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Thirty years after its first description, the knowledge regarding Brugada syndrome has greatly increased. Spontaneous type 1 ECG pattern (BrECG) is a well-defined prognostic marker in asymptomatic patients and is associated with a double risk of arrhythmic events during follow-up as compared to drug-induced ECG pattern. Due to the extreme variability of the ECG pattern over time, the spontaneous type 1 BrECG must be carefully sought, not only through periodic ECGs but especially with repeated 12-lead 24-h Holter monitoring, with V1 and V2 electrodes placed also on the second and third intercostal space, in order to explore the right ventricular outflow tract. 12-lead 24-h Holter should also be performed in all the patients with a dubious BrECG pattern even before the drug challenge with sodium channel blockers, which carries a low but definite risk of complications. In addition to spontaneous type 1, other electrocardiographic markers of increased arrhythmic risk have been described, such as first-degree AV block, QRS fragmentation, S wave in lead I and II, and increased QRS duration. The electrophysiological study in asymptomatic patients with a spontaneous ECG Brugada pattern is still under jury and further studies need to clarify its precise role.

Brugada syndrome is an inherited channelopathy with an increased risk of sudden cardiac death (SCD) due to ventricular arrhythmias (VA) and an increased incidence of supraventricular arrhythmias, as compared with the general population. For the prevention of SCD, the guidelines recommend the implantable cardioverter-defibrillator (ICD); however, ICD does not prevent VA. In this article, we provide a brief review of the literature on the Brugada syndrome pharmacological therapy, mainly focusing on quinidine treatment. The efficacy of quinidine therapy in the prevention of VA in Brugada syndrome has been demonstrated by several small studies in patients with ICD and recurrent shocks or in asymptomatic patients with inducible ventricular fibrillation (VF) at electrophysiological study. Quinidine has also been tested for the prophylaxis of supraventricular arrhythmias, especially atrial fibrillation/flutter, and in paediatric patients. In these studies, quinidine proved highly effective in preventing re-induction of VF and spontaneous recurrences of both ventricular and supraventricular arrhythmias. Unfortunately, this therapy is burdened by a high incidence of side effects, which may lead to drug discontinuation.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology. To this aim, we studied Class I metabotropic glutamate receptors 5 (mGluR5) because of their important role in the neuropathological signs produced by the lack of CDKL5 in-vivo, such as defective synaptogenesis, dendritic spines formation/maturation, synaptic transmission and plasticity. Importantly, mGluR5 function strictly depends on the correct expression of the postsynaptic protein Homer1bc that we previously found atypical in the cerebral cortex of Cdkl5-/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the binding strength of Homer1bc-mGluR5 complexes, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators (PAMs), i.e., 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioral defects shown by Cdkl5-/y mice. Notably, in the visual cortex of 2 CDD patients we found changes in synaptic organization that recapitulate those of mutant CDKL5 mice, including the reduced expression of mGluR5, suggesting that these receptors represent a promising therapeutic target for CDD.

Background and Aim The ability to recognize and monitor atherosclerotic lesion development using noninvasive imaging is crucial in preventive cardiology. The aim of the present study was to establish a protocol for longitudinal monitoring of plaque lipid, collagen, and macrophage burden as well as of endothelial permeability. Methods and Results Photoacoustic signals derived from endogenous or exogenous dyes assessed in vivo, in plaques of albino Apoe −/− mice, correlated with lesion characteristics obtained after histomorphometric and immunofluorescence analyses, thus supporting the validity of our protocol. Using models of atheroprogression and regression, we could apply our imaging protocol to the longitudinal observation of atherosclerotic lesion characteristics in mice. Conclusions The present study shows an innovative approach to assess arterial inflammation in a non-invasive fashion, applicable to longitudinal analyses of changes of atherosclerotic lesion composition. Such approach could prove important in the preclinical testing of therapeutic interventions in mice carrying pre-established lesions.

The oligomeric form of the peptide amyloid beta 42 (Abeta42) contributes to the development of synaptic abnormalities and cognitive impairments associated with Alzheimer's disease (AD). To date, there is a gap in knowledge regarding how Abeta42 alters the elementary parameters of GABAergic synaptic function. Here we found that Abeta42 increased the frequency and amplitude of miniature GABAergic currents as well as the amplitude of evoked inhibitory postsynaptic currents. When we focused on paired pulse depression (PPD) to establish whether GABA release probability was affected by Abeta42, we did not observe any significant change. On the other hand, a more detailed investigation of the presynaptic effects induced by Abeta42 by means of multiple probability fluctuation analysis and cumulative amplitude analysis showed an increase in both the size of the readily releasable pool responsible for synchronous release and the number of release sites. We further explored whether ryanodine receptors (RyRs) contributed to exacerbating these changes by stabilizing the interaction between RyRs and the accessory protein calstabin. We observed that the RyR-calstabin interaction stabilizer S107 restored the synaptic parameters to values comparable to those measured in control conditions. In conclusion, our results clarify the mechanisms of potentiation of GABAergic synapses induced by Abeta42. We further suggest that RyRs are involved in the control of synaptic activity during the early stage of AD onset and that their stabilization could represent a new therapeutical approach for AD treatment. KEY POINTS: Accumulation of the peptide amyloid beta 42 (Abeta42) is a key characteristic of Alzheimer's disease (AD) and causes synaptic dysfunctions. To date, the effects of Abeta42 accumulation on GABAergic synapses are poorly understood. The findings reported here suggest that, similarly to what is observed on glutamatergic synapses, Abeta42 modifies GABAergic synapses by targeting ryanodine receptors and causing calcium dysregulation. The GABAergic impairments can be restored by the ryanodine receptor-calstabin interaction stabilizer S107. Based on this research, RyRs stabilization may represent a novel pharmaceutical strategy for preventing or delaying AD.

Funding Acknowledgements Type of funding sources: None. Background Genotype-phenotype correlation and risk stratification for heart failure progression in patients with cardiolaminopathies are poorly defined. Purpose The primary aim of the present study is to characterize and correlate phenotype with genotype and sex. The secondary aim is to test the two main existing prognostic scores (the Arbustini and the Whabi score), both developed to predict ventricular arrhythmic events in cardiolaminopathies, for both major ventricular arrhythmias (MVA) and end-stage heart failure (ESHF). Methods This is a retrospective, single-center study, including patients with lamin (LMNA) and/or emerin (EMD) genetic variants. Data were collected from the first medical contact (FMC) to the last follow-up (FU). Results 28 patients (57% male, 82% probands, 68% with a family history of sudden death) were included: 96% harbored LMNA heterozygous variants, 15% had non-missense variants, 11% had variant previously never described. Functionally, 50% were variant of undetermined significance (VUS, C3), the rest were either pathogenetic or likely pathogenic (C4/C5) variants. Median age at FMC was 41 years (IQR 30-55 years), median FU was 11 years (IQR 8-18 years). At FMC, all patients had cardiac involvement, 54% had muscle involvement. By the last FU, 54% developed atrial fibrillation, 43% atrioventricular block (AVB) > I degree, 50% carried an implantable cardioverter defibrillator (21% with resynchronization), 50% had suffered at least one episode of MVA, 25% developed ESHF: 11% died due to refractory HF, 14% underwent heart transplantation (mean age 43.5 ± 9 years). The age of onset of the different types of cardiac phenotype was not influenced by sex. The penetrance of atrioventricular (AV) conduction defects (Figure 1 Panel A) and of atrial tachyarrhythmias (Figure 1 Panel B) was higher and earlier in subjects with non-missense variants. Subjects with VUS, compared to those with pathogenetic/likely pathogenetic variants, showed a significantly lower and later penetrance of MVA (Figure 2 Panel A) and a later penetrance of non- sustained ventricular tachycardia (NSVT, Figure 2, Panel B), but not of AV conduction disturbances, atrial arrhythmias, or contractile dysfunction. Arbustini score at FMC proved to be a predictor of both MVA and ESHF, while Whabi score only predicted MVA. Conclusions In our series, the prevalence and the age of appearance of the different cardiac phenotypes of cardiolaminopathies were not influenced by sex, while the presence of VUS correlated with a lower risk of ventricular arrhythmias, but not of the other cardiac manifestations including contractile disfunction and heart failure. Our data suggest the importance of a close cardiac monitoring and of larger prospective studies even in patients with VUS. All patients developed a sever cardiac phenotype by the age of 60.

