- Email: [email protected]
Epinephrine QT stress testing in congenital long QT syndrome
Journal of Electrocardiology 39 (2006) S107 – S113 www.elsevier.com/locate/jelectrocard
Epinephrine QT stress testing in congenital long QT syndromeB Himeshkumar Vyas, MD,a Michael J. Ackerman, MD, PhD, FACCa,b,c,4 a
Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA b Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA c Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA Received 11 May 2006; accepted 30 May 2006
Abstract
Epinephrine QT stress testing is an effective diagnostic tool to unmask concealed Long QT Syndrome (LQTS), particularly type 1 LQTS (LQT1). Unique responses have also been observed in patients with LQT2 and LQT3, making this test invaluable in the diagnostic work-up of LQTS. This article reviews the epinephrine QT stress test, explains the pathological basis of differential responses among patients and healthy individuals, and describes the methodology for conducting the test and the interpretation of the responses. We have also attempted to highlight the differences between the two major LQTS epinephrine QT stress test protocols, the Mayo protocol and the Shimizu protocol. D 2006 Elsevier Inc. All rights reserved.
Keywords:
Long QT syndrome; Ion channels; Epinephrine; Stress testing; Genetics
Introduction Congenital long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that affects nearly 1 in 3000 persons and has an estimated annual mortality of 1%.1 LQTS may lie dormant lifelong or present with syncope, seizures, or sudden death from its trademark arrhythmia of torsades de pointes (TdP) at a young age. Although the diagnosis has relied traditionally on the demonstration of a prolonged heart rate corrected QT interval (QTc), only 50% to 60% of patients with genetically proven LQTS have a diagnostically prolonged QTc at rest.2-4 These observations indicate that the overall penetrance associated with LQTS is much lower than previously thought. This large subset of individuals with genotype-positive/ECG-negative LQTS is referred to as bconcealed LQTS.Q More importantly, although the risk is lower than in patients with manifest LQTS, there persists a risk for clinical events, including sudden death, even among those with concealed LQTS. Consequently, there is significant clinical need for a provocative test to unmask patients with concealed LQTS. Early data from the work of Ackerman et al5 and Shimizu B
MJA’s research program is supported by a Mayo Foundation Clinician Research award, a clinical scientist development award from the Doris Duke Charitable Foundation, and the National Institutes of Health (HD42569). MJA is an established investigator of the American Heart Association. 4 Corresponding author. Long QT Syndrome Clinic and Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN 55905, USA. Tel.: +1 507 284 0101; fax: +1 507 284 3757. E-mail address: [email protected] (M.J. Ackerman). 0022-0736/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jelectrocard.2006.05.013
and Antzelevitch6 suggested that epinephrine may be a potential provocative stimulus. Further work from both these investigators’ LQTS research programs has produced a considerable body of literature that supports the epinephrine QT stress test as a safe, sensitive, and specific way to unmask LQTS, particularly type 1 LQTS (LQT1).7-11 Genespecific responses to epinephrine stress testing for the 2 most common subtypes of LQTS (LQT1 and LQT2) have been identified. This review article explores the genetic and pathophysiologic basis for the epinephrine QT stress test, the procedure for conducting the tests, responses observed, and the predictive values/diagnostic accuracy associated with epinephrine QT stress testing. We conclude by defining the clinical role for the epinephrine QT stress test in the evaluation of individuals suspected of having LQTS and discuss how this provocative test complements the now commercially available LQTS genetic test. Genetic and pathophysiologic basis for the epinephrine QT stress test To date, hundreds of mutations in 9 LQTS-susceptibility genes have been identified (Table 1). LQT7 and LQT8 are more properly referred to as type 1 Andersen-Tawil syndrome (ATS1) and type 1 Timothy syndrome (TS1), respectively. The majority of LQTS (~75%) is LQT1, LQT2, or LQT3 and stems from either perturbed phase 3 repolarizing potassium channels (LQT1 and LQT2) or phase 0 depolarizing sodium channels (LQT3). Interestingly, the most common form of LQTS (LQT1) is also the
S108
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
Table 1 Summary of LQTS-susceptibility genes LQTS subtype
Locus
Gene
Mode of inheritance
Current
Frequency (%)
LQT1 (JLNS1) LQT2 LQT3 LQT4 LQT5 (JLNS2) LQT6 ATS1 (LQT7) TS1 (LQT8) CAV3-LQT (LQT9)
11p15.5 7q35-36 3p21-p24 4q25-q27 21q22.1 21q22.1 17q23 12p13.3 3p25
KCNQ1 (KVLQT1) KCNH2 (HERG) SCN5A ANKB KCNE1 (minK) KCNE2 (MiRP1) KCNJ2 CACNA1C CAV3
AD (AR in JLNS) AD AD AD AD (AR in JLNS) AD AD Sporadic Sporadic
IKs(a) IKr(a) INa Na/Ca IKs(b) IKr(b) IK1(a) ICa.L(a) Caveolin-3 (INa)
30-35 25-30 5-10 b1 b1 b1 b 1 of LQTS, 50 of ATS b 1 of LQTS, 50 of TS b1
JLNS indicates Jervell and Lange-Nielsen syndrome; AD, autosomal dominant; AR, autosomal recessive; ATS, Andersen-Tawil syndrome; TS, Timothy syndrome.
subtype with the highest percentage of genotype-positive patients with concealed disease. Long QT syndrome–causing mutations exert their effect by creating a glitch during the repolarization process, causing prolongation and heterogeneity. This heterogeneity of repolarization provides the pathologic substrate for the generation of after-depolarizations that produce the hallmark arrhythmia of TdP. In the healthy heart, epinephrine shortens the repolarization phase (and thus the absolute QT interval) to facilitate the increasing chronotropy. It does this by phosphorylating potassium channels, particularly the KCNQ1-encoded IKs potassium channel, thereby increasing the open probability and the net outward potassium current.12,13 A small augmentation of the inward L-type calcium channel also occurs, which provides increased calcium entry and greater inotropy while also providing a depolarizing force that would otherwise prolong repolarization. However, this effect is more than offset by the far greater augmentation of repolarizing potassium currents. Considering this electrophysiologic milieu and the effect of epinephrine in mediating phosphorylation of the various ion channels that orchestrate the heart’s action potential, one may predict the response of both healthy individuals and those with various LQTS subtypes to epinephrine.
