A syndrome characterized by an ST segment elevation in leads V1 to V3 (unrelated to ischemia, electrolyte abnormalities, or obvious structural heart disease) with a right bundle branch block (RBBB) morphology of the QRS was reported as early as 1953, but it was rst described as a distinct clinical entity associated with a high risk of sudden cardiac death in 19921 (for review, see references 2 and 3). The clinical disorder was named after Pedro and Josep Brugada, who focused world attention on this syndrome as a life-threatening primary electrical disease.4 The Brugada syndrome phenotype is especially prevalent in males (8:1 ratio of males to females) of Asian origin. The syndrome is familial, displaying an autosomal dominant mode of inheritance with incomplete penetrance. Arrhythmic events are observed at an average age of 40 years (range 1 to 77). Although slight lipid in ltration into the deep subepicardium has been observed in isolated cases, the Brugada syndrome appears unrelated to any chromosomal loci thus far described for arrhythmogenic right ventricular dysplasia. The only gene thus far linked to the Brugada syndrome is the cardiac sodium channel gene SCN5A,5 ,6 which is the same gene implicated in the LQT3 form of the long QT syndrome. Bezzina et al.7 recently reported a mutation in SCN5A (1795InsD) capable of producing both the Brugada and LQT3 phenotypes.Defects in SCN5A linked to the Brugada syndrome include frameshift and deletion mutations that cause failure of the channel to express, thus importantly reducing INa density,5 and missense mutations that shift the voltage and time dependence of INa activation, inactivation, and reactivation. In the case of one missense mutation (T1620M), inactivation of INa was importantly accelerated,6 providing the substrate for the Brugada syndrome. Interestingly, this change in the function of the sodium channel is observed at physiologic temperatures, but not at room temperature typically used in studies of function in heterologous expression systems. The premature inactivation of the sodium channel is accelerated further at higher temperatures, suggesting that the Brugada phenotype may be uncovered or accentuated during a febrile state. Under varying conditions, the T1620M mutation also may cause the sodium channel to enter a intermediate inactivation state from which it recovers more slowly8 or fail to express due to traf cking problems.9 Under all of these conditions, the contribution of INa to the early phases of the action potential is reduced. The linkage to an ion channel mutation provides strong evidence in support of the hypothesis that the Brugada syndrome is a primary electrical disease. The cellular basis for the Brugada syndrome is thought to involve an outward shift of net transmembrane current active at the end of phase 1 of the right ventricular epicardial action potential (where Ito is most prominent).2 ,1 0 Such a shift can accentuate the action potential notch and eventually lead to all-or-none repolarization at the end of phase 1, causing loss of the epicardial action potential dome and marked abbreviation of the action potential. Pathophysiologic conditions (e.g., ischemia, metabolic inhibition, hypothermia, pressure) and some pharmacologic interventions cause loss of the dome and abbreviation of the action potential in canine and feline ventricular cells in which Ito is prominent. Under ischemic conditions and in response to agents that block INa or ICa or agents that activate IK-ATP or augment IKr, IKs, ICl(Ca), or Ito, canine ventricular epicardium may rst exhibit an accentuation of the spike-and-dome morphology of the action potential, resulting in a delay in the development of the dome and accentuation of the notch (Fig. 1). A further shift in the balance of currents could lead to failure of the dome to develop. In the case of the Brugada mutations discussed, accelerated inactivation of INa or reduction of INa by other mechanisms may leave Ito unopposed during phase 1 of the action potential, leading to a predominance of outward repolarizing current at the end of phase 1. The cellular mechanisms thought to underlie the Brugada phenotype are illustrated in Figure 1. The presence Supported by grants from the National Institutes of Health (HL 47678), the Masons of New York State and Florida, and the Walter Scott Savage and Dorothy W. Savage Fund.
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Open Access
Jul 1, 2005
Sergey N Kharin + 2