Funding Acknowledgements Type of funding sources: None. Introduction Besides the established class I indication for the evaluation of patients with recurrent syncope of uncertain origin, implantable loop recorders (ILRs) have been increasingly used for other diagnostic purposes (e.g. detection of atrial fibrillation (AF) following cryptogenic stroke). Purpose To describe the main indications to ILR and to investigate procedural parameters, outcomes and diagnostic yield of ILR in a single, high-volume tertiary care centre. Methods All patients undergoing ILR implantation between November 2007 and April 2022 were consecutively enrolled in this study. Clinical characteristics of patients, procedural data and outcomes were collected. The indications to ILR implantation were divided into four categories: 1) AF detection in patients with recent cryptogenic stroke or peripheral thromboembolism [CRYSP], 2) recurrent syncope of uncertain origin [RSUO], 3) monitoring of ventricular arrhythmic events [VAE] in patients with predisposing cardiomyopathy/channelopathy, 4) monitoring of AF burden or relapse [AFB]. The main endpoint of the study was the diagnostic yield (number of definitive diagnoses made) and the time to diagnosis following ILR implantation. The occurrence of acute or subacute complications was used as a secondary safety endpoint. Results Overall, 1442 patients underwent ILR implantation (mean age 65 years, 43% female). The two main indications to ILR were AF detection following CRYSP and RSUO (42% and 34% of all implantations respectively, table 1). The commonest site of implantation was the left parasternal position (902 patients, 63%), median procedural time was 20 minutes (IQR 15-25). During a median follow-up of 397 days (134-1094), infections requiring ILR extraction or pocket revision occurred in 13 patients (0.9%). A definitive diagnosis was achieved in 500 (35%) patients after a median time of 206 days (IQR 60-533) [table 1 shows details and action taken following diagnosis for each indication subgroup]. At multivariable analysis, age and PR interval duration were significantly associated with the need for PM/ICD implantation among patients receiving ILR for RSUO whilst age was associated with AF detection among those with CRYSP (table 2). Conclusions In this cohort of patients use of ILR was associated with a good diagnostic yield regardless of the initial indication, triggered timely therapeutic actions and was overall safe.

Despite aggressive therapeutic regimens, glioblastoma (GBM) represents a deadly brain tumor with significant aggressiveness, radioresistance and chemoresistance, leading to dismal prognosis. Hypoxic microenvironment, which characterizes GBM, is associated with reduced therapeutic effectiveness. Moreover, current irradiation approaches are limited by uncertain tumor delineation and severe side effects that comprehensively lead to unsuccessful treatment and to a worsening of the quality of life of GBM patients. Proton beam offers the opportunity of reduced side effects and a depth-dose profile, which, unfortunately, are coupled with low relative biological effectiveness (RBE). The use of radiosensitizing agents, such as boron-containing molecules, enhances proton RBE and increases the effectiveness on proton beam-hit targets. We report a first preclinical evaluation of proton boron capture therapy (PBCT) in a preclinical model of GBM analyzed via μ-positron emission tomography/computed tomography (μPET-CT) assisted live imaging, finding a significant increased therapeutic effectiveness of PBCT versus proton coupled with an increased cell death and mitophagy. Our work supports PBCT and radiosensitizing agents as a scalable strategy to treat GBM exploiting ballistic advances of proton beam and increasing therapeutic effectiveness and quality of life in GBM patients.

Few data are available regarding the prevalence of left atrium (LA) thrombi in atrial fibrillation (AF) patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). Methods: We evaluated the prevalence and predictors of LA/LA appendage (LAA) thrombi in non-valvular AF patients treated with NOACs referring to a single centre for a scheduled electrical cardioversion (ECV) or catheter ablation (CA). Transesophageal echocardiography (TEE) was performed within 12 h prior to the index procedure. A total of 352 consecutive patients with non-valvular AF treated with NOACs were included in this analysis (ECV group n = 176 and CA group n = 176) between 2013 and 2018. 85 patients (24.2%) were on dabigatran, 150 (42.7%) on rivaroxaban, 104 (29.6%) on apixaban and 13 (3.7%) on edoxaban. A LA/LAA thrombus was detected by TEE in 27 (7.7%) patients, 18 in the ECV group and nine in the ablation group; 18 (5.1%) patients presented dense LA/LAA spontaneous echo contrast (SEC). Predictors of LA/LAA thrombi were a CHA2DS2-VASc score > 3 (OR 4.54, 95% CI 1.50 − 13.70, p value = .007) and obesity (OR 6.01, 95% CI 1.95 − 18.50, p value = .001). Among real-world patients with non-valvular AF treated with NOACs, we found a high incidence of LA/LAA thrombi compared to previous reports. The main predictors of LA/LAA thrombosis were a CHA2DS2-VASc score > 3 and obesity.

During pregnancy, body composition alterations can be considered as markers of complications and in this context, a non-invasive and low-cost method such as Bioelectrical Impedance Vector Analysis (BIVA), can be employed to monitor such changes. This study aimed at identifying body compartments trend during physiological pregnancy.Classic and specific BIVA variables have been measured in a sample of 37 pregnant women approximately every 4 weeks of gestation and once postpartum. Researchers used both longitudinal and cross-sectional approach. The first case included data of women from the 11th to the 15th week along with data from the 28th to the 32nd week of gestation. The cross-sectional approach regarded two more specific moments (11th-12th weeks and 30th-31st weeks) and data within two months postpartum RESULTS: The longitudinal approach showed a significant decrease in classic BIVA variables (R/H, Xc/H, Z/H p 0.001) and a shortening of the vector, pointing out that TBW and hydration increased significantly. Specific vector length increased significantly, indicating a physiological gain of FM% (p 0.01). The cross-sectional approach showed lower values of R/H, Xc/H, Z/H between 12th-13th and 30th-31st weeks (p 0.01), while in the postpartum period values tended to those registered at the beginning of pregnancy. No changes have been found for the phase angle in both approaches, indicating that ECW/ICW ratio remained constant CONCLUSIONS: Among physiological pregnancies, bioelectric values showed a coherent trend and these results represent a first contribution to support routine exams, leading to an early detection of anomalous values potentially correlated to pathologies.

