Cardiac contractility modulation in patients with heart failure - A review of the literature.

Experimental in vivo and in vitro studies showed that electric currents applied during the absolute refractory period can modulate cardiac contractility. In preclinical studies, cardiac contractility modulation (CCM) was found to improve calcium handling, reverse the foetal myocyte gene programming associated with heart failure (HF), and facilitate reverse remodeling. Randomized control trials and observational studies have provided evidence about the safety and efficacy of CCM in patients with HF. Clinically, CCM therapy is indicated to improve the 6-min hall walk, quality of life, and functional status of HF patients who remain symptomatic despite guideline-directed medical treatment without an indication for cardiac resynchronization therapy (CRT) and have a left ventricular ejection fraction (LVEF) ranging from 25 to 45%. Although there are promising results about the role of CCM in HF patients with preserved LVEF (HFpEF), further studies are needed to elucidate the role of CCM therapy in this population. Late gadolinium enhancement (LGE) assessment before CCM implantation has been proposed for guiding the lead placement. Furthermore, the optimal duration of CCM application needs further investigation. This review aims to present the existing evidence regarding the role of CCM therapy in HF patients and identify gaps and challenges that require further studies.

Radiofrequency versus cryoballoon catheter ablation in patients with persistent atrial fibrillation: A randomized trial.

INTRODUCTION: Patients with persistent atrial fibrillation (AF) represent a challenging population for rhythm control therapies. Catheter ablation (CA) with pulmonary vein isolation (PVI) is an effective treatment option for the reduction of the arrhythmic burden. Data regarding the comparability between radiofrequency (RF) and cryoballoon ablation (CRYO) in persistent AF are limited. METHODS: This is a prospective, randomized, single-center study designed to compare the efficacy in terms of rhythm control between RF and CRYO in persistent AF. Eligible participants were randomized 2:1 in two arms: RF and CRYO. The primary endpoint of the study was arrhythmia relapse in the early postprocedural period (first 3 months) and in the middle term follow-up (3 months to 12 months). Secondary endpoints included procedure duration, fluoroscopy time, and complications. RESULTS: A total of 199 patients participated in the study (133 patients in the RF arm, 66 in the CRYO arm). No statistically significant difference occurred between the two groups regarding the primary endpoint (recurrences ≤3 months: 35.5% RF vs. 37.9% CRYO, p .755, recurrences >3 months: 26.3% RF vs. 27.3% CRYO, p .999). From the secondary endpoints, CRYO was a procedure of significantly shorter duration (75.15 ± 17.21 in CRYO vs. 136.6 ± 43.33 in RF group, p < .05). CONCLUSION: CRYO and RF ablation appear to be equally effective for rhythm control in patients with persistent AF. CRYO ablation is advantageous in terms of procedure duration.

Electrocardiographic changes after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: Data from the Hellenic Registry.

BACKGROUND: Balloon pulmonary angioplasty (BPA) has provided an effective invasive treatment for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). The hemodynamic improvement achieved by BPA has significantly increased the long-term prognosis of these patients, mostly by reversing the negative remodeling of the right ventricle (RV). MATERIALS AND METHODS: In a cohort of 17 patients with symptomatic CTEPH hemodynamic data were collected before and after the completion of BPA sessions. After the confirmation of statistically significant hemodynamic improvement, we examined the changes in certain prespecified electrocardiographic (ECG) parameters (PR interval duration, QRS duration, QTc interval duration, R wave and S wave amplitude in lead I, R wave and S wave amplitude in precordial leads V1, V5 and V6) before the initiation and one month after the completion of BPA sessions. In addition, ECGs were qualitatively assessed before and after treatment for the presence of ECG abnormalities related to PH, proposed by the guidelines of the European Society of Cardiology (ESC). The term ESC criteria 1-6 was used for their description. RESULTS: Statistically significant correlation (p < 0.05) was found between the reduction in mean pulmonary artery pressure (mPAP) and the decrease of the depth of the S wave in leads I (p 0.0069), V5 (p 0.0003), V6 (p 0.0011) and in the R wave amplitude in leads V5 (p 0.0122) and V6 (p 0.0185). From the ESC criteria, RV strain pattern was the commonest in the initial cohort, with significant improvement after therapies. CONCLUSION: Hemodynamic improvement after BPA therapies is correlated with improved ECG amplitude parameters in leads I, V5 and V6. RV strain pattern is common among untreated patients with significant improvement after therapies.

