Prognostic Electrocardiographic Signs in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a rare cardiac disease, characterized by the progressive replacement of myocardial tissue with fibrous and fatty deposits. It can involve both the right and left ventricles. It is associated with the development of life-threatening arrhythmias and culminates in sudden cardiac death. Electrocardiography (ECG) has emerged as a pivotal tool, offering diagnostic insights and prognostic information. The specific ECG abnormalities observed in ACM not only contribute to early detection but also hold the key to the prediction of the likelihood of severe complications. The recognition of these nuanced ECG manifestations has become imperative for clinicians as it guides them in the formulation of tailored therapeutic strategies that address both the present symptoms and the potential future risks.

Cardiac conduction disorders in young adults: Clinical characteristics and genetic background of an underestimated population.

BACKGROUND: Cardiac conduction disorder (CCD) in patients <50 years old is a rare and mostly unknown condition. OBJECTIVE: We aimed to assess clinical characteristics and genetic background of patients <50 years old with CCD of unknown origin. METHODS: We retrospectively reviewed a consecutive series of patients with a diagnosis of CCD before the age of 50 years referred to our center between January 2019 and December 2021. Patients underwent complete clinical examination and genetic evaluation. RESULTS: We enrolled 39 patients with a median age of 40 years (28-47 years) at the onset of symptoms. A cardiac implantable electronic device was implanted in 69% of the patients. In 15 of 39 CCD index patients (38%), we found a total of 13 different gene variations (3 pathogenic, 6 likely pathogenic, and 4 variants of uncertain significance), mostly in 3 genes (SCN5A, TRPM4, and LMNA). In our cohort, genetic testing led to the decision to implant an implantable cardioverter-defibrillator in 2 patients for the increased risk of sudden cardiac death. CONCLUSION: Patients with the occurrence of CCD before the age of 50 years present with a high rate of pathologic gene variations, mostly in 3 genes (SCN5A, TRPM4, and LMNA). The presence of pathogenic variations may add information about the prognosis and lead to an individualized therapeutic approach.

Comparative Study of Lesions Obtained through Radiofrequency between the Irrigated Ablation Catheter with a Flexible Tip and the Non-Irrigated Catheter in Ex Vivo Porcine Hearts.

BACKGROUND: At the same conditions of delivered power and contact force, open-irrigated radiofrequency ablation catheters are believed to create deeper lesions, while non-irrigated ones produce shallower lesions. This ex vivo study aims to directly compare the lesion dimensions and characteristics of an irrigated ablation catheter with a flexible tip and a non-irrigated solid-tip catheter. METHODS: Radiofrequency lesions were induced on porcine myocardial slabs using both open-tip irrigated and non-irrigated standard 4 mm catheters at three power settings (20 W, 30 W, and 40 W), maintaining a fixed contact force of 10 gr. A lesion assessment was conducted including the lesion depth, depth at the maximum diameter, and lesion surface diameters, with the subsequent calculation of the lesion volume and area being undertaken. RESULTS: Irrigated catheters produced lesions with significantly higher superficial widths at all power levels (3.8 vs. 4.4 mm at 20 W; 3.9 mm vs. 4.4 mm at 30 W; 3.8 mm vs. 4.5 mm at 40 W; p = 0.001, p = 0.019, p = 0.003, respectively). Non-irrigated catheters resulted in significantly higher superficial areas at all power levels (23 mm2 vs. 18 mm2 at 20 W; 25 mm2 vs. 19 mm2 at 30 W; 26 mm2 vs. 19 mm2 at 40 W; p = 0.001, p = 0.005, p = 0.001, respectively). Irrigated catheters showed significantly higher values of lesion maximum depth at 40 W (4.6 mm vs. 5.5 mm; p = 0.007), while non-irrigated catheters had a significantly higher calculated volume at 20 W (202 µL vs. 134 µL; p = 0.002). CONCLUSIONS: Radiofrequency ablation using an irrigated catheter with a flexible tip has the potential to generate smaller superficial lesion areas compared with those obtained using a non-irrigated catheter.

Ultrasound-Guided Venous Axillary Access Versus Standard Fluoroscopic Technique for Cardiac Lead Implantation: ZEROFLUOROAXI Randomized Trial.

