Implantable cardioverter-defibrillator explantation for overdiagnosed or overtreated congenital long QT syndrome

Author's Accepted Manuscript

Implantable Cardioverter Defibrillator Explantation for Overdiagnosed or Overtreated Congenital Long QT Syndrome Prakriti Gaba BS, J. Martijn Bos MD, PhD, Bryan C. Cannon MD, Yong-Mei Cha MD, Paul Friedman MD, Samuel Asirvatham MD, Michael J. Ackerman MD, PhD www.elsevier.com/locate/buildenv

PII: DOI: Reference:

S1547-5271(15)01521-0 http://dx.doi.org/10.1016/j.hrthm.2015.12.008 HRTHM6539

To appear in:

Heart Rhythm

Cite this article as: Prakriti Gaba BS, J. Martijn Bos MD, PhD, Bryan C. Cannon MD, Yong-Mei Cha MD, Paul Friedman MD, Samuel Asirvatham MD, Michael J. Ackerman MD, PhD, Implantable Cardioverter Defibrillator Explantation for Overdiagnosed or Overtreated Congenital Long QT Syndrome, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2015.12.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1

Implantable Cardioverter Defibrillator Explantation for Overdiagnosed or Overtreated Congenital Long QT Syndrome

Prakriti Gaba, BS1, J. Martijn Bos, MD, PhD2,3, Bryan C. Cannon, MD3, Yong-Mei Cha, MD4, Paul Friedman, MD4, Samuel Asirvatham4, MD, and Michael J. Ackerman, MD, PhD2,3,4

1) Mayo Medical School, Mayo Clinic, Rochester, MN 2) Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN 3) Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 4) Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN

Short title: ICD Explantation for LQTS

Disclosures: BCC is a consultant for Medtronic. MJA is consultant for Boston Scientific, Gilead Sciences, Medtronic, and St. Jude Medical and receives royalties from Transgenomics for FAMILION-LQTS and FAMILION-CPVT. PAF is a consultant for Boston Scientific, Leadax and Boston Scientific and receives royalties from Aegis, NeoChord, Preventice and Sorin. SJA is a consultant for Abiomed, Atricure, Biotronik, Biosense Webster, Boston Scientific, Medtronic, Medtelligence, St. Jude, Sanofi-Aventis, Wolters Kluwer, Elsevier, Zoll and

2

receives royalties from Aegis, Access Point Technologies, Nevro, Sanovas and Sorin Medical. None of these entities provided financial support for this study.

Address for correspondence: Michael J. Ackerman, MD, PhD Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory Guggenheim 501, Mayo Clinic, Rochester, MN 55905 507-284-0101 (phone), 507-284-3757 (fax), [email protected]

3

ABSTRACT Background Primary treatment of long QT syndrome (LQTS) currently consists of beta blocker therapy, although in high risk patients, an implantable cardioverter defibrillator (ICD) is considered. However, both overdiagnosis and overtreatment must be avoided as their sequelae can be significant. Objective To evaluate the prevalence and details of ICD explants in a cohort of patients from a tertiary genetic heart rhythm clinic for a previously rendered diagnosis of LQTS. Methods Overall, 1227 consecutive patients were included in this study. All patients had been referred to the Mayo Clinic for the evaluation of possible LQTS, and subsequently were either diagnosed with LQTS or dismissed as normal. Further stratification of patients was conducted to assess how many patients had an ICD and how many had a subsequent ICD explant. Results In total, 171 (14%) patients had an ICD, including 157/670 (23%) patients with confirmed LQTS and 13/557 (2%) patients who did not have LQTS. Among these, 12/1227 (1%) have had the ICD removed: 7/157 (4.5%) with LQTS compared to 5/14 (36%) non-LQTS patients. Prior to explant, 5/12 (42%) patients experienced inappropriate shocks ranging from 2 to as many as 54 shocks. In addition, 4 had a device-related infection and 9 had device malfunction (including lead dysfunction or fracture). None of these patients have had a breakthrough cardiac event since removal of their ICD during 5.5 ± 3.5 years followup. Conclusions Implications of overdiagnosis and overtreatment are profound as unnecessary ICD placement can be associated with infection, malfunction, inappropriate shocks, and subsequent anxiety.

