Ventricular arrhythmia during ajmaline challenge for the Brugada syndrome

Europace (2016) 18, 1501 1506 doi:10.1093/europace/euw008 REVIEW Ventricular arrhythmia during ajmaline challenge for the Brugada syndrome Bieke Dobbels 1 *, Dieter De Cleen 2,3, and Joris Ector 4,5 1 Department of Internal Medicine, University of Leuven, Leuven, Belgium; 2 Department of Cardiovascular Diseases, University Hospitals, Antwerp, Belgium; 3 Department of Cardiovascular Diseases, AZ Klina, Brasschaat 2930, Belgium; 4 Department of Cardiovascular Diseases, University Hospitals, Leuven, Belgium; and 5 Department of Cardiovascular Sciences, University of Leuven, Leuven 3000, Belgium Received 12 October 2015; accepted after revision 6 January 2016; online publish-ahead-of-print 3 March 2016 The Brugada syndrome is a genetic disease characterized by an abnormal electrocardiogram (ECG) and an elevated risk of sudden cardiac death. Sodium channel blockers (SCBs), such as ajmaline, are used to unmask the characteristic type 1 Brugada electrocardiographic pattern. We review the literature on the incidence of ventricular arrhythmia (VA) during SCB challenge. We evaluate the clinical and electrocardiographic characteristics of these patients as well as their prognosis. All articles published from January 2000 until August 2015, in which the incidence and predictors of VAs during SCB challenge were reported, are reviewed. The occurrence of VA during SCB challenge ranges from 0 to 17.8%. The weighted average for induction of any VA during sodium blocking challenge is 2.4%; for non-sustained ventricular tachycardia (VT), it is 0.34% and for sustained VT 0.59%. No fatal cases were reported. Predictors may be young age, conduction disturbance at baseline ECG, and mutations in the SCN5A gene. All other clinical and electrocardiographic characteristics failed to be consistent predictors. Life-threatening arrhythmias during SCB challenge are not an exceptional event. Therefore, provocation testing must necessarily be performed in an appropriate environment in which advanced life support facilities are present. Patients who have a higher risk for induced arrhythmias might be those who display a conduction disturbance at baseline ECG or have certain SCN5A mutations or are of a younger age. However, survivors of these induced arrhythmias do not seem to suffer from a worse prognosis. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Brugada syndrome Sodium channel blocker challenge Ajmaline challenge Ventricular arrhythmias Proarrhythmia Introduction Since its introduction as a clinical entity in 1992, the Brugada syndrome (BS) has progressed from being a rare disease to one that is responsible for at least 20% of all cases of sudden death in patients with a structurally normal heart. 1 Electrocardiographically, the syndrome is characterized by a coved-type ST-segment elevation in the right precordial leads (V1 V3). Isolated cases of ST-segment elevation in the inferior leads have been reported in Brugada-like syndromes. 1 In the case of a non-diagnostic baseline electrocardiogram (ECG), pharmacological challenge with intravenous administration of a sodium channel blocker (SCB) is performed to amplify or unmask the diagnostic ECG pattern. Flecainide, procainamide, and pilsicainide have been used as SCB agents but ajmaline is considered as the drug of choice because of its high sensitivity and specificity in combination with the shortest half-life. 2,3 The incidence of life-threatening ventricular arrhythmias (VAs) during SCB challenge is considered to be rather low. To date, no literature review about the occurrence of VA during SCB has been carried out. The objective of this study is to assess the overall incidence of VA during SCB challenge deduced from all previous literature reports and to identify patients at higher risk for these side effects. Furthermore, we will analyse whether patients with BS who developed VA during provocation test are at higher risks for long-term arrhythmic events. Literature review Methods All literature reports in English language examining VA during SCB challenge were reviewed from January 2000 to August 2015. In Pubmed, we searched for: sodium channel blocker challenge and Brugada Syndrome [Mesh], flecainide and Brugada Syndrome [Mesh], pilsicainide and Brugada Syndrome [Mesh], procainamide and Brugada Syndrome [Mesh], ajmaline and Brugada Syndrome [Mesh], ventricular arrhythmia and sodium channel blocker challenge, safety sodium channel blocker challenge and Brugada Syndrome [Mesh], ventricular * Corresponding author. Tel: +32 4 98637350. E-mail address: bieke.dobbels@student.kuleuven.be Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2016. For permissions please email: journals.permissions@oup.com.

