Author + information
- Received May 15, 2017
- Revision received August 16, 2017
- Accepted August 17, 2017
- Published online October 9, 2017.
- Jaime Hernandez-Ojeda, MD, PhDa,b,∗ (, )
- Elena Arbelo, MD, PhDa,b,
- Roger Borras, MSca,b,
- Paola Berne, MDa,b,
- Jose M. Tolosana, MD, PhDa,b,
- Andrea Gomez-Juanatey, MDa,b,
- Antonio Berruezo, MD, PhDa,b,
- Oscar Campuzano, BSc, PhDc,d,e,
- Georgia Sarquella-Brugada, MD, PhDf,
- Lluis Mont, MD, PhDa,b,
- Ramon Brugada, MD, PhDc,d,e,g and
- Josep Brugada, MD, PhDa,b,f
- aArrhythmia Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- bIDIBAPS, Institut d’Investigació August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- cCardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain
- dMedical Science Department, School of Medicine, University of Girona, Girona, Spain
- eCentro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- fArrhythmia Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
- gCardiology Service, Hospital Josep Trueta, Girona, Spain
- ↵∗Address for correspondence:
Dr. Jaime Hernandez-Ojeda, Hospital Clínic de Barcelona, C/ Villarroel, 170, 6º, escala 3, 08036 Barcelona, Spain.
Background Implantable cardioverter-defibrillator (ICD) indications for primary prevention in Brugada syndrome (BrS) are still debated.
Objectives The authors investigated the long-term outcome after ICD implantation in a large cohort of BrS patients.
Methods Of a total of 370 patients with BrS in follow-up (age 43 ± 14 years; 74% male), 104 patients (28.1%) were treated with ICDs. The authors analyzed the long-term incidence of shocks and complications.
Results An ICD was implanted for secondary prevention in 10 patients (9.6%) and for primary prevention in 94 patients (90.4%). After a follow-up of 9.3 ± 5.1 years, 21 patients (20.2%) experienced a total of 81 appropriate shocks (incidence rate 2.2 per 100 person-years). The rate of appropriate shocks was higher in secondary prevention patients (p < 0.01). However, 4 of the 45 asymptomatic patients (8.9%) experienced appropriate ICD therapy, all with a spontaneous type 1 electrocardiogram and inducible ventricular arrhythmias. In the multivariable analysis, type 1 electrocardiogram with syncope (hazard ratio: 4.96; 95% confidence interval: 1.87 to 13.14; p < 0.01) and secondary prevention indication (hazard ratio: 6.85; 95% confidence interval: 2.29 to 20.50; p < 0.01) were significant predictors of appropriate therapy. Nine patients (8.7%) experienced 37 inappropriate shocks (incidence rate 0.9 per 100 person-years). Twenty-one patients (20.2%) had other ICD-related complications (incidence rate 1.4 per 100 person-years). Three patients (2.9%) died (1 electrical storm and 2 noncardiovascular deaths).
Conclusions ICD therapy is an effective therapy in high-risk patients with BrS. However, it is also associated with a significant risk of device-related complications. Special care during ICD implantation, adequate device programming, and regular follow-up may allow reducing the number of adverse events.
Brugada syndrome (BrS) is an autosomal dominant with variable expression and incomplete penetrance hereditary disease, although only 30% to 35% of patients can be genetically diagnosed, indicating that 65% to 70% remain genetically unresolved. It is characterized by a ST-segment elevation in the right precordial electrocardiogram (ECG) leads, which predisposes to sudden death (SD) due to polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) in the absence of macroscopic structural heart disease (1).
To date, the only effective therapy for the prevention of SD in BrS is the use of an implantable cardioverter-defibrillator (ICD). Although quinidine treatment and catheter ablation therapy have demonstrated efficacy in recurrent ventricular arrhythmias (2), patients who have experienced a prior cardiac arrest or syncopal events secondary to VT/VF should undergo ICD implantation (3,4). However, ICD implantation for primary prevention in BrS patients is still debated due to the lack of appropriate risk stratification tools. Asymptomatic patients whose diagnostic ECG (type 1) is only documented after administration of sodium channel blocking drugs, should avoid triggers such as fever or contraindicated drugs and be regularly followed up without ICD implantation (3,4). Conversely, management in patients with spontaneous type 1 ECG and no prior history of SD remains controversial. In these patients, the annual incidence of malignant arrhythmic events varies among the series, but it has been estimated to be at ≈1% to 9% (5,6), and programmed ventricular stimulation (PVS) may be considered for risk stratification (3–5).
