Drug Challenge in Brugada Syndrome: How Valuable Is It? T. W

T. W

, E. S

-B

, M. P

, G. B

, L. E

Introduction

Since its introduction as a clinical entity in 1992 [1], Brugada syndrome has been the focus of increasing interest as a relevant cause of syncope and sud- den cardiac death in young and otherwise healthy subjects without structur- al heart disease.

The disease is characterised by ST-segment elevation in the right precor- dial surface ECG leads and a high incidence of otherwise unexplained syn- cope, polymorphic ventricular tachycardia, and sudden death in patients with structurally normal hearts. The disease is predominant in males and manifests in adolescence or early adulthood, with a mean age of approxi- mately 40 years at the time of sudden death. Brugada syndrome is estimated to be responsible for up to 4% of all sudden deaths and 20% of sudden deaths in patients with structurally normal hearts. The true prevalence of Brugada syndrome in the general population is unknown and difficult to estimate, because ECG features may be subtle, concealed, or transient.

The disease is endemic in Southeast Asia, where ECG findings diagnostic for Brugada syndrome (type-1 ECG) were reported in up to 12/10 000 inhabitants and non-diagnostic ECG findings (type-2 and type-3 ECG) in 58/10 000 individuals [2]. In European and North American populations, Brugada syndrome and Brugada-type ECG findings are much less prevalent (approx. 5/10 000 inhabitants).

University Hospital and Medical School of Münster, Department of Cardiology and

Angiology, Münster, Germany

Diagnostic Criteria

Diagnostic criteria of Brugada syndrome were recently proposed and sum- marised in a consensus document endorsed by the Heart Rhythm Society and the European Heart Rhythm Association [3]. The diagnosis is made in the presence of typical ECG manifestations in conjunction with clinical fea- tures, such as documented ventricular fibrillation (VF), polymorphic ven- tricular tachycardia (VT), unexplained syncope, a family history of sudden cardiac death at < 45 years, coved-type ECGs in family members, inducibili- ty of VT/VF during programmed electrical stimulation, or nocturnal agonal respiration.

ECG Manifestations

In Brugada syndrome, type-1 ECG is characterised by a coved ST-segment elevation ≥ 2 mm (0.2 mV) followed by a negative T-wave in the right precor- dial ECG leads (V

–V

). Type-2 ST-segment elevation has a saddle-back appearance with a high take-off ST-segment elevation of ≥ 2 mm, a trough displaying ≥ 1 mm ST elevation, and then either a positive or biphasic T- wave (Fig. 1). Type-3 ECG shows either a saddle-back or coved ST-segment elevation of < 1 mm.

Fig. 1. 12-lead surface

ECG demonstrating

the dynamic transition

of type-2 ECG (saddle-

back type) to type-1

ST-segment elevation

(‘coved-type’) in the

right precordial leads

during drug challenge

with intravenous ajma-

line in a patient with

Brugada syndrome

Type 1 ECG is diagnostic for Brugada syndrome if it occurs spontaneous- ly or after provocation with sodium channel blockers, vagotonic agents, or during febrile states. One or more of the above clinical criteria should also be present. Type 2 and type 3 ECG patterns are not diagnostic of Brugada syn- drome unless then can be converted to a type-1 ECG after administration of sodium channel blockers. Conversion of type-3 to type-2 ST-segment eleva- tion by drug challenge is considered inconclusive for the diagnosis of Brugada syndrome [3].

Pathophysiology of ECG Features

The ECG characteristics of Brugada syndrome are considered to result from an amplification of heterogeneities in the early phases of the action potential of cells residing in different transmural layers of the right ventricular wall.

A spike and dome (notch) morphology in epicardial (but not endocar- dial) layers mediated by transient outward current (I

) creates a transmural voltage gradient responsible for the J-wave in the surface ECG. Accentuation of the action potential notch in the right ventricular epicardium due to rebalancing of currents active at the end of phase 1 is considered responsible for the augmented J-wave and ST-segment elevation in Brugada syndrome [4]. Pathophysiological conditions (fever, abnormal vagotonus) or inhibition of the sodium channel current (I

) with drugs such as ajmaline, flecainide, or procainamide result in further accentuation of the action potential notch and subsequent exaggeration of the J-wave and ST-segment elevation. The resulting transmural dispersion of repolarisation and refractoriness creates an arrhythmogenic substrate. Premature ventricular extrasystoles occurring during a ‘vulnerable window’ may then trigger circus movement reentry, ultimately leading to polymorphic VT, VF, and sudden death.

