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Introduction: Nowadays, no clear predictors of atrial fibrillation in patients with embolic stroke of undetermined source (ESUS) are known. Some echocardiographic parameters have been proposed as potential predictors of atrial fibrillation in patients with ESUS. The ratio between left atrial volume and tissue Doppler (TDI) a' provides the left atrial volumetric/mechanical coupling index (LACI) and represents a feasible surrogate for left atrial function, and might be useful to identify atrial fibrillation in this subset of patients., Methods and Results: All consecutive patients having undergone an implantable loop recorder (ILR) for ESUS between 2017 and 2022 were retrospectively enrolled. All patients were followed through remote monitoring and telephone visit for a minimum follow-up of 6 months.A total number of 129 patients (mean age: 72.2 ± 8.8 years; 55% of men) were analyzed. Patients developing atrial fibrillation presented higher baseline LACI (5.53 ± 2.52 vs. 3.25 ± 1.19, P < 0.001). The multivariate analysis showed that LACI was independently and significantly associated with atrial fibrillation (hazard ratio = 1.21, 95% confidence interval 1.09-1.32, P < 0.01). The best cut-off value of LACI was found to be 4.24., Discussion: Our data confirm that LACI is independently associated with atrial fibrillation in patients with ILR following ESUS, accounting for clinical or echocardiographic factors., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Implantable loop recorders (ILRs) have been shown to significantly improve the detection of atrial fibrillation (AF) in patients with embolic stroke of undetermined source (ESUS). The incidence and characterization of bradyarrhythmias in this subset of patients is still unknown., Methods: All consecutive patients who received ILRs, after an ESUS, between March 2015 and December 2022 in our Center were retrospectively enrolled and analyzed. Bradyarrhythmias were defined as: (1) sinus node dysfunction defined as sinus bradycardia, pause or arrest, exit block; (2) second-degree heart block or complete atrioventricular block. The primary endpoint was to analyze the incidence and characterization of bradyarrhythmias; the secondary endpoint was the detection of possible risk factors for bradyarrythmias. All patients were followed through the remote monitoring., Results: A total of 150 consecutive patients (mean age 70.4 ± 10.3 years old, 52.7% males) were analyzed. Bradyarrythmias were identified in 13 patients (8.7%). On multivariable analysis the presence of AF and first degree AV block were independently associated with the occurrence of bradyarrhythmias (respectively, OR 4.95, 95% CI 1.12-21.89, p = 0.0.03 and OR 3.77, 95% CI 1.08-13.14, p = 0.04)., Conclusions: The incidence of bradyarrhythmias detected by ILRs in patients with ESUS was 8.7%. Atrial fibrillation, left atrial enlargement and first degree AV block due to prolonged P wave duration were associated with the occurrence of bradyarrhythmias during the follow up., (© 2024. Fondazione Società Italiana di Neurologia.)

The Anderson-Fabry disease (AFD) is a X-linked lysosomal storage disorder due to the deficiency in the α-galactosidase A enzyme. Cardiovascular mortality is a major cause of death in patients with AFD and sudden cardiac death (SCD) is one of the main causes of death. The storage of glycosphingolipid along with ionic channel impairment, inflammation and fibrosis are involved in the arrhythmogenesis. Some risk factors have been associated with ventricular tachycardia (VT)/ventricular fibrillation (VF) and SCD. Left ventricular hypertrophy (LVH), cardiac fibrosis, non-sustained VTs seem to be the most important. Older age and male gender might be associated with higher risk of ventricular arrhythmias and SCD. Currently, the implantable cardioverter-defibrillator (ICD) is recommended in patients with AFD who have survived a cardiac arrest secondary to VT/VF or who experienced sustained VT causing syncope or hemodynamic compromise, and have a life expectancy >1 year. ICD implantation is also recommended in patients considered to be at high risk (e.g., patients with severe LVH or fibrosis). The present review sought to summarize the risk of ventricular arrythmias in AFD, the indications for ICD, focusing on pathophysiology and analyzing the role of possible predictors of arrhythmias in preventing SCD, especially as primary prevention., Competing Interests: Declaration of competing interest No conflicts of interest to be declared., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The historical restriction of magnetic resonance imaging (MRI) for patients with cardiac implantable electronic devices (CIEDs) has been lifted by certified MRI-conditional systems in recent years. Mixed-brand CIED systems consisting of a generator from one manufacturer and at least one lead from another manufacturer are not certified for MRI. We evaluated the temporal trend in the prevalence of mixed-brand systems in the era of MRI-conditional systems. Data were analyzed on 5853 CIEDs implanted de novo between 2012 and 2022 in 81 Italian centers linked to the nationwide Home Monitoring Expert Alliance network. The percentage of mixed-brand implants was calculated by device type (pacemaker, implantable cardioverter-defibrillator [ICD], cardiac resynchronization therapy [CRT] device) and over time. A mixed-brand system was implanted in 4.1% (95% CI, 3.6-4.6%) of analyzed patients or, by device type, in 4.5% (3.5-5.7%) of pacemaker patients, 1.1% (0.7-1.7%) of ICD patients, and 6.8% (5.7-7.9%) of CRT pacemaker/defibrillator patients (p < 0.001). Prevalence of mixed-brand implants exhibited significant temporal fluctuations, first declining from 6.6% (2012-2014) to 1.3% (2019), and then increasing to 5.1% (2022). Temporal changes were statistically significant for pacemakers (p < 0.001) and CRT devices (p = 0.001), but not for ICDs (p = 0.438). In the decade between 2012 and 2022, mixed-brand CIED systems were more prevalent in patients treated with pacemakers and CRT devices than in ICD recipients. A decline in the prevalence of mixed-brand systems was observed after the introduction of MRI-conditional systems, reaching a minimum in 2019, followed by a progressive increase in the subsequent years., (© 2024. The Author(s).)