bparadoxical QT response.Q A paradoxical QT prolongation of 30 milliseconds or longer is both sensitive and specific as a marker for LQT1.8 Type 2 long QT syndrome Individuals with LQT2 have dysfunctional IKr channels. These constitute a distinct population of potassium channels responsible for the very early part of phase 3 repolarization. Thus, these individuals may have transient QT prolongation, but this is quickly followed by QT shortening as the normally functioning IKs channels are recruited. Instead, these individuals may show T-wave changes characterized by unusual notching patterns.7 Type 3 long QT syndrome Individuals with LQT3 uniformly shorten their QT interval with epinephrine infusion because of the recruitment of intact potassium channels. With this background in mind, we will now explore the technical and clinical aspects of conducting the test. Conducting the epinephrine QT stress test There are 2 major protocols for the epinephrine QT stress test, namely, the Mayo protocol and the Shimizu protocol.
Healthy individuals As described, healthy individuals will generally shorten their absolute QT interval slightly because of the relative increase of phase 3 potassium channel–mediated repolarization force compared with the increased inward current activity via L-type calcium channels. The resultant QTc, however, may increase markedly depending on how brisk the chronotropic response is. Remember, if the QT interval shortens modestly (typically seen) but the RR interval decreases significantly, the Bazett’s equation–derived QTc (QTc = QT/MRR) will increase. Type 1 long QT syndrome Individuals with LQT1 who have dysfunctional IKs channels prolong their QT interval because the augmented inward calcium current is unable to be fully countered by the dysfunctional IKs potassium channels and the remaining subpopulations of unaffected potassium channels such as IKr . We have termed this prolongation of the absolute (uncorrected) QT interval with epinephrine infusion as the
Fig. 1. A, Diagrammatic representation of the epinephrine QT stress test and the observed responses in LQT1. QT prolongation with low-dose epinephrine (Epi) is pathognomonic for LQTS subtype 1 (LQT1). B, Tracing from a patient with LQT1 at baseline. C, Tracing from the same patient during epinephrine infusion at a dose of 0.05 lg kg 1 min 1 showing the QT interval prolonging by 50 milliseconds.
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
S109
Fig. 1. (continued).
Mayo protocol The epinephrine QT stress test at the Mayo Clinic is conducted in the electrophysiology laboratory. The individ-
ual is connected to standard 12-lead ECG and studied while he/she is lying in the supine position. A peripheral intravenous line is started and the room is made quiet and darkened to allow the subject to relax. A noninvasive
S110
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
automated blood pressure and heart rate monitor is connected to the patient. Measurements of the QT and RR interval are obtained digitally on the CardioLab Pruka System (GE Medical Equipments, Milwaukee, Wis). The digital paper speed is set at 50 mm/s with the gains set at 5000 for optimal visualization of the T waves. An average of 4 measurements is generally obtained from lead II and lead V5. Baseline measurements are initially obtained after 5 minutes of rest. Epinephrine infusion is then started at 0.025 lg kg 1 min 1; this stage is continued for 10 minutes and measurements are obtained. Thereafter, each stage lasts only 5 minutes. The epinephrine infusion is then increased stepwise to 0.05, 0.1, and 0.2 lg kg 1 min 1 by doubling the infusion rate. Measurements are obtained at the end of each stage and then at 5 and 10 minutes of recovery after the infusion is turned off. The entire test generally lasts 45 minutes to 1 hour. Fig. 1 provides a diagrammatic representation of the Mayo protocol for conducting the epinephrine QT stress test and also shows the expected responses in LQT1 and other groups. We have found the test to be very safe. Many patients may be aware of increased heart rate and force of contraction, particularly at higher doses of epinephrine. Isolated premature ventricular extrasystoles may occur in up to 10%—both in healthy individuals and patients with LQTS. Ventricular bigeminy occurs in 4% and nonsustained ventricular tachycardia in 2% (same as in healthy controls). Macroscopic T-wave alternans is extremely rare, and we have not yet seen sustained ventricular tachycardia or ventricular fibrillation after conducting more than 250 epinephrine QT stress tests. Nevertheless, we continue to routinely apply the patches for external defibrillation for each study. Importance of using low-dose epinephrine It has been recognized that using doses of epinephrine greater than 0.2 lg kg 1 min 1 produces a significant rate (22%) of nonspecific false-positive responses. Our initial protocol used doses starting from 0.05 lg kg 1 min 1 increasing to 0.3 lg kg 1 min 1.5 In view of this finding, we have subsequently modified our protocol to start at a lower dose of 0.025 lg kg 1 min 1 and we do not use doses higher than 0.2 lg kg 1 min 1.7,8 For diagnostic purposes, we only use the repolarization measurements, with particular focus on the absolute QT interval, at a dose of 0.1 lg kg 1 min 1 or less.
Observed gene-specific responses in patients with LQTS Using the Mayo protocol Type 1 long QT syndrome In a series of 2 steps, Ackerman et al first established the difference between healthy volunteers and a small cohort of patients with genotyped LQTS (LQT1-3) and later validated these results and evaluated the sensitivity and specificity of the paradoxical QT response in a much larger cohort of those referred for LQTS testing including genotypenegative patients. The pilot article using healthy controls found every patient with LQT1 to show prolongation of their QT interval (paradoxical response), whereas no healthy volunteer had lengthening at low-dose epinephrine (although 22% of healthy controls did at high-doses of epinephrine).5 Although epinephrine did increase the QTc in patients with LQT1 also significantly, there is tremendous overlap between LQT1 patients and healthy volunteers such that that the predictive value of the response is reduced. Hence, the uncorrected QT interval has better diagnostic use. From this pilot study, we determined post hoc that a cutoff of 30 milliseconds or greater completely discriminated LQT1 from healthy volunteers. The follow-up study involved the prospective clinical validation of this diagnostic cutoff in defining the diagnostic use of the test. The epinephrine QT stress test was conducted on 125 genotyped patients referred for possible LQTS (40 LQT1, 30 LQT2, 11 LQT3, and 44 genotype negative) while excluding individuals on b-blockers. We found that a paradoxical QT lengthening of 30 milliseconds or more had a sensitivity of 92%, specificity of 86%, a positive predictive value of 75%, and a negative predictive value of 96%. In other words, a negative test almost certainly rules out LQT1, whereas a positive paradoxical response carries a 75% chance that the individual hosts a LQT1 mutation (Fig. 1).8 More importantly, the diagnostic use of the test is unchanged in individuals with concealed LQT1 (as defined by resting QTc V 460 milliseconds).8 In our analyses, we have found that some of the bfalse positivesQ may result from an interpretation error due to incorporation of the U wave at higher epinephrine doses
Shimizu protocol This is a slightly different protocol developed by Shimizu and is best described as a bolus and brief infusion protocol.6 An initial bolus of 0.1 lg/kg is immediately followed by a continuous infusion of 0.1 lg kg 1 min 1. The 12-lead ECG is then recorded at baseline, continuously for 5 minutes on epinephrine infusion, and for 5 minutes after termination of the infusion. With this approach, steady state is reached in 2 to 3 minutes, and the investigators have used steady-state data obtained at 3 to 5 minutes into epinephrine infusion for reporting their results.
