Atrial arrhythmias and heart failure: A "modern view" of an old paradox.

BACKGROUND: Heart failure (HF) and atrial arrhythmias (AAs) are two clinical conditions that characterize the daily clinical practice of cardiologists. In this perspective review, we analyze the shared etiopathogenetic pathways of atrial arrhythmias, which are the most common cause of atrial arrhythmias-induced cardiomyopathy (AACM) and HF. HYPOTHESIS: The aim is to explore the pathophysiology of these two conditions considering them as a "unicum", allowing the definition of a cardiovascular continuum where it is possible to predict the factors and to identify the patient phenotype most at risk to develop HF due to atrial arrhythmias. METHODS: Potentially eligible articles, identified from the Electronic database (PubMed), and related references were used for a literature search that was conducted between January 2022 and January 2023. Search strategies were designed to identify articles that reported atrial arrhythmias in association with heart failure and vice versa. For the search we used the following keywords: atrial arrhythmias, atrial fibrillation, heart failure, arrhythmia-induced cardiomyopathy, tachycardiomyopathy. We identified 620 articles through the electronic database search. Out of the 620 total articles we removed 320 duplicates, thus selecting 300 eligible articles. About 150 titles/abstracts were excluded for the following reasons: no original available data, no mention of atrial arrhythmias and heart failure crosstalk, very low quality analysis or evidence. We excluded also non-English articles. When multiple articles were published on the same topic, the articles with the most complete set of data were considered. We preferentially included all papers that could provide the best evidence in the field. As a result, the present review article is based on a final number of 104 references. RESULTS: While the pathophysiology of AACM and Heart Failure with reduced ejection fraction (HFrEF) has been studied in detail over the years, the causal link between atrial arrhythmias and heart failure with Preserved Ejection Fraction (HFpEF) has been often subject of interest. HFpEF is strictly related to AAs, which has always been considered significant risk factor. In this review we described the pathophysiological links between atrial fibrillation and heart failure. Furthermore, we illustrated and discussed the preclinical and clinical predicting factors of AF and HFpEF, and the corresponding targets of the available therapeutic agents. Finally, we outlined the patient phenotype at risk of developing AF and HFpEF (Central Illustration). CONCLUSIONS: In this review, we underline how these two clinical conditions (AF and HFpEF) represent a "unicum" and, therefore, should be considered as a single disease that can manifest itself in the same phenotype of patients but at different times. Furthermore, considering that today we have few therapeutic strategies to treat these patients, it would be good to make an early diagnosis in the initial stages of the disease or intervene even before the development of signs and symptoms of HF. This is possible only by paying greater attention to patients with predisposing factors and carrying out a targeted screening with the correct diagnostic methods. A systemic approach aimed at improving the immuno-metabolic profile of these patients by lowering the body mass index, threatening the predisposing factors, lowering the mean heart rate and reducing the sympathetic nervous system activation is the key strategy to reduce the clinical impact of this disease.

The economic impact of battery longevity in implantable cardioverter-defibrillators for cardiac resynchronization therapy: the hospital and healthcare system perspectives.

AIMS: Patients receiving cardiac resynchronization therapy defibrillators (CRT-Ds) are likely to undergo one or more device replacements, mainly for battery depletion. We assessed the economic impact of battery depletion on the overall cost of CRT-D treatment from the perspectives of the healthcare system and the hospital. We also compared devices of different generations and from different manufacturers in terms of therapy cost. METHODS AND RESULTS: We analysed data on 1792 CRT-Ds implanted in 1399 patients in 9 Italian centres. We calculated the replacement probability and the total therapy cost over 6 years, stratified by device generation and manufacturer. Public tariffs from diagnosis-related groups were used together with device prices and hospitalization costs. Generators were from 3 manufacturers: Boston Scientific (667, 37%), Medtronic (973, 54%), and St Jude Medical (152, 9%). The replacement probability at 6 years was 83 and 68% for earlier- and recent-generation devices, respectively. The need for replacement increased total therapy costs by more than 50% over the initial implantation cost for hospitals and by more than 30% for healthcare system. The improved longevity of recent-generation CRT-Ds reduced the therapy cost by ∼6% in both perspectives. Among recent-generation CRT-Ds, the replacement probability of devices from different manufacturers ranged from 12 to 70%. Consequently, the maximum difference in therapy cost between manufacturers was 40% for hospitals and 19% for the healthcare system. CONCLUSIONS: Differences in CRT-D longevity strongly affect the overall therapy cost. While the use of recent-generation devices has reduced the cost, significant differences exist among currently available systems.

