The polyglutamine protein ATXN2: from its molecular functions to its involvement in disease.

A CAG repeat sequence in the ATXN2 gene encodes a polyglutamine (polyQ) tract within the ataxin-2 (ATXN2) protein, showcasing a complex landscape of functions that have been progressively unveiled over recent decades. Despite significant progresses in the field, a comprehensive overview of the mechanisms governed by ATXN2 remains elusive. This multifaceted protein emerges as a key player in RNA metabolism, stress granules dynamics, endocytosis, calcium signaling, and the regulation of the circadian rhythm. The CAG overexpansion within the ATXN2 gene produces a protein with an extended poly(Q) tract, inducing consequential alterations in conformational dynamics which confer a toxic gain and/or partial loss of function. Although overexpanded ATXN2 is predominantly linked to spinocerebellar ataxia type 2 (SCA2), intermediate expansions are also implicated in amyotrophic lateral sclerosis (ALS) and parkinsonism. While the molecular intricacies await full elucidation, SCA2 presents ATXN2-associated pathological features, encompassing autophagy impairment, RNA-mediated toxicity, heightened oxidative stress, and disruption of calcium homeostasis. Presently, SCA2 remains incurable, with patients reliant on symptomatic and supportive treatments. In the pursuit of therapeutic solutions, various studies have explored avenues ranging from pharmacological drugs to advanced therapies, including cell or gene-based approaches. These endeavours aim to address the root causes or counteract distinct pathological features of SCA2. This review is intended to provide an updated compendium of ATXN2 functions, delineate the associated pathological mechanisms, and present current perspectives on the development of innovative therapeutic strategies.

Sex Differences in Left Bundle Branch Area Pacing Versus Biventricular Pacing for Cardiac Resynchronization Therapy.

BACKGROUND: Women respond more favorably to biventricular pacing (BIVP) than men. Sex differences in atrioventricular and interventricular conduction have been described in BIVP studies. Left bundle branch area pacing (LBBAP) offers advantages due to direct capture of the conduction system. We hypothesized that men could respond better to LBBAP than BIVP. OBJECTIVES: This study aims to describe the sex differences in response to LBBAP vs BIVP as the initial cardiac resynchronization therapy (CRT). METHODS: In this multicenter prospective registry, we included patients with left ventricular ejection fraction ≤35% and left bundle branch block or a left ventricular ejection fraction ≤40% with an expected right ventricular pacing exceeding 40% undergoing initial CRT with LBBAP or BIVP. The composite primary outcome was heart failure-related hospitalization and all-cause mortality. The primary safety outcome included all procedure-related complications. RESULTS: There was no significant difference in the primary outcome when comparing men and women receiving LBBAP (P = 0.46), whereas the primary outcome was less frequent in women in the BIVP group than men treated with BIVP (P = 0.03). The primary outcome occurred less frequently in men undergoing LBBAP (29.9%) compared to those treated with BIVP (46.5%) (P = 0.004). In women, the incidence of the primary endpoint was 24.14% in the LBBAP group and 36.2% in the BIVP group; however, this difference was not statistically significant (P = 0.23). Complication rates remained consistent across all groups. CONCLUSIONS: Men and women undergoing LBBAP for CRT had similar clinical outcomes. Men undergoing LBBAP showed a lower risk of heart failure-related hospitalizations and all-cause mortality compared to men undergoing BIVP, whereas there was no difference between LBBAP and BIVP in women.

Relative Fundamental Frequency: Only for Hyperfunctional Voices? A Pilot Study.

(1) Background: Assessing phonatory disorders due to laryngeal biomechanical alterations requires aerodynamic analysis, assessing subglottic pressure, transglottic flow, and laryngeal resistance. This study explores whether the acoustic parameter, the relative fundamental frequency (RFF), can be studied using the current acoustic analysis protocol at the University of Navarra's voice laboratory and its association with pathologies linked to laryngeal biomechanical alterations. (2) Methods: A retrospective cohort study included patients diagnosed with muscular tension dysphonia, organic lesions of the vocal fold, and vocal fold paralysis (VFP) at the Clínica Universidad de Navarra from 2019 to 2021. Each patient underwent endoscopic laryngeal exploration, followed by acoustic study, RFF calculation, and an aerodynamic study. Additionally, a control group was recruited. (3) Results: 79 patients and 22 controls were studied. Two-way ANOVA showed significant effects for groups and cycles in offset and onset cycles. Statistically significant differences were observed in cycle 1 onset among all groups and in cycles 1 and 2 between the control group and non-healthy groups. (4) Conclusions: RFF is a valuable indicator of phonatory biomechanics, distinguishing healthy and pathological voices and different disorders. RFF in onset cycles offers a cost-effective, accurate method for assessing biomechanical disorders without complex aerodynamic analyses. This study describes RFF values in VFP for the first time, revealing differences regardless of aerodynamic patterns.