Fig. 2. Comparison of the change in absolute QT intervals (DQT) among the genotypes. This figure combines the results of both the initial pilot study involving healthy volunteers and the later results of the larger cohort of 125 genotyped LQT referral studies. The markedly divergent genotypespecific response of LQT1 is immediately obvious.
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
when the T and U waves fuse. With experience, one can generally recognize this pattern and reduce the resultant error. In fact, in unpublished data from additional analysis following this published data set, we have had only 1 false positive out of 52 additional patients. Fig. 1B and C shows the actual tracings from a patient with LQT1 showing the paradoxical QT prolongation with epinephrine. Fig. 2 shows the median DQT among the groups combining the results of both the pilot study involving
S111
healthy volunteers and the later larger clinical study of all genotyped individuals referred for suspected LQT. Effect of b-blockers The diagnostic use of the test deteriorates significantly in patients that show b-blocker effect. Hence, we recommend a 2- to 3-day washout period before performing this test in individuals on b-blocker therapy. Clinically, b-blocker effect may be recognized by failure of the heart rate
Fig. 3. Upper panel: T-wave morphology in LQT2 showing an example of G2 notched T-waves on epinephrine infusion. This is most marked in lead 1 and the mid-precordial leads V2-4. Lower left panel: Representation of 4 patterns of T-wave morphology. A, Normal T-wave morphology. B, Biphasic T-waves. C, G1 T-waves characterized by a perceptible bulge at or below the apex. D, G2 T-waves characterized by a distinct protuberance above the apex. Lower right panel: Bar diagram showing frequency of the various T-wave morphologies among controls and patients with LQT1 and 2.
S112
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
to increase by 10 beats or more per minute along with a rise in blood pressure due to unopposed a-adrenergic effect of epinephrine. Type 2 long QT syndrome Khositseth et al evaluated the responses of patients with LQT2 to epinephrine infusion in a study involving 28 LQT2 patients matched with 30 LQT1 and 32 controls.7 Although patients with LQT2 do not show paradoxical QT prolongation with epinephrine, a significant number of them show unusual T-wave changes that have diagnostic value. Based on T-wave morphology, T waves may be classified as being 1. 2. 3. 4.
normal morphology, biphasic, G1 notched: notch at or below the apex, G2 notched: distinct protuberance above the apex.
These variants are shown in Fig. 3 along with an actual tracing from a patient with LQT2 showing development of G2 notched T waves with epinephrine. Low-dose epinephrine–induced G2 notching is almost exclusively seen in LQT2, although it is not a sensitive marker, being seen only in 18% of patients with LQT2. On the other hand, G1 notching is statistically more common in LQT2 (25%) as compared with LQT1 (3%) or controls (9%). However, practically speaking, because G1 notches can be seen among healthy controls, its presence alone is not clinically diagnostic. Interestingly, low-dose epinephrine elicits G1 or G2 notching in greater than 50% of patients with LQT2 who have a nondiagnostic resting ECG. A biphasic T-wave pattern on epinephrine testing is seen in controls and patients with LQT1 and LQT2 equally. Some patients with LQT2 may also show an initial prolongation of the QT interval followed by shortening as explained by the recruitment of normally functioning IKs channels. However, this feature is neither uniformly seen nor does it appear to be sufficiently specific to LQT2 to be of any diagnostic use. Genotype negative and LQT3 At present, we have not found any gene-specific responses to epinephrine in patients with LQT3 or in those with as yet undefined mutations. Patients with LQT3 uniformly show shortening of the QT interval to epinephrine. To date, we have never observed a paradoxical QT response in a patient with LQT3. In general, patients with LQT3 display a more robust shortening of the QT interval during epinephrine infusion than either controls or patients with LQT2. However, the overlap precludes defining an baccentuatedQ QT shortening cutoff that would serve as a diagnostic tool to predict LQT3 status. Using the Shimizu protocol In 2003, Shimizu et al9 evaluated and reported on the unmasking of latent mutation carriers with LQT1 by epinephrine infusion. This initial article evaluated 19 mutation carriers with baseline QTc 460 milliseconds or greater,
15 mutation carriers with baseline QTc less than 460 milliseconds, 12 non–mutation carriers (from families with LQT1), and 15 healthy controls. Reporting on the heart rate corrected QT intervals (QTc), they showed a significantly greater increase in the QTc, QTc(peak), Tc(peak-end) and dispersion of QTc(peak) in those with LQT1 mutations, whether manifest or concealed at rest, as compared with the other 2 groups. They reported the sensitivity of identifying LQT1 mutation carriers to be 91% and specificity to be 100% using a DQTc of 30 milliseconds or greater. A subsequent publication by Shimizu et al10 evaluated the differences between the various LQTS subtypes. Here, they prospectively attempted to separate a group of 31 LQT1, 23 LQT2, 6 LQT3, and 30 controls (20 non–mutation carrier family members and 10 healthy volunteers). They observed the following responses based upon underlying genotype. Type 1 long QT syndrome The mean QTc, QTc(peak), and QTc(peak-end) are significantly higher at peak epinephrine (after the bolus) and remained prolonged at steady state (3-4 minutes into the constant infusion). Type 2 long QT syndrome The mean QTc and QTc(peak) also dramatically prolong at peak epinephrine effect, but they return to baseline at steady state unlike in LQT1. The QTc(peak-end) remains unchanged with epinephrine. Type 3 long QT syndrome and controls The mean QTc and QTc(peak) are slightly prolonged at peak epinephrine and return to baseline at steady state. The QTc(peak-end) remains unchanged with epinephrine. An algorithm created for differentiating genotypes has been proposed by the authors. If the DQTc is 35 milliseconds or longer at steady state, LQT1 is most likely. If the steady state DQTc is less than 35 milliseconds, then the corrected DQTc at peak epinephrine is evaluated (because patients with LQT2 also show prolongation during peak epinephrine effect). If the DQTc is 80 milliseconds or greater at peak epinephrine, LQT2 is most likely, and if not, the patient has either LQT3 or is a control. They report a predictive value of a DQTc of 35 milliseconds or greater at steady-state epinephrine as 90% or higher predictive of LQT1, whereas a DQTc of 80 milliseconds or greater at peak epinephrine as 100% predictive of LQT2 phenotype. Differences between the Mayo and Shimizu epinephrine QT stress tests Although the protocols are both similarly highly effective in predicting LQT1 genotype, the Shimizu protocol appears to be able to discern the LQT2 from other groups by analysis of the temporal trend of QT response, namely, QTc prolongation at peak effect and negligible QTc increase at steady state. In using the Mayo protocol, one cannot distinguish patients with concealed LQT2 from genotypenegative subjects in terms of QT response. A diagnostic clue