Introduction: The ratio between tricuspid annular plane systolic excursion (TAPSE) and estimated pulmonary artery systolic pressure (PASP) has been shown to be a reliable, non-invasive surrogate of the right ventricular-pulmonary artery (RV-PA) coupling. The present study analysed the association between TAPSE/PASP and response to cardiac resynchronization therapy (CRT) and the prognostic role of RV-PA in patients undergoing CRT implantation. The primary endpoints were: the association between baseline TAPSE/PASP and CRT response/cardiovascular and all-cause death., Methods and Results: All patients having undergone CRT implantation in our Center from 2016 to 2020 were included in our retrospective analysis. The RV-PA coupling was assessed by echocardiography at baseline and 1 year follow up in CRT recipients. The cut-off value of TAPSE/PASP resulted from ROC curve analysis (i.e.<0.33 mm/mmHg). A total of 229 patients (age 69.9 ± 10.1 years; 77.7% men) were included. During a mean follow-up of 44.2 ± 17.9 months, 40 (17.5%) patients died. The baseline value of TAPSE/PASP was not significantly associated with CRT response. Patients with a more impaired TAPSE/PASP ratio had significantly worse survival rates. On multivariate Cox regression, only TAPSE/PASP ratio and estimated glomerular filtration rate were independently associated with all-cause death. Finally, the TAPSE/PASP ratio significantly increased after CRT implantation in the group of "responders" whereas it did not change in 'non-responders'., Conclusions: The baseline value of TAPSE/PASP ratio was not associated with CRT response. However, the TAPSE/PASP ratio was a strong predictor of both all-cause and cardiovascular death in CRT recipients., Competing Interests: Declarations Competing interests The authors report no relationships that could be construed as a conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Spiral ganglion neurons (SGNs) are primary sensory afferent neurons that relay acoustic information from the cochlear inner hair cells (IHCs) to the brainstem. The response properties of different SGNs diverge to represent a wide range of sound intensities in an action-potential code. This biophysical heterogeneity is established during pre-hearing stages of development, a time when IHCs fire spontaneous Ca 2+ action potentials that drive glutamate release from their ribbon synapses onto the SGN terminals. The role of spontaneous IHC activity in the refinement of SGN characteristics is still largely unknown. Using pre-hearing otoferlin knockout mice (Otof -/- ), in which Ca 2+ -dependent exocytosis in IHCs is abolished, we found that developing SGNs fail to upregulate low-voltage-activated K + -channels and hyperpolarisation-activated cyclic-nucleotide-gated channels. This delayed maturation resulted in hyperexcitable SGNs with immature firing characteristics. We have also shown that SGNs that synapse with the pillar side of the IHCs selectively express a resurgent K + current, highlighting a novel biophysical marker for these neurons. RNA-sequencing showed that several K + channels are downregulated in Otof -/- mice, further supporting the electrophysiological recordings. Our data demonstrate that spontaneous Ca 2+ -dependent activity in pre-hearing IHCs regulates some of the key biophysical and molecular features of the developing SGNs. KEY POINTS: Ca 2+ -dependent exocytosis in inner hair cells (IHCs) is otoferlin-dependent as early as postnatal day 1. A lack of otoferlin in IHCs affects potassium channel expression in SGNs. The absence of otoferlin is associated with SGN hyperexcitability. We propose that type I spiral ganglion neuron functional maturation depends on IHC exocytosis., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Atrial high-rate episodes (AHREs) are frequent in patients with cardiac implantable electronic devices. A decrease in device-detected P-wave amplitude may be an indicator of periods of increased risk of AHRE., Objective: The objective of this study was to assess the association between P-wave amplitude and AHRE incidence., Methods: Remote monitoring data from 2579 patients with no history of atrial fibrillation (23% pacemakers and 77% implantable cardioverter-defibrillators, of which 40% provided cardiac resynchronization therapy) were used to calculate the mean P-wave amplitude during 1 month after implantation. The association with AHRE incidence according to 4 strata of daily burden duration (≥15 minutes, ≥6 hours, ≥24 hours, ≥7 days) was investigated by adjusting the hazard ratio with the CHA 2 DS 2 -VASc score., Results: The adjusted hazard ratio for 1-mV lower mean P-wave amplitude during the first month increased from 1.10 (95% confidence interval [CI], 1.05-1.15; P < .001) to 1.18 (CI, 1.09-1.28; P < .001) with AHRE duration strata from ≥15 minutes to ≥7 days independent of the CHA 2 DS 2 -VASc score. Of 871 patients with AHREs, those with 1-month P-wave amplitude <2.45 mV had an adjusted hazard ratio of 1.51 (CI, 1.19-1.91; P = .001) for progression of AHREs from ≥15 minutes to ≥7 days compared with those with 1-month P-wave amplitude ≥2.45 mV. Device-detected P-wave amplitudes decreased linearly during the 1 year before the first AHRE by 7.3% (CI, 5.1%-9.5%; P < .001 vs patients without AHRE)., Conclusion: Device-detected P-wave amplitudes <2.45 mV were associated with an increased risk of AHRE onset and progression to persistent forms of AHRE independent of the patient's risk profile., Competing Interests: Disclosures Mauro Biffi has held educational activity and participated in speaker’s bureau on behalf of Boston Scientific, Biotronik, and Medtronic. Matteo Ziacchi has held educational activity and participated in speaker’s bureau on behalf of Medtronic. Daniele Giacopelli and Alessio Gargaro are employees of Biotronik Italia S.p.a. The remaining authors have no major conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Catheter ablation has become an established treatment option for premature ventricular complexes (PVCs). The use of fluoroscopy exposes patients and medical staff to potentially harmful stochastic and deterministic effects of ionizing radiations. We sought to analyze procedural outcomes in terms of safety and efficacy using a "zero fluoroscopy" approach for catheter ablation of PVCs., Methods: The present retrospective, multicenter, observational study included 131 patients having undergone catheter ablation of PVCs using "zero fluoroscopy" between 2019 and 2020 in four centers compared with another group who underwent the procedure with fluoroscopy., Results: Median age was 51.0 ± 15.9 years old; males were 77 (58.8%). Among the study population, 26 (19.8%) had a cardiomyopathy. The most frequent PVC origin was right ventricular outflow tract (55%) followed by the left ventricle (16%), LVOT and cusps (13.7%), and aortomitral continuity (5.3%). Acute suppression of PVC was achieved in 127 patients (96.9%). At 12 months, a complete success was documented in 109 patients (83.2%), a reduction in PVC burden in 18 patients (13.7%), and a failure was recorded in four patients (3.1%). Only two minor complications occurred (femoral