Are we able to predict the diagnosis of Brugada syndrome?

This editorial refers to ‘New electrocardiographic criteria to differentiate type 2 Brugada pattern from ECG of healthy athletes with r′-wave in leads V1/V2’ by Serra et al., on page 1639. Please let me provide you the answer right away: no, we are not able to predict the diagnosis of Brugada syndrome with 100% certainty … on non-diagnostic electrocardiograms (ECGs). But can we come close? That is the question which Dr Serra together with colleagues from Spain, Canada, Belgium, and Italy asked and wrote about in this issue of the Journal.1 The inheritable arrhythmia syndrome—Brugada syndrome—is characterized on the ECG by a specific coved-type or Type-1 right-precordial J-ST segment and by a propensity for malignant arrhythmias and sudden death. Until recently, this characteristic ECG pattern had to be accompanied by evidence or the suggestion of ventricular arrhythmias and/or familial segregation to make the diagnosis of Brugada syndrome. However, since the latest consensus report2 this prerequisite has been abandoned. With non-diagnostic ECGs in persons in whom the diagnosis is suspected, one may use provocation testing with potent sodium channel blockers (e.g. ajmaline) to confirm or to refute the diagnosis. Treatment is mostly conservative (i.e. avoidance of certain drugs,3 family screening, and long-term follow-up) but may include chronic drug therapy (with quinidine), cardioverter defibrillator implantation, and/or ablation of the arrhythmic substrate. Its prevalence is variable but is about 1 in every 2000 persons4 and its underlying pathophysiological mechanism is disputed but involves depolarization and/or repolarization abnormalities.5 While the Brugada syndrome gained increasing attention since the late 1990s, the number of persons suspected of being affected erupted. It is intuitive that only those persons who have a solid and guideline-approved diagnosis should be regarded as having the Brugada syndrome. However, as we have seen earlier in the long QT syndrome,6 it is most probable that there are hundreds or thousands of patients worldwide who received an erroneous Brugada syndrome diagnosis. These patients might well have undergone unjustified invasive studies or even invasive treatment. One should realize that these diagnostic miscues are either the outcome of misinterpretation of a non-Type-1 ECG pattern or Brugada phenocopy, or by erroneously translating genetic test results (such as a mutation or variant in the cardiac sodium channel gene SCN5A) to the diagnosis. When there apparently is variability in the identification of a diagnostic Type-1 Brugada ECG (although the guideline is very clear on this issue), what can we expect from studies into non-diagnostic ECGs and a suspicion of Brugada syndrome? Can we refute a possible diagnosis without provocation testing? And if that is true, how much will we increase the number of patients with Brugada syndrome who remain unrecognized because they were not tested? And could this result in morbidity or even mortality that might have been prevented when the diagnosis was accurately made? On a day-to-day basis, we use imperfect testing to confirm or to refute a possible diagnosis (there is no such thing as a perfect test). But should in this particular syndrome the gold standard, i.e. provocation testing, be abandoned in a particular group of patients? There are many reasons indeed to applaud this question. Often we judge ECGs of persons who are not at all suspected of any inheritable arrhythmia syndrome or cardiovascular disease. They might have had some non-specific complaint, they might undergo regular health check-ups, they might be scheduled for a non-cardiac operation, they might participate in sports or in a study, etc. It is probably wrong to aggressively react to each possible aberrant (right-precordial) J-ST segment or terminal r-wave, which can also be referred to as a ‘J-wave reflex’; overdiagnosis and overtreatment can result much to easily and can lead to morbidity and mortality as well.6 So it is our task to judge which J-ST segment will most probably not result in a positive provocation test for Brugada syndrome and to subsequently deny additional testing in the setting of a low pre-test likelihood. In 2011, the group from Lausanne, Switzerland, and the group from Nihon University, Tokyo, Japan, independently and simultaneously developed the same tool to better discriminate (incomplete) right bundle branch block and non-diagnostic Brugada ECGs which turn into a diagnostic Type-1 ECG upon provocation testing.7,8 In their small proof-of-concept studies, they used provocation testing in 38 and 22 patients, respectively. They both concluded that a slower downslope of the right-precordial J-ST or r′ on the baseline ECG made it more likely to produce a positive test result. The most sensitive measure was a higher β-angle or terminal QRS angle, which is the angle in degrees between the right-precordial S-upslope and the r′- or J-ST-downslope (Figure 1). Pedro Brugada, the senior author of the current paper, warmly welcomed this initiative in an accompanying editorial to the Lausanne paper.9 His enthusiasm emerged in part from the huge