Wearable cardioverter defibrillators for patients with long QT syndrome

International Journal of Cardiology 268 (2018) 132–136

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Wearable cardioverter defibrillators for patients with long QT syndrome Heidi J. Owen a,b,1, J. Martijn Bos b,c,d,1, Michael J. Ackerman b,c,d,⁎ a

Department of Nursing, Mayo Clinic, Rochester, MN, USA Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA c Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA d Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, Rochester, MN, USA b

a r t i c l e

i n f o

Article history: Received 22 February 2018 Received in revised form 29 March 2018 Accepted 2 April 2018

Keywords: Long QT syndrome LQTS Sudden cardiac death Syncope Wearable cardioverter defibrillator

a b s t r a c t Background: Long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy, but with the appropriate treatment strategy, such as beta-blockers, left cardiac sympathetic denervation (LCSD), and/or an implantable cardioverter defibrillator (ICD), most LQTS-triggered tragedies can be avoided. Since 2001, wearable cardioverter defibrillators (WCD:LifeVest™) have been available clinically. Objective: Herein, we evaluated the use and outcome of WCDs in patients with LQTS. Methods: We performed a retrospective review of 1027 patients with LQTS to identify patients who received a WCD, and collected pertinent clinical information regarding their LQTS diagnosis as well as indication and experience regarding use of the WCD. Results: Overall, 10 LQTS patients (1%, 8 females, age at diagnosis 29 ± 18 years, mean QTc 488 ± 34 ms) were prescribed a WCD. Most common indication for WCD was as bridge to treatment during (temporary) situation of assessed high risk of sudden cardiac arrest (SCA; n = 6). The mean time of WCD use was 24 days (range 0 to 114 days). One patient (female, age 42, LQT2) received an appropriate VF-terminating shock 2 days after receiving her WCD. No inappropriate treatments or adverse events from wearing the WCD have occurred. Conclusions: A WCD can be considered in patients with LQTS deemed to be at high risk for SCA while up-titrating beta blockers, considering ICD therapy, or when navigating short term periods of increased SCA-risk, like the post-partum period in LQT2 women, ICD revision or temporary inactivation, or during short term administration of known QT prolonging medications. © 2018 Elsevier B.V. All rights reserved.

1. Introduction Congenital long QT syndrome (LQTS) is a highly treatable yet still potentially lethal cardiac channelopathy. LQTS affects approximately 1 in 2000 people [1] and is a heritable cardiac disease whereby patients are at an increased risk for LQTS-triggered syncope, seizures, and sudden cardiac arrest (SCA) following the characteristic ventricular arrhythmia of torsades de pointes [2]. Although 17 LQTS-susceptibility genes have been identified, approximately 75% of LQTS can be explained by mutations in three genes (KCNQ1, KCNH2, and SCN5A) that encode pore-forming subunits of ion channels (Kv7.1, Kv11.1, and NaV1.5 respectively [3]. While each of the major LQTS subtypes has its unique pro-arrhythmic triggers, outside factors may also contribute to the risk level of an individual having a LQTS-triggered cardiac event. Aside from our standard, LQTS-directed preventative/safety measures (avoidance of QT prolonging drugs, daily fish oils supplement, ⁎ Corresponding author at: Mayo Clinic's Long QT Syndrome Clinic, Guggenheim 501, Mayo Clinic, Rochester, MN 55905, USA. E-mail address: [email protected]. (M.J. Ackerman). 1 HJO and JMB are co-equal first authors.

https://doi.org/10.1016/j.ijcard.2018.04.002 0167-5273/© 2018 Elsevier B.V. All rights reserved.

advice for proper hydration and fever reduction, and purchasing an automated external defibrillator (AED)), therapeutic options for LQTS include pharmacotherapy (principally beta-blockers),surgical therapy (principally left cardiac sympathetic denervation (LCSD)), and device therapy (primarily an implantable cardioverter defibrillator (ICD)). Since 2001, wearable cardioverter defibrillators (WCD; LifeVest™) have been available clinically and, although used primarily in adults with a recent myocardial infarction, could provide an option for patients with LQTS [4]. Not meant to be a permanent solution, WCDs can provide temporary protection during the evaluation period during periods of heightened risk for SCA or serve as a bridge to an ICD. Herein, we evaluated the use and outcome of WCDs in patients with LQTS. 2. Methods For this IRB-approved, retrospective study, we reviewed the electronic medical records of 1027 adult and pediatric LQTS patients evaluated at Mayo Clinic's Long QT Syndrome/Genetic Heart Rhythm Clinic between 2000 and 2017 to identify use of WCD. For patients who were prescribed a WCD, pertinent clinical information regarding their LQTS diagnosis as well as indication and experience regarding use of the WCD was collected, including but not limited to LQTS genotype, QTc measurement, symptomatology, family history of LQTS and SCA, duration of WCD use, complications, appropriate or

H.J. Owen et al. / International Journal of Cardiology 268 (2018) 132–136 inappropriate shocks, and additional outcomes. Overall utility of the WCD in this patient cohort as well as detailed experiences and outcome of patients prescribed the wearable device were evaluated and described.

3. Results Overall, ten patients (10/1027; 1%) were prescribed a WCD between 2000 and 2017 (nine adults and one pediatric patient). Demographics of these patients are summarized in Table 1. In brief, there were ten patients (eight females (80%)), with a mean age at LQTS diagnosis of 29 ± 18 years (range 10–66 years) and mean age at WCD of 34 ± 16 years (range 15–66 years). Baseline QTc was 488 ± 34 (438–543 ms). The genotypes included four patients with LQT1, four with LQT2, one with compound LQT2, and one with LQT3. Six patients (60%) had a family history of LQTS and six patients (60%) had a positive family history for SCA. The mean duration of WCD use was 24 days (range 0 to 114). One patient (Case 3; discussed below) ultimately chose not to wear her device explaining the low end of the range. Seven of the 10 patients (70%) were previously symptomatic, and documented symptoms included syncope, TdP and out of hospital cardiac arrest with VF-terminating shock from an automatic external defibrillator (AED). Clinical and WCD-related details for each of these ten patients are summarized in Table 2. The most common indication for use of the WCD was as a bridge to treatment during initial diagnostic work up and protection from SCA while either achieving a therapeutic dose of beta blocker – generally nadolol at 1–1.5 mg/kg/day [5–7] – or facilitating surgical date for LCSD surgery in six of ten patients (60%; Cases 1, 2, 4, 5, 7 and 9). For two of these six patients (Cases 1 and 7), this was compounded by an additional diagnosis, unrelated to LQTS, that required prescription of medications known to prolong the QT interval (levofloxacin and compazine respectively). Additionally, these patients were considered to be at temporary high risk due to frequent electrolyte imbalance and potential for febrile episodes. For the three remaining patients (Cases 6, 8, 10), the WCD was prescribed during a time of ICD malfunction. Patient 6 presented to his local cardiology clinic with a fractured ICD lead. His ICD was implanted in 2006 and he had remained asymptomatic from his LQT2 substrate since. The patient's ICD was deactivated due to risk of inappropriate shock from the fractured lead and he was outfitted with a WCD. He requested that the ICD revision be done at Mayo Clinic and due to long distance travel and scheduling conflicts for the patient, the WCD was prescribed as a bridge until his ICD lead revision. For patient 8, the LQT3 SCA-prevention program had been ICD solo therapy for the past 15 years during which she had been symptom free. She did however have two inappropriate ICD shocks due to a fractured lead for which lead revision was required. The patient was transferred to Mayo Clinic from her local emergency room after being fit for a WCD. Case 10 presented to her local cardiology clinic with an ICD lead fracture. This asymptomatic LQT2 female received her prophylactic ICD in 2004 and Table 1 Demographics of patients with WCD. Cohort (N = 10) Sex (male/female) Mean age at diagnosis yrs. (range) Age at WCD yrs. (range) Baseline QTc ms (range) Symptomatic prior to diagnosis n (%) Family history of LQTS n (%) Family history of SCA n (%) Duration of WCD Use Genotype positive n (%) LQT1 LQT2 LQT2 compound LQT3

2/8 29 ± 18 (10–66) 34 ± 16 (15–66) 488 ± 34 (438–543) 7 (70) 6 (60) 6 (60) 0 days to 114 days 10 (100) 4 (40) 4 (40) 1 (10) 1 (10)

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has not received an ICD shock. She was prescribed a WCD after her ICD was deactivated because of the risk of inappropriate shocks from the fractured ICD lead. The patient requested ICD lead revision at the Mayo Clinic and wore the WCD while this was facilitated. Herein, the WCD provided SCA protection while the ICD was deactivated and a surgical date for ICD replacement was facilitated in these three patients. In one young female patient (Case 4), the WCD was used for SCA prevention after she experienced a swimming-associated cardiac arrest. The patient and her family did not want to proceed directly to an ICD. A WCD was prescribed and the patient was referred to Mayo Clinic. Ultimately, she was diagnosed with LQT1, which was confirmed by genetic testing. The patient had minimally invasive LCSD surgery and was started on nadolol. She has not had any LQT1-triggered symptoms following LCSD and initiation of beta blocker therapy. During the time of WCD use, one patient (10%) received an appropriate VF-terminating shock from her WCD (Case 5). This patient was a 42year-old female with compound LQT2 secondary to variants in KCNH2 (V603I and L799sp) who came to Mayo Clinic seeking a second opinion and review of her current LQT2-directed treatment program. Previously, she had experienced seven to eight seizures or seizure-like episodes since the age of 20. She presented at age 42 to her local health care provider with palpitations and was evaluated subsequently by a cardiologist, where she was told she had a prolonged QT interval on her ECG with a recorded QTc of 543 ms. However, at that time, her local cardiologist did not make a definitive diagnosis or start treatment. The next day, she had a syncopal, seizure-like event at home, followed by another syncopal episode at her clinic appointment three days later. A Holter monitor was placed and a cardiologist notified. Because of the sequelae of events, the referring cardiologist became suspicious of LQTS and referred her to Mayo Clinic. Following phone consultation with our team, the cardiologist dismissed her with a WCD, but against our advice, did not initiate beta blocker therapy. Two days later, during an emotional moment hugging a family member, she lost consciousness. The WCD captured the event and appropriately discharged a VF-terminating shock (Fig. 1). An ICD was placed two days later and beta blocker therapy was initiated. In the four years since this event, she has had one appropriate, VF-terminating ICD shock during a period of postoperative vomiting and electrolyte imbalance. None of the ten patients with WCD received any inappropriate shocks from the vest. Other complications or side effects associated with WCD-use were related to annoyance of false alarms during (extended) time of wearing the device in two of ten patients (Cases 1 and 6). One patient (Case 6) removed the WCD during the night of one of the five days he was wearing it because of several episodes of false alarms caused by poor contact for ECG analysis. The other patient (Case 1), who wore the WCD for 70 days, complained that the straps became loose after extended wear causing false alarms due to poor connections. In addition, another patient (Case 9) explained that she lived in a warm and humid climate and the WCD made her feel overheated, but she continued to wear the WCD. Overall in this small cohort, the WCD was reasonably tolerated, with patients wearing the device for most of the day, only to take it off for changing clothes or showers. Nevertheless, one patient (Case 3) included in this cohort chose not to wear the device. This 28-year-old female with LQT1 had a history of syncope and had an ICD placed at the time of her diagnosis. She received multiple inappropriate ICD shocks and came to Mayo Clinic seeking additional treatment options. Her ICD was deactivated and beta blocker therapy treatment was started. The patient returned to Mayo Clinic after becoming pregnant. At that time, because of the family's personal uncertainty as to how the pregnancy would be tolerated as well as a fear of a LQT1-related event to the mother and risk associated to the unborn child, the patient and her family requested an additional safety measure. Despite an informed discussion of the risk of post-partum events being associated particularly with LQT2 and not – as in this patient – LQT1, she requested a WCD and was provided a prescription for the device. However, in the end, she decided not to wear the device, possibly because

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Table 2 Characteristics of Patients with WCD. Case 2