Spontaneous ECG Variations

It is well known that ECG features of Brugada syndrome may show consider-

able variations over time. Type-1 ST-segment elevation may not be present at

all recorded ECGs but may change to type-2 or type-3 findings, or may even

normalise completely [5]. The transient appearance of diagnostic ECG find-

ings hampers the estimation of disease prevalence, the diagnostic accuracy,

and risk stratification in Brugada syndrome, with important impact for

patient management. In that respect, all available previous ECGs should be

reviewed when Brugada syndrome is suspected. In addition, the sensitivity

of ECG diagnosis may be enhanced when recording the right precordial

leads in the second or third intercostals space instead of standard lead posi- tions (fourth intercostal space) with or without the use of body surface potential mapping and or additional drug challenge [6].

Modulation of ECG Features

A variety of conditions and drugs may modulate the ECG features of Brugada syndrome [7]. Adrenergic stimulation (i.e. tachycardia, isopro- terenol), parasympathetic blockers (i.e. atropine), and inhibition of the I

current (i.e. quinidine) diminish ST-segment elevation.

In contrast, ECG features of Brugada syndrome are unmasked or aggra- vated by increased body temperature (fever), hypokalemia, parasympathetic stimulation (bradycardia, vagal triggers, edrophonium), sympathetic block- ade (β-blockers, β-adrenergic blockers), inhibition of the I

current (i.e.

sodium channel blockers) and others. Autonomic dysfunction w ith decreased adrenergic activity, potentially contributing to autonomic dysbal- ance and increased net vagal tone, was recently confirmed by our group with the use of quantitative radionuclide imaging (SPECT and PET) of presynap- tic innervation [8, 9].

Unmasking of Brugada syndrome in response to drugs probably under- lies a rebalancing of currents active at the end of phase 1 of the action poten- tial. Vagotonic agents, I

-ATP activators and hypokalemia achieve this by augmenting outward currents whereas sodium channel blockers, β-blockers, cocaine, antidepressants, and antihistamines such as terfenadine likely accomplish this by reducing inward currents [10, 11].

An augmentation of right precordial ST-elevation in Brugada syndrome

is related to the arrhythmogenesis and increases the likelihood of sponta-

neous life-threatening arrhythmias. This is supported by the observation of

marked ST-segment elevation just prior to or following the onset of poly-

morphic VT or VF. In addition, our studies with body surface potential map-

ping demonstrated that the area of ST-segment elevation correlates with the

inducibility of VT in the absence of drug provocation [12]. These effects

must be taken into consideration and several drugs that accelerate ST-seg-

ment elevation must be considered contraindicated in patients with Brugada

syndrome (Table 1) [3]. However, under appropriate conditions, sodium

channel blockers may be used as a diagnostic challenge to unmask typical

ECG features of Brugada syndrome [5].

Drug Challenge in Brugada Syndrome

Drug challenge with intravenous administration sodium channel blockers (Fig. 1) may be used for diagnostic evaluation and risk stratification in patients with Brugada syndrome, patients with unexplained syncope or car- diac arrest, or asymptomatic individuals with ECG findings suspicious for Brugada syndrome. In addition, it may be helpful in the diagnostic assess- ment of relatives of an index patient. Current indications for drug challenge in Brugada syndrome are summarised in Table 2.

Table 1. Drugs inducing Brugada-like ECG patterns (adapted from [3])

Antiarrhythmic drugs 1. Sodium channel blockers

Class IC drugs (ajmaline, flecainide, propafenone, pilsicainide) Class IA drugs (ajmaline, procainamide, disopyramide) 2. Calcium channel blockers (verapamil)

3. Beta-blockers (propranolo, metoprolol, bisoprolol, etc.)

Antianginal drugs

1. Calcium channel blockers (nifedipine, diltiazem, etc.)

2. Nitrates (isosorbite dinitrate, isosorbite mononitrate, nitroglycerine) 3. Potassium channel openers (nicorandil)

Psychotropic drugs

1. Tricyclic antidepressants (amitryptiline, nortryptiline, desipramine, clomipramine) 2. Tetracyclic antidepressants (maprotiline)

3. Phenothiazine (perphenazine, cyamemazine) 4. Selective serotonin reuptake inhibitors (fluoxetine)

Other drugs and conditions 1. Dimenhydrinate

2. Cocaine intoxication 3. Alcohol intoxication 4. Febrile state

5. Vagotonic drugs and conditions

Diagnostic Impact

The importance of pharmacologic challenge in suspected Brugada syndrome was indicated in several large series [13, 14], where 30–50% of patients showed normal ECGs at baseline and the syndrome could only be diagnosed after challenge with sodium channel blockers. In contrast, drug challenge is generally not performed in patients with a diagnostic type-1 ECG under baseline conditions, because of its limited additional diagnostic and prog- nostic value and its potential for proarrhythmic adverse events [3].