BACKGROUND: Axillary vein puncture (AVP) and cephalic vein surgical cutdown are recommended in international guidelines because of their low risk of pneumothorax and chronic lead complications. Directly visualizing and puncturing the axillary vein under ultrasound guidance reduces radiation exposure, provides direct needle visualization, and lowers periprocedural complications. Our hypothesis is that ultrasound-guided axillary access is safer and more feasible than the standard fluoroscopic technique. OBJECTIVES: The purpose of this study was to assess the efficacy and safety of ultrasound-guided axillary venous access during cardiac lead implantation for pacemakers (PMs) and implantable cardioverter-defibrillator (ICD) implantations. METHODS: Patients were randomized in a 1:1 fashion to either axillary venous access under fluoroscopic guidance or ultrasound-guided axillary venous access. The composite outcome, including pneumothorax, hemothorax, inadvertent arterial puncture, pocket hematoma, pocket infection, lead dislodgement, and death, was evaluated 30 days after implantation. RESULTS: We randomized 270 patients into 2 groups: the standard group for fluoroguided AVP (n = 134) and the experimental group for ultrasound-guided AVP (n = 136). No disparities in baseline characteristics were observed between the groups. The median age of the patients was 81 years, with women comprising 41% of the population. The majority of patients received single- and dual-chamber PMs (87% vs 88%; P = 1.00), and slightly over 10% in both groups received ICDs (13% vs 12%; P = 0.85). In total, we placed 357 leads in PMs and 48 leads in ICDs. Among these, 295 leads were inserted via axillary vein access and 110 via cephalic vein access. Notably, the subclavian vein was never used as a vascular access. The composite outcome was lower in the ultrasound group according to intention-to-treat analysis (OR: 0.55; 95% CI: 0.31-0.99; P = 0.034). The main difference within the composite outcome was the lower incidence of inadvertent axillary arterial puncture in the experimental group (17% vs 6%; P = 0.004). The ultrasound group also exhibited lower total procedural x-ray exposure (10,344 µGy × cm2 vs 7,119 µGy × cm2; P = 0.002) while achieving the same rate of success at the first attempt (61% vs 69%; P = 0.375). CONCLUSIONS: Ultrasound-guided AVP is safer than the fluoroscopy-guided approach because it achieves the same rate of acute success while maintaining low total procedural radiation exposure. Ultrasound AVP should be considered the optimal venous access method for cardiac lead implantation. (Ultrasound Guided Axillary Access vs Standard Fluoroscopic Technique for Cardiac Lead Implantation [ZEROFLUOROAXI]; NCT05101720).

Trends in atrial fibrillation-related mortality in Europe, 2008-2019.

AIMS: Update data regarding the atrial fibrillation (AF)-related mortality trend in Europe remains scant. We assess the age- and sex- specific trends in AF-related mortality in the European states between the years 2008 and 2019. METHODS AND RESULTS: Data on cause-specific deaths and population numbers by sex for European countries were retrieved through the publicly available World Health Organization (WHO) mortality dataset for the years 2008 to 2019. AF-related deaths were ascertained when the ICD-10 code I48 was listed as the underlying cause of death in the medical death certificate. To calculate annual trends, we assessed the average (AAPC) annual % change with relative 95% confidence intervals (CIs) using Joinpoint regression. During the study period, 773 750 AF-related deaths (202 552 males and 571 198 females) occurred in Europe. The age-adjusted mortality rate (AAMR) linearly increased from 12.3 (95% CI: 11.2 to 12.9) per 100 000 population in 2008 to 15.3 (95% CI: 14.7 to 15.7) per 100 000 population in 2019 [AAPC: +2.0% (95% CI: 1.6 to 3.5), p < 0.001] with a more pronounced increased among men [AAPC: +2.7% (95% CI: 1.9 to 3.5), p < 0.001] compared to women [AAPC: +1.7% (95% CI: 1.1 to 2.3), p < 0.001] (p for parallelism 0.01). The higher AAMR increased was observed in some eastern European countries such as Latvia, Lithuania and Poland while the lower were mainly clustered in the central Europe. CONCLUSIONS: Over the last decade, the age-adjusted AF-related mortality has increased in Europe especially among males. Disparities still exist between western and eastern European countries.

SCN5A mutation is associated with a higher Shanghai Score in patients with type 1 Brugada ECG pattern.