hematoma and arteriovenous fistula conservatively treated)., Conclusions: The PVC ablation with a "zero" fluoroscopy approach appears to be a safe procedure with no major complications and good rates of success and recurrence in our multicenter experience., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming synapses with inner hair cells (IHCs) in the mammalian cochlea. The molecular mechanisms regulating the formation of the post-synaptic density (PSD) in the SGN afferent terminals are still unclear. Here, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1) is required for the clustering of AMPA receptors GluR2-4 (glutamate receptors 2-4) at the PSD. Adult Bai1-deficient mice have functional IHCs but fail to transmit information to the SGNs, leading to highly raised hearing thresholds. Despite the almost complete absence of AMPA receptor subunits, the SGN fibers innervating the IHCs do not degenerate. Furthermore, we show that AMPA receptors are still expressed in the cochlea of Bai1-deficient mice, highlighting a role for BAI1 in trafficking or anchoring GluR2-4 to the PSDs. These findings identify molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Limited data are available regarding venous thromboembolism (VTE), specifically deep vein thrombosis (DVT) and pulmonary embolism (PE), following right-sided ablations and electrophysiological (EP) studies. Compared to left-sided procedures, no guidelines on antithrombotic management strategies for the prevention of DVT and PE are available. The main purpose of the present European Heart Rhythm Association (EHRA) survey is to report the current management of right-sided EP procedures, focusing on anticoagulation and prevention of VTE. An online survey was conducted using the EHRA infrastructure. A total of 244 participants answered a 19-items questionnaire on the periprocedural management of EP studies and right-sided catheter ablations. The right femoral vein is the most common access for EP studies and right-sided procedures. An ultrasound-guided approach is employed by more than 2/3 of respondents. Intravenous heparin is not commonly given by the majority of participants. About 1/3 of participants (34%) routinely prescribe VTE prophylaxis during (mostly aspirin and low molecular weight heparin) and 1/4 of respondents (25%) commonly prescribe VTE prophylaxis after discharge (mostly aspirin). Of note, respectively 13% and 9% of participants observed at least one DVT and one PE related to right-sided ablation or EP study within the last year in their center. The present survey shows that only a minority of operators routinely gives intraprocedural intravenous heparin and prescribes VTE prophylaxis after right-sided EP procedures. Compared to left-sided procedures like atrial fibrillation (AF) ablation, there are no consistent systematic antithrombotic management strategies., Competing Interests: Conflict of interest: M.F. received speaker and consultation fees from Pfizer and Boehringer Ingelheim Poland. L.R. has received speaker and consulting fees from Abbott and Medtronic and a research grant to the institution from Medtronic. C.d.A. received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Livanova, Boston Scientific, Atricure, Acutus Medical, and Daiichi Sankyo. G.C. has received honoraria fees from Biosense Webster and Boston Scientific and research grants from Boston Scientific. S.B. is a consultant for Medtronic, Boston Scientific, Microport, and Zoll. J.K.R.C. received speaker, consultation, teaching, and proctoring honoraria from Medtronic, Boston Scientific, and Biosense Webster., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Infections resulting from cardiac implantable electronic device (CIED) implantation are severely impacting on patients' and on health care systems. The use of TYRXTM absorbable antibiotic-eluting envelope has proven to decrease major CIED infections within 12 months of CIED surgery. The aim is to evaluate the impact of the envelope use on infection-related clinical events in a real-world contemporary patient population., Methods and Results: Data on patients undergoing CIED surgery were collected prospectively by participating centers of the One Hospital ClinicalService project. Patients were divided into two groups according to whether TYRXTM absorbable antibiotic-eluting envelope was used or not. Out of 1819 patients, 872 (47.9%) were implanted with an absorbable antibiotic-eluting envelope and included in the Envelope group and 947 (52.1%) patients who did not receive an envelope were included in the Control group. Compared to control, patients in the Envelope group had higher thrombo-embolic or hemorrhagic risk, higher BMI, lower LVEF and more comorbidities. During a mean follow-up of 1.4 years, the incidence of infection-related events was significantly higher in the control compared to the Envelope group (2.4% vs. 0.8%, P = 0.007). The five-year cumulative incidence of infection-related events was 8.1% in the control and 2.1% in the Envelope group (HR: 0.34, 95%CI: 0.14-0.80, P = 0.010)., Conclusion: In our analysis, the use of an absorbable antibiotic-eluting envelope in the general CIED population was associated with a lower risk of systemic and pocket infection., Competing Interests: Conflict of interest: MZ received speaker’s fees from Abbott, Biotronik and Boston Scientific; GB reported small speaker fees from Bayer, Boehringer Ingelheim, Boston, Daiichi Sankyo, Janssen, and Sanofi outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The association between QRS narrowing and response to cardiac resynchronization therapy (CRT) has been investigated by several studies, but their findings remain inconclusive. Aim of our study was to explore the relationship between QRS Index and echocardiographic response to CRT., Methods: This multicenter, retrospective analysis included 326 consecutive patients (mean age was 70.0±10.1 years old; males 76.7%) who underwent CRT-D implantation in primary and secondary prevention between 2018 and 2020. The estimation of QRS shortening after CRT-D implantation was precisely assessed through the QRS Index, calculated as follows: [(QRS duration before implantation - paced QRS duration)/QRS duration before implantation]*100., Results: After a mean follow-up of 12.7±4.5 months, 55.2% (180/326) of the patients showed an echocardiographic response to CRT. The median [25-75 th ] QRS Index was 3.85% [-14.1% - +13.9%]. The best predictive cut-off value of QRS Index was 1.40% (sensitivity 70.4%, specificity 64.5%, AUC 0.70). In patients with left bundle branch block, the median [25-75 th ] QRS Index was 9.85% [+3.87% - +16.7%]. In this subgroup, the AUC was 0.737 and the best predictive cut-off of QRS Index was 2.20% (sensitivity 78.3%, specificity 67%). The multivariable model showed that only left ventricular ejection fraction and QRS Index were independently associated with CRT response (respectively OR 0.92, CI 95% 0.86-0.98, P=0.01 and OR 1.057, CI 95% 1.026-1.089, P<0.001)., Conclusions: The QRS Index tightly correlated with CRT response. Only LVEF and QRS Index were independently associated with echocardiographic response to CRT.

