Author + information
- Published online April 17, 2017.
- aPacific Rim Electrophysiology Research Institute, Bangkok, Thailand, and Los Angeles, California
- bHeart Centre, Academic Medical Centre in Amsterdam, Amsterdam, the Netherlands
- cPrincess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia
- ↵∗Address for correspondence:
Dr. Koonlawee Nademanee, Pacific Rim Electrophysiology Research Institute, 1700 Cesar Chavez Avenue, Suite 2700, Los Angeles, California 90033.
The intense but animated debate between the repolarization versus depolarization hypotheses as the underlying electrophysiologic mechanism of the Brugada syndrome (BrS) and its associated life-threatening ventricular arrhythmias (VA) has been ongoing for a decade (1). Regardless of the underlying electrophysiologic mechanism of BrS, however, virtually all investigators agree that the right ventricular outflow tract (RVOT) is the main substrate site. This supposition was confirmed from in vivo mapping of the heart, both endocardially and epicardially, of BrS patients who had frequent implantable cardioverter-defibrillator discharges due to recurrent ventricular fibrillation (2). They had abnormal low-voltage fractionated electrograms with markedly delayed conduction time and prolonged duration, clustering over the anterior RVOT epicardium. Importantly, ablations at these sites not only prevented ventricular fibrillation episodes, but also normalized the electrocardiogram. These findings now have been corroborated via case reports and collaborative studies (3,4), and they raise the key question: Are these fractionated electrograms caused by underlying myocardial pathology or by ionic channel abnormalities in the RVOT or both?
Our recent multicenter study demonstrated that BrS is unequivocally associated with increased collagen throughout the heart (4). There is significant epicardial and interstitial fibrosis and reduced gap junction expression at the RVOT, in particular. Biopsies taken from 6 BrS patients during open-heart ablation from RVOT epicardial sites with abnormal, fragmented, and delayed conduction confirmed the underlying pathology of fibrosis, as witnessed by Coronel et al. (5) from their study of the explanted heart of a BrS patient who underwent cardiac transplantation for implantable cardioverter-defibrillator storms. These fibrotic sites collocate to abnormal potentials, which, once ablated, abolish the BrS phenotype and VA. Thus, we fervently believe that abnormal myocardial structure and conduction abnormalities are the primary electrophysiologic abnormalities in BrS.
However, Patocskai et al. (6) in this issue of JACC: Clinical Electrophysiology present data from the RV-Wedge preparation illustrating that late fractionated low-voltage potentials in RV epicardium, but not endocardium, are associated with repolarization abnormalities. Their findings confirm the observation by Szél and Antzelevitch (7) from the same laboratory that in their models, repolarization defects could produce abnormal late fractionated potentials. The Patocskai et al. (6) study also found that elimination of these repolarization abnormalities by radiofrequency ablation of the abnormal epicardial sites does eliminate the electrocardiographic abnormalities (i.e., the BrS electrocardiogram pattern) and VA. Thus, their strong argument that epicardial RVOT substrates are due to repolarization defects is not surprising.
RV-Wedge Preparation Model Versus Brugada Syndrome in Humans
It is apparent that investigators who favor the repolarization abnormality hypothesis in BrS rely merely on data generated from the Wedge preparation. In contrast, those in favor of the depolarization abnormality hypothesis rely on observations from real cases of symptomatic BrS patients. Inevitably, one must ask: “Is the Wedge preparation model applicable to the same electrophysiologic disorders in BrS patients?” Thus far, there have never been documented repolarization abnormalities over the RVOT epicardium in BrS patients, except one case report in which epicardial and endocardial monophasic action potential (AP) recordings were taken simultaneously in a patient with BrS. Transmural gradient of AP between epicardium and endocardium was observed, but shortening of AP was not reported. In contrast, marked depolarization and conduction delay were observed in virtually all BrS patients who had undergone mapping for the substrate ablation procedure. And as indicated, every biopsy patient was found to have both epicardial and interstitial fibrosis.