AIMS: Brugada syndrome (BrS) is an inherited arrhythmic disease characterized by a coved ST-segment elevation in the right precordial electrocardiogram leads (type 1 ECG pattern) and is associated with a risk of malignant ventricular arrhythmias and sudden cardiac death. In order to assess the predictive value of the Shanghai Score System for the presence of a SCN5A mutation in clinical practice, we studied a cohort of 125 patients with spontaneous or fever/drug-induced BrS type 1 ECG pattern, variably associated with symptoms and a positive family history. METHODS: The Shanghai Score System items were collected for each patient and PR and QRS complex intervals were measured. Patients were genotyped through a next-generation sequencing (NGS) custom panel for the presence of SCN5A mutations and the common SCN5A polymorphism (H558R). RESULTS: The total Shanghai Score was higher in SCN5A+ patients than in SCN5A- patients. The 81% of SCN5A+ patients and the 100% of patients with a SCN5A truncating variant exhibit a spontaneous type 1 ECG pattern. A significant increase in PR (P = 0.006) and QRS (P = 0.02) was detected in the SCN5A+ group. The presence of the common H558R polymorphism did not significantly correlate with any of the items of the Shanghai Score, nor with the total score of the system. CONCLUSION: Data from our study suggest the usefulness of Shanghai Score collection in clinical practice in order to maximize genetic test appropriateness. Our data further highlight SCN5A mutations as a cause of conduction impairment in BrS patients.

A Comparative Assessment of Myocardial Work Performance during Spontaneous Rhythm, His Bundle Pacing, and Left Bundle Branch Area Pacing: Insights from the EMPATHY Study.

BACKGROUND: Physiological pacing has gained significant interest due to its potential to achieve optimal hemodynamic response. This study aimed to assess left ventricular performance in terms of electrical parameters, specifically QRS duration and mechanical performance, evaluated as myocardial work. We compared His Bundle Pacing (HBP) and Left Bundle Branch Area Pacing (LBBAP) to evaluate their effects. METHODS: Twenty-four patients with class I or IIa indications for pacing were enrolled in this study, with twelve patients undergoing HBP implantation and another twelve undergoing LBBAP implantation. A comprehensive analysis of myocardial work was conducted. RESULTS: Our findings indicate that there were no major differences in terms of spontaneous and HBP activation in myocardial work, except for global wasted work (217 mmHg% vs. 283 mmHg%; p 0.016) and global work efficiency (87 mmHg% vs. 82 mmHg%; p 0.049). No significant differences were observed in myocardial work between spontaneous activation and LBBAP. Similarly, no significant differences in myocardial work were found between HBP and LBBAP. CONCLUSIONS: Both pacing modalities provide physiological ventricular activation without significant differences when compared to each other. Moreover, there were no significant differences in QRS duration between HBP and LBBAP. However, LBBAP demonstrated advantages in terms of feasibility, as it achieved better lead electrical parameters compared to HBP (threshold@0.4 ms 0.6 V vs. 1 V; p = 0.045-sensing 9.4 mV vs. 2.4 mV; p < 0.001). Additionally, LBBAP required less fluoroscopy time (6 min vs. 13 min; p = 0.010) and procedural time (81 min vs. 125 min; p = 0.004) compared to HBP.

Brugada Syndrome: More than a Monogenic Channelopathy.

Brugada syndrome (BrS) is an inherited cardiac channelopathy first diagnosed in 1992 but still considered a challenging disease in terms of diagnosis, arrhythmia risk prediction, pathophysiology and management. Despite about 20% of individuals carrying pathogenic variants in the SCN5A gene, the identification of a polygenic origin for BrS and the potential role of common genetic variants provide the basis for applying polygenic risk scores for individual risk prediction. The pathophysiological mechanisms are still unclear, and the initial thinking of this syndrome as a primary electrical disease is evolving towards a partly structural disease. This review focuses on the main scientific advancements in the identification of biomarkers for diagnosis, risk stratification, pathophysiology and therapy of BrS. A comprehensive model that integrates clinical and genetic factors, comorbidities, age and gender, and perhaps environmental influences may provide the opportunity to enhance patients' quality of life and improve the therapeutic approach.

Trends in age- and sex-specific atrial fibrillation/flutter mortality in Italy between 2003 and 2017.

