Family history of Brugada syndrome is associated with increased risk of syncope, cardiac arrhythmias, and ICD-implantation

Background

Brugada syndrome (BrS) is a rare cardiac arrhythmia disorder associated with sudden death in young adults. Relatives of BrS probands can have an increased risk, making systematic family screening essential for early detection and prevention of life-threatening events.

Purpose

This study investigated the association between family history of BrS and the risk of developing BrS, syncope, nocturnal agonal respirations, cardiac arrhythmias, implantable cardioverter defibrillator (ICD) implantation, cardiac arrest, and all-cause mortality.

Method

Using Danish nationwide registry data (2006-2023), we identified patients (probands) diagnosed with BrS in Denmark, and their first- and second-degree relatives.  All relatives were matched 1:2 to the general population and followed from the BrS date of the proband, until BrS diagnosis, an event of syncope, nocturnal agonal respirations, cardiac arrythmias, ICD-implantation, cardiac arrest, death, emigration, or study end. Hazard ratios were calculated with Cox hazard regression models adjusted for sex, age, and calendar year.

Results

We identified 875 first-degree relatives and 1,072 second-degree relatives to 234 BrS probands (Figure 1). The median age at baseline was 21 [IQR: 7.7-44] years, and 53% of the relatives were male. At the BrS date of the proband, relatives had experienced significantly more VT, VF, ICD-implantation, and cardiac arrest compared to the general population. A total of 66/1947 (3%) relatives (56% male) were diagnosed with BrS at a median age of 39 [IQR: 26-54] and after a median of 1.4 [IQR: 0.3-4.4] years. Of the relatives diagnosed with BrS, 58 (88%) were first-degree relatives.

During a median follow-up of 7.7 [IQR: 4.3-11.3] years, we observed an increased risk for relatives of BrS probands of syncope (HR 1.59, 95% CI 1.10-2.30), ventricular tachycardia (VT) / ventricular fibrillation (VF) (HR 10.71, 95% CI 6.26-18.31), and ICD-implantation (HR 7.86, 95% CI 2.61-23.68) (Figure 2).

Conclusion

In this nationwide cohort, family history of BrS was associated with a 1.6-fold increased risk of syncope, 10.7-fold increased risk of VT/VF, and 7.9-fold increased risk of ICD-implantation. These data suggest that screening relatives of BrS probands is indicated.Flowchart study populationHR for relatives of BrS probands