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The cerebellum plays an important role in diverse brain functions, ranging from motor learning to cognition. Recent studies have suggested that molecular and cellular heterogeneity within cerebellar lobules contributes to functional differences across the cerebellum. However, the specific relationship between molecular and cellular heterogeneity and diverse functional outputs of different regions of the cerebellum remains unclear. Here, we describe a previously unappreciated form of synaptic heterogeneity at parallel fiber synapses to Purkinje cells in the mouse cerebellum (both sexes). In contrast to uniform fast synaptic transmission, we found that the properties of slow synaptic transmission varied by up to threefold across different lobules of the mouse cerebellum, resulting in surprising heterogeneity. Depending on the location of a Purkinje cell, the time of peak of slow synaptic currents varied by hundreds of milliseconds. The duration and decay time of these currents also spanned hundreds of milliseconds, based on lobule. We found that, as a consequence of the heterogeneous synaptic dynamics, the same brief input stimulus was transformed into prolonged firing patterns over a range of timescales that depended on Purkinje cell location. [ABSTRACT FROM AUTHOR]

The synapses between parallel fibers and Purkinje cells play a pivotal role in cerebellar function. They are intricately governed by a variety of presynaptic receptors, notably by type 4metabotropic glutamate (mGlu4) receptors and type 1 adenosine (A1) receptors both of which curtail glutamate release upon activation. Despite their pivotal role in regulating synaptic transmission within the cerebellar cortex, functional interactions between mGlu4 and A1 receptors have remained relatively unexplored. To bridge this gap, our study delves into how mGlu4 receptor activity influences A1 receptor-mediated alterations in excitatory transmission. Employing a combination of whole-cell patch clamp recordings of Purkinje cells and parallel fiber presynaptic fluorometric calcium measurements in acute rat andmouse cerebellar cortical slices, our results reveal functional interactions between these receptor types. These findings hold implications for understanding potential roles of these presynaptic receptors in neuroprotection during pathophysiological conditions characterized by elevated glutamate and adenosine levels. [ABSTRACT FROM AUTHOR]

Left bundle branch block (LBBB) represents a frequently encountered conduction system disorder. Despite its widespread occurrence, a continual dilemma persists regarding its intricate association with underlying cardiomyopathy and its pivotal role in the initiation of dilated cardiomyopathy. The pathologic alterations linked to LBBB-induced cardiomyopathy (LBBB-CM) have remained elusive. This study sought to investigate the chronologic dynamics of LBBB to left ventricular dysfunction and the pathologic mechanism of LBBB-CM. LBBB model was established through main left bundle branch trunk ablation in 14 canines. All LBBB dogs underwent transesophageal echocardiography and electrocardiography before ablation and at 1 month, 3 months, 6 months, and 12 months after LBBB induction. Single-photon emission computed tomography imaging was performed at 12 months. We then harvested the heart from all LBBB dogs and 14 healthy adult dogs as normal controls for anatomic observation, Purkinje fiber staining, histologic staining, and connexin43 protein expression quantitation. LBBB induction caused significant fibrotic changes in the endocardium and mid-myocardium. Purkinje fibers exhibited fatty degeneration, vacuolization, and fibrosis along with downregulated connexin43 protein expression. During a 12-month follow-up, left ventricular dysfunction progressively worsened, peaking at the end of the observation period. The association between myocardial dysfunction, hypoperfusion, and fibrosis was observed in the LBBB-afflicted canines. LBBB may lead to profound myocardial injury beyond its conduction impairment effects. The temporal progression of left ventricular dysfunction and the pathologic alterations observed shed light on the complex relationship between LBBB and cardiomyopathy. These findings offer insights into potential mechanisms and clinical implications of LBBB-CM. [Display omitted] [ABSTRACT FROM AUTHOR]

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. The cardiac conduction system consists of specialized cardiomyocytes that synchronize heart contractions. Here, Oh et al. provide comprehensive molecular profiles of the postnatal cardiac conduction system and elucidate gene regulatory mechanisms contributing to its heterogeneity. [ABSTRACT FROM AUTHOR]

Mitral valve prolapse (MVP) is the most common valve disease in the western world and recently emerged as a possible substrate for sudden cardiac death (SCD). It is estimated an annual risk of sudden cardiac death of 0.2 to 1.9% mostly caused by complex ventricular arrhythmias (VA). Several mechanisms have been recognized as potentially responsible for arrhythmia onset in MVP, resulting from the combination of morpho-functional abnormality of the mitral valve, structural substrates (regional myocardial hypertrophy, fibrosis, Purkinje fibers activity, inflammation), and mechanical stretch. Echocardiography plays a central role in MVP diagnosis and assessment of severity of regurgitation. Several abnormalities detectable by echocardiography can be prognostic for the occurrence of VA, from morphological alteration including leaflet redundancy and thickness, mitral annular dilatation, and mitral annulus disjunction (MAD), to motion abnormalities detectable with "Pickelhaube" sign. Additionally, speckle-tracking echocardiography may identify MVP patients at higher risk for VA by detection of increased mechanical dispersion. On the other hand, cardiac magnetic resonance (CMR) has the capability to provide a comprehensive risk stratification combining the identification of morphological and motion alteration with the detection of myocardial replacement and interstitial fibrosis, making CMR an ideal method for arrhythmia risk stratification in patients with MVP. Finally, recent studies have suggested a potential role in risk stratification of new techniques such as hybrid PET-MR and late contrast enhancement CT. The purpose of this review is to provide an overview of the mitral valve prolapse syndrome with a focus on the role of imaging in arrhythmic risk stratification. Clinical relevance statement: Mitral valve prolapse is the most frequent valve condition potentially associated with arrhythmias. Imaging has a central role in the identification of anatomical, functional, mechanical, and structural alterations potentially associated with a higher risk of developing complex ventricular arrhythmia and sudden cardiac death. Key Points: • Mitral valve prolapse is a common valve disease potentially associated with complex ventricular arrhythmia and sudden cardiac death. • The mechanism of arrhythmogenesis in mitral valve prolapse is complex and multifactorial, due to the interplay among multiple conditions including valve morphological alteration, mechanical stretch, myocardial structure remodeling with fibrosis, and inflammation. • Cardiac imaging, especially echocardiography and cardiac magnetic resonance, is crucial in the identification of several features associated with the potential risk of serious cardiac events. In particular, cardiac magnetic resonance has the advantage of being able to detect myocardial fibrosis which is currently the strongest prognosticator. [ABSTRACT FROM AUTHOR]

Idiopathic verapamil‐sensitive fascicular ventricular tachycardia (VT) is the most common form of Purkinje‐related ventricular tachycardia (PRVT). Left septal fascicle (LSF) involvement and its connections with the other fascicles, have been recently reported as a pathophysiologic mechanism for this form of PRVT. We describe a case of idiopathic PRVT with LSF involvement using omnipolar technology (OT) mapping in relation to a false tendon. Ablation in the area with concealed fusion entrainment did not terminate the tachycardia. However, radiofrequency application in the area of LSF with manifest fusion entrainment, resulted in immediate tachycardia termination. Six months follow‐up showed no tachycardia recurrence. [ABSTRACT FROM AUTHOR]