This study aimed at determining the effect of a passive exoskeleton on local perceived discomfort, perceived effort and low back muscles' activity. Thirteen volunteers performed two simulated working tasks with and without the exoskeleton. In the static task, the exoskeleton decreased the lumbar perceived discomfort, the perceived effort and the level of low back muscles' activity (∼10%) while increasing discomfort in the chest and feet. The percent decrease in EMG amplitude was correlated with the percent increase in perceived effort with exoskeleton. For the dynamic task, the exoskeleton increased the discomfort in the chest and decreased the level of back muscle activity (∼5%). Current findings suggest exoskeleton is effective in reducing the back load while increasing the perceived discomfort at non-targeted body regions in both working tasks. The concurrent increase of discomfort in non-targeted areas probably led to a higher perceived effort despite the reduction of low back muscle activity. Practitioner summary: This study provided insights into exoskeleton effects on local discomfort, perceived effort and muscle activity. Overall, the potential benefits of passive exoskeleton should be considered alongside its adverse effects on the non-targeted body regions that can lead to an increase of perceived effort despite the reduction of back muscle activity.

Aims Risk stratification in patients with advanced chronic heart failure (HF) is an unmet need. Circulating microRNA (miRNA) levels have been proposed as diagnostic and prognostic biomarkers in several diseases including HF. The aims of the present study were to characterize HF‐specific miRNA expression profiles and to identify miRNAs with prognostic value in HF patients. Methods and results We performed a global miRNome analysis using next‐generation sequencing in the plasma of 30 advanced chronic HF patients and of matched healthy controls. A small subset of miRNAs was validated by real‐time PCR (P

Background RNA–binding motif protein 20 (RBM20) regulates post–transcriptional splicing, particularly in sarcomeric, but also in other cardiac genes crucial for homeostasis. RBM20 variants are a rare cause of cardiomyopathy (CMP), but genotype–phenotype correlation is still elusive, starting from the type of CMP (dilated, non–compacted, hypertrophic, and even restrictive phenotypes have been described), and ranging to sex–dependent and arrhythmic expression. Purpose: To describe cardiac involvement in 8 patients with RBM20 variants. Methods 189 patients (pts) underwent genetic analysis in our center (2019–2022) for suspected genetic CMP (TruSight Cardio panel, Illumina); 72% had a positive genetic report, including pathogenic/likely pathogenic (P/LP) or variants of undetermined significance (VUS). Among them, 9 (5%, 6 males and 3 females, from 6 families) carried a heterozygous RBM20 variant: 5 a sole P variant, 3 an RBM20–VUS associated to a second VUS in another CMP related gene, one an RBM20–VUS associated to a LP variant in BAG3; the last patient was excluded (figure with 8 pts). Results Most pts (75%) had a positive family history (FH) for sudden death. Mean age at diagnosis was significantly lower for P variant carriers compared to VUS carriers (25±15 vs 46±2 years, p=0.04); no other significant differences were found between the 2 groups. At diagnosis, 4/8 pts (50%) had NYHA class>2, mean LVEF was 34±18% and mean LV end diastolic volume 83±14 ml/m2; most pts (6/8, 75%) presented with a dilated phenotype, one with a non–compacted and one with a hypertrophic phenotype. Cardiac magnetic resonance, available in 6 pts, showed non–ischemic fibrosis in 3 (50%). At presentation, two pts had non–sustained VT (NSVT), one atrial flutter, one first degree AV block. The median follow–up was 2 years (IQR 2–10). Four pts (50%) underwent ICD implantation at 40 ± 13 years old. One female patient underwent heart transplant at the age of 13 and no one died from end stage HF; 3 pts had NSVT, one patient had atrial fibrillation (successfully treated with ablation), and none developed advanced AV blocks. Conclusions This is the first Italian case series of RMB20 variants related CMP. In our case series, RBM20 variants are associated with an early onset cardiac expression both in male and female pts, with LV dilated CMP and heart failure being the most common presentation. None of the pts presented with or developed advanced AV blocks, most suffered from NSVT.

Background Nesprins are proteins encoded by synaptic nuclear envelope (SYNE)–1 and –2 genes, that concur, together with lamin A/C and emerin, to nuclear envelope function. Almost 140 disease–related variants were identified, mostly resulting in central nervous system and skeletal muscle disorders; only a few were associated with cardiomyopathy, mostly with relatively late onset and no specific arrhythmic profile. Purpose To describe cardiac involvement in 4 novel SYNE1 variants. Methods 189 patients underwent genetic analysis in our center (2019–2022) for suspected genetic cardiomyopathy (TruSight Cardio panel, Illumina); 72% had a positive genetic report, including pathogenic/likely pathogenic or variants of undetermined significance (VUS). Among them, 4 (2%) males presented with a sole SYNE1 heterozygous VUS (figure). Results None had muscle or neurological involvement. Patients 1 and 2 had negative family history (FH) and underwent pacemaker implantation under 50 years old for high–grade atrioventricular block (AVB). Transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) showed a mildly impaired left ventricular ejection fraction (LVEF) without oedema or fibrosis. During 3 and 6 years of follow–up (FU), several non–sustained episodes of fast ventricular tachycardia (VT) and of atrial tachycardia occurred. Patient 3 is a 55–year–old man with negative FH and a left bundle branch block (LBBB) known since the age of 45.In 2021, while playing football, he suffered a cardiac arrest due to ventricular fibrillation treated with two DC shocks; ECG showed first–degree AVB and LBBB; TTE and CMR revealed a mildly impaired LVEF without oedema or fibrosis. A subcutaneous ICD was implanted, which recorded 3 atrial fibrillation episodes in a 1–year FU. Patient 4 is a 49–year–old man, with FH of sudden death (mother’s brothers at 40 and 50 years) and of polycystic kidney, who underwent renal transplant. He had left anterior fascicular block and suffered 2 episodes of sustained monomorphic VT from the right ventricle treated with ablation. TTE and CMR showed mild LV concentric hypertrophy with normal LVEF, segmental abnormalities in right and LV strain, no fibrosis. Conclusions SYNE1 genetic variants were found to be associated with a complex cardiac phenotype, including early onset conduction disease, atrial and ventricular arrhythmias, and cardiomyopathy. Further studies are needed to determine the functional significance of the variants.

Introduction Radiofrequency transcatheter ablation (RFCA) for atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM) has been proven feasible. However, the long-term results of RFCA and its impact on clinical course of HCM are unknown. The aim of this study was to analyse clinical outcomes and long-term efficacy of RFCA in a multicentre cohort of patients with HCM and concomitant AF. Methods Patients with HCM and AF consecutively undergoing RFCA were included. Ablation failure was defined as recurrence of AF, atrial tachycardia or flutter lasting more than 3 minutes and occurring after the blanking period. Results Overall, 116 patients with symptomatic AF refractory to antiarrhythmic drugs were included. Over a median follow-up of 6.0 years (IQR 3.0-8.9 years) recurrence rate after a single RFCA was 32.3 per 100 patient/years with 26% of patients free from AF relapses at six years follow-up. Among patients experiencing AF recurrence, 51 (66%) underwent at least one redo-procedure. The overall recurrence rate considering redo-procedures was 12.6 per 100 patients/years with 53% of patients free from AF relapses at six years. At last follow-up, with an average of 1.6 procedures, 67 (61%) patients were in sinus rhythm (SR). Patients remaining in SR showed better functional status compared with those experiencing arrhythmic recurrences (NYHA class 1.6±0.1 vs. 2.0±0.1, p=0.009). Conclusions RFCA of AF in HCM patients is an effective and safe strategy favoring long-term SR maintenance, reduction of atrial arrhythmic events and improved functional status. However, most patients need repeat procedures and continuation of antiarrhythmic drugs. This article is protected by copyright. All rights reserved.