Atrial cardiomyopathy: Diagnosis, clinical implications and unresolved issues in anticoagulation therapy.

Atrial cardiomyopathy (AC) is an evolving pathophysiological entity that has expanded our understanding regarding the atrium and its role in arrhythmogenesis and cardiac thromboembolism. The pathological myocardium in AC promotes arrhythmogenesis through mechanical dysfunction (hypocontractility, fibrosis), adverse alterations of the endothelium and secretion of prothrombotic factors (IL-6, IL-8, TNF-a). 'Red flags', indicative of AC, can be recognized either non-invasively by electrocardiography, echocardiography and cardiac magnetic resonance imaging or invasively by high-density electroanatomical mapping as low bipolar voltage areas of the affected myocardium. Signs of AC have been strongly associated with an increased risk of ischemic stroke, even embolic strokes of undetermined source, regardless of the coexistence of atrial fibrillation (AF). The underlying existence of AC has been negatively correlated with the success rate of catheter ablation of AF. The clinical value of AC is the provision of a novel pathway regarding the potential mechanisms of cerebrovascular events of cardiac thromboembolic origin. In addition, AC may serve as a risk stratification tool to predict the long-term responders of AF catheter ablation.

Diagnostic and therapeutic dilemmas in a patient with myocarditis, Brugada syndrome and arrhythmic syncope.

We present a case of a previously healthy 23-year-old male who presented with chest pain, palpitations and spontaneous type 1 Brugada electrocardiographic (ECG) pattern. Positive family history for sudden cardiac death (SCD) was remarkable. Initially, clinical symptoms in combination with myocardial enzymes elevation, regional myocardial oedema with late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and inflammatory lymphocytoid-cell infiltrates in the endomyocardial biopsy (EMB) suggested the diagnosis of a myocarditis-induced Brugada phenocopy (BrP). Under immunosuppressive therapy with methylprednisolone and azathioprine, a complete remission of both symptoms and biomarkers was accomplished. However, the Brugada pattern did not resolve. The eventually spontaneous Brugada pattern type 1 established the diagnosis of Brugada syndrome (BrS). Due to his previous history of syncope, the patient was offered an ICD that he declined. After his discharge he experienced a new episode of arrhythmic syncope. He was readmitted and received an ICD.

Predictors of fatal arrhythmic events in patients with non-compaction cardiomyopathy: a systematic review.

Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease with autosomal dominant inheritance. This review aims to summarize the existing data about the predictors of fatal arrhythmias in patients with LVNC. Medline and Cochrane library databases were searched from inception to November 2021 for articles on LVNC. The reference lists of the relevant research studies as well as the relevant review studies and meta-analyses were also searched. Clinical symptoms and electrocardiogram findings such as left bundle branch block are significantly associated with ventricular arrhythmias. Other non-invasive tools such as Holter monitoring, echocardiography, and cardiac magnetic resonance (CMR) can provide additional value for risk stratification. CMR-derived left and right ventricular ejection fraction, left ventricular end-diastolic diameter, late gadolinium enhancement, and non-compacted to compacted myocardium ratio are predictive of ventricular arrhythmias. An electrophysiological study can provide additional prognostic data in patients with LVNC who are at moderate risk of ventricular arrhythmias. Risk stratification of LVNC patients with no prior history of a fatal arrhythmic event remains challenging. Symptoms assessment, electrocardiogram, Holter monitoring, and cardiac imaging should be performed on every patient, while an electrophysiological study should be performed for moderate-risk patients. Large cohort studies are needed for the construction of score models for arrhythmic risk stratification purposes.

The role of cardiac magnetic resonance in identifying appropriate candidates for cardiac resynchronization therapy - a systematic review of the literature.

Despite the strict indications for cardiac resynchronization therapy (CRT) implantation, a significant proportion of patients will fail to adequately respond to the treatment. This systematic review aims to present the existing evidence about the role of cardiac magnetic resonance (CMR) in identifying patients who are likely to respond better to the CRT. A systematic search in the MedLine database and Cochrane Library from their inception to August 2021 was performed, without any limitations, by two independent investigators. We considered eligible observational studies or randomized clinical trials (RCTs) that enrolled patients > 18 years old with heart failure (HF) of ischaemic or non-ischaemic aetiology and provided data about the association of baseline CMR variables with clinical or echocardiographic response to CRT for at least 3 months. This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA Statement). Following our search strategy, 47 studies were finally included in our review. CMR appears to have an additive role in identifying the subgroup of patients who will respond better to CRT. Specifically, the presence and the extent of myocardial scar were associated with increased non-response rates, while those with no scar respond better. Furthermore, existing data show that scar location can be associated with CRT response rates. CMR-derived markers of mechanical desynchrony can also be used as predictors of CRT response. CMR data can be used to optimize the position of the left ventricular lead during the CRT implantation procedure. Specifically, positioning the left ventricular lead in a branch of the coronary sinus that feeds an area with transmural scar was associated with poorer response to CRT. CMR can be used as a non-invasive optimization tool to identify patients who are more likely to achieve better clinical and echocardiographic response following CRT implantation.