number of variants of normal J-ST segments in the population, which might resemble non-diagnostic Brugada ECGs. Chung et al.10 from North Carolina, who studied the ECGs of 491 collegiate athletes, have recently underscored this and also drew attention to the fact that higher placed pre-cordial leads increase the number of Brugada-suggestive ECGs. So Serra et al., including the three Brugada brothers, now tried to find easier and even better discriminating parameters in non-diagnostic ECGs. Shown are the baseline and peak ajmaline ECG (standard calibration) of a patient with Brugada syndrome from our centre. Depicted are both the ‘β-angle’,8 a.k.a. ‘terminal QRS angle’,7 with corresponding degrees and the duration of the base of a triangle at 0.5 mV from the terminal high take-off in the leads V1 and V2,1 in both the standard fourth and the adjusted third intercostal space. Please note that the angles are rather shallow in all leads, and that the triangle baseline duration is extremely variable. In addition, only in lead V1 the triangle baseline duration exceeds the 160 ms cut-off value, which is indeed mirrored in a positive test result with a characteristic J-ST morphology change, i.e. to a Type-1 Brugada ECG, after ajmaline administration (arrows). Please also note that the ‘β-angle’ cut-off value as set by the Lausanne group (58°) is not reached. In the present proof-of-concept study of Serra et al.,1 the non-diagnostic baseline ECGs of 50 Brugada syndrome patients from the Brugada registry were re-analysed and compared with the ECGs of 58 healthy athletes. To increase usability, they tried to find parameters that could be measured in milliseconds instead of degrees. In the end, they found the most useful parameter to be a duration >160 ms of the base of a triangle at 0.5 mV from the terminal high take-off in lead V1 or V2 (Figure 1) with a positive predictive value of 94% and a negative predictive value of 88%, which also outperformed the β-angle a.k.a. the terminal QRS angle. Judging from the high-positive predictive value, this indeed seems to be a rather useful tool to get a feeling of the possibility of a positive provocation test. But the key to denying provocation testing is in the negative predictive value. In this respect, it is important to note that the authors did not confirm that the control group of healthy athletes was indeed a group of persons without the Brugada syndrome; they did not undergo provocation testing. So the negative predictive value might be slightly worse although their control group definitely has a low pre-test likelihood as opposed to the probably intermediate to high pre-test probability in the Lausanne and Tokyo studies. But there are more limitations that should be taken into account. It is (again) a very small study in which only the non-diagnostic ECGs of 50 Brugada syndrome patients were selected out of several hundreds in the Brugada registry and only slightly more (58) non-age-matched controls were selected. What we also do not know is whether this tool (with adjusted cut-off values) can be even more discriminative in complexes received from the more sensitive higher intercostal spaces, as has grown to be a standard procedure in Brugada syndrome.2 The earlier mentioned study by Chung et al. is also relevant in this respect, as it showed that non-diagnostic Brugada ECGs are indeed often found in the higher intercostal spaces in a comparable control population of healthy athletes.10 In addition, the method is not applicable to ECGs without r′ or J-elevation. And finally, day-to-day variability in the J-ST segment has not been studied but might be another important confounder to the study results. First, we should approach patients and their non-diagnostic Brugada ECGs with an interpretation of the pre-test likelihood. It is clear that a resuscitated male patient of 38 years who collapsed during a febrile episode is at much higher risk of developing Brugada syndrome than a 64-year-old healthy female who has had an ECG made because she underwent a medical check-up. Then we should await confirmative large studies, presumably using a control group with an intermediate to high pre-test likelihood of Brugada syndrome. The latter is relevant because we need to perform provocation testing in the control group (including higher placed leads) to be absolutely sure that these persons do not have Brugada syndrome. These studies should probably include several hundreds of affected patients and even more controls to gain sufficient data and to be able to confidently translate this to persons with a low pre-test likelihood. But until then the data of Serra et al. are extremely helpful in reducing the ‘J-wave reflex’ so often seen and they once again underscore the importance of our progression in the interpretation of non-diagnostic ECGs. The proof-of-principle study by Serra et al. documents that a duration >160 ms of the base of a triangle at 0.5 mV from the terminal high take-off in lead V1 or V2 is a promising tool to discriminate between non-diagnostic ECGs that will turn into a diagnostic Type-1 Brugada ECG and those that will not. Conflict of interest: none declared.

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