Background Bileaflet mitral valve prolapse (bMVP) has been linked to major arrhythmic events and sudden cardiac death (SCD). Solid evidence of consistent predictors of SCD in this setting is still lacking. Echocardiography is the best tool for the analysis of ventricle mechanics and for the correlation with electrical myocardial activation. The aim of this study was to find new predictors of malignant events within an arrhythmic MVP population. Methods We conducted a retrospective comparative analysis, selecting 22 patients with bMVP with a high arrhythmic risk profile. 6 of them had a previous major arrhythmic event (5 aborted SCD, one cardiogenic syncope) and previously received ICD implantation (ICD–MVP), while 16 presented with a high arrhythmic burden without major events (A–MVP). All patients underwent transthoracic echocardiography in the last year. Each echocardiogram followed a specific protocol focused on mitral valve anatomy and ventricular contraction using 2D imaging, 3D imaging, tissue doppler imaging and speckle tracking analysis. Results ICD–MVP group, compared with A–MVP group, presented a longer anterior leaflet (AML) length (28,6 mm, IQR: 24,1–31,1 mm; vs 21,4 mm, IQR: 20,4–24,0 mm; p = 0,03), larger mitral valve annulus (MVA) indexed area (6,88 cm2/m2, IQR 6,27–7,87 cm2/m2 vs 5,44 cm2/m2, IQR: 4,93–6,15 cm2/m2, p = 0,02), lower MVA anteroposterior diameter/AML length ratio (1,24, IQR: 1,21–1,41 vs 1,50, IQR 1,32–1,62; p = 0,049), higher inferolateral basal S3 velocity (26 cm/s, IQR: 20,8–29,6 cm/s vs 14,2 cm/s, IQR 10,1–21,3 cm/s; p = 0,02) and a greater mechanical dispersion (MD) of the basal and mid–ventricular segments calculated with speckle tracking (128 ms, IQR: 125–131 ms; vs 58 ms, IQR 45–106 ms; p = 0,03). Mitral regurgitation grading, instead, did not correlate with malignant events. Best predictors of malignant events were AML length and MD of basal and mid–ventricular segments. Cut–off values with highest sensibility and specificity above 80% were 26 mm for AML length and 122 ms for MD of basal and mid–ventricular segments. Logistic bivariate regression confirmed AML length as an independent predictor of malignant events (p = 0,01), while MD of basal and mid–ventricular segments showed a trend toward significancy (p = 0,07). Conclusion Five parameters were found to be predictors of malignant events in a high–risk MVP population. AML length and MD of the basal and mid–ventricular segments presented the best predictive value.

Background The structural alterations of arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC) mainly involve the RV outflow tract (RVOT), but RVOT systolic function has been poorly investigated. Purpose We aimed to evaluate the Doppler Velocity Ratio (DVR) as a novel echocardiographic parameter for ARVC diagnosis. Methods 30 consecutive ARVC adult patients, 45 asymptomatic healthy volunteers and 45 consecutive patients with RV dysfunction due to ARVC mimics were prospectively enrolled between May 2019 and December 2021 and received complete transthoracic echocardiography examinations. The DVR was calculated as the ratio of RV free wall systolic velocity to RVOT systolic velocity at Doppler tissue imaging. The main study outcomes were to compare the DVR among ARVC patients, healthy controls, and mimics and to assess its diagnostic value in ARVC. Results 120 patients were included. Mean age was 55±17 years; 46 (38.3%) patients were female. The DVR was significantly higher in ARVC subjects (1.59±0.41) compared to both healthy controls (1.16±0.14, P Conclusions The DVR is a simple novel echocardiographic parameter with high accuracy for ARVC diagnosis. Funding Acknowledgement Type of funding sources: None.

The occurrence of asbestos and asbestos-like minerals in natural sites may pose a risk to human health and the environment when rocks and soils are mobilized. Weathering and anthropic activities favour the liberation of potentially hazardous Elongated Mineral Particles (EMP, NIOSH 2011). The definition of EMP includes both asbestos and other fibrous minerals. The latter share several physical-chemical properties with asbestos, but their toxicological profile is still unknown. The assessment of risk requires the quantification of the occurrence and the estimation of the potential emissivity of EMP from the hosting matrix.We quantitatively described the potency of a rock to disperse EMPs in the environment with a quantitative parameter namely the “liberability factor” (Lf). Lf was measured for 40 meta-ophiolite fragments from the NOA-bearing units of Liguria (Voltri Group and Sestri-Voltaggio Zone) and Calabria (Gimigliano-Monte Reventino Unit, Southern Ligurian Domain). The mineral–petrographic characterization of these rocks showed the presence of veins of chrysotile, fibrous tremolite-actinolite, fibrous sepiolite and fibrous antigorite.By adapting the UNI EN 12457-2:2004 method for solid waste, we designed a weathering simulation test to quantify the EMPs and the fibres (according to the World Health Organization) possibly liberated by applying to the rock a standardized mechanical stress. Waterborne EMPs were filtered on membranes and counted by electron microscopy (SEM-EDS), by adapting the Italian Regional Agency for the Protection of the Environment (ARPA) procedure for waterborne asbestos (ARPA Piemonte, 2016). We obtained Lf values as the number of waterborne fibres suspended per unit volume of water (fibres/Litre). All analysed rock samples showed Lf values ranging from 30 Mf/L to 21’000 Mf/L. Chrysotile, tremolite, sepiolite, and antigorite, with asbestos-like habit, were detected.Lf proved to be a reliable, easy to use method for the characterization and prediction of EMP and fibre dispersion in the environment from NOA-bearing rocks subjected to a standardized mechanical stress. This study is part of the BRIC 2019 project (grant number ID 57.1) supported by INAIL (Italian National Institute for Insurance against Accidents at Work). ReferencesARPA Piemonte 2016. U.RP. M842 rev.03. Asbestos in water by Scanning Electron Microscopy. NIOSH, 2011. Asbestos fibers and other elongate mineral particles. Current Intelligence Bulletin 62. WHO, 1997. Determination of Airborne Fibre Number Concentrations. ISBN 92 4 154496 1

The polished stone industry of Chiomonte (Piedmont region, northwestern Italy), dating back to the middle to late Neolithic, has been studied with a multi-analytical approach, including mineralogical, petrographic and morpho-typological issues, with the aim of providing information about the sources of the raw materials and determining the function of this particular settlement in the prehistoric Western Alps. Most of the lithic tools are made of sensu stricto greenstones (i.e. “Na pyroxene rocks” and “Na pyroxene and garnet rocks”), though a large number of serpentinite tools (25 %) also exist. The combined application of X-ray powder diffraction (XRPD), polarising microscopy and Scanning Electron Microscopy coupled with Energy Dispersive Spectrometry (SEM-EDS) led to the detection of specific mineral and chemical “markers”, pointing to the Chiomonte tools likely having come from the Monviso area. However, other closer supply sources, e.g. small meta-ophiolite units in the Orsiera–Rocciavré mountain range or in the lower Susa valley, cannot be ruled out. The presence, on the many retrieved roughouts and broken tools, of raw, yet unpolished surfaces that are ascribable to pebbles and cobbles from alluvial or glacial deposits, suggests that these rocks had been picked up from local “secondary” sources. The abundance of roughouts and broken tools identifies Chiomonte as a second-order manufacturing site, although it is still unclear whether such an activity was restricted to serving local needs or if it contributed to the circulation of greenstone implements on a wider scale.