Background: In terms of safety and efficacy, cryoballoon ablation (CB-A) has become a valid option for achieving pulmonary vein isolation (PVI) in patients affected by symptomatic atrial fibrillation. However, CB-A data in octogenarians are still scarce and limited to single-centre experiences. The present multicentre study aimed to compare the outcomes and complications of index CB-A in patients older than 80 years with a cohort of younger patients., Methods and Results: We retrospectively enrolled 97 consecutive patients aged ≥80 years who underwent PVI using the second-generation CB-A. This group was compared with a younger cohort of patients using a 1:1 propensity score matching. After the matching, 70 patients from the elderly group were analysed and compared with 70 younger patients (control group). The mean age was 81.4 ± 1.9 years among octogenarians and 65.2 ± 10.2 years in the younger cohort. The global success rate after a median follow-up of 23 [18-32.5] months was 60.0% in the elderly group and 71.4% in the control group (P = 0.17). Phrenic nerve palsy was the most common complication occurring in a total of 11 patients (7.9%): in 6 (8.6%) patients in the elderly group and in 5 patients (7.1%) in the younger group (P = 0.51). Only two (1.4%) major complications occurred: one (1.4%) femoral artery pseudoaneurysm in the control group, which resolved with a tight groin bandage, and one (1.4%) case of urosepsis in the elderly group. Arrhythmia recurrence during the blanking period and the need for electrical cardioversion to restore sinus rhythm after PVI were found to be the only independent predictors of late arrhythmia relapses., Conclusions: The present study showed that CB-A PVI is as feasible, safe and effective among appropriately selected octogenarians as it is in younger patients., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: After an embolic stroke of undetermined source (ESUS), long-term monitoring is recommended to start an anticoagulation therapy in patients with documented atrial fibrillation (AF). Literature is sparse about the AF burden following an ESUS, although this might have significant implications in terms of clinical management and therapeutic strategy. Our primary aim was to evaluate a possible association between early detection of AF (within 90 days from the ILR implantation) and higher AF burden., Methods: This is a retrospective single-center study of 129 consecutive patients who received implantable loop recorders (ILRs) after an ESUS for detection of subclinical AF and their AF burden., Results: Mean age was 70.3 ± 10.4 years old (males: 51.9%). Atrial fibrillation was found in 40.3% of patients. Patients with AF were older, presented a higher CHAD 2 S 2 -Vasc Score and greater left atrial volume compared with patients without AF. The median AF burden was 1.2%; 59% of patients had the first AF episode within 90 days from the ILR implant while 41% experienced the first episode later than 90 days. The AF burden was significantly higher in the former group. Of note, the univariate analysis showed that only early AF detection was significantly associated with AF burden >1% (OR 20.0; 95% CI 1.68-238.6, p = 0.01)., Conclusions: The early AF detection was found to be significantly associated with a higher burden of AF., Competing Interests: The authors report no relationships that could be construed as a conflict of interest., (© 2023 The Authors.)

