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The atrioventricular (AV) conduction axis provides electrical continuity between the atrial and ventricular chambers. The "nodal" cardiomyocytes populating this region (AV canal in the embryo, AV node from fetal stages onward) propagate impulses slowly, ensuring sequential contraction of the chambers. Dysfunction of AV nodal tissue causes severe disturbances in rhythm and contraction, and human models that capture its salient features are limited. Here, we report an approach for the reproducible generation of AV canal cardiomyocytes (AVCMs) with in vivo-like gene expression and electrophysiological profiles. We created the so-called "assembloids" composed of atrial, AVCM, and ventricular spheroids, which effectively recapitulated unidirectional conduction and the "fast-slow-fast" activation pattern typical for the vertebrate heart. We utilized these systems to reveal intracellular calcium mishandling as the basis of LMNA-associated AV conduction block. In sum, our study introduces novel cell differentiation and tissue construction strategies to facilitate the study of complex disorders affecting heart rhythm.

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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.

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INTRODUCTION AND OBJECTIVE: His bundle pacing (HBP) could replace failed biventricular pacing (BVP) in guidelines (IIa Indication), but the high capture thresholds and backup lead pacing requirements limit its development. We assessed the efficacy and safety of HBP combined with atrioventricular node ablation (AVNA) for atrial fibrillation (AF) and compared with BVP and left bundle branch pacing (LBBP). METHODS: We reviewed PubMed, Embase, Web of Science, and Cochrane Library databases on left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) score, QRS duration (QRSd), and pacing threshold. RESULTS: Thirteen studies included 1115 patients (639 with HBP, 338 with BVP, and 221 with LBBP). Compared with baseline, HBP improved LVEF (mean difference [MD]: 9.24 [6.10, 12.37]; p < 0.01), reduced NYHA score (MD: -1.12 [-1.34, -0.91]; p < 0.01), increased QRSd (MD: 10.08 [4.45, 15.70]; p < 0.01), and rose pacing threshold (MD: 0.16 [0.05, 0.26]; p < 0.01). HBP had comparable efficacy to BVP and LBBP and lower QRSd (p < 0.05). HBP had a lower success rate (85.97%) and more complications (16.1%). CONCLUSION: HBP combined with AVNA is effective for AF, despite having a lower success rate and more complications. Further trials are required to determine whether HBP is superior to BVP and LBBP.

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Background: Atrioventricular node (AVN) ablation is an effective treatment for atrial fibrillation (AF) with uncontrolled ventricular rates despite maximal pharmacological treatment. Intracardiac echocardiography (ICE) can help with visualizing structures, positioning catheters, and guiding the ablation procedure. We compared only fluoroscopy-guided and ICE-guided AVN ablation regarding patients with permanent AF. Methods: Sixty-two consecutive patients underwent AVN ablation were enrolled in our retrospective single-center study (ICE group: 28 patients, Standard group: 34 patients). Procedural data, acute and long-term success rate, and complications were analyzed. Results: ICE guidance for AVN ablation significantly reduced fluoroscopy time (0.30 [0.06; 0.85] min vs. 7.95 [3.23; 6.59] min, p < 0.01), first-to-last ablation time (4 [2; 16.3] min vs. 26.5 [2.3; 72.5] min, p = 0.02), and in-procedure time (40 [34; 55] min vs. 60 [45; 110], p = 0.02). There was no difference in either the total ablation time (199 [91; 436] s vs. 294 [110; 659] s, p = 0.22) or in total ablation energy (8272 [4004; 14,651] J vs. 6065 [2708; 16,406] J, p = 0.28). The acute success rate was similar (ICE: 100% vs. Standard: 94%, p = 0.49) between the groups. Conclusions: In our retrospective trial, ICE-guided AVN ablation reduced fluoroscopy time, procedure time, and first-to-last ablation time. There was no difference in ablation time, total ablation energy, acute and long-term success, and complication rate.

