Cellular and Ionic Basis

The ability of the RV action potential to lose its dome, giving rise to phase 2 reentry and other characteristics of the Brugada syndrome, were identified in the early 1990s and evolved in parallel with the clinical syndrome (Antzelevitch et al. 1991, 2002; Krishnan and Antzelevitch 1991; Krishnan and Antzelevitch 1993).

The ST segment elevation in the Brugada syndrome is thought to be secondary to a rebalancing of the currents active at the end of phase 1, leading to accentuation of the action potential notch in RV epicardium (see Antzelevitch 2001a for references). A transient outward current (ito)-mediated spike and dome morphology, or notch, in ventricular epicardium, but not endocardium, generates a voltage gradient responsible for the inscription of the electrocar-diographic J wave in larger mammals and in man (Yan and Antzelevitch 1996). ST segment is normally isoelectric because of the absence of transmural voltage gradients at the level of the action potential plateau. Under pathophysiologic conditions, accentuation of the RV notch leads to exaggeration of transmural voltage gradients and thus to accentuation of the J wave, causing an apparent ST segment elevation (Antzelevitch 2001a). The repolarization waves take on a saddleback or coved appearance depending on the timing of repolarization of epicardium relative to endocardium. A delay in epicardial activation and repolarization time leads to progressive inversion of the T wave. The down-sloping ST segment elevation, or accentuated J wave, observed in the experimental wedge models often appears as an R', suggesting that the appearance of a right bundle branch block (RBBB) morphology in Brugada patients may be due at least in part to early repolarization of RV epicardium, rather than to marked impulse delay or conduction block in the right bundle. Indeed, RBBB criteria are not fully met in many cases of Brugada syndrome (Gussak et al. 1999).

Accentuation of the RV action potential notch can give rise to the typical Brugada ECG without creating an arrhythmogenic substrate (Fig. 2). The ar-rhythmogenic substrate arises when a further shift in the balance of currents leads to loss of the action potential dome at some epicardial sites but not others. Loss of the action potential dome in epicardium but not endocardium results in the development of a marked transmural dispersion of repolarization and refractoriness, responsible for the development of a vulnerable window. A closely coupled extrasystole can then capture this vulnerable window and induce a reentrant arrhythmia. Loss of the epicardial action potential dome is usually heterogeneous, leading to the development of epicardial dispersion of repolarization. Conduction of the action potential dome from sites at which it

A Control B Terfenadine (5 jiM) C Terfenadine D Terfenadine

A Control B Terfenadine (5 jiM) C Terfenadine D Terfenadine

Fig.2a-d Terfenadine-induced ST segment elevation, T wave inversion, transmural and epi-cardial dispersion of repolarization, and phase 2 reentry. Each panel shows transmembrane action potentials from one endocardial (top) and two epicardial sites together with a transmural ECG recorded from a canine arterially perfused right ventricular wedge preparation. a Control (BCL 400 ms). b Terfenadine (5 |M) accentuated the epicardial action potential notch creating a transmural voltage gradient that manifests as an ST segment elevation or exaggerated J wave in the ECG. First beat recorded after changing from BCL 800 ms to BCL 400 ms. c Continued pacing at BCL 400 ms results in all-or-none repolarization at the end of phase 1 at some epicardial sites but not others, creating a local epicardial dispersion of repolarization (EDR) as well as a transmural dispersion of repolarization (TDR). d Phase 2 reentry occurs when the epicardial action potential dome propagates from a site where it is maintained to regions where it has been lost. (Note: d was recorded from a different preparation.) (From Fish and Antzelevitch 2004, with permission)

Fig.2a-d Terfenadine-induced ST segment elevation, T wave inversion, transmural and epi-cardial dispersion of repolarization, and phase 2 reentry. Each panel shows transmembrane action potentials from one endocardial (top) and two epicardial sites together with a transmural ECG recorded from a canine arterially perfused right ventricular wedge preparation. a Control (BCL 400 ms). b Terfenadine (5 |M) accentuated the epicardial action potential notch creating a transmural voltage gradient that manifests as an ST segment elevation or exaggerated J wave in the ECG. First beat recorded after changing from BCL 800 ms to BCL 400 ms. c Continued pacing at BCL 400 ms results in all-or-none repolarization at the end of phase 1 at some epicardial sites but not others, creating a local epicardial dispersion of repolarization (EDR) as well as a transmural dispersion of repolarization (TDR). d Phase 2 reentry occurs when the epicardial action potential dome propagates from a site where it is maintained to regions where it has been lost. (Note: d was recorded from a different preparation.) (From Fish and Antzelevitch 2004, with permission)

