RASopathies are a group of genetic disorders caused by mutations in genes encoding components and regulators of the RAS/MAPK signaling pathway, resulting in overactivation of signaling. RASopathy patients exhibit distinctive facial features, cardiopathies, growth and skeletal abnormalities, and varying degrees of neurocognitive impairments including neurodevelopmental delay, intellectual disabilities, or attention deficits. At present, it is unclear how RASopathy mutations cause neurocognitive impairment and what their neuron-specific cellular and network phenotypes are. Here, we investigated the effect of RASopathy mutations on the establishment and functional maturation of neuronal networks. We isolated cortical neurons from RASopathy mouse models, cultured them on multielectrode arrays and performed longitudinal recordings of spontaneous activity in developing networks as well as recordings of evoked responses in mature neurons. To facilitate the analysis of large and complex data sets resulting from long-term multielectrode recordings, we developed MATLAB-based tools for data processing, analysis, and statistical evaluation. Longitudinal analysis of spontaneous network activity revealed a convergent developmental phenotype in neurons carrying the gain-of-function Noonan syndrome-related mutations Ptpn11D61Y and KrasV14l. The phenotype was more pronounced at the earlier time points and faded out over time, suggesting the emergence of compensatory mechanisms during network maturation. Nevertheless, persistent differences in excitatory/inhibitory balance and network excitability were observed in mature networks. This study improves the understanding of the complex relationship between genetic mutations and clinical manifestations in RASopathies by adding insights into functional network processes as an additional piece of the puzzle.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: During pulsed field ablation (PFA), electrode-tissue proximity optimizes lesion quality. A novel "single-shot" map-and-ablate spherical multielectrode PFA array catheter that is able to verify electrode-tissue contact was recently studied in a first-in-human trial of atrial fibrillation (AF). OBJECTIVE: The aim of this study was to report lesion durability data, safety, and 12-month effectiveness outcomes. METHODS: The spherical PFA catheter, an all-in-one mapping and ablation system, was used to render anatomy and to deliver biphasic pulses (ungated 1.7 kV pulses; ∼40 seconds/application). Ablation sites included pulmonary veins (PVs) and, in selected patients, posterior wall and mitral isthmus. Follow-up was invasive remapping at ∼3 months, electrocardiograms, Holter monitoring at 6 and 12 months, and symptomatic and scheduled transtelephonic monitoring. The primary and secondary efficacy end points were acute PV isolation (PVI), PVI durability, and atrial arrhythmia recurrence. RESULTS: In the 48-patient AF cohort (paroxysmal, 48%; persistent, 52%), lesion sets included PVI (n = 48; 1.2 applications/PV), posterior wall (n = 20; 3.6 applications/posterior wall), and mitral isthmus (n = 11; 2.9 applications/mitral isthmus). Lesions were acutely successful for all 187 of 187 PVs (100%), 20 of 20 posterior walls (100%), and 10 of 11 mitral isthmuses (91%). Pulse delivery time, left atrial catheter dwell time, and procedure time were 61.5 ± 32.8 seconds, 53.9 ± 26.5 minutes, and 87.8 ± 29.8 minutes, respectively. Remapping (43/48 patients [89.5%]) revealed that 158 of 169 PVs (93.5%) were durably isolated. The only complication was a drug-responsive pericarditis. The 1-year Kaplan-Meier estimates of freedom from atrial arrhythmia were 84.2% (paroxysmal AF) and 80.0% (persistent AF). CONCLUSION: The single-shot spherical array PFA catheter can safely achieve durable lesions, translating into good clinical efficacy.

• MeSH
• časové faktory MeSH
• design vybavení MeSH
• elektrokardiografie ambulantní metody   MeSH
• fibrilace síní * chirurgie   patofyziologie   MeSH
• katetrizační ablace * metody   přístrojové vybavení   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• převodní systém srdeční patofyziologie   MeSH
• recidiva MeSH
• senioři MeSH
• venae pulmonales * chirurgie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