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BACKGROUND: Pacemaker implantation combined with atrioventricular node ablation (AVNA) is a well-established strategy for uncontrolled atrial arrhythmias. Limited data are available regarding His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) in this setting. AIM: To compare the outcomes of HBP and LBBAP in patients undergoing pacemaker implantation combined with AVN in routine clinical practice. METHODS: We prospectively included all patients who underwent AVNA after successful conduction system pacing (CSP) in two hospitals between September 2017 and May 2023. The primary outcome was the 1-year composite of first episode of heart failure hospitalization, symptomatic atrioventricular node reconduction requiring a second AVNA procedure, lead revision or death from any cause. RESULTS: A total of 164 patients underwent AVNA following successful CSP (68 HBP and 96 LBBAP). Mean pacemaker implantation and AVNA procedure times were shorter in the LBBAP group than the HBP group (46±18 vs 59±23min; P<0.001 and 31±12 vs 43±22min, respectively; P<0.001). Complete atrioventricular block was more frequently obtained in the LBBAP group (88/96 patients [92%] vs 54/68 patients [79%]; P=0.04). One-year freedom from the composite outcome was more frequent in the LBBAP group (89.7% vs 72.9%; hazard ratio 0.32, 95% confidence interval 0.14-0.72; P=0.01). The strategy was similarly effective in both groups with a significant improvement in NYHA class and left ventricular ejection fraction. A secondary pacing threshold elevation >1V occurred only in the HBP group (11%). CONCLUSION: In this prospective, comparative study, LBBAP provided better 1-year outcomes than HBP.

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Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common form of paroxysmal supraventricular tachycardia, and its diagnostic and therapeutic approaches have been well-established. Traditionally, AVNRT is understood to be an intranodal reentry having two bystander pathways; the upper common pathway (UCP) which connects to the atrium and the lower common pathway which connects to the ventricle. However, the existence of the UCP remains a subject of ongoing debate. The assertion of the UCP's presence is supported by electrophysiological evidence suggesting that the atrium is not essential for the perpetuation of AVNRT. Nonetheless, numerous anatomical studies have failed to identify any structure that could be conclusively designated as the UCP. The histological and electrophysiological characteristics of the slow and fast pathways, which are the core components of AVNRT, suggest the inclusion of atrial myocardium in the reentry circuit. While clear interpretation of these discrepancies remains elusive, potential explanations may be derived from existing evidence and recent research findings concerning the actual AVNRT circuit.

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Despite lack of concrete evidence, right ventricular thrombus is generally considered to be a contraindication for intracardiac lead placement. We present a case of successful placement of a right ventricular defibrillator lead and left bundle branch pacing lead and atrioventricular node ablation in a patient with chronic right ventricle thrombus.

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Systemic diseases can cause heart block owing to the involvement of the myocardium and thereby the conduction system. Younger patients (<60) with heart block should be evaluated for an underlying systemic disease. These disorders are classified into infiltrative, rheumatologic, endocrine, and hereditary neuromuscular degenerative diseases. Cardiac amyloidosis owing to amyloid fibrils and cardiac sarcoidosis owing to noncaseating granulomas can infiltrate the conduction system leading to heart block. Accelerated atherosclerosis, vasculitis, myocarditis, and interstitial inflammation contribute to heart block in rheumatologic disorders. Myotonic, Becker, and Duchenne muscular dystrophies are neuromuscular diseases involving the myocardium skeletal muscles and can cause heart block.

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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.

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BACKGROUND: Atrioventricular node ablation (AVNA) with permanent pacing is an effective treatment of symptomatic atrial fibrillation (AF). Left bundle branch area pacing (LBBAP) prevents cardiac dyssynchrony associated with right ventricular pacing and could prevent worsening of heart failure (HF). METHODS: In this retrospective monocentric study, all patients who received AVNA procedure with LBBAP were consecutively included. AVNA procedure data, electrical and echocardiographic parameters at 6 months, and clinical outcomes at 1 year were studied and compared to a matched cohort of patients who received AVNA procedure with conventional pacing between 2010 and 2023. RESULTS: Seventy-five AVNA procedures associated with LBBAP were studied. AVNA in this context was feasible, with a success rate of 98.7% at first ablation, and safe without any complications. There was no threshold rise at follow-up. At 1 year, 6 (8%) patients were hospitalized for HF and 2 (2.7%) were deceased. Patients had a significant improvement in NYHA class and left ventricular ejection fraction (LVEF) (P ≤ 0.0001). When compared to a matched cohort of patients with AVNA and conventional pacing, AVNA data and pacing complications rates were similar. Patients with LBBAP had a better improvement of LVEF (+5.27 ± 9.62% vs. -0.48 ± 14%, P = 0.01), and a lower 1-year rate of composite outcome of hospitalization for HF or death (HR 0.39, 95% CI: 0.16-0.95, P = 0.037), significant on survival analysis (log-rank P-value = 0.03). CONCLUSION: AVNA with LBBAP in patients with symptomatic AF is feasible, safe, and efficient. Hospitalization for HF or death rate was significantly lower and LVEF improvement was greater.