Right ventricular outflow tract endocardial unipolar substrate mapping: implications in risk stratification of Brugada syndrome.

Brugada syndrome (BrS) is a complex arrhythmogenic disease displaying electrical and micro-structural abnormalities mainly located at the epicardium of the right ventricular outflow tract (RVOT). It is well-known that fibrosis, fatty infiltration, inflammation and reduced gap junction expression have been demonstrated at the epicardial anterior aspect of the RVOT providing the arrhythmogenic substrate for ventricular arrhythmic events in BrS. A number of models have been proposed for the risk stratification of patients with BrS. Endocardial unipolar electroanatomical mapping is an emerging tool that has been reintroduced to identify and quantify epicardial electrical abnormalities. Interestingly, current findings correlate the presence of large-sized endocardial unipolar electroanatomical abnormalities with either ventricular fibrillation inducibility during programmed ventricular stimulation or symptom status. This review aims to present existing data about the role of endocardial unipolar electroanatomical mapping for the identification of RVOT epicardial abnormalities as well as its potential clinical implications in risk stratification of BrS.

Modern mapping and ablation of idiopathic outflow tract ventricular arrhythmias.

Outflow tract (OT) premature ventricular complexes (PVCs) are being recognized as a common and often troubling, clinical electrocardiographic finding. The OT areas consist of the Right Ventricular Outflow Tract (RVOT), the Left Ventricular Outflow Tract (LVOT), the Aortomitral Continuity (AMC), the aortic cusps and the Left Ventricular (LV) summit. By definition, all OT PVCs will exhibit an inferior QRS axis, defined as positive net forces in leads II, III and aVF. Activation mapping using the contemporary 3D mapping systems followed by pace mapping is the cornerstone strategy of every ablation procedure in these patients. In this mini review we discuss in brief all the modern mapping and ablation modalities for successful elimination of OT PVCs, along with the potential advantages and disadvantages of each ablation technique.

Right ventricular outflow tract electroanatomical abnormalities in asymptomatic and high-risk symptomatic patients with Brugada syndrome: Evidence for a new risk stratification tool?

INTRODUCTION: Microstructural abnormalities at the epicardium of the right ventricular outflow tract (RVOT) may provide the arrhythmia substrate in Brugada syndrome (BrS). Endocardial unipolar electroanatomical mapping allows the identification of epicardial abnormalities. We evaluated the clinical implications of an abnormal endocardial substrate as perceived by high-density electroanatomical mapping (HDEAM) in patients with BrS. METHODS: Fourteen high-risk BrS patients with aborted sudden cardiac death (SCD) (12 males, mean age: 41.9 ± 11.8 years) underwent combined endocardial-epicardial HDEAM of the right ventricle/RVOT, while 40 asymptomatic patients (33 males, mean age: 42 ± 10.7 years) underwent endocardial HDEAM. Based on combined endocardial-epicardial procedures, endocardial HDEAM was considered abnormal in the presence of low voltage areas (LVAs) more than 1 cm2 with bipolar signals less than 1 mV and unipolar signals less than 5.3 mV. Programmed ventricular stimulation (PVS) was performed in all patients. RESULTS: The endocardial unipolar LVAs were colocalized with epicardial bipolar LVAs (p = .0027). Patients with aborted SCD exhibited significantly wider endocardial unipolar (p < .01) and bipolar LVAs (p < .01) compared with asymptomatic individuals. A substrate size of unipolar LVAs more than 14.5 cm2 (area under the curve [AUC]: 0.92, p < .001] and bipolar LVAs more than 3.68 cm2 (AUC: 0.82, p = .001) distinguished symptomatic from asymptomatic patients. Patients with ventricular fibrillation inducibility (23/54) demonstrated broader endocardial unipolar (p < .001) and bipolar LVAs (p < .001) than noninducible patients. The presence of unipolar LVAs more than 13.5 cm2 (AUC: 0.95, p < .001) and bipolar LVAs more than 2.97 cm2 (AUC: 0.78, p < .001) predicted a positive PVS. CONCLUSION: Extensive endocardial electroanatomical abnormalities identify high-risk patients with BrS. Endocardial HDEAM may allow risk stratification of asymptomatic patients referred for PVS.

