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Atrial fibrillation (AF) is a widespread arrhythmia, associated with higher risk of stroke, sleep disorders and dementia. In some conditions, electrical cardioversion (ECV) represents the best choice for rhythm control. Nowadays, there is a growing interest in developing new devices for screening and monitoring of AF patients. We aimed to improve acute efficacy of ECV procedure and to explore the feasibility of the use of new wearable devices for monitoring in candidates to AF ECV. We compared antero-apical pads vs antero-posterior patches approach for AF ECV, and we elaborated a decision algorithm to improve acute efficacy. After, we evaluated the feasibility of the use of new wearable devices for monitoring of candidates to AF ECV. In particular, we analysed the effect of AF ECV on heart rate variability and vascular age parameters derived from PPG signals registered with Empatica (CE 1876/MDD 93/42/EEC), and on EEG pattern registered with Neurosteer (Israel). From December 2005 to September 2019, 492 patients were enrolled. We evaluated acute efficacy of the two approaches for AF ECV and we elaborated a decision algorithm based on body surface area, weight, and height. The decision algorithm improved first shock efficacy (93.2% vs. 87.2%, p=0.025). From 1st November 2021 to 1st April 2022, 24 patients were enrolled in PPEEG-AF pilot study. Considering vascular age parameters, a significant reduction in TPR and a wave was observed (p

Refractory focal epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1, was codon optimized for human expression and mutated to accelerate the recovery of the channels from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a nonintegrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled preclinical trial, the EKC lentivector robustly reduced seizure frequency in a male rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. When packaged into an adeno-associated viral vector (AAV2/9), the EKC gene was also effective at suppressing seizures in a male rat model of temporal lobe epilepsy. This demonstration of efficacy in a clinically relevant setting, combined with the improved safety conferred by cell type-specific expression and integration-deficient delivery, identify EKC gene therapy as being ready for clinical translation in the treatment of refractory focal epilepsy.SIGNIFICANCE STATEMENT Pharmacoresistant epilepsy affects up to 0.3% of the population. Although epilepsy surgery can be effective, it is limited by risks to normal brain function. We have developed a gene therapy that builds on a mechanistic understanding of altered neuronal and circuit excitability in cortical epilepsy. The potassium channel gene KCNA1 was mutated to bypass post-transcriptional editing and was packaged in a nonintegrating lentivector to reduce the risk of insertional mutagenesis. A randomized, blinded preclinical study demonstrated therapeutic effectiveness in a rodent model of focal neocortical epilepsy. Adeno-associated viral delivery of the channel to both hippocampi was also effective in a model of temporal lobe epilepsy. These results support clinical translation to address a major unmet need.

Cardiac resynchronization therapy (CRT) is an effective and useful electrical treatment for appropriately selected heart failure patients with complete left bundle branch block, even for those with mild symptoms. It has been calculated that 3-12% of heart failure patients could benefit from a CRT device. According to the results of a series of trials, biventricular pacing improves quality of life and haemodynamic parameters and this is associated with a reduction in heart failure hospitalizations and mortality. The efficacy of CRT has been proven by a series of randomized controlled studies, and consensus guidelines now give precise recommendations for selecting candidates for CRT not only among patients with moderate to severe heart failure, but also among patients with mild heart failure. Despite some uncertainties concerning a series of issues (selection of candidates, prediction of response, phrenic nerve stimulation, optimization of device programming), CRT is now an accepted treatment for selected patients with heart failure and specific indications are included in consensus guidelines for heart failure treatment. Devices for CRT have a relatively high upfront cost, but when CRT is applied to appropriately selected patients it may be a worthwhile investment not only for our patients but also for our healthcare systems.