Table 2. Drug challenge in Brugada syndrome: proposed diagnostic protocol (modified from [17])

Indications:

Aborted sudden death, polymorphic VT, or unexplained syncope in patients without structural heart disease.

Family history of Brugada syndrome, sudden cardiac death and/or recurrent syncope of unknown origin.

Suspicious non-diagnostic ECG in asymptomatic patients without structural heart dis- ease.

Environment:

Patient in fasting, resting, and drug-free state.

Safe venous access, continuous 12-lead ECG recording, blood pressure monitoring.

Presence of physician with experience in intensive care medicine.

Advanced cardiopulmonary life-support facilities available including external defibril- lator, intubation set and drugs (atropine, isoproterenol).

Drugs and dosages:

Ajmaline: 1 mg/kg over 10 min i.v.

Flecainide: 2 mg/kg (150 mg max.) over 10 min i.v.

Procainamide: 10 mg/kg over 10 min i.v.

Pilsicainide: 1 mg/kg over 10 min i.v.

Performance:

Fractionated slow intravenous drug administration up to target dose over 10 min.

Continuous ECG documentation at paper speed of 10 mm/s (one strip at 25 or 50 mm/s every 2 min).

Patient and ECG supervision and monitoring until normalisation of the ECG.

Termination criteria:

Reached target dose.

QRS prolongation ≥ 130% of baseline.

Occurrence of type-1 ECG (J-point elevation or ST-segment elevation ≥2 mm in at least one right precordial lead.

Occurrence of premature ventricular beats, ventricular tachycardia, sinus arrest or AV-

block (2nd or 3rd degree).

Because ECG changes may be transient, concealed, or absent at the time of first evaluation of a patient with Brugada syndrome, pharmacologic chal- lenge represents an important tool in the identification of affected patients who are at potential risk of sudden death. Given that symptomatic patients at first evaluation may have a negative ECG at baseline, a false negative response to drug challenge may lead to underdiagnosis of Brugada syn- drome. Therefore, the highest possible sensitivity and reproducibility of sodium channel blocker administration for pharmacologic challenge are warranted.

Hong et al. [15] recently reported the value of drug challenge with ajma- line in 71 individuals representing four families with Brugada syndrome and documented SCN5A mutations. The test was positive in 28 of 35 mutation carriers and the penetrance of disease phenotype increased from 33 to 79%.

The sensitivity, specificity, and positive and negative predictive values were 80, 94, 93, and 83% respectively. Smits et al. [16] reported similar findings.

Drug challenge with sodium channel blockers did not differentiate between patients with and without SCN5A mutation with regard to the magnitude of the ST-segment elevation but showed a larger increase in QRS duration and PQ intervals in SCN5A mutation carriers. Therefore, drug challenge may be helpful in identifying mutation carriers by unmasking latent conduction defects, as evidenced by prolonged HV intervals, PQ intervals, and QRS dura- tions at baseline or after sodium channel blockade.

Our group previously reported the results of drug challenge with ajma- line in 158 patients [17]. Overall, a positive test was found in 23% of the patients, in 50% of patients with a suspicious pattern of the basal ECG, and in 45% of patients with aborted sudden death and structurally normal hearts. Nine out of 63 patients with syncope had a positive test, the majority having a family history of unexplained sudden death and a suspicious ECG at baseline. These data suggest that the test is highly effective in correctly diagnosing the syndrome in patients with the strong suspicion of having a primary electrical disease. Because of the prognostic implications, patients with survived cardiac arrest and unexplained syncope in the absence of structural heart disease should therefore undergo drug challenge for the potential unmasking of Brugada syndrome.

However, the possibility of a positive drug challenge in individuals not

having the Brugada syndrome raises concern because of the potential thera-

peutic implications, i.e. in patients after unexplained syncope. In our previ-

ous study [17], only two of 94 patients with syncope and a normal ECG at

baseline had a positive ajmaline test. Whether these are false-positive tests or

very subtle manifestations of the disease will be clarified only when genetic

diagnosis becomes available. Currently, the diagnostic meaning and thera-

peutic impact of a positive test in such patients remains unclear.