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Numerous studies have clarified the histological characteristics of the area surrounding the atrioventricular (AV) node, commonly referred to as the triangle of Koch (ToK). Although it is suggested that the conduction of electric impulses from the atria to the ventricles via the AV node involves myocytes possessing distinct conduction properties and gap junction proteins, a comprehensive understanding of this complex conduction has not been fully established. Moreover, although various pathways have been proposed for both anterograde and retrograde conduction during atrioventricular nodal reentrant tachycardia (AVNRT), the reentrant circuits of AVNRT are not fully elucidated. Therefore, the slow pathway ablation for AVNRT has been conventionally performed, targeting both its anatomical location and slow pathway potential obtained during sinus rhythm. Recently, advancements in high-density three-dimensional (3D) mapping systems have facilitated the acquisition of more detailed electrophysiological potentials within the ToK. Several studies have indicated that the activation pattern, the low-voltage area within the ToK obtained during sinus rhythm, and the fractionated potentials acquired during tachycardia may be optimal targets for slow pathway ablation. This review provides an overview of the tissue surrounding the AV node as reported to date and summarizes the current understanding of AV conduction and AVNRT circuits. Furthermore, we discuss recent findings on slow pathway ablation utilizing high-density 3D mapping systems, exploring strategies for optimal slow pathway ablation.

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Introduction: Information about autonomic nervous system (ANS) activity may offer insights about atrial fibrillation (AF) progression and support personalized AF treatment but is not easily accessible from the ECG. In this study, we propose a new approach for ECG-based assessment of respiratory modulation in atrioventricular (AV) nodal refractory period and conduction delay. Methods: A 1-dimensional convolutional neural network (1D-CNN) was trained to estimate respiratory modulation of AV nodal conduction properties from 1-minute segments of RR series, respiration signals, and atrial fibrillatory rates (AFR) using synthetic data that replicates clinical ECG-derived data. The synthetic data were generated using a network model of the AV node and 4 million unique model parameter sets. The 1D-CNN was then used to analyze respiratory modulation in clinical deep breathing test data of 28 patients in AF, where an ECG-derived respiration signal was extracted using a novel approach based on periodic component analysis. Results: We demonstrated using synthetic data that the 1D-CNN can estimate the respiratory modulation from RR series alone with a Pearson sample correlation of r = 0.805 and that the addition of either respiration signal (r = 0.830), AFR (r = 0.837), or both (r = 0.855) improves the estimation. Discussion: Initial results from analysis of ECG data suggest that our proposed estimate of respiration-induced autonomic modulation, a resp, is reproducible and sufficiently sensitive to monitor changes and detect individual differences. However, further studies are needed to verify the reproducibility, sensitivity, and clinical significance of a resp.

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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.

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Several anatomical, demographic, clinical, electrocardiographic, procedural, and valve-related variables can be used to predict the probability of developing conduction abnormalities after transcatheter aortic valve replacement (TAVR) that necessitate permanent pacemaker (PPM) implantation. These variables include calcifications around the device landing zone and in the mitral annulus; pre-existing electrocardiographic abnormalities such as left and right bundle branch blocks (BBB), first- and second-degree atrioventricular blocks, as well as bifascicular and trifascicular blocks; male sex; diabetes mellitus (DM); hypertension; history of atrial fibrillation; renal failure; dementia; and use of self-expanding valves. The current study supports existing literature by demonstrating that type 2 DM and baseline right BBB are significant predictors of PPM implantation post-TAVR. Regardless of the side of the BBB, this study demonstrated, for the first time, a linear association between the incidence of PPM implantation post-TAVR and every 20 ms increase in baseline QRS duration (above 100 ms). After a 1-year follow-up, patients who received PPM post-TAVR had a higher rate of hospitalization for heart failure and nonfatal myocardial infarction.