GTPases of the Rho family are components of signaling pathways linking extracellular signals to the control of cytoskeleton dynamics. Among these, RAC1 plays key roles during brain development, ranging from neuronal migration to neuritogenesis, synaptogenesis, and plasticity. RAC1 activity is positively and negatively controlled by guanine nucleotide exchange factors (GEFs), guanosine nucleotide dissociation inhibitors (GDIs), and GTPase-activating proteins (GAPs), but the specific role of each regulator in vivo is poorly known. ARHGAP15 is a RAC1-specific GAP expressed during development in a fraction of migrating cortical interneurons (CINs) and in the majority of adult CINs. During development, loss of ARHGAP15 causes altered directionality of the leading process of tangentially migrating CINs, along with altered morphology in vitro. Likewise, time-lapse imaging of embryonic CINs revealed a poorly coordinated directional control during radial migration, possibly due to a hyper-exploratory behavior. In the adult cortex, the observed defects lead to subtle alteration in the distribution of CALB2-, SST-, and VIP-positive interneurons. Adult Arhgap15-knock-out mice also show reduced CINs intrinsic excitability, spontaneous subclinical seizures, and increased susceptibility to the pro-epileptic drug pilocarpine. These results indicate that ARHGAP15 imposes a fine negative regulation on RAC1 that is required for morphological maturation and directional control during CIN migration, with consequences on their laminar distribution and inhibitory function.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology.To this aim, we studied metabotropic glutamate receptors 5 (mGluR5) for their important role in critical mechanisms involved in CDD, i.e.: synaptogenesis, dendritic spines formation/maturation and synaptic plasticity, and because mGluR5 function depends on the postsynaptic protein Homer1bc that is downregulated in the cerebral cortex of CDKL5−/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the strength of Homer1bc-mGluR5 binding, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators, i.e.: 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioural defects shown by CDKL5−/y mice. Notably, the cerebral cortex of 2 CDD patients show similar changes in the synaptic organization to mutant CDKL5 mice, including a reduced mGluR5 expression, suggesting that mGluR5 represent a promising therapeutic target for CDD patients.

Aims A subset of patients with mitral valve prolapse (MVP) are affected by a still not well understood condition characterized by frequent ventricular arrhythmias (mostly originating from papillary muscles) and sudden cardiac death (SCD). It is called MVP malignant syndrome (MVP MS). In these patients, the high arrhythmic burden may lead to left ventricular (LV) dyssynchrony and dysfunction, determining a tachycardia-induced cardiomyopathy (TIC). Reduction in arrhythmic burden determines LV recovery and ejection fraction improvement and interrupts LV progressive dilatation. Methods and reports We report the case of a 52-year-old woman with MVP and family history of both MVP and SCD who was referred to our department for symptomatic extrasystoles and dyspnoea during exercise. Palpitations begun 11 years before: in that occasion she performed a 3-lead-ECG-Holter monitoring which documented 3457 ventricular extrasystoles. Transthoracic echocardiography (TTE) showed normal LV dimension and function and a myxomatous mitral valve with prolapse of both leaflets. At that time beta-blocker therapy was introduced, but soon suspended because of patient’s clinical intolerance (bradycardia and hypotension). Since then she was lost at follow-up for years, until symptoms worsened. When she came to our attention, TTE showed dilated and hypokinetic LV (ejection fraction was 38%, S2 wave at TDI was 6.4 cm/s and global longitudinal strain value was −13%). CMR was performed and confirmed TTE findings. Mitral-annulus disjunction was described in anterior, lateral, and posterior wall and late gadolinium enhancement analyses showed subendocardial fibrosis in correspondence of the posterior papillary muscle (PM) and in the mid-inferior wall. Holter monitoring enlightened a high arrhythmic burden with 24 065 premature ventricular complexes (PVCs) of two morphologies (right bundle branch block-like and −120° axis and right bundle branch block-like and −75° axis). During stress test, PVCs increased as the heart rate increased, resulting in bigeminism at peak exercise. Considering all these features, we hypothesized a case of MVP MS in which the high ventricular arrhythmic burden resulted in TIC. Any available pharmacological attempt to reduce arrhythmias failed. Transcatheter (TC) ablation of PVCs was then proposed. Electrophysiological study identified the inner part of the posterior papillary muscle implantation region and the antero-lateral basal wall as PVCs sites of origin. Radiofrequency ablation was performed in both sites. After the procedure, despite an incomplete suppression of the posterior PM focus, 12-lead 24-h Holter monitoring and TTE performed during the hospitalization showed a consistent arrhythmic burden reduction and LV function improvement. At 6 months from the procedure, symptoms improved and Holter monitoring showed 7515 PVCs with a 54% arrhythmic burden reduction compared with the presentation. TE showed lower LV end-diastolic volume and an increase in ejection fraction up to 47%; global longitudinal strain was −17% and TDI showed a S2 wave on lateral wall of 11 cm/s, confirming left ventricle improvement after the arrhythmic burden reduction. Conclusions Complete suppression of PMs PVCs with TC ablation is difficult to obtain, especially when the focus is in the inner part of the PM and TC ablation of ventricular arrhythmias in MVP patients has not yet demonstrated his efficacy in reducing SCD. Nevertheless, it should be taken into consideration to obtain at least PVCs reduction in patients with high arrhythmic burden leading to TIC.

Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS). We found that the integrin α5β1, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide (

ObjectiveThe ECG has been traditionally used to support the diagnosis of pericarditis. However, the pericardium is electrically silent and ECG changes may imply concurrent myocardial involvement rather than simple pericarditis. The aim of the present paper is to analyse the frequency, type and clinical implication of ECG changes in patients with pericarditis compared with those with myocarditis.MethodsConsecutive patients with pericarditis and/or myocarditis were included in a prospective cohort study from January 2017 to December 2020. A clinical and echocardiographic follow-up was performed at 1, 3, 6 months and then every 6 months. Cardiac magnetic resonance was used to diagnose concurrent myocarditis.Results166 patients (median age 47 years, 95% CI 44 to 51) with 66 men (39.8%) were included: 110 cases with pericarditis (mean age 47.7 years, 29.1% male) and 56 cases with myocarditis (mean age 44.8, 60.7% male). ECG changes were reported in 61 of 166 (36.7%) patients: 27 of 110 (24.5%) among those with pericarditis and 34 of 56 (60.7%) among those with myocarditis (pConclusionsECG changes, mainly widespread ST-segment elevation, can be recorded in about one-quarter of patients with pericarditis, and were not associated with a worse prognosis. These changes may reflect concurrent myocarditis that should be ruled out.