The present case describes a dilated cardiomyopathy associated with both antidromic and orthodromic atrio-ventricular reentrant tachycardias supported by multiple right accessory pathways. Both right accessory pathways were successfully eliminated by catheter ablation and the patient progressively recovered during the follow up. The following etiologies might be involved: 1) primitive dilated cardiomyopathy (or post-inflammatory); 2) septal dyssinchrony due to ventricular pre-excitation; 3) tachycardiomyopathy., Competing Interests: Declaration of Competing Interest No conflicts of interest to be declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Thromboembolic events (TEE) associated with atrial fibrillation (AF) are highly recurrent and usually severe, causing permanent disability or, even, death. Previous data consistently showed significantly lower TEE in anticoagulated patients. While warfarin, a vitamin K antagonist, is still used worldwide, direct-acting oral anticoagulants (DOACs) have shown noninferiority to warfarin in the prevention of TEE, and represent, to date, the preferred treatment. DOACs present favorable pharmacokinetic, safety and efficacy profiles, especially among vulnerable patients including the elderly, those with renal dysfunction or previous TEE. Yet, regarding specific settings of AF patients it is unclear whether oral anticoagulation therapy is beneficial, or otherwise it is the maintenance of sinus rhythm, mostly achieved through a catheter ablation-based rhythm control strategy, that prevents the causal complications linked to AF. While it is known that low-risk patients [CHA2DS2-VASc 0 (males), or score of 1 (females)] present low ischemic stroke or mortality rates (<1%/year), it remains unclear whether they need any prophylaxis. Furthermore, the appropriate anticoagulation regimen for those individuals requiring cardioversion, either pharmacologic or electric, as well as peri-procedural anticoagulation in patients undergoing trans-catheter ablation that nowadays encompasses different energies, are still a matter of debate. In addition, AF concomitant with other clinical conditions is discussed and, lastly, the choice of prescribing anticoagulation to asymptomatic patients diagnosed with subclinical AF at either wearable or implanted devices. The aim of this review will be to provide an update on current strategies in the above-mentioned settings, and to suggest possible therapeutic options, finally focusing on AF-related cognitive decline., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Aims: Recent studies suggest an association between epicardial adipose tissue (EAT) and atrial fibrillation. The aim of the study is to evaluate the quantitative and qualitative characteristics of EAT in relation to atrial fibrillation burden after coronary artery bypass graft (CABG)., Methods: This prospective single-centre study included patients undergoing CABG. The patients underwent transthoracic echocardiography and collection of a bioptic sample containing right appendage and EAT during CABG for histological characterization. After surgery, clinical and telemetry data were collected., Results: Fifty-six consecutive patients were enrolled. The mean postsurgical hospitalization was 7.9 ± 3.7 days. Twenty-two patients had at least one episode of atrial fibrillation. In the atrial fibrillation group, there was a bigger atrial volume, a higher degree of diastolic disfunction, a thicker layer of EAT and an older median age in comparison with the group that did not develop it. EAT with a cut-off of 4 mm was a predictor of atrial fibrillation with an odds ratio (OR) of 1.49 (confidence interval (CI) 1.09-2.04), 73% of sensibility and 89% of specificity. From the histological analyses, the patients with atrial fibrillation had a significantly higher percentage of fibrosis. At univariate analysis, atrial volume [OR 1.05, CI 1.01-1.09, P = 0.022], E/A rate (OR 0.04, CI 0.02-0.72 P = 0.29), the percentage of fibrosis (OR 1.12, CI 1.00-1.25, P = 0.045) and age (OR 1.17, CI 1.07-1.28, P = 0.001) were predictors of atrial fibrillation. At multivariate analysis, atrial volume (P = 0.027), fibrosis (P = 0.003) and age (P = 0.039) were independent predictors of atrial fibrillation., Conclusion: Postcardiac surgical atrial fibrillation is frequent. EAT thickness, atrial volume, fibrosis and age are predictors of postcardiac surgical atrial fibrillation., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Species living in high mountain areas are currently threatened by climate change and human land use changes. High-elevation birds frequently inhabit island-like suitable patches around mountain peaks, and in such conditions the capability to exchange individuals among patches is crucial to maintain gene flow. However, we lack information regarding the dispersal ability of most of these species and the possible influence of landscape features on dispersal. In this study, we used population genomics and landscape resistance modelling to investigate dispersal in a high-elevation specialist migratory bird, the water pipit Anthus spinoletta. We aimed to assess the levels of gene flow in this species within a wide area of the European Alps, and to assess the effects of environmental characteristics on gene flow, by testing the isolation by distance (IBD) hypothesis against the isolation by resistance (IBR) hypothesis. We found clear support for IBR, indicating that water pipits preferentially disperse across suitable breeding habitat (i.e., high-elevation grassland). IBR was stronger in the part of the study area with less extended suitable habitat. Landscape resistance was slightly better described by habitat suitability models than landscape connectivity models. Despite the observed IBR, gene flow within the study area was high, probably also because of the still wide and relatively continuous breeding range. The forecasted reduction of range of this species may lead to stronger effects of IBR on gene flow. Other high-elevation specialist birds may show similar IBR patterns, but with possibly stronger effects on gene flow because of their more reduced and patchy habitats., (© 2023 John Wiley & Sons Ltd.)

Competing Interests: The authors declare no conflicts of interest.