1502 B. Dobbels et al. arrhythmia and ajmaline challenge, adverse events, and ajmaline challenge. Sustained ventricular tachycardia (VT) is defined as a wide QRS complex (.120 ms) tachycardia with a rate.100 b.p.m. for a period of 30 s or with haemodynamic compromise within 30 s. All single case reports were excluded, and minimal population size for inclusion was arbitrarily set at 20 subjects. Only studies with the exact prevalence of VA during SCB challenge and with patient characteristics were included. Studies that reported no adverse events during SCB challenge were not excluded. When the study was not initially designed to estimate the prevalence of VA during SCB challenge, we included only those studies with clear numbers of prevalence of VA and with clinical characteristics of these patients. These studies are indicated as off note in Table 1. In each study, we searched for the following characteristics: population size; number of patients with Brugada type 1 ECG at baseline, a positive test result, and occurrence of VA during the test; number of symptomatic patients; the sodium channel blocking agent used; and criteria used for discontinuation of drug infusion. Results The 16 literature reports of the risk of VA during pharmacological testing that met the inclusion criteria are summarized in Table 1. In summary, 0 17.8% of the patients undergoing SCB challenge developed VA. The overall incidence of VA without premature ventricular complexes (PVCs), thus VT and ventricular fibrillation, ranged from 0 to 10.7%. The weighted average for the induction of VA in all patients undergoing sodium channel blocking challenge is 2.4% (i.e. 86 VA/ 3515 tests), which is more representative because of the various sizes of populations used in the several studies. If we only take into account the prevalence of VA without PVC, thus VT and ventricular fibrillation, the weighted average is 0.9% (i.e. 33 events/3515 tests). Non-sustained VT occurs in 0.34% of SCB challenges and sustained VT/VF in 0.59% of SCB tests. Several studies did not find or investigate risk factors for developing VA during pharmacological testing. 4,8,10,13 15,17 19 Associated risk factors found in the other reports are summarized in Table 2. Regarding ECG characteristics, a longer QRS interval before and after SCB administration, macroscopic T-wave alternans, higher ST-segment elevation in V2 before and after SCB administration, longer QTc interval, and a sinus node dysfunction at baseline ECG are found to be associated with a higher proarrhythmic risk during provocation test. 5,9,16 However, only a macroscopic T-wave alternans and sinus node dysfunction at baseline were not refuted risk factors by other reports. 5,9,11,16 An SCN5A mutation seems to be a consistent risk factor for SCB-induced VA throughout the two studies investigating this subject. 7,16 Studies show that the incidence of serious arrhythmic events induced by SCB is substantially lower as long as the protocol of the Brugada consensus conference is followed and subjects included in the study did not display a Brugada type 1 ECG at baseline. 6 A lower age at the time of ajmaline challenge was an interesting proarrhythmic risk factor found by Conte et al. 16 and could not be refuted by any other report. Patients with SCB-induced arrhythmias seem to be previously asymptomatic in up to 66% of the cases. 5 7,9,11,16 In the 16 literature reports we reviewed, a total of 3322 patients underwent SCB challenge and not one fatal arrhythmia has been reported. Only one patient had neurological sequelae after resuscitation with extracorporeal membrane oxygenation. 16 The prognosis of patients who developed VA during SCB challenge has been evaluated by Chinushi et al., who found no significant difference in prognosis between patients who did and did not develop VA during a mean follow-up of 45 + 37 months. Conte et al. 16 confirmed this finding: during a mean follow-up of 29 + 8 months, no patients with ajmaline-induced VA suffered from further arrhythmia. Discussion Prevalence of sodium channel in Brugada syndrome With an estimated prevalence of 0.9%, we highlight that severe VA is an infrequent but not an exceptional event during SCB challenge. Because there is quite some heterogeneity between the studies, it is difficult to estimate the exact prevalence of adverse events during ajmaline challenge. First of all, several studies used other SCBs than ajmaline. To our knowledge, no studies have been performed to assess the difference in proarrhythmic risk between the different sodium channel