Subcutaneous and transvenous implantable cardioverter defibrillator in high-risk long-QT syndrome type 3 associated with Val411Met mutation in SCN5A

Abstract

Congenital long-QT syndrome type 3 (LQT3) with SCN5A-V411M mutation has been reported as a malignant case of LQT3 with highest risk for sudden cardiac death (SCD). Here, we present two cases of LQT3 with SCN5A-V411M who had been implanted with subcutaneous (S-) or transvenous (TV-) implantable cardioverter defibrillators (ICD).

Case 1, a 2-year-old boy, although he had no symptoms, was diagnosed as having LQT3 (V411M-SCN5A) due to family history. The QTc interval was still longer than 500 ms during follow-up even under oral mexiletine. Case 2 (his aunt) diagnosed as LQT3 suffered from syncope caused by ventricular fibrillation at 35-years-old despite taking mexiletine. Furthermore, case 1’s father and half-brother, both had the V411M mutation with LQT3, had suddenly died. Thus, case 1 was recommended S-ICD when he was 15-years-old for primary prevention of SCD but not necessary for pacing therapy, while, case 2 had been implanted TV-ICD for secondary prevention of SCD. They had no event after ICD implantation, however, case 2 had to have added an extra ICD-lead due to lead failure when she was 44-years-old.

The S-ICD may be a potent therapeutic option for high-risk LQTS when patients are younger and do not need pacing therapy.

<Learning objective: In congenital long-QT syndrome (LQTS) type 3, some of the first events are lethal, particularly, LQT3 with V411M-SCN5A mutation is the highest risk for sudden cardiac death (SCD). Which implantable cardioverter defibrillator (ICD), transvenous (TV-ICD) or subcutaneous (S-ICD) is better for primary prevention of SCD in LQTS is still controversial. The S-ICD rather than TV-ICD may have a potent benefit for high-risk LQTS when patients are younger and do not need pacing therapy.>

Introduction

Congenital long-QT syndrome (LQTS) is characterized by mutations or variants in several ion channel genes such as KCNQ1 (long-QT syndrome type1: LQT1), KCNH2 (LQT2), and SCN5A (LQT3). Compared to the LQT1 and LQT2, risk stratification and efficacy of β-blocker therapy for LQT3 patients are still controversial [1]. Moreover, in LQT3, some of the first events are lethal. In particular, LQT3 patients with V411M-SCN5A mutation have been reported as malignant with a highest risk for sudden cardiac death (SCD) [2], [3].

Recently, implantable cardiac defibrillators (ICD) have been used prophylactically for high-risk SCD patients with heart failure who had lower left ventricular ejection fraction <35% and non-sustained ventricular tachycardia. Furthermore, most of the ICD used for primary prevention of SCD are the subcutaneous ICD (S-ICD). However, there has never been a report on the prophylactic use of S-ICD in a high-risk juvenile LQT3 patient.

To the best of our knowledge, this is the first report indicating S-ICD for primary prevention of SCD in a pediatric high-risk LQT3 patient, and we compared efficacy and safety between S-ICD and transvenous (TV-ICD) among the same LQT3 families with V411M mutation.

Case report

Case 1

A 2-year-old boy, whose electrocardiogram showed a QT interval prolongation (QTc = 462 ms by Bazett’s formula) (Fig. 1A), was genetically diagnosed as LQT3 by identification of a missense mutation (V411M) in SCN5A gene (Fig. 2A). The echocardiographic findings revealed a normal left ventricular function without any chamber enlargement or wall motion abnormalities. He had no symptoms, however, both his father (proband: II-3, Fig. 2B) and half-brother (III-2, Fig. 2B) were diagnosed as having the same LQT3 and had suddenly died when they were 32 and 8 years old, respectively. His sister (III-4) and aunt (case 2, II-1, Fig. 2B) had also been diagnosed as having LQT3 (Fig. 1C, D). Although he had carefully been followed up under oral mexiletine (300 mg/day), the QTc interval had still been prolonged more than 500 ms (Fig. 1B). Therefore, after induction of ventricular fibrillation by programmed electrophysiological stimuli (Fig. 3A), S-ICD (but not TV-ICD) was implanted when he was 15-years-old because he was still younger and cardiac pacing was not necessary (Fig. 3B).

Fig. 1.

Standard 12-lead electrogram of patients. (A) Case 1 at 2-years-old, the first visit: Heart rate: 125 bpm QTc:462 ms by Bazett’s formula. (B) Case 1 at 15-years-old, on admission with mexiletine 250 mg: Heart rate: 60 bpm QTc: 548 ms. (C) Case 2 at 35-years-old, with mexiletine 300 mg. Heart rate: 91 bpm QTc: 471 ms. (D) Case 1`s sister at 18-years-old, with mexiletine 300 mg: Heart rate: 68 bpm QTc: 458 ms.