is maintained to sites at which it is lost causes local re-excitation via a phase 2 reentry mechanism, leading to the development of the very closely coupled extrasystole, which triggers a circus movement reentry in the form of VT/VF (Lukas and Antzelevitch 1996; Yan and Antzelevitch 1999). The phase 2 reentrant beat fuses with the negative T wave of the basic response. Because the extrasystole originates in epicardium, the QRS complex is largely composed of a negative Q wave, which serves to accentuate the inverted T wave, giving the ECG a more symmetrical appearance, a morphology commonly observed in the clinic preceding the onset of polymorphic VT. Support for these hypotheses derives from experiments involving the arterially perfused RV wedge preparation (Yan and Antzelevitch 1999). Further evidence in support of these mechanisms derives from the recent studies of Kurita et al. in which monopha-sic action potential (MAP) electrodes where positioned on the epicardial and endocardial surfaces of the RV outflow tract (RVOT) in patients with the Brugada syndrome (Kurita et al. 2002; Antzelevitch et al. 2002).

Figure 3 shows the ability of terfenadine-induced phase 2 reentry to generate an extrasystole, couplet, and polymorphic VT/VF. Figure 3d illustrates an example of programmed electrical stimulation-induced VT/VF under similar conditions.

Fig. 3a-d Spontaneous and programmed electrical stimulation-induced polymorphic VT in RV wedge preparations pretreated with terfenadine (5-10 |M). a Phase 2 reentry in epicardium gives rise to a closely coupled extrasystole. b Phase 2 reentrant extrasystole triggers a brief episode of polymorphic VT. c Phase 2 reentrant extrasystole triggers brief reentry. d Same impalements and pacing conditions as c, however an extra stimulus (S1-S2 = 250 ms) applied to epicardium triggers a polymorphic VT. (From Fish and Antzelevitch 2004, with permission)

Fig. 3a-d Spontaneous and programmed electrical stimulation-induced polymorphic VT in RV wedge preparations pretreated with terfenadine (5-10 |M). a Phase 2 reentry in epicardium gives rise to a closely coupled extrasystole. b Phase 2 reentrant extrasystole triggers a brief episode of polymorphic VT. c Phase 2 reentrant extrasystole triggers brief reentry. d Same impalements and pacing conditions as c, however an extra stimulus (S1-S2 = 250 ms) applied to epicardium triggers a polymorphic VT. (From Fish and Antzelevitch 2004, with permission)

Although the genetic mutation is equally distributed between the sexes, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this sex-related distinction was recently shown to be due to a more prominent Ito-mediated action potential notch in the RV epicardium of males vs females (Di Diego et al. 2002). The more prominent Ito causes the end of phase 1 of the RV epicardial action potential to repolarize to more negative potentials in tissue and arterially perfused wedge preparations from males, facilitating loss of the action potential dome and the development of phase 2 reentry and polymorphic VT. The gender distinction is not seen in all families; a recent report describes a familywithout a male predominance of the Brugada phenotype (Hong et al. 2004).

The available information supports the hypothesis that the Brugada syndrome is the result of amplification of heterogeneities intrinsic to the early phases of the action potential among the different transmural cell types. The amplification is secondary to a rebalancing of currents active during phase 1, including a decrease in INa or ICa or augmentation of any one of a number of outward currents including IKr, IKs, Icl(ca), or Ito (Fig. 4). ST segment elevation

Coronary Perfusion Pressure Cpr

Fig. 4 Proposed mechanism for the Brugada syndrome. A shift in the balance of currents serves to amplify existing heterogeneities by causing loss of the action potential dome at some epicardial, but not endocardial sites. A vulnerable window develops as a result of the dispersion of repolarization and refractoriness within epicardium as well as across the wall. Epicardial dispersion leads to the development of phase 2 reentry, which provides the extrasystole that captures the vulnerable window and initiates VT/VF via a circus movement reentry mechanism. (Modified from Antzelevitch 2001b, with permission)

Fig. 4 Proposed mechanism for the Brugada syndrome. A shift in the balance of currents serves to amplify existing heterogeneities by causing loss of the action potential dome at some epicardial, but not endocardial sites. A vulnerable window develops as a result of the dispersion of repolarization and refractoriness within epicardium as well as across the wall. Epicardial dispersion leads to the development of phase 2 reentry, which provides the extrasystole that captures the vulnerable window and initiates VT/VF via a circus movement reentry mechanism. (Modified from Antzelevitch 2001b, with permission)

occurs as a consequence of the accentuation of the action potential notch, eventually leading to loss of the action potential dome in RV epicardium, where Ito is most prominent. Loss of the dome gives rise to both a transmural as well as epicardial dispersion of repolarization. The transmural dispersion is responsible for the development of ST segment elevation and the creation of a vulnerable window across the ventricular wall, whereas the epicardial dispersion leads to phase 2 reentry, which provides the extrasystole that captures the vulnerable window, thus precipitating VT/VF. The VT generated is usually polymorphic, resembling a very rapid form of torsade de pointes (TdP) (Fig. 4).

+1 0

Post a comment