Introduction: Clinical outcomes of long‐term ventricular septal pacing (VSP) without His‐Purkinje capture remain unknown. This study evaluated the differences in clinical outcomes between conduction system pacing (CSP), VSP, and right ventricular pacing (RVP). Methods: Consecutive patients with bradycardia indicated for pacing from 2016 to 2022 were prospectively followed for the clinical endpoints of heart failure (HF)‐hospitalizations and all‐cause mortality at 2 years. VSP was defined as septal pacing due to unsuccessful CSP implant or successful CSP followed by loss of His‐Purkinje capture within 90 days. Results: Among 1016 patients (age 73.9 ± 11.2 years, 47% female, 48% atrioventricular block), 612 received RVP, 335 received CSP and 69 received VSP. Paced QRS duration was similar between VSP and RVP, but both significantly longer than CSP (p <.05). HF‐hospitalizations occurred in 130 (13%) patients (CSP 7% vs. RVP 16% vs. VSP 13%, p =.001), and all‐cause mortality in 143 (14%) patients (CSP 7% vs. RVP 19% vs. VSP 9%, p <.001). The association of pacing modality with clinical events was limited to those with ventricular pacing (Vp) > 20% (pinteraction <.05). Adjusting for clinical risk factors among patients with Vp > 20%, VSP (adjusted hazard ratio [AHR]: 4.74, 95% confidence interval [CI]: 1.57–14.36) and RVP (AHR: 3.08, 95% CI: 1.44‐6.60) were associated with increased hazard of HF‐hospitalizations, and RVP (2.52, 95% CI: 1.19–5.35) with increased mortality, compared to CSP. Clinical endpoints did not differ between VSP and RVP with Vp > 20%, or amongst groups with Vp < 20%. Conclusion: Conduction system capture is associated with improved clinical outcomes. CSP should be preferred over VSP or RVP during pacing for bradycardia. [ABSTRACT FROM AUTHOR]

The donkey's extraordinary capacity to endure substantial loads over long distances while maintaining equilibrium suggests a distinctive cerebellar architecture specialized in balance regulation. Consequently, our study aims to investigate the intricate histophysiology of the donkey's cerebellum using advanced ultrastructural and immunohistochemical methodologies to comprehend the mechanisms that govern this exceptional ability. This study represents the pioneering investigation to comprehensively describe the ultrastructure and immunohistochemistry within the donkey cerebellum. Five adult donkeys' cerebella were utilized for the study, employing stains such as hematoxylin, eosin, and toluidine blue to facilitate a comprehensive histological examination. For immunohistochemical investigation, synaptophysin (SP), calretinin, and glial fibrillary acidic protein were used and evaluated by the Image J software. Furthermore, a double immunofluorescence staining of SP and neuron‐specific enolase (NSE) was performed to highlight the co‐localization of these markers and explore their potential contribution to synaptic function within the donkey cerebellum. This investigation aims to understand their possible roles in regulating neuronal activity and synaptic connectivity. We observed co‐expression of SP and NSE in the donkey cerebellum, which emphasizes the crucial role of efficient energy utilization for motor coordination and balance, highlighting the interdependence of synaptic function and energy metabolism. The Purkinje cells were situated in the intermediate zone of the cerebellum cortex, known as the Purkinje cell layer. Characteristically, the Purkinje cell's bodies exhibited a distinct pear‐like shape. The cross‐section area of the Purkinje cells was 107.7 ± 0.2 µm2, and the Purkinje cell nucleus was 95.7 ± 0.1 µm2. The length and diameter of the Purkinje cells were 36.4 × 23.4 µm. By scanning electron microscopy, the body of the Purkinje cell looked like a triangular or oval with a meandrous outer surface. The dendrites appeared to have small spines. The Purkinje cells' cytoplasm was rich with mitochondria, rough endoplasmic reticulum, ribosomes, Golgi apparatus, multivesicular bodies, and lysosomes. Purkinje cell dendrites were discovered in the molecular layer, resembling trees. This study sheds light on the anatomical and cellular characteristics underlying the donkey's exceptional balance‐maintaining abilities. Highlights: The donkey's remarkable ability to endure substantial loads over long distances while maintaining equilibrium suggests the presence of a specialized cerebellar architecture dedicated to balance regulation.The objective of this study is to investigate the intricate histophysiology of the donkey's cerebellum using advanced ultrastructural and immunohistochemical methodologies, aiming to comprehend the mechanisms governing this exceptional balancing ability.This study pioneers the comprehensive description of the ultrastructure and immunohistochemistry within the donkey cerebellum, representing a groundbreaking investigation in the field.Five adult donkeys' cerebella were utilized in this study, employing staining techniques such as hematoxylin, eosin, and toluidine blue to facilitate a comprehensive histological examination.Immunohistochemical investigation involved synaptophysin, calretinin, and glial fibrillary acidic protein, evaluated using Image J software, providing valuable insights into their potential roles in regulating neuronal activity and synaptic connectivity.Double immunofluorescence staining of synaptophysin and neuron‐specific enolase highlighted their co‐localization and potential contribution to synaptic function within the donkey cerebellum.Scanning electron microscopy revealed that Purkinje cells had a triangular or oval shape with a meandering outer surface, and the dendrites appeared to have small spines.Transmission electron microscopy showed that the cytoplasm of Purkinje cells contained various organelles, including mitochondria, rough endoplasmic reticulum, ribosomes, Golgi apparatus, multivesicular bodies, and lysosomes.In conclusion, this study sheds light on the anatomical and cellular characteristics underlying the donkey's exceptional balance‐maintaining abilities. [ABSTRACT FROM AUTHOR]

Epicardial adipose tissue (EAT) has been reported to promote myocardial fibrosis and to affect intracardiac conduction. The PR interval reflects the conduction from the atria to the Purkinje fibers and may be associated with the EAT volume, especially in persistent atrial fibrillation (AF) patients. We aimed to investigate the relationship between the EAT and PR interval in patients with persistent AF. We enrolled 268 persistent AF patients who underwent catheter ablation (CA) and divided the patients into two groups: the normal PR interval group (PR interval less than 200 ms: Group N) and long PR interval group (PR interval 200 ms or more: Group L). We then analyzed the association between the total EAT volume around the heart and PR interval and calculated the ratio of the duration of the P wave (PWD) to the PR interval (PWD/PR interval). Moreover, we investigated whether a long PR interval was associated with the outcomes after ablation. The total EAT volume was significantly larger in Group L than Group N (Group N: 131.4 ± 51.8 ml vs. Group L: 151.3 ± 63.3 ml, p = 0.039). A positive correlation was also observed between the PWD/PR interval and EAT volume in Group L (r = 0.345, p = 0.039). A multivariate analysis also revealed that a long PR interval was independently associated with AF recurrence after CA (hazard ratio [HR] 2.071, p = 0.032). The total EAT volume was associated with a long PR interval, and a long PR interval was a significant risk factor for recurrence after ablation in persistent AF patients. [ABSTRACT FROM AUTHOR]

Background: The anatomic extent of the reentry circuit in idiopathic left posterior fascicular ventricular tachycardia (LPF‐VT) is yet to be fully elucidated. We hypothesized that entrainment mapping could be used to delineate the reentry circuit of an LPF‐VT, especially including the upper turnaround point. Methods: Twenty‐three consecutive LPF‐VT patients (mean age, 29 ± 9 years, 18 males) were included. We performed overdrive pacing with entrainment attempts at the left bundle branch (LBB) and the left His bundle (HB) region. Results: Overdrive pacing from the LBB region showed concealed fusion in all 23 patients (post‐pacing interval [PPI], 322.1 ± 64.3 ms; tachycardia cycle length [TCL], 319.0 ± 61.6 ms; PPI‐TCL, 3.1 ± 4.6 ms) with a long stimulus‐to‐QRS interval (287.9 ± 58.0 ms, approximately 90% of the TCL). Pacing from the same LBB region at a slightly faster pacing rate showed manifest fusion with antidromic conduction to the LBB and minimal in‐and‐out time to the LBB potential (PPI‐TCL, 21.3 ± 13.7 ms). Overdrive pacing from the left HB region showed manifest fusion with a long PPI‐TCL (53.9 ± 22.5 ms). Conclusions: Our pacing study results suggest that the upper turnaround point in a reentry circuit of the LPF‐VT may extend to the proximal His‐Purkinje conduction system near the LBB region but below the left HB region. The LPF may constitute the retrograde limb of the reentry circuit. [ABSTRACT FROM AUTHOR]

