- Email: [email protected]
Implantable cardioverter defibrillator therapy for congenital long QT syndrome: A single-center experience
Implantable cardioverter defibrillator therapy for congenital long QT syndrome: A single-center experience Justin M. Horner, MD, MPH,* Masayoshi Kinoshita, MD,† Tracy L. Webster, RN,† Carla M. Haglund,* Paul A. Friedman, MD, FHRS,† Michael J. Ackerman, MD, PhD*†‡ From the *Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology, †Department of Medicine/ Division of Cardiovascular Diseases, and ‡Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, Minnesota. BACKGROUND Long QT syndrome’s (LQTS) marked heterogeneity necessitates both evidence-based and individualized therapeutic approaches.
.0001) were most predictive of an appropriate therapy. Importantly, no LQT-related deaths have occurred among the 408 nonICD–treated patients.
OBJECTIVE This study sought to analyze a single LQTS specialty center’s experience regarding the relationship between risk factors and appropriate ventricular fibrillation (VF)–terminating therapies among LQTS patients treated with an implantable cardioverterdefibrillator (ICD).
CONCLUSION The vast majority of LQTS patients can be treated effectively without an ICD. Potentially life-saving therapies were rendered at a 5% to 6% per year rate among those selected for ICD therapy; similar inappropriate shock frequencies were also noted. Secondary prevention, genotype, and QTc predicted those most likely to receive appropriate therapy. Although the ICD implant frequency is greatest among LQT3 patients, the greatest “save” rate has occurred among LQT2 women, who were assessed to be at high risk.
METHODS An internal review board–approved, retrospective analysis of the electronic medical records of 459 patients with genetically confirmed LQTS including the 51 patients (14 LQT1, 22 LQT2, and 15 LQT3) who received an ICD from 2000 to 2010 was performed. RESULTS Twelve patients (24%, 4 LQT1, 8 LQT2) experienced an appropriate, VF-terminating therapy with an average follow-up of 7.3 years, including 7 of 17 LQT2 female patients but none of the 15 LQT3 patients. Conversely, 15 (29%) patients (8 LQT3) have experienced an inappropriate shock. Secondary prevention indications (P ⫽ .008), non-LQT3 genotype (P ⫽ .02), QTc ⱖ 500 ms (P ⫽ .0008), documented syncope (P ⫽ .05), documented torsades de pointes (P ⫽ .003), and a negative family history (P ⫽
Introduction
KEYWORDS Long QT syndrome; Genetic testing; Sudden cardiac death; Ion channels; Implantable cardioverter defibrillator ABBREVIATIONS ACA ⫽ aborted cardiac arrest; ECG ⫽ electrocardiogram; ICD ⫽ implantable cardioverter-defibrillator; LCSD ⫽ left cardiac sympathetic denervation; LQTS ⫽ long QT syndrome; LQT1-3 ⫽ types 1 to 3 LQTS; SCD ⫽ sudden cardiac death; SVT ⫽ supraventricular tachycardia; TdP ⫽ torsades de pointes; VF ⫽ ventricular fibrillation (Heart Rhythm 2010;7:1616 –1622) © 2010 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
Congenital long QT syndrome (LQTS) clinically affects an estimated 1 in 2,500 individuals and typically presents with syncope, seizures, or sudden death. The fundamental abnormality in LQTS is a genetic defect leading to abnormal ion channel function.1–3 Hundreds of mutations throughout at least 12 LQTS susceptibility genes have been identified.4,5
The risk of life-threatening arrhythmias among patients with LQTS is based on conventional cardiac risk factors and genotypes.6,7 The heterogeneity of the phenotypic presentation of LQTS has resulted in multiple individualized therapeutic approaches that include pharmacotherapy, device implantation, and/or left cardiac sympathetic denervation (LCSD) surgery.
Drs. Horner and Kinoshita contributed equally to this work. Dr. Ackerman’s research program is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Dr. Ackerman is a consultant for PGxHealth and chairs their FAMILION Medical/Scientific Advisory Board (approved by Mayo Clinic’s Medical-Industry Relations Office and Conflict of Interests Review Board). In addition, “cardiac channel gene screen” and “know-how relating to long QT genetic testing” license agreements, resulting in consideration and royalty payments, were established between Genaissance Pharmaceuticals (now PGxHealth) and Mayo Medical Ventures (now Mayo Clinic Health Solutions) in 2004. Dr. Ackerman is also a consultant for Medtronic, Boston Scientific Corporation, and St. Jude Medical Inc; none of these entities provided financial support for this study.
Tracy Webster receives honoraria from Boston Scientific. Dr. Paul Friedman’s research is supported by Medtronic, Boston Scientific, Bard, St. Jude Medical, Pfizer Intellectual Property Rights - Bard EP, Hewlett Packard, Medical Positioning, Inc., Aegis Medical, NeoChord. Dr. Friedman is a consultant for Medtronic, Boston Scientific, and St. Jude Medical. However, none of these entities provided financial support for this study. Address reprint requests and correspondence: Dr. Michael J. Ackerman, Long QT Syndrome Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, Rochester, MN 55905. E-mail address: [email protected] (Received June 1, 2010; accepted August 29, 2010.)
1547-5271/$ -see front matter © 2010 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
doi:10.1016/j.hrthm.2010.08.023
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Table 1 Alphabetical listing of possible evidence-based risk factors for sudden death in LQTS used in the calculation of an individual’s ICD risk factor score Documented TdP Family history of sudden death Female patient ⱖ13 years old Infant with documented 2:1 atrioventricular block Intolerance to pharmacotherapy Jervelle and Lange-Nielsen syndrome LQT2 LQT3 Macroscopic T-wave alternans Male patient ⱕ12 years old QTc ⱖ 500 ms Syncope Syncope requiring cardiopulmonary resuscitation/external defibrillation Syncope while on pharmacotherapy LQT 2,3 ⫽ types 2 or 3 LQTS.
Despite compelling evidence indicating excellent protection by beta-blocker pharmacotherapy for the majority of patients with LQTS, the implantable cardioverter-defibrillator (ICD) has been used increasingly for patients with LQTS in general and LQT3 in particular.8 –11 Although ICD implantation is an important therapeutic approach for LQTS patients at high risk for sudden cardiac death (SCD), evidence regarding the subsets of LQTS patients who may benefit the most from ICD therapy remain limited.10,12,13 We therefore sought to describe the relationship between a variety of possible risk factors and appropriate VF-terminating ICD therapies among patients with genetically confirmed LQTS treated at a single tertiary/quaternary center.
Methods Study cohort and study design Between January 2000 and January 2010, more than 1,000 patients completed an evaluation at Mayo Clinic’s Long QT Syndrome Clinic in Rochester, Minnesota. Of those, 459 patients had genetically probable/possible types 1 to 3 LQTS (LQT1-3), including 231 with LQT1, 165 with LQT2, and 63 with LQT3, of which, 51 (11%) underwent ICD implantation at our institution. An internal review board–approved, retrospective analysis of the patients’ electronic medical records, including analysis of Mayo’s ICD databases for documentation of appropriate or inappropriate discharges, was conducted. Secondary prevention indications for ICD implantation included a documented history of syncope requiring cardiopulmonary resuscitation and/or external defibrillation. Primary-prevention ICD implantation was based on risk factor assessment, in the absence of antecedent cardiac arrest.7,14 Individual ICD risk factor assessment included positivity for characteristics in Table 1. Patients were given ⫹1 score for each risk factor criteria present, and then numbers were totaled to assign each patient a total risk factor score. No particular a priori weighting of the various risk factors was applied in this study.
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ICD device programming A single investigator (T.L.W.) blinded to patient clinical history, diagnoses, and genotype reviewed the ICD shock electrogram data retrospectively. Gathered information included pacing mode, lower rate limit, tachycardia detection rate and time, rate of episode, appropriate ICD shock versus inappropriate ICD shock, postshock mode and rate, and number of episodes.
