Elsevier

Heart Rhythm

Volume 2, Issue 3, March 2005, Pages 254-260
Heart Rhythm

Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome

https://doi.org/10.1016/j.hrthm.2004.11.025Get rights and content

Objectives

The purpose of this study was to compare the effect of intravenous flecainide and ajmaline with respect to their ability to induce or accentuate the typical ECG pattern of Brugada syndrome.

Background

Brugada syndrome is associated with a high incidence of sudden cardiac death. The typical ECG pattern of ST-segment elevation in the right precordial leads often is concealed, but it can be unmasked with sodium channel blockers such as flecainide and ajmaline. Little is known about the relative effectiveness of these provocative agents in unmasking Brugada syndrome.

Methods

Intravenous pharmacologic challenge with flecainide and ajmaline was performed. Whole-cell patch clamp techniques were used to assess the relative potency of ajmaline and flecainide to inhibit the transient outward current (Ito).

Results

A coved-type ST-segment elevation in the right precordial leads was induced or enhanced in 22 of 22 patients following ajmaline administration. Among the 22 patients, only 15 patients showed positive response to flecainide, resulting in a positive concordance of 68%. Both drugs produced equivalent changes in QRS and PQ intervals, suggesting similar effects on sodium channel current. Whole-cell patch clamp experiments revealed a reduction of the total charge provided by Ito with an IC50 of 216 and 15.2 μM for ajmaline and flecainide, respectively.

Conclusions

Our data demonstrate disparate response of Brugada patients to flecainide and ajmaline, with a failure of flecainide in 7 of 22 cases (32%). Greater inhibition of Ito by flecainide may render it less effective. These observations have important implication for identification of patients at risk for sudden death.

Introduction

Brugada syndrome is characterized by an ECG pattern of right bundle branch block and ST-segment elevation in the right precordial leads (V1–V3).1 Intensive screening among patients with aborted sudden death or syncope has increased the number of patients since the first report by Brugada et al.2 Pharmacologic challenge with intravenous administration of sodium channel blockers has been suggested to unmask the ECG pattern in patients with Brugada syndrome.3, 4 A variety of drugs, such as flecainide, ajmaline, procainamide, and pilsicainide, reportedly provoke typical ST-segment elevation.5, 6, 7, 8, 9 However, comparative studies for ajmaline and flecainide are lacking. Therefore, in the present study the effects of intravenous flecainide and ajmaline were studied with respect to their ability to unmask the typical Brugada ECG and their effects on the 12-lead surface ECG. In addition, the effect of ajmaline and flecainide on the Ito current in canine ventricular epicardial cells was measured in in vitro experiments to determine the mechanisms for possible differences in the response to the two sodium channel blockers in patients diagnosed with Brugada syndrome.

Section snippets

Patients and methods

A total of 22 consecutive, unrelated patients with Brugada syndrome diagnosed between August 2000 and March 2003 were prospectively enrolled into the study. All patients gave informed consent to clinical investigation. Diagnostic work-up included full noninvasive and invasive testing, including echocardiography, exercise testing, pharmacologic challenge, right ventricular angiography, coronary angiography, and programmed stimulation. Up to three extrastimuli at three different basic driving

Results

A total of 22 patients diagnosed with Brugada syndrome underwent ajmaline and flecainide challenge. No ventricular tachyarrhythmias were observed during the pharmacologic challenge, except for isolated premature ventricular beats in three patients. No severe side effects occurred. One of 22 patients developed urticaria and flush during ajmaline infusion. At baseline immediately before drug testing, seven patients displayed a type I ECG in no more than one right precordial lead. The remaining

Discussion

In this prospective study, we investigated the response of the surface ECG to two different intravenously administered sodium channel blockers—ajmaline and flecainide. In 15 of 22 patients (68%) with Brugada syndrome, the study of intravenous drug challenge with flecainide and ajmaline revealed concordant results, whereas a discordant result was found in another seven patients (32%). In the seven patients, intravenous flecainide did not produce the typical ECG changes diagnostic of Brugada

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      Excessive QRS widening and frequent premature ventricular beats indicate high-risk of complications and encourage interruption of the challenge [33]. The used drugs have presented good reproducibility [38], but flecainide has been shown to present significantly lower sensitivity than ajmaline (77% against 100%, respectively) [39,40]. A negative result in the provocative test supports the diagnosis of Brugada phenocopy; nevertheless, it must not be overlooked that there may be up to 23% of false-negatives [39] when using flecainide, and cases of delayed diagnosis of Brugada syndrome have been reported [41].

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    Supported by Grant HL47678 from the National Heart, Lung and Blood Institute to Dr. Antzelevitch and a grant from the American Heart Association to Dr. Antzelevitch.

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