Sensory-independent Ca 2+ spiking regulates the development of mammalian sensory systems. In the immature cochlea, inner hair cells (IHCs) fire spontaneous Ca 2+ action potentials (APs) that are generated either intrinsically or by intercellular Ca 2+ waves in the nonsensory cells. The extent to which either or both of these Ca 2+ signalling mechansims are required for IHC maturation is unknown. We find that intrinsic Ca 2+ APs in IHCs, but not those elicited by Ca 2+ waves, regulate the maturation and maintenance of the stereociliary hair bundles. Using a mouse model in which the potassium channel Kir2.1 is reversibly overexpressed in IHCs (Kir2.1-OE), we find that IHC membrane hyperpolarization prevents IHCs from generating intrinsic Ca 2+ APs but not APs induced by Ca 2+ waves. Absence of intrinsic Ca 2+ APs leads to the loss of mechanoelectrical transduction in IHCs prior to hearing onset due to progressive loss or fusion of stereocilia. RNA-sequencing data show that pathways involved in morphogenesis, actin filament-based processes, and Rho-GTPase signaling are upregulated in Kir2.1-OE mice. By manipulating in vivo expression of Kir2.1 channels, we identify a "critical time period" during which intrinsic Ca 2+ APs in IHCs regulate hair-bundle function., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Aims: The safety and efficacy of leadless intracardiac-permanent pacemaker (L-PM) have been demonstrated in multiple clinical trials, but data on comparisons with conventional transvenous-permanent pacemaker (T-PM) collected in a consecutive, prospective fashion are limited. The aim of this analysis was to compare the rate and the nature of device-related complications between patients undergoing L-PM vs. T-PM implantation., Methods and Results: Prospective, multicentre, observational project enrolling consecutive patients who underwent L-PM or T-PM implantation. The rate and nature of device-related complications were analysed and compared between the two groups. Individual 1:1 propensity matching of baseline characteristics was performed. A total of 2669 (n = 665 L-PM) patients were included and followed for a median of 39 months, L-PM patients were on average older and had more co-morbidities. The risk of device-related complications at 12 months was significantly lower in the L-PM group (0.5% vs. 1.9%, P = 0.009). Propensity matching yielded 442 matched pairs. In the matched cohort, L-PM patients trended toward having a lower risk of overall device-related complications (P = 0.129), had a similar risk of early complications (≤30 days) (P = 1.000), and had a significantly lower risk of late complications (>30 days) (P = 0.031). All complications observed in L-PM group were early. Most (75.0%) of complications observed in T-PM group were lead- or pocket-related., Conclusion: In this analysis, the risk of device-related complications associated with L-PM implantation tended to be lower than that of T-PM. Specifically, the risk of early complications was similar in two types of PMs, while the risk of late complications was significantly lower for L-PM than T-PM., Competing Interests: Conflict of interest: P.P. reports no conflicts with regard to the content of the present work, outside this work small speaker fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novartis; M.Z. reports no conflicts with regard to the content of the present work, outside this work small speaker fees from Abbott, Boston Scientific, and Biotronik. No other conflicts of interest were reported., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: To explore the impact of the use of intracardiac echocardiography (ICE) in the ablation of supraventricular arrhythmias requiring transseptal catheterization (TSC), whilst analyzing the reduction in periprocedural complications and complications specifically related to TSC., Methods: A retrospective multicenter study collecting data from consecutive atrial fibrillation (AF) and supraventricular ablation procedures that required TSC was performed in five Italian centers. Based on physician discretion, TSC was performed with or without ICE. Periprocedural complications, separating all complications from complications directly related to TSC, were collected. Independent predictors of periprocedural complications and TSC-related complications were investigated., Results: A total of 2181 TSCs were performed on 1862 patients at five Italian centers from 2006 to 2021, in 76% of cases by AF ablation and in 24% by ablation of other arrhythmias with a circuit in the left atrium. Overall, 1134 (52%) procedures were performed with ICE support and 1047 (48%) without ICE. A total of 67 (3.1%) complications were detected, 19 (1.7%) in the ICE group and 48 (4.6%) in the no ICE group, p < 0.001. A total of 42 (1.5%) complications directly related to TSC: 0.9% in the ICE group and 3.1% in the no ICE group ( p < 0.001). The independent predictors of all complications were age (OR 1,02 95% C.I 1.00-1.05; p = 0.036), TSC with the use of ICE (OR 0.27 95% C.I 0.15-0.46; p < 0.001) and AF ablation (OR 2,25 95%C.I 1.05-4.83; p = 0.037). The independent predictors for TSC complications were age (OR 1.03 95% C.I 1.01-1.06; p = 0.013) and TSC with the use of ICE (OR 0.24 95% C.I 0.11-0.49; p < 0.001)., Conclusions: ICE reduced periprocedural and TSC-related complications during electrophysiological procedures for ablation of left atrial arrhythmias.

Background: The second-generation cryoballoon (CB) has proven to be a highly effective ablative strategy in patients with symptomatic atrial fibrillation (AF). This study sought to investigate the anatomical characteristics of pulmonary veins (PVs) and the relationship between their size, ovality, and late reconnections in a large cohort of patients undergoing repeat ablation for recurrence of atrial arrhythmias., Methods and Results: A total of 152 consecutive patients (98 males, 64.5%; mean age 64.9 ± 9.6 years) underwent a repeat ablation for recurrent atrial tachyarrhythmias after a median time of 6.5 months [IQR 11] from the index CB ablation. All repeat ablations were performed using a 3-dimensional electro-anatomical mapping system. Among all 593 PVs, 134 (22.6%) showed a late PV reconnection in 95 patients (0.88 per patient), at the time of repeat ablation procedure. There was a significant difference in ovality between left- and right-sided PVs (p < 0.001). Greater diameters of left superior PV, left inferior PV, and right inferior PV ostia (both maximum and minimum) and higher index ovality were significantly associated with late PV reconnection., Conclusions: The rate of late PV reconnection after CB ablation was low (0.88 PVs/patient). Left-sided PVs were more oval than septal PVs. Larger PV dimensions and higher ovality index were significantly associated with reconnections in all PVs except for RSPV., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The basis of the less severe clinical presentation of coronavirus disease 2019 (COVID-19) in children as compared with adults remains incompletely understood. Studies have suggested that a more potent boosting of immunity to endemic common cold coronaviruses (HCoVs) may protect children., Methods: To test this hypothesis, we conducted a detailed analysis of antibodies induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children aged 2 months to 14 years., Results: Younger children had higher titers of antibodies to SARS-CoV-2 receptor binding domain (RBD), S1 but not S2 domain, and total spike (S) protein, higher avidity RBD immunoglobulin G, and higher titers of neutralizing and complement-activating antibodies as compared with older children. In contrast, older children had higher titers of antibodies to HCoVs, which correlated with antibodies to the SARS-CoV-2 