Feasibility, Efficacy, and Safety of Fluoroless Ablation of VT in Patients With Structural Heart Disease.

BACKGROUND: Catheter ablation of ventricular tachycardia (VT) typically requires radiation exposure with its potential adverse health effects. A completely fluoroless ablation approach is achievable using a combination of electroanatomical mapping and intracardiac echocardiography. Nonetheless, data in patients undergoing VT ablation are limited. OBJECTIVES: This study aimed to determine the feasibility, efficacy, and safety of VT ablation in patients with structural heart disease using a zero-fluoroscopy approach. METHODS: This multicenter study included consecutive patients with ischemic and nonischemic cardiomyopathy undergoing fluoroless VT ablation. Patients requiring epicardial access or coronary angiography were excluded. RESULTS: Between 2017 and 2023 a total of 198 patients (aged 66.4 ± 13.4 years, 76% male, 48% ischemic) were included. Most patients (95.4%) underwent left ventricular (LV) mapping and/or ablation, which was conducted via transseptal route in 54.5% (n = 103), via retrograde aortic route in 43.4% (n = 82), and using a combined approach in 2.1% (n = 4). Two-thirds of patients had a cardiac device, including a biventricular device in 15%; 2 patients had a LV assist device, and 1 patient had a mechanical aortic valve prosthesis. The mean total procedural time was 211 ± 70 minutes, and the total radiofrequency time was 30 ± 22 minutes. During a follow-up period of 22 ± 18 months, the freedom from VT recurrence was 80%, and 7.6% of patients underwent a repeated ablation. Procedural-related complications occurred in 6 patients (3.0%). CONCLUSIONS: Fluoroless ablation of VT in structural heart disease is feasible, effective, and safe when epicardial mapping/ablation is not required.

Real-world data of radiofrequency catheter ablation in paroxysmal atrial fibrillation: Short- and long-term clinical outcomes from the prospective multicenter REAL-AF Registry.

BACKGROUND: The safety and long-term efficacy of radiofrequency (RF) catheter ablation (CA) of paroxysmal atrial fibrillation (PAF) has been well established. Contemporary techniques to optimize ablation delivery, reduce fluoroscopy use, and improve clinical outcomes have been developed. OBJECTIVE: The purpose of this study was to assess the contemporary real-world practice approach and short and long-term outcomes of RF CA for PAF through a prospective multicenter registry. METHODS: Using the REAL-AF (Real-world Experience of Catheter Ablation for the Treatment of Symptomatic Paroxysmal and Persistent Atrial Fibrillation; ClincalTrials.gov Identifier: NCT04088071) Registry, patients undergoing RF CA to treat PAF across 42 high-volume institutions and 79 experienced operators were evaluated. The procedures were performed using zero or reduced fluoroscopy, contact force sensing catheters, wide area circumferential ablation, and ablation index as a guide with a target of 380-420 for posterior and 500-550 for anterior lesions. The primary efficacy outcome was freedom from all-atrial arrhythmia recurrence at 12 months. RESULTS: A total of 2470 patients undergoing CA from January 2018 to December 2022 were included. Mean age was 65.2 ±11.14 years, and 44% were female. Most procedures were performed without fluoroscopy (71.5%), with average procedural and total RF times of 95.4 ± 41.7 minutes and 22.1±11.8 minutes, respectively. At 1-year follow-up, freedom from all-atrial arrhythmias was 81.6% with 89.7% of these patients off antiarrhythmic drugs. No significant difference was identified comparing pulmonary vein isolation vs pulmonary vein isolation plus ablation approaches. The complication rate was 1.9%. CONCLUSION: Refinement of RF CA to treat PAF using contemporary tools, standardized protocols, and electrophysiology laboratory workflows resulted in excellent short- and long-term clinical outcomes.