Prognostic Impact

Brugada et al. [13] reported that patients with an initial presentation of resuscitated cardiac arrest carry the highest risk of life-threatening recur- rences (69% at 54 ± 54 months of follow-up), followed by patients with syn- cope and spontaneous type-1 ECG (19% at 26 ± 36 months of follow-up).

Similar results were found by others [14, 18], however with lower event rates.

While Brugada et al. [13] reported an 8% cardiac event rate in initially asymptomatic patients, Priori et al. [14] reported event rates of approximate- ly 4%, and Eckardt et al. [18] observed a cardiac event in only one of 123 (0.8%) patients that were asymptomatic at baseline.

According to Brugada et al. [13], among asymptomatic individuals with Brugada-type ECG features, male patients with inducible VT or VF and spon- taneous type-1 ECG appear to carry the highest risk. In contrast, patients in whom ST-segment elevation occurred only after provocation with sodium channel blockers appeared to be at minimal or no risk. Studies by others [14, 19] and by our own group [18] did not find a relationship between the inducibility of VT or VF during programmed electrical stimulation and the recurrence of VT or VF among either symptomatic or asymptomatic patients with Brugada syndrome. This controversy may be due to differences in patient selection, diagnostic criteria, and non-comparable or non-standardised stimu- lation protocols [18, 20].

In a study involving 547 patients with Brugada syndrome but no history of cardiac arrest [21], the risk of arrhythmic events in patients with a spon- taneously abnormal type-1 ECG was 7.7-fold higher risk than in patients in whom diagnostic type-1 ECG developed only after drug challenge. Male gen- der and inducible sustained VT or VF were associated with a 5.5- and 8-fold higher risk of sudden death, respectively. A positive family history was not related to an adverse outcome when compared with sporadic cases of Brugada syndrome. This correlates well with the findings of Smits et al. [16], who did not observe differences in gender, age, family history, index event, and inducibility of VT or VF in patients with or without the presence of SCN5A mutations in Brugada syndrome.

In summary, drug challenge has a limited additional prognostic impact

within the risk stratification of patients with Brugada syndrome. According

to the current Consensus Report [3], symptomatic patients with type-1 ECG

at baseline or after drug challenge who present with aborted sudden death

should receive an ICD without additional need for electrophysiologic study

(class I recommendation). A similar approach applies for patients with syn-

cope, seizure, or nocturnal agonal respiration after exclusion of noncardiac

causes of these symptoms (class IIa). In asymptomatic patients, an electro-

physiologic study is recommended in patients with a spontaneous type-1

ECG (class IIa) or in patients with drug-induced type-1 ECG and a positive family history (class IIb). If VT or VF is inducible, the patient should receive an ICD. Asymptomatic patients without a family history and who develop type-1 ECG only after drug challenge should be closely followed [3]. This concept, however, remains controversial due to limited data available from controlled clinical trials or registries. It requires continuous update as more data become available in the future.

Drugs and Dosages

Drug challenge in suspected Brugada syndrome may be performed by intra- venous administration of class IC sodium channel blockers, such as ajmaline (IA/IC), flecainide, propafenone, or pilsicainide. The class IA sodium channel blockers procainamide and disopyramide have been used less frequently because of their lesser potency to unmask the ECG characteristics of Brugada syndrome. The recommended dosages and infusion rates are listed in Table 2.

Intravenous ajmaline (1 mg/kg) has been reported as the most effective and most sensitive drug to unmask Brugada-type ECG features (Fig. 1). Early studies reported 100% sensitivity in selected patients [5]. In larger cohorts, the sensitivity remained high, reaching up to 90%. Further advantages of the drug include its short half-life, which allows short monitoring times after intravenous administration for drug challenge. Unfortunately, the low price and limited number of indications have led to withdrawal from the market in the majority of countries. Therefore, sodium channel blockers other than ajmaline are frequently used for drug challenge in Brugada syndrome.

However, flecainide and procainamide are both less effective and less sensi- tive in unmasking Brugada syndrome and require longer monitoring due to prolonged effect. The reproducibility of test results with ajmaline and fle- cainide has been reported to be high [17, 22].