S2 domain but not with neutralizing or complement-activating antibodies., Conclusions: These results reveal a unique capacity of young children to develop effector antibody responses to SARS-CoV-2 infection independently of their immunity to HCoVs., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: A better selection of patients with left bundle branch block (LBBB) might increase the response to cardiac resynchronization therapy (CRT). The aim of the study was to investigate the association between the Strauss criteria, absence of S wave in V 5 -V 6, the Selvester score and response to CRT., Methods and Results: The retrospective analysis included all consecutive patients having undergone implantation of biventricular defibrillators in primary prevention between 2018 and 2020. The final analysis included 236 patients (mean age 69.7 ± 9.9; 77.5% of males). The Strauss criteria were significantly associated with CRT response (p < 0.01) with a sensitivity of 71.3% and specificity of 64.1%. The Strauss criteria along with the absence of S wave in V 5 and V 6 showed a sensitivity of 56.7%, a specificity of 82.6% and a positive predictive value of 90.5%. The Selvester score was significantly and inversely associated with CRT response (OR 0.818, 95% CI 0.75-0.89; p < 0.001). The multivariable model showed that left ventricular ejection fraction (LVEF) and QRS duration (≥140 ms in males and ≥ 130 ms in females) were independently associated with CRT response (respectively OR 0.92, CI 95% 0.86-0.98, p = 0.01 and OR 3.70, CI 95% 1.12-12.21, p = 0.03)., Conclusions: Strauss criteria, especially in association with absence of S wave in V 5 and V 6 , were able to increase specificity and positive predictive value for predicting CRT response. The Selvester score was inversely associated with CRT response. Finally, LVEF and QRS duration were independently associated with echocardiographic response to CRT., Competing Interests: Declaration of Competing Interest No conflicts of interest to be declared., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Safety and efficacy of leadless pacemakers (L-PM) have been demonstrated in multiple clinical trials, but real-world data on patient selection, implantation technique, and peri-procedural patient management in a clinical practice setting are lacking., Methods: Consecutive patients undergoing L-PM implantation in 14 Italian centers were followed in a prospective, multicentre, observational project. Data on baseline patient characteristics, clinical indications, implantation procedure, and peri-procedural patient management were collected. The rate and nature of device-related complications were also recorded., Results: A total of 782 L-PM patients (68.4% male, 75.6 ± 12.4 years) were included in the analysis. The main patients-related reason leading to the choice of implanting a L-PM rather than a conventional PM was the high-risk of device infection (29.5% of cases). The implantation success rate was 99.2%. The median duration of the procedure was 46 min. In 90% of patients the device was implanted in the septum. Of patients on oral anticoagulant therapy (OAT) (n = 498) the implantation procedure was performed without interrupting (17.5%) or transiently interrupting OAT without heparin bridging (60.6%). During a median follow-up of 20 months major device-related complications occurred in 7 patients (0.9%): vascular access-site complications in 3 patients, device malfunction in 2 patients, pericardial effusion/cardiac tamponade in one patient, device migration in one patient., Conclusions: In the real world setting of Italian clinical practice L-PM is often reserved for patients at high-risk of infection. The implantation success rate was very high and the risk of major complications was low. Peri-procedural management of OAT was consistent with available scientific evidence., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Real-world safety data on the use of transcatheter pacing systems particularly in very elderly patients is still limited. The aim of this analysis was to investigate the effect of age on the safety and efficacy of leadless pacemaker implant., Methods: From May 2016 through July 2019, 577 patients were implanted with a leadless single-chamber pacemaker according to current pacing indication in 15 Italian cardiologic centers. The population was divided into age quartiles for evaluation, including (1) < 70 years, (2) 70-77 years, (3) 78-83 years, and (4) ≥ 83 years. Procedural data, complications, and electrical parameters were collected at baseline and during the follow-up., Results: Procedural-related complication occurrence was very low (< 1.0%) and similar in the four subgroups according to age even if the older patients were more frail. No cardiac tamponade was reported. Among the groups, no difference was observed in procedural time, fluoroscopy time duration, and electrical parameters (mean pacing impedance: 750 ± 192 and 599 ± 156, mean pacing threshold: 0.7 ± 0.5 and 0.7 ± 0.6, and mean right ventricular sensing 10.7 ± 6.1 and 11.5 ± 4.8 at implant and last follow-up, respectively)., Conclusions: The reported data demonstrated a high degree of safety during leadless implant across all patient ages. Procedural complications and device electrical measurements were similar among the different ages., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Idiopathic pulmonary fibrosis (IPF) is a particularly deadly form of pulmonary fibrosis of unknown cause. In patients with IPF, high serum and lung concentrations of CHI3L1 (chitinase 3 like 1) can be detected and are associated with poor survival. However, the roles of CHI3L1 in these diseases have not been fully elucidated. We hypothesize that CHI3L1 interacts with CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) to stimulate profibrotic macrophage differentiation and the development of pulmonary fibrosis and that circulating blood monocytes from patients with IPF are hyperresponsive to CHI3L1-CRTH2 signaling. We used murine pulmonary fibrosis models to investigate the role of CRTH2 in profibrotic macrophage differentiation and fibrosis development and primary human peripheral blood mononuclear cell culture to detect the difference of monocytes in the responses to CHI3L1 stimulation and CRTH2 inhibition between patients with IPF and normal control subjects. Our results showed that null mutation or small-molecule inhibition of CRTH2 prevents the development of pulmonary fibrosis in murine models. Furthermore, CHI3L1 stimulation induces a greater increase in CD206 expression in IPF monocytes than control monocytes. These results demonstrated that monocytes from patients with IPF appear to be hyperresponsive to CHI3L1 stimulation. These studies support targeting the CHI3L1-CRTH2 pathway as a promising therapeutic approach for IPF and that the sensitivity of blood monocytes to CHI3L1-induced profibrotic differentiation may serve as a biomarker that predicts responsiveness to CHI3L1- or CRTH2-based interventions.