Unfortunately, BrS affects young and otherwise healthy and active individuals with a life expectancy >30 years. As a result, it has been described that these patients are more likely to encounter device-related complications, including inappropriate shocks and electrode-related problems (between 20% and 36% after 21 to 47 months’ follow-up) (7–12). It remains unknown whether the potential adverse effects offset the efficacy of ICD implantation in the BrS population.
We now report the experience of more than 20 years of a large single-center cohort of ICD recipients with BrS, assessing the benefits and adverse effects of this therapy after a long-term follow-up.
This is a prospective single-center registry. In this analysis, we include all patients diagnosed with BrS at our institution between January 1, 1994, and December 31, 2015, who had the indication for ICD therapy was set and who subsequently underwent ICD implantation.
BrS was diagnosed only in the presence of a type 1 Brugada pattern on the ECG (coved type), either at baseline or after the administration of a sodium channel blocking agent, in the absence of any structural cardiomyopathy (3,13,14). A type 1 ECG pattern was defined as the presence of a terminal r′-wave with a J-point elevation of at least 0.2 mV, with a slowly descending ST-segment followed by a negative T-wave in ≥1 right precordial lead (V1 to V3), placed in the fourth, third, or second intercostal space. Flecainide (2 mg/kg) or ajmaline (1 mg/kg) were administered intravenously over a 10-min period to unmask the diagnostic ECG pattern of BrS in case of a nondiagnostic baseline ECG. In all patients, significant structural cardiomyopathy was ruled out by transthoracic echocardiogram and, in case of suspicious findings, by cardiac magnetic resonance. All ICDs were programmed using a single VF zone at ≥200 beats/min, with 1 rapid burst of antitachycardia pacing (ATP) in the VF zone (if available) and 3 shocks with maximum output (41 J). Patients were followed annually in the dedicated cardiogenetic outpatient clinic and every 6 to 12 months in the ICD clinic (unless shorter periods of follow-up were required). Patients with ICD remote monitoring capabilities were interrogated transtelephonically every 3 months and in the event of any device alert. Patients with a follow-up of <6 months were excluded.
This registry was approved by the institutional review board, and all patients gave informed consent.
Patients’ sociodemographic and clinical data were prospectively collected from the time of diagnosis to the last follow-up. Baseline clinical data included age at diagnosis, sex, race, family history of SD or BrS, symptoms before diagnosis, circumstances of diagnosis, baseline ECG data, results of pharmacological testing, genotype and characteristics, and results of PVS. Baseline ICD-related data included type of ICD, type of lead, indication for implantation, and electrode measurements at implantation. Indication for ICD implantation was reviewed in each patient, with emphasis on basal ECG characteristics, multiple syncope history, prolonged HV interval in the electrophysiological study (EPS), inducible VT of VF during PVS, family history of SD, and history of VF or resuscitated cardiac arrest.
Follow-up variables included clinical (presence of symptoms) and electrocardiographic evaluation and device interrogation data (complications during implantation and follow-up, the presence of sustained and nonsustained VT/VF episodes, and the occurrence of inappropriate and appropriate therapy). ICD therapy was classified as appropriate or inappropriate. Number of shocks per episode, number of episodes shocked, time to shock since ICD implantation, and whether the shock was successful in restoring sinus or paced rhythm were documented.
BrS-related symptoms before diagnosis were defined as the presence of an aborted SD or nonvasovagal syncope. Nonvasovagal syncope was suspected in case of absent or brief prodrome (<10 s), absence of specific triggering circumstance, brief loss of consciousness (<1 min), and fast return to consciousness. Recurrent syncope was defined arbitrarily as ≥3 episodes of nonvasovagal syncope.