Background: Precise mapping of the Purkinje fiber network is essential in catheter ablation of Purkinje‐related ventricular arrhythmias (PrVAs). We sought to evaluate the mapping ability of a multi‐spline duodecapolar catheter (PentaRay) for PrVAs. Methods: Mappings of Purkinje fibers by PentaRay catheters were compared with those by conventional mapping catheters in consecutive patients undergoing catheter ablation of PrVAs from 2015 to 2022. Results: Sixteen PrVAs (7 premature ventricular contractions or non‐reentrant fascicular tachycardias [PVCs/NRFTs] and 9 fascicular ventricular tachycardias [FVTs]) were retrospectively studied. In PVCs/NRFTs, earliest preceding Purkinje potentials (PPs) could be recorded by the PentaRay catheters but not by the mapping and ablation catheters in 5 cases. At the earliest PP sites, the precedence from the QRS onset was greater, and the amplitude of the preceding potentials was higher in the PentaRay catheter compared with those in the mapping and ablation catheter (−62.0 ± 42.8 vs. −29.4 ± 34.2 ms, P = 0.02; 0.45 ± 0.43 vs. 0.09 ± 0.08 mV, P = 0.02). In FVTs, late diastolic potentials (P1) were recorded by the PentaRay catheters but not by the mapping and ablation catheters or the linear duodecapolar catheter in 2 cases. The amplitude of P1 was higher in the PentaRay catheter compared with that in the linear duodecapolar catheter and the mapping and ablation catheters (0.72 ± 0.49 vs. 0.17 ± 0.18 vs. 0.27 ± 0.21 mV, P = 0.0006, P = 0.002). The localized critical PPs, defined as the earliest preceding potentials in PVCs/NRFTs and P1 in FVTs, could be recorded in all the patients by the PentaRay catheter. The mapping ability of critical PPs of PrVAs was better with the PentaRay catheter than with the conventional mapping catheters (16/16 vs. 9/16, P = 0.004 by McNemar exact test). Conclusions: The PentaRay catheter has clinical advantages in mapping of the Purkinje fiber network to reveal critical PPs as ablation targets of PrVAs. [ABSTRACT FROM AUTHOR]

Myocardial sleeve around human pulmonary veins plays a critical role in the pathomechanism of atrial fibrillation. Besides the well‐known arrhythmogenicity of these veins, there is evidence that myocardial extensions into caval veins and coronary sinus may exhibit similar features. However, studies investigating histologic properties of these structures are limited. We aimed to investigate the immunoreactivity of myocardial sleeves for intermediate filament desmin, which was reported to be more abundant in Purkinje fibers than in ventricular working cardiomyocytes. Sections of 16 human (15 adult and 1 fetal) hearts were investigated. Specimens of atrial and ventricular myocardium, sinoatrial and atrioventricular nodes, pulmonary veins, superior caval vein and coronary sinus were stained with anti‐desmin monoclonal antibody. Intensity of desmin immunoreactivity in different areas was quantified by the ImageJ program. Strong desmin labeling was detected at the pacemaker and conduction system as well as in the myocardial sleeves around pulmonary veins, superior caval vein, and coronary sinus of adult hearts irrespective of sex, age, and medical history. In the fetal heart, prominent desmin labeling was observed at the sinoatrial nodal region and in the myocardial extensions around the superior caval vein. Contrarily, atrial and ventricular working myocardium exhibited low desmin immunoreactivity in both adults and fetuses. These differences were confirmed by immunohistochemical quantitative analysis. In conclusion, this study indicates that desmin is abundant in the conduction system and venous myocardial sleeves of human hearts. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the three deadliest malignant tumors in the world, posing a severe hazard to human health. Nonetheless, the 5-year survival rate for advanced CRC remains unsatisfactory. Grid2 interacting protein (GRID2IP) is a Purkinje fiber postsynaptic scaffold protein implicated in a number of signal transduction pathways in the nervous system. Previous studies have shown that Grid2 is closely related to the occurrence and prognosis of gastric cancer and many other diseases. Therefore, we aim to identify the relationship between GRID2IP and the occurrence and prognosis of CRC. Methods: Transcriptome data were retrieved from The Cancer Genome Atlas (TCGA) database to analyze the differential expression of GRID2IP in a variety of malignant tumors and then validate it by quantitative real time polymerase chain reaction(Q-PCR) and Western Blot in HT29 and SW480 cells. "DESeq2" package was used to analyze the differentially expressed genes (DEGs) between the high- and low-GRID2IP subgroups. In relation to DEGs, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. In addition, gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA) were employed to examine DEGs-associated signaling pathways and GRID2IP-associated immune cell infiltration levels. Besides, overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) were compared between the two subgroups using a Kaplan–Meier analysis. In addition, a prognostic model for GRID2IP and clinical characteristics was developed using the univariate Cox regression method. The "pRRophetic" package was applied to predict the drug sensitivity of different subgroups. Moreover, we also performed single-cell analysis of GRID2IP using the TISCH database. Results: GRID2IP is upregulated in CRC patients. The rise of GRID2IP inhibits the invasion of tumor-associated immune cells resulting in a lower immune score. In addition, high GRID2IP expression was associated with poor prognosis in different clinical subgroups. Analysis of single cells revealed that GRID2IP was predominantly expressed in immune cells, myofibroblasts, and cancerous cells. In terms of chemotherapy drug sensitivity, the subgroup with high GRID2IP expression was less sensitive to gemcitabine. Conclusions: Our results suggest that rising GRID2IP promotes tumor-associated immune cell infiltration and suggests adverse outcomes in CRC patients, which may be a useful biomarker for determining the prognosis of CRC and a potential target molecule for CRC therapy. [ABSTRACT FROM AUTHOR]

Introduction: In left bundle branch area pacing (LBBAP), several methods allow determination of lead depth during active fixation inside the septum: among these, visualization of a Purkinje potential indicates that the subendocardial area has been reached. In LBB block (LBBB) patients, fascicular potentials are visible as presystolic only in rare conditions. Methods and Results: Since October 2022 until August 2023, LBBAP was attempted in 21 patients with LBBB at our Center: among the 18 consecutive patients (86%) in which it was successful, focusing on the terminal part of the unipolar ventricular electrogram (VEGM) recorded in the LBBA (where fixation beats occurred and conduction system (CS) capture was confirmed), we always observed discrete high‐frequency, low‐amplitude signals during spontaneous rhythm with LBBB morphology, showing a consistent coupling with the QRS onset, falling in a portion of QRS interval ranging from 58% to 80% of its overall duration, and disappearing during pacing. As found in a recently published case report, these sharp signals could represent the activation of left ventricular CS fibers, occurring passively from the septal working myocardium, and thus appearing lately in the VEGM. Conclusion: The possibility of recognizing discrete high‐frequency, low‐amplitude signals within the terminal portion of the unipolar VEGM, possibly representing left CS potentials, even in patients with LBBB, may constitute a useful additional means to notice operators about having reached the LBBA, thus helping to avoid perforation in the left ventricle. [ABSTRACT FROM AUTHOR]