Longevity of implantable cardioverter-defibrillators for cardiac resynchronization therapy in current clinical practice: an analysis according to influencing factors, device generation, and manufacturer.

AIMS: Device replacement at the time of battery depletion of implantable cardioverter-defibrillators (ICDs) may carry a considerable risk of complications and engenders costs for healthcare systems. Therefore, ICD device longevity is extremely important both from a clinical and economic standpoint. Cardiac resynchronization therapy defibrillators (CRT-D) battery longevity is shorter than ICDs. We determined the rate of replacements for battery depletion and we identified possible determinants of early depletion in a series of patients who had undergone implantation of CRT-D devices. METHODS AND RESULTS: We retrieved data on 1726 consecutive CRT-D systems implanted from January 2008 to March 2010 in nine centres. Five years after a successful CRT-D implantation procedure, 46% of devices were replaced due to battery depletion. The time to device replacement for battery depletion differed considerably among currently available CRT-D systems from different manufacturers, with rates of batteries still in service at 5 years ranging from 52 to 88% (log-rank test, P < 0.001). Left ventricular lead output and unipolar pacing configuration were independent determinants of early depletion [hazard ratio (HR): 1.96; 95% 95% confidence interval (CI): 1.57-2.46; P < 0.001 and HR: 1.58, 95% CI: 1.25-2.01; P < 0.001, respectively]. The implantation of a recent-generation device (HR: 0.57; 95% CI: 0.45-0.72; P < 0.001), the battery chemistry and the CRT-D manufacturer (HR: 0.64; 95% CI: 0.47-0.89; P = 0.008) were additional factors associated with replacement for battery depletion. CONCLUSION: The device longevity at 5 years was 54%. High left ventricular lead output and unipolar pacing configuration were associated with early battery depletion, while recent-generation CRT-Ds displayed better longevity. Significant differences emerged among currently available CRT-D systems from different manufacturers.

Incidence and predictors of post-surgery atrial fibrillation occurrence: A cohort study in 53,387 patients.

Introduction: Atrial fibrillation (AF) represents the most common arrhythmia in the postoperative setting. We aimed to investigate the incidence of postoperative AF (POAF) and determine its predictors, with a specific focus on inflammation markers. Methods: We performed a retrospective single tertiary center cohort study including consecutive adult patients who underwent a major surgical procedure between January 2016 and January 2020. Patients were divided into four subgroups according to the type of surgery. Results: Among 53,387 included patients (79.4% male, age 64.5 ± 9.5 years), POAF occurred in 570 (1.1%) with a mean latency after surgery of 3.4 ± 2.6 days. Ninety patients died (0.17%) after a mean of 13.7 ± 8.4 days. The 28-day arrhythmia-free survival was lower in patients undergoing lung and cardiovascular surgery (p < .001). Patients who developed POAF had higher levels of C-reactive protein (CRP) (0.70 ± 0.03 vs. 0.40 ± 0.01 log10 mg/dl; p < .001). In the multivariable Cox regression analysis, adjusting for confounding factors, CRP was an independent predictor of POAF [HR per 1 mg/dL increase in log-scale = 1.81 (95% CI 1.18-2.79); p = .007]. Moreover, independent predictors of POAF were also age (HR/1 year increase = 1.06 (95% CI 1.04-1.08); I < .001), lung and cardiovascular surgery (HR 23.62; (95% CI 5.65-98.73); p < .001), and abdominal and esophageal surgery (HR 6.26; 95% CI 1.48-26.49; p = .013). Conclusions: Lung and cardiovascular surgery had the highest risk of POAF in the presented cohort. CRP was an independent predictor of POAF and postsurgery inflammation may represent a major driver in the pathophysiology of the arrhythmia.

The importance of increased percentage of biventricular pacing to improve clinical outcomes in patients receiving cardiac resynchronization therapy.

PURPOSE OF REVIEW: To describe the growing evidence that a maximal biventricular pacing is needed to gain the maximal benefits from cardiac resynchronization therapy (CRT). RECENT FINDINGS: Even small gains in the biventricular (BIV) pacing percentage are clinically important both to prevent acute heart failure and, more importantly, to improve survival. SUMMARY: Every effort should be made in all patients receiving CRT to approach 100% BIV pacing by a correct device programming, a correct pharmacologic regimen and atrioventricular nodal ablation in atrial fibrillation patients.