blocking agents. Furthermore, the population undergoing the ajmaline challenge showed great diversity. The risk of proarrhythmia was higher as the study included more patients with a Brugada type 1 ECG at baseline. This finding appears to be true regardless of the type of SCB used. Finally, the criteria for discontinuation differ between the different studies. Studies in which the protocol for SCB challenge was strictly followed reported lower rates of serious side effects. According to the second consensus conference, SCB administration should be terminated if a full target dose reached, occurrence of J-point elevation.2 mm in at least one right precordial lead (Brugada type 1 ECG), occurrence of PVC/VT/sinus arrest/high-degree atrioventricular block, or QRS prolongation.30%. 1 Predictors for sodium channel Because these events do not occur very often, it is difficult to define characteristics associated with higher risks at SCB-induced VA. The incidence of severe VA is higher when infusion was not terminated in the case of a diagnostic Brugada type 1 ECG or the occurrence of PVC. 4,5,7,9 Most studies terminate SCB administration when a QRS prolongation of.30% occurs. A wider QRS at baseline and a statistically significant longer QRS prolongation after pilsicainide administration were reported in patients who developed VA during the test when compared with those who did not. However, this has not been confirmed in other reports. 9,11,16 In 2009, this discontinue criterion was challenged by Batchvarov et al., 11 who found that in 40% of the positive tests, the diagnostic Brugada type 1 ECG appeared only after the QRS had prolonged by.30%. This QRS prolongation by.30% was not associated with

Table 1 VA during pharmacological testing for BS Study reference Population Baseline type 1 Drug used Test N (VA) in group N (VA) in group with N (VA) in group Total N (VA)/ Brugada ECG (%) positivity (%) with 1 test asymptomatic with test total N (tests) patients and 1 test... Brugada et al. 4 (off note) 106 32 Ajmaline (73%) Flecainide (13%) Procainamide (14%) Morita et al. 5 65 100 Pilsicainide 100 6 PVC 4 ns PVT Rolf et al. 6 158 3.8 Ajmaline 23 1 nsvt 1sVT Gasparini et al. 7 22 patients (41 tests) 86.4 Flecainide 100 3 svt 1VF Meregalli et al. 8 160 0 Flecainide 40 11 PVC 0VT Chinushi et al. 9 28 64.3 Pilsicainide 100 2 PVC 3VT Veltmann et al. 10 677 0 Ajmaline 39 8 PVC 1nsPVT 1VF Batchvarov et al. 11 (off note) 148 0 Ajmaline 20.3 7 PVC 1 nsvt Dassonvalle et al., 12 part II 386 10 Ajmaline 47.4 2 PVC 1 nspvt 1VF 42.5 1 VF, 5 PVC Not sp. 0 0.9% VF 4.7% PVC 3 PVC 1 PVT / 9.2% PVC 6.2% ns PVT 1nsVT Not sp. 0.6% nsvt 0.6% svt Not sp. / 7.3% svt 2.4% VF 0 0 6.8% PVC 0% VT Not sp. / 7.1% PVC 10.7% VT 0 0 1.2% PVC 0.1% nspvt 0.1% VF 1 nsvt 12 PVC 2 nsvt a 12.8% PVC 2.0% nsvt 1 VF 0 0.5% PVC 0.3% nvt 0.3% VF Sorgente et al. 13 179 0 Ajmaline 75 1 nsmvt 0 0 0.6% nsmvt Gielerak et al. 14 (off note) 59 0 Ajmaline 11.9 0 0 0 0% Zorzi et al. 15 (off note) 153 0 Flecainide (48%) 49.7 0 0 0 0% Ajmaline (52%) Conte et al. 16 1043 0 Ajmaline 48.2 9 VF/sPVT 5 VF/sPVT 0 0.9% VF/sPVT McMillan et al. 17 95 0 Ajmaline 20 0 0 0 0% Conte et al. 18 (off note) 43 0 Ajmaline 23.3 1 VF Not sp. Not sp. 2.3%VF Somani et al. 19 (off note) 174 0 Procainamide 6.9 0 0 1 nspvt 0.6% nspvt This table shows a summary of 16 studies in which the incidence of VA during SCB challenge was investigated. ECG, electrocardiogram; MVT, monomorphic ventricular tachycardia; Not sp., not specified; ns, non-sustained,,30 s; PVC, premature ventricular complexes (including both single and frequent premature ventricular complexes); PVT, polymorphic ventricular tachycardia; s, sustained,.30 s; VA, ventricular arrhythmia; VF, ventricular fibrillation; VT, ventricular tachycardia; /, not applicable. atwo patients with ajmaline-induced VA had a negative test outcome; however, one of the patients had a Brugada type 1 pattern in the inferior leads. This patient was previously asymptomatic. VA during ajmaline challenge 1503