AIMS: We sought to assess the atrial fibrillation/flutter (AF/AFL) mortality rates and relative trends among the Italian population between 2003 and 2017. METHODS: Data regarding the cause-specific mortality and population size by sex in 5-year age groups were extracted from the World Health Organization (WHO) global mortality database. Decedents reporting the codes I48 were extracted accordingly to the International Classification of Disease-10 (ICD-10) coding system. The age-adjusted mortality rates (AAMRs), with relative 95% confidence intervals (CIs), also stratified by sex, were determined using the direct method. Joinpoint regression analyses were used to identify periods with statistically distinct log linear trends in AF/AFL-related death rates. To calculate nationwide annual trends in AF/AFL-related mortality, we assessed the average annual percentage change (AAPC) and relative 95% CIs. RESULTS: Over the study period, 90 623 (57 109 females) AF-related deaths were recorded. The AF/AFL AAMR increased from 8.1 (95% CI: 7.8-8.2) deaths per 100 000 to 18.7 (16.9-20.0) deaths per 100 000 population. Joinpoint regression analysis revealed a linear increase in age-standardized AF/AFL-related mortality [AAPC: +3.6 (95% CI: 3.0-4.3, P  < 0.0001)] in the entire Italian population. Moreover, the mortality rate increased with age, showing a seemingly exponential distribution with a similar trend between males and females. Although the increase was more pronounced among women [AAPC: +3.7 (95% CI: 3.1-4.3, P  < 0.0001)] compared with men [AAPC: +3.4 (95% CI: 2.8-4.0, P  < 0.0001)], the difference did not reach statistical significance ( P  = 0.16). CONCLUSIONS: In Italy, the AF/AFL-related mortality rates linearly increased from 2003 to 2017.

Incidence of ventricular arrhythmias related to COVID infection and vaccination in patients with Brugada syndrome: Insights from a large Italian multicenter registry based on continuous rhythm monitoring.

INTRODUCTION: Brugada syndrome (BrS) has a dynamic ECG pattern that might be revealed by certain conditions such as fever. We evaluated the incidence and management of ventricular arrhythmias (VAs) related to COVID-19 infection and vaccination among BrS patients carriers of an implantable loop recorder (ILR) or implantable cardioverter-defibrillator (ICD) and followed by remote monitoring. METHODS: This was a multicenter retrospective study. Patients were carriers of devices with remote monitoring follow-up. We recorded VAs 6 months before COVID-19 infection or vaccination, during infection, at each vaccination, and up to 6-month post-COVID-19 or 1 month after the last vaccination. In ICD carriers, we documented any device intervention. RESULTS: We included 326 patients, 202 with an ICD and 124 with an ILR. One hundred and nine patients (33.4%) had COVID-19, 55% of whom developed fever. Hospitalization rate due to COVID-19 infection was 2.76%. After infection, we recorded only two ventricular tachycardias (VTs). After the first, second, and third vaccines, the incidence of non-sustained ventricular tachycardia (NSVT) was 1.5%, 2%, and 1%, respectively. The incidence of VT was 1% after the second dose. Six-month post-COVID-19 healing or 1 month after the last vaccine, we documented NSVT in 3.4%, VT in 0.5%, and ventricular fibrillation in 0.5% of patients. Overall, one patient received anti-tachycardia pacing and one a shock. ILR carriers had no VAs. No differences were found in VT before and after infection and before and after each vaccination. CONCLUSIONS: From this large multicenter study conducted in BrS patients, followed by remote monitoring, the overall incidence of sustained VAs after COVID-19 infection and vaccination is relatively low.

Structural Abnormalities in Brugada Syndrome and Non-Invasive Cardiac Imaging: A Systematic Review.