A family history of SD was defined as a SD at <55 years of age in ≥1 family members of first or second degree. The EPS included basal measurements of conduction intervals and ventricular stimulation. The stimulation protocol used a single site of stimulation (right ventricular apex), 3 basic pacing cycle lengths (600, 500, and 430 ms), and introduction of up to 3 ventricular premature beats (using 10-ms decrements), down to the refractory period or a minimum of 200 ms. A patient was considered inducible if sustained ventricular arrhythmias of more than 30 s (or requiring emergency intervention) were induced.
ICD implantation for secondary prevention was considered after resuscitated cardiac arrest or documented sustained VT or VF. All other indications for ICD implantation were defined as primary prevention.
Appropriate ICD therapy was defined as shocks or ATP delivered for sustained ventricular arrhythmias (monomorphic VT, polymorphic VT or VF with a cycle length within the therapy zone of the device). Electrical storm was defined as the occurrence of ≥3 separate episodes of ventricular arrhythmia requiring an ICD shock within 24 h. Inappropriate ICD therapy was defined as a shock delivered for reasons other than ventricular arrhythmia and was categorized according to the most probable cause (T-wave oversensing, sinus tachycardia, atrial flutter, atrial fibrillation, and other form of supraventricular tachycardia). Every shock or ATP episode was analyzed by an experienced electrophysiologist to evaluate the appropriateness of the intervention delivered and stratified accordingly.
Early and late ICD complications included pocket hematoma, lead failure, pneumothorax, undersensing or oversensing, device malfunction, lead dislodgment, pocket and other infections, erosion, and migration of the device. ICD complications were considered periprocedural if they occurred within 30 days of implantation and late if they occurred after 30 days after implantation (15).
Continuous variables presented as the mean ± SD. To compare means of 2 variables, we used the Student t test or analysis of variance as appropriate. Categorical variables were expressed as total number (percentages) and compared between groups using the chi-square test. The (event-free) survival of patients was evaluated with the Kaplan-Meier method. The effect of different variables on (event-free) survival was investigated using the Cox proportional hazards model. Variables that showed a statistically significant effect on (event-free) survival in univariate analyses were entered in a multivariate Cox proportional hazards model using a backward stepwise selection to obtain the final model. At each step, the least significant variable was discarded from the model until all variables in the model reached a p value below 0.10. The number of variables that could enter the multivariate was limited using the 10% rule of preventive maintenance to prevent overfitting the model. For all tests, a p value < 0.05 was considered significant. Statistical analysis was performed using R software for Windows version 3.3.0 (R Project for Statistical Computing; Vienna, Austria).
Of a total of 370 patients with BrS, 104 patients (28%) were treated with ICD implantation between January 1994 and December 2015. Baseline characteristics are summarized in Table 1. Family history of BrS was present in 87 patients (83.7%) and of SD in 35 patients (33.7%). A spontaneous type 1 ECG pattern was documented in 65 patients (62.5%). The diagnostic ECG pattern was induced by a sodium channel blocker test in the remaining 39 patients (37.5%). Genetic testing was done in 68 patients (64.4%); 16 patients (23.5%) were positive for pathogenic mutations on the SCN5A gene.
The diagnosis of BrS was done following an episode of aborted SD in 10 patients (9.6%), all male with a mean age of 41.3 ± 14 years. Spontaneous type 1 ECG pattern was present in 4 patients (40%) and a family history of SD in 1 (10%). SD occurred at rest in 9 patients (90%) and during fever in 1 (10%). In 8, SD was the first symptom of BrS, whereas the 2 remaining had experienced syncopal episodes at the age of 28 and 29 years, respectively (2 episodes each). One previously asymptomatic male experienced an electrical storm during an ajmaline drug challenge done for family screening. He had no family history of SD nor spontaneous type 1 ECG. Genetic test performed afterward resulted positive for a pathogenic SCN5A mutation. All patients were indicated an ICD implantation for secondary prevention (Figure 1).