Statistical analysis Summary statistics for categorical data were reported as number (percentage). Continuous data were reported as average (mean ⫾ SD). Comparisons of the data were made using chi-square tests. The Kaplan-Meier method and Cox proportional hazard models were also used for the appropriate end points. Data analysis was completed using JMP version 8.0 (SAS Institute, Cary, NC). In all cases, a P value ⬍ .05 was considered statistically significant. The authors had full access to the data and take responsibility for their integrity. All authors have read and agree to the article as written.
Results Population characteristics Table 2 summarizes the demographics for the 51 patients who underwent implantation at an average age of 25 ⫾ 12 years (range 4 to 54 years) including 14 of 231 (6%) with LQT1, 22 of 165 (13%) with LQT2, and 15 of 63 (24%) with LQT3. Thirty-six patients (71%) were female, and 43 (84%) received an ICD as primary prevention. At baseline, 31 patients (61%) were also prescribed pharmacological therapy (mostly betablockers). The average resting QTc was 497 ms, with 26 patients (51%) having a resting QTc ⱖ 500 ms. Twenty-seven patients (53%) had a history of syncope, and 11 (22%) had a history of syncope with resuscitation by cardiopulmonary resuscitation/external defibrillation. LQT3 genotype-positive patients had a higher percentage of positive family history of sudden death (80%), and they also received an ICD as primary prevention at a higher rate (100%). With each conventional risk factor receiving 1 point, the total average risk factor score was 3.9 ⫾ 1.5. Importantly, none of the non-ICD–treated, genotype-positive LQT1-3 patients (N ⫽ 408) experienced an LQT-related death during the same follow-up period of 80 ⫾ 33 months. Table 2
Demographics for the LQTS/ICD cohort
Male/female Average age (yrs) Positive sudden death family history QTc ⱖ 500 ms Beta-blocker use Follow-up time (mos)
LQT1 (N ⫽ 14)
LQT2 (N ⫽ 22)
LQT3 (N ⫽ 15)
5/9 20 ⫾ 11 7 (50%)
5/17 26 ⫾ 10 8 (36%)
5/10 30 ⫾ 14 12 (80%)
6 (43%) 10 (71%) 88 ⫾ 30
14 (64%) 14 (64%) 77 ⫾ 35
6 (40%) 7 (47%) 77 ⫾ 32
ICD ⫽ implantable cardioverter-defibrillator; LQT 1-3 ⫽ types 1, 2, or 3 LQTS; LQTS ⫽ long QT syndrome.
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ICD programming data The ICD pacing mode settings were VVI (32 patients), DDD (11), DDI (5), other (3). The ICD lower rate settings included 41 patients with settings between 30 and 40 beats/ min and 10 patients between 50 and 70 beats/min. Only 2 patients had ventricular rate smoothing programmed (both female, 1 LQT1 and 1 LQT2). Tachycardia detection time included 31 patients between 5 and 9 seconds and 20 patients between 2.7 and 4.8 seconds. Tachyarrhythmia duration included 15 patients ⬍5 seconds and 36 patients ⬎5 seconds (3.5 to 8.96 seconds). Postshock pacing mode settings were VVI (32 patients), DDD (12), DDI (4), and other (3). The ICD postshock pacing rate included 29 patients with settings between 30 and 40 beats/min and 22 patients between 50 and 100 beats/min. The ventricular fibrillation (VF) zone was generally programmed to ⬎220 beats/min for patients ⱕ30 years old and ⬎200 beats/min for those ⬎30 years old.
Appropriate ICD therapy Twelve patients (24%) received appropriate VF or torsades de pointes (TdP)-terminating ICD therapies, including 4 of 14 (29%) with LQT1 and 8 of 22 (36%) with LQT2. Nine of the 12 patients (75%) were ⱕ18 years old. Notably, 7 of
Heart Rhythm, Vol 7, No 11, November 2010 the 8 LQT2 patients who received an appropriate ICD therapy were female. In other words, 7 of the 17 LQT2 female patients who underwent implantation (41%) have received a VF-terminating therapy during the ICD’s first generator. The average ventricular rate recorded for all appropriate ICD therapies was 262 beats/min (range 213 to 343 beats/min). The average time from implantation to first inappropriate ICD therapy was 30 months. Eleven of these 12 patients had a negative family history for sudden death as well as a QTc ⱖ 500 ms. Ten of 12 patients experienced syncope, and 5 of the 12 patients had a documented history of TdP. Seven of 12 patients (4 of 4 LQT1 and 3 of 8 LQT2) who received appropriate ICD therapy were seemingly compliant with their nadolol/propranolol– based beta-blocker therapy at the time of their discharge. Of those, only 2 of the 12 patients (1 female patient on beta-blocker and 1 male patient not on beta-blocker, both LQT2) who received appropriate ICD therapy were asymptomatic at the time of implantation. Five patients have received more than 1 appropriate ICD therapy (2 LQT1, 3 LQT2). To date, none of the 15 LQT3 patients have received an appropriate discharge. Figure 1 and Table 3 summarize the Kaplan-Meier analysis P values of the clinical risk factor characteristics related to
Figure 1 Individual/cumulative risk factors and likelihood of an appropriate VF-terminating ICD therapy. (A) Primary versus secondary prevention and occurrence of appropriate ICD therapies over time. Patients who received implantations as “secondary prevention” (solid line) were far more likely to receive an appropriate ICD shock. (B) QTc and occurrence of appropriate ICD therapies over time. Patients with a QTc ⱖ 500 ms (solid line) were more likely to receive an appropriate ICD shock. (C) Genotype and occurrence of appropriate ICD therapies over time. So far, none of the patients with LQT3 (dashed line) have received an appropriate ICD shock. (D) Family history of premature sudden death and occurrence of appropriate ICD therapies over time. Patients with a positive (⫹) family history (dashed line) were far less likely to receive an appropriate ICD shock compared with those patients with a negative (⫺) family history (solid line) . ICD ⫽ implantable cardioverter-defibrillator; LQT 1-3 ⫽ types 1, 2, or 3 LQTS; VF ⫽ ventricular fibrillation.
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Table 3 Summary of individual and cumulative ICD risk factor scorecard elements related to appropriate ICD therapies (listed alphabetically) ICD risk factor scorecard Individual characteristics Documented torsades de pointes Female patient ⱖ13 years old Gender Intolerance to pharmacotherapy LQT1 genotype LQT2 genotype LQT3 genotype Male patient ⱕ12 years old Positive family history of sudden death QTc ⱖ 500 ms Syncope Syncope requiring cardiopulmonary resuscitation/external defibrillation Syncope while on pharmacotherapy Cumulative characteristics Secondary prevention Total risk factor score ⱖ5
P value .003* NS NS .25 .02* .02* NS NS NS .0008* .025* .05* .0005* .008* .0001*
Abbreviations as in Table 2. *P value ⱕ.05 is statistically significant.
appropriate ICD therapy. Secondary prevention indications (Figure 1A, P ⫽ .008), QTc ⬎ 500 ms (Figure 1B, P ⫽ .0008), non-LQT3 genotype (Figure 1C, P ⫽ .02), documented syncope P ⫽ .05), documented TdP (P ⫽ .003), and notably a negative sudden death family history (Figure 1D, P ⫽ .0001) predicted those ICD recipients most likely to receive an appropriate VF/TdP-terminating ICD therapy. At 7.3 years of follow-up, more than 80% of those patients implanted with an ICD as primary prevention remained free of an appropriate discharge, compared with just 40% to 50% of those who received implantations for secondary prevention indications. Forty-two percent of the QTc ⬎ 500 ms subset have received an appropriate ICD discharge during this follow-up period. In contrast, among the 28 patients (55%) who underwent implantation principally because of a positive family of sudden death, only 1 (LQT2 female patient) has received an appropriate ICD discharge. Instead, those patients without a family history of sudden death have experienced the majority of the appropriate discharges. Overall, genotype-positive LQT2 female patients with a QTc ⬎ 500 ms showed the highest rates of appropriate ICD therapy (data not shown). Cumulatively, those patients with a total risk factor score ⱖ5 were more likely to have an appropriate ICD therapy (Figure 2, P ⫽ .0001). This was associated with a statistically significant risk factor hazard ratio of 1.69.