The aim of this review is to identify possible structural abnormalities of BrS and their potential association with symptoms, risk stratification, and prognosis. (1) Background: BrS has always been considered a purely electrical disease and imaging techniques do not currently play a specific role in the diagnosis of this arrhythmic syndrome. Some authors have recently hypothesized the presence of structural and functional abnormalities. Therefore, several studies investigated the presence of pathological features in echocardiography and cardiac magnetic resonance imaging (MRI) in patients with BrS, but results were controversial. (2) Methods: We performed a systematic review of the literature on the spectrum of features detected by echocardiography and cardiac MRI. Articles were searched in Pubmed, Cochrane Library, and Biomed Central. Only papers published in English and in peer-reviewed journals up to November 2021 were selected. After an initial evaluation, 596 records were screened; the literature search identified 19 relevant articles. (3) Results: The imaging findings associated with BrS were as follows: right ventricular dilation, right ventricular wall motion abnormalities, delayed right ventricular contraction, speckle and feature tracking abnormalities, late gadolinium enhancement, and fat infiltration in the right ventricle. Furthermore, these features emerged more frequently in patients carrying the genetic mutation on the sodium voltage-gated channel α-subunit 5 (SCN5A) gene. (4) Conclusions: Specific imaging features detected by echocardiography and cardiac magnetic resonance are associated with BrS. However, this population appears to be heterogeneous and imaging anomalies emerged to be more frequent in patients carrying genetic mutations of SCN5A. Future studies with an evaluation of BrS patients are needed to identify the specific association linking the Brugada pattern, imaging abnormalities and their possible correlation with prognosis.

TeleNEwCARe: An Italian case-control telegenetics study in patients with Hereditary NEuromuscular and CARdiac diseases.

Telemedicine provides healthcare services remotely and represents a fundamental resource for the management of rare and fragile patients. Tele-health implementation is a main objective of the European Reference Networks (ERNs) mission to accelerate diagnosis for rare diseases. TeleNewCARe is a pilot case-control project which evaluates the efficacy and satisfaction of telegenetics for neuromuscular and cardiac adult patients, compared to face-to-face genetic counselling. The virtual sessions were co-hosted by a medical geneticist and a neurologist/cardiologist. Specific questionnaires (Clinical Genetics Satisfaction Questionnaire (CGS), Telemedicine Satisfaction Questionnaire (TSQ) and a Satisfaction Questionnaire for medical geneticists) were used to assess the effectiveness and fulfilment of telecounselling, both for patients and health care providers. Satisfaction expressed for telegenetics did not significantly differ from face-to-face counselling. The virtually enrolled patients declared they had the possibility to relate confidentially with the specialists, to share information and to be informed in an exhaustive way about their disease. Almost all patients declared themselves willing to reuse the telecounselling in the future. The multidisciplinary care was perceived as a significant added value. No overt technical problems were reported although the need for digital skills and tools can limit patients' compliance. Our experience supports telegenetics as a valid alternative to traditional genetic counselling in cardiac and neuromuscular patients. This innovative approach facilitates multidisciplinary care, grants a periodical follow up, without forcing patients to discomfortable travelling, and allows to maintain expert care. This result meets the ERNs needs to reduce patients' burden to access and monitor their healthcare.

Vascular Accesses in Cardiac Stimulation and Electrophysiology: An Italian Survey Promoted by AIAC (Italian Association of Arrhythmias and Cardiac Pacing).

Cardiac implantable electronic device (CIED) implants and electrophysiological procedures share a common step: vascular access. On behalf of the AIAC Ricerca Investigators' Network, we conducted a survey to outline Italian common practice regarding vascular access in EP-lab. All Italian physicians with experience in CIED implantation and electrophysiology were invited to answer an online questionnaire (from May 2020 to November 2020) featuring 20 questions. In total, 103 cardiologists (from 92 Italian hospitals) answered the survey. Vascular access during CIED implants was considered the most complex step following lead placement by 54 (52.4%) respondents and the most complex for 35 (33.9%). In total, 54 (52.4%) and 49 (47.6%) respondents considered the cephalic and subclavian vein the first option, respectively (intrathoracic and extrathoracic subclavian/axillary vein by 22 and 27, respectively). In total, 45 (43.7%) respondents performed close arterial femoral accesses manually; only 12 (11.7%) respondents made extensive use of vascular closure devices. A total of 46 out of 103 respondents had experience in ultrasound-guided vascular accesses, but only 10 (22%) used it for more than 50% of the accesses. In total, 81 (78.6%) respondents wanted to increase their ultrasound-guided vascular access skills. Reducing complications is a goal to reach in cardiac stimulation and electrophysiological procedures. Our survey shows the heterogeneity of the vascular approaches used in Italian centres. Some vascular accesses were proved to be superior to others in terms of complications, with ultrasound-guided puncture as an emerging technique. More effort to produce the standardization of vascular accesses could be made by scientific societies.