Forty-nine patients (47.1%) were diagnosed after experiencing at least 1 episode of nonvasovagal syncope before diagnosis (median 2 episodes, interquartile range [IQR]: 1 to 10). Spontaneous type 1 ECG pattern was present in 28 patients (57.1%) and a family history of SD in 15 (30.6%). Syncope occurred at rest in 46 patients (93.9%) and during a febrile episode in 3 patients (6.1%). The mean age at the first syncope episode was 36 ± 19 years.
The remaining 45 patients (43.3%) were asymptomatic at diagnosis: 39 were probands diagnosed after a suspicious ECG, whereas the rest (n = 6) were identified during family screening. Spontaneous type 1 ECG pattern was present in 33 patients (73.3%) and a family history of SD in 19 (42.2%). ICD implantation in asymptomatic patients was indicated for the following reasons: inducible ventricular arrhythmias in the EPS in 35 patients (77.8%); family history of SD in 5 patients (11.1%); prolonged HV interval in 3 patients (6.7%); and spontaneous type 1 ECG as the only risk factor in 2 patients (4.4%). Of note, all out-of-guidelines ICD implantations were performed before 2005, when ICD indications were not clearly established (Figure 2).
An ICD was implanted for secondary prevention in 10 patients (9.6%) and for primary prevention in 94 patients (90.4%) (Figure 1). The symptom status and the overall indications by year of ICD placement are shown in Figure 2.
The mean age at ICD implantation was 46.2 ± 13 years. Seventy-five patients (72.1%) received 1-chamber transvenous ICDs, 29 patients (27.9%) a dual-chamber transvenous ICD; and 1 patient (0.9%) received a subcutaneous ICD. Single-coil ICDs were implanted in 8 patients (7.7%); and dual-coil ICDs in 96 patients (92.3%). Active fixation leads were placed in 5 patients (4.8%); and passive fixation in 99 patients (95.2%). Mean R-wave amplitude at implantation was 10.6 ± 4.2 mV; lead impedance was 951.8 ± 337.2 Ω; charge impedance was 51.7 ± 7.9 Ω; and stimulation threshold 0.9 ± 0.5 V.
Three patients experienced procedure-related complications before discharge. Two patients experienced left pneumothorax following the ICD implantation, requiring pleural drainage in 1. A third patient experienced a cardiac perforation using a single-coil active fixation electrode treated with pericardiocentesis. There was no pocket hematoma.
Table 2 shows clinical outcomes in this cohort after a follow-up of 9.3 ± 5.1 years after ICD implantation. No patient was lost to follow-up.
During this period, 73 patients (70.2%) underwent ICD battery replacement: 1 in 54 (51.9%) patients, 2 in 7 (6.7%) patients, 3 in 6 (5.8%) patients, and ≥4 in 6 (5.8%) patients. Thirteen subjects (12.5%) had a total of 33 episodes of neurally mediated syncope; the rate of ventricular pacing in these patients was <1%, and no ventricular arrhythmias were detected during the episodes. Eleven patients (10.6%) developed paroxysmal atrial fibrillation: 5 patients (10.2%) in the asymptomatic group, 5 patients (11.1%) in the syncope group, and 1 patient (10.0%) in the aborted SD group (p = 0.98). Pharmacological treatment for atrial fibrillation included quinidine in 9 patients (81.8%) and beta-blockers in 2 (18.2%). Three patients (27.3%) underwent pulmonary vein isolation by radiofrequency catheter ablation.
A total of 21 patients (20.2%) experienced a total of 81 appropriate shocks (median 1 shock/patient, IQR: 1 to 1): 7 patients (33.3%) had only 1 ICD therapy; 4 patients (19.1%) had 2; and 10 patients (47.6%) experienced ≥3 therapies anytime during follow-up (1 patient had up to 12 defibrillations). One patient experienced an electrical storm (1%) during a lead extraction procedure (see the Mortality section later in the text). Five patients (4.8%) experienced 1 episode of fast monomorphic VT (≥200 beats/min), 1 of them under treatment with quinidine; 3 VT episodes were successfully treated with ATP.
The mean time to first therapy was 48.8 ± 54 months (range 3 to 193 months) (Central Illustration). Two patients (1.9%) experienced their first appropriate therapy >10 years after implantation (1 with previous SD and 1 asymptomatic). The age at first shock was 47.3 ± 15.2 years. The incidence rate for appropriate ICD therapy was 2.2 per 100 person-years.