Inappropriate ICD therapy Fifteen (29%) patients received an inappropriate ICD discharge, including 8 of the 15 LQT3 patients. Seven (47%) were ⱕ18 years old. Thus far, the LQT3 genotype-positive cohort has only received inappropriate discharges. The average ventricular rate recorded for these inappropriate ICD
therapies was 211 beats/min (range 185 to 260 beats/min). The average time from implantation to first inappropriate ICD therapy was 29 months. These 15 LQT3 patients were more likely to have a total risk factor score ⬍5 (P ⬍ .0001, average risk factor score 3). Nine of the 15 patients had a positive family history for sudden death, and 5 of the 15 patients had a QTc ⱖ 500 ms. Five of the 15 patients experienced syncope, and only 1 of the 15 patients had a documented history of TdP. Seven patients have received more than 1 inappropriate ICD therapy (1 LQT1, 2 LQT2, and 4 LQT3), whereas only 2 patients (1 male and 1 female patient, both LQT2) have received both appropriate and inappropriate ICD therapies. For reasons not clear, male rather than female patients were more likely to receive an inappropriate ICD therapy (P ⫽ .002, data not shown). Although most of these 15 patients had elected to discontinue beta-blocker therapy and have ICD monotherapy instead, 4 patients (1 with LQT1, 2 with LQT2, and 1 with LQT3) were purportedly compliant on beta-blockers at the time of their inappropriate shock. Despite a VF zone set at ⬎200 beats/min and according to the ICD recordings, the reasons for inappropriate therapies included: T-wave oversensing (n ⫽ 4, 1 LQT1 and 3 LQT3); sinus tachycardia (n ⫽ 4, 1 LQT1, 1 LQT2, and 2 LQT3); noise (n ⫽ 3, 1 LQT1 and 2 LQT2); supraventricular tachycardia (SVT) (n ⫽ 2, 1 LQT1 and 1 LQT3); and other (atrial fibrillation and lead failure (n ⫽ 2, LQT3). The most common reasons of inappropriate therapy overall were T-wave oversensing (35%) and sinus tachycardia (19%). The average supraventricular rate triggering inappropriate therapies was 207 beats/min.
Other adverse events So far, only 2 of 51 patients (4%; 29 and 41 years old) experienced pocket infections after implantation; the older patient required extraction. One patient (2%; 22 years old)
Figure 2 Patient’s “torsadogenic” risk factor score and occurrence of appropriate VF-terminating ICD therapy. Shown is the distribution of the number of “torsadogenic” risk factors for each patient with an appropriate VF-terminating ICD therapy (black diamonds) compared with those patients who have not yet received an appropriate ICD therapy (white diamonds). Note that a dot in the center of the diamond indicates that one of the risk factor points for that patient included a positive family history of sudden death. Abbreviations as in Figure 1.
1620 required surgical tricuspid valve repair because of severe regurgitation and symptomatic right heart failure. Two patients (4%) experienced a right ventricular perforation after implantation, 1 requiring pericardial tap and thoracentesis (18 years old) and the other direct surgical closure (8 years old). Finally, 13 patients (25%, 2 of 13 ⬍18 years old) have required lead revision or extraction/replacement because of lead sensing or failure issues during this ⬎7-year follow-up. Excepting the possible concomitant presence of inappropriate discharges, no patient has experienced more than 1 of these 4 aforementioned adverse events.
Discussion Concerns regarding the adequacy of protection afforded by beta-blocker therapy and the reportedly higher lethality/ event rate in LQT3 have likely compelled a relatively higher implant rate for patients with LQT3.6,8 Even in our center, nearly one quarter of the LQT3 patients, compared with only 6% of the LQT1 patients, were managed with a treatment strategy that included an ICD during this contemporary time period. However, to date, none of the LQT3 patients have experienced an appropriate ICD therapy (only inappropriate shocks), suggesting an over-implant rate even for this particular genotype. Currently, ICD therapy is a class IIb indication for patients with clinically diagnosed LQTS regardless of symptomatic status, QTc, and genotype.11 This guideline recommendation has perhaps fueled the currently observed “reflex” in North America whereby a diagnosis of LQTS seemingly equals an ICD. Unpublished comments have suggested that the ICD implantation rate exceeds 75% for patients diagnosed with LQTS in some centers. This is in stark contrast to our center’s experience, in which the vast majority of LQTS patients (approximately 90%) are successfully being managed without an ICD. Importantly, there have been no LQT-related deaths among either the vast majority of patients who have not received an ICD or this smaller subset of ICD-treated patients since the inception of Mayo Clinic’s LQTS clinic in 1998. Of those patients in our study with an ICD, nearly 85% received their device as primary prevention. Interestingly, LQT1 and LQT2 patients were more likely to be associated with appropriate ICD discharges compared with LQT3 patients, even after adjustment for gender, QTc, and primary or secondary prevention (LQT1 vs. LQT3, P ⬍ .02; LQT2 vs. LQT3, P ⬍ .02). Presently, the greatest “save” rate occurred among the LQT2-positive female patients deemed at high risk; a total risk score ⱖ5. In this single-center study, we observed that genotype (especially LQT2 female patients), a QTc ⬎ 500 ms, and secondary prevention indications were most predictive of receiving an appropriate ICD therapy. Sauer et al.15 observed similar findings, hence such patients (i.e., previously symptomatic LQT2 female patients with a QTc ⬎ 500 ms) may represent an actual evidencebased indication for ICD placement in LQTS. Importantly, however, a QTc ⬎ 500 ms should not prompt an ICD
Heart Rhythm, Vol 7, No 11, November 2010 recommendation by itself because a significant number (approximately 20%) of the 408 non-ICD–treated LQTS patients treated here exceeded this QTc threshold and are as alive as the 26 ICD-implanted patients who had a QTc ⬎ 500 ms (data not shown). Recognizing that the appropriate VF-terminating ICD therapies occurred in 4 LQT1 and 3 LQT2 patients while seemingly compliant on adequate doses of nadolol or propranolol suggests that the ICD was well chosen. However, dissecting precisely what it was that culled out these particular patients for an ICD recommendation compared with the non-ICD–treated patient population who remain on a conventional pharmacotherapy strategy requires further investigation. On the other hand, the individual risk factor score assessment proposed in this study gives hope for a more precise risk stratification of these patients. Past risk stratification studies including genotype in LQTS patients have used cardiac event end points such as syncope, cardiac arrest, and/or SCD.6,7 However, syncope is not as unambiguously detected as cardiac arrest and SCD. In contrast, all of the ventricular arrhythmia cardiac events in this study were recorded by the ICDs (concrete end points), allowing for more precise risk stratification. However, it should be acknowledged that appropriate ICD therapies are not necessarily equivalent surrogates to cardiac arrest given that some of these ventricular arrhythmias might have spontaneously terminated if an ICD was not in place. Nevertheless, in this study, those patients with a total risk factor score ⱖ 5 were much more likely to receive such an appropriate therapy. Therefore, systematically classifying these patients according to multiple risk factors could lead to more appropriate use of ICD therapy. Importantly, family history of sudden death is a powerful factor that influences the patient’s and physician’s decision process for an ICD indication. Yet Kaufman et al.16 discovered that family history of aborted cardiac arrest (ACA) or SCD may be principally an emotion-based risk factor rather than an evidence-based risk factor in LQTS, in contrast to other heritable sudden-death-predisposing, genetic heart diseases such as hypertrophic cardiomyopathy. This observation has been borne out in our single-center study as well, in which only 1 of the patients who underwent implantation primarily because of a positive family history of sudden death has received an appropriate shock to date. Although the follow-up period is still short (approximately 7 years on average), an ICD decision based solely on a positive family history should be discouraged in the management of patients with LQTS. Goldenberg et al.17 suggested that specific genotypes (LQT1, LQT2, and LQT3) in children did not contribute to the end points of ACA or SCD. Hobbs et al.18 also suggested the same result during adolescence. However, they also concluded that the LQT3 genotype was at higher risk of ACA or SCD in adults (age ⬎ 40 years).19 These studies suggested that gender, QTc, and history of syncope were associated with ACA or SCD. In contrast, our single-center
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study would support that genotype is an important risk factor to consider when stratifying a LQTS patient for treatment options. Nevertheless, both registry data and our single-center data indicate that an LQT2 woman with a resting QTc ⬎ 500 ms profiles the highest risk subject from the standpoint of a primary prevention ICD indication. Given that beta-blockers are less efficacious in the LQT2 host compared with the LQT1 host, our current clinical practice is to strongly consider prophylactic ICD therapy for previously symptomatic LQT2 women with a QTc ⬎ 500 ms.8 In addition, if legitimate levels of beta-blocker therapy cannot be introduced before encountering unacceptable side effects, an ICD recommendation or prophylactic left cardiac sympathetic denervation extends to the asymptomatic LQT2/QTc ⬎ 500 ms female patient. For those who receive an ICD, inappropriate discharges is an anticipated complication, with chances of inappropriate ICD discharges reported as high as 30%.20 –22 This frequency of inappropriate shocks (15 in 51, 29%) has been realized in our cohort as well, including 8 of the 15 LQT3 patients (⬎50%) having experienced an inappropriate ICD discharge. For reasons unknown, male patients were more likely to receive inappropriate therapies, and the most common reason for an inappropriate ICD discharge was T-wave oversensing. Interestingly, T-wave oversensing was more prevalent in the younger patients (ⱕ20 years old on average). On the other hand, the age of those patients who received an inappropriate ICD discharge because of SVT was greater than 38 years old on average. Notably, the prevalence of SVT in LQTS patients was higher than the normal population less than 50 years old, which is consistent with previous reports suggesting that genetically positive LQTS patients may have significantly higher rates of early-onset atrial fibrillation when compared with normal population-based rates.23 Friedman et al.20 showed that dual-chamber ICDs reduced the rates of SVT episodes, which originally were inappropriately classified as ventricular tachycardia, to 31% when compared with 40% in single-chamber ICDs. Among our population, 20 patients (39%) received dual-chamber ICDs. In this study, however, device type did not impact the chances of an inappropriate shock. Of the 15 patients who experienced an inappropriate shock, 8 had a single-chamber ICD and 7 had a dual-chamber ICD. Only 2 patients had an inappropriate shock secondary to SVT, occurring in 1 patient with a single-chamber ICD and in 1 patient with a dual-chamber ICD.
Study limitations A few limitations must be considered in this study. First, the patients included in this study were limited to the majority (75%) of LQTS patients having 1 of the 3 canonical LQTS genotypes. Therefore, no conclusions can be drawn regarding risk factors and ICD therapy for the subset of patients (25%) with genotype-negative/phenotype-positive LQTS. Second, the overall number of patients who received an ICD was small (n ⫽ 51), which did not allow appropriate hazard
1621 ratios to be calculated for all analyses, resulting in only a P value to be used. Third, the numbers are too small to permit an assessment of the exact location of the channel mutations for each patient to determine whether intragenic risk stratification (i.e., mutation type and mutation location for the LQT1/LQT2 patients) was additionally informative as previously shown.24,25 Fourth, although this study strongly suggests that the vast majority of patients with LQTS do not need an ICD because there have been no LQTS-related deaths in over 2,000 patient-years for the approximately 90% of patients treated without an ICD, further longitudinal studies are needed. Fifth, although it makes sense that an increased burden of the discrete risk factors itemized in Table 1 will predict those most likely to receive an appropriate VF-terminating ICD shock, it is unlikely that each of these risk factors are equipotent. It is possible that weighting the various risk factors could help identify the most at-risk host. Presently, we see that those ICD-implanted subjects with a cumulative risk score ⱖ 5 were 1.69 times more likely to receive an appropriate ICD shock during their first generator. However, compared with the data extraction from the electronic medical record for the 51 LQTS/ICD patients described in this study, the clinical phenotypes and cumulative risk factor scores have not been systematically analyzed for the majority population (N ⫽ 408) with genetically and clinically evident LQT1-3 who have not been treated with an ICD. Thus, we are not yet able to elucidate, for example, the overall likelihood of an appropriate VFterminating therapy in a LQT2-positive female patient with a QTc ⬎ 500 ms. Currently, there are over 140 LQT2positive patients being managed without an ICD in Mayo’s LQTS Clinic. Scrutinizing the phenotypes and determining a cumulative risk factor score for all of the patients without an ICD is necessary to identify patient phenotype(s) for which a prophylactic ICD is most clearly indicated. In so doing, it is likely that the current, universal class IIb indication for ICD therapy in LQTS will need to be revisited.
Conclusions In contrast to reports of high implantation rates in North America for LQTS in general and LQT3 in particular, the vast majority of LQTS patients can effectively be treated without an ICD. So far, just over 10% of the LQT1-3 genotype-positive patients seen at Mayo Clinic have received an ICD, and there have been no LQTS-related deaths in the much larger cohort of patients who have been managed without an ICD treatment strategy. This study revealed potentially lifesaving therapies occurring at a rate of 5% to 6% per year among those selected for ICD therapy, yet similar inappropriate therapy frequencies were also noted. Secondary prevention, non-LQT3 genotype, documented syncope, documented TdP, QTc ⬎ 500 ms, and notably a negative family history predicted those ICD recipients who were most likely to receive an appropriate therapy. The greatest “save” rate was seen in LQT2 genotype-positive high-risk female patients. Although the reflex to implant an ICD is arguably most rapid in LQT3, here the subpopulation
1622 of LQT3 patients who have received an implant prophylactically have only experienced ICD-related complications because no appropriate VF-terminating therapies have occurred in nearly 100 LQT3 patient-ICD years. In hopes of a more standard ICD therapeutic approach for LQTS patients, more research is needed to further delineate the phenotype(s) of the LQTS patient most in need of a prophylactic ICD. An individual risk factor scorecard, such as the one proposed in this study, may help identify the LQTS patients most in need of a prophylactic ICD, and as importantly, may provide evidence-based reassurance to short circuit the ICD in LQTS reflex.
Acknowledgements The authors thank the patients and families who have sought clinical evaluation at Mayo Clinic’s Long QT Syndrome Clinic.