Background: Infections of cardiovascular implantable electronic devices (CIED) are mainly due to Gram-positive bacteria (GPB). Data about Gram-negative bacteria CIED (GNB-CIED) infections are limited. This study aimed to investigate risk factors, clinical and diagnostic characteristics, and outcome of patients with GNB-CIED. Methods: A multicentre, international, retrospective, case-control-control study was performed on patients undergoing CIED implantation from 2015 to 2019 in 17 centres across Europe. For each patient diagnosed with GNB-CIED, one matching control with GPB-CIED infection and two matching controls without infection were selected. Results: A total of 236 patients were enrolled: 59 with GNB-CIED infection, 59 with GPB-CIED infection and 118 without infection. No between-group differences were found regarding clinical presentation, diagnostic and therapeutic management. A trend toward a higher rate of fluorodeoxyglucose positron emission computed tomography (FDG PET/CT) positivity was observed among patients with GNB than in those with GPB-CIED infection (85.7% vs. 66.7%; P = 0.208). Risk factors for GNB-CIED infection were Charlson Comorbidity Index Score (relative risk reduction, RRR = 1.211; P = 0.011), obesity (RRR = 5.122; P = 0.008), ventricular-pacing ventricular-sensing inhibited-response pacemaker implantation (RRR = 3.027; P = 0.006) and right subclavian vein site of implantation (RRR = 5.014; P = 0.004). At 180-day survival analysis, GNB-CIED infection was associated with increased mortality risk (HR = 1.842; P = 0.067). Conclusions: Obesity, high number of comorbidities and right subclavian vein implantation site were associated with increased risk of GNB-CIED infection. A prompt therapeutic intervention that may be guided using FDG PET/CT is suggested in patients with GNB-CIED infection, considering the poorer outcome observed in this group.

Atrial fibrillation (AF) is a multifaceted disease requiring personalised treatment. The aim of our study was to explore the prognostic impact of a patient-specific therapy (PT) for rate control, including the use of non-dihydropyridine calcium channel blockers (NDDC) in patients with heart failure (HF) or in combination with beta-blockers (BB), compared to standard rate control therapy (ST), as defined by previous ESC guidelines. This is a single-centre prospective observational registry on AF patients who were followed by our University Hospital. We included 1112 patients on an exclusive rate control treatment. The PT group consisted of 125 (11.2%) patients, 93/125 (74.4%) of whom were prescribed BB + NDCC (±digoxin), while 85/125 (68.0%) were HF patients who were prescribed NDCC, which was diltiazem in all cases. The patients treated with a PT showed no difference in one-year overall survival compared to those with an ST. Notably, the patients with HF in ST had a worse prognosis (p < 0.001). To better define this finding, we performed three sensitivity analyses by matching each patient in the PT subgroups with three subjects from the ST cohort, showing an improved one-year survival of the HF patients treated with PT (p = 0.039). Our results suggest a potential outcome benefit of NDCC for rate control in AF patients, either alone or in combination with BB and in selected patients with HF.

Photoplethysmographic (PPG) signals are mainly employed for heart rate estimation but are also fascinating candidates in the search for cardiovascular biomarkers. However, their high susceptibility to motion artifacts can lower their morphological quality and, hence, affect the reliability of the extracted information. Low reliability is particularly relevant when signals are recorded in a real-world context, during daily life activities. We aim to develop two classifiers to identify PPG pulses suitable for heart rate estimation (Basic-quality classifier) and morphological analysis (High-quality classifier). We collected wrist PPG data from 31 participants over a 24 h period. We defined four activity ranges based on accelerometer data and randomly selected an equal number of PPG pulses from each range to train and test the classifiers. Independent raters labeled the pulses into three quality levels. Nineteen features, including nine novel features, were extracted from PPG pulses and accelerometer signals. We conducted ten-fold cross-validation on the training set (70%) to optimize hyperparameters of five machine learning algorithms and a neural network, and the remaining 30% was used to test the algorithms. Performances were evaluated using the full features and a reduced set, obtained downstream of feature selection methods. Best performances for both Basic- and High-quality classifiers were achieved using a Support Vector Machine (Acc: 0.96 and 0.97, respectively). Both classifiers outperformed comparable state-of-the-art classifiers. Implementing automatic signal quality assessment methods is essential to improve the reliability of PPG parameters and broaden their applicability in a real-world context.

Cardiac implantable electronic device (CIED) infection represents a dramatic event with a high mortality rate (>3x) despite antibiotic therapy and device extraction; therefore, the real winning strategy in this situation could be represented by prevention. Antibiotic prophylaxis and antibiotic-releasing envelope are effective in improving patient outcome; however, healthcare costs related to CIED infections remain high over the years. In this review we would keep the attention on a pre-surgical checklist to reduce the risk of CIED infections. In fact, checklist is an effective instrument for medical care quality improvement mainly used in surgery, but not very commonly in cath-lab and electrophysiology procedures. All steps of this checklist are of proven effectiveness in reducing the risk of CIED infections but, up till now, they are not considered together in a pre-surgical approach.

