Abstract

I am pleased to comment on the interesting article published in this issue by Kawata et al.1Kawata H. Noda T. Yamada Y. et al.Effect of sodium channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndrome.Heart Rhythm. 2012; 9: 77-83Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar The early repolarization (ER) pattern has long been thought to be a “benign condition” or “normal variant.” However, in isolated case reports and small case series, several authors note that it could represent a “danger sign” that could herald ventricular fibrillation (VF).2Gussak I. Antzelevitch C. Bjerregaard P. ECG phemonena of the early ventricular repolarization: early repolarization syndrome.in: Gussak I. Antzelevitch C. Cardiac Repolarization: Bridging Basic and Clinical Science. 1st ed. Humana Press, Totowa, NJ2003: 407-425Crossref Google Scholar It was not until 2008 when the paradigm of ER as a normal variant was dramatically changed by 2 groups at the same time, one led by Haïssaguerre in France and the other by Viskin in Israel.3Haïssaguerre M. Derval N. Sacher F. et al.Sudden cardiac arrest associated with early repolarization.N Engl J Med. 2008; 358: 2016-2023Crossref PubMed Scopus (1098) Google Scholar, 4Rosso R. Kogan E. Belhassen B. et al.J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance.J Am Coll Cardiol. 2008; 52: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar They described a high prevalence of this electrocardiographic (ECG) pattern (defined as J-point elevation [JPE]) in idiopathic VF, thus seeming to confirm previous hypotheses. From a clinical point of view, this new evidence forced us to look for this pattern in subjects classified until then as idiopathic VF. At the same time, it is necessary to establish the “reverse association”: that is, are healthy individuals with this pattern, without any other risk factor, at risk for sudden cardiac death (SCD)? This turns out to be a major clinical dilemma due to the high prevalence of this pattern in the normal population, and this was the subject of an excellent recent review.5Rosso R. Adler A. Halkin A. Viskin S. Risk of sudden death among young individuals with J waves and early repolarization: putting the evidence into perspective.Heart Rhythm. 2011; 8: 923-929Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Kawata et al provide further knowledge relating to the study of subjects with idiopathic VF. They investigated many clinical and ECG differences between patients with idiopathic VF with an ER pattern and those with Brugada syndrome (BrS), in particular their response to sodium-channel blockers. In the following sections I will attempt to place the research of Kawata et al in perspective. Traditionally, a distinction has been made among JPE, ST-segment elevation, and the presence of J waves based on which one of these 3 elements predominates over the other. When the relevant finding is ST elevation, only this is described, as is the case in acute coronary syndromes where modifications of the J point always accompany alterations of the ST. When the morphology is a deflection (“dome,” “hump”), it is named “J wave” (an upward deflection between the end of the QRS complex and the beginning of the ST), as in hypothermia. In traditional electrocardiography, repolarization of the ventricles is represented by the T wave and the term “ER” was assigned to any “small” ST elevation in normal subjects. Actually, the JPE and J waves are also included as ER.2Gussak I. Antzelevitch C. Bjerregaard P. ECG phemonena of the early ventricular repolarization: early repolarization syndrome.in: Gussak I. Antzelevitch C. Cardiac Repolarization: Bridging Basic and Clinical Science. 1st ed. Humana Press, Totowa, NJ2003: 407-425Crossref Google Scholar The current accepted hypothesis is that these manifestations observed in the human scalar ECG have the same pathophysiology as their counterparts observed in transmural ECG (bipolar direct leads) of experimental models, in which not only the JPE or the J wave (depending on its relation to the QRS complex) is coincident with the appearance of the notch of phase 1 of the action potential (initial repolarization) in the epicardium but also its magnitude is directly correlated with the magnitude of this notch.6Antzelevitch C. Yan G.X. Viskin S. Rationale for the use of the terms J-wave syndromes and early repolarization.J Am Coll Cardiol. 2011; 57: 1587-1590Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Assumption is made that the same applies to the conventional clinical 12-lead ECG composed of distant unipolar and bipolar leads. Although, in strict electrophysiological terms, this is not “early” as it has to occur with some conduction delay from the endocardium to the epicardium (especially for a J wave to be clearly seen), but rather an increased, augmented, initial repolarization in the epicardium. The relevant point is that this evidence establishes that the ER pattern of the human ECG could actually represent a repolarization process. Saying this, an “ER pattern” is an ECG morphology or, more correctly, an ECG diagnosis. Based on the new evidence, the predominant ECG features are as follows: JPE in leads other than V1 to V3, with or without the presence of a J wave (either small “notches” or frank waves), with or without ST-segment elevation (either upsloping, horizontal, or downsloping). When the JPE is above the ST segment, it confers a characteristic appearance to the downstroke of the R wave that has been described as “slurring.” The presence of an ER pattern in a survivor