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
suggesting the presence of concealed LQT2 is provided by eliciting G2 notched T waves. Although the ability to identify temporal trends of QT response is an advantage of the Shimizu protocol, the studies using the Mayo protocol have included the important group of index cases referred for gene evaluation of LQTS and subsequently found not to have a mutation (gene negative). This group actually constitutes the majority of patients in our series, and it is the response of this challenging group that most closely matches that of the LQT2 response and whose separation we find difficult. This is also the group that generates the most false-positive paradoxical QT prolongation responses. Thus, the 75% positive predictive value of the Mayo protocol in identifying LQT1 vs greater than 90% by Shimizu protocol must be viewed with this in mind. It is essential to include the responses to epinephrine from this large gene-negative group of patients because inclusion of such patients is what the clinician faces in clinical practice. Nonetheless, both groups have clearly established by these elegant studies the value of the epinephrine QT stress test in the evaluation of congenital LQTS.
S113
an uncommon finding with the epinephrine QT stress test, the induction of macroscopic T-wave alternans or nonsustained TdP with infusion of epinephrine suggests a potentially unstable arrhythmogenic substrate and is likely to prompt significant intervention. Conclusions The epinephrine QT stress test is a useful diagnostic tool in the clinical evaluation of patients suspected to have congenital LQTS. Whether using the Mayo protocol or the Shimizu protocol, concealed LQT1 can be exposed with a high degree of accuracy by eliciting either (1) a paradoxical QT response to low-dose epinephrine (DQT z 30 milliseconds, Mayo protocol) or (2) DQTc 35 milliseconds or longer during steady-state epinephrine following the bolus and infusion Shimizu protocol. G2 notched T waves during low-dose epinephrine may unmask concealed LQT2. More importantly, epinephrine QT stress test must be viewed as principally a diagnostic test, not a prognostic one.
Role of the epinephrine QT stress test in the evaluation of congenital LQTS
References
At Mayo Clinic’s Long QT Syndrome Clinic, we perform the epinephrine QT stress test for all as yet ungenotyped individuals (typically aged N 10 years) who present for evaluation of LQTS. If the clinical suspicion is low but the individuals have already been started on b-blocker therapy, we recommend a 2- to 3-day period of washout before conducting the test. We view the epinephrine QT stress test as essentially uninterpretable with the confounding presence of b-blockers. For ungenotyped patients, the presence of a paradoxical QT response is sufficient for the presumptive clinical diagnosis of LQT1 (75% positive predictive value). Because no LQT3 patient has shown this paradoxical response to date, b-blocker therapy can be initiated safely while awaiting definitive confirmation of LQT1 status by genetic testing, which can take 4 to 6 weeks. Besides its role in the evaluation of ungenotyped patients, we recommend the test for patients who have a newly received genetic diagnosis of LQT1, particularly if the patient’s resting ECG is unremarkable and the mutation is novel. Recognizing that an estimated 5% of healthy subjects host rare variants in KCNQ1 of uncertain functional significance and given the near universality of the paradoxical QT response in LQT1 (96% negative predictive value), this provocation study provides an in vivo physiologic confirmation and corroboration of the pathogenic status assigned to the novel mutation. In addition, this test is performed on patients who host concealed LQT2 to determine whether T-wave notching can be induced with low-dose epinephrine. At this time, an epinephrine QT stress test is not recommended for patients with clinically and genetically established LQT3. Although
1. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001;104:569. 2. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992;327:846. 3. Miller MD, Porter C, Ackerman MJ. Diagnostic accuracy of screening electrocardiograms in long QT syndrome I. Pediatrics 2001;108:8. 4. Kaufman ES, Priori SG, Napolitano C, Schwartz PJ, Iyengar S, Elston RC, et al. Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members. J Cardiovasc Electrophysiol 2001;12:455. 5. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB. Epinephrine-induced QT interval prolongation: a genespecific paradoxical response in congenital long QT syndrome. Mayo Clin Proc 2002;77:413. 6. Shimizu W, Antzelevitch C. Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J Am Coll Cardiol 2000;35:778. 7. Khositseth A, Hejlik J, Shen W-K, Ackerman MJ. Epinephrine induced T-wave notching in Congenital Long QT syndrome. Heart Rhythm 2005;2:141. 8. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation 2006;113:1385. 9. Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Satomi K, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol 2003;41:633. 10. Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, et al. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm 2004; 1:276. 11. Noda T, Takaki H, Kurita T, Suyama K, Nagaya N, Taguchi A, et al. Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome. Eur Heart J 2002;23:975. 12. Ackerman MJ, Clapham DE. Ion channels—basic science and clinical disease. N Engl J Med 1997;336:1575. 13. Roden DM, George Jr AL. The cardiac ion channels: relevance to management of arrhythmias. Annu Rev Med 1996;47:135.