Neuroinflammation is a complex biological process that typically originates as a protective response in the brain. This inflammatory process is triggered by the release of pro-inflammatory substances like cytokines, prostaglandins, and reactive oxygen and nitrogen species from stimulated endothelial and glial cells, including those with pro-inflammatory functions, in the outer regions. While neuronal inflammation is common in various central nervous system disorders, the specific inflammatory pathways linked with different immune-mediated cell types and the various factors influencing the blood-brain barrier significantly contribute to disease-specific characteristics. The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids, and enzymes responsible for synthesizing and metabolizing endocannabinoids. The primary cannabinoid receptor is CB1, predominantly found in specific brain regions such as the brainstem, cerebellum, hippocampus, and cortex. The presence of CB2 receptors in certain brain components, like cultured cerebellar granular cells, Purkinje fibers, and microglia, as well as in the areas like the cerebral cortex, hippocampus, and cerebellum is also evidenced by immunoblotting assays, radioligand binding, and autoradiography studies. Both CB1 and CB2 cannabinoid receptors exhibit noteworthy physiological responses and possess diverse neuromodulatory capabilities. This review primarily aims to outline the distribution of CB1 and CB2 receptors across different brain regions and explore their potential roles in regulating neuroinflammatory processes. [ABSTRACT FROM AUTHOR]

The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of plasticity. Given their important role in both short-term and long-term coordination of cerebellum-dependent behaviors, it is paramount to understand the factors that determine the output of olivary neurons. Here, we use mouse models to investigate how the inhibitory and excitatory inputs to the olivary neurons interact with each other, generating spiking patterns of olivary neurons that align with their intrinsic oscillations. Using dual color optogenetic stimulation and whole-cell recordings, we demonstrate how intervals between the inhibitory input from the cerebellar nuclei and excitatory input from the mesodiencephalic junction affect phase and gain of the olivary output at both the sub- and suprathreshold level. When the excitatory input is activated shortly (~50 ms) after the inhibitory input, the phase of the intrinsic oscillations becomes remarkably unstable and the excitatory input can hardly generate any olivary spike. Instead, when the excitatory input is activated one cycle (~150 ms) after the inhibitory input, the excitatory input can optimally drive olivary spiking, riding on top of the first cycle of the subthreshold oscillations that have been powerfully reset by the preceding inhibitory input. Simulations of a large-scale network model of the inferior olive highlight to what extent the synaptic interactions penetrate in the neuropil, generating quasi-oscillatory spiking patterns in large parts of the olivary subnuclei, the size of which also depends on the relative timing of the inhibitory and excitatory inputs. [ABSTRACT FROM AUTHOR]

The existence of "transitional muscular structures" between subendocardial branches (Purkinje fibers) and ventricular working muscle fibers (WF) was first described by the German anatomist, Kurt Goerttler, in 1964. He designated them as "subendocardial nucleus organs." He supposed such fibers functioned as mechanoreceptors, controlling of the intensity of contraction of the ventricular musculature. Brazilian anatomist Ferraz de Carvalho described similar structures in 1993. A thorough literature search failed to identify any other research articles confirming or denying their existence. The objective of this work was to find such structures in subendocardial ventricular walls in human hearts. We collected fifteen formalin-preserved hearts from the Anatomy Department of São Paulo University and sectioned the apical portions on the right and left ventricles according to method used by Goerttler. We utilized conventional histology (light microscopy-LM), scanning electron microscopy (SEM), and a new preservation method called microplastination (MP). At the anterior wall of the right ventricle in the subendocardial region between the interventricular septum and moderator band, we found several bundles of fusiform and helicoidal fibers of similar histology to the WF. The bundles measured between 400 and 1150 µm in length and were separated from adjacent muscular fibers by thin collagen fiber, thus acting as a "pseudo capsule." Some structures seemed to be linked to PF and were appeared to be lymphatic and blood vessels and nerves. We called those structures "cardiac corpuscles" (CC). The observation of the previously "unknown" CC in this initial study confirmed the previous descriptions and its discovery may contribute to new perspectives in the study of cardiac muscle structure and function. [ABSTRACT FROM AUTHOR]

The efficacy of cardiac resynchronization therapy (CRT) in heart failure patients with left bundle branch block (LBBB) is well established with Class I or IIa recommendation according to 2021 ESC Guidelines on cardiac pacing and CRT, whereas non‐LBBB morphology is less recommended. There is insufficient evidence that proves patients with NICD could benefit from CRT. As patients with NICD are characterized by heterogeneity, the effect of CRT on these patients is still controversial. Although the proportion of NICD in the population is lower than that of LBBB patients, it is still worth investigating the effects of CRT on patients with NICD in an era of His‐Purkinje conduction system pacing (HPCSP). [ABSTRACT FROM AUTHOR]

The cerebellum is involved in learning of fine motor skills, yet whether presynaptic plasticity contributes to such learning remains elusive. Here, we report that the EPAC-PKCε module has a critical role in a presynaptic form of long-term potentiation in the cerebellum and motor behavior in mice. Presynaptic cAMP−EPAC−PKCε signaling cascade induces a previously unidentified threonine phosphorylation of RIM1α, and thereby initiates the assembly of the Rab3A−RIM1α− Munc13-1 tripartite complex that facilitates docking and release of synaptic vesicles. Granule cell-specific blocking of EPAC−PKCε signaling abolishes presynaptic long-term potentiation at the parallel fiber to Purkinje cell synapses and impairs basic performance and learning of cerebellar motor behavior. These results unveil a functional relevance of presynaptic plasticity that is regulated through a novel signaling cascade, thereby enriching the spectrum of cerebellar learning mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Conduction system pacing (CSP), in the form of His bundle pacing (HBP) or left bundle branch pacing (LBBP), is emerging as a valuable cardiac resynchronization therapy (CRT) delivery method. However, patient selection and therapy personalization for CSP delivery remain poorly characterized. We aim to compare pacing‐induced electrical synchrony during CRT, HBP, LBBP, HBP with left ventricular (LV) epicardial lead (His‐optimized CRT [HOT‐CRT]), and LBBP with LV epicardial lead (LBBP‐optimized CRT [LOT‐CRT]) in patients with different conduction disease presentations using computational modeling. Methods: We simulated ventricular activation on 24 four‐chamber heart geometries, including His–Purkinje systems with proximal left bundle branch block (LBBB). We simulated septal scar, LV lateral wall scar, and mild and severe myocardium and LV His–Purkinje system conduction disease by decreasing the conduction velocity (CV) down to 70% and 35% of the healthy CV. Electrical synchrony was measured by the shortest interval to activate 90% of the ventricles (90% of biventricular activation time [BIVAT‐90]). Results: Severe LV His–Purkinje conduction disease favored CRT (BIVAT‐90: HBP 101.5 ± 7.8 ms vs. CRT 93.0 ± 8.9 ms, p <.05), with additional electrical synchrony induced by HOT‐CRT (87.6 ± 6.7 ms, p <.05) and LOT‐CRT (73.9 ± 7.6 ms, p <.05). Patients with slow myocardium CV benefit more from CSP compared to CRT (BIVAT‐90: CRT 134.5 ± 24.1 ms; HBP 97.1 ± 9.9 ms, p <.01; LBBP: 101.5 ± 10.7 ms, p <.01). Septal but not lateral wall scar made CSP ineffective, while CRT was able to resynchronize the ventricles in the presence of septal scar (BIVAT‐90: baseline 119.1 ± 10.8 ms vs. CRT 85.1 ± 14.9 ms, p <.01). Conclusion: Severe LV His–Purkinje conduction disease attenuates the benefits of CSP, with additional improvements achieved with HOT‐CRT and LOT‐CRT. Septal but not lateral wall scars make CSP ineffective. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic ventricular fibrillation (IVF) is mainly associated with and triggered by short‐coupled (R‐on‐T) ventricular ectopics. However, little is known about the risk of VF associated with long‐coupled premature ventricular complexes (LCPVCs). Objective: To examine the prevalence and characteristics of IVF patients presenting with LCPVCs. Methods: Consecutive patients with IVF and PVCs from five arrhythmia referral centers were reviewed. We included patients presenting LCPVCs, defined as PVCs falling after the end of the T wave, with a normal QTc interval. We evaluated demographics, medical history, and clinical circumstances associated with PVCs and VF episodes. The origin of PVCs was determined by invasive mapping. Results: Seventy‐nine patients with IVF were reviewed. Among them, 12 (15.2%) met the inclusion criteria (8 women, age 36 ± 14 years). Eleven patients had documented LCPVCs initiating repetitive PVCs or sustained VF, whereas 1 had only documented isolated PVCs. In 10 of 12 patients, PVCs were recorded showing both long and short coupling intervals of 418 ± 46 and 304 ± 33 ms, respectively. Mapping showed that PVCs originated from the left Purkinje in 10 patients, from the right Purkinje in 1 patient, and both in 1 patient. Compared to other patients from the initial cohort, IVF with LCPVCs was associated with a left‐sided origin of PVCs (92% in long‐coupled IVF vs. 46% of left Purkinje PVCs in short‐coupled IVF, p =.004). Conclusion: Long‐coupled fascicular PVCs, traditionally recognized as benign, can be associated with IVF in a subset of patients. They can induce IVF by themselves or in association with short‐coupled PVCs. [ABSTRACT FROM AUTHOR]