The rate of appropriate shock was significantly higher in secondary prevention patients (p < 0.01) (Table 2), as was the mean number of shocks (2.1 ± 2.8 episodes per patient in secondary prevention vs. 0.6 ± 2.1 episodes per patient in primary prevention; p = 0.04). The triggers of appropriate shocks were sustained monomorphic VT in 5 patients (23.8%), polymorphic VT in 2 patients (9.5%), and VF in 14 patients (66.7%).
Six patients (28.6%) were treated with oral quinidine after recurrent appropriate ICD shocks due to VF: 4 patients (66.7%) had no more recurrence after treatment. No epicardial ablation was attempted.
Of the 27 patients diagnosed with a positive sodium channel blocker test who had prior episodes of syncope and/or SD, 6 patients (22.2%) presented a total of 11 appropriate shocks during follow-up (1.8 ± 0.9 episodes per patient). Four (14.8%) were secondary prevention patients due to SD, and 2 (7.4%) presented with previous syncope. One patient died during follow-up due to an electrical storm (see the Mortality section later in the text).
Four of the 45 asymptomatic patients (8.9%) experienced appropriate ICD therapy during follow-up: 3 patients (6.7%) due to VF and 1 (2.2%) due to monomorphic VT. All 4 patients had a spontaneous type 1 ECG and inducible ventricular arrhythmias in the EPS: 3 patients (6.7%) with 3 premature ventricular beats and 1 (2.2%) with 2 premature ventricular beats. One patient (2.2%) had a family history of SD. Genetic testing was done in 2 patients (4.4%): 1 carried a pathogenic mutation in the SCN5A gene (Online Figure 1). Asymptomatic patients whose ICD indication was only a family history of SD or prolonged HV interval experienced no appropriate shocks during follow-up.
Clinical characteristics of patients experiencing appropriate shocks are compared with those without therapy in Table 3. On the univariate analysis, an ICD indication for secondary prevention due to aborted SD (hazard ratio [HR]: 5.30; 95% confidence interval [CI]: 2.13 to 13.25; p < 0.01) and type 1 ECG in the presence of syncope (HR: 3.00; 95% CI: 1.25 to 7.20; p = 0.01) were shown to confer a higher risk for experiencing an appropriate ICD shock during follow-up. In multivariable analysis, type 1 ECG in the presence of syncope (HR: 4.96; 95% CI: 1.87 to 13.14; p < 0.01) and secondary prevention indication (HR: 6.85; 95% CI: 2.29 to 20.50; p < 0.01) remained as significant predictors of appropriate ICD therapy (Table 4).
Three male patients (2.9%) died after 5.7 ± 2.5 years of follow-up. The mean age at death was 58.0 ± 23.3 years. The mean time from BrS diagnosis to death was 5.7 ± 2.5 years. Two patients died of septic shock due to pneumonia (1 had severe concomitant chronic obstructive pulmonary disease and the other hypoxic encephalopathy following a first event of resuscitated SD). Finally, a 34-year-old man presented with electrical storm during a surgical lead extraction procedure 42 months after ICD implantation. This patient had shown no prior spontaneous type 1 ECG. He was a member of a SCN5A-negative family and only had a family history of SD in 2 first-degree family members. Diagnosis of BrS was done with ajmaline test challenge, and no ventricular arrhythmias were induced during the EPS. An ICD was implanted for recurrent syncope (3 episodes before diagnosis). A lead dysfunction was detected 3 years after ICD implantation. Incessant VT and VF were developed during lead extraction procedure, with subsequent irreversible neurological damage, and the patient did not survive.