Epinephrine QT stress testing in congenital long QT syndromeB Himeshkumar Vyas, MD,a Michael J. Ackerman, MD, PhD, FACCa,b,c,4 a
Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA b Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA c Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA Received 11 May 2006; accepted 30 May 2006
Abstract
Epinephrine QT stress testing is an effective diagnostic tool to unmask concealed Long QT Syndrome (LQTS), particularly type 1 LQTS (LQT1). Unique responses have also been observed in patients with LQT2 and LQT3, making this test invaluable in the diagnostic work-up of LQTS. This article reviews the epinephrine QT stress test, explains the pathological basis of differential responses among patients and healthy individuals, and describes the methodology for conducting the test and the interpretation of the responses. We have also attempted to highlight the differences between the two major LQTS epinephrine QT stress test protocols, the Mayo protocol and the Shimizu protocol. D 2006 Elsevier Inc. All rights reserved.
Keywords:
Long QT syndrome; Ion channels; Epinephrine; Stress testing; Genetics
Introduction Congenital long QT syndrome (LQTS) is a potentially lethal cardiac channelopathy that affects nearly 1 in 3000 persons and has an estimated annual mortality of 1%.1 LQTS may lie dormant lifelong or present with syncope, seizures, or sudden death from its trademark arrhythmia of torsades de pointes (TdP) at a young age. Although the diagnosis has relied traditionally on the demonstration of a prolonged heart rate corrected QT interval (QTc), only 50% to 60% of patients with genetically proven LQTS have a diagnostically prolonged QTc at rest.2-4 These observations indicate that the overall penetrance associated with LQTS is much lower than previously thought. This large subset of individuals with genotype-positive/ECG-negative LQTS is referred to as bconcealed LQTS.Q More importantly, although the risk is lower than in patients with manifest LQTS, there persists a risk for clinical events, including sudden death, even among those with concealed LQTS. Consequently, there is significant clinical need for a provocative test to unmask patients with concealed LQTS. Early data from the work of Ackerman et al5 and Shimizu B
MJA’s research program is supported by a Mayo Foundation Clinician Research award, a clinical scientist development award from the Doris Duke Charitable Foundation, and the National Institutes of Health (HD42569). MJA is an established investigator of the American Heart Association. 4 Corresponding author. Long QT Syndrome Clinic and Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN 55905, USA. Tel.: +1 507 284 0101; fax: +1 507 284 3757. E-mail address: [email protected] (M.J. Ackerman). 0022-0736/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jelectrocard.2006.05.013
and Antzelevitch6 suggested that epinephrine may be a potential provocative stimulus. Further work from both these investigators’ LQTS research programs has produced a considerable body of literature that supports the epinephrine QT stress test as a safe, sensitive, and specific way to unmask LQTS, particularly type 1 LQTS (LQT1).7-11 Genespecific responses to epinephrine stress testing for the 2 most common subtypes of LQTS (LQT1 and LQT2) have been identified. This review article explores the genetic and pathophysiologic basis for the epinephrine QT stress test, the procedure for conducting the tests, responses observed, and the predictive values/diagnostic accuracy associated with epinephrine QT stress testing. We conclude by defining the clinical role for the epinephrine QT stress test in the evaluation of individuals suspected of having LQTS and discuss how this provocative test complements the now commercially available LQTS genetic test. Genetic and pathophysiologic basis for the epinephrine QT stress test To date, hundreds of mutations in 9 LQTS-susceptibility genes have been identified (Table 1). LQT7 and LQT8 are more properly referred to as type 1 Andersen-Tawil syndrome (ATS1) and type 1 Timothy syndrome (TS1), respectively. The majority of LQTS (~75%) is LQT1, LQT2, or LQT3 and stems from either perturbed phase 3 repolarizing potassium channels (LQT1 and LQT2) or phase 0 depolarizing sodium channels (LQT3). Interestingly, the most common form of LQTS (LQT1) is also the
S108
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
Table 1 Summary of LQTS-susceptibility genes LQTS subtype
Locus
Gene
Mode of inheritance
Current
Frequency (%)
LQT1 (JLNS1) LQT2 LQT3 LQT4 LQT5 (JLNS2) LQT6 ATS1 (LQT7) TS1 (LQT8) CAV3-LQT (LQT9)
11p15.5 7q35-36 3p21-p24 4q25-q27 21q22.1 21q22.1 17q23 12p13.3 3p25
KCNQ1 (KVLQT1) KCNH2 (HERG) SCN5A ANKB KCNE1 (minK) KCNE2 (MiRP1) KCNJ2 CACNA1C CAV3
AD (AR in JLNS) AD AD AD AD (AR in JLNS) AD AD Sporadic Sporadic
IKs(a) IKr(a) INa Na/Ca IKs(b) IKr(b) IK1(a) ICa.L(a) Caveolin-3 (INa)
30-35 25-30 5-10 b1 b1 b1 b 1 of LQTS, 50 of ATS b 1 of LQTS, 50 of TS b1
JLNS indicates Jervell and Lange-Nielsen syndrome; AD, autosomal dominant; AR, autosomal recessive; ATS, Andersen-Tawil syndrome; TS, Timothy syndrome.
subtype with the highest percentage of genotype-positive patients with concealed disease. Long QT syndrome–causing mutations exert their effect by creating a glitch during the repolarization process, causing prolongation and heterogeneity. This heterogeneity of repolarization provides the pathologic substrate for the generation of after-depolarizations that produce the hallmark arrhythmia of TdP. In the healthy heart, epinephrine shortens the repolarization phase (and thus the absolute QT interval) to facilitate the increasing chronotropy. It does this by phosphorylating potassium channels, particularly the KCNQ1-encoded IKs potassium channel, thereby increasing the open probability and the net outward potassium current.12,13 A small augmentation of the inward L-type calcium channel also occurs, which provides increased calcium entry and greater inotropy while also providing a depolarizing force that would otherwise prolong repolarization. However, this effect is more than offset by the far greater augmentation of repolarizing potassium currents. Considering this electrophysiologic milieu and the effect of epinephrine in mediating phosphorylation of the various ion channels that orchestrate the heart’s action potential, one may predict the response of both healthy individuals and those with various LQTS subtypes to epinephrine.
bparadoxical QT response.Q A paradoxical QT prolongation of 30 milliseconds or longer is both sensitive and specific as a marker for LQT1.8 Type 2 long QT syndrome Individuals with LQT2 have dysfunctional IKr channels. These constitute a distinct population of potassium channels responsible for the very early part of phase 3 repolarization. Thus, these individuals may have transient QT prolongation, but this is quickly followed by QT shortening as the normally functioning IKs channels are recruited. Instead, these individuals may show T-wave changes characterized by unusual notching patterns.7 Type 3 long QT syndrome Individuals with LQT3 uniformly shorten their QT interval with epinephrine infusion because of the recruitment of intact potassium channels. With this background in mind, we will now explore the technical and clinical aspects of conducting the test. Conducting the epinephrine QT stress test There are 2 major protocols for the epinephrine QT stress test, namely, the Mayo protocol and the Shimizu protocol.