Introduction: The anatomical substrate for idiopathic left ventricular tachycardia (ILVT) remains speculative. Purkinje networks surrounding false tendons (FTs) might be involved in the reentrant circuit of ILVT. The objective was to evaluate the anatomical and electrophysiological features of false tendons FTs in relation to ILVT. Methods: Intracardiac echocardiography (ICE) was conducted on patients with ILVT. The relationship of the FTs with ILVT was determined using electro‐anatomical mapping. Results: Electrophysiological evaluation and radiofrequency ablation were conducted in 23 consecutive patients with ILVT. FTs were identified in 19/23 cases (82.6%) with P1 potentials during VT recorded at the FT in 14 of these patients (73.7%). Three FT types were identified. In type 1, the FT attached the septum to the base of the posteromedial papillary muscle (PPM) (4/19); type 2 FTs ran between the septum and the PPM apex (3/19), while in type 3, the connection occurred between the septum and apex (11/19) or between the septum and the LV free wall (1/19). The effective ILVT ablation sites were situated at the FT‐PPM (3/19) and the FT‐septum (16/19) attachment sites. Conclusions: This series demonstrates the association between Purkinje fibers and FTs during catheter ablation of ILVT and verifies that left ventricular FTs are an important substrate in this type of tachycardia. [ABSTRACT FROM AUTHOR]

Background: The Purkinje fibers convey the electrical impulses at much higher speed than the working myocardial cells. Thus, the distribution of the Purkinje network is of paramount importance for the timing and coordination of ventricular activation. The Purkinje fibers are found in the subendocardium of all species of mammals, but some mammals also possess an intramural Purkinje fiber network that provides for relatively instantaneous, burst‐like activation of the entire ventricular wall, and gives rise to an rS configuration in lead II of the ECG. Aim: To relate the topography of the horse heart and the distribution and histology of the conduction system to the pattern of ventricular activation as a mechanism for the unique electrical axis of the equine heart. Methods: The morphology and distribution of the cardiac conduction system was determined by histochemistry. The electrical activity was measured using ECG in the Einthoven and orthogonal configuration. Results: The long axis of the equine heart is close to vertical. Outside the nodal regions the conduction system consisted of Purkinje fibers connected by connexin 43 and long, slender parallel running transitional cells. The Purkinje fiber network extended deep into the ventricular walls. ECGs recorded in an orthogonal configuration revealed a mean electrical axis pointing in a cranial‐to‐left direction indicating ventricular activation in an apex‐to‐base direction. Conclusion: The direction of the mean electrical axis in the equine heart is determined by the architecture of the intramural Purkinje network, rather than being a reflection of ventricular mass. [ABSTRACT FROM AUTHOR]

Previous studies on dolphin electrocardiograms have shown that they are mainly composed of increased negative waves, similar to ungulates. The electrocardiogram waveform was determined by the distribution of the Purkinje fibers. Based on the waveform of the dolphin electrocardiogram, Hamlin predicted that the Purkinje fibers would be distributed within the ventricular muscle, as in ungulates. The purpose of this study was to confirm the histological distribution of Purkinje fibers in dolphins. In the present study, bottlenose dolphin hearts were observed both grossly and histologically, and the effects of Purkinje fiber distribution and cardiac morphology on electrocardiogram waveforms were examined. This study showed that the Purkinje fibers of dolphins run just below the endocardium, as in humans, dogs, and cats, whose electrocardiograms mainly show positive waves. When the cardiac morphology of dolphins was observed carefully, the right ventricle was found to be extremely dilated compared to that of terrestrial mammals. In human recreational divers, right ventricular dilatation is induced by diving. We hypothesized that the dolphin's heart is in a state similar to that of the right heart dilatation in terrestrial animals. The dolphin electrocardiogram waveform was considered to be due to right axis deviation. Based on the above, we concluded that the dolphin electrocardiogram waveform was due to its ability to live in water. We found that the dolphins are genetically related to ungulates, particularly the hippopotamus, but that their hearts have evolved differently. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recurrence of atrial fibrillation (AF) is common in patients with persistent AF even after multiple ablation procedures. His-Purkinje conduction system pacing (HPCSP) combined with atrioventricular node ablation (AVNA) is effective in managing patients with AF and heart failure. This study aimed to determine whether HPCSP combined with AVNA can improve quality of life and alleviate symptoms in older patients with symptomatic persistent AF refractory to multiple ablation procedures, as well as evaluate the feasibility and safety of this therapy. METHODS: Older patients (≥ 65 years) with symptomatic persistent AF refractory to at least two ablation procedures were treated with combined HPCSP and AVNA. The success rates and complications were recorded. Pacing parameters, European Heart Rhythm Association (EHRA) scores, and Atrial Fibrillation Effect on Quality-of-Life (AFEQT) scores obtained perioperatively were compared with those recorded at the 6-month follow-up examination. RESULTS: Thirty-one patients were enrolled; of those, only thirty patients were eventually treated with AVNA because one patient developed a complete atrioventricular block following the withdrawal of the His bundle pacing lead. The success rates were 100% for HPCSP (22 cases with His bundle pacing, and 9 cases with left bundle branch pacing) and 93.3% (28/30) for AVNA, respectively. By the 6-month follow-up examination, EHRA scores improved significantly (3.00 ± 0.73 vs. 2.44 ± 0.63, P = 0.014) and AFEQT scores increased markedly (49.6 ± 20.6 vs. 70.9 ± 14.0, P = 0.001). No severe complications developed. CONCLUSIONS: When used in older patients with symptomatic persistent AF refractory to multiple ablation procedures, HPCSP combined with AVNA significantly alleviated symptoms and improved quality of life during short-term follow-up. This therapy was proved to be safe and effective in this patient population. [ABSTRACT FROM AUTHOR]

The article focuses on investigating the mechanism behind varying HV intervals observed during wide QRS tachycardia in a 32-year-old female. Topics include the identification of pathway-to-pathway atrioventricular re-entry tachycardia involving right and left free wall pathways, the role of retrograde conduction via a left lateral accessory pathway, and the implications of these findings for electrophysiological study and ablation therapy in managing recurrent palpitations and arrhythmias.