In a direct comparison of ajmaline and flecainide in 22 patients, the posi- tive concordance of test results was 68%. Intravenous flecainide (2 mg/kg) proved less effective and failed to unmask ECG signs of Brugada syndrome produced with ajmaline (1 mg/kg) in seven of 22 patients (32%), despite equivalent changes in QRS and PQ intervals, suggesting similar effects on sodium channel current. Experimental studies in a canine model suggested that the lesser effectiveness of flecainide largely results from its more potent inhibition of I

which counters the sodium-blocking effects of the drug [11].

Although the class IA drug procainamide produces does not block I

at clin-

ically relevant drug concentrations, it has proved to be less potent than class

IC drugs (ajmaline, flecainide) in unmasking Brugada syndrome, probably

because of a lower level of use-dependent sodium channel block [23].

An experimental model recently demonstrated that the combined block of sodium (I

) and calcium (I

) currents by class IC sodium channel block- ers and verapamil may be even more effective in unmasking Brugada syn- drome than sodium channel blockade alone [24]. The addition of verapamil resulted in an enhancement of the effect of sodium channel blockers to cre- ate the Brugada phenotype. Although this concept might improve the diag- nostic sensitivity of the test, caution is warranted when extrapolating these findings to clinical practice before appropriate studies provide confirmation in humans with Brugada syndrome.

Adverse Events

The most relevant adverse effects of drug challenge in Brugada syndrome relate to proarrhythmia. Nonsustained or sustained polymorphic VT or VF may occur during the test. The arrhythmias may be symptomatic and even life-threatening because they may range from frequent extrasystoles and ventricular runs to polymorphic VT and cardiac arrest due to VF [17, 22].

These arrhythmias may be difficult to terminate after administration of sodium channel blocking drugs. In addition, these drugs may provoke inces- sant VT or VF (possibly by conduction slowing), which may be difficult or impossible to terminate [25]. Therefore, when performing drug challenge in Brugada syndrome, appropriate safety precautions must be ensured, and cri- teria for termination of drug administration should be defined. Avoiding drug overdose and respecting stopping criteria can effectively prevent proar- rhythmic events during drug challenge in Brugada syndrome [17].

Standardised Protocol

To provide reproducible results and to avoid procedure-related complica- tions and adverse events, pharmacological drug challenge in Brugada syn- drome should follow a standardised protocol. Such a protocol has recently been proposed by our group (Table 2) [17].

Drug challenge should be performed with the patient in a fasting, resting, and drug-free state under continuous ECG monitoring (speed of 10 mm/s, interposed with recordings at 25 or 50 mm/s at each dose step). The test should only be performed in a setting fully equipped for resuscitation (defib- rillation, emergency medication, intubation, mechanical ventilation) in the presence of a physician with experience in intensive care medicine [3, 17].

Intravenous sodium channel blockers should be administered slowly and

with great caution according to recommended dosage and infusion rate

(Table 2). In young and otherwise healthy individuals, the test may be per- formed as a bedside procedure. Particular caution should be exercised in patients with pre-existing conduction disturbance (atrial, ventricular, or both) or in the presence of wide QRS, wide P waves, or prolonged PR inter- vals in order to avoid complete AV block. In such patients, drug challenge with sodium channel blocker may better be performed during an electro- physiological study with temporary pacing electrodes in place to prevent complications related to conduction block [3].

Drug challenge should be stopped when the diagnostic type-1 ECG devel- ops, the type-2 ST-segment elevation increases by ≥ 2 mm, premature ven- tricular beats or other arrhythmias occur, or when the QRS complex widens to ≥ 130% of baseline. Following these safety rules, proarrhythmic or other relevant complications are very unlikely and have rarely been observed.

However, in case arrhythmic complications do occur, isoproterenol and sodi- um lactate may be effective antidotes to reverse the effect of sodium channel blockers [3, 17].

Conclusions

In patients with structurally normal hearts and unexplained syncope or car- diac arrest, Brugada syndrome is considered a frequent underlying condition.

In patients with suspected Brugada syndrome but inconclusive or normal ECG findings at baseline, drug challenge with intravenous administration of sodium channel blockers according to a standardised protocol is a powerful tool to unmask diagnostic type-1 Brugada ECG features and thereby identify patients at risk of sudden death. The additional impact of drug challenge in the risk stratification algorithms of patients already diagnosed with Brugada syndrome is less well-established and requires additional studies.

Acknowledgements

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (SFB 556, projects A1 and C4), Bonn, Germany, and by the Leducq Foundation, Paris France.

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