The values of defibrillation testing at implantable cardioverter defibrillator implantation: 'and then there were none'.

PURPOSE OF REVIEW: Since its advent, implantable cardioverter defibrillator (ICD) intra-operative defibrillation testing (DFT) has been a standard practice to confirm its optimal configuration. However, due to advances in device and lead technology, which now facilitate successful device implantation, and due to growing number of ICD primary prevention patients, the need for DFT has recently been questioned. The purpose of this review is to summarize the pro and contra DFT arguments, according to benefits, risk and clinical relevance, trying to identify the candidates for whom DFT is really indicated. RECENT FINDINGS: There is an ongoing debate on the need for DFT at ICD implant due to significant DFT-related complications; recently, many electrophysiologists have chosen not to perform DFT in many cases. Recent literature findings document large differences of practice between different centres and countries. In particular, there has been major debate and concern over performing DFT in patients with heart failure, indicated for CRT-D implants (cardiac resynchronization therapy with defibrillator). SUMMARY: Due to the potential for serious complications during DFT and expanding primary prevention ICD candidates, we agree with the growing tendency not to routinely perform DFT at implant, as the risks may overweigh the benefits.

Cardiac resynchronization therapy in heart failure patients with atrial fibrillation.

Cardiac resynchronization therapy (CRT) is an important device-based, non-pharmacological approach that has shown, in large randomized trials, to improve left ventricular (LV) function and reduce both morbidity and mortality rates in selected patients affected by advanced heart failure (HF): New York Heart Association (NYHA) functional class III-IV, reduced LV systolic function with an ejection fraction (EF) or=120 ms, on optimal medical therapy, and who were in sinus rhythm. For the first time, the latest ESC and AHA/ACC/HRS Guidelines have considered atrial fibrillation (AF) patients, who constitute an important subgroup of HF patients, as eligible to receive CRT. Nevertheless, these Guidelines did not include a strategy for defining differentiated approaches according to AF duration or burden. In this review, the authors explain in which way AF may interfere with adequate CRT delivery, how to manage different AF burden, and finally present a brief overview on the effects of CRT in AF patients.

Remission of left ventricular systolic dysfunction and of heart failure symptoms after cardiac resynchronization therapy: temporal pattern and clinical predictors.

BACKGROUND: The aim of the study was to determine whether cardiac resynchronization therapy (CRT) may induce a heart failure (HF) remission phase (recovery to New York Heart Association functional class I-II and regression of left ventricular [LV] dysfunction: LV ejection fraction [EF] > or = 50%) and to define the incidence and predictors of such a process. METHODS: Cardiac resynchronization therapy devices were successfully implanted in 520 consecutive HF patients from 1999 to 2006 (mean age 66 years, 82% male sex, New York Heart Association class > or = II, LVEF 28%, QRS 164 milliseconds, 6-minute hall walk distance 302 m) at our institution. Follow-up data were prospectively collected every 3 to 6 months. Continuous variables were stratified in tertiles. RESULTS: Over a median follow-up of 28 months, 26% of patients achieved LV remission (rate: 16 per 100 person-years). At univariate analysis, female sex (P = .032), non-coronary artery disease (CAD) etiology (P < .001), mitral regurgitation < 2/4 (P = .022), higher EF tertile (P < .001), lower diameter and volume tertiles (both P < .001), previous conventional right ventricle pacing (P = .029), and post-CRT-paced QRS (P = .008) predicted remission. At multivariate analysis, non-CAD etiology, LVEF 30% to 35%, and LV end-diastolic volume < 180 mL were strongly associated with HF remission phase (all P < .001). Concomitance of these 3 factors yielded a significantly higher remission rate compared with either no or only 1 factor (respectively, 60 vs 7 and 11 per 100 person-years, P < .001). CONCLUSIONS: Cardiac resynchronization therapy induces HF remission phase in 26% of patients, even after 3 years. Non-CAD etiology and moderately compromised LV function at baseline may easily predict this process.

