The Brugada syndrome: clinical, electrophysiologic and genetic aspects
Ihor Gussak, MD, PhD*,
Charles Antzelevitch, PhD, FACC ,
Preben Bjerregaard, MD, DMSc, FACC*,
Jeffrey A. Towbin, MD, FACC and
Bernard R. Chaitman, MD, FACC*
* St. Louis University Health Science Center, St. Louis, Missouri, USA
Masonic Medical Research Laboratory, Utica, New York, USA
Baylor College of Medicine, Houston, Texas, USA
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Figure 1 (A) Twelve-lead electrocardiogram of a patient with the Brugada syndrome. The right precordial leads, V1 to V3, display a down-sloping ST segment elevation. QRS is normal but QT dispersion between V2 and V6 is larger than normal (120 ms). (B) Self-terminating polymorphic ventricular tachycardia (continuous recording) in a patient with the Brugada syndrome. Closely coupled premature ventricular contractions precede the onset of tachyarrhythmia. Note the disappearance of the repolarization abnormalities following the arrhythmia.
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Figure 2 Phase 2 reentry. Reentrant activity was induced by exposure of a canine ventricular epicardial preparation to simulated ischemia. Microelectrode recordings were obtained from four sites as shown in the schematic (upper right). After 35 min of ischemia, the action potential dome develops normally at site 4, but not at sites 1, 2 or 3. The dome then propagates in a clockwise direction, reexciting sites 3, 2 and 1 with progressive delays, thus generating a reentrant extrasystole with a coupling interval of 156 ms at site 1. basic cycle length = 700 ms. A similar phenomenon is observed upon exposure of right ventricular epicardium to acetylcholine, potassium channel openers and inhibitors of sodium and calcium inward currents. Adapted with permission from Lukas and Antzelevitch (92).
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Figure 3 Phase 2 reentry-initiated circus movement tachycardia abolished with transient outward current inhibition. (A) Exposure of canine right ventricular epicardial sheet to simulated ischemia results in loss of the dome at sites 3 and 4 but not at sites 1 and 2 (basic cycle length = 1100 ms). Conduction of the basic beat proceeds normally from the stimulation site (site 2; see schematic a). Propagation of the action potential dome from the right half of the preparation causes reexcitation of the left half via a phase 2 reentry mechanism (see schematic b). The extrasystolic beat generated by phase 2 reentry then initiates a run of tachycardia that is sustained for four additional cycles via a typical (phase 0) circus movement reentry mechanism. The proposed reentrant path is shown in Schematic c. Note that phase 2 reentry provides an activation front roughly perpendicular to that of the basic beat. (B) Recorded 5 min after addition of 1 mmol/L 4-aminopyridine (4-AP), an inhibitor of the transient outward current. In the continued presence of ischemia, 4-AP restores the dome at all epicardial recording sites within 3 min. Thus electrical homogeneity is restored and all reentrant activity abolished. Adapted with permission from Lukas and Antzelevitch (92).
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Figure 4 Cardiac sodium channel gene SCN5A missense mutation cosegregating with the Brugada syndrome. (A) Electrocardiogram of an affected individual. Note the elevated ST segment in leads V1 to V3. (B) Pedigree structure and mutation analysis using single strand conformation polymorphism analysis with primers amplifying exon 28 of the cardiac sodium channel gene, SCN5A. Affected individuals are filled circles (female) and filled squares (male). Unaffected individuals are empty symbols, and individuals without clinical data are shown as hatched. The individual who suffered sudden cardiac death is slashed. (C) Deoxyribonucleic acid and amino-acid sequences of the SCN5A missense mutation associated with the Brugada syndrome. Deoxyribonucleic acid sequence analysis revealed a C to T substitution, which causes the substitution of a highly conserved threonine by a methionine at codon 1,620 (T1620M mutation) in the extracellular loop between DIVS3 and DIVS4. Adapted with permission from Chen et al. (55).
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Figure 5 The predicted secondary structure of the cardiac sodium channel and locations of mutations causing the Brugada syndrome and chromosome 3–linked long QT syndrome. The channel consists of four putative transmembrane domains (DI–DIV), with each domain containing six transmembrane segments (S1–S6). The Brugada syndrome mutations are shown in circles with dark lettering and long QT syndrome–associated mutations are in circles with white lettering. Adapted with permission from Chen et al. (55).
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