Healthy individuals As described, healthy individuals will generally shorten their absolute QT interval slightly because of the relative increase of phase 3 potassium channel–mediated repolarization force compared with the increased inward current activity via L-type calcium channels. The resultant QTc, however, may increase markedly depending on how brisk the chronotropic response is. Remember, if the QT interval shortens modestly (typically seen) but the RR interval decreases significantly, the Bazett’s equation–derived QTc (QTc = QT/MRR) will increase. Type 1 long QT syndrome Individuals with LQT1 who have dysfunctional IKs channels prolong their QT interval because the augmented inward calcium current is unable to be fully countered by the dysfunctional IKs potassium channels and the remaining subpopulations of unaffected potassium channels such as IKr . We have termed this prolongation of the absolute (uncorrected) QT interval with epinephrine infusion as the
Fig. 1. A, Diagrammatic representation of the epinephrine QT stress test and the observed responses in LQT1. QT prolongation with low-dose epinephrine (Epi) is pathognomonic for LQTS subtype 1 (LQT1). B, Tracing from a patient with LQT1 at baseline. C, Tracing from the same patient during epinephrine infusion at a dose of 0.05 lg kg 1 min 1 showing the QT interval prolonging by 50 milliseconds.
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
S109
Fig. 1. (continued).
Mayo protocol The epinephrine QT stress test at the Mayo Clinic is conducted in the electrophysiology laboratory. The individ-
ual is connected to standard 12-lead ECG and studied while he/she is lying in the supine position. A peripheral intravenous line is started and the room is made quiet and darkened to allow the subject to relax. A noninvasive
S110
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
automated blood pressure and heart rate monitor is connected to the patient. Measurements of the QT and RR interval are obtained digitally on the CardioLab Pruka System (GE Medical Equipments, Milwaukee, Wis). The digital paper speed is set at 50 mm/s with the gains set at 5000 for optimal visualization of the T waves. An average of 4 measurements is generally obtained from lead II and lead V5. Baseline measurements are initially obtained after 5 minutes of rest. Epinephrine infusion is then started at 0.025 lg kg 1 min 1; this stage is continued for 10 minutes and measurements are obtained. Thereafter, each stage lasts only 5 minutes. The epinephrine infusion is then increased stepwise to 0.05, 0.1, and 0.2 lg kg 1 min 1 by doubling the infusion rate. Measurements are obtained at the end of each stage and then at 5 and 10 minutes of recovery after the infusion is turned off. The entire test generally lasts 45 minutes to 1 hour. Fig. 1 provides a diagrammatic representation of the Mayo protocol for conducting the epinephrine QT stress test and also shows the expected responses in LQT1 and other groups. We have found the test to be very safe. Many patients may be aware of increased heart rate and force of contraction, particularly at higher doses of epinephrine. Isolated premature ventricular extrasystoles may occur in up to 10%—both in healthy individuals and patients with LQTS. Ventricular bigeminy occurs in 4% and nonsustained ventricular tachycardia in 2% (same as in healthy controls). Macroscopic T-wave alternans is extremely rare, and we have not yet seen sustained ventricular tachycardia or ventricular fibrillation after conducting more than 250 epinephrine QT stress tests. Nevertheless, we continue to routinely apply the patches for external defibrillation for each study. Importance of using low-dose epinephrine It has been recognized that using doses of epinephrine greater than 0.2 lg kg 1 min 1 produces a significant rate (22%) of nonspecific false-positive responses. Our initial protocol used doses starting from 0.05 lg kg 1 min 1 increasing to 0.3 lg kg 1 min 1.5 In view of this finding, we have subsequently modified our protocol to start at a lower dose of 0.025 lg kg 1 min 1 and we do not use doses higher than 0.2 lg kg 1 min 1.7,8 For diagnostic purposes, we only use the repolarization measurements, with particular focus on the absolute QT interval, at a dose of 0.1 lg kg 1 min 1 or less.
Observed gene-specific responses in patients with LQTS Using the Mayo protocol Type 1 long QT syndrome In a series of 2 steps, Ackerman et al first established the difference between healthy volunteers and a small cohort of patients with genotyped LQTS (LQT1-3) and later validated these results and evaluated the sensitivity and specificity of the paradoxical QT response in a much larger cohort of those referred for LQTS testing including genotypenegative patients. The pilot article using healthy controls found every patient with LQT1 to show prolongation of their QT interval (paradoxical response), whereas no healthy volunteer had lengthening at low-dose epinephrine (although 22% of healthy controls did at high-doses of epinephrine).5 Although epinephrine did increase the QTc in patients with LQT1 also significantly, there is tremendous overlap between LQT1 patients and healthy volunteers such that that the predictive value of the response is reduced. Hence, the uncorrected QT interval has better diagnostic use. From this pilot study, we determined post hoc that a cutoff of 30 milliseconds or greater completely discriminated LQT1 from healthy volunteers. The follow-up study involved the prospective clinical validation of this diagnostic cutoff in defining the diagnostic use of the test. The epinephrine QT stress test was conducted on 125 genotyped patients referred for possible LQTS (40 LQT1, 30 LQT2, 11 LQT3, and 44 genotype negative) while excluding individuals on b-blockers. We found that a paradoxical QT lengthening of 30 milliseconds or more had a sensitivity of 92%, specificity of 86%, a positive predictive value of 75%, and a negative predictive value of 96%. In other words, a negative test almost certainly rules out LQT1, whereas a positive paradoxical response carries a 75% chance that the individual hosts a LQT1 mutation (Fig. 1).8 More importantly, the diagnostic use of the test is unchanged in individuals with concealed LQT1 (as defined by resting QTc V 460 milliseconds).8 In our analyses, we have found that some of the bfalse positivesQ may result from an interpretation error due to incorporation of the U wave at higher epinephrine doses
Shimizu protocol This is a slightly different protocol developed by Shimizu and is best described as a bolus and brief infusion protocol.6 An initial bolus of 0.1 lg/kg is immediately followed by a continuous infusion of 0.1 lg kg 1 min 1. The 12-lead ECG is then recorded at baseline, continuously for 5 minutes on epinephrine infusion, and for 5 minutes after termination of the infusion. With this approach, steady state is reached in 2 to 3 minutes, and the investigators have used steady-state data obtained at 3 to 5 minutes into epinephrine infusion for reporting their results.
