Successful treatment of arrhythmia with β‐blocker and flecainide combination in pregnant patients with Andersen–Tawil syndrome: A case report and literature review

Abstract Andersen–Tawil syndrome (ATS) is a rare disorder characterized by a triad of ventricular arrhythmia (VA), dysmorphic features, and periodic paralysis. Due to the rarity of this condition, less is known about physiologic effect of pregnancy to ATS and arrhythmia. There is no established guideline for peripartum or postpartum treatment and prevention of arrhythmia in ATS; thus, the clinical management is challenging. We reported two KCNJ2‐associated ATS patients who got pregnant and underwent vaginal birth safely. Both individuals had VA, micrognathia without periodic paralysis. β‐blocker plus flecainide could be an effective treatment combination when monotherapy failed to control arrhythmia. VA of two pregnant patients with ATS could be controlled by either physiologic changes associated pregnancy or the combination treatment of β‐blocker and flecainide.


| INTRODUC TI ON
Andersen-Tawil syndrome (ATS) is a rare autosomal dominant channelopathy characterized by clinical triad of ventricular arrhythmia (VA), periodic paralysis, and distinctive dysmorphic features.
Due to the rarity of this condition, less is known about physiologic effect of pregnancy to ATS and arrhythmia. There is no established guideline for prenatal or postpartum treatment and prevention of arrhythmia in ATS; thus, the clinical management is challenging (Roston et al., 2020;Subbiah et al., 2008). Here, we reported two pregnant ATS patients whose VA could be controlled by antiarrhythmic drug combination.

| Case #1
A 32-year-old Thai woman (Figure 1, ATS-003) came for a medical advice on pregnancy planning in 2014. She had a history of abnormal heart rhythm found at general checkup since childhood.
She was asymptomatic and grew up normally. The patient had one sister (ATS-002) and three brothers. Her mother (ATS-001) and sister experienced a similar history of abnormal heart rhythm. Both of them were also asymptomatic. All of her brothers were not affected. There was no history of sudden unexpected death in the family. She had another postmarital health checkup, and polymorphic premature ventricular contractions (PVC) with a short run of nonsustained polymorphic ventricular tachycardia (PMVT) were uncovered by electrocardiography (ECG) (Figure 2a) Figure 1). Treatment plan had been discussed between healthcare team and the patient. Oral metoprolol was given. The medication dose was gradually increased to 100 mg daily with no significant change of arrhythmias by periodic ECG monitoring. The patient decided to discontinue metoprolol after she became pregnant.
Her pregnancy was uneventful, and cardiac evaluation was done regularly. The ventricular ectopy became less frequent ( Figure 2b).
suppress the arrhythmia. The patient continued to do well until now at 5 months postpartum with occasional ectopic rhythm without ventricular tachycardia (VT).

| Case #2
A 33-year-old woman (ATS-002), sister of case #1 (ATS-003), was also invited to our hospital for ATS evaluation. She was asymptomatic. Frequent bidirectional VT was noted on ECG (Figure 3a). TTE revealed systolic function at lower limits of normal with LVEF at 52%.
Metoprolol was administered and gradually increased to 100 mg daily but her VA was not significantly reduced. One hundred mg of flecainide per day was then added, and cardiac monitoring showed ventricular ectopy becoming less frequent without VT (Figure 3b).

Four months after treatment combination, 24-hr Holter monitoring
showed sinus rhythm with prominent U wave and occasional ventricular ectopy, and good biventricular systolic function with trivial mitral valve regurgitation was observed by TTE.
Similar to her sister, the patient decided to undergo her pregnancy without medication after extensive discussion with healthcare team. Her pregnancy was uneventful, and she delivered her child successfully. VT was noticed during postpartum monitoring; therefore, flecainide and metoprolol combination was resumed. Cardiac arrhythmia remained suppressed at 3-month follow-up visit (Figure 3c).  (Fox et al., 2008). Current management strategy of ATS is mainly focused on suppression of ventricular ectopy and prevents tachycardia-induced cardiomyopathy (Pellizzón et al. 2008).

| D ISCUSS I ON
These two KCNJ2 [c.557C > G (p.Pro186Arg)]-associated ATS patients who got pregnant and underwent vaginal birth safely without any medications were first reported. Both individuals had VA, micrognathia without periodic paralysis. β-blocker plus flecainide were shown to be effective when β-blocker alone could not suppress their arrhythmias.
Though the mechanism remains unknown, physiologic changes associated with pregnancy could have significant impact on cardiac conduction in patients with ATS. QTc interval is hormonally regulated, and increased estradiol is associated with shorter QTc interval via enhanced membrane trafficking of KCNH2 (Anneken et al., 2016).
In concordance with previously reported cases, the combination of flecainide and β-blocker was useful in patients with ATS when β-blocker monotherapy failed to control cardiac arrhythmias.

| CON CLUS IONS
We reported 2 ATS patients who underwent an uneventful pregnancy and childbirth and had effective control of ventricular arrhythmias with combination treatment of β-blocker and flecainide.

ACK N OWLED G M ENTS
We wish to thank our patients for their cooperation and contribution to our study. We thank all physicians and health professionals for the patient's clinical care.

CO N FLI C T O F I NTE R E S T
The authors have declared that no conflict of interests exist.

E TH I C S A PPROVA L
The study protocol was approved by the Siriraj Institutional Review Board (Protocol number 197/2561).

CO N S E NT FO R PU B LI C ATI O N
Verbal and written consent for publication was obtained from the patient.