Brugada syndrome (BrS) is an inherited channelopathy associated with ventricular tachyarrhythmias and sudden cardiac death (SCD) in individuals with a structurally normal heart. The electrocardiography (ECG) of BrS is characterized by QRS morphology similar to right bundle branch block (RBBB) and ST-segment elevation in the right precordial leads. BrS is categorized into three types according to ECG morphology, but the ECG of BrS may be intermittent, fluctuating, and occasionally concealed, which can present a diagnostic and therapeutic dilemma. Moreover, the BrS ECG pattern, or Brugada phenocopy, can be provoked by various pharmacological agents or conditions such as fever, electrolyte disturbances, alcohol and cocaine intoxication, and physical activity. Exercise is known to induce Brugada ECG phenocopy or mask ST-segment changes in BrS patients, depending on autonomic nervous system activity.¹²³ Herein, we describe a case of a patient with a normal baseline ECG who developed a type-1 BrS ECG phenocopy and prominent bradycardia during the recovery phase of exercise stress testing (EST) and discuss possible pathogenetic mechanisms in light of the existing literature.

A 38-year-old Caucasian male patient was admitted to the cardiology outpatient clinic with the complaint of atypical chest pain. He had a history of diabetes mellitus and hyperlipidemia, treated with metformin and atorvastatin. He had no history of smoking, alcohol or drug abuse, and no family history of SCD or cardiovascular disease. He denied dyspnea, palpitations, syncope, and presyncope. Physical examination and blood tests were all within normal limits. The 12-lead ECG showed normal sinus rhythm with T-wave inversion in lead V1 (Figure 1). Transthoracic echocardiography demonstrated normal systolic and diastolic functions without significant valvular pathology.

The patient then underwent exercise stress testing (EST) using the Bruce treadmill protocol. He completed the test with no symptoms at 6 minutes and 48 seconds, achieving 91% of the target heart rate and 11.1 metabolic equivalents. The pretest ECG obtained in the supine position showed RBBB and T-wave inversion in leads V1-3, without prominent ST-segment elevation. At peak exercise, coved-type ST-segment elevations developed in leads V1-3, suggestive of a type-1 Brugada phenocopy. During the early recovery phase, significant bradycardia, with a heart rate of 30 beats per minute, developed along with the classical type-1 Brugada phenocopy on ECG, and the patient reported dizziness. The bradycardia resolved spontaneously within 10 seconds (Figure 2A-D).

Afterwards, basal and upper intercostal space 12-lead ECG recordings in the supine position were performed to confirm the Brugada phenocopy pattern (Figure 3A-B). Subsequent diagnostic workup, including ambulatory rhythm Holter monitoring, coronary angiography, and electrophysiological study, were all within normal limits. A provocative drug challenge test and cardiac magnetic resonance imaging were recommended, but the patient refused further testing. Thus, conservative management, including lifestyle changes and education with close follow-up, was planned. He has been asymptomatic and has not experienced any cardiac events for one year.

Brugada syndrome (BrS) was initially described in 1992, and our understanding of its genotypic and phenotypic principles, as well as clinical and therapeutic management, continues to evolve. Due to the asymptomatic nature and concealed or transient ECG pattern of the disease, the true prevalence of BrS is difficult to assess. Moreover, various conditions such as fever, electrolyte disturbances, alcohol and cocaine intoxication, and physical activity can induce the BrS ECG pattern in the absence of a clinical history, known as Brugada phenocopy. Thus, it is not surprising that many patients are diagnosed incidentally during or after an exercise stress test (EST). On the other hand, EST might induce arrhythmias in an asymptomatic or yet undiagnosed BrS patient.¹²³

Limited data exists about exercise stress testing (EST) in Brugada syndrome (BrS) or Brugada phenocopy, and the current literature mostly consists of case reports involving patients with diverse clinical conditions (Table 1).^{45678910111213141516171819202122232425} Generally, exercise is known to decrease typical coved-type ST-segment elevations due to increased sympathetic activity, which raises the heart rate. In contrast, ST-segment elevation often increases during the recovery phase due to heightened vagal activity through activation of the parasympathetic nervous system. This is why arrhythmias and SCD in BrS patients occasionally occur during sleep and/or rest periods and are often associated with bradycardia.¹³ However, some reports indicate augmentation of the ST-segment during exercise and normalization during recovery.^{3131820222325} The mechanistic basis for this paradoxical response is not well understood but may relate to differences in autonomic nervous system modulation and/or specific genetic mutations in patients. For instance, a specific SCN5A mutation involving the C-terminal portion of the sodium channel has been suggested to be associated with a heart rate-dependent ECG phenotype, specifically ST-segment augmentation, in BrS patients.²⁶

In our patient, the pretest ECG obtained in the supine position did not show prominent ST-segment elevation. However, coved-type ST-segment elevations with RBBB in the right precordial leads suggestive of Brugada phenocopy developed at peak exercise. The classical type-1 Brugada phenocopy pattern with significant bradycardia occurred on ECG during the early phase of the recovery period. The ECG changes observed in our patient may be mutation-specific, but we could not perform genetic testing due to unavailability. A provocative drug challenge test was recommended to the patient, as well as cardiac magnetic resonance imaging, due to the possibility that some cases of arrhythmogenic right ventricular dysplasia can overlap with BrS. However, the patient refused further testing.

Exercise stress testing is not part of routine screening for the diagnosis and follow-up of BrS. However, it has been suggested for prognostication of BrS patients. For example, ST-segment augmentation during the recovery phase of EST was found to be associated with adverse cardiac events in BrS patients in a previous study.²⁷ Moreover, various electrocardiographic alterations during EST, such as an increase in S wave upslope duration ratio >30% at peak exercise, augmentation of J-point elevation in lead aVR >2 mm in late recovery, and delayed heart rate recovery, have been identified as independent predictors of arrhythmic events in asymptomatic BrS patients.²⁸ Additionally, EST may provoke clinically significant or lethal arrhythmias linked with BrS, such as ventricular tachycardia.^491216182425

In our patient, significant bradycardia accompanied by a classical type-1 Brugada phenocopy pattern developed on the ECG during the early recovery phase of EST, and the patient reported dizziness. However, both the bradycardia and dizziness resolved quickly. We believe that the bradycardia resulted from increased vagal activity. Furthermore, ambulatory rhythm Holter monitoring and electrophysiological studies did not reveal any significant arrhythmias. Consequently, we decided to follow up with the patient conservatively and diagnosed the condition as exercise-induced Brugada phenocopy rather than BrS, due to the absence of arrhythmic history, family history, genetic testing, provocative drug challenge testing, and normal electrophysiological studies.

In conclusion, exercise stress testing (EST) might be beneficial in Brugada syndrome (BrS) for unmasking ECG alterations and arrhythmias, particularly in undiagnosed and/or asymptomatic patients. The occurrence of Brugada phenocopies during EST is a rare phenomenon that warrants further investigation in future studies.