Inappropriate ICD therapy
The incidence rate for inappropriate ICD therapy was 0.9 per 100 person-years. Nine patients (8.7%) experienced 37 inappropriate shocks (median 1 shock/patient, IQR: 1 to 1, range 1 to 13): 2 patients experienced 1 shock, 3 patients had 2 shocks, and 4 patients had ≥3 shocks. Most subjects had an ICD indication for primary prevention (n = 7, 77.8%). In particular, in the group of asymptomatic patients in whom an ICD was implanted for VF inducibility in the EPS, 3 experienced inappropriate ICD shocks (6.7% of asymptomatic patients). The incidence of inappropriate shocks did not differ depending on patients’ previous symptom status. One-third of patients with inappropriate shocks (n = 3) also experienced appropriate ICD therapies.
Causes of inappropriate shocks included: atrial fibrillation in 2 patients (1.9%); sinus tachycardia in 1 patient (1%); T-wave oversensing in 1 patient (1%); and lead noise in 5 patients (4.8%) (Table 2). Overall, using our ICD programming protocol, the incidence rate for inappropriate ICD therapy due to atrial arrhythmia (sinus tachycardia and atrial fibrillation) was only 0.3 per 100 person-years. Both patients with inappropriate shocks due to atrial fibrillation underwent pulmonary vein isolation because of drug-resistant paroxysmal arrhythmia and remained asymptomatic thereafter. Patients with sinus tachycardia and T-wave oversensing remained asymptomatic after adjusting ICD programming. Three patients (2.9%) with lead noise underwent lead reimplantation for lead fracture. One of them was complicated with infection after the procedure.
From the group of asymptomatic patients to whom an ICD was implanted for VF inducibility in the EPS, 3 experienced inappropriate ICD shocks (2.9%): 1 patient (1%) for lead dysfunction 4 years after ICD implantation (2 shocks); another due to atrial fibrillation with fast ventricular rates (6 shocks); and the third patient because of T-wave oversensing (1 shock). Inappropriate therapy was managed by lead exchange, atrial fibrillation ablation, and ICD reprogramming, respectively, with no further recurrences.
In the Cox regression analysis, atrial fibrillation before diagnosis (HR: 8.16; 95% CI: 1.94 to 34.43; p < 0.01) was the only predictor of inappropriate ICD shocks during follow-up. Neither age (HR: 4.52; 95% CI: 0.40 to 49.80; p = 0.23) nor time since first ICD implantation (HR: 0.96; 95% CI: 0.78 to 1.19; p = 0.72) were associated with an increased risk of inappropriate shocks.
Twenty-one patients (20.2%) had other ICD-related complications during follow-up (incidence rate of 1.4 per 100 person-years). Nine patients (8.7%) had periprocedural complications: 7 patients (6.7%) had early device infection (incidence rate of 0.7 per 100 person-years), 5 following a first implant, and 2 after battery exchange, all of which underwent extraction of the ICD system and later reimplantation; in 1 case, the ICD infection resulted in infective endocarditis; 1 patient (1%) had a cardiac tamponade after ICD implantation. Late complications were registered in 13 patients (12.5%): 12 patients (11.5%) had lead dysfunction (incidence rate of 1.3 per 100 person-years) that required a lead exchange; 1 patient (1%) had device migration and required device reimplantation. Finally, 2 patients (1.9%) had to undergo psychiatric evaluation/treatment due to ICD-related anxiety.
The main findings of this study are that patients with an ICD for BrS have a considerable risk of potentially life-threatening ventricular arrhythmias during a long-term follow-up (life-time risk of 20.2%; incidence rate of 2.2 per 100 person-years). Appropriate ICD therapies were significantly associated with the presence of aborted SD and syncope with the presence of type 1 ECG pattern. However, appropriate shocks also occurred in 8.9% of asymptomatic patients in which ventricular arrhythmias were induced on EPS.
On the other hand, in this single-center prospective cohort, the risk of ICD-related adverse events was 23% (incidence rate for all ICD-related complications 2.5 per 100 person-years), including an 8.7% of inappropriate shocks and 20.2% or other device-related complications, although only 4 of 104 (3.8%) were considered to be major (1 death due to electrical storm during a lead extraction; 1 pneumothorax treated with thoracocentesis; 1 tamponade treated with periocardiocentesis; 1 infection complicated with infective endocarditis). However, possibly the most remarkable finding of this prospective single-center cohort, was the considerably lower rate of shocks due to rapid atrial rhythms (including sinus tachycardia, atrial fibrillation, and other supraventricular arrhythmias) compared with other prior studies despite the longer follow-up (life-time risk of 2.9%, incidence rate of 0.3 per 100 person-years) (7–10,12,16–22) (Online Figure 2).