Background Incessant pericarditis is defined as pericarditis with persistent symptoms without a symptom-free interval of 4 to 6 weeks despite therapy. On the contrary, recurrent pericarditis is characterized by recurring symptoms after a symptom-free interval of at least 4 to 6 weeks, allowing the completion of therapy. Aims The aim of this study is to assess the risk of complicated pericarditis and related hospitalizations according to the clinical pattern of incessant or recurrent pericarditis. Methods From January 2017 to December 2018, all consecutive patients admitted to AOU Città della Salute (Turin, IT) for pericarditis were included in a prospective cohort study with a clinical and echocardiographic follow-up at 1, 3, and 6 months, and then every 6 months. Results We included 147 patients (median age, 50.9 years [IQR, 28.5]; 49.7% women, 89% had idiopathic aetiology, 11% had pericarditis related to systemic inflammatory disease/postcardiac injury syndrome, 80% had pericardial effusion, and 62% had elevated C-reactive protein >5 mg/L). Patients were treated according to ESC guidelines. After a median follow-up of 14 months (IQR, 9 months), adverse events were recorded in 54/147 patients (36.7%): nonidiopathic/viral aetiology in 16 of 147 cases (10.9%), recurrent pericarditis/persistent symptoms in 53 of 147 cases (36.1%), cardiac tamponade in 4/147 cases (2.7%), persistent CP in 4/147 cases (2.7%), and hospitalization related to pericarditis in 38/147 cases (25.9%). An incessant course was reported in 18 of 147 cases (12%). The risk of complications was higher in patients with incessant pericarditis (Figure) – especially CP – compared to nonincessant course (22.2% versus 0%, respectively; P5 mg/L (hazard ratio, 5.55 [95% CI, 1.87–16.44]), and incessant course (HR, 17.10 [95% CI, 7.63–38.33]). Conclusions This study highlights that an incessant course of pericarditis is a possible new risk factor for complications and especially for developing constriction. In clinical practice, the detection of an incessant course, as well as imaging findings of constriction and pericardial thickening, should prompt more diagnostic testing, a close follow-up, and more aggressive therapy to prevent complications and persistent constriction. Funding Acknowledgement Type of funding sources: None. Figure 1

Background Exercise restriction is a non-pharmacological treatment of pericarditis that could reduce symptoms by slowing heart rate (HR). Beta-blockers allow pharmacological control of HR. Aim To explore the possible efficacy of beta-blockers to improve control of symptoms in patients with pericarditis. Methods We analysed consecutive cases with pericarditis referred to our centre. Beta-blockers were prescribed on top of standard anti-inflammatory therapy in symptomatic patients (chest pain and palpitations) with rest HR>75 beats/min. The primary end point was the persistence of pericardial pain at 3 weeks. The secondary end point was the occurrence of recurrent pericarditis at 18 months. Propensity score matching was used to generate 2 cohorts of 101 patients with and without beta-blockers with balanced baseline features. A clinical and echocardiographic follow-up was performed at 3 weeks, 1, 3, 6 months and then every 12 months. Results A total of 347 patients (mean age 53 years, 58% females, 48% with a recurrence, 81% with idiopathic/viral aetiology) were included. Among them, 128 patients (36.9%) were treated with beta-blockers. Peak C-reactive protein values were correlated with heart rate on first observation (r=0.48, p Conclusions The use of beta-blockers on top of standard anti-inflammatory therapies was associated with improved symptom control. Additional studies are warranted to verify the efficacy of these drugs in this setting. Funding Acknowledgement Type of funding sources: None.

Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene,Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, andThe study group comprised 392 probands: 92 (23.5%)The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing., Amsterdam Cardiovascular Sciences fellowship; Dutch Heart Foundation (CVON Predict-2/Concor-genes); Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [VICI 016.150.610]; Fondation LeducqLeducq Foundation, R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict-2/Concor-genes), Netherlands Organization for Scientific Research (VICI 016.150.610), and Fondation Leducq. See Supplement for all Acknowledgements.

No therapy is currently available for CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the CDKL5 gene. Although delivery of a wild-type copy of the mutated gene to cells represents the most curative approach for a monogenic disease, proof-of-concept studies highlight significant efficacy caveats for brain gene therapy. Herein, we used a secretable TATk-CDKL5 protein to enhance the efficiency of a gene therapy for CDD. We found that, although AAVPHP.B_Igk-TATk-CDKL5 and AAVPHP.B_CDKL5 vectors had similar brain infection efficiency, the AAVPHP.B_Igk-TATk-CDKL5 vector led to a higher CDKL5 protein replacement due to secretion and transduction of the TATk-CDKL5 protein into the neighboring cells. Importantly, Cdkl5 KO mice treated with the AAVPHP.B_Igk-TATk-CDKL5 vector showed a behavioral and neuroanatomical improvement in comparison with vehicle-treated Cdkl5 KO mice or Cdkl5 KO mice treated with the AAVPHP.B_CDKL5 vector, indicating that a gene therapy based on a secretable recombinant TATk-CDKL5 protein is more effective at compensating Cdkl5-null brain defects than gene therapy based on the expression of the native CDKL5.

The real prognostic impact of MitraClip in patients with significant functional mitral regurgitation (FMR) and left ventricular (LV) dysfunction remains to be elucidated. Two randomized controlled trials (RCTs) with conflicting results have been recently published. We conducted a comprehensive meta-analysis of all RCTs and adjusted observational studies to evaluate the clinical impact of percutaneous mitral valve repair when compared with optimal medical therapy (OMT) alone, in patients with symptomatic FMR and LV dysfunction. Death from any cause and heart failure rehospitalizations at the longest available follow-up were the primary endpoints. Cardiac death, one year and short-term death were the secondary ones. 2255 patients (1207 for MitraClip and 1048 for OMT-only) from 8 studies (2 RCTs and 6 observational studies) were included. At a median (mid-term) follow-up of 438 days (IQR 360-625) MitraClip was associated with a significant reduction of all-cause death (odds Ratio [OR] 0.55, 95%CI 0.41-0.73, p 0.001; [ORadj] 0.66, 95%CI 0.49-0.90, p = 0.009) and rehospitalization (OR 0.49, 95%CI 0.24-1.00, p = 0.05 and ORadj 0.63, 95%CI 0.43-0.94, p = 0.02). At one year, adjusted analysis demonstrated a trend favoring the experimental cohort (ORadj 0.73, 95%CI 0.53-1.02, p = 0.07). Meta-regression suggested that benefit of MitraClip on mid-term survival persists even after accounting for the prevalence of implanted CRT, burden of comorbidities, NYHA class, cardiomyopathy etiology and LV function and dimensions. In conclusion, MitraClip for FMR in patients with LV dysfunction is associated with a considerable reduction of death and HF hospitalization at mid-term follow-up. Further ongoing RCTs are needed to strengthen present results.

