UNLABELLED: The Brugada syndrome (BS) has been linked to mutations in SCN5A. Despite equal hereditary transmission of the mutation between the sexes, the syndrome is 8 to 10 times more likely to occur in males. As recently reported, SCN5A mutations such as G1406R lead to development of BS phenotype principally in males and conduction disease phenotype in females. We hypothesized that these differences may be related to a larger transient outward current (Ito)-mediated right ventricular (RV) epicardial (Epi) action potential (AP) notch in males versus females, resulting in a higher incidence of all-or-none repolarization at the end of phase 1 and phase 2 re-entry (P2R) when challenged with sodium and calcium channel block. Using canine RV wedge preparations, we developed an experimental model of the BS using terfenadine to depress the AP dome in RV Epi. RESULTS: RV Epi AP phase 1 amplitude corrected to phase 2 amplitude was 12% smaller in males (n=18) compared to females (n=8, P<.05) at a cycle length of 2,000 ms. When exposed to 5 microM terfenadine for up to 2 hours, 6 of 7 male but only 2 of 7 female preparations exhibited spontaneous P2R, generating a closely coupled extrasystole. Two of 6 male and 1 of 2 female preparations displaying P2R developed polymorphic VT/VF. Female and male preparations that failed to develop P2R displayed progressive conduction impairment with continued exposure to terfenadine and developed polymorphic and monomorphic VT/VF when paced at rapid rates. Male preparations pretreated with 4-aminopyridine to inhibit Ito displayed progressive conduction impairment but not Brugada syndrome. CONCLUSION: Our data suggest that the presence of a more prominent Ito-mediated notch in the Epi of males predisposes males to the development of the Brugada phenotype and that a smaller Epi notch in females relegates them to development of progressive conduction problems under conditions in which inward currents are compromised.
UNLABELLED: The Brugada syndrome (BS) has been linked to mutations in SCN5A. Despite equal hereditary transmission of the mutation between the sexes, the syndrome is 8 to 10 times more likely to occur in males. As recently reported, SCN5A mutations such as G1406R lead to development of BS phenotype principally in males and conduction disease phenotype in females. We hypothesized that these differences may be related to a larger transient outward current (Ito)-mediated right ventricular (RV) epicardial (Epi) action potential (AP) notch in males versus females, resulting in a higher incidence of all-or-none repolarization at the end of phase 1 and phase 2 re-entry (P2R) when challenged with sodium and calcium channel block. Using canine RV wedge preparations, we developed an experimental model of the BS using terfenadine to depress the AP dome in RV Epi. RESULTS: RV Epi AP phase 1 amplitude corrected to phase 2 amplitude was 12% smaller in males (n=18) compared to females (n=8, P<.05) at a cycle length of 2,000 ms. When exposed to 5 microM terfenadine for up to 2 hours, 6 of 7 male but only 2 of 7 female preparations exhibited spontaneous P2R, generating a closely coupled extrasystole. Two of 6 male and 1 of 2 female preparations displaying P2R developed polymorphic VT/VF. Female and male preparations that failed to develop P2R displayed progressive conduction impairment with continued exposure to terfenadine and developed polymorphic and monomorphic VT/VF when paced at rapid rates. Male preparations pretreated with 4-aminopyridine to inhibit Ito displayed progressive conduction impairment but not Brugada syndrome. CONCLUSION: Our data suggest that the presence of a more prominent Ito-mediated notch in the Epi of males predisposes males to the development of the Brugada phenotype and that a smaller Epi notch in females relegates them to development of progressive conduction problems under conditions in which inward currents are compromised.
Authors: Jonathan M Cordeiro; Hector Barajas-Martinez; Kui Hong; Elena Burashnikov; Ryan Pfeiffer; Anne-Marie Orsino; Yue Sheng Wu; Dan Hu; Josep Brugada; Pedro Brugada; Charles Antzelevitch; Robert Dumaine; Ramon Brugada Journal: Circulation Date: 2006-10-30 Impact factor: 29.690
Authors: Dan Hu; Hector Barajas-Martinez; Vladislav V Nesterenko; Ryan Pfeiffer; Alejandra Guerchicoff; Jonathan M Cordeiro; Anne B Curtis; Guido D Pollevick; Yuesheng Wu; Elena Burashnikov; Charles Antzelevitch Journal: Pacing Clin Electrophysiol Date: 2009-12-16 Impact factor: 1.976
Authors: José M Di Diego; Serge Sicouri; Rachel C Myles; Francis L Burton; Godfrey L Smith; Charles Antzelevitch Journal: J Mol Cell Cardiol Date: 2012-11-09 Impact factor: 5.000
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