Several prior experiences in the use of ICD in patients with BrS have been published (Online Table 1) (7–12,16–24). Many of these studies are retrospective (7–12,16–22,24), have included fewer than 50 patients (8,11,16–20,24) and/or only provide a mid-term follow-up (<5 years) (7–9,16,17,19–22,24).
Overall, there is great variation in the reported rate of appropriate therapy in BrS patients (Online Table 1). One of the most outstanding differences between studies is the incidence of appropriate therapies in previously asymptomatic individuals. Although several authors report no therapy in this group during an average follow-up of 2.3 to 7.3 years (9,16,18–21), other studies (including ours) report an overall rate of 4% to 13% after an average follow-up of 3.2 to 9.3 years (7,10,12,17,22). Differences in the study population is the most likely explanation for this observation; unfortunately, owing to the small numbers in studies and the limited published information of this patient group, it is difficult to elucidate whether this is due to a different risk stratification strategy among centers or other ethnic/sociodemographic/genetic factors. Our group has traditionally used the EPS for risk stratification in asymptomatic patients with a spontaneous BrS type 1 pattern on the ECG, which is supported by a recent pooled individual patient data analysis (5). It is also important to highlight the fact that 33% of asymptomatic patients experienced their first appropriate ICD shock ≥10 years after initial implantation.
The incidence of monomorphic VT in this study was 4.8%. ICD programming with a single VF zone at ≥200 beats/min, with 1 rapid burst of ATP in the VF was effective in all of these cases. In a recent large multicenter study, monomorphic VT was reported in 4.2% of BrS patients. Significant structural heart disease was ruled out by echocardiography and/or cardiac magnetic resonance imaging, although in the absence of epicardial mapping to confirm it, it is possible that layered scar may have been missed (25). These data imply that the occurrence of monomorphic VT should not rule out the possibility of BrS.
The flipside of ICD therapy is the still not negligible incidence of device-related complications (26–29). These include a periprocedural risk of pneumothorax of 0.6% to 1.1% (26,28), of perforation of 0.4% to 0.8% (26), of lead displacement of device infection of 0.6% to 3.0% (26,28,29). Device infection has consistently been shown to be higher in generator replacement procedures compared with first implants (26,28), which may explain the somewhat higher incidence in our cohort, having the longest follow-up duration of all. One of the most common long-term ICD complication is lead malfunction (10% to 30% of patients) (27,28), which may provoke inappropriate shocks and in most (if not all) cases, require lead replacement. This complication has consistently been associated with the patient’s age and the follow-up duration (27,28). In fact, in our prospective >20-year cohort, we had an 11.5% incidence of lead dysfunctions/fractures, all of which occurred in young patients (age at implantation 43.7 ± 13.1 years) 8.2 ± 6.3 years after implantation (range 3 to 16 years).
The other frequent adverse event is the occurrence of inappropriate therapy due to either T-wave oversensing or rapid atrial rhythms, appearing in 13% of patients with an ICD (28). The former has become a rare complication with the newer device algorithms and can usually be corrected by reprogramming the device (30). On the other hand, inappropriate shocks due to rapid atrial rhythms may sometimes be difficult to manage. In our prospective cohort of over 20 years, we have had a significantly lower incidence of these adverse events compared with previously published data (7–10,12,16–22) (Online Table 1, Online Figure 2). There could be 3 possible reasons for this finding: First, there may be differences in the study population, which we believe are unlikely if we compare baseline characteristics of sex, age at inclusion, prior history of atrial fibrillation and/or familial SD, and presence of symptoms and/or an SCN5A mutation (7–9,16,17,19–22,24). Second, the use a unified protocol for ICD programming using a single VF zone ≥200 beats/min with longer detection times has been proven to reduce inappropriate shocks (23,31,32). In fact, the only published study with a comparable low incidence of inappropriate shocks due to supraventricular tachycardia in patients with BrS, used a single high-rate VF zone (23). Finally, patients were regularly seen in a highly specialized inherited arrhythmia clinic, which has shown to be associated with a low incidence of SD despite low ICD utilization (33).