Background: Optimal timing for catheter ablation of ventricular tachycardia is an important unresolved issue. There are no randomized trials evaluating the benefit of ablation after the first implantable cardioverter defibrillator (ICD) shock., Methods: We conducted a 2-phase, prospective, multicenter, randomized clinical trial. Patients with ischemic or nonischemic dilated cardiomyopathy and primary or secondary prevention indication for ICD were enrolled in an initial observational phase until first appropriate shock (phase A). After reconsenting, patients were randomly assigned 1:1 in phase B to immediate ablation (within 2 months from shock delivery) or continuation of standard therapy. The primary end point was a composite of death from any cause or hospitalization for worsening heart failure. Amiodarone intake was not allowed except for documented atrial tachyarrhythmias. On July 23, 2021, phase B of the trial was interrupted as a result of the first interim analysis on the basis of the Bayesian adaptive design., Results: Of the 517 patients enrolled in phase A, 154 (30%) had ventricular tachycardia, 56 (11%) received an appropriate shock over a median follow-up of 2.4 years (interquartile range, 1.4-4.4), and 47 of 56 (84%) agreed to participate in phase B. After 24.2 (8.5-24.4) months, the primary end point occurred in 1 of 23 (4%) patients in the ablation group and 10 of 24 (42%) patients in the control group (hazard ratio, 0.11 [95% CI, 0.01-0.85]; P =0.034). The results met the prespecified termination criterion of >99% Bayesian posterior probability of superiority of treatment over standard therapy. No deaths were observed in the ablation group versus 8 deaths (33%) in the control group ( P =0.004); there was 1 worsening heart failure hospitalization in the ablation group (4%) versus 4 in the control group (17%; P =0.159). ICD shocks were less frequent in the ablation group (9%) than in the control group (42%; P =0.039)., Conclusions: Ventricular tachycardia ablation after first appropriate shock was associated with a reduced risk of the combined death or worsening heart failure hospitalization end point, lower mortality, and fewer ICD shocks. These findings provide support for considering ventricular tachycardia ablation after the first ICD shock., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01547208.

Importance: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) may experience life-threatening arrhythmic events (LTAEs) despite β-blocker treatment. Further complicating management, the role of implantable cardioverter defibrillator (ICD) in CPVT is debated., Objective: To investigate the long-term outcomes of patients with RYR2 CPVT treated with β-blockers only and the cost to benefit ratio of ICD., Design, Settings, and Participants: This prospective cohort study conducted from January 1988 to October 2020 with a mean (SD) follow-up of 9.4 (7.5) years included patients who were referred to the Molecular Cardiology Clinics of ICS Maugeri Hospital, Pavia, Italy. Participants included consecutive patients with CPVT who were carriers of a pathogenic or likely pathogenic RYR2 variant with long-term clinical follow-up., Exposures: Treatment with selective and nonselective β-blocker only and ICD implant when indicated., Main Outcome and Measures: The main outcome was the occurrence of the first LTAE while taking a β-blocker. LTAE was defined as a composite of 3 hard end points: sudden cardiac death, aborted cardiac arrest, and hemodynamically nontolerated ventricular tachycardia., Results: The cohort included 216 patients with RYR2 CPVT (121 of 216 female [55%], median [IQR] age 14, [9-30] years). During a mean (SD) follow-up of 9.4 (7.5) years taking β-blockers only, 28 of 216 patients (13%) experienced an LTAE (annual rate, 1.9%; 95% CI, 1.3-2.7). In multivariable analysis, experiencing either an LTAE (hazard ratio [HR], 3.3; 95% CI, 1.2-8.9; P = .02) or syncope before diagnosis (HR, 4.5; 95% CI, 1.8-11.1; P = .001) and carrying a C-terminal domain variant (HR, 18.1; 95% CI, 4.1-80.8; P < .001) were associated with an increased LTAE risk during β-blocker therapy only. The risk of LTAE among those taking selective β-blockers vs nadolol was increased 6-fold (HR, 5.8; 95% CI, 2.1-16.3; P = .001). Conversely, no significant difference was present between propranolol and nadolol (HR, 1.8; 95% CI, 0.4-7.3; P = .44). An ICD was implanted in 79 of 216 patients (37%) who were followed up for a mean (SD) of 8.6 (6.3) years. At the occurrence of LTAE, ICD carriers were more likely to survive (18 of 18 [100%]) than non-ICD carriers (6 of 10 [60%]; P = .01)., Conclusions and Relevance: In this cohort study, selective β-blockers were associated with a higher risk of LTAE as compared with nadolol. Independently from treatment, LTAE and syncope before diagnosis and C-terminal domain variants identified patients at higher risk of β-blocker failure, and the ICD was associated with reduced mortality in high-risk patients with CPVT.

Introduction: The second-generation cryoballoon (CB) has emerged in the last decade as an effective treatment for atrial fibrillation (AF). This study sought to analyze the rate of PV reconnection following CB ablation, evaluate the most frequent PV sites of conduction recovery and finally to assess procedural and biophysical indicators of reconnection in a large cohort of patients undergoing repeat ablation for recurrence of atrial arrhythmias., Methods and Results: A total of 300 consecutive patients (189 males, 63%; mean age 63.0 ± 11.1 years) underwent a repeat ablation after 18.2 ± 10.8 months from the index CB ablation. All repeat ablations were performed using a 3-dimensional electro-anatomical mapping system. Among all 1178 PVs, 209 (17.7%) showed a late PV reconnection in 177 patients (1.18 per patient), at the time of repeat ablation procedure. Overall, persistent PV isolation could be documented in 969 of 1178 PVs (82.3%). In 123 of 300 patients (41%), persistent isolation could be demonstrated in all PVs, whereas PV reconnection could be documented in 177 patients (59%). In the multivariable analysis, nadir temperature (p = 0.03), time to PV isolation (p = 0.01) and failure to achieve - 40 °C within 60 s (p = 0.05) were independently associated with late PV reconnection., Conclusions: The rate of late PV reconnection after CB ablation was low (1.18 PVs/patient). The most frequent sites of reconnections were the superior-anterior portions for the upper PVs and the inferior-posterior portions for the lower PVs. Faster time to isolation, colder nadir temperatures and achievement of - 40 °C within 60 s were associated with durable PV isolation., Competing Interests: GBC reports speaker fees for Medtronic, Biotronik, Biosense Webster, and Abbott; teaching honoraria from Medtronic and Biotronik; proctoring honoraria from Medtronic; C.d.A. reports speaker fees for Medtronic, Biotronik, Biosense Webster, Abbott, and Boston Scientific; teaching honoraria from Medtronic, Biotronik, Abbott, and Boston Scientific; proctoring honoraria from Medtronic, Abbott, and Biotronik. Funding: research support from the Heart Rhythm Research Center., (© 2022 The Authors.)