The mammalian cardiac conduction system (CCS) is a multifaceted continuum of electrically distinct, interconnected constructs within the myocardial mass. The key components are the sinus node (SAN), the atrioventricular node (AVN), the His bundle (HB), and the Purkinje fiber network (PF), the latter serendipitously discovered by Jan Evangelista Purkinje in 1839 in the sheep ventricle. In 1893, Wilhelm His, Jr. described a ventricular muscular tract conveying SAN-generated action potentials from the AVN (discovered by Sunao Tawara and Karl Albert Aschoff in 1906) to the PF. In 1906, Keith and Flack completed these explorations by localizing the SAN, the primum movens of CCS, which functions as a biologic oscillator emitting cadenced impulses that travel via the Bachmann bundle to the atrial myocytes and, via internodal pathways, to the AVN. Here these impulses are briefly delayed, enabling atrial systole before continuing via the AVN and the high-speed His-Purkinje conduction axis to signal ventricular contraction. The CCS canonical discoverers (Keith and Flack, Aschoff and Tawara, His, and Purkinje), historical controversies, fundamental notions of anatomy, physiology, and pathology, and therapeutic interventions pertaining to the CCS are the main themes of this review. Any scientist mentioned or unmentioned in this report who contributed directly or indirectly, with correct or inaccurate hypotheses, to the characterization of the CCS deserves our deepest gratitude for the long and painstaking hours spent microscopically scrutinizing heart specimens from multiple mammalian species, including humans. NEW & NOTEWORTHY This report presents the first comprehensive summary of the factors enabling the discovery of the cardiac conduction system (CCS). Biographical highlights and achievements of the CCS canonical discoverers, hypotheses concerning mechanisms underlying sinus node (SAN) automaticity, use of eponyms to denominate a discovery, famous controversies, possible reproachable behavior (e.g., intellectual support for eugenics in post-World War I Germany) by two of the discoverers, and examples of historical mentor-pupil relationships are discussed. [ABSTRACT FROM AUTHOR]

Background: Focal Purkinje ventricular arrhythmias (VAs) might originate from the vicinity of the proximal portion of the cardiac conducting system. This study aimed to clarify the features associated with focal Purkinje VAs originating from the proximal conduction system. Methods: A total of 18 patients with focal Purkinje VAs undergoing radiofrequency catheter ablation (RFCA) were retrospectively examined and divided into the proximal type or the non‐proximal type. The proximal type was defined as having the origin at the proximal half of the interventricular septum, or the proximal half and the septal side of the anterior wall. The 12‐lead electrocardiogram and electrophysiological findings were investigated. Results: Seven patients met criteria for proximal type of focal Purkinje VA. Out of the 7, 4 patients with proximal VAs had multiple QRS morphologies of VAs clinically, whereas out of 11 patients with non‐proximal VAs, only 1 had multiple morphologies (p =.047). VA QRS duration was shorter in the proximal type than in the non‐proximal type (111.2 ± 19.8 ms vs. 135.7 ± 17.7 ms; p =.003). The absolute axis difference between sinus rhythm and VA was smaller in the proximal type (80.4 ± 46.1°vs. 138.8 ± 59.6°; p =.014). The absolute axis difference ≤134° was useful in distinguishing the two types. Recurrence of VA was recorded in 3 proximal type patients and 3 non‐proximal type patients. No procedure‐related conduction block was observed. Conclusion: A VA of absolute axis difference ≤134°, and multiple QRS morphologies of clinical VAs indicate a proximal origin. Focal Purkinje VAs from proximal origins can be suppressed by RFCA without severe conduction disturbance. [ABSTRACT FROM AUTHOR]

Ventricular fibrillation (VF) is a common cause of sudden cardiac death (SCD) and is unfortunately without a cure. Current therapies focus on prevention of SCD, such as implantable cardioverter-defibrillator (ICD) implantation and anti-arrhythmic agents. Significant progress has been made in improving our understanding and ability to target the triggers of VF, via advanced mapping and ablation techniques, as well as with autonomic modulation. However, the critical substrate for VF maintenance remains incompletely defined. In this review, we discuss the evidence behind the basic mechanisms of VF and review the current role of catheter ablation in patients with VF. [ABSTRACT FROM AUTHOR]

Ever since they were first observed in Purkinje fibers of the heart, funny channels have had close connections to potassium channels. Indeed, funny channels were initially thought to produce a potassium current in the heart called IK2. However, funny channels are completely unlike potassium channels in ways that make their contributions to the physiology of cells unique. An important difference is the greater ability for sodium to permeate funny channels. Although it does not flow through the funny channel as easily as does potassium, sodium does permeate well enough to allow for depolarization of cells following a strong hyperpolarization. This is critical for the function of funny channels in places like the heart and brain. Computational analyses using recent structures of the funny channels have provided a possible mechanism for their unusual permeation properties. [ABSTRACT FROM AUTHOR]

Aim: The goal of this study is to compare fuzzy based purkinje fiber cell(PFC) synchronization and coordination categorization using potassium(K+) channel parameters with K Nearest Neighbor (KNN) and Artificial Neural Network (ANN). Materials and Methods: The PFC Aslanidi model(AM) is used to classify cardiac arrhythmias of K+ channel at different malfunction conditions. In AM, the K+ channel dynamics are well described based on the PFC dataset. ANN and KNN classifiers are used to classify the different PFC classification. Sample size was calculated by keeping threshold 0.05, G Power 80%, confidence interval 95% and enrolment ratio as 1. 20 samples are taken for each analysis to predict the accuracy of the Novel ANN and KNN classifier. Finally, using the Statistical Package for the Social Science (SPSS) programme, the collected dataset(resultant accuracy) can be calculated. Result: PFC normal Action Potential (AP) having AP Duration (APD) is 290ms and Total Cycle Length (TCL) is 1000ms at K+ extracellular levels as 5.4mM. Whereas in abnormal AP indicates APD is 280ms and TCL is 900ms at K+ extracellular levels as 10.4mM. A 10% decrease in APD with normal PFC AP and 10% drop in TCL is responsible for Tachycardia (fast heartbeat), Then PFC data(Normal, Tachycardia, Bradycardia) are sent into the Novel ANN and KNN classifier algorithms. Using SPSS software, the results reveal that ANN accuracy is higher than KNN. Group 1 KNN has a mean of 63.410, a standard deviation of 4.3533, and a standard error mean of .9734, whereas group 2 ANN has a mean of 66.055, a standard deviation of 1.0329, and a standard error mean of .2310. Conclusion: Therefore the changes in PFC K+ channel leads to Hypokalemia which results in cardiac arrhythmia of resting membrane potential and the duration of both the action potential, to a higher extent than the normal. The paper concludes that the ANN classifier predicts better classification in identifying the accuracy of potassium channel parameters when compared to the KNN classifier of PFC synchronization and coordination. [ABSTRACT FROM AUTHOR]