4

KEYWORDS: ICD, explantation, LQTS, defibrillation, inappropriate shock

ABBREVIATIONS Automated external defibrillator, AED Electrocardiogram, ECG Implantable cardioverter defibrillator, ICD Left cardiac sympathetic denervation, LCSD Long QT syndrome, LQTS Sudden Cardiac Death, SCD

5

INTRODUCTION Prolongation of the QT interval can either be acquired or congenital. Acquired LQTS is typically the result of electrolyte imbalances, comorbidities or drugs known to prolong the QT interval. Congenital long QT syndrome (LQTS) is an uncommon, inherited arrhythmia syndrome characterized by prolongation of the QT interval and is commonly causes by mutations in cardiac ion channels.1-3 LQTS can present with syncope, seizures or sudden cardiac death (SCD). The prevalence of congenital LQTS is reported to be as high as 1 in 2500 and may even be higher since it can often be difficult to diagnose due to mild presentation of the disease or the presence of normal QT intervals in a patient with true LQTS.4-6 While some patients are diagnosed after cardiac arrest or several episodes of syncope, others may remain asymptomatic.2, 3 Consequently, accurate diagnosis and management of this condition can be difficult. Currently, primary therapy for LQTS includes beta blocker therapy coupled with preventive measures like QT drug avoidance and reactive measures like an automated external defibrillator (AED).3, 7 In high risk patients however, more invasive measures, including left cardiac sympathetic denervation (LCSD) or an implantable cardioverter defibrillator (ICD), may be warranted.8 Difficulties in making the LQTS diagnosis accompanied by the possible dire outcomes of a missed diagnosis sometimes leads to over-diagnosis of the disease and possibly overaggressive treatment, including overzealous implantation of an ICD. This decision also introduces the potential for device-related complications including infection, malfunction, inappropriate shocks, and possible anxiety.9 As a result, appropriate risk

6

stratification is extremely important. Here, the prevalence and details of ICD explants are assessed in a cohort of patients evaluated at a tertiary genetic heart rhythm clinic for a previously rendered diagnosis of LQTS.

METHODS Study Population In this IRB-approved study, 1227 consecutive patients, who had been referred to the Mayo Clinic in Rochester, MN for borderline or definite QT prolongation and suspicion of LQTS, were reviewed. All cases were evaluated thoroughly for LQTS and were subsequently either diagnosed with LQTS or dismissed as not having LQTS (non-LQTS) because of insufficient evidence to diagnose the disease. For all patients, demographic and electrocardiogram (ECG) data were collected as well as comprehensive details surrounding a possible diagnosis of LQTS, including but not limited to prior LQTS-associated symptoms, family history of LQTS and/or SCD, LQTS treatment, and outcomes. For genotype positive LQTS positive patients, gene and mutation-specific data were collected. Furthermore, for all patients, it was determined whether or not an ICD was implanted, either at Mayo Clinic or elsewhere and outcomes of ICD (appropriate or inappropriate shocks, side effects) were collected.

ICD Risk Stratification Assessment For those patients with an ICD, indications for initial ICD implantation were evaluated from clinical notes using the criteria from the 2013 HRS/EHRA/APHRS guidelines10 listed in Table 1 10. A Class III recommendation was further stratified to

7

identify patients for which implantation was considered reasonable due to “special circumstances” (Class III-SC) (a QTc > 550 ms in a patient other than LQT1; a LQT2 woman with QTc > 500 ms; JLNS diagnosis; strong family history of LQTS), or those who had “no special circumstance” (Class III-NSC) and ICD was not recommended.

Explantation Cohort Details The main aim of our study was to identify which of the patients with an ICD were overdiagnosed (misdiagnosed as LQTS) or potentially overtreated (ICD implant was outside a class I or class II recommendation) and detail the patients whose device was explanted. Each of these patients’ records was further reviewed to obtain the reasons behind their ICD explant, the details surrounding initial implantation, and the time interval from implant to explant. Furthermore, details on post-ICD implantation outcomes (i.e. appropriate/inappropriate shocks, infection, etc.), procedure of ICD removal (i.e. whole system removed, device inactivated, generator or lead removed), explantation method (laser or thoracotomy), and details on LQTS-directed treatment and outcome after explantation were collected.

Statistical Methods All data are reported as mean ± standard deviation, fractions, or percentages unless otherwise mentioned. Excel and JMP statistical software (Version 10.0, SAS Inc) were utilized for statistical analysis. Student’s t-Test or Chi square analyses were performed as appropriate. A p-value <0.05 was considered statistically significant.