Fig. 2. Comparison of the change in absolute QT intervals (DQT) among the genotypes. This figure combines the results of both the initial pilot study involving healthy volunteers and the later results of the larger cohort of 125 genotyped LQT referral studies. The markedly divergent genotypespecific response of LQT1 is immediately obvious.
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
when the T and U waves fuse. With experience, one can generally recognize this pattern and reduce the resultant error. In fact, in unpublished data from additional analysis following this published data set, we have had only 1 false positive out of 52 additional patients. Fig. 1B and C shows the actual tracings from a patient with LQT1 showing the paradoxical QT prolongation with epinephrine. Fig. 2 shows the median DQT among the groups combining the results of both the pilot study involving
S111
healthy volunteers and the later larger clinical study of all genotyped individuals referred for suspected LQT. Effect of b-blockers The diagnostic use of the test deteriorates significantly in patients that show b-blocker effect. Hence, we recommend a 2- to 3-day washout period before performing this test in individuals on b-blocker therapy. Clinically, b-blocker effect may be recognized by failure of the heart rate
Fig. 3. Upper panel: T-wave morphology in LQT2 showing an example of G2 notched T-waves on epinephrine infusion. This is most marked in lead 1 and the mid-precordial leads V2-4. Lower left panel: Representation of 4 patterns of T-wave morphology. A, Normal T-wave morphology. B, Biphasic T-waves. C, G1 T-waves characterized by a perceptible bulge at or below the apex. D, G2 T-waves characterized by a distinct protuberance above the apex. Lower right panel: Bar diagram showing frequency of the various T-wave morphologies among controls and patients with LQT1 and 2.
S112
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
to increase by 10 beats or more per minute along with a rise in blood pressure due to unopposed a-adrenergic effect of epinephrine. Type 2 long QT syndrome Khositseth et al evaluated the responses of patients with LQT2 to epinephrine infusion in a study involving 28 LQT2 patients matched with 30 LQT1 and 32 controls.7 Although patients with LQT2 do not show paradoxical QT prolongation with epinephrine, a significant number of them show unusual T-wave changes that have diagnostic value. Based on T-wave morphology, T waves may be classified as being 1. 2. 3. 4.
normal morphology, biphasic, G1 notched: notch at or below the apex, G2 notched: distinct protuberance above the apex.
These variants are shown in Fig. 3 along with an actual tracing from a patient with LQT2 showing development of G2 notched T waves with epinephrine. Low-dose epinephrine–induced G2 notching is almost exclusively seen in LQT2, although it is not a sensitive marker, being seen only in 18% of patients with LQT2. On the other hand, G1 notching is statistically more common in LQT2 (25%) as compared with LQT1 (3%) or controls (9%). However, practically speaking, because G1 notches can be seen among healthy controls, its presence alone is not clinically diagnostic. Interestingly, low-dose epinephrine elicits G1 or G2 notching in greater than 50% of patients with LQT2 who have a nondiagnostic resting ECG. A biphasic T-wave pattern on epinephrine testing is seen in controls and patients with LQT1 and LQT2 equally. Some patients with LQT2 may also show an initial prolongation of the QT interval followed by shortening as explained by the recruitment of normally functioning IKs channels. However, this feature is neither uniformly seen nor does it appear to be sufficiently specific to LQT2 to be of any diagnostic use. Genotype negative and LQT3 At present, we have not found any gene-specific responses to epinephrine in patients with LQT3 or in those with as yet undefined mutations. Patients with LQT3 uniformly show shortening of the QT interval to epinephrine. To date, we have never observed a paradoxical QT response in a patient with LQT3. In general, patients with LQT3 display a more robust shortening of the QT interval during epinephrine infusion than either controls or patients with LQT2. However, the overlap precludes defining an baccentuatedQ QT shortening cutoff that would serve as a diagnostic tool to predict LQT3 status. Using the Shimizu protocol In 2003, Shimizu et al9 evaluated and reported on the unmasking of latent mutation carriers with LQT1 by epinephrine infusion. This initial article evaluated 19 mutation carriers with baseline QTc 460 milliseconds or greater,
15 mutation carriers with baseline QTc less than 460 milliseconds, 12 non–mutation carriers (from families with LQT1), and 15 healthy controls. Reporting on the heart rate corrected QT intervals (QTc), they showed a significantly greater increase in the QTc, QTc(peak), Tc(peak-end) and dispersion of QTc(peak) in those with LQT1 mutations, whether manifest or concealed at rest, as compared with the other 2 groups. They reported the sensitivity of identifying LQT1 mutation carriers to be 91% and specificity to be 100% using a DQTc of 30 milliseconds or greater. A subsequent publication by Shimizu et al10 evaluated the differences between the various LQTS subtypes. Here, they prospectively attempted to separate a group of 31 LQT1, 23 LQT2, 6 LQT3, and 30 controls (20 non–mutation carrier family members and 10 healthy volunteers). They observed the following responses based upon underlying genotype. Type 1 long QT syndrome The mean QTc, QTc(peak), and QTc(peak-end) are significantly higher at peak epinephrine (after the bolus) and remained prolonged at steady state (3-4 minutes into the constant infusion). Type 2 long QT syndrome The mean QTc and QTc(peak) also dramatically prolong at peak epinephrine effect, but they return to baseline at steady state unlike in LQT1. The QTc(peak-end) remains unchanged with epinephrine. Type 3 long QT syndrome and controls The mean QTc and QTc(peak) are slightly prolonged at peak epinephrine and return to baseline at steady state. The QTc(peak-end) remains unchanged with epinephrine. An algorithm created for differentiating genotypes has been proposed by the authors. If the DQTc is 35 milliseconds or longer at steady state, LQT1 is most likely. If the steady state DQTc is less than 35 milliseconds, then the corrected DQTc at peak epinephrine is evaluated (because patients with LQT2 also show prolongation during peak epinephrine effect). If the DQTc is 80 milliseconds or greater at peak epinephrine, LQT2 is most likely, and if not, the patient has either LQT3 or is a control. They report a predictive value of a DQTc of 35 milliseconds or greater at steady-state epinephrine as 90% or higher predictive of LQT1, whereas a DQTc of 80 milliseconds or greater at peak epinephrine as 100% predictive of LQT2 phenotype. Differences between the Mayo and Shimizu epinephrine QT stress tests Although the protocols are both similarly highly effective in predicting LQT1 genotype, the Shimizu protocol appears to be able to discern the LQT2 from other groups by analysis of the temporal trend of QT response, namely, QTc prolongation at peak effect and negligible QTc increase at steady state. In using the Mayo protocol, one cannot distinguish patients with concealed LQT2 from genotypenegative subjects in terms of QT response. A diagnostic clue