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25.
arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e385– e484. Zareba W, Moss AJ, Daubert JP, Hall WJ, Robinson JL, Andrews M. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol 2003;14:337–341. Monnig G, Kobe J, Loher A, Eckardt L, Wedekind H, Scheld HH, et al. Implantable cardioverter-defibrillator therapy in patients with congenital long-QT syndrome: a long-term follow-up. Heart Rhythm 2005;2:497–504. Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998;97:2237–2244. Sauer AJ, Moss AJ, McNitt S, Peterson DR, Zareba W, Robinson JL, et al. Long QT syndrome in adults. J Am Coll Cardiol 2007;49:329 –337. Kaufman ES, McNitt S, Moss AJ, Zareba W, Robinson JL, Hall WJ, et al. Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm 2008;5:831– 836. Goldenberg IMD, Moss AJMD, Peterson DRP, McNitt SMS, Zareba WMDP, Andrews MLBBA, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 2008;117:2184 –2191. Hobbs JB, Peterson DR, Moss AJ, McNitt S, Zareba W, Goldenberg I, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA 2006;296:1249 –1254. Goldenberg IMD, Moss AJMD, Bradley JMS, Polonsky SMS, Peterson DRP, McNitt SMS, et al. Long-QT syndrome after age 40. Circulation 2008;117: 2192–2201. Friedman PAMD, McClelland RLP, Bamlet WRMS, Acosta HMD, Kessler DMD, Munger TMMD, et al. Dual-chamber versus single-chamber detection enhancements for implantable defibrillator rhythm diagnosis: the Detect Supraventricular Tachycardia Study. Circulation 2006;113:2871–2879. Deisenhofer I, Kolb C, Ndrepepa G, Schreieck J, Karch M, Schmieder S, et al. Do current dual chamber cardioverter defibrillators have advantages over conventional single chamber cardioverter defibrillators in reducing inappropriate therapies? A randomized, prospective study. J Cardiovasc Electrophysiol 2001; 12:134 –142. Hintringer F, Schwarzacher S, Eibl G, Pachinger O. Inappropriate detection of supraventricular arrhythmias by implantable dual chamber defibrillators: a comparison of four different algorithms. Pacing Clin Electrophysiol 2001;24:835– 841. Johnson JN, Tester DJ, Perry J, Salisbury BA, Reed CR, Ackerman MJ. Prevalence of early-onset atrial fibrillation in congenital long QT syndrome. Heart Rhythm 2008;5:704 –709. Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007;115:2481–2489. Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol 2009;54:2052–2062.
.0001) were most predictive of an appropriate therapy. Importantly, no LQT-related deaths have occurred among the 408 nonICD–treated patients.
OBJECTIVE This study sought to analyze a single LQTS specialty center’s experience regarding the relationship between risk factors and appropriate ventricular fibrillation (VF)–terminating therapies among LQTS patients treated with an implantable cardioverterdefibrillator (ICD).
CONCLUSION The vast majority of LQTS patients can be treated effectively without an ICD. Potentially life-saving therapies were rendered at a 5% to 6% per year rate among those selected for ICD therapy; similar inappropriate shock frequencies were also noted. Secondary prevention, genotype, and QTc predicted those most likely to receive appropriate therapy. Although the ICD implant frequency is greatest among LQT3 patients, the greatest “save” rate has occurred among LQT2 women, who were assessed to be at high risk.
METHODS An internal review board–approved, retrospective analysis of the electronic medical records of 459 patients with genetically confirmed LQTS including the 51 patients (14 LQT1, 22 LQT2, and 15 LQT3) who received an ICD from 2000 to 2010 was performed. RESULTS Twelve patients (24%, 4 LQT1, 8 LQT2) experienced an appropriate, VF-terminating therapy with an average follow-up of 7.3 years, including 7 of 17 LQT2 female patients but none of the 15 LQT3 patients. Conversely, 15 (29%) patients (8 LQT3) have experienced an inappropriate shock. Secondary prevention indications (P ⫽ .008), non-LQT3 genotype (P ⫽ .02), QTc ⱖ 500 ms (P ⫽ .0008), documented syncope (P ⫽ .05), documented torsades de pointes (P ⫽ .003), and a negative family history (P ⫽
Introduction
KEYWORDS Long QT syndrome; Genetic testing; Sudden cardiac death; Ion channels; Implantable cardioverter defibrillator ABBREVIATIONS ACA ⫽ aborted cardiac arrest; ECG ⫽ electrocardiogram; ICD ⫽ implantable cardioverter-defibrillator; LCSD ⫽ left cardiac sympathetic denervation; LQTS ⫽ long QT syndrome; LQT1-3 ⫽ types 1 to 3 LQTS; SCD ⫽ sudden cardiac death; SVT ⫽ supraventricular tachycardia; TdP ⫽ torsades de pointes; VF ⫽ ventricular fibrillation (Heart Rhythm 2010;7:1616 –1622) © 2010 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
Congenital long QT syndrome (LQTS) clinically affects an estimated 1 in 2,500 individuals and typically presents with syncope, seizures, or sudden death. The fundamental abnormality in LQTS is a genetic defect leading to abnormal ion channel function.1–3 Hundreds of mutations throughout at least 12 LQTS susceptibility genes have been identified.4,5
The risk of life-threatening arrhythmias among patients with LQTS is based on conventional cardiac risk factors and genotypes.6,7 The heterogeneity of the phenotypic presentation of LQTS has resulted in multiple individualized therapeutic approaches that include pharmacotherapy, device implantation, and/or left cardiac sympathetic denervation (LCSD) surgery.
Drs. Horner and Kinoshita contributed equally to this work. Dr. Ackerman’s research program is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Dr. Ackerman is a consultant for PGxHealth and chairs their FAMILION Medical/Scientific Advisory Board (approved by Mayo Clinic’s Medical-Industry Relations Office and Conflict of Interests Review Board). In addition, “cardiac channel gene screen” and “know-how relating to long QT genetic testing” license agreements, resulting in consideration and royalty payments, were established between Genaissance Pharmaceuticals (now PGxHealth) and Mayo Medical Ventures (now Mayo Clinic Health Solutions) in 2004. Dr. Ackerman is also a consultant for Medtronic, Boston Scientific Corporation, and St. Jude Medical Inc; none of these entities provided financial support for this study.
Tracy Webster receives honoraria from Boston Scientific. Dr. Paul Friedman’s research is supported by Medtronic, Boston Scientific, Bard, St. Jude Medical, Pfizer Intellectual Property Rights - Bard EP, Hewlett Packard, Medical Positioning, Inc., Aegis Medical, NeoChord. Dr. Friedman is a consultant for Medtronic, Boston Scientific, and St. Jude Medical. However, none of these entities provided financial support for this study. Address reprint requests and correspondence: Dr. Michael J. Ackerman, Long QT Syndrome Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, Rochester, MN 55905. E-mail address: [email protected] (Received June 1, 2010; accepted August 29, 2010.)
1547-5271/$ -see front matter © 2010 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
doi:10.1016/j.hrthm.2010.08.023
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Table 1 Alphabetical listing of possible evidence-based risk factors for sudden death in LQTS used in the calculation of an individual’s ICD risk factor score Documented TdP Family history of sudden death Female patient ⱖ13 years old Infant with documented 2:1 atrioventricular block Intolerance to pharmacotherapy Jervelle and Lange-Nielsen syndrome LQT2 LQT3 Macroscopic T-wave alternans Male patient ⱕ12 years old QTc ⱖ 500 ms Syncope Syncope requiring cardiopulmonary resuscitation/external defibrillation Syncope while on pharmacotherapy LQT 2,3 ⫽ types 2 or 3 LQTS.
Despite compelling evidence indicating excellent protection by beta-blocker pharmacotherapy for the majority of patients with LQTS, the implantable cardioverter-defibrillator (ICD) has been used increasingly for patients with LQTS in general and LQT3 in particular.8 –11 Although ICD implantation is an important therapeutic approach for LQTS patients at high risk for sudden cardiac death (SCD), evidence regarding the subsets of LQTS patients who may benefit the most from ICD therapy remain limited.10,12,13 We therefore sought to describe the relationship between a variety of possible risk factors and appropriate VF-terminating ICD therapies among patients with genetically confirmed LQTS treated at a single tertiary/quaternary center.
