Fish Jeffrey M, Antzelevitch Charles
Masonic Medical Research Laboratory, Utica, NY 13501-1787, USA.
J Electrocardiol. 2003;36 Suppl:173-9. doi: 10.1016/j.jelectrocard.2003.09.054.
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.
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.
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.
Brugada综合征（BS）与SCN5A基因突变有关。尽管该突变在两性之间的遗传传递相同，但该综合征在男性中发生的可能性要高8至10倍。正如最近报道的那样，诸如G1406R之类的SCN5A突变主要在男性中导致BS表型的发展，而在女性中导致传导疾病表型的发展。我们假设这些差异可能与男性和女性之间更大的瞬时外向电流（Ito）介导的右心室（RV）心外膜（Epi）动作电位（AP）切迹有关，当受到钠和钙通道阻滞剂刺激时，在1期和2期折返（P2R）结束时全或无复极化的发生率更高。使用犬右心室楔形标本，我们使用特非那定抑制右心室心外膜动作电位圆顶，建立了Brugada综合征的实验模型。
在2000毫秒的心动周期长度下，男性（n = 18）的右心室心外膜动作电位1期幅度相对于2期幅度校正后比女性（n = 8，P <.05）小12％。当暴露于5微摩尔特非那定长达2小时时，7只雄性标本中有6只出现自发P2R，产生紧密耦合的期前收缩，而7只雌性标本中只有2只出现自发P2R。显示P2R的6只雄性标本中有2只和2只雌性标本中有1只发展为多形性室性心动过速/心室颤动。未发生P2R的雌性和雄性标本在持续暴露于特非那定后显示进行性传导障碍，在快速起搏时发展为多形性和单形性室性心动过速/心室颤动。用4-氨基吡啶预处理以抑制Ito的雄性标本显示进行性传导障碍，但未发生Brugada综合征。
我们的数据表明，男性心外膜中更突出的Ito介导的切迹使男性易患Brugada表型，而女性较小的心外膜切迹使她们在内向电流受损的情况下易发生进行性传导问题。
