Follow-up From Childhood to Adulthood of Individuals With Family History of Brugada Syndrome and Normal Electrocardiograms

Brugada syndrome is an inherited primary arrhythmia syndrome characterized by coved-type ST-segment elevation in the right precordial leads without structural heart disease and is associated with increased risk of sudden death.¹ The syndrome is genetically and clinically heterogeneous and can present within the first months of life, although more typically in the fourth or fifth decade. The diagnostic type 1 electrocardiogram (ECG) may manifest spontaneously, increasing with age.² Sex hormones have been suggested as potential responsible factors.³

Ajmaline challenge is recommended to unmask the diagnostic ECG pattern in patients with suspected disease.⁴ Although screening of first-degree relatives is common, no evidence-based guidelines exist, particularly for children with normal ECGs. We investigated the clinical significance of repeat testing after puberty in asymptomatic children with a family history of Brugada syndrome who had an initial negative ajmaline test.

All asymptomatic individuals with a first-degree relative with Brugada syndrome and negative ajmaline test performed before 16 years of age between 1992 and 2010 seen at the university hospital of Brussels, Belgium (UZ Brussel-VUB) had an ECG repeated annually and were scheduled to repeat the test after puberty (≥16 years of age with onset of secondary sexual characteristics). Ajmaline challenges were repeated between 2008 and 2013, at least 3 years after the first test, and were performed and evaluated as previously described.⁵ Follow-up of patients with positive repeat tests continued until February 2014. Written informed consent was obtained from parents or patients older than 18 years. The ethics committee of the UZ Brussel-VUB approved the study protocol.

Statistical analyses were conducted using SPSS software version 22 (SPSS Inc). The χ² and Fisher exact tests were used to analyze categorical variables and the unpaired or paired t test was used for continuous variables. A 2-tailed probability value of <.05 was deemed significant.

There were 53 asymptomatic children scheduled to repeat the ajmaline test after puberty. Nine are younger than 16 years and 1 presented with spontaneous Brugada type 1 ECG at age 16 years. The remaining 43 individuals from 23 different families repeated the test (Table 1). Ajmaline challenge unmasked type 1 ECG in 10 patients (23%) (Table 2). Age at the time of the repeat test was similar between individuals with positive (mean [SD], 21.2 [1.3] years) and negative (mean [SD], 19.3 [2.2] years) results (P = .15).

Before the repeat test, 4 patients developed symptoms (3 had syncope and 1 had nocturnal agonal respiration). The mean (SD) age at symptom appearance was 22.5 (3.2) years. A significantly higher proportion of symptomatic than asymptomatic patients had a positive repeat test (3 [75%] vs 7 [18%], respectively, P = .03). During the repeat test, 1 patient experienced refractory ventricular fibrillation. Genetic testing was obtained in all patients with a positive repeat test and 5 had a SCN5A mutation. Two patients received an implantable cardioverter-defibrillator.

After a mean (SD) follow-up of 42 (14) months (range, 11.0-67.0 months), no patient with a positive repeat test died suddenly. One patient who experienced syncope 7 years after the first ajmaline challenge had an episode of spontaneous ventricular fibrillation successfully treated with an implantable cardioverter-defibrillator. Spontaneous type 1 ECG occurred in another patient during a febrile episode. The follow-up of the remaining patients was uneventful.

Repeat ajmaline challenge after puberty unmasked Brugada syndrome in 23% of relatives with a previously negative drug test performed during childhood.

The ECG phenotype does not appear during childhood in most cases, but may develop later in response to hormonal, autonomic, or genetic factors.^4,6 To our knowledge, this is the first report of changes in the response to ajmaline over time.

Limitations of the study include the small number of patients, which limits the ability to analyze subgroups.

Screening of asymptomatic first-degree relatives of patients with Brugada syndrome is advisable, although the ideal timing is unknown. Relatives developing symptoms should always be investigated with ajmaline challenge even if they had a negative drug test performed before puberty. These findings support the need for repeat monitoring of family members of patients with Brugada syndrome, including those initially considered at low risk because of young age.

Corresponding Author: Giulio Conte, MD, Heart Rhythm Management Centre, UZ Brussel-VUB, Laarbeeklaan 101, 1090 Brussels, Belgium (giulioconte.cardio@gmail.com).

Author Contributions: Dr Conte had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Conte, de Asmundis, Julià, Brugada.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Conte, de Asmundis, Ciconte, Julià, Sieira, Chierchia.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Conte, de Asmundis, Ciconte, Julià, Sieira.

Obtained funding: de Asmundis, Julià, Brugada.

Administrative, technical, or material support: Conte, de Asmundis, Ciconte, Julià, Brugada.

Study supervision: All authors.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Brugada reported receiving research grants from Biotronik, Biosense Webster, Medtronic, Sorin-Ela Medical, and St Jude Medical; and serving as a teaching consultant to Biotronik, Boston Scientific and Medtronic. No other disclosures were reported.