Management of macro-reentrant right atrial tachycardia around multiple leads aided by high-density mapping.

BACKGROUND: A 61-year-old male with Steinert Dystrophy and prior history of cardiac implantable device complained of highly symptomatic right atrial tachycardia. Unresponsive to pharmacological therapy. METHODS: The patient underwent catheter ablation procedure aided by high-density mapping. RESULTS: Ablation procedure was succesful. CONCLUSIONS: This unique case report highlights the role of high-density mapping in the identification of critical isthmus and management of macro-reentrant tachycardia in complex situations such as the presence of multiple leads in the chamber.

Antibiotic prophylaxis based on individual infective risk stratification in cardiac implantable electronic device: the PRACTICE study.

AIMS: In patients undergoing cardiac implantable electronic device (CIED) intervention, routine pre-procedure antibiotic prophylaxis is recommended. A more powerful antibiotic protocol has been suggested in patients at high risk of infection. Stratification of individual infective risk could guide the prophylaxis before CIED procedure. METHODS AND RESULTS: Patients undergoing CIED surgery were stratified according to the Shariff score in low and high infective risk. Patients in the 'low-risk' group were treated with only two antibiotic administrations while patients in the 'high-risk' group were treated with a prolonged 9-day protocol, according to renal function and allergies. We followed-up patients for 250 days with clinical outpatient visit and electronic control of the CIED. As primary endpoint, we evaluated CIED-related infections. A total of 937 consecutive patients were enrolled, of whom 735 were stratified in the 'low-risk' group and 202 in the 'high-risk' group. Despite different risk profiles, CIED-related infection rate at 250 days was similar in the two groups (8/735 in 'low risk' vs. 4/202 in 'high risk', P = 0.32). At multivariate analysis, active neoplasia, haematoma, and reintervention were independently associated with CIED-related infection (HR 5.54, 10.77, and 12.15, respectively). CONCLUSION: In a large cohort of patients undergoing CIED procedure, an antibiotic prophylaxis based on individual stratification of infective risk resulted in similar rate of infection between groups at high and low risk of CIED-related infection.

Zero-Fluoroscopy Cardiac Ablation: Technology Is Moving Forward in Complex Procedures-A Novel Workflow for Atrial Fibrillation.

BACKGROUND AND RATIONALE: A fluoroscopy-based approach to an electrophysiological procedure is widely validated and has been recognized as the gold standard for a long time. The use of fluoroscopy exposes both the healthcare staff and the patient to a non-negligible dose of radiation. To minimize the risks associated with the use of fluoroscopy, it would be reasonable to perform ablation procedures with zero fluoroscopy. This approach is widely used in simple ablation procedures, but not in complex procedures. In atrial fibrillation (AF) ablation procedures, fluoroscopy remains the main technology used, in particular to guide the transseptal puncture. Main results and Implications. We present a workflow to perform a complete zero-fluoroscopy ablation for AF ablation procedures using a 3D electro-anatomical mapping system, intracardiac echocardiography and a novel steerable guiding sheath that can be visualized on the mapping system. We present two cases, one with paroxysmal AF and the other one with persistent AF during which we applied this novel workflow achieving a successful pulmonary vein isolation without complications and complete zero-fluoroscopy exposure.

Left Ventricular Myocardial Noncompaction with Advanced Atrioventricular Conduction Disorder and Ventricular Arrhythmias in a Young Patient: Role of MIB1 Gene.

Left ventricular noncompaction (LVNC) is a structural abnormality of the left ventricle, usually described as an isolated condition, or sometimes associated with other structural cardiac diseases. LVNC is generally asymptomatic, although it may present conduction disorders, arrhythmias, and heart failure. Here, we present the case of a patient who came to our attention with a severe LVNC phenotype associated with advanced AV conduction disorder, and supraventricular and ventricular arrhythmias at young age, in which a novel MIB1, likely pathogenic, variation has been identified.

Functional Characterization of Two Novel Mutations in SCN5A Associated with Brugada Syndrome Identified in Italian Patients.

BACKGROUND: Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by "coved type" ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20-30% of BrS cases and is considered clinically relevant. METHODS: Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel SCN5A mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. RESULTS: Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. CONCLUSIONS: Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention.