# Unmasked Brugada Pattern by Ajmaline Challenge in Patients with Myotonic Dystrophy Type 1

Thomas Pambrun, Agustin Bortone, Patrick Bois, Bruno Degand, Sylvie Patri, Aurélie Mercier, Mohamed Chahine, Aurélien Chatelier, Damien Coisne, Alain Amiel

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Thomas Pambrun, Agustin Bortone, Patrick Bois, Bruno Degand, Sylvie Patri, et al. Unmasked Brugada Pattern by Ajmaline Challenge in Patients with Myotonic Dystrophy Type 1. Annals of Noninvasive Electrocardiology, 2015, 20 (1), pp.28-36. 10.1111/anec.12168. hal-05024497

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# Unmasked Brugada Pattern by Ajmaline Challenge in Patients with Myotonic Dystrophy Type 1

Thomas Pambrun, M.D.,*† Agustín Bortone, M.D.,† Patrick Bois, Ph.D.,‡ Bruno Degand, M.D.,* Sylvie Patri, Ph.D.,‡ Aurélie Mercier, Ph.D.,‡ Mohamed Chahine, Ph.D.,§ Aurélien Chatelier, Ph.D.,‡ Damien Coisne, M.D., Ph.D.,* and Alain Amiel, M.D.*

From the *Cardiology Department, University Hospital of Poitiers, Poitiers, France; †Cardiology Department, Les Franciscaines Private Hospital, Nîmes, France; ‡Institute of Cellular Physiology and Biology, ERL CNRS 7368, University of Poitiers, Poitiers, France; and §Research Center of the IUSMQ, Québec, Canada

**Background:** Myotonic dystrophy type 1 (DM1) generates missplicing of the *SCN5A* gene, encoding the cardiac sodium channel (Na<sub>v</sub>1.5). Brugada syndrome, which partly results from Na<sub>v</sub>1.5 dysfunction and causes increased VF occurrence, can be unmasked by ajmaline. We aimed to investigate the response to ajmaline challenge in DM1 patients and its potential impact on their sudden cardiac death risk stratification.

**Methods:** Among 36 adult DM1 patients referred to our institution, electrophysiological study and ajmaline challenge were performed in 12 patients fulfilling the following criteria: (1) PR interval >200 ms or QRS duration >100 ms; (2) absence of complete left bundle branch block; (3) absence of permanent ventricular pacing; (4) absence of implantable cardioverter-defibrillator (ICD); (5) preserved left-ventricular ejection fraction >50%; and (6) absence of severe muscular impairment. Of note, DM1 patients with ajmaline-induced Brugada pattern (BrP) were screened for *SCN5A*.

**Results:** In all the 12 patients studied, the HV interval was <70 ms. A BrP was unmasked in three patients but none carried an *SCN5A* mutation. Ajmaline-induced sustained ventricular tachycardia occurred in one patient with BrP, who finally received an ICD. The other patients did not present any cardiac event during the entire follow-up (15 ± 4 months).

**Conclusion:** Our study is the first to describe a high prevalence of ajmaline-induced BrP in DM1 patients. The indications, the safety, and the implications of ajmaline challenge in this particular setting need to be determined by larger prospective studies.

**Ann Noninvasive Electrocardiol 2015;20(1):28-36**

myotonic dystrophy type 1; Brugada syndrome; ajmaline challenge; sodium channels; cardiac arrhythmia

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder due to an abnormal accumulation of a (CTG)n triplet repeat in the untranslated 3' region of the gene encoding dystrophia myotonica protein kinase (DMPK).¹ DM1 can be associated with various clinical manifestations including myotonia, muscle weakness, respiratory insufficiency, and cardiac rhythm

disturbances, such as complete atrioventricular block, sustained ventricular tachycardia (VT), or ventricular fibrillation (VF).² Cardiac rhythm disturbances are of major concern, as they can lead to sudden cardiac death (SCD) in up to one-third of DM1 patients.³ Accordingly, considerable efforts have been made in order to identify patients at high risk of SCD. Hence, electrocardiographic and
electrophysiological criteria have been described, mainly based on the analysis of the progressive cardiac conduction defects that can affect the DM1 population.³,⁴ When such criteria are met, permanent prophylactic pacing is currently recommended.⁵ However, since DM1 patients can also develop VT or VF, additional parameters specifically focused on ventricular arrhythmias are needed to assess SCD risk in this population.

DMPK CTG-expansion leads to the nuclear accumulation of mutant messenger ribonucleic acids (mRNAs) generating aberrant alternative splicing of numerous pre-mRNAs.⁶ Of interest, a missplicing of *SCN5A*, the most frequently implicated gene in Brugada syndrome (BrS),⁷ has recently been demonstrated in DM1.⁸ Moreover, in comparison to the generally healthy European population, a 50-fold higher prevalence of Brugada pattern (BrP) has been described in a retrospective ECG screening of 914 DM1 patients.⁸ This substantial prevalence of BrP could partly explain the occurrence of SCD in DM1, since BrS is associated to an increased risk of VF. However, as no ajmaline test or systematic use of V₁–V₂ leads at the third intercostal space have been performed in DM1 patients so far, BrP prevalence might still be underestimated in this population and its impact on the SCD occurrence unknown.

In this study, we sought to prospectively assess the specific response to ajmaline challenge in a series of DM1 patients and describe its impact on the SCD risk stratification of this specific population.

# METHODS

## Patient Population

This prospective study, which conforms to the guiding principles of the Declaration of Helsinki, was approved by our local institutional committee on human research. Written informed consent was obtained from all patients. All adult patients admitted from 2005 to 2013 in our institution with DM1 confirmed by genetic were screened. In accordance with the recent European Society of Cardiology guidelines, patients whose progressive conduction disturbances needed to be evaluated by an electrophysiological study were selected. Furthermore, as repolarization had to be reliably analyzable during ajmaline challenge, pacemaker

(PM) recipients with permanent ventricular pacing or patients presenting with complete left bundle branch block were also excluded. Finally, patients with an impaired left ventricular ejection fraction (LVEF) and overt clinical congestive heart failure were also excluded, as these conditions are contraindications to ajmaline administration. Of note, for ethical reasons, ajmaline challenge was neither performed in DM1 patients having already beneficiated from an implantable cardioverter-defibrillator (ICD) nor in patients with severe neuromuscular and respiratory impairment owing to their high vulnerability and poor prognosis.

Overall, DM1 patients were included when they fulfilled all the following criteria: (1) PR interval >200 ms or QRS duration >100 ms;⁴,⁵ (2) absence of complete left bundle branch block >120 ms; (3) absence of permanent ventricular pacing; (4) absence of ICD prior to the ajmaline test; (5) preserved LVEF >50%; and (6) absence of severe muscular impairment, defined as a score of five on a five-points rating scale.⁹ The patients were numbered from 1 to 12. Each family was represented by a letter from -a to -i, in order to highlight the kinship ties between patients.

## Clinical Evaluation

### Physical Examination

All patients underwent complete physical examination in order to disclose congestive heart failure. The severity of muscular weakness was scored by a standardized five-points muscular impairments rating scale (Table 1).⁹

### Electrocardiogram and Holter

PR interval and QRS duration were automatically calculated on the 12-lead surface electrocardiograms, recorded at 25 mm/s. Repolarization abnormalities were systematically screened in leads V₁ to V₃. Only the coved type pattern (type 1), defined by an initial ST elevation >2 mm followed by a negative T wave, in at least one lead from V₁ to V₃, was considered conclusive. The saddle-back pattern (type 2), precisely defined by the consensus report, was considered suspicious but not conclusive.⁷ Acute conduction disorders and ventricular arrhythmias were systematically disclosed by a 24-hour Holter monitoring.

### Echocardiography

Transthoracic echocardiograms were recorded before ajmaline test, using a ViVid nine system (GE Healthcare, Milwaukee, WI, USA). LVEF
<table><caption>**Table 1.** Baseline Clinical Characteristics of Individual Patients</caption><thead><tr><th>Patient-Family</th><th>1-a</th><th>2-b</th><th>3-c</th><th>4-c</th><th>5-d</th><th>6-e</th><th>7-f</th><th>8-g</th><th>9-h</th><th>10-h</th><th>11-i</th><th>12-d</th></tr></thead><tbody><tr><td>Age-sex</td><td>34-M</td><td>49-M</td><td>29-F</td><td>18-M</td><td>43-F</td><td>39-M</td><td>38-F</td><td>46-F</td><td>29-M</td><td>65-M</td><td>54-M</td><td>44-F</td></tr><tr><td>Muscular impairment<sup>a</sup></td><td>2</td><td>3</td><td>1</td><td>1</td><td>1</td><td>2</td><td>3</td><td>2</td><td>2</td><td>1</td><td>1</td><td>1</td></tr><tr><td>Heart failure<sup>b</sup></td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Syncope</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Aborted SCD</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>SCD-BrS family history</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Pacemaker</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>ICD</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr></tbody></table>

<sup>a</sup>A score of 1 indicates no clinical muscular impairment, 2 minimal signs without distal weakness except for digit flexor, 3 distal weakness without proximal weakness except for elbow extensors, 4 moderate proximal weakness, and 5 severe proximal weakness;

<sup>b</sup>New York Heart Association (NYHA) functional class II to IV. M = male; F = female; SCD = sudden cardiac death; ICD = implantable cardioverter-defibrillator.

was calculated by left ventricular (LV) biplane Simpson's method. The LV dimensions and mass were analyzed using two-dimensional echocardiogram-directed M-mode. The right ventricular (RV) function was estimated by the tricuspid annular plane systolic excursion (TAPSE) method, using two-dimensional echocardiogram-directed M-mode.

### Cardiac Computed Tomography

Coronary imaging by multislice-computed tomography was performed before ajmaline challenge was done in order to exclude ischemic cardiomyopathy and confirm the absence of manifest structural heart disease.

### Ajmaline Challenge

Ajmaline was intravenously administered at the dose of 1 mg/kg for 5 minutes, under constant digital ECG monitoring (LabSystem PRO, Bard EP, Lowell, Massachusetts), in the electrophysiological laboratory.⁷ V₁ and V₂ leads were simultaneously recorded from the standard fourth intercostal space (then named V₁-V₂) and from the third intercostal space (then named V₁H-V₂H), as this two-tiered approach for V₁-V₂ leads proves highly sensitive for the BrP detection.¹⁰,¹¹ After a baseline acquisition, ECG monitoring was performed every minute during ajmaline infusion, then during the 10 minutes following the end of infusion in case of negative test or until ECG completely normalized in case of positive test. Ajmaline challenge was considered positive if a BrP developed in at least one right precordial lead placed in a standard or superior position.⁷ The second consensus report recommends that the intravenous administration of ajmaline should be halted when BrP develops, ventricular arrhythmias occur or QRS widens up

to 130% of baseline or goes beyond this value. Therefore, we took into account the occurrence of sustained ventricular arrhythmias (sVA), which was defined by VT lasting >30 seconds or VF. Furthermore, negative tests were classified according to whether or not the QRS widening was ≥130% of baseline.

### Electrophysiological Study

Based on the recently proven benefit of an invasive strategy and the potential deleterious impact of ajmaline on the impulse propagation in this category of patients, described as having a natural history of progressive conduction defect, an electrophysiological study was systematically performed before ajmaline challenge.⁴,⁵ A quadripolar nondeflectable catheter was introduced through the femoral vein and placed under fluoroscopic guidance at the His bundle position. The HV interval was then measured at baseline. Subsequently, the catheter was advanced to the RV apex and used as a backup temporary pacing electrode during ajmaline challenge, according to the recommendations of the Second Consensus Conference for patients at high risk of drug-induced complete atrioventricular block.⁷

### Molecular Genetics

Genomic DNA was extracted from peripheral lymphocytes isolated from the patients. Analysis of the CTG repeat sequence in the 3' untranslated region of the DMPK was performed with the use of polymerase chain reaction (PCR). DM1 was diagnosed when the size of the CTG expansion measured with Southern blot technique was ≥50 triplets.¹ Patients with ajmaline-induced BrP
or excessive QRS widening were systematically
screened for the *SCN5A* gene, which encodes the
Na<sub>v</sub>1.5 voltage gated cardiac sodium channel. All
*SCN5A* coding exons were amplified by PCR using
primers designed with intronic flanking sequences.
PCR and direct sequencing were used to identify
any specific mutation in the index patient and the
family members.<sup>12</sup>

Follow-Up

Patients were clinically evaluated every 6
months. At each visit, symptoms assessment was
followed by complete physical examination and 12-
lead ECG acquisition. Finally, device interrogation
was performed in patients with implantable loop-
recorder, PM, or ICD.

