br Mechanisms of ventricular fibrillation electrical storm

Mechanisms of ventricular fibrillation/electrical storm in the Brugada syndrome patients One of the most consistent features of BrS is that premature ventricular contraction (PVC), which triggers VF, is almost always short-coupling [3,4]. An interesting phenomenon is that many of the VF episodes in BrS patients are self-terminating, contradicting the conventional wisdom that VF episodes are equivalent to death. Indeed, after experiencing the growing numbers of patients with this syndrome, we have learned that VF in patients with a structurally normal heart, unlike those with ischemic heart disease, often spontaneously reverts back to sinus rhythm [3,4]. In recent years, there has been a well-recognized debate of the pathophysiologic and electrophysiologic mechanisms underlying BrS: repolarization vs. depolarization [11]. Shortly after the syndrome was introduced, Antzelevitch and colleagues proposed the repolarization theory as the electrophysiologic abnormalities of the BrS that were largely based on their arterially perfused wedge preparation of the canine right ventricle (RV) [12]. They found that a combination of sodium channel blockers and fbpase caused a loss of the action potential (AP) dome in RV epicardium, but not in RV endocardium, and created a transmural voltage gradient. And when the wedge preparation was exposed to these 2 drugs, this area then developed a notch and dome appearance of the epicardium AP, leading to a coved type ST-segment elevation in the right precordial leads. The RV epicardium is well known to have abundant Ito, which in turn makes this area more conducive to the accentuation of the AP dome and shortening of AP. If the loss of the AP dome is further accentuated, then it causes the marked shortening of the epicardial AP in certain regions, causing pronounced heterogeneity of transmembrane voltage potentials and, in turn, causing phase 2 reentry and triggered VF. The clinical relevance to support this theory is the findings that there is a good correlation between a long RR interval and the magnitude of ST-elevation over the right precordial leads. Matsuo et al. presented a case report of a patient with BrS in whom 12-lead ECGs were recorded just before and after an episode of VF [13]. They demonstrated a progressive elevation of both the RS–T segment and J waves just preceding and following the VF, and a close relationship between the amplitude of the RS–T segment and the preceding R–R intervals during atrial fibrillation. Similarly, Mizumaki et al. showed that ST elevation over the right precordial leads was augmented during bradycardia to a similar extent in both symptomatic and asymptomatic patients [14]. These findings along with the evidence that isoproterenol attenuates ST-elevation in BrS suggest that the mechanism underlying a pause dependent augmentation of the ST elevation in BrS may be due to an increase in Ito after prolonged RR interval—in turn supporting repolarization disorder. Kurita et al. presented a case report in which monophasic AP recordings from epicardium and endocardium were performed simultaneously in the BrS patient [15]. The transmembrane gradient of AP between the epicardium and endocardium were observed; however, the authors did not find the shortening of the epicardial AP. Perhaps this observational study shows that quinidine, a strong Ito blocker, is effective in treating BrS patients also indirect evidence that supports the repolarization theory [16]. While the repolarization theory enjoyed its popularity early on, the lack of more strong clinically relevant findings to convincingly support the concept led to the other theory, depolarization disorder. The depolarization disorder hypothesis considers that conduction delay, particularly in the RV outflow tract (RVOT), plays a role in the pathogenesis of BrS. Using an electrical guidewire to record an epicardial electrogram from a conus branch of the right coronary artery, Negase et al. were the first to show abnormal electrograms characterized by late potential after QRS, which were recorded from the free wall of the RVOT epicardium in the BrS patients [17]. Their findings suggest conduction delay in the RVOT epicardium. Coronel et al. reported their findings from the explanted heart of a BrS patient who had SCN5A mutation with medically-treated failure VF storms, necessitating heart transplantation surgery [18]. The explanted heart showed no evidence of repolarization abnormality; instead, they found evidence of interstitial fibrosis causing conduction delay. The RVOT endocardium showed activation slowing, and was the origin of VF without a transmural repolarization gradient. The investigators then proposed the depolarization hypothesis, which contends that in BrS, the RVOT depolarizes last after the rest of the ventricular myocardium has completely depolarized [19]. As a result, the delay in the AP of the RVOT causes the electrical gradient from the more positive RV to RVOT, leading to the ST-elevation of the right precordial leads similar to the situation of a myocardial injury at the RVOT and as the RVOT depolarizes later (during repolarization of the RV), this gradient is reversed and the net current flows toward the RV, resulting in a negative T wave in the same right precordial leads. The experiment from the same group in this explanted heart also showed that this site is the arrhythmogenic site during programmed stimulation-induced VF. Frustaci et al. also reported the biopsy findings showing fibrosis in patients with the Brugada phenotype [20]. And there are a number of clinical studies showing that the delayed activation of the RVOT in BrS patients indeed occurred [21–27]. Regardless of which theory is correct, it becomes quite clear from the preceding studies as well as from the study by Moriata et al. [28], that the RVOT is the likely arrhythmogenic substrate site of the BrS.