Case 3

Case 4

Case 5

Case 6

Case 7

Case 8

Case 9

Case 10

Sex Female (male/female) LQTS genotype LQT1

Case 1

Female

Female

Female

Female

Male

Male

Female

Female

Female

LQT1

LQT1

LQT1

LQT2

LQT2

LQT3

LQT2

LQT2

Gene Mutation

KCNQ1 S225 L

KCNQ1 L266P

KCNQ1 A341V

KCNH2 G604S

KCNH2 A1035fs

SCN5A E1784K

KCNH2 E876X

KCNH2 R1033fs/23

Age at diagnosis (yrs) QTc (ms) Symptomatic prior to diagnosis Cardiac symptoms and relevant comorbidities

46

18

26

KCNQ1 IVS4 + 5G N A 15

Compound LQT2 KCNH2 L799SP and V630I 42

12

66

10

29

23

474 No

500 Yes

492 Yes

468 Yes

543 Yes

463 Yes

518 Yes

452 No

528 Yes

438 No

QT prolongation in setting of multiple myeloma and hypokalemia Bridge to treatment plan, temporary high risk 46 70

Syncope requiring CPR

Syncope

SCA with two Multiple AED shocks syncopal episodes and seizures

Bridge to treatment plan

Post -partum

Bridge to treatment plan

Bridge to treatment plan

Bridge to ICD revision (lead fracture)

Bridge to treatment plan, temp high risk

Bridge to ICD revision (lead fracture)

Bridge to treatment plan

Bridge to ICD revision(lead fracture)

18 20

28 0

15 15

42 4

20 5

66 114

26 1

43 11

38 4

No Successful titration to correct beta blocker dose

No Declined use of WCD

No Combination beta blocker therapy and LCSD, event free to date

No WCD discontinued post successful ICD revision

No ICD advised but declined by patient. WCD discontinued. LQTS preventative measures in place

No WCD discontinued post successful ICD revision

No Successful titration to correct beta blocker dose

No WCD discontinued post successful ICD revision

No

No

Yes Appropriate VF terminating therapy from WCD; ICD implanted and therapeutic level beta blocker achieved No

WCD beeped during night time hours and patient removed it.

No

No

Felt overheated wearing WCD in warm and humid climate.

No

Indication forWCD

Age at WCD Duration of WCD use (days) Shock Follow up

WCD complications

No Successful titration to correct beta blocker dose, treatment for myeloma completed

WCD straps No became loose after extended use and caused false alarms.

she and her husband became comfortable with the awareness that increased post-partum risk was not associated with her specific LQTS genotype. No arrhythmias occurred in this patient during or after her pregnancy. 4. Discussion A WCD can provide an excellent, interim solution to protect a patient from the consequences of a life-threatening cardiac arrhythmia. As our evaluation shows, the utilization of WCD in patients with LQTS is rare, but it can play a significant role for highly selected, high risk patients undergoing diagnostic evaluation and SCA risk stratification, or during a period of increased SCA risk. The 2016 WCD Science Advisory issued by the American Heart Association (AHA) states that the use of WCDs may be reasonable when there is concern about a heightened risk of SCA that may resolve (Class IIb recommendation) [8]. This advisory also recommends the use of WCDs as appropriate bridging therapy in situations associated with increased risk of death in which ICDs have been shown to reduce SCA, but not overall survival. This was included a class IIb recommendation as well [8]. In one of the largest LQTS specialty centers in the world, the WCD is only rarely used (~1% of patients for a maximum of 3 months), which

Syncope with Drug induced TdP TdP in setting of lymphoma and bone marrow transplant