The anisotropic electrical nature of the cardiac tissue, dependent on the fiber orientations and corresponding conductivity tensor components, plays an important role in computational simulations of the electrophysiology of the heart. To date, no accurate technique is utilized to assess how these variations in fiber angles and conductivity change the electrical behavior of the heart. Herein, we make use of six-lead electrocardiograms to demonstrate how this variability affect electrical responses of the heart. To generate an electrocardiogram, consistent with the clinical outputs, the simulation of the Purkinje fibers is also crucial. Moreover, an action potential duration heterogeneity exists among different cells based on their position in the ventricles. In this regard, we simulate a transmural distribution for the action potential duration where the longest repolarization time belongs to the midmyocardial cells. It is demonstrated that variations in fiber angles, from the endocardium to the epicardium, have no significant effect not only on the computational results but also on the clinical response of the electrocardiograms. We also show that different conduction velocities have major effects on the six leads. All together, our results demonstrate that different bounds of fiber angles do not play an important role in electrical cardiac models; however, conduction velocities should be measured and taken into account precisely due to their significant electrophysiological effects. [ABSTRACT FROM AUTHOR]

Erratum to "Investigating Cardiac Stimulation Limits of MRI Gradient Coils Using Electromagnetic and Electrophysiological Simulations in Human and Canine Body Models" (MRM 2021, 85[2]:1047-1061) In other words, the simulated CS thresholds, as determined by the Purkinje fiber response to gradient coil switching, are substantially higher than the IEC limit (9-fold to 46-fold) and higher than the peripheral nerve stimulation (PNS) limit (6-fold to 25-fold). We have identified a coding error in our cardiac electrophysiological model that led to erroneously high thresholds in our modeling of cardiac stimulation by gradient coils. [Extracted from the article]

The moderator band (MB) is an intracavitary structure of the right ventricle composed of muscular fibers encompassing specialized Purkinje fibers, separated each other by collagen and adipose tissue. In the last decades, premature ventricular complexes originating within the Purkinje network have been implicated in the genesis of life-threatening arrhythmias. However, right Purkinje network arrhythmias have been much less reported in the literature compared to the left counterpart. The MB has unique anatomical and electrophysiological properties, which may account for its arrhythmogenicity and may be responsible for a significant portion of idiopathic ventricular fibrillation. MB embodies autonomic nervous system cells, with important implications in arrhythmogenesis. Some idiopathic ventricular arrhythmias, defined as the absence of any identifiable structural heart disorder, can begin from this site. Due to these complex structural and functional peculiarities strictly interplayed each other, it is arduous to determine the precise mechanism underlying MB arrhythmias. MB-related arrhythmias should be differentiated from other right Purkinje fibers arrhythmias because of the opportunity for intervention and the unusual site for the ablation poorly described in the literature. In the current paper, we report the characteristics and electrical properties of the MB, their involvement in arrhythmogenesis, clinical and electrophysiological peculiarities of MB-related arrhythmias, and current treatment options.

Background: The role of the Purkinje network in triggering ventricular fibrillation (VF) has been studied; however, its involvement after onset and in early maintenance of VF is controversial. Aim: We studied the role of the Purkinje‒muscle junctions (PMJ) on epicardial–endocardial activation gradients during early VF. Methods: In a healthy, porcine, beating‐heart Langendorff model [control, n = 5; ablation, n = 5], simultaneous epicardial–endocardial dominant frequent mapping was used (224 unipolar electrograms) to calculate activation rate gradients during the onset and early phase of VF. Selective Purkinje ablation was performed using Lugol's solution, followed by VF re‐induction and mapping and finally, histological evaluation. Results: Epicardial activation rates were faster than endocardial rates for both onset and early VF. After PMJ ablation, activation rates decreased epicardially and endocardially for both onset and early VF [Epi: 9.7 ± 0.2 to 8.3 ± 0.2 Hz (p <.0001) and 10.9 ± 0.4 to 8.8 ± 0.3 Hz (p <.0001), respectively; Endo: 8.2 ± 0.3 Hz to 7.4 ± 0.2 Hz (p <.0001) and 7.0 ± 0.4 Hz to 6.6 ± 0.3 Hz (p =.0002), respectively]. In controls, epicardial–endocardial activation rate gradients during onset and early VF were 1.7 ± 0.3 Hz and 4.5 ± 0.4 Hz (p <.001), respectively. After endocardial ablation of PMJs, these gradients were reduced to 0.9 ± 0.3 Hz (onset VF, p <.001) and to 2.2 ± 0.3 Hz (early VF, p <.001). Endocardial–epicardial Purkinje fiber arborization and selective Purkinje fiber extinction after only endocardial ablation (not with epicardial ablation) was confirmed on histological analysis. Conclusions: Beyond the trigger paradigm, PMJs determine activation rate gradients during onset and during early maintenance of VF. [ABSTRACT FROM AUTHOR]

Heart failure is associated with electrical remodeling of the electrical properties and kinetics of the ion channels and transporters that are responsible for cardiac action potentials. However, it is still unclear whether heart failure-induced ionic remodeling can affect the conduction of excitation waves at the Purkinje fiber-ventricle junction contributing to pro-arrhythmic effects of heart failure, as the complexity of the heart impedes a detailed experimental analysis. The aim of this study was to employ computational models to investigate the pro-arrhythmic effects of heart failure-induced ionic remodeling on the cardiac action potentials and excitation wave conduction at the Purkinje fiber-ventricle junction. Single cell models of canine Purkinje fiber and ventricular myocytes were developed for control and heart failure. These single cell models were then incorporated into one-dimensional strand and three-dimensional wedge models to investigate the effects of heart failure-induced remodeling on propagation of action potentials in Purkinje fiber and ventricular tissue and at the Purkinje fiber-ventricle junction. This revealed that heart failure-induced ionic remodeling of Purkinje fiber and ventricular tissue reduced conduction safety and increased tissue vulnerability to the genesis of the unidirectional conduction block. This was marked at the Purkinje fiber-ventricle junction, forming a potential substrate for the genesis of conduction failure that led to re-entry. This study provides new insights into proarrhythmic consequences of heart failure-induced ionic remodeling. [ABSTRACT FROM AUTHOR]

• LBBAP and LOT-CRT improves electrical biomarkers versus conventional CRT. • Fusion pacing improves therapy outcome in conventional and newer CRT approaches. • Benefits of conventional and new CRT approaches depends on scar location. • Purkinje system survivability in the scar changes cardiac activation and CRT outcome. Cardiac resynchronization therapy (CRT) is a technique used in the clinical setting to solve dyssynchronization problems in ventricular contraction. The goal of this study was to evaluate in silico the performance of conventional and new CRT approaches under left bundle branch block (LBBB) and heart failure (HF) conditions, and especially under myocardial scar presence. The simulations were run in a 3D realistic biventricular model including the His-Purkinje system, where the different pathologies were modeled. Stimulation protocols corresponding to each of the CRT approaches assessed were applied. Importantly, the presence of infarcted tissue was systematically evaluated according to the American Heart Association segmentation of the heart. To assess CRT performance, a set of six biomarkers obtained from simulated ECG signals and activation maps was defined. Our simulations showed that under LBBB and HF conditions with or without infarction scar, the newer CRT approaches performed better. Interestingly, the inclusion of scarred tissue in some basal and septal segments had detrimental effects on the biomarkers that particularly worsened when Purkinje fibers were considered as non-conductive. This study sheds light on the effects that several heart disruptions have in cardiac activation before and after traditional and newest CRT methods. Moreover, the utilization of fusion pacing and Purkinje fibers survivability post-infarction, has demonstrated an improvement in the overall outcome of CRT. In silico models could constitute a powerful tool to understand, evaluate, and optimize different CRT approaches, which could help clinicians to plan personalized CRT procedures and reduce patient's risk. [ABSTRACT FROM AUTHOR]

The article presents the discussion on short or long‐coupled idiopathic ventricular fibrillation. Topics include arrhythmias originated from the left posterior fascicle, the left anterior fascicle and presumably the right ventricular moderator band; and performing with the high suspicion where syncope being related to aborted malignant tachyarrhythmias.