Statistical Analysis

Data are presented as mean ± standard devia-
tion.

RESULTS

Population Characteristics

Among 36 adult DM1 patients followed in our
institution since 2005, 12 patients presenting the
predefined inclusion criteria underwent ajmaline
challenge and electrophysiological study from July
2012 to June 2013 (Fig. 1). All patients had a
genetically confirmed DM1. The mean age of
the cohort was 41 ± 13 years and 58% were
men. No patients experienced previous syncope
or aborted SCD. No family history of BrS or
SCD was reported. Of note, one patient included
in our series had a PM. However, the PM was
implanted for sinus node dysfunction, with a
very low percentage of ventricular pacing (<1%).
Patient clinical characteristics are summarized in
Table 1. The mean PR interval was 190 ± 25
ms and the mean QRS duration was 108 ± 11
ms. One patient (2-b) had a spontaneous saddle-
back pattern at baseline. No transient complete
atrioventricular block or VT was documented dur-
ing the 24-hour Holter monitoring. Transthoracic
echocardiography excluded ventricular dysfunc-
tion, as the mean LVEF was 63% ± 7% and the
mean TAPSE was 21 ± 4 mm. Two patients had a
moderate LV hypertrophy with an LV mass index
>100 g/m². No coronary artery disease was iden-

tified by cardiac computed tomography. Patient
electrocardiographic and echocardiographic char-
acteristics are listed in Table 2. It is worth noting
that a familial bind was found, two by two, in six
patients (patient 3-c is patient 4-c's sister, patient
5-d is patient 12-d's sister and patient 9-h is patient
10-h's son).

Electrophysiological Study, Ajmaline
Challenge, and Genetic Screening

All antiarrhythmic drugs were ceased at least
>5 half-life before electrophysiological study and
ajmaline challenge. The mean baseline HV interval
was 57 ± 9 ms. As the baseline HV interval
never exceeded 70 ms, no prophylactic PM were
implanted after the electrophysiological study.⁴,⁵
Ajmaline response was divided into three groups
(Fig 2., panels 1 and 2). A typical BrP occurred
in three (25%) patients, one of whom (3-c)
developed a marked QRS widening followed by
an sVA (Fig. 2, panel 3). Four other patients
presented an important QRS widening ≥130% of
baseline, with an equal repartition between right
bundle branch block and left bundle branch block
pattern. The other five (42%) patients had no ECG
modifications. Ajmaline challenge was stopped in
six (50%) patients before reaching the theoretical
dose, due to BrP occurrence in one patient and
a QRS widening ≥130% in five patients. The
mean QRS widening was 139% ± 28% with regard
to the baseline. *SCN5A* mutation screening was
negative for the three patients with unmasked BrP.
Interestingly, neither patients with BrP nor with
QRS widening ≥130% had any familial bind within
their respective group. EP study, ajmaline test, and
genetic screening parameters are shown in Table 3.

Drug-Induced Sustained Ventricular
Arrhythmia

One patient (3-c), a 29-year-old woman who
presented rare episodes of palpitations over the
past few years, developed sVA during the ajmaline
challenge (Fig. 2, panel 3). This polymorphic
VT was a source of hemodynamic instability.
However, before any external defibrillation could
be done, sinus rhythm resumed spontaneously,
unmasking a typical BrP. At that time, no data
on the prognostic value of sVA during ajmaline
challenge were available yet.¹³ Moreover, the
patient was strongly reluctant to receive an
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Flow of patients from the initial screening to the final selection for electrophysiological study and ajmaline test.</figcaption></figure>

<table><caption>**Table 2.** Individual Electrocardiographic and Echocardiographic Characteristics at Inclusion</caption><thead><tr><th>Patient-Family</th><th>1-a</th><th>2-b</th><th>3-c</th><th>4-c</th><th>5-d</th><th>6-e</th><th>7-f</th><th>8-g</th><th>9-h</th><th>10-h</th><th>11-i</th><th>12-d</th></tr></thead><tbody><tr><td>PR interval (ms)</td><td>152</td><td>217</td><td>182</td><td>195</td><td>201</td><td>183</td><td>194</td><td>156</td><td>191</td><td>246</td><td>172</td><td>190</td></tr><tr><td>QRS duration (ms)</td><td>102</td><td>102</td><td>112</td><td>110</td><td>95</td><td>135</td><td>100</td><td>101</td><td>116</td><td>97</td><td>118</td><td>111</td></tr><tr><td>Saddle-back pattern</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Coved pattern</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>VT<sup>a</sup></td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>SND</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>High-degree AVB</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>EF (%)</td><td>63</td><td>55</td><td>61</td><td>55</td><td>62</td><td>67</td><td>76</td><td>63</td><td>57</td><td>59</td><td>64</td><td>73</td></tr><tr><td>EDD (mm/m<sup>2</sup>)</td><td>28</td><td>27</td><td>25</td><td>25</td><td>27</td><td>27</td><td>27</td><td>29</td><td>28</td><td>34</td><td>27</td><td>26</td></tr><tr><td>LV mass index (g/m<sup>2</sup>)</td><td>59</td><td>70</td><td>68</td><td>51</td><td>58</td><td>70</td><td>52</td><td>49</td><td>74</td><td>138</td><td>133</td><td>55</td></tr><tr><td>TAPSE (mm)</td><td>25</td><td>27</td><td>26</td><td>26</td><td>16</td><td>28</td><td>19</td><td>23</td><td>19</td><td>21</td><td>22</td><td>25</td></tr></tbody></table>

<sup>a</sup>VT was defined by the succession of >4 premature ventricular complexes.

VT = ventricular tachycardia; SND = sinus node dysfunction; AVB = atrioventricular block; EF = ejection fraction; EDD = end-diastolic diameter; LV = left ventricular; TAPSE = tricuspid annular plane systolic excursion; LA = left atrial.

ICD. Therefore, we jointly agreed to implant a loop-recorder (Reveal, Medtronic, Minneapolis, MN, USA). Nonetheless, the patient was clearly informed that the detection of any spontaneous VT would lead to ICD implantation.

## Follow-Up

After a mean follow-up of 15 ± 4 months, none of the 11 patients without drug-induced sVA died suddenly or experienced any symptoms.
<figure><img src="image_3.png" /><figcaption>**Figure 2.** Standard and high V₁–V₂ ECG-leads recorded during ajmaline test respectively from the fourth (V₁–V₂) and the third (V₁H–V₂H) intercostal space. (Panel 1) Recording at baseline, before ajmaline injection. All patients were in sinus rhythm and none presented with a spontaneous BrP. (Panel 2) Recording during ajmaline administration. Red-framed patients developed a BrP. Blue-framed patients displayed QRS widening ≥130% of baseline. Green-framed patients had no substantial electrocardiographic modifications. (Panel 3) Detailed recording of patient 3-c. (A) At 5 minutes from the beginning of ajmaline injection, sudden QRS widening associated with premature ventricular complexes. QRS narrowing is not obtained despite isoproterenol infusion at low dose (0.05 mg/H). (B) At 10 minutes, appearance of a sustained polymorphic ventricular tachycardia at 180 bpm, poorly tolerated, with patient close to losing consciousness. (C) At 11 minutes, sinus rhythm resumes spontaneously (black arrows) before external defibrillation could be done, unmasking a marked BrP. The patient is conscious and hemodynamically stable. (D) At 15 minutes, a typical BrP is observed.</figcaption></figure>
<table><caption>Table 3. Results of Electrophysiological Study, Ajmaline Test, and SCN5A Screening</caption><thead><tr><th>Patient-Family</th><th>1-a</th><th>2-b</th><th>3-c</th><th>4-c</th><th>5-d</th><th>6-e</th><th>7-f</th><th>8-g</th><th>9-h</th><th>10-h</th><th>11-i</th><th>12-d</th></tr></thead><tbody><tr><td>HV interval (ms)</td><td>54</td><td>56</td><td>58</td><td>54</td><td>68</td><td>55</td><td>52</td><td>65</td><td>48</td><td>66</td><td>38</td><td>64</td></tr><tr><td>Ajmaline dose (%)<sup>a</sup></td><td>100</td><td>80</td><td>60</td><td>80</td><td>60</td><td>60</td><td>80</td><td>100</td><td>100</td><td>100</td><td>100</td><td>100</td></tr><tr><td>QRS widening (%)<sup>b</sup></td><td>124</td><td>115</td><td>169</td><td>179</td><td>189</td><td>147</td><td>153</td><td>126</td><td>107</td><td>125</td><td>126</td><td>106</td></tr><tr><td>Drug-induced BrP</td><td>Yes</td><td>Yes</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>Drug-induced sVA</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td></tr><tr><td>SCN5A mutation</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>-</td><td>-</td><td>-</td><td>-</td><td>-</td></tr></tbody></table>

In contrast, 1 month after the loop-recorder implantation, as the patient with drug-induced sVA was dancing late at night after alcohol intake, she experienced a brief episode of palpitations with a faintness sensation. The control of the loop-recorder documented a fast (220 bpm), disorganized, and sustained (40 seconds) VT, which spontaneously converted into sinus rhythm. The combination of unmasked BrP with spontaneous VT fulfilled the criteria for BrS. The patient was finally implanted with an ICD. The subsequent 9-months follow-up period has been uneventful.

## DISCUSSION

### High Prevalence of Unmasked BrP in DM1 Patients

To the best of our knowledge, this study is the first to describe BrP unmasking by ajmaline challenge in DM1. In this setting, the combination of ajmaline challenge with a two-tiered $V_1-V_2$ approach proved highly sensitive, as 3 (25%) out of 12 DM1 patients developed a BrP without any familial bind. This result strengthens the observation of Wahbi et al. who retrospectively identified, among the 914 patients of their *DM1 Heart Registry*, 7 patients (0.8%) with a spontaneous BrP, while the prevalence observed in an apparently healthy European population is 0.017%.⁸ Furthermore, the absence of *SCN5A* mutation in our DM1 patients presenting a BrP during ajmaline challenge (a powerful sodium channel blocker) supports the recent hypothesis that $Na_v$1.5 channel function alteration may play a role, as a result of *SCN5A* missplicing.⁸ Interestingly, one study previously analyzed the impact of ajmaline on DM1 patients, but no BrP could be identified as it was published prior to the first BrS description.¹⁴ An

additional explanation could be the presence of structural cardiac abnormalities in DM1, with focal fibrosis and fatty infiltration notably affecting the right ventricle.¹⁵,¹⁶ Histological remodeling is also described in the right ventricular outflow tract of BrS patients, leading to depolarization disturbances and conduction delays.¹⁷,¹⁸ Therefore, ajmaline-induced BrP in DM1 patients might be the outcome of subtle yet relevant tissue modifications mimicking those described in BrS.

Of note, ajmaline challenge has been performed so far in populations selected on the basis of criteria reinforcing the pretest sensitivity, such as symptoms (unexplained syncope, aborted cardiac arrest), suspicious ECG ("saddle-back" pattern, documented VT), or evocative family history (BrS, SCD). For this reason, the overall percentage of positive ajmaline challenge in these high-risk populations ranges from 17% to 39%.¹¹,¹⁹ Interestingly, our DM1 population could have been classified at low risk of developing a drug-induced BrP, since only patient 2-b ("saddle-back" pattern) met one of these high-risk criteria. However, we observed an unexpectedly high prevalence of unmasked BrP (25%) in DM1 patients. Hence, our study adds DM1 to arrhythmogenic right ventricular cardiomyopathy and Chagas disease, as a condition which can harbor the Brugada substrate.

### Ajmaline Challenge as a Potential Tool for SCD Risk Stratification in DM1

Evaluation of SCD risk in DM1 has been based on the analysis of the conduction system impairment so far. Thus, a recent study showed that a systematic electrophysiological study was necessary in DM1 patients with PR interval >200 ms or QRS duration >100 ms.⁴ Moreover,

<footnote>ªResults are given in % of the theoretical dose of ajmaline, based on the recommendations of the Second Consensus Conference on Brugada Syndrome (0.2 mg/kg per min for 5 minutes).</footnote>

<footnote>ᵇResults are given in % of the baseline QRS.</footnote>

<footnote>NA = not available.</footnote>
prophylactic PM in case of HV interval ≥70 ms proved to be effective for decreasing the incidence of SCD.⁵ However, in Groh's series, one-third of the SCD was related to fatal ventricular arrhythmias, of which one-third occurred in PM recipients.³ This finding points out the need for complementary tools to determine in which cases ICD should be preferred to PM.