Fig. 2.

(A) Sanger sequence analysis of exon 10 of SCN5A identifying a mutation, c.1231G > A p.V411M (upper panel) located in the segment (S) 6 (pore area) of domain I of cardiac Nav1.5 channel (lower panel). (B) Family pedigree of LQT3 with V411M-SCN5A mutation.

LQT, long QT syndrome; PVT, pulseless ventricular tachycardia; SCD, sudden cardiac death; +: V411M-SCN5A mutation carrier; -: no SCN5A mutation.

Fig. 3.

(A) Ventricular fibrillation induced by programmed electrophysiological stimuli in case 1. (B) Chest X-ray in case 1 after implantation of S-ICD. (C) ICD-lead noise induced by myopotentials in case 2. (D) Chest X-ray in case 2 after implantation of an extra ICD-ventricular lead.

ICD, implantable cardioverter defibrillator; S-ICD, subcutaneous implantable cardioverter defibrillator.

Case 2

A 30-year-old woman (II-1, Case 1’s aunt) was genetically diagnosed with the same LQT3 because her brother (proband: II-3) had suddenly died. She had taken mexiletine because her QTc was 471 ms (Fig. 1C). However, she had suffered from syncope caused by ventricular fibrillation at 35-years-old. Therefore, TV-ICD was implanted for secondary prevention of SCD. S-ICD was not yet clinically applicable at that time.

The pacing via ICD for bradycardia was very little (<1%), only for back-up pacing (heart rate <60 bpm). Furthermore, there was no appropriate ICD shocks except for non-sustained ventricular tachycardia. However, a total eight years after implantation of TV-ICD, a ventricular lead impedance suddenly increased to abnormally high, and lead noise was induced by myopotentials (Fig. 3C), indicating the ICD-lead failure. She had to have added an extra ventricular lead for appropriate ICD therapies (Fig. 3D).

Discussion

In this case report, case 1 was indicated for S-ICD for primary prevention of SCD when he was 15-years-old, because he had a high-risk genetic background (V411M-SCN5A) with family history of SCD within the first and second degrees and the QTc interval was still prolonged ≥500 ms even after oral mexiletine (5 mg/kg/day). On the other hand, his sister (III-4, Fig. 2B) is also asymptomatic with LQT3 but not yet recommended for ICD since her QTc interval (Fig. 1D) was shorter than that of case 1 under the same mexiletine dose. However, even though a normalized QTc by mexiletine, we cannot completely exclude risk of SCD for her because LQT3 patients with pathogenetic variants in the S5-pore-S6, pore region of Nav1.5 channel (Fig. 2A, including V411M) had a much higher risk of arrhythmic events than others [4].

Prophylactic use of ICD for asymptomatic LQT patients who had a family history of SCD is controversial. Furthermore, it is still unclear whether the TV- or S-ICD is more suitable for pediatric patients with LQT [5]. According to the Japanese Circulation Society (JCS) guidelines, those with a family history of SCD and insufficient β blocker efficacy, are recommended for ICD as class IIa [6]. However, American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) guideline [7] showed these as class I, while, still class IIb in European Society of Cardiology (ESC) guideline [8]. Moreover, all these guidelines recommend S-ICD as class IIa indication when patients (not particularly for LQT) do not need pacing therapy for bradycardia, cardiac resynchronization, and anti-tachycardia therapies. There is no systematic review for indication of S-ICD in LQT patients who were asymptomatic but had a severe genetic background.

β-blocker therapy is clinically indicated as class I in all symptomatic and even asymptomatic patients with QTc interval more than 470 ms [6]. In LQT3, however, β-blockers are less effective than in other LQTS, and β-blocker therapy may reduce the risk in females; efficacy in male LQT3 (like case 1) could not be determined conclusively [1]. On the other hand, mexiletine significantly abbreviated QTc interval and reduced mortality [9]. In our case 1, β-blocker therapy might be effective, but further bradycardia caused by the β-blocker may need pacing therapy by pacemaker or TV-ICD. Combined therapy, pacing and mexiletine may reduce Torsades de Pointes (TdP) in patients with LQT3, however, it is still unclear how these interventions could prevent SCD.

In TV-ICD cases for LQT (like case 2), cardiac pacing is a significant advantage for abbreviation of QT interval, leading to suppress TdP in LQT2 or LQT3, however, ICD-lead failure and troubles increase depending on the time after implantation, almost 20% per 10 years after the implantation [10]. In our case 2, the ICD-lead failure occurred eight years after TV-ICD implantation. To avoid the time-dependent increased lead troubles, S-ICD is much better for younger patients. Although more data about efficacy and safety of S-ICD may have to be required, S-ICD may be a potent therapeutic option for primary prevention of SCD in juvenile patients with high-risk LQTS.

Conflict of interest

The authors declare that there is no conflict of interest.