Objective: To compare women's experience of first-trimester combined screening (FTCS), with women's experience of an approach that uses the combination of a detailed early anatomy scan and cell-free DNA (cfDNA) analysis. Methods: This was single-center, open label, parallel group, randomized clinical trial. Pregnant women were randomized at the time of their first prenatal visit to either a policy of first-trimester risk assessment based on FTCS, or to a policy of first-trimester risk assessment based on ultrasound findings and cfDNA. Control group included first-trimester risk assessment based on FTCS. FTCS included ultrasound evaluation with crown-rump length, nuchal translucency (NT) measurement, and a detailed ultrasound scan, along with biochemistry (PAPP-A and free beta hCG). In this group, diagnostic testing was offered to patients with risk >1 in 100, or NT >3.5 mm, or any fetal abnormalities on ultrasound. Women randomized in the intervention group received an approach of first-trimester risk assessment based on ultrasound findings and cfDNA. cfDNA analysis included a simultaneous microarray-based assay of non-polymorphic (chromosomes 13, 18, 21, X and Y) and polymorphic loci to estimate chromosome proportion and fetal fraction. In the intervention group, diagnostic testing was offered to patients with abnormal cfDNA screening results, or NT >3.5 mm, or any fetal abnormalities on ultrasound. Participants received pre-test and post-test questionnaires regarding to measure reassurance, satisfaction, and anxiety. The primary outcome was the post-test reassurance, defined as mean score of reassurance post-test questionnaire. The effect of the assigned screening test on the cumulative incidence or on the mean of each outcome was quantified as the relative risk (RR) or mean difference (MD) with 95% confidence interval (CI). Results: 40 women with singleton gestations were included in the trial. Mean score for reassurance was significantly higher in the cfDNA group compared to the FTCS group in the pre-test questionnaire (MD 0.80 points, 95% CI 0.27 to 1.33) and in the post-test questionnaire (MD 16.50 points, 95% CI 2.18 to 30.82). Women randomized to the cfDNA group had higher satisfication and lower mean anxiety score as assessed in the STAI pre-test questionnaire. Conclusions: First-trimester risk assessment for trisomy 21 with a combination of a detailed ultrasound examination and cfDNA is associated with better maternal reassurance and better maternal satisfaction compared to the standard first-trimester combined screening with nuchal trasclucency, and maternal serum free beta-human chorionic gonadotrophin (FbetahCG) and pregnancy-associated plasma protein A (PAPP-A). This article is protected by copyright. All rights reserved.

KEY TEACHING POINTS • Cardiac resynchronization therapy (CRT) implantation is feasible via the left superior access to the coronary sinus. Lead fixation can help the difficult left ventricle lead placement. • A pentapolar VDD lead can ensure atrial detection without the need of a dedicated atrial lead. • Two-lead CRT may reduce intravascular hardware when atrial stimulation is not needed. Open in a separate window Persistent left superior vena cava (PLSVC) is a congenital developmental abnormality of the sinus venosus with an incidence of 0.47% in patients undergoing cardiac implantable electronic devices.1 The 2 variants include a double superior vena cava (right and left SVC, with or without an innominate vein connecting the two) or a single left-sided SVC (without a right SVC), which may occur in one third of PLSVC subjects.1 This anatomic variant may hinder pacemaker / cardiac resynchronization therapy (CRT) device implantation, especially when the placement of the left ventricular (LV) lead is concerned.

Background: Ventricular sensing in transvenous cardiac implantable electronic devices (CIEDs) occurs conventionally from the right ventricular (RV) channel, though it evolved from epicardial sensing both in pacemakers and implantable cardioverter-defibrillators (ICDs). Hypothesis: The objective of this study was to observe the reliability of left ventricular (LV) sensing by transvenous leads placed in coronary veins. Methods: LV leads were used for sensing and arrhythmia detection in clinical situations where placement of an RV lead across the tricuspid valve was either not preferred or not feasible, or RV signal was unsuitable for arrhythmia detection, or in the event of sensing failure of an RV lead under advisory in cardiac resynchronization therapy defibrillator (CRTD) recipients. Results: Thirty-seven patients had an IS-1 LV lead connected to the RV port of CIEDs (17 pacemakers, 5 cardiac resynchronization therapy pacemaker [CRTP], 2 ICDs, and 13 CRTDs). Along a median 41 (25-67) months follow-up, lead performance remained stable; there were neither undersensing nor oversensing of non-cardiac signals. VT/VF were correctly detected and terminated by ATP and shocks (one and three patients, respectively); no inappropriate arrhythmia detection. Device reprogramming occurred in four CRTD recipients because of transient counting the QRS (short intervals) when paced in LV-only, and in two with T-wave oversensing. Conclusions: Ventricular sensing by an LV lead is feasible in transvenous devices. Sensing programmability is an unmet need: to fix RV lead sensing issues in cardiac resynchronization therapy (CRT) recipients at no risk of infection (no pocket opening); to avoid interaction with the tricuspid valve; to avoid lead redundancy in the vasculature. Moreover, it will be mandatory owing to the loss of lead interchangeability due to the adoption of DF-4 and quadripolar leads.