Use of high-density activation and voltage mapping in combination with entrainment to delineate gap-related atrial tachycardias post atrial fibrillation ablation.

AIMS: An incomplete understanding of the mechanism of atrial tachycardia (AT) is a major determinant of ablation failure. We systematically evaluated the mechanisms of AT using ultra-high-resolution mapping in a large cohort of patients. METHODS AND RESULTS: We included 107 consecutive patients (mean age: 65.7 ± 9.2 years, males: 81 patients) with documented endocardial gap-related AT after left atrial ablation for persistent atrial fibrillation (AF). We analysed the mechanism of 134 AT (94 macro-re-entries and 40 localized re-entries) using high-resolution activation mapping in combination with high-density voltage and entrainment mapping. Voltage in the conducting channels may be extremely low, even <0.1 mV (0.14 ± 0.095 mV, 51 of 134 AT, 41%), and almost always <0.5 mV (0.03-0.5 mV, 133 of 134 AT, 99.3%). The use of multipolar Orion, HDGrid, and Pentaray catheters improved our accuracy in delineating ultra-low-voltage areas critical for maintenance of the circuit of endocardial gap-related AT. Conventional ablation catheters often do not detect any signal (noise level) even using adequate contact force, and only multipolar catheters of small electrodes and shorter interelectrode space can detect clear fractionated low-amplitude and high frequency signals, critical for re-entry maintenance. We performed a diagnosis in 112 out of 134 AT (83.6%) using only activation mapping and in 134 out of 134 AT (100%) using the combination of activation and entrainment mapping. CONCLUSION: High-resolution activation mapping in combination with high-density voltage and entrainment mapping is the ideal strategy to delineate the critical part of the circuit in endocardial gap-related re-entrant AT after AF ablation.

Ligament of Marshall ablation for persistent atrial fibrillation.

Beyond pulmonary vein isolation, the two main additional strategies: Cox-Maze procedure or targeting of electrical signatures (focal bursts, rotational activities, meandering wavelets), remain controversial. High-density mapping of these arrhythmias has demonstrated firstly that a patchy lesion set is highly proarrhythmogenic, favoring macro-re-entry through conduction slowing and providing pivots for localized re-entry. Secondly, discrete anatomical structures such as the Vein or Ligament of Marshall (VOM/LOM) and the coronary sinus (CS) have epicardial muscular bundles that are more frequently involved in re-entry than previously thought. The Marshall Bundle can be ablated at any point along its course from the mid-to-distal coronary sinus to the left atrial appendage. If necessary, the VOM may be directly ablated using ethanol infusion to eliminate PV contributions and produce conduction block across the mistral isthmus. Ethanol ablation of the VOM, supplemented with RF ablation, may be more effective in producing conduction block at the mitral isthmus than repeat RF ablation alone.

KCNE2 gene mutation and Brugada syndrome.

KCNE2 gene mutations have been associated with atrial fibrillation, long QT syndrome, Brugada syndrome and unexplained sudden cardiac death. Herein, we describe a case of Brugada syndrome carrying an heterozygous variant in the KCNE2 gene [NM_172201.2:c.161 T > C, p.(Met54Thr, M54T)]. Gain of function of the Ito current possibly explains the Brugada ECG phenotype in this case.

Atrial substrate characterization in patients with atrial fibrillation and hypertrophic cardiomyopathy: Evidence for an extensive fibrotic disease.

