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Effect of amiodarone on the descending limb of the T wave

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Effect of amiodarone on the descending limb of the T wave
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  Effect of  Amiodarone   on the Descending Limb of theT Wave Peter Smetana,  MD , Esther Pueyo,  BSc , Katerina Hnatkova,  PhD ,Velislav Batchvarov,  MD , A. John Camm,  MD , and Marek Malik,  PhD ,  MD Comparing patients treated after myocardial infarc-tion with amiodarone or with placebo, we found asignificant rate-dependent prolongation of TpTe inter- val in patients who received amiodarone. Patients who had arrhythmic death had significantly longerTpTe intervals than others on placebo but not onamiodarone. Assuming that TpTe reflects transmuralrepolarization heterogeneity, our findings suggest that heterogeneity and arrhythmic risk are increasedby amiodarone. This contradicts the finding of de-creased transmural repolarization heterogeneity by amiodarone and the appreciated antiarrhythmic effi-cacy of this drug.   2003 by Excerpta Medica, Inc.(Am J Cardiol 2003;92:742–746) T here are substantial differences in the electrical prop-erties between different layers of the ventricularmyocardium. 1 Basedoninvitroexperiments,theintervalbetween the peak and the end of the T wave (TpTe) wasproposed to quantify transmural heterogeneity in actionpotential duration (APD). 2 Also based on in vitro exper-iments, the antiarrhythmic effect of amiodarone waspartly attributed to decreased transmural repolarizationheterogeneity. 3 However, there is no evidence that thisdrug has this effect in the clinical setting. We thereforeexamined the following assumptions. (1) If TpTe ex-presses transmural repolarization heterogeneity and if amiodarone decreases this heterogeneity, will the TpTeintervals in patients receiving placebo after infarction belonger than in those receiving amiodarone? (2) If theantiarrhythmic effect of amiodarone is at least in partachieved by the decrease of transmural repolarizationheterogeneity, will patients who experience arrhythmicdeath while receiving amiodarone have longer TpTeintervals than those who do not? We therefore investi-gated QT, Q to T peak (QTp), and TpTe intervals inHolter recordings of patients who were enrolled into theEuropean Myocardial Infarction Amiodarone Trial 4 (i.e.,patients randomized to placebo and amiodarone afterinfarction). • • • The study used data collected during the EuropeanMyocardial Infarction Amiodarone Trial. 4 In short,enrolled patients were survivors of acute myocardialinfarction (aged 18 to 75 years) who had left ventric-ular ejection fraction  40% as assessed by multiple-gated nuclear angiography between days 5 and 21after the index infarction. The median follow-up of thetrial was 21 months. A total of 866 3-lead Holterrecordings (462 from patients receiving amiodaroneand 404 from patients receiving placebo) obtained 1month after treatment randomization were availablefor this study. Clinical characteristics of the studypopulation are listed in Table 1.RR, QT, and QTp intervals in all 24-hour record-ings were automatically measured on a beat-to-beatbasis by a commercial Holter system (Pathfinder, DelMar Reynolds Medical, Irvine, California). TpTe in-tervals were computed as the difference of QT andQTp intervals. The automatic measurement was per-formed under careful visual control, and artifacts wereeliminated manually. Only beats with accepted QTand RR intervals were considered. In each recording,the analysis was performed using the lead with mostaccepted measurements.Instead of using only the RR interval precedingeach beat, weighted averages of RR intervals (RR)within a window preceding each beat were consid-ered. Using a previously described technology, 5 car-diac cycles in a window previous to the QT measure-ment were weighted for their impact on its rateadaptation. For each cardiac beat, the correspondingnumeric representation of the RR interval history andthe corresponding RR interval value was derived. Theoptimum averaging window was identified individu-ally in each patient by best-fitting QT/RR data to a setof 10 a priori defined regression models designed tocover a physiologic variety of QT/RR patterns. 