Exercise Stress Test in The Assessment of Brugada Syndrome Patients

Abstract Brugada syndrome (BS) is a genetic channelopathy, clinically characterized by an increased risk of sudden cardiac death. The diagnosis requires a typical electrocardiographic pattern, and data on risk stratification are limited in the literature. The aim of this study was to conduct a review on the importance of exercise stress test (EST) in risk stratification in BS. Articles were searched in the PubMed, Scielo and Google Scholar databases. From the 200 articles retrieved, eight were included, with a total of 712 patients (95% men) aged between 35 and 60 years. Severe symptoms and ventricular arrhythmias were reported by 256 patients before the EST, with syncope being reported in 70% of cases. The reviewed articles suggest that the EST is a safe method that can help in the diagnosis and risk stratification for malignant arrhythmias in patients with BS. Potential predictors of poor prognosis were: augmentation in ST-segment elevation > 0.5 mV in V1, V2 or V3 in early recovery; J-point elevation in lead > 2mm in aVR in late recovery; heart rate reduction < 40% from maximum heart rate in late recovery and occurrence of ventricular extrasystoles in early recovery.


Introduction
Brugada syndrome (BS) is a genetic channelopathy with a typical electrocardiogram (ECG) and an increased risk of sudden cardiac death (SCD), secondary to polymorphic ventricular tachycardia in the absence of gross structural heart disease. 1 BS is one of the most common channelopathies, with a worldwide prevalence of 0.05%, 2 and higher prevalence among Asian populations.A Japanese study showed characteristic echocardiographic features of BS in 0.12-0.14% of the population, 3 whereas the prevalence of BS was 0.01-0.03%among Europeans and North-Americans. 4BS is more prevalent among men, with mean age of 41± 15 years, of Japanese descent, and from the Southeast Asia.It is estimated that BS accounts for 4% of all SCDs, and most patients are diagnosed only after the arrhythmic event. 4e electrocardiographic pattern, called type 1 pattern, is characterized by J-point elevation and ST-segment elevation ≥2 mm, with a coved morphology in one or more right precordial leads (V1 and V2), followed by a symmetric negative T wave.Either spontaneous or druginduced, this is the only definite pattern for the diagnosis of BS.The type 2 pattern is defined by a saddleback-type ST-segment elevation ≥2 mm, followed by a positive or biphasic T-wave.This pattern has diagnostic value when conversion to the type 1 pattern occurs either spontaneously or after administration of class 1 sodium channel blocker according to the Vaughn-Williams classification. 5ugada ECG patterns may present in a continuous, intermittent or concealed manner, and be unmasked by modulating factors that affect transmembrane ionic currents, such as vagal tone, elevation of body temperature, male sex hormones, and some drugs. 6wer ventricular arrhythmia rates are seen in asymptomatic patients, especially in those without previous history of arrhythmia.Recent studies have shown arrhythmia rates of 0.8-1.2% a year in asymptomatic patients, 6 and up to four times higher in the presence of syncope.However, despite having a DOI: https://doi.org/10.36660/ijcs.20220079more benign course, many patients with BS and history of aborted SCD had been asymptomatic and classified as low risk for arrhythmic events.Besides, the risk seems to be cumulative with time, achieving up to 10% at ten years.Thus, risk stratification of SCD in BS must improve. 7 this context, exercise stress test (EST), a low-morbidity, low-cost test, has been shown to be potentially useful in the diagnosis of patients with type 1 electrocardiographic pattern, either intermittently present or concealed, and in risk stratification of ventricular arrhythmic events in these individuals.This study aimed to conduct a comprehensive literature review on the importance of EST in risk stratification in BS.

Methods
The articles were searched in the PubMed, Scielo and Google Scholar databases, using the search terms

((exercise [Title/Abstract]) OR (treadmill [Title/Abstract])) AND (Brugada [Title/Abstract]).
The abstracts were read and full texts of articles addressing EST in the diagnosis or in risk stratification of BS patients were reviewed.Articles published in Portuguese, English or Spanish between 1992 and 2021 were retrieved.Case reports, duplicates, different articles from the same population, review articles, articles that had not been published in scientific papers and articles for which only the abstract was available were excluded.Articles in which EST was performed using different analysis parameters from the ones used in clinical practice were also excluded.

Results
The initial search identified 137 articles in PubMed.After analysis of the titles, the number of articles possibly related to the search topic was reduced to 33 articles.After full text reading, 25 articles met the exclusion criteria, and eight were included for analysis.
From the Google Scholar database, 59 articles were retrieved and assessed; 51 met the exclusion criteria, and then eight were included for analysis, which were the same as those identified in PubMed (Figure 1 and Table 1).

Brugada syndrome and exercise stress test
PubMed: 137 articles

articles assessed
Excluded: -17 case reports  Four articles were retrieved from Scielo, and all were excluded as they were all case reports (Figure 1).
In the eight articles included in the analysis, 712 patients with BS were studied for the effects of exercise stress; 95% of them were men, aged from 35 to 60 years.One article, by Morita et al., 11 accounted for 42% of the patients.Most studies were conducted in Asia.
Symptoms or severe ventricular arrhythmias (ventricular fibrillation/ ventricular tachycardia) were reported by 256 patients before the EST, and syncope was reported by 70% of the cases.Most patients (64%) were asymptomatic.
Regarding the EST, the treadmill exercise test was the most common, while bicycle exercise testing was used in two studies, by Chanavirut et al., 9 and by Pospiech et al., 12 One episode of ventricular tachycardia during the exercise test was reported in the article by Subramanian et al. 13

Discussion
Although BS is a rare disease, it accounts for up to 20% of sudden deaths in young patients with structurally normal hearts.Several studies have tried to determine a more accurate method to diagnose the syndrome and stratify the risk for adverse events.
In the France, Italy, Netherlands, Germany Brugada syndrome Registry (FINGER), 16 in which most patients (64%) were asymptomatic, the role of six risk factors in the prediction of arrhythmic events were assessed -syncope, spontaneous type 1 ECG, male sex, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation.Syncope and spontaneous type 1 ECG were the only significant predictors.In the Programmed Electrical Stimulation Predictive Value (PRELUDE) study, 17 308 patients with type 1 ECG were followed-up for 34 months.