INTRODUCTION: Data regarding the left atrial (LA) electroanatomical substrate in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) are missing. In this electroanatomical mapping (EAM) study, we evaluated the extent of LA fibrosis and its impact on catheter ablation outcomes in patients with HCM and AF. MATERIALS AND METHODS: High-density LA EAM was performed during AF in 28 consecutive patients with obstructive HCM and AF (42.9% displayed paroxysmal AF and 57.1% persistent AF). Propensity score (PS) matching analysis was performed to reduce the impact of potential confounding factors. PS were derived to match patients at a 1:1 ratio. Patients were matched according to age, sex and LA diameter. After PS, 28 non-HCM patients with AF were selected, and served as controls. Two different cut-off values of bipolar signal amplitude were investigated for fibrosis characterization (≤0.25 mV and ≤ 0.4 mV). HCM patients underwent pulmonary vein antral isolation (PVAI) and roof line, while non-HCM patients PVAI only. RESULTS: After the 3-month blanking period, 10 HCM patients (35.7%) displayed atrial arrhythmia recurrence. HCM patients with arrhythmia recurrence showed significantly greater low voltage areas defined as either bipolar voltage ≤0.25 mV (22.5 ± 10% vs. 5.5 ± 6.4%, p = 0.001) or ≤ 0.4 mV (32 ± 13.9% vs. 5.9 ± 5.1%, p < 0.001). The presence of low voltage areas ≤0.4 mV greater than 14.1% of the total LA area also predicted arrhythmia recurrence with excellent sensitivity (100%) and specificity (100%). Univariate analysis revealed that the extent of LA fibrosis was the only predictor of AF recurrence. After PS matching with non-HCM patients, patients with HCM exhibited wider fibrotic regions ≤0.25 mV compared to non-HCM patients (p = 0.016). CONCLUSIONS: High-density EAM reveals extensive LA fibrotic disease in patients with HCM, an event with certain implications in catheter ablation outcomes.

Association of QRS narrowing with response to cardiac resynchronization therapy-a systematic review and meta-analysis of observational studies.

Prolonged QRS duration, which reflects a higher degree of mechanical dysynchrony, is a predictor of response to CRT. However, the association of QRS narrowing after biventricular pacing with CRT response rates is not clear. Our aim was to conduct a systematic review and meta-analysis on the association between QRS narrowing after cardiac resynchronization therapy (CRT) and clinical and echocardiographic response to CRT in patients with heart failure. Two independent investigators searched MedLine and EMBASE databases through July 2018 without any limitations. Studies providing estimates (continuous data) on the association of QRS shortening with either clinical (defined as New York Heart Association (NYHA) reduction ≥ 1) or echocardiographic (defined as left ventricular end-systolic volume (LVESV) reduction ≥ 15%) response to CRT were finally included in the quantitative synthesis. We included 32 studies (14 studies (1274 patients mean age 64 years old, males 79.3%) using clinical CRT response and 18 studies (1270 patients, mean age 64 years old, males 69.1%) using echocardiographic CRT response). A significant association between QRS narrowing and shorter attained QRS duration with clinical and echocardiographic CRT response was observed. The observed association was independent of the timing of QRS width measurement after CRT implantation. Acute and late improvement of electrical dysynchrony as depicted by QRS narrowing following biventricular pacing is associated with clinical and echocardiographic response to CRT. However, large prospective studies are needed to further examine our findings.

The aortic cusps are the predominant successful ablation site of idiopathic outflow-tract ventricular arrhythmias.

BACKGROUND: Data regarding the successful ablation site of idiopathic outflow tract (OT) ventricular arrhythmias (VAs) in the modern era of mapping and ablation are limited. METHODS AND RESULTS: Over a 4-year period, a total of 309 patients underwent detailed activation mapping of OT VAs including the right ventricular outflow tract (RVOT), the left ventricular outflow tract (LVOT) and the aortic cusps (AC), and the coronary venous system. 244 cases were successfully ablated at the index procedure (78.9%). The successful ablation site was more frequently located at the LVOT/ACs (51.6%) followed by RVOT (36.2%). In particular, the ACs was the predominant successful ablation site of idiopathic OT VAs (46.7%). An epicardial site of origin was predictor of ablation failure (p < 0.05). CONCLUSIONS: The ACs is the predominant successful ablation site of idiopathic OT VAs. TAKE-HOME MESSAGE: The aortic cusps are the predominant successful ablation site of idiopathic idiopathic outflow tract ventricular arrhythmias.

Right ventricular outflow tract low-voltage areas identify the site of origin of idiopathic ventricular arrhythmias: A high-density mapping study.