IMPORTANCE: In treating atrial fibrillation, pulsed field ablation (PFA) is a novel energy modality with comparable efficacy to conventional thermal ablation, such as radiofrequency ablation (RFA), but with the benefit of some preferentiality to myocardial tissue ablation. Studies have demonstrated important safety advantages, including the absence of esophageal injury or pulmonary vein stenosis and only rare phrenic nerve injury. However, there is emerging evidence of coronary artery vasospasm provoked by PFA. OBJECTIVE: To compare the incidence and severity of left circumflex arterial vasospasm between PFA and RFA during adjacent ablation along the mitral isthmus. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study enrolled consecutive adult patients receiving first-ever PFA or RFA of the mitral isthmus during catheter ablation of atrial fibrillation in 2022 with acute follow-up at a single referral European center. EXPOSURE: A posterolateral mitral isthmus line was created using either a multielectrode pentaspline PFA catheter (endocardial ablation) or a saline-irrigated RFA catheter. Simultaneous diagnostic coronary angiography was performed before, during, and after catheter ablation. Nitroglycerin was planned for spasm persisting beyond 20 minutes or for significant electrocardiographic changes. MAIN OUTCOMES AND MEASURES: The frequency and severity of left circumflex arterial vasospasm was assessed and monitored, as were time to remission and any need for nitroglycerin administration. RESULTS: Of 26 included patients, 19 (73%) were male, and the mean (SD) age was 65.5 (9.3) years. Patients underwent either PFA (n = 17) or RFA (n = 9) along the mitral isthmus. Coronary spasm was observed in 7 of 17 patients (41.2%) undergoing PFA: in 7 of 9 (77.8%) when the mitral isthmus ablation line was situated superiorly and in 0 of 8 when situated inferiorly. Conversely, coronary spasm did not occur in any of the 9 patients undergoing RFA. Of 5 patients in whom crossover PFA was performed after RFA failed to achieve conduction block, coronary spasm occurred in 3 (60%). Most instances of spasm (9 of 10 [90%]) were subclinical, with 2 (20%) requiring nitroglycerin administration. The median (range) time to resolution of spasm was 5 (5-25) minutes. CONCLUSION AND RELEVANCE: When creating a mitral isthmus ablation line during catheter ablation of atrial fibrillation, adjacent left circumflex arterial vasospasm frequently occurred with PFA and not RFA but was typically subclinical.

• MeSH
• dospělí MeSH
• fibrilace síní * chirurgie   patofyziologie   MeSH
• katetrizační ablace * škodlivé účinky   MeSH
• koronární vazospasmus * etiologie   MeSH
• lidé MeSH
• nitroglycerin MeSH
• prospektivní studie MeSH
• senioři MeSH
• srdeční síně patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH

BACKGROUND: The study is intended to evaluate the acute and long-term effectiveness and peri-procedural safety in ablation of persistent atrial fibrillation (PsAF) using the CartoFinder algorithm guided ablation (CFGA) targeting on repetitive activation patterns (RAPs) and focal impulses (FIs) identified in dynamic maps. METHODS: This is a prospective, single-arm, multicenter study. A 64-pole multielectrode basket catheter was used for intracardiac global electrogram (EGM) mapping. The RAPs or FIs were repeatedly mapped and ablated for up to five iterations by the CartoFinder algorithm to achieve sinus rhythm (SR) or organized atrial tachycardia (AT), which were followed by PVI. All patients were followed up for 12 months after procedure. RESULTS: Sixty-four PsAF patients (age, 60.7 ± 9.1 years; male, 76.6%; median PsAF duration, 6.0 months) underwent CFGA on RAPs/FIs. Six patients (9.4%) reported primary adverse event (PAE) including groin hematoma (2), complete heart block (1), tamponade (1), pericarditis (1), and pseudoaneurysm (1). Repeated mapping and ablation on RAPs/FIs resulted in the cycle length (CL) increase from 191.0 ± 167.6 ms at baseline to 365.7 ± 296.7 ms in the LA and from 167.8 ± 41.6 ms to 379.4 ± 293.5 ms in the RA and 30.2% (19/63) AF termination to SR or organized AT. The 12-month arrhythmia-free and symptomatic AF-free rates were 60.9% and 75.0%, respectively. Patients with acute AF termination showed a higher 12-month arrhythmia-free rate (76.9%) than those without (50.0%, p = .04). CONCLUSIONS: The study demonstrated that the CartoFinder algorithm can be used for global activation mapping during PsAF ablation. Patients with acute AF termination had a lower 12-month AF recurrence rate compared to patients without.

• MeSH
• fibrilace síní * MeSH
• katetrizační ablace * metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• recidiva MeSH
• senioři MeSH
• supraventrikulární tachykardie * MeSH
• venae pulmonales * chirurgie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