Molecular diagnosis and characterization of Anaplasma marginale and Ehrlichia ruminantium infecting beef cattle of Maputo Province, Mozambique.

BACKGROUND: Members of the Anaplasmataceae family, such as the Anaplasma and Ehrlichia species, cause economic losses and public health risks. However, the exact economic impact has not been comprehensively assessed in Mozambique due to limited data available on its basic epidemiology. Therefore, we investigated the molecular occurrence and identity of Anaplasma and Ehrlichia spp. infecting beef cattle in Maputo province, Mozambique. METHODS: A total of 200 whole blood samples were collected from apparently healthy beef cattle. Whole blood DNA was extracted and tested for presence of Anaplasma spp. and Ehrlichia ruminantium DNA through amplification of the 16S rRNA and map1 genes. Positive samples to Anaplasma spp. were subject to PCR assay targeting the A. marginale-msp5 gene. Amplicons obtained were purified, sequenced and subject to phylogenetic analyses. RESULTS: Anaplasma spp., A. marginale and E. ruminantium were detected in 153 (76.5%), 142 (71%) and 19 (9.5%) of all the samples analyzed, respectively. On this same sample group, 19 (9.5%) were co-infected with A. marginale and E. ruminantium. The 16S rRNA sequences of Anaplasma spp. obtained were phylogenetically related to A. marginale, A. centrale and A. platys. Phylogenetic analysis revealed that A. marginale-msp5 nucleotide sequences were grouped with sequences from Asia, Africa and Latin America, whereas E. ruminantium-map1 DNA nucleotide sequences were positioned in multiple clusters. CONCLUSION: Cattle in Maputo Province are reservoirs for multiple Anaplasma species. A high positivity rate of infection by A. marginale was observed, as well as high genetic diversity of E. ruminantium. Furthermore, five new genotypes of E. ruminantium-map1 were identified.

Improved all-cause mortality with left bundle branch area pacing compared to biventricular pacing in cardiac resynchronization therapy: a meta-analysis.

BACKGROUND: Left bundle branch area pacing (LBBAP) has emerged as a physiological alternative pacing strategy to biventricular pacing (BIVP) in cardiac resynchronization therapy (CRT). We aimed to assess the impact of LBBAP vs. BIVP on all-cause mortality and heart failure (HF)-related hospitalization in patients undergoing CRT. METHODS: Studies comparing LBBAP and BIVP for CRT in patients with HF with reduced left ventricular ejection fraction (LVEF) were included. The coprimary outcomes were all-cause mortality and HF-related hospitalization. Secondary outcomes included procedural and fluoroscopy time, change in QRS duration, and change in LVEF. RESULTS: Thirteen studies (12 observational and 1 RCT, n = 3239; LBBAP = 1338 and BIVP = 1901) with a mean follow-up duration of 25.8 months were included. Compared to BIVP, LBBAP was associated with a significant absolute risk reduction of 3.2% in all-cause mortality (9.3% vs 12.5%, RR 0.7, 95% CI 0.57-0.86, p < 0.001) and an 8.2% reduction in HF-related hospitalization (11.3% vs 19.5%, RR 0.6, 95% CI 0.5-0.71, p < 0.00001). LBBAP also resulted in reductions in procedural time (mean weighted difference- 23.2 min, 95% CI - 42.9 to - 3.6, p = 0.02) and fluoroscopy time (- 8.6 min, 95% CI - 12.5 to - 4.7, p < 0.001) as well as a significant reduction in QRS duration (mean weighted difference:- 25.3 ms, 95% CI - 30.9 to - 19.8, p < 0.00001) and a greater improvement in LVEF of 5.1% (95% CI 4.4-5.8, p < 0.001) compared to BIVP in the studies that reported these outcomes. CONCLUSION: In this meta-analysis, LBBAP was associated with a significant reduction in all-cause mortality as well as HF-related hospitalization when compared to BIVP. Additional data from large RCTs is warranted to corroborate these promising findings.

Otic Capsule Dehiscences Simulating Other Inner Ear Diseases: Characterization, Clinical Profile, and Follow-Up-Is Ménière's Disease the Sole Cause of Vertigo and Fluctuating Hearing Loss?