Of interest, based on current criteria, our DM1 patients would have been considered at low risk of SCD, since their HV interval was <70 ms. However, three patients developed an ajmaline-induced BrP and were finally classified at higher risk of SCD. In practice, they have benefited from advices with prophylactic aim, such as lowering of body temperature in case of fever, limitation of alcohol intake, and avoidance of specific drugs listed on www.brugadadrugs.org. Moreover, one of them (3-c) developed a sustained and hemodynamically unstable VT. This patient is the first described case of ajmaline-induced sVA in DM1, since the VF reported by Otten et al. was initiated by a programmed electrical stimulation performed during a negative pharmacological provocation with procainamide.²⁰ Patient 3-c required further investigation with the implantation of a loop-recorder. After the detection of a spontaneous sustained VT, she was finally implanted with an ICD.

These findings highlight the potential interest of the ajmaline challenge as an additional tool for SCD risk stratification in the DM1 population.

## The Need for a Tailored Approach

Ajmaline is recognized to depress ventricular propagation by decreasing Purkinje fibers impulse velocity.²¹ Hence, up to one-third of the patients with ajmaline-induced high-degree atrioventricular block will develop a complete atrioventricular block before 3 years.²² Therefore, ajmaline challenge is still indicated to explore syncope in patients with bundle branch block and PM implantation is recommended when a second- or third-degree atrioventricular block is induced.⁵ Caution must be paid, however, as DM1 generates a markedly reduced distal conduction reserve,²³ which could be rapidly depleted by sodium channel blockade. To date, the only available data about ajmaline impact on the distal cardiac conduction in DM1 are provided by our study and Komajda's series,¹⁴ representing a total of 24 patients. Interestingly,

none of them developed complete atrioventricular block during ajmaline administration. In our case series, this result was in total accordance with the electrophysiological study and no PM was implanted. Nevertheless, in 5 (42%) out of our 12 patients, ajmaline infusion was stopped before reaching the theoretical dose, due to QRS widening ≥130%. Of note, this result is by far more frequent than the 1.2% observed in Veltmann's series.¹⁹ Moreover, among the 24 DM1 patients, 1 (4.2%) experienced sVA, whereas a recent large series comprising 1043 patients tested with ajmaline only found 9 (0.9%) cases of sVA.¹³ These findings show that side effects during ajmaline challenge may not be anecdotal in DM1, and should be taken into account.

The key points lie in the appropriate selection of the DM1 candidate for sodium channel blockade and the utmost caution while performing this challenge. Hence, exclusion of DM1 patients with marked conduction defects at baseline such as major bundle branch block (QRS duration >150 ms) or documented transient complete atrioventricular block might appear reasonable. Furthermore, the systematic introduction of a diagnostic catheter into the RV before ajmaline challenge could be useful in order to provide temporary pacing in case of induced complete atrioventricular block. Finally, avoidance of prolonged half-time class I antiarrhythmic drugs (flecainide, procainamide) and slower administration of ajmaline (10 rather than 5 minutes) should be considered in this particular setting, in order to respectively limit their side effects duration and manage as promptly as possible the occurrence of serious induced cardiac rhythm disturbances. Larger prospective studies are needed, however, to assess the safety and define the appropriate modality of ajmaline challenge in DM1.

## Study Limitations

First, our study is based on selected DM1 patients with slight conduction defects on the surface ECG. This section of DM1 population may not be fully representative of all possible forms of DM1 cardiac manifestations. Thus, although higher than previously assumed, the exact prevalence of unmasked BrP in the entire DM1 population is still difficult to assess. Second, regarding the small sample size and the absence of extended follow-up, our case series cannot draw firm conclusion on
the prognostic value of ajmaline challenge in terms of SCD risk in DM1. However, our findings could pave the way toward larger prospective studies.

## CONCLUSION

Our study is the first to describe a high prevalence of ajmaline-induced BrP in DM1 patients. It also emphasizes the potential interest of ajmaline challenge in their SCD risk stratification. Larger prospective studies are needed to assess the indications, the safety, and the clinical significance of ajmaline challenge in DM1 patients.

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