BACKGROUND: Pulsed field ablation is a novel nonthermal cardiac ablation modality using ultra-rapid electrical pulses to cause cell death by a mechanism of irreversible electroporation. Unlike the traditional ablation energy sources, pulsed field ablation has demonstrated significant preferentiality to myocardial tissue ablation, and thus avoids certain thermally mediated complications. However, its safety and effectiveness remain unknown in usual clinical care. METHODS: MANIFEST-PF (Multi-National Survey on the Methods, Efficacy, and Safety on the Post-Approval Clinical Use of Pulsed Field Ablation) is a retrospective, multinational, patient-level registry wherein patients at each center were prospectively included in their respective center registries. The registry included all patients undergoing postapproval treatment with a multielectrode 5-spline pulsed field ablation catheter to treat atrial fibrillation (AF) between March 1, 2021, and May 30, 2022. The primary effectiveness outcome was freedom from clinical documented atrial arrhythmia (AF/atrial flutter/atrial tachycardia) of ≥30 seconds on the basis of electrocardiographic data after a 3-month blanking period (on or off antiarrhythmic drugs). Safety outcomes included the composite of acute (<7 days postprocedure) and latent (>7 days) major adverse events. RESULTS: At 24 European centers (77 operators) pulsed field ablation was performed in 1568 patients with AF: age 64.5±11.5 years, female 35%, paroxysmal/persistent AF 65%/32%, CHA2DS2-VASc 2.2±1.6, median left ventricular ejection fraction 60%, and left atrial diameter 42 mm. Pulmonary vein isolation was achieved in 99.2% of patients. After a median (interquartile range) follow-up of 367 (289-421) days, the 1-year Kaplan-Meier estimate for freedom from atrial arrhythmia was 78.1% (95% CI, 76.0%-80.0%); clinical effectiveness was more common in patients with paroxysmal AF versus persistent AF (81.6% versus 71.5%; P=0.001). Acute major adverse events occurred in 1.9% of patients. CONCLUSIONS: In this large observational registry of the postapproval clinical use of pulsed field technology to treat AF, catheter ablation using pulsed field energy was clinically effective in 78% of patients with AF.

• MeSH
• fibrilace síní * diagnóza   chirurgie   farmakoterapie   MeSH
• flutter síní * etiologie   MeSH
• funkce levé komory srdeční MeSH
• katetrizační ablace * škodlivé účinky   metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• recidiva MeSH
• registrace MeSH
• retrospektivní studie MeSH
• senioři MeSH
• tepový objem MeSH
• venae pulmonales * MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Preclinical studies have revealed that pulsed field ablation (PFA) lesion dimensions increase with repetitive applications at a similar electric field. OBJECTIVES: This study investigated whether pulmonary vein isolation (PVI) durability varies with single vs repetitive pulsed field (PF) applications. METHODS: Atrial fibrillation patients underwent PVI using a spherical multielectrode array PFA catheter delivered with a 19-F deflectable sheath under intracardiac echocardiographic guidance. Esophagogastroduodenoscopy and brain magnetic resonance imaging were performed within 1 to 3 days, and invasive remapping at ∼2 to 3 months. RESULTS: The patient cohort (n = 21; age 63 ± 11 years; 67% women) underwent PVI in either of 2 groups: group 1 (n = 11)-single PF application/PV; and group 2 (n = 10)-3 PF applications/PV. In both groups, PVI was acutely successful in all (100%) patients. Despite significantly longer pulse delivery times (75.2 ± 7.4 s/patient vs 24.5 ± 5.5 s/patient) the procedure times (73.2 ± 13.7 minutes vs 93.7 ± 18.5 minutes) were shorter with group 2 vs group 1. There was no stroke/transient ischemic attack, pericardial effusion, phrenic nerve injury, or esophageal complications. Esophagogastroduodenoscopy was normal in both groups of patients (n = 9). Screening brain magnetic resonance imaging revealed asymptomatic cerebral lesions (diffusion weighted imaging+/fluid attenuated inversion recovery-) in 3 of 16 (18.7%) patients. PV remapping revealed durable PVI in 62.5% PVs in group 1 (n = 10), compared with all 100% PVs in group 2 (n = 9); this translates to all PVs being durably isolated in 30% vs 100% (P < 0.05) of patients in groups 1 and 2, respectively. CONCLUSIONS: In his first-in-human trial, the "single-shot" spherical array PFA catheter was shown to safely isolate PVs. Repetitive PF application is key for lesion consolidation to maximize PVI durability.

• MeSH
• časové faktory MeSH
• katetrizační ablace * metody   MeSH
• katétry MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• srdeční frekvence MeSH
• venae pulmonales * chirurgie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Objective.Vagus nerve stimulation (VNS) is a promising approach for the treatment of a wide variety of debilitating conditions, including autoimmune diseases and intractable epilepsy. Much remains to be learned about the molecular mechanisms involved in vagus nerve regulation of organ function. Despite an abundance of well-characterized rodent models of common chronic diseases, currently available technologies are rarely suitable for the required long-term experiments in freely moving animals, particularly experimental mice. Due to challenging anatomical limitations, many relevant experiments require miniaturized, less invasive, and wireless devices for precise stimulation of the vagus nerve and other peripheral nerves of interest. Our objective is to outline possible solutions to this problem by using nongenetic light-based stimulation.Approach.We describe how to design and benchmark new microstimulation devices that are based on transcutaneous photovoltaic stimulation. The approach is to use wired multielectrode cuffs to test different stimulation patterns, and then build photovoltaic stimulators to generate the most optimal patterns. We validate stimulation through heart rate analysis.Main results.A range of different stimulation geometries are explored with large differences in performance. Two types of photovoltaic devices are fabricated to deliver stimulation: photocapacitors and photovoltaic flags. The former is simple and more compact, but has limited efficiency. The photovoltaic flag approach is more elaborate, but highly efficient. Both can be used for wireless actuation of the vagus nerve using light impulses.Significance.These approaches can enable studies in small animals that were previously challenging, such as long-termin vivostudies for mapping functional vagus nerve innervation. This new knowledge may have potential to support clinical translation of VNS for treatment of select inflammatory and neurologic diseases.

