Koonlawee NademaneeHariharan RajuSofia V. De NoronhaMichael PapadakisLaurence RobinsonStephen RotheryNaomasa MakitaShinya KowaseNakorn BoonmeeVorapot VitayakritsirikulSamrerng RatanarapeeSanjay SharmaAllard C. Van Der WalMichael ChristiansenHanno L. TanArthur A. WildeAkihiko NogamiMary N. SheppardGumpanart VeerakulElijah R. BehrPacific Rim Electrophysiology Research InstituteSt George's University of LondonHammersmith HospitalNagasaki UniversityYokohama Rosai HospitalRoyal Thai Air ForceMahidol UniversityAcademic Medical Centre, University of AmsterdamStatens Serum InstitutPrincess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary DisordersUniversity of Tsukuba2018-11-232018-11-232015-11-03Journal of the American College of Cardiology. Vol.66, No.18 (2015), 1976-198615583597073510972-s2.0-84945296649https://repository.li.mahidol.ac.th/handle/20.500.14594/36254© 2015 American College of Cardiology Foundation. Background The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial. Objectives This study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation. Methods Six whole hearts from male post-mortem cases of unexplained sudden death (mean age 23.2 years) with negative specialist cardiac autopsy and familial BrS were used and matched to 6 homograft control hearts by sex and age (within 3 years) by random risk set sampling. Cardiac autopsy sections from cases and control hearts were stained with picrosirius red for collagen. The RVOT was evaluated in detail, including immunofluorescent stain for connexin-43 (Cx43). Collagen and Cx43 were quantified digitally and compared. An in vivo study was undertaken on 6 consecutive BrS patients (mean age 39.8 years, all men) during epicardial RVOT ablation for arrhythmia via thoracotomy. Abnormal late and fractionated potentials indicative of slowed conduction were identified, and biopsies were taken before ablation. Results Collagen was increased in BrS autopsy cases compared with control hearts (odds ratio [OR]: 1.42; p = 0.026). Fibrosis was greatest in the RVOT (OR: 1.98; p = 0.003) and the epicardium (OR: 2.00; p = 0.001). The Cx43 signal was reduced in BrS RVOT (OR: 0.59; p = 0.001). Autopsy and in vivo RVOT samples identified epicardial and interstitial fibrosis. This was collocated with abnormal potentials in vivo that, when ablated, abolished the type 1 Brugada electrocardiogram without ventricular arrhythmia over 24.6 ± 9.7 months. Conclusions BrS is associated with epicardial surface and interstitial fibrosis and reduced gap junction expression in the RVOT. This collocates to abnormal potentials, and their ablation abolishes the BrS phenotype and life-threatening arrhythmias. BrS is also associated with increased collagen throughout the heart. Abnormal myocardial structure and conduction are therefore responsible for BrS.Mahidol UniversityMedicineArticleSCOPUS10.1016/j.jacc.2015.08.862