Asymptomatic Auditory-triggered syncope and seizures

Asymptomatic

stands in stark contrast to its use in the high risk period for the prevention of SCA in patients after myocardial infarction (MI; 27%), coronary revascularization with coronary artery bypass graft or percutaneous coronary intervention (8%), non-ischemic cardiomyopathy (38%), or new diagnosis of heart failure as a bridge to ICD therapy (2%) [4]. The AHA 2016 WCD advisory focuses on the broader use of WCD in cases of ICD infection or contraindication to implant of ICD, bridge to cardiac transplantation, ischemic heart disease with recent revascularization or recent MI, new diagnosis of non-ischemic DCM in patients with guideline directed medial therapy or secondary cardiomyopathy with potentially treatable cause [8]. Our small cohort demonstrates a potential strategy for clinicians to utilize the WCD in patients with LQTS. Although used sparingly, the device did provide a possible life-saving therapy in one of the ten LQTS patients that were ultimately outfitted with a WCD. Overall, among the patients with LQTS and a WCD, the spectrum of indications was diverse, including undiagnosed and untreated, symptomatic LQTS patients with syncope not requiring external defibrillation; where the WCD enabled a dose escalation treatment strategy over a few weeks rather than proceeding directly to an ICD. Also included were patients with an ICD malfunction whereby the WCD facilitated outpatient scheduling of device replacement. This correlates

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Fig. 1. WCD tracing of VF-terminating event. Shown are WCD tracings of the VF-terminating event in patient #6 with a segment of normal sinus rhythm (0–16 s), deteriorating to VF (16– 63 s) followed by a VF-terminating shock (red) with restoration of sinus rhythm.

with an earlier guideline stating patients may be monitored and protected with the WCD until confirmation of either no permanent risk or a persisting arrhythmic abnormality [9]. The WCD can also be utilized in LQTS patients that are entering a transient higher risk time period, such as a clinical need to treat with medications that can prolong the QT interval or that are contra-indicated in patients with congenital LQTS (www.crediblemeds.org) [10,11]. While it is usually better to avoid administering these medications to a patient with LQTS, there are patients who after careful assessment and discussion by the health care team are intentionally put on such a drug for treatment of a chronic health issue, as in the case of antidepressants for treatment of depression, or antibiotics in a patient with concomitant cancer and course of chemotherapy. In some situations, a suitable, effective alternative might not always be available and often indicates the benefit of (temporarily) treating with the proper drug trumps risk of a drug-induced QT event. The intent of this recommendation is not to state that all LQTS patients taking a known QT prolonging medication should be prescribed a WCD, however, it may be appropriate for the clinician to prescribe a WCD for LQTS patients with a demonstrated, documented increase in QTc, or an arrhythmia while taking one or more medications that are known QT offenders. Consideration to the disease process requiring the administration of the QT drug should also be measured as it may contribute to potential increased risk of a LQTS-triggered arrhythmia. Nevertheless, it must be recognized that not all drugs on the QT drugs-list [11] should be treated equal and careful examination of the intended drug, its QT prolonging and torsadogenic potential as well as all other QT-mitigating risk factors (particularly hypokalemia) should be examined carefully in each situation. The use of the WCD provided temporary protection from SCA in LQTS patients facing unanticipated health crisis requiring treatment modalities that have the potential to increase the chance of SCA. The WCD will provide protection in case of an LQTS-triggered arrhythmia

without introducing the potential complications and surgical risk associated with an ICD. Although primarily indicated for adult patients, it is possible to use WCD for pediatric patients. The WCD is in fact approved by the FDA for use in the pediatric population. Nevertheless, the physical, developmental, and emotional capability of a young patient should be assessed carefully prior to prescribing the device. In this study, a WCD was utilized for a 15-year-old patient (Case 4) who experienced SCA while swimming which required an external shock from an AED. In this situation, the adolescent was measured and appropriately fitted with a WCD prior to discharge from the hospital after her sentinel event. The WCD was utilized until a definitive treatment program could be reviewed with the patient and etiology of her SCA established, thereby enabling her to fully participate in her own care. It is therefore reasonable to consider the WCD as a therapy for pediatric patients who are at high risk of SCA but who have contraindications to or would like to defer placement of a permanent ICD [12]. The use of the WCD can be beneficial in pediatrics but should be discussed with the family and the provider to assess if the use is appropriate and safe for the patient. The role of the WCD in patients whose origin of their syncopal episodes remains unknown, presents a challenge to the clinician. The process of thoroughly investigating possible structural issues, electrical, inherited channelopathies, or a possible neurological connection to the syncopal episode may take time and should be systematically completed. The current genomic era also plays a key role in the clinical management of LQTS. It must be remembered that in inherited arrhythmias, the relationship between genotype and clinical phenotype is not necessarily linear [13]. For those patients with inherited structural heart disease and/or inherited arrhythmia syndromes, future studies in genomic medicine may more precisely define the role of antiarrhythmic therapy, particularly the use of the ICD in individuals [14]. In fact, a retrospective evaluation of the US National Cardiovascular Data Registry revealed that