6 In thisway, the influence of QT/RR hysteresis on the assess-ment of the QT/RR relation was eliminated.Because transmural repolarization heterogeneity isknown to be influenced by cycle length, 1 uncorrectedQT, QTp, and TpTe intervals and TpTe/QT ratioswere averaged in each recording across 10-ms RRinterval bins ranging from 550 to 1,150 ms.Statistical analysis was based on the intention totreat at randomization. Arrhythmic death was used asthe outcome event. The classification of the mode of death srcinally performed by the event committee of the trial was used. A comparison was also performedbetween patients who did and did not have arrhythmicdeath. Averaged values of QT, QTp, and TpTe inindividual RR bins were pooled together in amioda-rone- and placebo-treated patients. Student’s  t   test forunpaired samples was used for the comparison. A p From the Department of Cardiological Sciences, St. George’s HospitalMedical School, London, United Kingdom. This study was supportedin part by the Primara¨rzteverein des Wilhelminenspitals, Vienna, Aus-tria; and the Wellcome Trust and the British Heart Foundation, London,United Kingdom. Dr. Malik’s address is: Department of CardiologicalSciences, St. George’s Hospital Medical School, Cranmer Terrace,London SW17 0RE, United Kingdom. E-mail: m.malik@sghms.ac.uk.Manuscript received March 25, 2003; revised manuscript receivedand accepted May 27, 2003. 742  ©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/03/$–see front matterThe American Journal of Cardiology Vol. 92 September 15, 2003 doi:10.1016/S0002-9149(03)00845-2  value   0.05 was considered statistically significant.Data are presented as mean  SD.The rate relations of the QT and QTp intervals areshown in Figure 1, and the rate relation of the TpTeinterval and TpTe/QT ratio in the investigated groups isshown in Figure 2. Because it is obvious from thesefigures that the difference between the groups is ratedependent, Table 2 shows the statistical evaluation of theQT, QTp, and TpTe intervals and the TpTe/QT ratio at2 different RR interval bins (i.e., 550 to 560 ms and1,140 to 1,150 ms, respectively).QTp and QT intervals were longer in patients with-out arrhythmic death who received amiodarone. Thedifference was rate dependent as evidenced by beingmore marked at long RR intervals. However, patientswith arrhythmic death who received amiodarone hadshorter QTp intervals than did patients who receivedplacebo. Although this was less obvious at short RRintervals, it became increasingly more marked atlonger RR intervals (Table 2; arrhythmic death onamiodarone vs no arrhythmic death on placebo: 550 to560 ms, p  0.216, and 1,140 to 1,150 ms, p  0.005,respectively). For patients receiving placebo, therewas no significant difference between those with andwithout arrhythmic death at any RR interval bin.Among patients receiving amiodarone, the TpTeinterval did not significantly differ between those whodid and did not have arrhythmic death. However,irrespective of the arrhythmic outcome, TpTe wassignificantly longer in patients receiving amiodaronecompared with those receiving pla-cebo, with the difference being moremarked at slow heart rates. For pa-tients receiving placebo, those hav-ing arrhythmic death showed signif-icantly longer TpTe intervals at shortRR intervals.In patients without arrhythmicdeath, the ratio of the TpTe intervalto QT showed no rate dependence inpatients receiving amiodarone orthose receiving placebo and washigher in patients receiving amioda-rone. However, among the patientsreceiving amiodarone, those with ar-rhythmic death had a higher ratiothan did those without arrhythmicdeath; the difference was statisticallysignificant at slow heart rates. Thus,although QTp and TpTe were pro-longed proportionally in patientswithout arrhythmic death who werereceiving amiodarone, TpTe was rel-atively longer in those patients witharrhythmic death because of a rela-tive decrease in the QTp interval. • • • We found a significant rate-de-pendent prolongation of QTp and theTpTe interval in patients who receivedamiodarone after infarction who didnot have arrhythmic death. Althoughpatients who received placebo who had arrhythmic deathhad significantly longer TpTe intervals than those whodid not have arrhythmic death, there was no significantdifference among patients who received amiodarone.Assuming that TpTe reflects transmural repolariza-tion heterogeneity, these findings suggest that thisheterogeneity is increased by amiodarone. This con-tradicts the finding of decreased transmural repolar-ization heterogeneity by amiodarone in cardiac tissuemodels. 3 Although direct in vivo evidence of this drugeffect is missing, 2 other studies that investigated theelectrophysiologic effects of amiodarone in isolatedLangendorff-perfused rabbit hearts 7,8 also describedno changes in dispersion of APD across the epicardi-al 7 or between various right and left ventricular endo-cardial and epicardial sites. 