8

RESULTS Study Population Among the 1227 consecutive patients that were reviewed retrospectively, 670 were diagnosed with LQTS while 557 were dismissed without this diagnosis. For the purpose of this study, this subset is referred to as “non-LQTS”. Clinical demographics of both cohorts are summarized in Table 1. In brief, 279 (42%) of the LQTS patients were male compared to 233 (42%) of the non-LQTS patients. Consistent with the diagnosis, the QTc was significantly longer in patients with LQTS than those dismissed without a LQTS diagnosis (467 ± 52 ms vs. 426 ± 28 ms; p<0.001). For patients with LQTS, 466(69%) had a family history of LQTS and 286 (43%) with a family history significant for SCD. A majority of LQTS patients (530/670(79%)) were genotype positive for one of the major LQTSassociated genes (KCNQ1, 276/670 (41%); KCNQ2, 187/670 (28%); SCN5A, 51/670 (8%)). Of the remaining LQTS patients, 15/670 (2%) were genotype positive for a less common LQTS-associated gene, while 141/670 (21%) patients were either genotype negative or their genotype was unknown. Among non-LQTS patients, 174 (31%) presented with symptoms like syncope that could have been viewed as a possible LQTS-associated symptom (similar to patients diagnosed with LQTS (182 (27%); p = 0.1), however there was a significantly lower frequency of family history of LQTS (108 (19%); p<0.0001). Only 19 (3%) non-LQTS patients had a genetic variant in one of the LQTS –associated genes, although all variants were classified as variant of uncertain significance (VUS). Overall, 170/1240 (14%) had an ICD including 157/670 (23%) patients with confirmed LQTS and 13/557 (2%) non-LQTS patients (Table 1).

9

ICD Risk Stratification Assessment LQTS and non-LQTS patients with ICD were evaluated to determine the indication for their initial ICD implantation according to the previously established ICD guidelines. Of the 157 LQTS patients with an ICD, 34 (22%) had a class I indication for their ICD implantation, 59 (38%) had a class IIa indication, and 64 (40%) had a class III indication (Table 2). Among patients with a class III indication, there were 43 (27%) patients for whom a special circumstance was identified while no special circumstance could be identified for 21 (13%). Among the 13 non-LQTS patients who nevertheless had been implanted , the majority had no specific indication for an ICD (9/13; 69%). Among the remainder of the non-LQTS patients with an ICD, 1 (8%) had a class I indication due to a prior cardiac arrest without clear underlying pathology, and 3 (23%) had a class III indication with a special circumstance cited in (Table 2). Explantation Cohort Details To date, 7/157 (4.5%) LQTS-ICD patients (3 male/4 female) have had their ICD system explanted or inactivated after being deemed either over-treated or following severe complications, while 5/13 (38%) of the non-LQTS-ICD subjects (2 male/3 female) underwent device explantation (p=0.0007), yielding a total of 12 ICD explant patients. Details for each of the explants are summarized in Table 3. A LQTS-associated mutation was identified in all 7 of the LQTS explanted patients with 5 (83%) of the 7 patients having KCNQ1-mediated LQTS (LQT1). As expected, the average baseline QTc interval was higher in the LQTS explants group (456 ± 31 ms) than in

10

the non-LQTS explants group (425 ± 28 ms). The age of initial LQTS diagnosis for the LQTS explants was 29 ± 13 years. In these 7 LQTS-ICD patients, an ICD was not indicated by the guidelines, but was implanted because of the presumed presence of special circumstances (Class III-SC), i.e. all having a positive family history of LQTS and/or SCD. In contrast, none of the non-LQTS explants had a true ICD indication apart from the erroneously rendered diagnosis of LQTS. All 5 (100%) were classified as a Class III-NSC indication for an ICD with the majority only having syncope and temporarily prolonged QTc on ECG (Table 3). Of note, all 12 of the explanted patients were diagnosed and implanted with an ICD elsewhere initially. Implantation of the ICD led to severe complications in both LQTS and non-LQTS patients. Nine patients (6 LQTS vs. 3 non-LQTS) experienced device malfunction, including inappropriate shocks requiring lead replacement and lead fractures, while 4 patients had an ICD-related infection (2 LQTS vs. 2 non-LQTS) (Table 3). None of the patients experienced an appropriate shock while they had their device. Instead, 4 of the LQTS explant patients and 1 of the non-LQTS explant patients received inappropriate shocks, ranging from 2 to as many as 54 shocks. Moreover, 4 patients (3 LQTS vs. 1 non-LQTS) developed severe anxiety and fear of a subsequent shock. Patients that underwent ICD explants had their device for an average of 6.2 ± 3.0 years. The reason for explantation most commonly was instigated by the aforementioned complications the patients suffered as a result of their device particularly in the LQTS explants cohort. Among the explanted LQTS patients, malfunction of the device was the common reason for explantation (5/7; 71%) followed by infection (1/7; 14%) and severe anxiety (1/7; 14%) (Table 3). In the non-LQTS explants patients, a re-classification to