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almost 23% of all implanted ICD devices between 2006 and 2009 were non-evidenced-based implantations [15]. Therefore, as the diagnostic process takes place, the patient could be protected by the WCD allowing thorough investigation to be completed and the appropriate treatment strategy, including accurate ICD recommendation, to be initiated. Patients presenting with syncope without documented VT/VF, but who have high-risk factors for a malignant arrhythmia as a cause of syncope, may be at high risk for recurrence while being evaluated [4]. Until confirmation of either no permanent risk or a persisting arrhythmic abnormality, patients may be monitored with the WCD [9]. In our clinic's experience, only one patient proved to “need” her WCD. Registries and other single-site studies have shown a low incidence of appropriate WCD discharges [16,17] during typical duration of use of 3 months. The WCD is able to protect the patient during the first 2–3 months after infarction until the arrhythmia risk has either diminished if LVEF has improved or the indication for an ICD can be established with the persistence of poor LV function [18]. In a study of thirty-four patients with suspected tachy-arrhythmic origin found ventricular tachycardia/ventricular fibrillation or torsades de pointes occurred in seven patients (20%), leading to four delivered and three withheld shocks. Two patients with inherited cardiac syndromes (LQT1 and Brugada syndrome) experienced WCD shocks [9]. In a study of 354 patients at high risk for cardiac arrhythmias because of various underlying conditions in Germany using the WCD, 18% wore the WCD (average use 106 days) during diagnostic evaluation periods, including for syncope or after cardiac arrest, and 13% of these patients had ventricular arrhythmias requiring a shock [18]. Inherent to retrospective research, there are a few limitations that prevent describing the full experience of WCD use in these patients. As most patients were not specifically surveyed about their experience with the device, we were not able to evaluate such parameters as discomforts in wearing, skin irritation. As best we can glean, the WCD's were well tolerated and device discomfort precipitated its early termination in only one of the cases. If needed, because of the connectivity with the device's manufacturer, providers have access to details on total wearing time, wearing interruptions, all recordings and details on shocks delivered. Additionally, it is unclear whether the WCD is reimbursed universally by health insurance companies, which could prohibit this being an option for some patients. For the cases detailed herein, their WCD was deemed appropriate, prior authorization was obtained easily, and none of our patients had problems with reimbursement. In the United States, for patients with private health insurance, such coverage as observed in this study depends on their durable equipment plan. Whether patients with LQTS and a WCD indication can be equipped with this device is beyond the scope of this work. Perhaps, our current experience might aid in illuminating those rare circumstances (b1% use rate in our entire cohort) where the WCD is an appropriate and important part of the patient's comprehensive treatment program. 5. Conclusions A WCD can be considered in patients with LQTS deemed to be at high risk for SCA as a bridge to treatment while undergoing LQTS risk stratification and initiation of a personalized LQTS-directed treatment plan. In addition, when either i) navigating a reversible, short term complication from ICD therapy or ii) during short term administration of known QT prolonging medications for the treatment of non-cardiac diagnosis that will place the patient at increased risk, the WCD may be a helpful non-invasive intervention. Funding source This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (MJA).

Conflicts of interest MJA is consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, Myokardia, and St. Jude Medical. MJA and Mayo Clinic have equity/royalty relationships (without remuneration so far) with AliveCor, Blue Ox Health, and Stemonix. However, none of these entities provided financial support for this study. The other authors have no conflicts of interest to disclose.

Ethical publication The authors confirm to have read the Journal's publication on issues involved in ethical publication and affirm this report is consistent with those guidelines.