One final relevant observation is the fact that 7 patients (33.3%) who had ICD-related adverse events presented with appropriate ICD therapies as well: 5 of the 12 patients with lead dysfunction and 2 of the 7 periprocedural ICD infection had experienced appropriate ICD therapies years before. It is, therefore, our belief that great care should be taken to prevent complications, but questioning the need of ICD implantation in high-risk individuals should be avoided. The subcutaneous ICD is a promising tool in this young and active population because it appears to have a significantly lower incidence of ICD-related adverse events (34,35). However, the unique characteristics of the QRS and T-wave in the BrS type 1 pattern raises concerns about rhythm discrimination algorithms in subcutaneous ICDs, which are based on morphology, and some authors suggest that pre-implantation screening during ajmaline/flecainide challenge is advisable (36,37). On the other hand, recent data have suggested a relationship among the abnormal ECG pattern, the extent of abnormal epicardial substrate, and VT/VF inducibility in BrS patients, and have shown that substrate ablation can eliminate the BrS phenotype (2). Further long-term follow-up studies are required to know the clinical implications of substrate ablation in BrS patients.
The present study has several strengths. It is a prospective registry of a relatively large cohort of consecutive BrS patients with an ICD from a single center, and no patient was lost after the long follow-up.
First, we have only included patients with diagnosed BrS, but a significant proportion of individuals with BrS are not diagnosed, and their first symptom may be SD (38,39). Second, ICD indications have not been homogeneous throughout the study; in the early years, arrhythmic risk factors were less clear, and therefore, some patients had an ICD implanted for reasons other than symptoms or VF inducibility. Third, only SCN5A mutations were analyzed in this population; thus, there may be mutations in other minority genes. However, the yield of genetic testing in BrS is low, and consequently, we do not believe that additional testing would significantly change the findings of the present study. Fourth, due the low number of events, analysis of predictors may have lacked statistical power. Finally, even though this is the longest follow-up reported in the published reports, 9.3 ± 5.1 years may not be sufficient time to fully understand the true outcome of BrS patients with an ICD.
ICD therapy is an effective therapy in high-risk patients with BrS. However, it is also associated with a significant risk of device-related complications. Special care during ICD implantation, adequate device programming, and regular follow-up in a specialized cardiogenetic unit may allow reducing the number of adverse events.
COMPETENCY IN MEDICAL KNOWLEDGE: Implanted defibrillators can prevent lethal arrhythmias in high-risk patients with BrS, but the risk of device-related complications should be considered, requiring special care during implantation, programming, and follow-up.
TRANSLATIONAL OUTLOOK: Additional studies are needed to improve risk stratification in patients with BrS and clarify the role of ICD implantation following epicardial ablation procedures.
This work was funded by Concession Instituto de Salud Carlos III, FIS PI16/01203, co-funded by ERDF/ESF, “Investing in Your Future”; Concession Instituto de Salud Carlos III, FIS_RETIC12, File Nº: RD12/0042/0044, Red Cardiovascular; Concession Agencia de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) Generalitat de Catalunya, File Nº: 2014_SGR_471; Concession Instituto de Salud Carlos III, FIS_CIBER16, File Nº: CB16/11/00354, Centro de Investigación Biomedica en Red; and Concession Instituto de Salud Carlos III, FIS _PI14/01773, Obra Social “La Caixa”. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Hernandez-Ojeda and Arbelo contributed equally to this work.
- Abbreviations and Acronyms
- antitachycardia pacing
- Brugada syndrome
- confidence interval
- electrophysiological study
- hazard ratio
- implantable cardioverter-defibrillator
- interquartile range
- programmed ventricular stimulation
- sudden death
- ventricular fibrillation
- ventricular tachycardia
- Received May 15, 2017.
- Revision received August 16, 2017.
- Accepted August 17, 2017.
- 2017 American College of Cardiology Foundation
- Brugada P.,
- Brugada J.
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