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Background: A jump in the atrioventricular (AV) conduction curve is the current clinical criterion of dual-pathway electrophysiology. However, the assumption that a jump indicates a switch from fast pathway (FP) to slow pathway (SP) conduction remains unconfirmed. This study was carried out to investigate whether a jump indeed indicates a transition from FP to SP conduction, and if not, what the potential cause is. Methods: Eighty-one experimental records from rabbit AV nodal preparations containing the following data were analyzed: 1) had at least one AV conduction curve and 2) had recording of His electrogram alternans (a validated new index of dual-pathway conduction). Most cases also had intracellular action potential recordings from the AV nodal fibers. Results: Of the 81 preparations, 11 (13%) showed a jump in the AV conduction curve. The jumps always occurred after the FP to SP transition. The FP-SP transition occurred at prematurity at 196 ± 39 ms versus the jump at 114 ± 13 ms (p < 0.001). The beat with a jump showed an SP-FP pattern in seven and an SP-SP pattern in four preparations. The jumps were always associated with and most likely caused by the formation of intranodal/nodal-atrial reentry and its subsequent conduction, rather than a switch from FP to SP conduction. Conclusion: Contrary to what has been assumed, a transition from FP to SP conduction does not produce a jump in the AV conduction curve. A jump in the AV conduction curve is most likely caused by the formation of intranodal/nodal-atrial reentry and its subsequent conduction.

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BACKGROUND: Fast-conducting atrial fibrillation misinterpreted as ventricular tachycardia is the leading cause for inappropriate shocks in patients with implantable cardiac defibrillators (ICD). These inappropriate shocks are associated with significant morbidity and mortality and cause great discomfort and stress. CASE PRESENTATION: We report the case of a patient with ischemic cardiomyopathy, permanent atrial fibrillation, and a single-chamber DF-1 ICD implanted for the primary prevention of sudden cardiac death, who presented for multiple inappropriate internal shocks due to very fast-conducting atrial fibrillation, which was mislabeled as ventricular fibrillation by the ICD. Since the patient was under maximal atrioventricular nodal blocking medical therapy (beta-blockers and digitalis) and we didn`t find any reversible causes for the heart rate acceleration, we opted for rate control with atrioventricular node ablation. To counteract the risk of pacing-induced cardiomyopathy in this patient who would become totally pacemaker-dependent, we successfully performed left bundle branch area pacing. Because the patient`s ICD had a DF-1 connection and the battery had a long life remaining, we connected the physiological pacing lead to the IS-1 sense-pace port of the ICD. The 6-month follow-up showed an improvement in left ventricular function with no more inappropriate shocks. CONCLUSIONS: Left bundle branch area pacing and atrioventricular node ablation in patients with an implantable single-chamber DF-1 defibrillator and fast-conducting permanent atrial fibrillation is a cost-efficient and very effective method to prevent and treat inappropriate shocks, avoiding the use of an additional dual-chamber or CRT-D device.

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INTRODUCTION: Postoperative atrial fibrillation (POAF) is common following open heart surgery, and is associated with significant morbidity. Medications used for ventricular rate control of POAF may not be effective in controlling rapid ventricular rates during the postoperative period because of increased sympathetic tone. The purpose of this study was to develop nonpharmacologic rate control of POAF by atrioventricular node (AVN) fat pad stimulation using clinically available temporary pacing wires in the canine sterile pericarditis model. METHODS: We studied 10 sterile pericarditis dogs in the closed-chest state on postoperative days 1-3. The AVN fat pad stimulation (amplitude 2-15 mA; frequency 20 Hz; pulse width 0.03-0.2 ms) was performed during sustained POAF (>5 min). We measured ventricular rate and inefficient ventricular contractions during sustained POAF and compared it with and without AVN fat pad stimulation. Also, the parameters of AVN fat pad stimulation to achieve a rate control of POAF were measured over the postoperative days. RESULTS: Eleven episodes of sustained POAF were induced in 5/10 sterile pericarditis dogs in the closed-chest state on postoperative days 1-2. During POAF, the AVN fat pad stimulation decreased the ventricular rate from 178 ± 52 bpm to 100 ± 8 bpm in nine episodes. Nonpharmacologic rate control therapy successfully controlled the ventricular rate and eliminated inefficient ventricular contractions during POAF for the duration of the AVN fat pad stimulation. The AVN fat pad stimulation output remained relatively stable over the postoperative days. CONCLUSION: During sustained POAF, nonpharmacologic rate control by AVN fat pad stimulation effectively and safely controlled rapid ventricular rates throughout the postoperative period.

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