11

normal (i.e. overdiagnosis) was the primary reason for explantation with complications playing an important role in the ultimate decision to look for a second opinion leading to reversal of their previously rendered diagnosis of LQTS. With respect to device removal, risks and benefits were assessed on a case-by-case basis for each patient prior determining method of device removal/inactivation. In the LQTS explant patients, 4 of the patients had device explantation via laser while the others had either generator removal (n = 1) or device inactivation without surgical removal (n= 2). In contrast, among the non-LQTS patients, 2 had the entire device removed via laser, 1 had only the leads removed via laser, 1 had a thoracotomy to remove the entire device along with its leads, and 1 had the generator removed only. Post-explantation, 5 of the LQTS patients were treated successfully by alternate methods with no events occurring after implementation of either a beta blocker pharmacotherapy (cases 2, 3, 5 and 7) or LCSD (case 4) (Table 3). Case 1 was not treated with further therapy post-explantation due to beta blocker intolerance (significant fatigue, mood change) and asymptomatic history while Case 6 was not treated with further therapy in order to monitor her in a non-treated state (as she was the most recent explant in June 2015). None of these patients have had syncope or a breakthrough cardiac event since removal of their ICD with 5.5 ± 3.5 years follow-up.

DISCUSSION Long QT syndrome (LQTS) is an uncommon, potentially lethal yet highly treatable medical condition that often presents a diagnostic challenge due to its heterogeneous

12

presentations.2, 3 High risk patients might require ICD therapy or LCSD to counter or prevent a potentially lethal cardiac arrhythmia.3, 7 ICD implantation is an invasive surgical procedure and the presence of an ICD can come with significant side effects, including infection, lead fracture, inappropriate shocks as well as anxiety and fear for possible (in)appropriate shocks. Due to the challenging diagnosis, invasiveness of the ICD treatment for LQTS, and the significant risk for side-effects from therapy, appropriate risk stratification of patients with LQTS is crucial to avoid overtreatment. While several studies have pointed out previously the complexity of making a LQTS diagnosis,11-14 to our knowledge, this is the first large case series that illustrates how improper diagnosis and/or treatment of LQTS can lead to significant ICD-related complications. Among 170 ICD recipients, 12 needed to have their device explanted or deactivated for either overdiagnosis or overtreatment with the complications far outweighing the possible benefits of the device. Note, not all overdiagnosed patients had their entire device removed due to greater risks of device explantation than simple inactivation.15 In fact, two only had their generator removed and another two only had their device inactivated with the leads remaining in the patients. Seven of the 12 patients had LQTS (4.5% of the LQTS cohort) but should not have received the ICD in the first place as family history alone is not sufficient to warrant ICD implantation and in fact, Horner et al have shown previously that a negative family history is predictive of appropriate ICD therapy in patients with LQTS,16 while 5 patients (35% of the ‘non-LQTS’ patients) were actually dismissed from their Mayo evaluation without the diagnosis of LQTS. Interestingly, in those 5 patients without LQTS who were misdiagnosed, the original indication for implantation was syncope and a temporarily prolonged QT interval. While these are concerning for LQTS, transient QT