INTRODUCTION: We present a series of six cases whose clinical presentations exhibited audiovestibular manifestations of a third mobile window mechanism, bearing a reasonable resemblance to Ménière's disease and otosclerosis. The occurrence of these cases in such a short period has prompted a review of the underlying causes of its development. Understanding the pathophysiology of third mobile window syndrome and considering these entities in the differential diagnosis of conditions presenting with vertigo and hearing loss with slight air-bone gaps is essential for comprehending this group of pathologies. MATERIALS AND METHODS: A descriptive retrospective cohort study of six cases diagnosed at a tertiary center. All of them went through auditive and vestibular examinations before and after a therapeutic strategy was performed. RESULTS: Out of 84 cases of dehiscences described in our center during the period from 2014 to 2024, 78 belonged to superior semicircular canal dehiscence, while 6 were other otic capsule dehiscences. Among these six patients with a mean age of 47.17 years (range: 18-73), all had some form of otic capsule dehiscence with auditory and/or vestibular repercussions, measured through hearing and vestibular tests, with abnormalities in the results in five out of six patients. Two of them were diagnosed with Ménière's disease (MD). Another two had cochleo-vestibular hydrops without meeting the diagnostic criteria for MD. In two cases, the otic capsule dehiscence diagnosis resulted from an intraoperative complication due to a gusher phenomenon, while in one case, it was an accidental radiological finding. All responded well to the proposed treatment, whether medical or surgical, if needed. CONCLUSIONS: Otic capsule dehiscences are relatively new and unfamiliar entities that should be considered when faced with cases clinically suggestive of Ménière's disease, with discrepancies in complementary tests or a poor response to treatment. While high-sensitivity and specificity audiovestibular tests exist, completing the study with imaging, especially petrous bone CT scans, is necessary to locate and characterize the otic capsule defect responsible for the clinical presentation.

Intracardiac Echocardiography-guided Left Atrial Appendage Occlusion.

Left atrial appendage occlusion (LAAO) is a suitable alternative to oral anticoagulant therapy to prevent stroke in patients with AF. Most procedures are performed under transoesophageal echocardiography (TOE) guidance, which facilitates transseptal puncture, reduces the risk of procedurerelated complications and provides an additional method for device selection and real-time monitoring during device deployment. However, TOE has significant shortcomings, including the need for general anaesthesia/deep sedation as well as a significant risk of procedure-related adverse events. More recently, intracardiac echocardiography has been proposed as an alternative to TOE guidance during LAAO procedures. In this review, we summarise the available evidence as well as providing a step-by-step approach for intracardiac echocardiography-guided LAAO.

Bipolar ablation involving coronary venous system for refractory left ventricular summit arrhythmias.

Background: Catheter ablation of premature ventricular complexes (PVCs) and ventricular tachycardia (VT) from the left ventricular summit (LVS) may require advanced ablation techniques. Bipolar ablation from the coronary veins and adjacent endocardial structures can be effective for refractory LVS arrhythmias. Objective: The aim of this study was to investigate the outcomes of bipolar ablation performed between the coronary venous system and adjacent endocardial left ventricular outflow tract (LVOT) or right ventricular outflow tract (RVOT). Methods: This multicenter study included consecutive patients with LVS PVC/VT who underwent bipolar ablation between the anterior interventricular vein (AIV) or great cardiac vein (GCV) and the endocardial LVOT/RVOT after failed unipolar ablation. Ablation was started with powers of 10-20 W and uptitrated to achieve an impedance drop of at least 10%. Angiography was performed in all cases to confirm a safe distance (>5 mm) of the catheter from the major coronary arteries. Results: Between 2013 and 2023, bipolar radiofrequency ablation between the AIV/GCV and the adjacent LVOT/RVOT was attempted in 20 patients (4 female; age 57 ± 16 years). Unipolar ablation from sites of early activation (AIV/GCV, LVOT, aortic cusps, RVOT) failed to effectively suppress the PVC/VT in all subjects. Bipolar ablation was delivered with a maximum power of 30 ± 8 W and total duration of 238 ± 217 s and led to acute PVC/VT elimination in all patients. No procedural-related complications occurred. Over a follow-up period of 30 ± 24 months, the freedom from arrhythmia recurrence was 85% (1 recurrence in the VT group and 2 in the PVC group). PVC burden was reduced from 22% ± 10% to 4% ± 8% (P <.001). Conclusion: In cases of LVS PVC/VT refractory to unipolar ablation, bipolar ablation between the coronary venous system and adjacent endocardial LVOT/RVOT is safe and effective if careful titration of power and intraprocedural angiography are performed to ensure a safe distance from the coronary arteries.