1504 B. Dobbels et al. Table 2 Factors associated with VAs during SCB challenge Study reference Factors predicting VA occurrence during Factors not significantly different between patients with the test and without SCB-induced VA... Morita et al. 5 Longer QRS interval before and after pilsicainide Level of ST-segment, QTc interval, PQ interval, HV interval, and administration depth of S wave before and after administration of pilsicainide Macroscopic T-wave alternans after pilsicainide administration Rolf et al. 6 Gasparini et al. 7 Chinushi et al. 9 Not terminating ajmaline infusion when diagnostic Brugada-type ECG changes occurred during challenge SCN5A mutation Higher ST-segment elevation in V2 before and after pilsicainide administration Longer QTc interval after pilsicainide Prior cardiac events, results of ECG, HV interval, inducibility of ventricular fibrillation by programmed electrical stimulation, QRS duration Batchvarov et al. 11 (off note) Positive test outcome QRS prolongation to.130% after ajmaline infusion Dassonvalle et al. 12 Slow or rapid infusion of ajmaline Conte et al. 16 Lower age at the time of ajmaline challenge Lower age at the first onset of symptoms Sinus node dysfunction at baseline ECG SCN5A mutation Age younger or older than 18 years Sex Family history of sudden death Personal history of aborted sudden death, syncope, or palpitations History of atrial fibrillation or advanced atrioventricular block PR interval, QRS duration, QTc interval at baseline ECG VA, ventricular arrhythmias; SCB, sodium channel blocker; ECG, electrocardiogram. a higher incidence of VA. Perhaps, early termination of provocation testing because of QRS prolongation should depend on baseline QRS duration and the presence of intraventricular conduction abnormalities. 11 This hypothesis is yet to be tested. As more patients with a spontaneous Brugada type 1 ECG were included for provocation testing, the proarrhythmic risk tended to be higher. 4,5,7,9 The rate of drug infusion did not seem to alter the proarrhythmic risk of SCB challenge, 6 although a fractionated application manner might be preferred over a bolus administration. A very low degree of malignant response to sodium channel blocking agents in patients with a negative test has been reported. 11,19 Patients who experience VA tend to be younger at the time of the SCB challenge and to present their first symptoms at a younger age when compared with those who do not experience any malignant event during challenge. 16 In this regard, it is important to note that no study could prove that the paediatric population (,18 years) is at higher risk of having VA during SCB challenge. 13,16,17 All authors agree that SCB challenge is a safe diagnostic tool in the paediatric population, when performed in an appropriate environment. Other patient characteristics, such as gender or a family history of sudden death, cannot predict the occurrence of SCB-induced VA. 16 Symptoms such as a history of palpitations, syncope, or atrial fibrillation or aborted sudden cardiac death also failed to be appropriate predictors of SCB-induced arrhythmia. 9,16 A correlation between conduction disturbances at baseline ECG and a higher risk of VA during SCB challenge has been suggested. The presence of sinus node dysfunction was significantly higher in patients with a proarrhythmic effect of ajmaline. 16,20 Regarding ECG characteristics, several authors tried to define predictors for malignant SCB response, unfortunately without identifying clear risk factors. The appearance of macroscopic T-wave alternans after SCB administration is significantly associated with an increased risk of VA during provocation testing, as reported by Morita et al. 5 However, the potential value of T-wave alternans needs to be evaluated further in predicting tachyarrhythmic events during SCB challenge. In patients experiencing drug-induced VA, several studies found a higher frequency of SCN5A mutations. 7,16,20 It seems reasonable that there are several mutations that predispose patients to an increased sensitivity to SCB. This assumption is supported by a report of familial ajmaline-induced VA. 20 Treatment of sodium channel A sodium channel blocker test should always be performed by experienced doctors and nurses in a room fully equipped for resuscitation. As in some cases, VAs occur minutes to hours after SCB challenge; 5 monitoring afterwards is necessary. There are no strict guidelines concerning timing after ajmaline challenge. The termination of VA in the BS might be more difficult after administration of sodium channel blocking agents. 16 It has been reported that the amount of energy required to terminate a VF is higher in animals treated with cardiac sodium channel blockers. 7 The treatment of an ajmaline-induced VA includes external/ internal cardioverter defibrillator shocks and isoproterenol. 5,9,12,16 As a last resort, resuscitation with a venoarterial extracorporeal membrane oxygenator can be used. 16 As no fatal arrhythmias were reported in our literature review, the efficacy of Advanced Life Support for these arrhythmias seems to be reassuring.