Aim An underlying atrial vulnerability or a preexisting misdiagnosed atrial fibrillation in some patients who are candidates for patent foramen ovale (PFO) closure may lead to an unnecessary percutaneous intervention. The aim of this work was to define paroxysmal atrial fibrillation rate, through a 6-month insertable loop-recorder monitoring, in patients over 55 years old with cryptogenic stroke and PFO. Methods PFO closure criteria: significant right-to-left shunt and at least one high-risk feature (permanent right-to-left shunt, atrial septal aneurysm, prominent Eustachian valve, recurrent brain ischemia, previous deep vein thrombosis, thrombophilia). Insertable cardiac monitoring criteria: previous cryptogenic stroke, more than 55 years and at least one atrial fibrillation risk factor (heart failure, hypertension, age older than 65 years, diabetes, atrial runs, left atrium dilatation, left ventricle hypertrophy, pulmonary disease, thyroid disease, obesity). Atrial fibrillation detection threshold: arrhythmia duration longer than 5 min. Results From January 2008 to March 2017, 195 patients underwent to loop-recorder monitoring. A total of 70 (36%) patients were candidates for PFO closure. The 6-month silent atrial fibrillation rate was 11.4%. In the arrhythmia-free cohort, 28 patients (45.2%) underwent percutaneous foramen ovale closure (group A) and 34 (54.8%) were medically treated (group B). Atrial fibrillation detection rate was 14.3% in group A and 0% in group B. The 36-month atrial fibrillation-free survival was 76%. Conclusion An occult preexisting atrial fibrillation may lead to unnecessary percutaneous foramen ovale closure in a significant proportion of patients. A 6-month loop-recorder monitoring may improve the patient oriented decision-making.

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce.Methods and results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy.

Background Transcatheter ablation is the most effective treatment for patients with symptomatic or high-risk accessory pathways (AP). At present, no clear recommendations have been issued on the optimal approach for left sided AP ablation. We performed this meta-analysis to compare the safety and efficacy of transaortic retrograde versus transseptal approach for left sided AP ablation. Methods and results MEDLINE/PubMed and Cochrane database were searched for pertinent articles from 1990 until 2016. Following inclusion/exclusion criteria application, 29 studies were selected including 2030 patients (1013 retrograde, 1017 transseptal) from 28 observational single Centre studies and one randomized trial. Patients approached by transseptal puncture presented a significantly higher acute success (98% vs. 94%, p = 0.040). The incidence of late recurrences ( p = 0.381) and complications ( p = 0.301) did not differ among the two groups, but the pattern of complications differed: vascular complications were more frequent with transaortic retrograde approach, while cardiac tamponade was the main transseptal complication. No difference was noted in terms of procedural duration and fluoroscopy time ( p = 0.230 and p = 0.980, respectively). Meta-regression analysis showed no relation between year of publication and acute success ( p = 0.325) or incidence of complications ( p = 0.795); additionally, no direct relation was found between age and acute success ( p = 0.256) or complications ( p = 0.863). Conclusions Left sided AP transcatheter ablation is effective in around 95% of the cases, with a very limited incidence of complications. Transseptal access provides higher acute success in achieving AP ablation; late recurrences are rare but observed similarly following both approaches. Retrograde approach is affected by a relatively high incidence of vascular complications.

Current guidelines on the management of pericardial diseases suggest to identify high-risk features associated with an increased risk of non-idiopathic aetiology and complications. The aim of this study is to evaluate a "pericarditis score" to assess potential complicated pericarditis in order to facilitate initial clinical triage. Consecutive patients with pericarditis were included in a prospective cohort study from January 2017 to December 2018. Complicated pericarditis was defined as pericarditis with a non-idiopathic aetiology, and/or complications, and/or requiring hospitalization. A clinical and echocardiographic follow-up were performed at 1, 3, 6 months and then every 6 months. The study population was randomized in derivation and validation cohorts. In the derivation cohort, female gender (HR 2.57, p = 0.016), fever 38 °C (HR 2.86, p = 0.005), previous lack of colchicine use (HR 3.16, p = 0.006), previous use of corticosteroids (HR 3.01, p = 0.009), and echocardiographic signs of constriction (HR 2.26, p = 0.018) were selected by a stepwise procedure in a Cox regression model and constituted the score showing a C-statistics of 0.81. In the validation group, the score was significantly associated with the risk of complicated pericarditis (HR 1.438 per 10-points increase, 95% CI 1.208-1.711, p 0.001) and showed an increase in event rate with increasing score (low risk ≤ 20 points: complicated pericarditis in 4/19 patients, incidence 21%, p = 0.003, high risk 40 points: complicated pericarditis in 18/24 patients, incidence 75%, p = 0.006). In this study, we developed and tested a simple score to efficiently identify at presentation patients at high risk of developing complicated pericarditis.

BACKGROUND The aim of this study is to identify clinical, electrocardiographic (ECG) and procedural predictors for permanent pacemaker (PPM) requirement after transaortic valve implantation (TAVI). METHODS All consecutive patients with severe symptomatic aortic stenosis (SSAS) undergoing TAVI at our single center were included in the study and prospectively followed. All patients had standard 12-leads ECGs recordings before and after TAVI and continuous ECG monitoring during hospital stay. Primary endpoint was to identify electrocardiographic predictors of PPM implantation after TAVI; secondary endpoint was to ascertain other clinical or procedure-related predictive factors of PPM need. PPM implantation was further arbitrarily divided into early and late one (beyond the 3rd day). RESULTS Among the 431 patients undergoing TAVI between 2008 and 2018, 77 (18%) needed PPM implantation; 47 (11%) had an early procedure, and 30 (7%) a late implant. Preoperative right bundle branch block (RBBB) implies more than five-fold increase of the risk of PPM implantation (OR 5.19, CI 1.99-13.56, P=0.001), whereas the use of a self-expandable prosthesis is associated with an almost three-fold increase of the risk (OR 2.60, CI 1.28-5.28, P=0.008). In the late PPM implantation subgroup, only the history of syncope retains a significant association with such an increased risk (OR 2.71, CI 1.09-6.75, P=0.032). CONCLUSIONS The need of a PPM in the individual TAVI patient is hardly predictable. However, the finding of pre-existing RBBB, the use of self-expandable prosthesis and history of syncope can individuate patients at increased risk.

Additional file 1. Fig. S1 Brainstem of Mecp2y/- male mice presents a strong p-c-jun immunoreactivity compared to wild-type mice. Representative section of p-c-jun immuno-staining in the brain of wt (a) and higher magnification (b) of a brainstem area show a low number of p-c-jun immunopositive cells. Representative section of p-c-jun immuno-staining in the brain of Mecp2y/- (c) and higher magnification (d) of a brainstem area show an higher number of p-c-jun immunopositive cells

Exercise restriction is a nonpharmacological treatment of pericarditis that could reduce symptoms by slowing heart rate (HR). Beta-blockers allow pharmacological control of HR. Aim of this paper is to explore the possible efficacy of beta-blockers to improve control of symptoms in patients with pericarditis. We analyzed consecutive cases with pericarditis referred to our center. Beta-blockers were prescribed on top of standard anti-inflammatory therapy in symptomatic patients (chest pain and palpitations) with rest HR75 beats/min. The primary end point was the persistence of pericardial pain at 3 weeks. The secondary end point was the occurrence of recurrent pericarditis at 18 months. Propensity score matching was used to generate 2 cohorts of 101 patients with and without beta-blockers with balanced baseline features. A clinical and echocardiographic follow-up was performed at 3 weeks, 1, 3, 6 months and then every 12 months. A total of 347 patients (mean age 53 years, 58% females, 48% with a recurrence, 81% with idiopathic/viral etiology) were included. Among them, 128 patients (36.9%) were treated with beta-blockers. Peak C-reactive protein values were correlated with heart rate on first observation (r=0.48, p0.001). Using propensity-score matched cohorts, patients treated with beta-blockers had a lower frequency of symptoms persistence at 3 weeks (respectively 4% vs. 14%; p = 0.024) and a trend towards a reduction of recurrences at 18 months (p = 0.069). In conclusion the use of beta-blockers on top of standard anti-inflammatory therapies was associated with improved symptom control.