• MeSH
• bezdrátová technologie * MeSH
• myši MeSH
• vagová stimulace * přístrojové vybavení   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Electrical stimulation of peripheral nerves is a cornerstone of bioelectronic medicine. Effective ways to accomplish peripheral nerve stimulation (PNS) noninvasively without surgically implanted devices are enabling for fundamental research and clinical translation. Here, it is demonstrated how relatively high-frequency sine-wave carriers (3 kHz) emitted by two pairs of cutaneous electrodes can temporally interfere at deep peripheral nerve targets. The effective stimulation frequency is equal to the offset frequency (0.5 - 4 Hz) between the two carriers. This principle of temporal interference nerve stimulation (TINS) in vivo using the murine sciatic nerve model is validated. Effective actuation is delivered at significantly lower current amplitudes than standard transcutaneous electrical stimulation. Further, how flexible and conformable on-skin multielectrode arrays can facilitate precise alignment of TINS onto a nerve is demonstrated. This method is simple, relying on the repurposing of existing clinically-approved hardware. TINS opens the possibility of precise noninvasive stimulation with depth and efficiency previously impossible with transcutaneous techniques.

• MeSH
• elektrická stimulace MeSH
• myši MeSH
• nervus ischiadicus fyziologie   MeSH
• transkutánní elektrická neurostimulace * metody   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The recently introduced orientation selective deep brain stimulation (OS-DBS) technique freely controls the direction of the electric field's spatial gradient by using multiple contacts with independent current sources within a multielectrode array. The goal of OS-DBS is to align the electrical field along the axonal track of interest passing through the stimulation site. Here we utilized OS-DBS with a planar 3-channel electrode for stimulating the rat entorhinal cortex (EC) and medial septal nucleus (MSN), two promising areas for DBS treatment of Alzheimer's disease. The brain responses to OS-DBS were monitored by whole brain functional magnetic resonance imaging (fMRI) at 9.4 T with Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT). Varying the in-plane OS-DBS stimulation angle in the EC resulted in activity modulation of multiple downstream brain areas involved in memory and cognition. Contrary to that, no angle dependence of brain activations was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. We conclude that tuning the OS-DBS stimulation angle modulates the activation of brain areas relevant to Alzheimer's disease, thus holding great promise in the DBS treatment of the disease.

• MeSH
• Alzheimerova nemoc * diagnostické zobrazování   terapie   MeSH
• cortex entorhinalis diagnostické zobrazování   fyziologie   MeSH
• hluboká mozková stimulace * metody   MeSH
• kognice MeSH
• krysa rodu rattus MeSH
• magnetická rezonanční tomografie metody   MeSH
• mozek MeSH
• septální jádra * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: The tissue specificity of pulsed field ablation (PFA) makes it an attractive energy source for pulmonary vein (PV) isolation (PVI). However, beyond each PFA lesion's zone of irreversible electroporation and cell death, there may be a surrounding zone of reversible electroporation and cell injury that could potentially normalize with time. OBJECTIVE: The purpose of this study was to assess whether the level of electrical PVI that is observed acutely after PFA regresses over time. METHODS: In a clinical trial, patients with paroxysmal atrial fibrillation underwent PVI using a biphasic PFA waveform delivered through a dedicated, variably deployable multielectrode basket/flower catheter. Detailed voltage maps were created using a multispline diagnostic catheter immediately after PFA and again ∼3 months later in a prospective, protocol-specified reassessment procedure. We analyzed 20 patients who underwent PFA with durable PVI and available maps from both time points. To compare the ablated zones, the left- and right-sided PV antral isolation areas and nonablated posterior wall area were quantified and the distances between left and right PV low-voltage edges were measured. RESULTS: A comparison of voltage maps immediately after PFA and at a median of 84 days (interquartile range 69-90 days) later revealed that there was no significant difference in either the left- and right-sided PV antral isolation areas or nonablated posterior wall area. The distances between low-voltage edges on the posterior wall were also not significantly different between the 2 time points. CONCLUSION: This study demonstrates that the level of PV antral isolation after PFA with a multielectrode PFA catheter persists without regression.

• MeSH
• časové faktory MeSH
• fibrilace síní patofyziologie   chirurgie   MeSH
• katetrizační ablace metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• prospektivní studie MeSH
• studie proveditelnosti MeSH
• venae pulmonales chirurgie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH