Sodium Channel Blocker Test Research Articles

Use, misuse, and pitfalls of the drug challenge test in the diagnosis of the Brugada syndrome.

The diagnosis of Brugada syndrome (BrS) requires the presence of a coved (Type 1) ST segment elevation in the right precordial leads of the electrocardiogram (ECG). The dynamic nature of the ECG is well known, and in patients with suspected BrS but non-diagnostic ECG at baseline, a sodium channel blocker test (SCBT) is routinely used to unmask BrS. There is little doubt, however, that in asymptomatic patients, a drug-induced Brugada pattern is associated with a much better prognosis compared to a spontaneous Type 1 ECG. The SCBT is also increasingly used to delineate the arrhythmogenic substrate during ablation studies. In the absence of a "gold standard" for the diagnosis of BrS, sensitivity and specificity of the SCBT remain elusive. By studying patient groups with different underlying diseases, it has become clear that the specificity of the test may not be optimal. This review aims to discuss the pitfalls of the SCBT and provides some directions in whom and when to perform the test. It is concluded that because of the debated specificity and the overall very low risk for future events in asymptomatic individuals, patients should be properly selected and counseled before SCBT is performed and that SCBT should not be performed in asymptomatic patients with a Type 2 Brugada pattern and no family history of BrS or sudden death.

Changes of sports habits and psychological impact of pharmacologically induced Brugada type 1 pattern in young patients

Abstract Funding Acknowledgements Type of funding sources: None. Background Brugada syndrome (BrS) is an inherited disease characterized by an increased risk of sudden cardiac death (SCD). According to the latest ESC guidelines, provocation with sodium channel blocker test is less specific than previously thought, especially in asymptomatic patients(1). In these cases, in which the diagnosis of BrS itself can be controversial, management currently consists in clinical follow-up only. However, we still observe a big gap between the patient’s perception and medical recommendations of living a normal life. Objective The goal of this study was to analyze exercise habits before and after positive ajmaline testing (AT), focusing on its psychological impact on a population of low-risk young patients. Methods We enrolled all-comers patients with ajmaline-induced Brugada type 1 pattern who came to our department between 2015 and 2022. Patients were asked to rate their heart-focused anxiety using the German version of the Cardiac Anxiety Questionnaire (CAQ) (2) at last medical contact after ajmaline challenge. The intensity of habitual physical exercise was estimated in METs and divided in 3 categories: mild (<3 METs), moderate (3-6 METs), intense (>6 METs). Different groups were compared using Student’s t-test for continuous variables. Significance level was set to p<0.05. Results A total of 87 patients resulted positive to ajmaline challenge; among these, 16 (18.4%) underwent EPS and 4 (4.6%) of them underwent ICD implantation. Therefore, our population included 83 patients. Mean age was 45.1±13.5 years; M/F ratio was 1.4/1. 12 patients (14.5%) had family history of SCD. Mean follow-up duration was 31.6±25.3 months. After positive AT, 5 patients (5.7%) did intense physical activity (PA), 27 (31.0%) did moderate PA, 51 (58.6%) were sedentary or practiced low-intensity PA. Mean CAQ score in the overall population was 19.1±6.6 points (fig. 1A), noticeably higher than the general population (2). As shown in fig. 1B, anxiety levels were significantly lower in patients who did almost moderate PA (p=0.03), independently from previous sport habits. This suggests sport to be a protective factor against anxiety. A total of 23 people (27.7%) reduced PA (fig. 2). We compared this population to the two groups of patients whose habits were not affected by the test: respectively high-high (n=22; 25.3%) and low-low groups (n=34; 39.1%). Anxiety in high-low group patients was not significantly different from the other two (fig. 1C), although it was higher than the general population. Conclusions After positive AT, many patients lead a sedentary lifestyle. Regardless of this, anxiety after the test is higher than the normal population. Anxiety levels do not change significantly between patients who reduced PA and those who did not change their habits. Further investigation is needed to assess the trade-offs between individual arrhythmic risk and global cardiovascular risk due to sedentary lifestyle in these patients.

Malignant Purkinje ectopy induced by sodium channel blockers.

Sodium channel blocker (SCB) infusion is used to unmask the electrocardiographic pattern of Brugada syndrome. The test may also induce premature ventricular complexes (PVCs) in individuals without Brugada pattern, the clinical relevance of which is little known. The purpose of this study was to describe the prevalence of short-coupled (Sc) PVCs induced by ajmaline or flecainide in patients with suspected or documented severe ventricular arrhythmias. We reviewed the SCB tests performed in 335 patients with suspected ventricular arrhythmias and structurally normal hearts in 9 centers. ScPVCs were defined as frequent and repetitive PVCs with an R-on-T pattern on SCB tests. Repeated SCB tests wereperformed in 7 patients and electrophysiological mapping of ScPVCs in9. Sixteen patients (8 men; mean age 36 ± 11 years) showed ScPVCs and were included. ScPVCs appeared 229 ± 118 secondsafter the initiation of infusion and displayed coupling intervalsof 288 ± 28 ms. ScPVC patterns were monomorphic in 12 patients, originating from the Purkinje systemin mapped patients. Repetitive PVCs were induced in 15 patients (94%) including polymorphic ventricular tachycardias in 9 (56%). SCB infusionwas repeated 45 (interquartile range 0.6-46) months later and induced identical ScPVC in all. SCB test was the only mean to reveal the malignant arrhythmia in 6 patients. Catheter ablation was performed in 9 patients, resulting in arrhythmia elimination in 8 with a follow-up of 6 (interquartile range 2-9) years. SCB can induce ScPVC, mostly from Purkinje tissue, in a small subset of patients with idiopathic ventricular arrhythmias. Its high reproducibility suggests a distinct individual mechanism.

Lamotrigine-induced Brugada syndrome: A rare adverse event

Brugada syndrome is a rare inherited channelopathy predisposing to ventricular arrhythmias and leading to an increased risk of sudden cardiac death, despite a structurally normal heart. The most common mutation is a loss-of-function mutation in SCN5A gene, rsesponsible for encoding the α-subunit of the sodium channel. Diagnosis is based on a specific electrocardiogram (ECG) pattern, observed either spontaneously or during a sodium channel blocker test. Considering the two different Brugada pattern types, type 1 is the most frequently associated with the SCN5A gene mutation [1].

Clinical characterization of the first Belgian SCN5A founder mutation cohort

We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected. The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS. The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families.

Idiopathic ventricular fibrillation: the ongoing quest for diagnostic refinement

Prior to the recognition of distinct clinical entities, such as Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome, all sudden cardiac arrest (SCA) survivors with ventricular fibrillation (VF) and apparently structurally normal hearts were labelled as idiopathic ventricular fibrillation (IVF). Over the last three decades, the definition of IVF has changed substantially, mostly as result of the identification of the spectrum of SCA-predisposing genetic heart diseases (GHDs), and the molecular evidence, by post-mortem genetic analysis (aka, the molecular autopsy), of cardiac channelopathies as the pathogenic basis for up to 35% of unexplained cases of sudden cardiac death (SCD) in the young. The evolution of the definition of IVF over time has led to a progressively greater awareness of the need for an extensive diagnostic assessment in unexplained SCA survivors. Nevertheless, GHDs are still underdiagnosed among SCA survivors, due to the underuse of pharmacological challenges (i.e. sodium channel blocker test), misrecognition of electrocardiogram (ECG) abnormalities/patterns (i.e. early repolarization pattern or exercise-induced ventricular bigeminy) or errors in the measurement of ECG parameters (e.g. the heart-rate corrected QT interval). In this review, we discuss the epidemiology, diagnostic approaches, and the controversies related to role of the genetic background in unexplained SCA survivors with a default diagnosis of IVF.

P2279First clinical evaluation of subcutaneous implantable cardiac defibrillator in Brugada patients

Abstract Background Brugada syndrome (BrS) is an inherited arrhythmia syndrome with an increased risk of SCD. While Subcutaneous ICD (S-ICD) is a seductive approach to treat these patients, questions raised on the risk of inappropriate shock in this specific population. Objective The aim of this study was to evaluate the safety and the effectiveness of the S-ICD in BrS patients. Methods We prospectively enrolled 112 BrS patients implanted with S-ICD in 17 European centers. During the screening at least 2 vectors must be suitable but it was not necessary to check for the suitability of the ECG during sodium channel blocker or exercise test. S-ICD indications follow the current guidelines. Results Mean age of patients was 45±13 years, with 95 (85%) males. Implantation was performed in 91 (83%) patients for primary prevention and in 18 (16%) patients for secondary prevention. There is an indication of ICD replacement for 16 patients (14%): 13 lead defect (81%), 1 infection (6%) and 2 ICD end of life (13%). In this cohort, 57 patients (51%) had spontaneous type I BrS, 60 patients (55%) were symptomatic: 10 resuscitated SCD (17%) and 48 (83%) syncope. Implantation was performed under general anesthesia in 79 patients (71%). The mean operation time was 56±19 min. The lead was placed at the left side of the sternum in 102 patients (92%) and at the right side in 9 (8%). Sensing configuration was the primary vector for 46 patients (41%), secondary vector for 57 (51%) and alternative vector for 9 (8%). No complications occurred during implantation. During a mean follow-up of 15.6 months (0–39 months), 6 patients (5%) had at least one appropriate shock (n=9). The rate of appropriate shock was 4.5%/y. All the VF episodes were successfully treated with the first shock. One patient had VF ablation for recurrent VF. Among the 6 patients who received an appropriate shock, 3 (50%) were implanted for secondary prevention and 3 (50%) were implanted for primary prevention including 2 patients with a history of syncope and one asymptomatic patient. Twelve patients (11%) had at least one inappropriate shock (n=22) including 2 patients with respectively 8 and 4 inappropriate shocks due to T-wave oversensing. With the SMART pass system the first patient had no more inappropriate shock for now 2 years. The rate of inappropriate shock was 9%/y. One patient died of myocardial infarction. Five patients (4%) were hospitalized for complications (4 pocket or scar infections and 1 electrode failure). Conclusion Our initial experience showed that S-ICD is efficient to treat VF episode in BrS patients. In this population, the rate of inappropriate shock was 9%/y. In view of these results, S-ICD implantation seems to be efficient to protect BrS patients against SCD. Acknowledgement/Funding Investigator-Sponsored Research program, Boston Scientific

THE UTILITY AND INCREMENTAL VALUE OF THE SIGNAL AVERAGED ECG: A NOVEL MODEL FOR STRATIFYING PATIENTS WITH SUSPECTED BRUGADA SYNDROME

Patients with suspected Brugada syndrome often undergo a procainamide challenge to stratify their risk for sudden death and arrhythmic events. Patients that develop a Type 1 Brugada pattern during procainamide infusion are at greater risk for cardiac arrest. The signal-averaged ECG (SAECG) can detect late potentials in Brugada syndrome, which may have prognostic significance. We used historical and clinical features, and the SAECG to predict the yield of the procainamide and ajmaline tests in patients with suspected Brugada syndrome. 251 patients were enrolled across Canada with a procainamide challenge and standard, high precordial, and signal-averaged ECGs. A second cohort of 97 patients were enrolled in the United Kingdom, undergoing ajmaline challenge. We evaluated 6 variables including: sex, syncope, palpitations, previous cardiac arrest, baseline ST-elevation (STE; Type 2 or 3 Brugada pattern), and abnormal SAECG. We derived and validated a parsimonious model to predict the outcome of the sodium channel blocker challenge. The average age was 43±15 years (61% male). 100 patients (40%) had a cardiac arrest, 54 (22%) had syncope, and 24 (10%) had palpitations prior to assessment. 83 patients (33%) had baseline STE and 20 patients (8%) had a positive procainamide challenge. Univariate and multivariate analysis identified baseline STE (OR 50.7) and SAECG (OR 1.84 per parameter) to be associated with a positive procainamide challenge (see Table). A simple 2-factor, 6-point model derived using baseline STE (3 points) and SAECG (1 point per parameter) was strongly predictive of the procainamide challenge (AUC 0.876). This model was validated in a second cohort, and found to be moderately predictive of the ajmaline challenge (AUC 0.730). Patients that scored 0 were unlikely to have a positive test (100% sensitivity), and patients that scored 6 were very likely to have a positive test (93% specificity). In this combined cohort of 348 patients, we derived and validated a simple 2-factor, 6-point score that can be effectively used to triage the role of the procainamide and ajmaline challenge in patients with suspected Brugada syndrome. Our findings also highlight the utility and incremental value of the SAECG in stratifying patients with suspected Brugada syndrome, prior to a sodium channel blocker test. We identified two populations where the sodium channel blocker test could be avoided to prevent adverse events and ensure appropriate use of resources.

Identifying the high-risk Brugada syndrome patient: Let us get personal

There are several reasons why risk stratification in the Brugada syndrome (BrS) continues to pose significant challenges. Prevalence of the syndrome in the general population is low, yet high-risk individuals can manifest with sudden cardiac death at a young age when the implantable cardioverter-defibrillator comes with a heavier burden of lifestyle change and cumulative long-term complications. Many patients will be asymptomatic on presentation and electrocardiographic (ECG) changes can fall in a nondiagnostic category. Despite significant and ongoing advancements in genetic discovery and technology, the yield of genetic testing in overall patients with BrS remains well below 50%. 1 The 2005 Consensus Conference established that conversion of a nondiagnostic ECG (saddle pattern type 2 or 3 ECG) to a diagnostic ECG (type 1 Brugada pattern) with a sodium-channel blocker (SCB) test indicated a positive diagnosis of the BrS. 1 This is an important issue, since increased awareness of this condition has resulted in a referral stream to electrophysiologists and cardiologists of patients with a nondiagnostic Brugada-pattern ECG who have vague or no symptoms. However, more recently, the largest BrS registry (FINGER Registry, 1029 consecutive subjects from 4 European countries) concluded that event rates in asymptomatic patients with BrS were low (0.5% per year) and that inducibility of ventricular arrhythmias and family history of sudden cardiac death were not predictive of sudden cardiac death. 2 Spontaneous type 1 ECG changes and the presence of symptoms were the only predictors of arrhythmic events in this population. In this issue of HeartRhythm, Zorzi el al 3 specifically address the utility of the SCB test among 198 patients with a nondiagnostic Brugada-pattern ECG recruited at 2 medical centers of the Veneto region of Italy. Of the total, 27 who developed spontaneous type 1 ECG changes were excluded and 18 were not available for follow-up. The remaining 153 subjects with type 2 or 3 Brugada ECGs were followed up for a mean period of 59 months. A positive SCB test result was associated with a significantly higher event rate in symptomatic patients but not in asymptomatic patients. These results suggest that the clinical utility of the SCB test in asymptomatic patients with nondiagnostic ECGs is likely to be low. This careful study incorporated placement of the right precordial leads in a superior position in order to increase sensitivity for detecting type 1 ECG changes. 4 What is the clinical message of this study and what are the caveats to keep in mind? The findings of this study provide more evidence to clinicians that SCB testing may not be indicated in asymptomatic patients with a nondiagnostic Brugada-pattern ECG. We should keep in mind that this was a relatively small study with a relatively short follow-up period given the natural history of the BrS. Also, event rates were low and the study did not provide information on pre-2005 (Consensus Conference publication) vs post-2005 clinical management. Most important, if the findings of the FINGER registry remain consistent, our clinical attention is likely to focus largely on symptomatic patients with a spontaneous type 1 BrS ECG.

Should all individuals with a nondiagnostic Brugada-electrocardiogram undergo sodium-channel blocker test?

The diagnostic Brugada-electrocardiogram (Br-ECG) is characterized by "coved-type" ST-segment elevation (type 1) in V(1) to V(2)/V(3). The sodium-channel blocker test is clinically used to unmask diagnostic Br-ECG in patients with nondiagnostic "saddle-back" Br-ECG (type 2 and type 3). To assess the prognostic value of the sodium-channel blockers test in individuals with a nondiagnostic Br-ECG. We studied 153 consecutive patients (128 men; age 41.7 ± 14.0 years) with a type 2/3 Br-ECG who underwent a sodium-channel blocker test with either flecainide (48%) or ajmaline (52%). Nondiagnostic Br-ECGs were identified during the evaluation of cardiac arrest in 5 patients (3%), syncope in 36 (24%), cascade family screening in 48 (31%), and incidental ECG in 64 (42%). A spontaneous type 1 Br-ECG was systematically excluded by serial ECGs (6.1 ± 0.4) and recording of right precordial leads both at standard and second and third intercostal spaces. The sodium-channel blocker test result was positive in 76 (50%) patients. During a follow-up of 59 ± 33 months, 9 (5.9%) patients experienced events such as syncope (n = 4), appropriate interventions of defibrillator (n = 4), or sudden death (n = 1). A positive sodium-channel blocker test was associated with a significantly higher event rate in symptomatic patients (P = .01) but not in asymptomatic individuals (P = .18). No events occurred among asymptomatic individuals with an incidental nondiagnostic Br-ECG. In asymptomatic individuals with a nondiagnostic Br-ECG, the incidence of events is low regardless of the sodium-channel blocker test result while in symptomatic patients a positive sodium-channel blocker test result is associated with an adverse arrhythmic outcome and may contribute to risk stratification.

The Brugada syndrome in Canada: A unique French-Canadian experience

The Brugada syndrome (BS) is a clinical entity involving cardiac sodium channelopathy, typical electrocardiogram (ECG) changes and predisposition to ventricular arrhythmia. This syndrome is mainly recognized by specialized cardiologists and electrophysiologists. Data regarding BS largely come from multicentre registries or Asian countries. The present report describes the Quebec Heart Institute experience, including the clinical characteristics and prognosis of native French-Canadian subjects with the Brugada-type ECG pattern. BS has been diagnosed in 35 patients (mean age 51 +/- 12 years) at the Quebec Heart Institute since 2001. Patients were referred from primary care physicians for ECG abnormalities, syncope or ventricular arrhythmia, or were diagnosed incidentally on an ECG obtained for other purposes. The abnormal ECG was recognized after a syncopal spell in four patients and during family screening in four patients. All of the others were incidental findings following a routine ECG. No patient had a family history of sudden cardiac death at younger than 45 years of age. In this population, right bundle branch block pattern with more than 2 mm ST segment elevation in leads V1 to V3 was recorded spontaneously in 25 patients and was induced by sodium blockers in 10 patients. The sodium channel blocker test was performed in 21 patients and was positive in 18 patients (86%). An electrophysiological study was performed in 20 of 35 patients, during which ventricular fibrillation was induced in five patients; three of the five patients were previously asymptomatic. An implantable cardioverter-defibrillator was implanted in six of 35 patients (17%), including three of four patients with a history of syncope. A loop recorder was implanted in three patients. After a mean follow-up of 36 +/- 18 months, one patient died from a noncardiac cause and one patient (with a history of syncope) received an appropriate shock from his implantable cardioverter-defibrillator. No event occurred in the asymptomatic population. BS is present in the French-Canadian population and is probably under-recognized. Long-term prognosis of individuals with BS, especially in sporadic, asymptomatic cases, needs to be clarified.