Insulin-treated type 2 diabetes is associated with a decreased survival in heart failure patients after cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves cardiac performance and survival in patients with congestive heart failure. Recent observations suggest that diabetes is associated with a worse outcome in these patients. The aim of the study was to investigate the effect of diabetes and insulin treatment on outcome after CRT. METHODS: Diabetic status and insulin treatment were assessed in 447 patients who underwent CRT (males 80.8%, mean age 65.7 +/- 9.7 years, ejection fraction 29.9 +/- 6.11%). Patients were stratified in three groups according to the presence or absence of diabetes and insulin treatment. RESULTS: Nondiabetic patients were 366 (79.6%), noninsulin-treated diabetic patients 62 (13.9%), insulin-treated diabetic patients 29 (6.5%). The estimated death rate was 5.15 per 100 patients-year in the nondiabetic group, 8.63 in noninsulin-treated diabetics (HR 1.59, P = 0.240), and 15.84 in insulin-treated diabetics (HR 3.05, P = 0.004). Cardiac mortality accounted for 81% of deaths in nondiabetic patients and for 56% of deaths in diabetic patients. Diabetic patients tended to have a worse recovery of left ventricular ejection fraction over time (P = 0.057) and of the distance at 6-minute walking test (6MWT) (P = 0.018). CONCLUSIONS: Insulin-treated diabetes is associated with a worse functional recovery and a higher mortality in patients with advanced heart failure after CRT. While cardiac death accounts for the majority of deaths in nondiabetic patients, a relevant proportion of the mortality in diabetic patients seem to result from noncardiac causes.

Applications of shape memory alloys for neurology and neuromuscular rehabilitation.

Shape memory alloys (SMAs) are a very promising class of metallic materials that display interesting nonlinear properties, such as pseudoelasticity (PE), shape memory effect (SME) and damping capacity, due to high mechanical hysteresis and internal friction. Our group has applied SMA in the field of neuromuscular rehabilitation, designing some new devices based on the mentioned SMA properties: in particular, a new type of orthosis for spastic limb repositioning, which allows residual voluntary movement of the impaired limb and has no predetermined final target position, but follows and supports muscular elongation in a dynamic and compliant way. Considering patients in the sub-acute phase after a neurological lesion, and possibly bedridden, the paper presents a mobiliser for the ankle joint, which is designed exploiting the SME to provide passive exercise to the paretic lower limb. Two different SMA-based applications in the field of neuroscience are then presented, a guide and a limb mobiliser specially designed to be compatible with diagnostic instrumentations that impose rigid constraints in terms of electromagnetic compatibility and noise distortion. Finally, the paper discusses possible uses of these materials in the treatment of movement disorders, such as dystonia or hyperkinesia, where their dynamic characteristics can be advantageous.

Three years of cardiac resynchronization therapy: could superior benefits be obtained in patients with heart failure and narrow QRS?

AIM OF THE STUDY: To examine the long-term effects of cardiac resynchronization therapy (CRT) in patients presenting with heart failure (HF) and QRS 120 ms in the remaining 331 patients. The baseline characteristics of the 2 groups were similar. We evaluated indices of cardiac function, percentage of responders, and survival rates over a mean 28-month follow-up. RESULTS: Both groups experienced similar long-term increases in 6-MHW, and decreases in New York Heart Association functional class and LV end-systolic volume (all comparisons P < 0.0001 in both groups). Time interaction of changes in LVEF and percentage of responders were significantly different (P = 0.03 and P = 0.004, respectively), in favor of the narrow QRS group, where the changes were sustained and persisted at 2 and 3 years. The long-term death rate from HF was lower in the group with narrow than in the group with wide QRS complex (P = 0.04; log-rank test). CONCLUSIONS: CRT confers considerable long-term clinical, functional, and survival benefits in patients presenting with HF and narrow QRS, not preselected by echocardiographic criteria of dyssynchrony. Caution is advised before denying CRT to these patients on the basis of QRS width only.

Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation.

OBJECTIVES: The goal of this study was to investigate the effects of cardiac resynchronization therapy (CRT) in heart failure patients with permanent atrial fibrillation (AF) and the role of atrioventricular junction (AVJ) ablation. BACKGROUND: Cardiac resynchronization therapy has been proven effective in heart failure patients with sinus rhythm (SR). However, little is known about the effects of CRT in heart failure patients with permanent AF. METHODS: Efficacy of CRT on ventricular function, exercise performance, and reversal of maladaptive remodeling process was prospectively compared in 48 patients with permanent AF in whom ventricular rate was controlled by drugs, thus resulting in apparently adequate delivery of biventricular pacing (>85% of pacing time), and in 114 permanent AF patients, who had undergone AVJ ablation (100% of resynchronization therapy delivery). The clinical and echocardiographic long-term outcomes of both groups were compared with those of 511 SR patients treated with CRT. RESULTS: Both SR and AF groups showed significant and sustained improvements of all assessed parameters (model p < 0.001 for all parameters). However, within the AF group, only patients who underwent ablation showed a significant increase of ejection fraction (p < 0.001), reverse remodeling effect (p < 0.001), and improved exercise tolerance (p < 0.001); no improvements were observed in AF patients who did not undergo ablation. CONCLUSIONS: Heart failure patients with ventricular conduction disturbance and permanent AF treated with CRT showed large and sustained long-term (up to 4 year) improvements of left ventricular function and functional capacity, similar to patients in SR, only if AVJ ablation was performed.

Delayed defibrillation testing in patients implanted with biventricular ICD (CRT-D): a reliable and safe approach.

BACKGROUND: Defibrillation testing (DT) at the end of the implantation of cardiac resynchronization pacemaker with a defibrillator (CRT-D) exposes heart failure (HF) patients to increased procedural risks. However, until now, delayed DT has not been assessed as a possible option in HF patients implanted with CRT-D. OBJECTIVE: Aim of the present study is to assess safety and feasibility of delayed DT in HF patients treated with CRT-D. MATERIAL AND METHODS: Two hundred and eleven consecutive patients (mean age: 65 years, mean NYHA class 3.0, mean EF: 29.3%) underwent CRT-D implantation from October 1999 to December 2004. In the first 17 patients, DT was performed at the end of CRT-D implantation. In the other 194 consecutive patients, DT was performed at 2 months after CRT-D implantation. Outcome of DT, as well as "acute" LV lead dislodgment rate were evaluated in the latter group of 194 patients undergoing a delayed DT. Also, ICD function was assessed through device telemetry analysis at 2 months. RESULTS: At delayed DT, first shock was effective in 187 of 194 patients (96%), ineffective VF interruption at maximum energy occurred only in one patient (0.5%), and acute LV lead dislodgment was 1%. No ICD therapy failure occurred in the 2-month untested period. CONCLUSION: DT performed 2 months after CRT-D implantation is safe and feasible; this is possibly related to the improvement of clinical conditions and hemodynamic status as well as greater lead stability 2 months after CRT-D.

Relief of drug refractory angina by biventricular pacing in heart failure.

Since cardiac resynchronization therapy (CRT) improves LV function at the cost of low energetic expenditure, the authors hypothesized that it may increase the threshold of drug refractory angina in selected patients with CHF and CAD who are not amenable to myocardial revascularization. From October 1999 to April 2002, 75 patients with CHF and CAD were treated with CRT. Drug refractory angina occurred nearly daily in 8 of the 75 patients. The mean age of these eight men was 71 years, mean NYHA functional Class 3.4 +/- 0.5, mean QRS duration (QRSd) 168 +/- 20 ms, and mean left ventricular ejection fraction (LVEF) 0.29 +/- 0.4. Diffuse CAD not amenable to myocardial revascularization was confirmed on angiography. At baseline, no patient was able to complete a 6-minute walk test because of angina. In the 6 months before CRT, the mean number of hospitalizations per patient for management of CHF or angina was 3.1 +/- 0.3. All patients underwent successful CRT. Mean QRSd decreased to 141 +/- 16 ms (P = 0.01 vs baseline). After 9 +/- 6.1 months, LVEF increased to 0.317 +/- 0.028 (P = 0.03 vs baseline), while the NYHA class decreased to 2.6 +/- 0.5 (P = 0.02 vs baseline). All patients also experienced a marked decrease in angina episodes, from a mean of 8.3 +/- 11.6 to 0.6 +/- 1.3 episodes/week (P < 0.05), and completed a 6-minute walk test, covering a mean distance of 337 +/- 68 m (vs 237 +/- 136 m at baseline, P = 0.007). No further hospitalization was necessary. The beneficial effects of CRT on overall cardiac function may include a better control of angina in severely symptomatic patients.

Biventricular pacing via a persistent left superior vena cava: report of four cases.