13

prolongation can occur due to electrolyte imbalances or medications known to prolong the QT interval, and thus must be carefully evaluated and excluded before rendering a diagnosis of LQTS or risk stratifying for ICD implantation .17 All overdiagnosed/overtreated patients had suffered from ICD-related complications, including inappropriate shock, anxiety, among others, at some point while they had their device. Such complications are not specific to our study; in fact, several studies have demonstrated an increase in anxiety and depression symptoms in patients with an ICD and recommend regular psychiatric follow up in such patients.18-20 This is compounded by the finding that ICD explants were not acute reversals as the patients had their device for an average of 6.2 ± 3.0 years and none of the patients had received an appropriate shock while having their device. Together, these findings demonstrate the gravity of the complications caused by ICD overtreatment and mandate improved physician understanding of what phenotype warrants a LQTS diagnosis and when appropriately diagnosed, what compels an ICD recommendation. For our study, we re-evaluated the ICD implantation indications for each case according to the most recent guidelines10 and it became clear that among patients who had their device explanted, an ICD was not necessarily recommended (Class III) unless special circumstances (which in themselves are debatable) were identified that convinced the provider to suggest an ICD. This is evidenced by the fact that the majority of cases received the device because of a positive family history of disease or death. Although cited as a special circumstance, a positive family history is not a strong, evidence-based risk factor for patients with LQTS.21 However, it is imaginable that in these cases the tragic death of a

14

family member might have prompted the family and physician to implant a device, even if not fully warranted by the guidelines. While there may have been other factors that had influenced the diagnosis and subsequent ICD implantation of these individuals, this data raises an important question and issue for the providers in the management of LQTS: why were these patients implanted with an ICD in the first place? Previously, the possibility of overdiagnosed LQTS was raised in 2007 when at that time, 40% of the patients with a heart rhythm specialistrendered diagnosis of LQTS were dismissed from Mayo Clinic as normal.17 In 2010, Data from the European LQTS ICD Registry found that 41% of patients received an ICD without first having adequate trials of pharmacological therapy and that the majority of patients that were asymptomatic and yet still implanted with an ICD were those with confirmed or presumed LQT3.22 In this present study, not only are patients continuing to be overdiagnosed, but among those patients correctly diagnosed with LQTS, there appears to be a premature rush to an ICD. Overtreatment in children and young adults with inherited cardiac diseases is striking as overzealous ICD use can affect quality of life profoundly.23 As noted in Table 1, in our cohort, 5/12 (41.7%) of patients were implanted inappropriately prior to the age of 18 years with 3 of them having genetically inherited LQTS. Furthermore, not only is implanting an ICD a difficult decision, but explanting an ICD is an equally if not more difficult decision as evidenced by the observation that 8/13 (62%) non-LQTS patients in our cohort still have their ICD and only one of these patients actually has an ICD indication secondary to his/her prior cardiac arrest. Laser removal of leads and thoracotomy are serious medical procedures which can have life-threatening consequences.24 Specifically, any time a defibrillator lead is disentangled from myocardial

15

tissue in which it was implanted, there is risk of hemorrhage and potential perforation.15 These consequences must be weighed carefully with the benefits of removal of the device. In some patients particularly those with existing scar tissue, inactivation of the device may be preferred over explantation. None of the patients overtreated or overdiagnosed ever received an appropriate ICD shock nor have any of these patients had a cardiac event since removal of their ICD with 5.5 ± 3.5 years follow-up, consistent with the conclusion (overdiagnosed/overtreated) at their second opinion evaluation. Proper management of LQTS patients with alternative means, including pharmacotherapy and LCSD, should be the top priority of healthcare providers prior to trying ICD therapy. Beta blockers significantly reduce the risk of a subsequent cardiac event and thereby reduce overall mortality of patients with LQTS.25, 26 Because all of the over-treated patients in our cohort (cases 1-7) had not had a cardiac event while on betablocker therapy, a sufficient trial of beta blockers was necessary prior to rushing towards ICD therapy. In the case that beta blocker therapy was not sufficient, then LCSD could have been considered in the low/medium risk patients, after which ICD therapy may have been tried. Instead, in our cohort of over-treated patients, the majority switched to ICD therapy primarily due to the side effects of pharmacotherapy. Here, LCSD would have been a reasonable alternative to an ICD in patients with medication-related side effects.27 However, in all of the over-treated patients, LCSD was not tried prior to ICD therapy. Ultimately, treatment for LQTS should be conducted in a step-wise manner with implantation of an ICD being the last option once others have failed or there are special circumstances that warrant its implant. Referral to tertiary care centers should be encouraged in such difficult diagnostic situations.

16

Limitations There are several limitations in this study. The first involves the limited sample size of the cohort studied. Patients from only a single tertiary care center were reviewed, and therefore, subsequent studies, combining data from other tertiary centers, may provide more comprehensive insight into the actual frequency of over-diagnosed and/or overtreated LQTS. In fact, the frequency of ICD explantation might be somewhat overestimated as some patients came specifically for the re-evaluation of their implanted device. Moreover, our study might be biased by the nature of Mayo Clinic being a tertiary referral center for patients presented in this study, and the fact that patients with ICD problems (such as those evaluated in the present paper) may be more likely to seek additional external opinions than those patients with LQTS and a well-functioning ICD thus far devoid of adverse effects. As such, although this provided this study with the numbers to present our analyses, they might overstate the true scope of the problem. Additionally, retrospective review of class indication for ICD implantation can be subjective. Interpretation of each patient’s original reason for ICD implantation may have been subject to bias as they were not always clearly specified. While it may be difficult to eliminate such a bias completely when evaluating referral patients from a variety of institutions, this does not take away from the fact that a significant number of patients received an ICD outside of the guidelines or after being diagnosed erroneously in the first place. Although the experience within Mayo Clinic’s dedicated LQTS clinic is substantial, we recognize that the expert opinions rendered regarding the diagnosis and treatment of

17

LQTS cannot be viewed as the irrefutable gold standard. In fact, there is no test currently that can provide a 100% sensitivity and specificity of confirming a LQTS diagnosis.

CONCLUSIONS The implications of overdiagnosis and overtreatment are profound as demonstrated in our single tertiary center study. Unnecessary ICD placement can be associated with drastic complications, including infection, malfunction, inappropriate shocks, and subsequent anxiety, for patients. Further study is warranted to better understand the national and international scope of both overdiagnosed LQTS and overtreated LQTS culminating in an ICD.

18

REFERENCES 1.

Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C, Escande D, Franz M, Malik M, Moss A, Shah R. The potential for QT prolongation and proarrhythmia by nonantiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J 2000;21:1216-1231.

2.

Cahoon WD, Jr. Acquired QT prolongation. Prog Cardiovasc Nurs Mar 2009;24:30-33.

3.

Barsheshet A, Dotsenko O, Goldenberg I. Congenital long QT syndromes: prevalence, pathophysiology and management. Paediatr Drugs 2014;16:447-456.

4.

Schwartz PJ. The long QT syndrome. Curr Probl Cardiol 1997;22:297-351.

5.

Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A, Jr., et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation 1991;84:1136-1144.

6.

Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med 10 2008;358:169-176.

7.

Pundi KN, Bos JM, Cannon BC, Ackerman MJ. Automated External Defibrillator Rescues Among Children with Diagnosed and Treated Long QT Syndrome. Heart Rhythm 2015;12:776-781.

8.

DeSimone CV, Bos JM, Bos KM, Liang JJ, Patel NA, Hodge DO, Noheria A, Asirvatham SJ, Ackerman MJ. Effects on Repolarization using Dynamic QT Interval Monitoring in Long QT Patients following Left Cardiac Sympathetic Denervation. J Cardiovasc Electrophysiol 2015;26:434-439.

9.

Gaba P, Bos JM, Shah MJ, Ackerman MJ. Device explantation following overdiagnosed and overtreated Jervell and Lange-Nielsen syndrome. Heart Rhythm 2014;11:2310-2313.

10.

Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes:

19

document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;10:1932-1963. 11.

Hurst D, Hirsh DA, Oster ME, Ehrlich A, Campbell R, Mahle WT, Mallory M, Phelps H. Syncope in the Pediatric Emergency Department - Can We Predict Cardiac Disease Based on History Alone? J Emerg Med 2015;49:1-7.

12.

Hofman N, Wilde AA, Tan HL. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? Eur Heart J 2007;28:1399.

13.

Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993;88:782-784.

14.

Maron BJ, Moller JH, Seidman CE, Vincent GM, Dietz HC, Moss AJ, Towbin JA, Sondheimer HM, Pyeritz RE, McGee G, Epstein AE. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome, and marfan syndrome : A statement for healthcare professionals from the councils on clinical cardiology, cardiovascular disease in the young, and basic science, american heart association. Circulation 1998;98:1460-1471.

15.

Buch E, Boyle NG, Belott PH. Pacemaker and defibrillator lead extraction. Circulation 2011;123:e378-380.

16.

Horner JM, Kinoshita M, Webster TL, Haglund CM, Friedman PA, Ackerman MJ. Implantable cardioverter defibrillator therapy for congenital long QT syndrome: a single-center experience. Heart Rhythm 2010;7:1616-1622.

17.

Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007;115:2613-2620.

18.

Pedersen SS, van Domburg RT, Theuns DA, Jordaens L, Erdman RA. Concerns about the implantable cardioverter defibrillator: a determinant of anxiety and depressive symptoms independent of experienced shocks. Am Heart J 2005;149:664-669.

20

19.

Kamphuis HC, de Leeuw JR, Derksen R, Hauer RN, Winnubst JA. Implantable cardioverter defibrillator recipients: quality of life in recipients with and without ICD shock delivery: a prospective study. Europace 2003;5:381-389.

20.

Bilge AK, Ozben B, Demircan S, Cinar M, Yilmaz E, Adalet K. Depression and anxiety status of patients with implantable cardioverter defibrillator and precipitating factors. Pacing Clin Electrophysiol 2006;29:619-626.

21.

Kaufman ES, McNitt S, Moss AJ, et al. Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm 2008;5:831-836.

22.

Schwartz PJ, Spazzolini C, Priori SG, et al. Who are the long-QT syndrome patients who receive an implantable cardioverter-defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. Circulation 2010;122:1272-1282.

23.

Olde Nordkamp LR, Wilde AA, Tijssen JG, Knops RE, van Dessel PF, de Groot JR. The ICD for primary prevention in patients with inherited cardiac diseases: indications, use, and outcome: a comparison with secondary prevention. Circ Arrhythm Electrophysiol 2013;6:91-100.

24.

Farooqi FM, Talsania S, Hamid S, Rinaldi CA. Extraction of cardiac rhythm devices: indications, techniques and outcomes for the removal of pacemaker and defibrillator leads. Int J Clin Pract 2010;64:1140-1147.

25.

Abu-Zeitone A, Peterson DR, Polonsky B, McNitt S, Moss AJ. Efficacy of different betablockers in the treatment of long QT syndrome. J Am Coll Cardiol 2014;64:1352-1358.

26.

Bennett MT, Gula LJ, Klein GJ, Skanes AC, Yee R, Leong-Sit P, Chattha I, Sy R, Jones DL, Krahn AD. Effect of beta-blockers on QT dynamics in the long QT syndrome: measuring the benefit. Europace 2014;16:1847-1851.

21

27.

Bos JM, Bos KM, Johnson JN, Moir C, Ackerman MJ. Left cardiac sympathetic denervation in long QT syndrome: analysis of therapeutic nonresponders. Circ Arrhythm Electrophysiol 2013;6:705-711.

22

CLINICAL PERSPECTIVES In this manuscript, we present the prevalence and details of implantable cardioverter defibrillator (ICD) explants in a cohort of patients evaluated at a tertiary genetic heart rhythm clinic for diagnosis of and treatment for long QT syndrome (LQTS) or reversal of an incorrectly rendered LQTS diagnosis. LQTS is a serious condition which is treated currently with beta blocker therapy and/or an IC) in high risk cases. Implantation with an ICD can be a life-saving therapy for patients with channelopathies. Yet, its side effects, consisting of infection, anxiety, and device malfunction, among others, are not inconsequential. Thus, overdiagnosis and overtreatment must be avoided as their sequelae can be significant. Data presented in our manuscript may shed light on ways practicing physicians can make smarter decisions for risk stratifying patients for ICD therapy, precluding overdiagnosis and overtreatment. Specifically, physicians should be encouraged to verify a patient’s clinical history and (transiently) prolonged QT with genetic studies or trial of pharmacological therapy prior to suggestion of ICD therapy for patients suspected to have LQTS.

23

TABLES Table 1: Cohort Demographics Cohort

LQTS

Non-LQTS

670

557

Male/female n

279/391

233/324

0.9

QTc (ms)

467 ± 52

426 ± 28

<0.001

Age at LQTS diagnosis/evaluation (years)

20.3 ± 17

20.1 ± 14.4

0.9

Symptomatic at diagnosis/evaluation n(%)

182 (27)

174 (31)

0.1

Fam Hx of LQTS n(%)

464 (69)

108 (19)

<0.001

Fam Hx of SCD n(%)

286 (43)

245 (44)

0.7

Genotype positive n(%)

528 (79)

19 (3)

<0.001

LQT1 (KCNQ1)

276 (41)

3 (0.5)

LQT2 (KCNH2)

186 (28)

6 (1)

LQT3 (SCN5A)

51 (8)

8 (1.4)

Other

15 (2)

2 (0.2)

141 (21)

538 (97)

<0.001

157 (23)

13 (3)

<0.001

7 (4.5)

5 (36)

<0.001

N

Unknown/genotype negative ICD ICD explanted

p-value

24

Table 2: Recommendations for ICD Implantation and Number of Patients Implanted with ICD along with their Respective Indication in our cohort

Circumstance

Recommendation

LQTS patients with ICD (n =157)

Non-LQTS patients with ICD (N=13)

I

Prior cardiac arrest

ICD Recommended

34 (22%)

1 (8%)

IIa

Recurrent syncope while treated

ICD can be useful

59 (38%)

0 (0%)

III

Asymptomatic, not treated with beta blocker

ICD not indicated, except under special circumstances

64 (40%)

12 (92%)

Special circumstances (SC): • QTc > 550ms, not LQT1 • LQT2 female, QTc >500ms • JLNS diagnosis • Family history

43 (27%)

3 (23%)

No special circumstance (NSC) identified

21 (13%)

9 (69%)

Class

25

Table 3: ICD Explantation Cohort Demographics and Details of Overtreatment/Overdiagnosis.

Ca se

1

Se x (M /F)

M

Dx

LQT S

Mutat ion

G168R – KCNQ 1

Q Tc ( m s)

43 3

A g e at D x (y r)

1 5

ICD Indic ation

Class III – SC

Detai ls on indic ation

Famil y histor y

F

LQT S

R192C fsX91 – KCNQ 1

45 5

4 6

Class III SC

Famil y Histo ry

M

LQT S

G269S – KCNQ 1

42 4

2 5

Class III – SC

Famil y histor y

4

F

LQT S

A341V – KCNQ 1

50 9

2 6

Class III – SC

5

M

LQT S

L362A – KCNQ 1

43 7

1 0

6

F

LQT S

A301L KCNH 2

44 7

1 3

2

3

Age at Imp lant

15

Appro priate shock?

ICD Compli cations

Length of ICD Implan tation (years)

Reason for Explant ation

Metho d of Explan tation

Alt. ther apy

Eve ntfree FU (ye ars)

No

Infectio n, anxiety, chronic pain syndro me

2.3

Anxiety, pain syndro me

Whole system remove d

-

11.5

Whole system remove d

Rx

2.7

Device inactiv ated

Rx

3.1

Device inactiv ated

LCS D

6.4

Genera tor remove d only

Rx

7.6

Whole system remove d

-

0.1

Whole system remove d

Rx

3.0

-

6.9

-

9.8

-

6.2

-

4.1

Asympt omatic & Malfunc tion (Fidelis lead dysfunc tion) Malfunc tion (Inappr opriate shock) Malfunc tion (Inappr opriate shock) Malfunc tion (Inappr opriate shock) Malfunc tion (lead fracture )

No

Lead dysfunct ion

5.5

25

No

Inappro priate shock, anxiety

6.0

Famil y histor y

26

No

Inappro priate shock

2.7

Class III – SC

Famil y histor y

10

No

Inappro priate shock

2.3

Class III SC

Famil y histor y

13

No

Lead fracture

7.5

39

No

Infectio n, Inappro priate shock, anxiety

5.0

Infectio n

46

7

F

LQT S

E1784 K– SCN5A

48 6

3 9

Class III – SC

Famil y histor y

8

F

Nor mal

-

41 2

-

Class III – NSC

Synco pe, ECG

19

No

Lead dysfunct ion

7.9

Overdia gnosis

9

M

Nor mal

-

40 7

-

Class III – NSC

Synco pe, ECG

16

No

Anxiety

4.4

Overdia gnosis

10

M

Nor mal

-

39 3

-

Class III – NSC

Synco pe, ECG

19

No

Infectio n

12.0

Overdia gnosis

11

F

Nor mal

-

46 9

-

Class III – NSC

Synco pe, Holte

41

No

Infectio n, Inappro

10.1

Overdia gnosis

Genera tor remove d only Whole system remove d Whole system remove d Leads remove d

26

r test

12

F

Nor mal

-

44 5

-

Class III – NSC

Synco pe, ECG

priate shock 10

No

Lead fracture

7.3

Overdia gnosis

Whole system remove d

-

0.27

*Alt, alternative; Dx, diagnosis; FU, follow-up; ICD, implantable cardioverter defibrillator; LCSD, left cardiac sympathetic denervation; NSC, no special circumstances; Rx, prescription medication (beta blockers); SC, special circumstances.