Methods Study cohort and study design Between January 2000 and January 2010, more than 1,000 patients completed an evaluation at Mayo Clinic’s Long QT Syndrome Clinic in Rochester, Minnesota. Of those, 459 patients had genetically probable/possible types 1 to 3 LQTS (LQT1-3), including 231 with LQT1, 165 with LQT2, and 63 with LQT3, of which, 51 (11%) underwent ICD implantation at our institution. An internal review board–approved, retrospective analysis of the patients’ electronic medical records, including analysis of Mayo’s ICD databases for documentation of appropriate or inappropriate discharges, was conducted. Secondary prevention indications for ICD implantation included a documented history of syncope requiring cardiopulmonary resuscitation and/or external defibrillation. Primary-prevention ICD implantation was based on risk factor assessment, in the absence of antecedent cardiac arrest.7,14 Individual ICD risk factor assessment included positivity for characteristics in Table 1. Patients were given ⫹1 score for each risk factor criteria present, and then numbers were totaled to assign each patient a total risk factor score. No particular a priori weighting of the various risk factors was applied in this study.
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ICD device programming A single investigator (T.L.W.) blinded to patient clinical history, diagnoses, and genotype reviewed the ICD shock electrogram data retrospectively. Gathered information included pacing mode, lower rate limit, tachycardia detection rate and time, rate of episode, appropriate ICD shock versus inappropriate ICD shock, postshock mode and rate, and number of episodes.
Statistical analysis Summary statistics for categorical data were reported as number (percentage). Continuous data were reported as average (mean ⫾ SD). Comparisons of the data were made using chi-square tests. The Kaplan-Meier method and Cox proportional hazard models were also used for the appropriate end points. Data analysis was completed using JMP version 8.0 (SAS Institute, Cary, NC). In all cases, a P value ⬍ .05 was considered statistically significant. The authors had full access to the data and take responsibility for their integrity. All authors have read and agree to the article as written.
Results Population characteristics Table 2 summarizes the demographics for the 51 patients who underwent implantation at an average age of 25 ⫾ 12 years (range 4 to 54 years) including 14 of 231 (6%) with LQT1, 22 of 165 (13%) with LQT2, and 15 of 63 (24%) with LQT3. Thirty-six patients (71%) were female, and 43 (84%) received an ICD as primary prevention. At baseline, 31 patients (61%) were also prescribed pharmacological therapy (mostly betablockers). The average resting QTc was 497 ms, with 26 patients (51%) having a resting QTc ⱖ 500 ms. Twenty-seven patients (53%) had a history of syncope, and 11 (22%) had a history of syncope with resuscitation by cardiopulmonary resuscitation/external defibrillation. LQT3 genotype-positive patients had a higher percentage of positive family history of sudden death (80%), and they also received an ICD as primary prevention at a higher rate (100%). With each conventional risk factor receiving 1 point, the total average risk factor score was 3.9 ⫾ 1.5. Importantly, none of the non-ICD–treated, genotype-positive LQT1-3 patients (N ⫽ 408) experienced an LQT-related death during the same follow-up period of 80 ⫾ 33 months. Table 2
Demographics for the LQTS/ICD cohort
Male/female Average age (yrs) Positive sudden death family history QTc ⱖ 500 ms Beta-blocker use Follow-up time (mos)
LQT1 (N ⫽ 14)
LQT2 (N ⫽ 22)
LQT3 (N ⫽ 15)
5/9 20 ⫾ 11 7 (50%)
5/17 26 ⫾ 10 8 (36%)
5/10 30 ⫾ 14 12 (80%)
6 (43%) 10 (71%) 88 ⫾ 30
14 (64%) 14 (64%) 77 ⫾ 35
6 (40%) 7 (47%) 77 ⫾ 32
ICD ⫽ implantable cardioverter-defibrillator; LQT 1-3 ⫽ types 1, 2, or 3 LQTS; LQTS ⫽ long QT syndrome.
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ICD programming data The ICD pacing mode settings were VVI (32 patients), DDD (11), DDI (5), other (3). The ICD lower rate settings included 41 patients with settings between 30 and 40 beats/ min and 10 patients between 50 and 70 beats/min. Only 2 patients had ventricular rate smoothing programmed (both female, 1 LQT1 and 1 LQT2). Tachycardia detection time included 31 patients between 5 and 9 seconds and 20 patients between 2.7 and 4.8 seconds. Tachyarrhythmia duration included 15 patients ⬍5 seconds and 36 patients ⬎5 seconds (3.5 to 8.96 seconds). Postshock pacing mode settings were VVI (32 patients), DDD (12), DDI (4), and other (3). The ICD postshock pacing rate included 29 patients with settings between 30 and 40 beats/min and 22 patients between 50 and 100 beats/min. The ventricular fibrillation (VF) zone was generally programmed to ⬎220 beats/min for patients ⱕ30 years old and ⬎200 beats/min for those ⬎30 years old.
Appropriate ICD therapy Twelve patients (24%) received appropriate VF or torsades de pointes (TdP)-terminating ICD therapies, including 4 of 14 (29%) with LQT1 and 8 of 22 (36%) with LQT2. Nine of the 12 patients (75%) were ⱕ18 years old. Notably, 7 of
Heart Rhythm, Vol 7, No 11, November 2010 the 8 LQT2 patients who received an appropriate ICD therapy were female. In other words, 7 of the 17 LQT2 female patients who underwent implantation (41%) have received a VF-terminating therapy during the ICD’s first generator. The average ventricular rate recorded for all appropriate ICD therapies was 262 beats/min (range 213 to 343 beats/min). The average time from implantation to first inappropriate ICD therapy was 30 months. Eleven of these 12 patients had a negative family history for sudden death as well as a QTc ⱖ 500 ms. Ten of 12 patients experienced syncope, and 5 of the 12 patients had a documented history of TdP. Seven of 12 patients (4 of 4 LQT1 and 3 of 8 LQT2) who received appropriate ICD therapy were seemingly compliant with their nadolol/propranolol– based beta-blocker therapy at the time of their discharge. Of those, only 2 of the 12 patients (1 female patient on beta-blocker and 1 male patient not on beta-blocker, both LQT2) who received appropriate ICD therapy were asymptomatic at the time of implantation. Five patients have received more than 1 appropriate ICD therapy (2 LQT1, 3 LQT2). To date, none of the 15 LQT3 patients have received an appropriate discharge. Figure 1 and Table 3 summarize the Kaplan-Meier analysis P values of the clinical risk factor characteristics related to
Figure 1 Individual/cumulative risk factors and likelihood of an appropriate VF-terminating ICD therapy. (A) Primary versus secondary prevention and occurrence of appropriate ICD therapies over time. Patients who received implantations as “secondary prevention” (solid line) were far more likely to receive an appropriate ICD shock. (B) QTc and occurrence of appropriate ICD therapies over time. Patients with a QTc ⱖ 500 ms (solid line) were more likely to receive an appropriate ICD shock. (C) Genotype and occurrence of appropriate ICD therapies over time. So far, none of the patients with LQT3 (dashed line) have received an appropriate ICD shock. (D) Family history of premature sudden death and occurrence of appropriate ICD therapies over time. Patients with a positive (⫹) family history (dashed line) were far less likely to receive an appropriate ICD shock compared with those patients with a negative (⫺) family history (solid line) . ICD ⫽ implantable cardioverter-defibrillator; LQT 1-3 ⫽ types 1, 2, or 3 LQTS; VF ⫽ ventricular fibrillation.