VA during ajmaline challenge 1505 Result of sodium channel blocker challenge: implication for prognosis and therapy? Today, risk stratification in patients with BS remains controversial. Resuscitated sudden cardiac death and the history of syncope, especially in combination with a spontaneous type 1 ECG, are recognized risk factors for a worse prognosis, and SCB testing provides no additional information. 21,22 As proposed by the ESC Guidelines published in August 2015, these patients should receive an implantable cardioverter defibrillator. 23 The prognostic role of SCB challenge depends on whether a BS patient is symptomatic or not. A positive SCB test result in symptomatic patients predicts an increased risk of arrhythmic events. 1 3,15,23 It is as high as 5.2% during a 59-month follow-up among survivors of cardiac arrest and 1.44% during a 40-month follow-up in patients with a history of syncope, according to the FINGER study. 21 As proposed by the International Consensus published in August 2015, these patients should also receive an implantable cardioverter defibrillator. 23 On the contrary, SCB challenge does not provide additional information in asymptomatic patients regarding long-term prognosis, as the incidence of events in this population is low, regardless of the SCB test result. 15,21,22 The FINGER study reported an event rate of 0.5% in asymptomatic Brugada patients (with or without spontaneous type 1 ECG). Treatment strategies for asymptomatic patients remain controversial in literatures. However, it is well established that the indication for an implantable cardioverter defibrillator does not depend on the outcome of SCB challenge. The result of SCB challenge in children is even more difficult to interpret towards therapy and prognosis. Several studies have shown an age-dependent response at SCB challenge, in which an initial negative test result changes to a positive result at a second sodium channel blocker challenge after puberty. 17,18 Therapeutic strategies in children affected with BS are not well established. Further research is required to develop paediatric-specific guidelines and to determine the prognostic value of SCB challenge in childhood. Benefit risk balance of sodium channel blocker challenge We can conclude that in symptomatic patients the ajmaline challenge should be performed without a doubt. It influences both risk assessment and therapy. It can be questioned whether an SCB challenge is necessary in all asymptomatic patients with a suspicious ECG baseline or a family history of BS, considering the good prognosis of asymptomatic patients. The outcome of the test does change neither the indication of an implantable cardioverter defibrillator nor the prognosis. In contrast, life-threatening VA can occur in both symptomatic and asymptomatic patients during SCB challenge, and a positive test outcome may have severe consequences in terms of psychological distress. 15 However, it seems too simple to conclude that the risk of SCB-induced arrhythmia outweighs the potential benefits of the SCB challenge in asymptomatic patients. A positive test result certainly has implications for a patient and his/her family. Sodium channel blocking agents are contraindicated as a future therapy in patients with a positive test result. Changes in life style are critical to prevent arrhythmia, even in asymptomatic BS patients. Patients must avoid fever and contraindicated medications (www. brugadasyndrome.org) such as SCB. 2 Perhaps, treatment with medications will also be used for asymptomatic patients in the future. 2,3 Finally, a negative test result in an asymptomatic BS family member may provide peace of mind to the patient. The psychological impact of a possible diagnosis with a deadly syndrome may not be underestimated. Prognosis of patients with sodium channel No significant difference in prognosis was found between patients who developed VA during SCB challenge and patients who did not. Thus despite its challenging treatment, VA during SCB test might not predict a higher risk at further life-threatening arrhythmias. Conclusion The SCB challenge is a well-established diagnostic tool for the BS. From our literature review, severe VAs during challenge are not a rare event, and their prevalence is estimated at 1%. Young age, conduction disturbances at baseline ECG, and SCN5A mutations seem to be more frequent in patients with VA during provocation testing. Other patient and ECG characteristics failed to predict SCB-induced VA. Further research seems to be necessary in this area. The SCB challenge can certainly have an added value for both symptomatic and asymptomatic patients. In symptomatic patients, a positive test result does have clear-cut implications regarding treatment and prognosis, whereas this is lacking for asymptomatic patients. In this population, the outcome of the test is mostly important regarding life-style changes. The treatment of ajmaline-induced VA can be challenging. However, despite these life-threatening events, these patients seem not to be at higher risk for further arrhythmic events. Conflict of interest: none declared. References 1. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D et al. 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