INTRODUCTION: Electronatomical mapping allows direct and accurate visualization of myocardial abnormalities. This study investigated whether high-density endocardial bipolar voltage mapping of the right ventricular outflow tract (RVOT) during sinus rhythm may guide catheter ablation of idiopathic ventricular arrhythmias (VAs). METHODS AND RESULTS: Forty-four patients (18 males, mean age: 38.1 ± 13.8 years) with idiopathic RVOT VAs and negative cardiac magnetic resonance imaging underwent a stepwise mapping approach for the identification of the site of origin (SOO). High-density electronatomical mapping (1096.6 ± 322.3 points) was performed during sinus rhythm and identified at least two low bipolar voltage areas less than 1 mV (mean amplitude of 0.20 ± 0.10 mV) in 39 of 44 patients. The mean low-voltage surface area was 1.4 ± 0.8 cm2 . Group 1 consisted of 28 patients exhibiting low-voltage areas and high-arrhythmia burden during the procedure. Pace match to the clinical VAs was produced in one of these low-voltage areas. Activation mapping established the SOO at these sites in 27 of 28 cases. Group 2 comprised 11 patients exhibiting abnormal electroanatomical mapping, but very low-arrhythmia burden during the procedure. Pace mapping produced a near-perfect or perfect match to the clinical VAs in one of these areas in 9 of 11 patients which was marked as potential SOO and targeted for ablation. During the follow-up period, 25 of 28 patients from group 1 (89%) and 7 of 9 patients from group 2 (78%) were free from VAs. CONCLUSIONS: Small but detectable very low-voltage areas during mapping in sinus rhythm characterize the arrhythmogenic substrate of idiopathic RVOT VAs and may guide successful catheter ablation.

Targeted ablation of specific electrogram patterns in low-voltage areas after pulmonary vein antral isolation in persistent atrial fibrillation: Termination to an organized rhythm reduces atrial fibrillation recurrence.

BACKGROUND: Ablation strategies have been developed to improve outcomes in patients with persistent atrial fibrillation (PsAF). However, the impact of atrial fibrillation (AF) termination on late AF recurrence is not well known. The aim of our study was to evaluate the impact of AF termination to atrial tachycardia (AT) or sinus rhythm (SR) during catheter ablation on late AF recurrence after the 3-month blanking period. METHODS AND RESULTS: We prospectively recruited 140 patients (mean age: 58.5 ± 12.3 years old, 74.3% males) with uninterrupted PsAF of a mean duration of 3.7 months. Pulmonary vein antral isolation (PVAI) was the first ablation step, and if AF did not terminate (to SR or AT), we ablated low-voltage areas less than 0.4 mV with specific electrogram characteristics. We successfully converted AF to AT or SR in 56 patients (40%) during PVAI (n = 24) or low-voltage ablation ( n = 32). The remaining 84 patients (60%) were electrically cardioverted to SR at the end of the procedure. One hundred patients (71.4%) maintained SR after a single procedure during a mean follow-up of 21.1 ± 0.8 months. Of the 56 patients with AF termination, 46 (82.1%) had no recurrence, while in the group of 84 patients without AF termination, 54 patients (64.3%) remained in SR ( P < 0.02). CONCLUSION: Ablation of PVAI and specific electrograms in low-voltage areas less than 0.4 mV can lead to encouraging outcomes with a low recurrence rate as well as a lower need for redo procedures.

Clinical characteristics and long-term clinical course of patients with Brugada syndrome without previous cardiac arrest: a multiparametric risk stratification approach.

AIMS: Risk stratification in Brugada syndrome (BrS) still represents an unsettled issue. In this multicentre study, we aimed to evaluate the clinical characteristics and the long-term clinical course of patients with BrS. METHODS AND RESULTS: A total of 111 consecutive patients (86 males; aged 45.3 ± 13.3 years) diagnosed with BrS were included and followed-up in a prospective fashion. Thirty-seven patients (33.3%) were symptomatic at enrolment (arrhythmic syncope). An electrophysiological study (EPS) was performed in 59 patients (53.2%), and ventricular arrhythmias were induced in 32 (54.2%). A cardioverter defibrillator was implanted in 34 cases (30.6%). During a mean follow-up period of 4.6 ± 3.5 years, appropriate device therapies occurred in seven patients. Event-free survival analysis (log-rank test) showed that spontaneous type-1 electrocardiogram pattern (P = 0.008), symptoms at presentation (syncope) (P = 0.012), family history of sudden cardiac death (P < 0.001), positive EPS (P = 0.024), fragmented QRS (P = 0.004), and QRS duration in lead V2 > 113 ms (P < 0.001) are predictors of future arrhythmic events. Event rates were 0%, 4%, and 60% among patients with 0-1 risk factor, 2-3 risk factors, and 4-5 risk factors, respectively (P < 0.001). Current multiparametric score models exhibit an excellent negative predictive value and perform well in risk stratification of BrS patients. CONCLUSIONS: Multiparametric models including common risk factors appear to provide better risk stratification of BrS patients than single factors alone.