of an episode of SCD confirms the so-called ER syndrome. It makes perfect sense in clinical practice to use the terms “pattern” and “syndrome” in a similar way as we used the terms “Brugada pattern” (ECG pattern only) and “BrS” (ECG pattern plus SCD or its equivalents). This apparently simple distinction is clinically relevant to avoid overdiagnosis and to prevent labeling healthy subjects as “sick,” taking into consideration that these terms were used indistinctly before. Although BrS and the ER syndrome probably differ in their localization (BrS is viewed as a “right ventricular disease,” while ER is not known but the localization of the alterations in those leads exploring the inferior and anterolateral walls suggests a left ventricular involvement), many similarities have been described among them. Both are associated with SCD. Clinical presentation is similar in both groups of patients, including not only age (younger people), gender (male predominance), time of arrhythmias (predominantly nocturnal), and triggers of events but also the therapeutic response to isoproterenol and quinidine.7Haïssaguerre M. Sacher F. Nogami A. et al.Characteristics of recurrent ventricular fibrillation associated with inferolateral early repolarization: role of drug therapy.J Am Coll Cardiol. 2009; 53: 612-619Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Finally, some patients with BrS can also have an ER pattern in inferolateral leads. Thus, it is clinically relevant to know whether the ER pattern seen in BrS is an integral part of the disease or constitutes an associated illness. The observations by Kawata et al clearly establish that BrS and the ER syndrome are different entities, at least in their response to sodium-channel blockers. This is not a minor point. For years, we have used sodium-channel blockers to unmask the BrS. So, although the BrS and the ER syndrome may share a common ionic and cellular basis, the differential effect of sodium-channel blockers suggests that they must differ in some basic pathophysiological mechanism. As mentioned before, it could be speculated that the former occurs in the right and the latter in the left ventricle and that they have different magnitudes, based on the different amplitudes that the ST-segment elevation and J waves can have in BrS versus the ER syndrome. The known discrepancy in Ito-mediated notches between right and left ventricular epicardial cells could account for these differences. The authors' main finding is that the ER pattern observed in the inferior and/or lateral leads has the same response to sodium-channel blockers when it presents either isolated (idiopathic VF) or associated to BrS. A reduction in the amplitude of the JPE and/or diminution of the J wave, when present, is clearly demonstrated by the authors. The study of Kawata et al confirms that subjects with BrS had more late potentials than did subjects with the ER syndrome. Although this is true only for the comparison between the ER syndrome with the entire cohort of patients with BrS but not for the comparison with the subgroup of BrS with ER, the authors correctly state that this may be due to the small sample size of the BrS with ER group. Again, the low prevalence of late potentials in the ER syndrome suggests that JPE really represents a repolarization process rather than delayed depolarization abnormalities.3Haïssaguerre M. Derval N. Sacher F. et al.Sudden cardiac arrest associated with early repolarization.N Engl J Med. 2008; 358: 2016-2023Crossref PubMed Scopus (1098) Google Scholar, 4Rosso R. Kogan E. Belhassen B. et al.J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance.J Am Coll Cardiol. 2008; 52: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar The study of Kawata et al gives us a great insight into the ER syndrome: the JPE of this syndrome normalizes with sodium-channel blockers. Would this constitute a new marker of the disease? We do not have an answer yet. Studies comparing this response in “normal” subjects (without a history of SCD) and individuals with diagnosis or suspicion of the ER syndrome (ie, ER pattern and family history of SCD) are urgently needed. It will also be important to know whether this “pharmacological correction” of the ER pattern could represent a marker of risk, either in normal individuals or in those with the ER syndrome. Another relevant clinical implication is that sodium-channel blockers are not forbidden drugs in the ER syndrome as they are in BrS, and formal clinical studies on the possible therapeutic effects of this class of drugs are needed. This study helps to further delineate the ER syndrome and to separate it from the “backpack” of idiopathic VF. Taking into consideration all these new findings, cardiologists will need to change their previous paradigm of ER, always as a trivial ECG finding, with few specific characteristics, and learn to recognize the “new spectrum” that truly constitutes the ER syndrome. Effect of sodium-channel blockade on early repolarization in inferior/lateral leads in patients with idiopathic ventricular fibrillation and Brugada syndromeHeart RhythmVol. 9Issue 1PreviewA high incidence of early repolarization (ER) pattern in the inferolateral leads has been reported in patients with idiopathic ventricular fibrillation (IVF). Brugada syndrome (BS) is characterized by J-point or ST-segment elevation in the right precordial leads and ventricular fibrillation, and some patients with BS also have ER in the inferolateral leads. Full-Text PDF

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