Conduction System Stimulation to Avoid Left Ventricle Dysfunction.

BACKGROUND: Right ventricular apical pacing (RVAP) can produce left ventricle dysfunction. Conduction system pacing (CSP) has been used successfully to reverse left ventricle dysfunction in patients with left bundle branch block. To date, data about CSP prevention of left ventricle dysfunction in patients with preserved left ventricular ejection fraction (LVEF) are scarce and limited mostly to nonrandomized studies. Our aim is to demonstrate that CSP can preserve normal ventricular function compared with RVAP in the setting of a high burden of ventricular pacing. METHODS: Consecutive patients with a high-degree atrioventricular block and preserved or mildly deteriorated LVEF (>40%) were included in this prospective, randomized, parallel, controlled study, comparing conventional RVAP versus CSP. RESULTS: Seventy-five patients were randomized, with no differences between basal characteristics in both groups. The stimulated QRS duration was significantly longer in the RVAP group compared with the CSP group (160.4±18.1 versus 124.2±20.2 ms; p<0.01). Seventy patients were included in the intention-to-treat analyses. LVEF showed a significant decrease in the RVAP group at 6 months compared with the CSP group (mean difference, -5.8% [95% CI, -9.6% to -2%]; P<0.01). Left ventricular end-diastolic diameter showed an increase in the RVAP group compared with the CSP group (mean difference, 3.2 [95% CI, 0.1-6.2] mm; P=0.04). Heart failure-related admissions were higher in the RVAP group (22.6% versus 5.1%; P=0.03). CONCLUSIONS: Conduction system stimulation prevents LVEF deterioration and heart failure-related admissions in patients with normal or mildly deteriorated LVEF requiring a high burden of ventricular pacing. These results are only short term and need to be confirmed by further larger studies. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06026683.

Impact of intracardiac echocardiography versus transesophageal echocardiography guidance on left atrial appendage occlusion procedures: A meta-analysis.

BACKGROUND: Intracardiac echocardiography (ICE) is increasingly used during left atrial appendage occlusion (LAAO) as an alternative to transesophageal echocardiography (TEE). The objective of this study is to evaluate the impact of ICE versus TEE guidance during LAAO on procedural characteristics and acute outcomes, as well the presence of peri-device leaks and residual septal defects during follow-up. METHODS: All studies comparing ICE-guided versus TEE-guided LAAO were identified. The primary outcomes were procedural efficacy and occurrence of procedure-related complications. Secondary outcomes included lab efficiency (defined as a reduction in in-room time), procedural time, fluoroscopy time, and presence of peri-device leaks and residual interatrial septal defects (IASD) during follow-up. RESULTS: Twelve studies (n = 5637) were included. There were no differences in procedural success (98.3% vs. 97.8%; OR 0.73, 95% CI 0.42-1.27, p = .27; I2 = 0%) or adverse events (4.5% vs. 4.4%; OR 0.81 95% CI 0.56-1.16, p = .25; I2 = 0%) between the ICE-guided and TEE-guided groups. ICE guidance reduced in in-room time (mean-weighted 28.6-min reduction in in-room time) without differences in procedural time or fluoroscopy time. There were no differences in peri-device leak (OR 0.93, 95% CI 0.68-1.27, p = 0.64); however, an increased prevalence of residual IASD was observed with ICE-guided versus TEE-guided LAAO (46.3% vs. 34.2%; OR 2.23, 95% CI 1.05-4.75, p = 0.04). CONCLUSION: ICE guidance is associated with similar procedural efficacy and safety, but could result in improved lab efficiency (as established by a significant reduction in in-room time). No differences in the rate of periprocedural leaks were found. A higher prevalence of residual interatrial septal defects was observed with ICE guidance.