TRNSC tiene el potencial de ser una herramienta de pronóstico cuantitativo para la necesidad de futuros implantes de marcapasos en pacientes con disfunción del nodo sinusal, resultado de aleteo atrial pos-ablación. Esto podría ayudar a diagnosticar más temprano una disfunción del nodo sinusal, resultando en la reducción de la pérdida a largo plazo de la función cardíaca como efecto de la remodelación.

Age-dependent contribution of intrinsic mechanisms to sinoatrial node function in humans.

Average beat interval (BI) and beat interval variability (BIV) are primarily determined by mutual entrainment between the autonomic-nervous system (ANS) and intrinsic mechanisms that govern sinoatrial node (SAN) cell function. While basal heart rate is not affected by age in humans, age-dependent reductions in intrinsic heart rate have been documented even in so-called healthy individuals. The relative contributions of the ANS and intrinsic mechanisms to age-dependent deterioration of SAN function in humans are not clear. We recorded ECG on patients (n = 16 < 21 years and n = 23 41-78 years) in the basal state and after ANS blockade (propranolol and atropine) in the presence of propofol and dexmedetomidine anesthesia. Average BI and BIV were analyzed. A set of BIV features were tested to designated the "signatures" of the ANS and intrinsic mechanisms and also the anesthesia "signature". In young patients, the intrinsic mechanisms and ANS mainly contributed to long- and short-term BIV, respectively. In adults, both ANS and intrinsic mechanisms contributed to short-term BIV, while the latter also contributed to long-term BIV. Furthermore, anesthesia affected ANS function in young patients and both mechanisms in adult. The work also showed that intrinsic mechanism features can be calculated from BIs, without intervention.

A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.

In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.