H. Vyas, M.J. Ackerman / Journal of Electrocardiology 39 (2006) S107–S113
suggesting the presence of concealed LQT2 is provided by eliciting G2 notched T waves. Although the ability to identify temporal trends of QT response is an advantage of the Shimizu protocol, the studies using the Mayo protocol have included the important group of index cases referred for gene evaluation of LQTS and subsequently found not to have a mutation (gene negative). This group actually constitutes the majority of patients in our series, and it is the response of this challenging group that most closely matches that of the LQT2 response and whose separation we find difficult. This is also the group that generates the most false-positive paradoxical QT prolongation responses. Thus, the 75% positive predictive value of the Mayo protocol in identifying LQT1 vs greater than 90% by Shimizu protocol must be viewed with this in mind. It is essential to include the responses to epinephrine from this large gene-negative group of patients because inclusion of such patients is what the clinician faces in clinical practice. Nonetheless, both groups have clearly established by these elegant studies the value of the epinephrine QT stress test in the evaluation of congenital LQTS.
S113
an uncommon finding with the epinephrine QT stress test, the induction of macroscopic T-wave alternans or nonsustained TdP with infusion of epinephrine suggests a potentially unstable arrhythmogenic substrate and is likely to prompt significant intervention. Conclusions The epinephrine QT stress test is a useful diagnostic tool in the clinical evaluation of patients suspected to have congenital LQTS. Whether using the Mayo protocol or the Shimizu protocol, concealed LQT1 can be exposed with a high degree of accuracy by eliciting either (1) a paradoxical QT response to low-dose epinephrine (DQT z 30 milliseconds, Mayo protocol) or (2) DQTc 35 milliseconds or longer during steady-state epinephrine following the bolus and infusion Shimizu protocol. G2 notched T waves during low-dose epinephrine may unmask concealed LQT2. More importantly, epinephrine QT stress test must be viewed as principally a diagnostic test, not a prognostic one.
Role of the epinephrine QT stress test in the evaluation of congenital LQTS
References
At Mayo Clinic’s Long QT Syndrome Clinic, we perform the epinephrine QT stress test for all as yet ungenotyped individuals (typically aged N 10 years) who present for evaluation of LQTS. If the clinical suspicion is low but the individuals have already been started on b-blocker therapy, we recommend a 2- to 3-day period of washout before conducting the test. We view the epinephrine QT stress test as essentially uninterpretable with the confounding presence of b-blockers. For ungenotyped patients, the presence of a paradoxical QT response is sufficient for the presumptive clinical diagnosis of LQT1 (75% positive predictive value). Because no LQT3 patient has shown this paradoxical response to date, b-blocker therapy can be initiated safely while awaiting definitive confirmation of LQT1 status by genetic testing, which can take 4 to 6 weeks. Besides its role in the evaluation of ungenotyped patients, we recommend the test for patients who have a newly received genetic diagnosis of LQT1, particularly if the patient’s resting ECG is unremarkable and the mutation is novel. Recognizing that an estimated 5% of healthy subjects host rare variants in KCNQ1 of uncertain functional significance and given the near universality of the paradoxical QT response in LQT1 (96% negative predictive value), this provocation study provides an in vivo physiologic confirmation and corroboration of the pathogenic status assigned to the novel mutation. In addition, this test is performed on patients who host concealed LQT2 to determine whether T-wave notching can be induced with low-dose epinephrine. At this time, an epinephrine QT stress test is not recommended for patients with clinically and genetically established LQT3. Although
1. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001;104:569. 2. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med 1992;327:846. 3. Miller MD, Porter C, Ackerman MJ. Diagnostic accuracy of screening electrocardiograms in long QT syndrome I. Pediatrics 2001;108:8. 4. Kaufman ES, Priori SG, Napolitano C, Schwartz PJ, Iyengar S, Elston RC, et al. Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members. J Cardiovasc Electrophysiol 2001;12:455. 5. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB. Epinephrine-induced QT interval prolongation: a genespecific paradoxical response in congenital long QT syndrome. Mayo Clin Proc 2002;77:413. 6. Shimizu W, Antzelevitch C. Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J Am Coll Cardiol 2000;35:778. 7. Khositseth A, Hejlik J, Shen W-K, Ackerman MJ. Epinephrine induced T-wave notching in Congenital Long QT syndrome. Heart Rhythm 2005;2:141. 8. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation 2006;113:1385. 9. Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Satomi K, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol 2003;41:633. 10. Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, et al. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm 2004; 1:276. 11. Noda T, Takaki H, Kurita T, Suyama K, Nagaya N, Taguchi A, et al. Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome. Eur Heart J 2002;23:975. 12. Ackerman MJ, Clapham DE. Ion channels—basic science and clinical disease. N Engl J Med 1997;336:1575. 13. Roden DM, George Jr AL. The cardiac ion channels: relevance to management of arrhythmias. Annu Rev Med 1996;47:135.