Electrophysiologic Study in Brugada Syndrome: More Questions Than Answers?

More Questions Than Answers?

C. W

, C. E

, C. V

, R. S

, M. B

Introduction

Brugada syndrome is an inherited arrhythmogenic disorder characterised by typical ECG changes in the right precordial leads and an increased risk of sudden cardiac death. Since the patient population is heterogeneous with respect to family history, symptoms, and age, there is a major focus on diag- nostics and risk stratification. The prognostic value of electrophysiologic studies is controversial. Since the first reports on patients with Brugada syn- drome, the data on outcome in this population at risk of sudden death has changed towards a better prognosis for asymptomatic patients. An intensi- fied screening process and the inclusion of more sporadic and asymptomatic cases as well as younger patients is probably the main reason for this.

Whereas in early reports programmed stimulation played a major role in risk prediction, in terms of a higher arrhythmia risk in the presence of inducible VT/VF, recent reports have not always confirmed these results even in larger patient populations. Therefore, the role of programmed stimulation remains unclear.

Which Stimulation Protocol Should Be Performed in Patients with Brugada Syndrome?

In the previous investigations, especially in multicentre studies, different stimulation protocols in patients with Brugada syndrome were tested [1–11].

To compare the results of programmed electrical stimulation, the following

1

Department of Medicine-Cardiology, University Hospital Mannheim, Faculty of

Clinical Medicine of the University of Heidelberg, Mannheim, Germany

protocol has been suggested: stimulation at two sites (right ventricular apex and right ventricular outflow tract), three driving-cycle lengths (600, 430, 330) and 1, 2, or 3 premature extrastimuli with a minimum coupling interval of 200 ms. Nonetheless, different protocols are currently in use. For example, the driving-cycle lengths differ; some investigators use only 2 extrastimuli and others reduce the last premature-stimulus cycle length until refractori- ness. This renders results of programmed electrical stimulation less compa- rable. Interestingly, when comparing the inducibility of sustained VT or VF between groups using a minimum cycle length of 200 ms and groups that stimulate until ventricular refractoriness, the overall amount of inducible VT/VF remains quite constant. It is even more striking that, e.g. Eckardt et al. [4] and our own group [unpublished data] found an overall VT/VF inducibility in 28/41 (67%) and 21/31 patients (68%), respectively. These results are comparable to those of other investigators who used a minimum cycle length of 200 ms but obtained a VT/VF inducibility of only 36% [4], and 31% (12/31) when restricting the coupling interval of the last extrastim- ulus to a minimum of 200 ms. It would therefore be desirable to follow a common protocol or to prospectively compare both protocols with respect to their predictive power of arrhythmia risk.

Are the Results of Programmed Stimulation Reproducible?

Assuming a predictive value of VT/VF inducibility, a major question is whether it is reproducible or whether there are different responses to pro- grammed stimulation caused by various factors, such as vagal activity, sym- pathetic activation, sedation, hormonal status, or chance, which may lead to positive or negative results at different time points. Gasparini et al. [1]

addressed this question by administering repeated programmed electrical stimulation in patients with Brugada syndrome. They demonstrated that the results remained comparable from one EP study to the other in 82% of the patients. Only the number of extrastimuli necessary for induction and the coupling interval of the premature extrastimulus varied in some patients.

However, the authors also considered non-sustained VT between 6 and 30 s

as inducible, which limits interpretation of the results because most physi-

cians would consider this as non-inducible. Thus, it remains to be investigat-

ed in greater detail whether the results of programmed electrical stimulation

are reproducible, since, especially in a subgroup of symptomatic patients,

inducibility plays a major role in deciding whether to prophylactically

implant a defibrillator.

Are Symptomatic Patients With Inducible Ventricular Arrhythmias at Higher Risk of Ventricular Fibrillation Than Patients Without Inducible VT/VF?

For symptomatic patients with Brugada syndrome, reports on the role of inducibility of VT/VF for risk stratification are controversial. In a study with 144 symptomatic patients with Brugada syndrome, Brugada et al. [9] identi- fied VT/VF inducibility as a strong predictor of a future malignant ventricular tachyarrhythmia or sudden death. Other variables, such as family history or abnormal ECG only after therapy with class I drugs, were not predictive. In contrast, Priori [5] and co-workers did not find VT/VF inducibility to be a pre- dictor for future arrhythmias or sudden death in a study of 86 patients who underwent programmed electrical stimulation. In a recent report by Eckardt et al. [11], inducibility also failed to predict future sudden death or VT/VF docu- mented by an implantable cardioverter defibrillator (ICD) in 186 patients with Brugada syndrome who were followed over a mean duration of 40 ± 50 months. However, the results showed a higher likelihood of inducibility in patients with previous symptoms or aborted sudden death compared to asymptomatic patients. The mean follow-up period of 45 patients investigated by Morita et al. [3] was 38 ± 27 months. There was no significant difference between the frequency of cardiac events in symptomatic patients with induced VF (cardiac event 1.5 ± 0.1 times/year) and in those without induced VF (car- diac event 2.0 ± 1.6 times/year). One reason for the conflicting reports of Brugada et al. and other authors may be a certain selection bias, because the percentage of symptomatic patients is higher in the Brugada registry reported by Brugada et al. [8–10] Therefore, there is a strong need for further studies in more homogeneous populations in order to re-evaluate the role of pro- grammed electrical stimulation in Brugada syndrome.

Should Programmed Stimulation Be Performed in Asymptomatic Patients and If So, When?

It is still a matter of discussion whether asymptomatic patients with a sur- face ECG that displays typical Brugada-like changes should undergo pro- grammed electrical stimulation. Whereas in early reports Brugada et al.

[8–10] demonstrated a significant risk of VT/VF in asymptomatic patients

with inducible VT/VF, more recent reports describe a better outcome of

asymptomatic patients irrespective of inducibility. Therefore, the Second

Brugada Consensus Conference [12] recommended programmed electrical

stimulation only for asymptomatic patients with a family history of sudden death suspected to be due to Brugada syndrome and a spontaneous abnor- mal ECG. If patients display the ECG only after sodium-channel-blocker challenge and no family history is present, electrophysiologic studies are not recommended. This recommendation is, at least to a certain extent question- able, since it is well known that the typical ECG pattern may transiently not be present and that it fluctuates in a significant proportion of patients, so that a typical ECG recording may be a result of chance or other influencing factors. At least in our own population, 20% of the patients with a negative index ECG display an abnormal basal ECG during repetitive recording dur- ing further follow-up [unpublished data].

Clinical Implications

Electrophysiologic studies are an important diagnostic tool in the character- isation of patients with Brugada syndrome, especially for scientific reasons.

For clinical issues, its value has somewhat changed, and the new recommen- dations of the Brugada Consensus Conference do not require electrophysio- logic studies in asymptomatic patients with a normal baseline ECG and no family history of sudden death. However, how much one can rely on single ECG recordings to say that there is no basal abnormal ECG in a patient, remains to be assessed in a larger population, because ECGs display a great amount of fluctuation. Finally, there are different stimulation protocols in use with either less or more aggressive coupling intervals, which may lead to a decreased sensitivity or specificity. The answer to the question whether there is a difference in positive or negative predictive value for sudden death risk depending on the protocol used needs to be further evaluated in com- parative studies of large populations.

References

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