Aims Mapping data of human ventricular fibrillation (VF) are limited. We performed detailed mapping of the activities underlying the onset of VF and targeted ablation in patients with structural cardiac abnormalities. Methods and results We evaluated 54 patients (50 ± 16 years) with VF in the setting of ischaemic (n  = 15), hypertrophic (n  = 8) or dilated cardiomyopathy (n  = 12), or Brugada syndrome (n  = 19). Ventricular fibrillation was mapped using body-surface mapping to identify driver (reentrant and focal) areas and invasive Purkinje mapping. Purkinje drivers were defined as Purkinje activities faster than the local ventricular rate. Structural substrate was delineated by electrogram criteria and by imaging. Catheter ablation was performed in 41 patients with recurrent VF. Sixty-one episodes of spontaneous (n  = 10) or induced (n  = 51) VF were mapped. Ventricular fibrillation was organized for the initial 5.0 ± 3.4 s, exhibiting large wavefronts with similar cycle lengths (CLs) across both ventricles (197 ± 23 vs. 196 ± 22 ms, P  = 0.9). Most drivers (81%) originated from areas associated with the structural substrate. The Purkinje system was implicated as a trigger or driver in 43% of patients with cardiomyopathy. The transition to disorganized VF was associated with the acceleration of initial reentrant activities (CL shortening from 187 ± 17 to 175 ± 20 ms, P  < 0.001), then spatial dissemination of drivers. Purkinje and substrate ablation resulted in the reduction of VF recurrences from a pre-procedural median of seven episodes [interquartile range (IQR) 4–16] to 0 episode (IQR 0–2) (P  < 0.001) at 56 ± 30 months. Conclusions The onset of human VF is sustained by activities originating from Purkinje and structural substrate, before spreading throughout the ventricles to establish disorganized VF. Targeted ablation results in effective reduction of VF burden. Key question The initial phase of human ventricular fibrillation (VF) is critical as it involves the primary activities leading to sustained VF and arrhythmic sudden death. The origin of such activities is unknown. Key finding Body-surface mapping shows that most drivers (≈80%) during the initial VF phase originate from electrophysiologically defined structural substrates. Repetitive Purkinje activities can be elicited by programmed stimulation and are implicated as drivers in 37% of cardiomyopathy patients. Take-home message The onset of human VF is mostly associated with activities from the Purkinje network and structural substrate, before spreading throughout the ventricles to establish sustained VF. Targeted ablation reduces or eliminates VF recurrence. [ABSTRACT FROM AUTHOR]

Background: His‐Purkinje conduction system pacing (HPCSP) has been proposed as an alternative to Cardiac Resynchronization Therapy (CRT); however, predictors of echocardiographic response have not been described in this population. Septal flash (SF), a fast contraction and relaxation of the septum, is a marker of intraventricular dyssynchrony. Methods: The study aimed to analyze whether HPCSP corrects SF in patients with CRT indication, and if correction of SF predicts echocardiographic response. This retrospective analysis of prospectively collected data included 30 patients. Left ventricular ejection fraction (LVEF) was measured with echocardiography at baseline and at 6‐month follow‐up. Echocardiographic response was defined as increase in five points in LVEF. Results: HPCSP shortened QRS duration by 48 ± 21 ms and SF was significantly decreased (baseline 3.6 ± 2.2 mm vs. HPCSP 1.5 ± 1.5 mm p <.0001). At 6‐month follow‐up, mean LVEF improvement was 8.6% ± 8.7% and 64% of patients were responders. There was a significant correlation between SF correction and increased LVEF (r =.61, p =.004). A correction of ≥1.5 mm (baseline SF – paced SF) had a sensitivity of 81% and 80% specificity to predict echocardiographic response (area under the curve 0.856, p =.019). Conclusion: HPCSP improves intraventricular dyssynchrony and results in 64% echocardiographic responders at 6‐month follow‐up. Dyssynchrony improvement with SF correction may predict echocardiographic response at 6‐month follow‐up. [ABSTRACT FROM AUTHOR]

Development of the heart is a very intricate and multiplex process as it involves not only the three spatial dimensions but also the fourth or time dimension. Over time, the heart of an embryo needs to adapt its function to serve the increasing complexity of differentiation and growth towards adulthood. It becomes even more perplexing by expanding time into millions of years, allocating related species in the tree of life. As the evolution of soft tissues can hardly be studied, we have to rely on comparative embryology, supported heavily by genetic and molecular approaches. These techniques provide insight into relationships, not only between species, but also between cell populations, signaling mechanisms, molecular interactions and physical factors such as hemodynamics. Heart development depends on differentiation of a mesodermal cell population that - in more derived taxa - continues in segmentation of the first and second heart field. These fields deliver not only the cardiomyocytes, forming the three-dimensionally looping cardiac tube as a basis for the chambered heart, but also the enveloping epicardium. The synchronized beating of the heart is then organized by the conduction system. In this Review, the epicardium is introduced as an important player in cardiac differentiation, including the conduction system., Competing Interests: Competing interests The author declares no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: His‐Purkinje conduction system pacing (HPCSP) has emerged as an effective alternative to overcome the limitations of right ventricular pacing (RVP) via physiological left ventricular activation, but there remains a paucity of comparative information for His bundle pacing (HBP) and left bundle branch pacing (LBBP). Methods: A Bayesian random‐effects network analysis was conducted to compare the relative effects of HBP, LBBP, and RVP in patients with bradycardia and conduction disorders. PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from database inception until September 21, 2021. Results: Twenty‐eight studies involving 4160 patients were included in this meta‐analysis. LBBP significantly improved success rate, pacing threshold, pacing impedance, and R‐wave amplitude compared with HBP. LBBP also demonstrated a nonsignificant trend towards superior outcomes of lead complications, heart failure hospitalization, atrial fibrillation, and all‐cause death. However, HBP was associated with significantly shorter paced QRS duration relative to LBBP. Despite higher success rates, shorter procedure/fluoroscopy duration, and fewer lead complications, patients receiving RVP were more likely to experience reduced left ventricular ejection fraction, longer paced QRS duration, and higher rates of heart failure hospitalization than those receiving HPCSP. No statistical differences were observed in the remaining outcome measures. Conclusions: This network meta‐analysis demonstrates the efficacy and safety of HPCSP for the treatment of bradycardia and conduction disorders, with differences in pacing parameters, electrophysiology characteristics, and clinical outcomes between HBP and LBBP. Larger‐scale, long‐term comparative studies are warranted for further verification. [ABSTRACT FROM AUTHOR]

The cardiac conduction system is formed of histologically and electrophysiologically distinct specialized tissues uniquely located in the human heart. Understanding the anatomy and pathology of the cardiac conduction system is imperative to an interventional electrophysiologist to perform safe ablation and device therapy for the management of cardiac arrhythmias and heart failure. The current review summarizes the normal and developmental anatomy of the cardiac conduction system, its variation in the normal heart and congenital anomalies, and its pathology and discusses important clinical pearls for the proceduralist. [ABSTRACT FROM AUTHOR]