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Table 3 Summary of individual and cumulative ICD risk factor scorecard elements related to appropriate ICD therapies (listed alphabetically) ICD risk factor scorecard Individual characteristics Documented torsades de pointes Female patient ⱖ13 years old Gender Intolerance to pharmacotherapy LQT1 genotype LQT2 genotype LQT3 genotype Male patient ⱕ12 years old Positive family history of sudden death QTc ⱖ 500 ms Syncope Syncope requiring cardiopulmonary resuscitation/external defibrillation Syncope while on pharmacotherapy Cumulative characteristics Secondary prevention Total risk factor score ⱖ5
P value .003* NS NS .25 .02* .02* NS NS NS .0008* .025* .05* .0005* .008* .0001*
Abbreviations as in Table 2. *P value ⱕ.05 is statistically significant.
appropriate ICD therapy. Secondary prevention indications (Figure 1A, P ⫽ .008), QTc ⬎ 500 ms (Figure 1B, P ⫽ .0008), non-LQT3 genotype (Figure 1C, P ⫽ .02), documented syncope P ⫽ .05), documented TdP (P ⫽ .003), and notably a negative sudden death family history (Figure 1D, P ⫽ .0001) predicted those ICD recipients most likely to receive an appropriate VF/TdP-terminating ICD therapy. At 7.3 years of follow-up, more than 80% of those patients implanted with an ICD as primary prevention remained free of an appropriate discharge, compared with just 40% to 50% of those who received implantations for secondary prevention indications. Forty-two percent of the QTc ⬎ 500 ms subset have received an appropriate ICD discharge during this follow-up period. In contrast, among the 28 patients (55%) who underwent implantation principally because of a positive family of sudden death, only 1 (LQT2 female patient) has received an appropriate ICD discharge. Instead, those patients without a family history of sudden death have experienced the majority of the appropriate discharges. Overall, genotype-positive LQT2 female patients with a QTc ⬎ 500 ms showed the highest rates of appropriate ICD therapy (data not shown). Cumulatively, those patients with a total risk factor score ⱖ5 were more likely to have an appropriate ICD therapy (Figure 2, P ⫽ .0001). This was associated with a statistically significant risk factor hazard ratio of 1.69.
Inappropriate ICD therapy Fifteen (29%) patients received an inappropriate ICD discharge, including 8 of the 15 LQT3 patients. Seven (47%) were ⱕ18 years old. Thus far, the LQT3 genotype-positive cohort has only received inappropriate discharges. The average ventricular rate recorded for these inappropriate ICD
therapies was 211 beats/min (range 185 to 260 beats/min). The average time from implantation to first inappropriate ICD therapy was 29 months. These 15 LQT3 patients were more likely to have a total risk factor score ⬍5 (P ⬍ .0001, average risk factor score 3). Nine of the 15 patients had a positive family history for sudden death, and 5 of the 15 patients had a QTc ⱖ 500 ms. Five of the 15 patients experienced syncope, and only 1 of the 15 patients had a documented history of TdP. Seven patients have received more than 1 inappropriate ICD therapy (1 LQT1, 2 LQT2, and 4 LQT3), whereas only 2 patients (1 male and 1 female patient, both LQT2) have received both appropriate and inappropriate ICD therapies. For reasons not clear, male rather than female patients were more likely to receive an inappropriate ICD therapy (P ⫽ .002, data not shown). Although most of these 15 patients had elected to discontinue beta-blocker therapy and have ICD monotherapy instead, 4 patients (1 with LQT1, 2 with LQT2, and 1 with LQT3) were purportedly compliant on beta-blockers at the time of their inappropriate shock. Despite a VF zone set at ⬎200 beats/min and according to the ICD recordings, the reasons for inappropriate therapies included: T-wave oversensing (n ⫽ 4, 1 LQT1 and 3 LQT3); sinus tachycardia (n ⫽ 4, 1 LQT1, 1 LQT2, and 2 LQT3); noise (n ⫽ 3, 1 LQT1 and 2 LQT2); supraventricular tachycardia (SVT) (n ⫽ 2, 1 LQT1 and 1 LQT3); and other (atrial fibrillation and lead failure (n ⫽ 2, LQT3). The most common reasons of inappropriate therapy overall were T-wave oversensing (35%) and sinus tachycardia (19%). The average supraventricular rate triggering inappropriate therapies was 207 beats/min.
Other adverse events So far, only 2 of 51 patients (4%; 29 and 41 years old) experienced pocket infections after implantation; the older patient required extraction. One patient (2%; 22 years old)
Figure 2 Patient’s “torsadogenic” risk factor score and occurrence of appropriate VF-terminating ICD therapy. Shown is the distribution of the number of “torsadogenic” risk factors for each patient with an appropriate VF-terminating ICD therapy (black diamonds) compared with those patients who have not yet received an appropriate ICD therapy (white diamonds). Note that a dot in the center of the diamond indicates that one of the risk factor points for that patient included a positive family history of sudden death. Abbreviations as in Figure 1.
1620 required surgical tricuspid valve repair because of severe regurgitation and symptomatic right heart failure. Two patients (4%) experienced a right ventricular perforation after implantation, 1 requiring pericardial tap and thoracentesis (18 years old) and the other direct surgical closure (8 years old). Finally, 13 patients (25%, 2 of 13 ⬍18 years old) have required lead revision or extraction/replacement because of lead sensing or failure issues during this ⬎7-year follow-up. Excepting the possible concomitant presence of inappropriate discharges, no patient has experienced more than 1 of these 4 aforementioned adverse events.
Discussion Concerns regarding the adequacy of protection afforded by beta-blocker therapy and the reportedly higher lethality/ event rate in LQT3 have likely compelled a relatively higher implant rate for patients with LQT3.6,8 Even in our center, nearly one quarter of the LQT3 patients, compared with only 6% of the LQT1 patients, were managed with a treatment strategy that included an ICD during this contemporary time period. However, to date, none of the LQT3 patients have experienced an appropriate ICD therapy (only inappropriate shocks), suggesting an over-implant rate even for this particular genotype. Currently, ICD therapy is a class IIb indication for patients with clinically diagnosed LQTS regardless of symptomatic status, QTc, and genotype.11 This guideline recommendation has perhaps fueled the currently observed “reflex” in North America whereby a diagnosis of LQTS seemingly equals an ICD. Unpublished comments have suggested that the ICD implantation rate exceeds 75% for patients diagnosed with LQTS in some centers. This is in stark contrast to our center’s experience, in which the vast majority of LQTS patients (approximately 90%) are successfully being managed without an ICD. Importantly, there have been no LQT-related deaths among either the vast majority of patients who have not received an ICD or this smaller subset of ICD-treated patients since the inception of Mayo Clinic’s LQTS clinic in 1998. Of those patients in our study with an ICD, nearly 85% received their device as primary prevention. Interestingly, LQT1 and LQT2 patients were more likely to be associated with appropriate ICD discharges compared with LQT3 patients, even after adjustment for gender, QTc, and primary or secondary prevention (LQT1 vs. LQT3, P ⬍ .02; LQT2 vs. LQT3, P ⬍ .02). Presently, the greatest “save” rate occurred among the LQT2-positive female patients deemed at high risk; a total risk score ⱖ5. In this single-center study, we observed that genotype (especially LQT2 female patients), a QTc ⬎ 500 ms, and secondary prevention indications were most predictive of receiving an appropriate ICD therapy. Sauer et al.15 observed similar findings, hence such patients (i.e., previously symptomatic LQT2 female patients with a QTc ⬎ 500 ms) may represent an actual evidencebased indication for ICD placement in LQTS. Importantly, however, a QTc ⬎ 500 ms should not prompt an ICD