Not only did the study by Patocskai et al. (6) not include structural abnormality in their 2 models, the Wedge preparation is set up to enhance repolarization abnormality by using an agent designed to mimic a gain of Ito, the Ito agonist NS5806 (4 to 10 μmol/l) and verapamil (0.5 to 2 μmol/l) designed to mimic loss of function of ICa in their first model. The second model was designed to mimic a gain of function of the adenosine triphosphate (ATP)-sensitive potassium current (IK-ATP) using the IK-ATP agonist pinacidil (1 to 5 μmol/l) and a loss of function of fast sodium channel current (INa), ajmaline (2 to 10 μmol/l). The rationale for these 2 models was to reproduce ion-channel currents affected by mutations associated with BrS. However, one must point out that in BrS, the relevance of these variants, except those in SCN5a, to the BrS phenotype is questioned (8). Therefore, it is unclear whether the Patocskai et al. (6) models are applicable to BrS patients.
Moreover, fractionated electrograms produced by the Wedge preparation, as shown in the Patocskai et al. (6) study, are characterized by split electrograms: The first component is a high amplitude sharp deflection of the electrogram; the second component is the fractionated electrogram caused by the concealed phase 2 re-entry. In contrast, the fractionated electrograms recorded in BrS patients predominantly are low-voltage multiple component signals from the onset of the electrogram with prolonged duration lasting beyond the QRS complexes. The clear differences in the characteristics of electrograms between those observed in the Wedge preparation and those from BrS patients suggest that different electrophysiologic mechanisms underlie such electrograms.
Last, various laboratories now have shown that in BrS patients, the substrate sites that harbor fractionated electrograms could be expanded substantially by sodium channel blockade (i.e., ajmaline, flecainide) (3,9). The expansion could extend down to the RV body and inferior aspect of the RV, suggesting that the drugs unmask subclinical pathologic substrate areas in the RV. On the other hand, Patocskai et al. (6) show that ajmaline failed to produce fractionated electrogram and electrocardiogram abnormalities in the Wedge preparation that had displayed a significantly lower J-wave and AP notch area at baseline. Thus, the difference in the responses of ajmaline unmasking the substrate site between the experimental studies and in vivo BrS patients suggests also a different electrophysiologic disorder occurring in the Wedge preparation versus BrS patients.
A Tale of 2 Different Electrophysiologic Settings
Clearly, the debate between the repolarization versus depolarization hypotheses will boil down to whether the outward disproportional shift in Ito current density in the RVOT, as shown by the Potocskai et al. (6) study, causing phase-2 re-entry arrhythmia, takes place in human BrS. The other possibility is that BrS is a heterogeneous disease, which could be: 1) the clinical entity consistently shown in BrS patients that is associated with epicardial fibrosis causing conduction abnormalities, and 2) the pure ion channelopathy causing repolarization defects, which, under the burden of proof, has not yet had strong evidence that it indeed occurs in humans. Also, one cannot exclude the possibility that the 2 mechanisms coexist. Further human studies using an electrophysiologic maneuver such as pacing or ajmaline or direct mapping during open thoracotomy with biopsy of the substrate may eventually resolve this controversy.
Clearly, more research on BrS is needed so that we can eventually settle this decade-old debate and, by better understanding RV electrophysiological derangement in BrS, will enable us to gain insights into underlying mechanisms of VA that occur in other disease states such as inherited arrhythmia syndrome, ischemia, etc. In the meantime, one must acknowledge that the findings of Potocskai et al. (6) are relevant in alerting clinicians who treat BrS patients to beware of drugs that will affect outward repolarizing currents or conditions that will increase Ito. However, one also should hesitate to draw any inference from their findings into human BrS; as Opthof et al. (10) pointed out, “a wedge is not a heart.”
↵∗ Editorials published in JACC: Clinical Electrophysiology reflect the views of the authors and do not necessarily represent the views of JACC: Clinical Electrophysiology or the American College of Cardiology.
Dr. Nadamanee is supported by Adventist Healthcare, Vejdusit, and Duangtawan Foundation of Thailand, Bumrungrad Hospital Research Grant in Aid; and is a consultant for and has received royalties from Biosense Webster. Dr. Wilde is a consultant for and a member of the Scientific Advisory Board for Sorin; and receives support from the Netherlands CardioVascular Research Initiative (the Dutch Heart Foundation, the Dutch Federation of University Medical Center, Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Science).
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- 2017 American College of Cardiology Foundation
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