Aim: This study aims to describe prevalence and clinical significance of latent Brugada syndrome (BrS) in a young population with atrial fibrillation (AF). Methods: Between September 2015 and November 2017, among 111 AF patients below 45 years of age, those without pre-existing pathologies and/or known risk factors were selected for the study. Based on baseline 12-lead−24-h Holter electrocardiogram (ECG), previous class 1C antiarrhythmic drug therapy, or ajmaline testing, patients were stratified as latent type 1 BrS or not. Results: Within the 78 enrolled patients, 13 (16.7%; group 1) revealed a type 1 BrS ECG pattern, while 65 (83.3%; group 2) did not. Mean age was 37 ± 8 vs. 35 ± 7 (p = 0.42), and males were 7 (54%) vs. 54 (83%) (p = 0.02) in the two groups, respectively. Family history of BrS was significantly more common within group 1 patients (2, 15% vs. 0; p = 0.03), and 4 (31%) patients experienced syncope in group 1 vs. 5 (8%) in group 2 (p = 0.02). After a mean follow-up of 42 ± 18 months from the index AF event, more than 80% of the patients, in both study groups, were in sinus rhythm. Conclusion: In young patients with AF without pre-existing pathologies and/or known risk factors, latent BrS should be suspected. Syncope and a family history of BrS emerge as easily identifiable factors related to BrS. Long-term sinus rhythm maintenance appears satisfactory, either in the presence or not of BrS.

CDKL5 (cyclin-dependent kinase-like 5) deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early-onset epilepsy and intellectual disability. Studies in mouse models have linked CDKL5 deficiency to defects in neuronal maturation and synaptic plasticity, and disruption of the excitatory/inhibitory balance. Interestingly, increased density of both GABAergic synaptic terminals and parvalbumin inhibitory interneurons was recently observed in the primary visual cortex of Cdkl5 knockout (KO) mice, suggesting that excessive GABAergic transmission might contribute to the visual deficits characteristic of CDD. However, the functional relevance of cortical GABAergic circuits abnormalities in these mutant mice has not been investigated so far. Here we examined GABAergic circuits in the perirhinal cortex (PRC) of Cdkl5 KO mice, where we previously observed impaired long-term potentiation (LTP) associated with deficits in novel object recognition (NOR) memory. We found a higher number of GABAergic (VGAT)-immunopositive terminals in the PRC of Cdkl5 KO compared to wild-type mice, suggesting that increased inhibitory transmission might contribute to LTP impairment. Interestingly, while exposure of PRC slices to the GABA

Background Brugada syndrome (BrS) is an inherited channelopathy with an increased risk of supraventricular, ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Implantable cardioverter-defibrillator (ICD) is a cornerstone of SCD prevention, but it does not reduce the incidence of life-threatening VAs and it can carry substantial complications. Hydroquinidine (HQ) is a class IA antiarrhythmic drug used for electrical storms, to reduce ICD's appropriate discharges and as an alternative to ICD in children with BrS or in patients with a contraindication to ICD. Nevertheless, HQ's side effects may undermine treatment compliance. Purpose The aim of this study was to evaluate the efficacy and safety of HQ in reducing VAs (ventricular fibrillation, sustained and non-sustained ventricular tachycardia) inducibility at electrophysiology study (EPS) and atrial fibrillation/flutter (AF/AFL) or VAs recurrence in patients with BrS. Methods From the prospective Piedmont Brugada Registry, patients treated with HQ were selected and divided into three groups according to the indication for HQ initiation: index EPS positive for VAs induction (group 1), secondary prevention of AF/AFl (group 2), secondary prevention of VAs (group 3). In group 3 recurrence of VAs was monitored by implantable devices or by periodic 24-hour ECG Holter monitoring. In 5 patients HQ was started for reasons different from the above mentioned, so they were considered only for safety outcomes. Safety was assessed considering the occurrence of HQ side effects and their impact on treatment discontinuation. Results A total of 98 patients (79 males, 80,6%) were included. Median follow-up was 61 months (IQR 31–89 months). None of the baseline clinical characteristics was associated with arrhythmic recurrences. Among 46 patients in group 1 HQ was effective in reducing EPS inducibility in 91.9% of patients (p Overall, 28.6% of patients presented HQ-related side effects, mainly due to gastrointestinal intolerance (18.3%). Treatment discontinuation rate was 25% but only about half of these patients discontinued HQ for adverse events (29.2% for GI intolerance, 16.7% for drug-induced QTc prolongation, 8.3% for elevated liver enzymes; 45.8% self-discontinuation). Conclusions In patients with BrS, HQ was effective in reducing VAs inducibility at EPS, AF/AFL and VAs recurrences; moreover, it was effective in reducing symptoms. Overall, HQ proved to be safe and well-tolerated. Funding Acknowledgement Type of funding source: None

Background About 40% of patients undergoing transcatheter aortic valve replacement (TAVR) have a history of atrial fibrillation (AF) and an additional 10% develop AF after TAVR. However, there is paucity of data regarding the optimal antithrombotic regimen following TAVR in patients with a clinical indication for oral anticoagulants (OAC). Purpose To compare the prognostic impact of OAC plus at least one antiplatelet agent (APT) versus OAC therapy alone in patients undergoing TAVR. Methods We systematically searched the literature for studies evaluating the comparative efficacy and safety of OAC + APT versus OAC alone in TAVR. Random-effect meta-analysis was performed comparing clinical outcomes between the two groups. All-cause mortality and cardiovascular mortality were the efficacy outcomes. Stroke and major bleeding, defined as Bleeding Academic Research Consortium bleeding types 3 to 5, constituted the safety outcome. Results Overall, 398 titles and abstracts were identified through database searching. Four observational studies were selected, for a total of 1929 patients. After a median follow-up of 18.5 months (IQR 11.3–29.3), OAC + APT increased major bleeding events compared to OAC alone (OR=1.79; 95% CI 1.21–2.66; P=0.004) with no difference in stroke (OR 01.02; 95% CI 0.52–2.01; P=0.95), all-cause mortality (OR=1.07; 95% CI 0.78–1.47; P=0.66) and cardiovascular mortality (OR=1.08; 95% CI 0.79–1.47; P=0.62). Conclusion A combination strategy of OAC + APT provides increased risk of bleeding compared to OAC therapy alone in patients undergoing TAVR with similar outcomes in terms of stroke, all-cause mortality and cardiovascular mortality; therefore, when feasible, it should be advised not to add APT on top of OAC therapy in patients without other clinical indications for APT treatment. Funding Acknowledgement Type of funding source: None