Background Despite the improvements in transvenous lead extraction (TLE), patients with cardiac implantable device related infection (CIEDI) have a poor prognosis at long term. We explored the possible role of factors associated with development of CIEDI as predictors of post-TLE survival. Methods We performed a multi-center prospective observational study in a population of consecutive patients referred for TLE for CIEDI. We adopted a previously developed 10-point scale for CIEDI risk stratification and assessed its performance in predicting post-TLE survival. Results We enrolled 169 consecutive patients with CIEDI (systemic infection in 48.5% and vegetations in 24.5%). A Shariff score ≥ 3 was present in 102/169 (60.4%) of the enrolled patients. Complete radiological success of TLE was obtained in 163 patients. Twenty-seven patients (15.9%) died after a mean follow-up of 20.8 ± 12.0 months. Two factors were independently associated with post-TLE death: a Shariff score ≥ 3 (HR 10.833, 95% CI 2.544–46.129; p = 0.001) and the presence of vegetations at transesophageal echocardiography (HR 3.324, 95% CI 1.530–7.221; p = 0.002). Conclusions Risk factors for development of CIEDI are also predictive of post TLE mortality, together with the presence of vegetations. Improvement of our preventive strategies for CIEDI is crucial for enhancing the outcomes of CIED patients overall.

Background: Chronic kidney disease (CKD) is associated with adverse outcomes in presence of atrial fibrillation (AF). However, the literature shows limited data on non-pharmacological management of AF in CKD patients. Aim: summarizing the available data on outcomes associated with electrical cardioversion (ECV) and AF catheter ablation (CA) in CKD patients. Methods: We searched MEDLINE and the Cochrane Central Register of Controlled Trials and performed a metaanalysis. The primary outcome was recurrence of AF. The secondary outcomes were occurrence of thromboembolic events (TEs) and estimated glomerular filtration rate (eGFR) modification. Results: Literature search yielded 26 eligible papers: 22 on CA and 4 concerning ECV. CKD patients presented more AF recurrences 30 days after ECV (OR 2.62, 95%CI 1.28-5.34; p Conclusion: ECV and CA for sinus rhythm restoration/maintenance in AF patients, albeit theoretically promising, seem to be associated with lower efficacy at medium to long-term in patients with CKD. Further studies are needed to better define the role of ECV and CA in CKD.

Background Atrial fibrillation (AF) is associated with high morbidity and mortality, also among anticoagulated patients. Our aim was to evaluate the predictive role for long-term mortality of a series of risk stratification scores associated with cardiovascular or thromboembolic outcomes (CHADS 2 , CHA 2 DS 2 -VASc, ATRIA, TIMI-AF), and bleeding complications (HAS-BLED) in an unselected population of patients with AF. Methods Single center, observational, prospective registry of consecutive patients with AF, undergoing clinical/echocardiographic evaluation in a University Hospital, as either in-patients or out-patients. We assessed the role of each single score as predictors of long-term survival according to clinical setting. Results We enrolled 1051 patients, mean age 72 ± 12 years, who were followed for 797 ± 298 days. All the tested scores showed a good performance in prediction of mortality, together with several clinical factors (older age, chronic heart failure, diabetes, renal impairment, previous transient ischemic attack, left ventricular ejection fraction). The values at C-statistics ranged between modest (0.608–0.684) of inpatients to good (0.708–0.751) in outpatients without any statistical difference between the scores, excepted a lower performance of HAD-BLED. Conclusions Risk scores currently adopted for decision making on starting oral anticoagulation provide good prediction of long-term survival in unselected AF patients, especially in the outpatient setting.