References [1] D.J. Tester, M.J. Ackerman, Genetic testing for potentially lethal, highly treatable inherited cardiomyopathies/channelopathies in clinical practice, Circulation 123 (2011) 1021–1037. [2] A.J. Moss, W. Zareba, W.J. Hall, P.J. Schwartz, R.S. Crampton, J. Benhorin, et al., Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome, Circulation 101 (2000) 616–623. [3] G.M. Vincent, K. Timothy, J. Fox, L. Zhang, The inherited long QT syndrome: from ion channel to bedside, Cardiol. Rev. 7 (1999) 44–55. [4] M.K. Chung, The role of the wearable cardioverter defibrillator in clinical practice, Cardiol. Clin. 32 (2014) 253–270. [5] M.J. Ackerman, S.G. Priori, A.M. Dubin, P. Kowey, N.J. Linker, D. Slotwiner, et al., Betablocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: are all beta-blockers equivalent? Heart Rhythm. 14 (2017), e41-e4. [6] S.G. Priori, C. Blomstrom-Lundqvist, A. Mazzanti, N. Blom, M. Borggrefe, J. Camm, et al., 2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), Eur. Heart J. 36 (2015) 2793–2867. [7] S.G. Priori, A.A. Wilde, M. Horie, Y. Cho, E.R. Behr, C. Berul, et al., HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013, Heart Rhythm 10 (2013) 1932–1963. [8] J.P. Piccini Sr., L.A. Allen, P.J. Kudenchuk, R.L. Page, M.R. Patel, M.P. Turakhia, et al., Wearable cardioverter-defibrillator therapy for the prevention of sudden cardiac death: a science advisory from the American Heart Association, Circulation 133 (2016) 1715–1727. [9] H.U. Klein, I. Goldenberg, A.J. Moss, Risk stratification for implantable cardioverter defibrillator therapy: the role of the wearable cardioverter-defibrillator, Eur. Heart J. 34 (2013) 2230–2242. [10] C.J. Murray, C. Atkinson, K. Bhalla, G. Birbeck, R. Burstein, D. Chou, et al., The state of US health, 1990–2010: burden of diseases, injuries, and risk factors, JAMA 310 (2013) 591–608. [11] CredibleMpeds - QT drug list. www.crediblemeds.org. Last accessed 04/05/2018. [12] K.K. Collins, J.N. Silva, E.K. Rhee, M.S. Schaffer, Use of a wearable automated defibrillator in children compared to young adults, Pacing Clin. Electrophysiol. 33 (2010) 1119–1124. [13] P.J. Schwartz, L. Crotti, R. Insolia, Long-QT syndrome: from genetics to management, Circ. Arrhythm. Electrophysiol. 5 (2012) 868–877. [14] R.D. Mitrani, R.J. Myerburg, Ten advances defining sudden cardiac death, Trends Cardiovasc. Med. 26 (2015) 23–33. [15] E.T. Zishiri, S. Williams, E.M. Cronin, E.H. Blackstone, S.G. Ellis, E.E. Roselli, et al., Early risk of mortality after coronary artery revascularization in patients with left ventricular dysfunction and potential role of the wearable cardioverter defibrillator, Circ. Arrhythm. Electrophysiol. 6 (2013) 117–128. [16] M.K. Chung, S.J. Szymkiewicz, M. Shao, E. Zishiri, M.J. Niebauer, B.D. Lindsay, et al., Aggregate national experience with the wearable cardioverter-defibrillator: event rates, compliance, and survival, J. Am. Coll. Cardiol. 56 (2010) 194–203. [17] R.D. Mitrani, A. McArdle, M. Slane, J. Cogan, R.J. Myerburg, Wearable defibrillators in uninsured patients with newly diagnosed cardiomyopathy or recent revascularization in a community medical center, Am. Heart J. 165 (2013) 386–392. [18] H.U. Klein, U. Meltendorf, S. Reek, J. Smid, S. Kuss, I. Cygankiewicz, et al., Bridging a temporary high risk of sudden arrhythmic death. Experience with the wearable cardioverter defibrillator (WCD), Pacing Clin. Electrophysiol. 33 (2010) 353–367.