Persistence of left superior vena cava (LSVC) is an uncommon finding during pacemaker implantation, which may be particularly relevant in performing LV transvenous pacing. Rarely, it is further complicated by the presence of atresia of the coronary sinus ostium (CSO). This article reports the authors experience with biventricular pacing (Biv-P) in this unusual clinical setting. From October 1999 to April 2002, 158 patients underwent biventricular pacing. In four of them (mean age 62.2 years), the presence of a persistent LSVC draining into the coronary sinus (CS) was detected at implantation, associated with atresia of the CSO in two patients. A common characteristic was the angiographic finding of a large CS with few tributaries. The LV leads were successfully positioned in the middle cardiac vein in three patients and in a posterolateral vein in one patient. All vessels were large and their cannulation via downstream CS catheterization required the lead to be manipulated through sharp angles. Mean fluoroscopic exposure and procedural times were not significantly different from the overall Biv-P population. In all patients, at a mean follow-up of 11 months, sensing and capture threshold remained stable and a significant decrease in NYHA functional class and increase in LVEF were noted. The direct lead placement in large CS tributaries in the presence of persistent LSVC was feasible and safe. The leads remained stable up to a mean follow-up of nearly 1 year.

Programmed electrical stimulation in Brugada syndrome: how reproducible are the results?

INTRODUCTION: Inducibility of ventricular arrhythmias at programmed electrical stimulation (PES) ranges between 50% and 80% of patients with Brugada syndrome. However, the variety of PES protocols and the lack of data relative to a control group or to ventricular arrhythmia reproducibility contribute to a still undefined interpretation of PES outcome in Brugada syndrome. METHODS AND RESULTS: Twenty-one patients with Brugada syndrome (18 men and 3 women; mean age 34 years; 9/21 symptomatic; 8/21 with SCN5A gene mutation) underwent a PES protocol from two right ventricular sites. The endpoint was PES protocol completion or induction of sustained or reproducible (>6 consecutive inductions) nonsustained (>6 beats) fast ventricular arrhythmia. In 17 of 21 patients with Brugada syndrome, PES was repeated 2 months later to test ventricular arrhythmia reproducibility. Twenty-five healthy patients (17 men; mean age 36 years) formed the control group. In patients with Brugada syndrome, ventricular arrhythmia inducibility rate at PES was high (18/21 patients [85%]) and increased with protocol aggressiveness, independent of clinical presentation. In control subjects, no ventricular arrhythmias were induced. Among patients with Brugada syndrome, 14 (82%) of 17 patients remained inducible at a second PES. CONCLUSION: In our experience, ventricular arrhythmia inducibility in patients with Brugada syndrome, at variance with healthy controls, is high and does not correlate with clinical presentation. PES inducibility is deeply influenced by the protocol used. PES outcome is reproducible at a mid-term follow-up mainly if a categorical endpoint (inducible vs noninducible) is used. The need to assess the predictive value of specific PES protocols in targeted studies is widely emerging and is confirmed by our results.

Flecainide test in Brugada syndrome: a reproducible but risky tool.

The flecainide test is widely used in Brugada syndrome. However, its reproducibility and safety remain ill-defined. This study included 22 patients (18 men, mean age 34 years). Mutations in the SCN5A gene were found in eight patients. Two patients had aborted sudden cardiac death, 8 had syncope/presyncope, and 12 were asymptomatic. The ECG was diagnostic in 19 patients and suggestive in 3. At baseline, 21 of 22 patients underwent a flecainide test (2 mg/kg IV bolus over 10 minutes). In 21 of 21 patients the test was diagnostic or amplified the typical ECG pattern. At the end of drug infusion, sustained VT lasting 7-10 minutes developed in two patients. A second flecainide test was performed within 2 months in 20 patients. The test was not repeated in the two patients with prior development of VT. The flecainide test was diagnostic in 20 of 20 patients. Sustained VT occurred in one patient and recurrent VF in another. The reproducibility of the flecainide test was 100%. In 4 (18%) of 22 patients major VAs were documented after the end of flecainide infusion. VA occurred in 3 (43%) of 7 patients with, versus 1 (7%) 15 without SCN5A gene mutation (P < 0.05). No diagnostic ECG changes or arrhythmias developed in 25 control patients without structural heart disease who underwent the same study protocol. This study shows a high flecainide reproducibility, supporting its diagnostic value in Brugada syndrome. However, the occurrence of major VA, significantly higher in patients with documented SCN5A gene mutation, including in asymptomatic patients, mandates the performance under appropriate medical supervision. Whether a slower rate of drug infusion can lower the risk of VA induction, while maintaining the sensitivity of the test should be explored.