Review Article
The following predictors of events were identified: history of syncope and spontaneous type 1 ECG, ventricular refractory period < 200 ms and QRS fragmentation.
Insertion of an ICD is the only therapy recommended for cardiac arrest survivors.However, identifying those patients at increased risk for ventricular arrhythmias in primary prevention, and who would potentially benefit from an ICD is still challenging and controversial. 7ICD insertion is an invasive, expensive approach, and not free of complications including pneumothorax, hematoma, displacement or breakage of the leads, infections and high incidence of inappropriate therapies. 18,19 this context, the EST, which is known to be useful in the diagnostic definition of patients with intermittent or even concealed Brugada electrocardiographic pattern due to positive modulating factors (increased vagal tone and decreased adrenergic tone at recovery and increase of body temperature with exercise), has been shown to be relevant in the prognostic stratification of these patients, as suggested in Table 1.Amin et al., 8 observed that exercise aggravates the ECG phenotype in BS and the presence of an SCN5A mutation is associated with slower conduction at fast heart rates.The authors also found that an increase in ST-segment elevation in early recovery from EST was a strong predictor of spontaneous ventricular fibrillation.Subramanian et al., 13 studied 75 asymptomatic patients with BS, who underwent treadmill exercise testing and followed-up for six years.Of these, 11.1% had a major arrhythmic event (appropriate shock of ICD or CSD).Three independent predictors of major arrhythmic event during exercise testing were identified: (1) increase in S wave upslope (ratio of the duration between the S-wave nadir and the J-point to the duration between the beginning of QRS and the J-point) >30% at peak exercise in precordial leads; (2) J-point elevation in lead aVR of 2 mm in late recovery; and (3) heart rate fall < 40% from maximum heart rate in late recovery.Of patients who had an unfavorable result, 80% had the three predictors.The authors concluded that EST is a simple, safe test, with high predictive accuracy for risk stratification in asymptomatic patients with type 1 BS pattern (Figures 2 and 3).
Makimoto et al., 10 reported that one third of patients with BS undergoing EST had augmentation of ST-segment elevation in early recovery.This was an independent predictor for ventricular fibrillation during the follow-up.Augmentation of ST-segment elevation was considered when > 0.05mV in early recovery (1 -4 minutes) compared with ECG at rest, in one or more right precordial leads (V1-V3).Also, the authors observed a higher heart rate recovery in patients with ST-segment elevation at early recovery, suggesting that this response is predominantly vagally mediated. 10t J Cardiovasc Sci.2023;36:e20220079 Miná et al.

Review Article
With respect to the safety of EST in patients with BS, of the 712 cases reported, one patient (prevalence of 0.1%; 1:1000) had non-sustained ventricular tachycardia, with spontaneous resolution during exercise.The incidence is higher than that of ventricular fibrillation or tachycardia during EST in the general population, 1:5000 tests. 20It is worth mentioning, however, that the Brazilian Society of Cardiology recommends the presence of a qualified physician in case of cardiological emergencies throughout the EST. 21r group is currently developing a historical prospective study with BS patients in Brail, not only evaluating the electrocardiographic variables described in these previous studies, but also correlating them with prognosis, inducibility in invasive electrophysiological study, and presence of appropriate shocks in patients with ICDs.This is the subject of a Master's thesis in Cardiovascular Sciences at the Federal University of Ceara.

Limitations
The small number of studies available in the literature (mostly case reports) was a limitation of the present study.

Conclusion
The articles reviewed suggest that EST can be help in the diagnosis and risk stratification for malignant arrhythmias.Potential predictors of poor prognosis were: augmentation in ST-segment elevation > 0.5 mV in V1, V2 or V3 in early recovery; J-point elevation in lead > 2mm in aVR in late recovery; heart rate reduction < 40% from maximum heart rate in late recovery and occurrence of ventricular extrasystoles in early recovery.

Figure 1 -
Figure 1 -Flowchart of article selection; *the eight articles identified in PubMed were the same as those identified in Google Scholar.EST: exercise stress test.

Figure 2 -
Figure 2 -Electrocardiographic changes during exercise stress test in patients with Brugada syndrome (BS).Left panel: ST-segment elevation in precordial leads and lead aVR during early recovery in a patient with type 1 BS.Vertical lines indicate the end of QRS from the V5 lead, representing the peak St elevation.Right panel: example of J-point elevation (arrows) in precordial leads and aVR during early and late recovery; adapted from Subramanian et al.13

Figure 3 - 13 Table 2 -
Figure 3 -S-wave slope: ratio between duration of the S-wave upslope and the QRS duration (A/B); A: duration (milliseconds) from S-wave nadir to the J-point.B: duration (milliseconds) from the QRS deflection to the J-point (RJ interval).Adapted from Subramanian et al.13