Heart Rhythm, Vol 7, No 11, November 2010 recommendation by itself because a significant number (approximately 20%) of the 408 non-ICD–treated LQTS patients treated here exceeded this QTc threshold and are as alive as the 26 ICD-implanted patients who had a QTc ⬎ 500 ms (data not shown). Recognizing that the appropriate VF-terminating ICD therapies occurred in 4 LQT1 and 3 LQT2 patients while seemingly compliant on adequate doses of nadolol or propranolol suggests that the ICD was well chosen. However, dissecting precisely what it was that culled out these particular patients for an ICD recommendation compared with the non-ICD–treated patient population who remain on a conventional pharmacotherapy strategy requires further investigation. On the other hand, the individual risk factor score assessment proposed in this study gives hope for a more precise risk stratification of these patients. Past risk stratification studies including genotype in LQTS patients have used cardiac event end points such as syncope, cardiac arrest, and/or SCD.6,7 However, syncope is not as unambiguously detected as cardiac arrest and SCD. In contrast, all of the ventricular arrhythmia cardiac events in this study were recorded by the ICDs (concrete end points), allowing for more precise risk stratification. However, it should be acknowledged that appropriate ICD therapies are not necessarily equivalent surrogates to cardiac arrest given that some of these ventricular arrhythmias might have spontaneously terminated if an ICD was not in place. Nevertheless, in this study, those patients with a total risk factor score ⱖ 5 were much more likely to receive such an appropriate therapy. Therefore, systematically classifying these patients according to multiple risk factors could lead to more appropriate use of ICD therapy. Importantly, family history of sudden death is a powerful factor that influences the patient’s and physician’s decision process for an ICD indication. Yet Kaufman et al.16 discovered that family history of aborted cardiac arrest (ACA) or SCD may be principally an emotion-based risk factor rather than an evidence-based risk factor in LQTS, in contrast to other heritable sudden-death-predisposing, genetic heart diseases such as hypertrophic cardiomyopathy. This observation has been borne out in our single-center study as well, in which only 1 of the patients who underwent implantation primarily because of a positive family history of sudden death has received an appropriate shock to date. Although the follow-up period is still short (approximately 7 years on average), an ICD decision based solely on a positive family history should be discouraged in the management of patients with LQTS. Goldenberg et al.17 suggested that specific genotypes (LQT1, LQT2, and LQT3) in children did not contribute to the end points of ACA or SCD. Hobbs et al.18 also suggested the same result during adolescence. However, they also concluded that the LQT3 genotype was at higher risk of ACA or SCD in adults (age ⬎ 40 years).19 These studies suggested that gender, QTc, and history of syncope were associated with ACA or SCD. In contrast, our single-center
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study would support that genotype is an important risk factor to consider when stratifying a LQTS patient for treatment options. Nevertheless, both registry data and our single-center data indicate that an LQT2 woman with a resting QTc ⬎ 500 ms profiles the highest risk subject from the standpoint of a primary prevention ICD indication. Given that beta-blockers are less efficacious in the LQT2 host compared with the LQT1 host, our current clinical practice is to strongly consider prophylactic ICD therapy for previously symptomatic LQT2 women with a QTc ⬎ 500 ms.8 In addition, if legitimate levels of beta-blocker therapy cannot be introduced before encountering unacceptable side effects, an ICD recommendation or prophylactic left cardiac sympathetic denervation extends to the asymptomatic LQT2/QTc ⬎ 500 ms female patient. For those who receive an ICD, inappropriate discharges is an anticipated complication, with chances of inappropriate ICD discharges reported as high as 30%.20 –22 This frequency of inappropriate shocks (15 in 51, 29%) has been realized in our cohort as well, including 8 of the 15 LQT3 patients (⬎50%) having experienced an inappropriate ICD discharge. For reasons unknown, male patients were more likely to receive inappropriate therapies, and the most common reason for an inappropriate ICD discharge was T-wave oversensing. Interestingly, T-wave oversensing was more prevalent in the younger patients (ⱕ20 years old on average). On the other hand, the age of those patients who received an inappropriate ICD discharge because of SVT was greater than 38 years old on average. Notably, the prevalence of SVT in LQTS patients was higher than the normal population less than 50 years old, which is consistent with previous reports suggesting that genetically positive LQTS patients may have significantly higher rates of early-onset atrial fibrillation when compared with normal population-based rates.23 Friedman et al.20 showed that dual-chamber ICDs reduced the rates of SVT episodes, which originally were inappropriately classified as ventricular tachycardia, to 31% when compared with 40% in single-chamber ICDs. Among our population, 20 patients (39%) received dual-chamber ICDs. In this study, however, device type did not impact the chances of an inappropriate shock. Of the 15 patients who experienced an inappropriate shock, 8 had a single-chamber ICD and 7 had a dual-chamber ICD. Only 2 patients had an inappropriate shock secondary to SVT, occurring in 1 patient with a single-chamber ICD and in 1 patient with a dual-chamber ICD.
Study limitations A few limitations must be considered in this study. First, the patients included in this study were limited to the majority (75%) of LQTS patients having 1 of the 3 canonical LQTS genotypes. Therefore, no conclusions can be drawn regarding risk factors and ICD therapy for the subset of patients (25%) with genotype-negative/phenotype-positive LQTS. Second, the overall number of patients who received an ICD was small (n ⫽ 51), which did not allow appropriate hazard
1621 ratios to be calculated for all analyses, resulting in only a P value to be used. Third, the numbers are too small to permit an assessment of the exact location of the channel mutations for each patient to determine whether intragenic risk stratification (i.e., mutation type and mutation location for the LQT1/LQT2 patients) was additionally informative as previously shown.24,25 Fourth, although this study strongly suggests that the vast majority of patients with LQTS do not need an ICD because there have been no LQTS-related deaths in over 2,000 patient-years for the approximately 90% of patients treated without an ICD, further longitudinal studies are needed. Fifth, although it makes sense that an increased burden of the discrete risk factors itemized in Table 1 will predict those most likely to receive an appropriate VF-terminating ICD shock, it is unlikely that each of these risk factors are equipotent. It is possible that weighting the various risk factors could help identify the most at-risk host. Presently, we see that those ICD-implanted subjects with a cumulative risk score ⱖ 5 were 1.69 times more likely to receive an appropriate ICD shock during their first generator. However, compared with the data extraction from the electronic medical record for the 51 LQTS/ICD patients described in this study, the clinical phenotypes and cumulative risk factor scores have not been systematically analyzed for the majority population (N ⫽ 408) with genetically and clinically evident LQT1-3 who have not been treated with an ICD. Thus, we are not yet able to elucidate, for example, the overall likelihood of an appropriate VFterminating therapy in a LQT2-positive female patient with a QTc ⬎ 500 ms. Currently, there are over 140 LQT2positive patients being managed without an ICD in Mayo’s LQTS Clinic. Scrutinizing the phenotypes and determining a cumulative risk factor score for all of the patients without an ICD is necessary to identify patient phenotype(s) for which a prophylactic ICD is most clearly indicated. In so doing, it is likely that the current, universal class IIb indication for ICD therapy in LQTS will need to be revisited.
Conclusions In contrast to reports of high implantation rates in North America for LQTS in general and LQT3 in particular, the vast majority of LQTS patients can effectively be treated without an ICD. So far, just over 10% of the LQT1-3 genotype-positive patients seen at Mayo Clinic have received an ICD, and there have been no LQTS-related deaths in the much larger cohort of patients who have been managed without an ICD treatment strategy. This study revealed potentially lifesaving therapies occurring at a rate of 5% to 6% per year among those selected for ICD therapy, yet similar inappropriate therapy frequencies were also noted. Secondary prevention, non-LQT3 genotype, documented syncope, documented TdP, QTc ⬎ 500 ms, and notably a negative family history predicted those ICD recipients who were most likely to receive an appropriate therapy. The greatest “save” rate was seen in LQT2 genotype-positive high-risk female patients. Although the reflex to implant an ICD is arguably most rapid in LQT3, here the subpopulation
1622 of LQT3 patients who have received an implant prophylactically have only experienced ICD-related complications because no appropriate VF-terminating therapies have occurred in nearly 100 LQT3 patient-ICD years. In hopes of a more standard ICD therapeutic approach for LQTS patients, more research is needed to further delineate the phenotype(s) of the LQTS patient most in need of a prophylactic ICD. An individual risk factor scorecard, such as the one proposed in this study, may help identify the LQTS patients most in need of a prophylactic ICD, and as importantly, may provide evidence-based reassurance to short circuit the ICD in LQTS reflex.
Acknowledgements The authors thank the patients and families who have sought clinical evaluation at Mayo Clinic’s Long QT Syndrome Clinic.
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