Background: We compared clinical and technical outcome of CRT recipients treated either with a conventional 3-leads (3L) CRTD or with the new 2-leads (DX) CRTD that enables atrial signal detection by a floating dipole built on a pentafilar RV lead. Methods: Echocardiography and cardiopulmonary exercise tests were repeated either before CRTD implantation and between 6 and 12 months follow up in consecutively implanted patients who had a resting heart rate. >. 40. bpm at maximum tolerated beta-blocker dosage. HF status, reverse LV remodeling, exercise tolerance and chronotropic incompetence were assessed at 12 months FU. Device diagnostics were obtained twice yearly until December 2016. Results: 37 patients aged 66 (58-73) years were consecutively implanted in 2013-2014 according to current guidelines, 25 with a 3L CRTD and 12 with a DX CRTD. Beta-blocker dosage was similar, and no difference between the 2 groups was observed in terms of NYHA class improvement, LV reverse remodeling, peak cardiopulmonary performance and presence of chronotropic incompetence at 12 months follow up. There was no difference in: amount delivered CRT; occurrence of VT/VF; occurrence of AT/AF. No patients developed need of atrial stimulation at 3-years FU. Atrial undersensing never occurred in any patient, whereas Far-field R-wave oversensing was more common in 3L patient than in DX patients (8/25 vs none, P

Dronedarone was found to have divergent safety profiles in randomized controlled trials (RCT) in term of cardiac death and overall mortality. We decided to evaluate all available evidence on the cardiovascular safety of this drug. A systematic search was made of the MEDLINE and the Cochrane Central Register of Controlled Trials from January 2003 through April 2016 for RCT comparing dronedarone to placebo/active control, to provide the most accurate estimate of the effects of this agent and observational cohort studies (OBS) reporting clinical outcomes in patients treated with dronedarone, according to current guidelines, to obtain a real-life comparator for the findings summarized by RTC analysis. The literature search yielded 2335 papers and after careful review we identified 12 RCT and 7 OBS studies. RCT meta-analysis showed that, despite high heterogeneity, dronedarone was not associated with increased all-cause mortality [OR (Odds Ratio) 1.36, 95%CI (Confidence Interval) 0.79-2.33; p=0.732, I2=57.0%] or cardiovascular mortality [OR 1.51 95%CI 0.74-3.08; p=0.860, I2=64.4%]. OBS studies had a trend toward a better survival with respect to RCT [ES (Effect Size) 2.03, 95%CI 0.53-3.53 vs. ES 3.03, 95%CI 1.23-4.83; p=0.115], reaching the significance when restricted to the cardiovascular mortality [ES 0.52, 95%CI 0.36-0.69 vs. ES 1.86, 95%CI 0.62-3.09; p

PURPOSE: Oncological patients are at increasing risk of QT prolongation, a risk factor for ventricular arrhythmia. We assessed impact and risk factors for corrected QT (QTc) prolongation during multiple-cycle chemotherapy. METHODS: We enrolled 100 outpatients initiating chemotherapy in a university center specializing in female cancer. Clinical, drug, laboratory, and 12-lead ECG data collection at baseline and at each chemotherapy cycle was performed. RESULTS: Enrolled patients were followed for 992 chemotherapy cycles (median 7; interquartile range 6-13); 2438 ECGs were recorded (20; 18-31) 36.8% pre-therapy, 36.8% following chemotherapy, and 22.5% 7-10 days after chemotherapy. Maximum QTc (Max-QTc) was recorded after 4 chemotherapy administrations in >50% of the entire cohort and also within every subset of patients with prolonged QTc (57% 471-480 ms; 54% 481-500 ms; 66% >500 ms). No cumulative effect on QTc was shown. QTc prolongation was comparable among the various protocols. Prophylactic/supportive drugs were not associated with additional QTc prolongation. Variables independently associated with QTc prolongation >470 ms were age (OR 1.056 95% CI 1.006-1.108, p = 0.028) and the baseline-first chemotherapy averaged QTc (BC-QTc) (OR 1.092 95% CI 1.051-1.136), a novel parameter devised for this study. Only BC-QTc maintained significance for QTc >480 ms. BC-QTc >435 ms identified 100 % of patients with Max-QTc >500 ms, 96% with Max-QTc 481-500 ms, and 66% with Max-QTc 471-480 ms. Only 29% of patients with Max-QTc ≤470 ms presented a BC-QTc >435 ms. CONCLUSIONS: Our results confirm the high prevalence of QTc prolongation after chemotherapy. Most of the patients reached Max-QTc after several cycles. BC-QTc may help in stratifying arrhythmic risk in real-world clinical practice.