8 Thus, a marked increasein transmural repolarization heterogeneity by amioda-rone seems unlikely.It seems therefore questionable whether the TpTeinterval measured in clinical Holter recordings reflectstransmural repolarization heterogeneity. Using a ca-nine ventricular wedge model, it was demonstrated 2 that the inscription of the T wave of the electrocar-diogram stems mainly from differences in APD indifferent layers of the ventricular wall. It was shownthat the peak of the T wave marks full repolarizationof the epicardium, whereas the end of the T wavemarks full repolarization of the M region. Therefore,in vitro TpTe interval was shown to measure trans-mural dispersion of APD. 2 By recording epicardial TABLE 1  Baseline Characteristics of Patients* CharacteristicsAmiodaronen  462Placebon  404 p Value † Age (yrs) ‡ 60  10 61  9 0.323Men/women 391 (85)/71 (15) 345 (85)/59 (15) 0.754Myocardial infarction 144 (31) 121 (30) 0.899Angina pectoris 177 (38) 144 (36) 0.275Hypertension 164 (35) 112 (28) 0.011Diabetes 72 (16) 68 (17) 0.619New York Heart Association ClassI 223 (48) 213 (53)II 207 (45) 157 (39) 0.381III 31 (7) 31 (8)Baseline measures ‡ Left ventricular ejection fraction (%) 31  7 30  8 0.468Systolic blood pressure (mm Hg) 119  17 118  17 0.459Diastolic blood pressure (mm Hg) 73  11 74  11 0.352Heart rate (ms) 73  14 73  13 0.884QRS duration (ms) 91  19 91  19 1.000QT interval (ms) 389  48 391  47 0.694Concomitant medicationThrombolytics 266 (58) 235 (58) 0.860Digoxin 61 (13) 47 (12) 0.486   blocker 198 (43) 200 (50) 0.050Calcium antagonist 70 (15) 62 (15) 0.937Angiotensin-converting enzyme inhibitors 260 (56) 219 (54) 0.542Follow-up end points n  59 (13) n  53 (13) 0.879Noncardiac death 11 (2) 8 (2) 0.688Cardiac death 48 (10) 45 (11) 0.723Nonarrhythmic death 30 (6) 19 (5) 0.256Arrhythmic death 18 (4) 26 (6) 0.090 *Values in parentheses represent the percentage of the total number in each arm. † p Value refers to comparison between amiodarone group and placebo group. ‡ Mean  SD. BRIEF REPORTS  743  monophasic action potentials fromdifferent areas of the heart in open-chested dogs simultaneously with 2surface electrocardiographic leads,an earlier study 9 also suggested thatTpTe interval bear a certain relationto the dispersion of repolarization inthe entire heart.Clinical evidence of this relationin humans is missing, and the extentof transmural gradients of APD invivo remains to be established. 10,11 Additionally, recent evidence sug-gests that transmural heterogeneitiesmight be even more variable thanexpected. 12 Considering the 3-di-mensional structure of the intactheart and the multitude of gradientspreviously described 9,11,13,14 (e,g.,apico-basal, right–left ventricular,anterior–posterior, and transmural),it seems unlikely, in a clinical set-ting, that the projection of the repo-larization dipole onto the body sur-face could be attributed to just thetransmural APD gradient. Still, al-though it was assumed already in thesrcinal study 2 that “the T wave mea-sured in the intact organism is gener-ated by more than transmural ventric-ular gradients,” clinically measuredTpTe intervals are being increasinglyused as a surrogate of transmural repo-larization heterogeneity. 15,16 Clinical studies describing in-creased TpTe values in various high-risk populations 15–18 suggest that in-creased TpTe is, under somecircumstances, related to arrhythmicrisk. However, these observations donot prove that TpTe reflects transmu-ral repolarization heterogeneity, andthey also do not prove that increasedTpTe is a general risk marker in eachclinically defined population. Ourfinding of prolonged TpTe intervalsin patients receiving amiodarone—together with the widely appreciatedantiarrhythmic efficacy 4,19 and lowproarrhythmicity 19,20 of the drug—isclearly not compatible with the no-tion that clinical TpTe measurestransmural repolarization heteroge-neity and that an increase in such aheterogeneity is an arrhythmic risk factor.Viitasalo et al 16 recently de-scribed increased TpTe intervals inpatients with long QT syndromewithout a difference between symp-tomatic and asymptomatic patients.This challenges the association of  FIGURE 1. Uncorrected mean QT and QTp intervals in patients on amiodarone  (open circles)  or on placebo  (filled circles)  plotted against 10-ms RR interval bins. Compari-son are made in patients with  (left panel)  and without   (right panel)  arrhythmic death.FIGURE 2. Uncorrected mean TpTe interval and TpTe/QT ratio in patients on amioda-rone  (open circles)  or on placebo  (filled circles)  plotted against 10-ms RR interval bins.Comparison are made in patients with  (left panel)  and without   (right panel)  arrhyth-mic death. 744  THE AMERICAN JOURNAL OF CARDIOLOGY   VOL. 92 SEPTEMBER 15, 2003  TpTe prolongation with arrhythmic risk. Consistentwith this finding, we did not observe any difference inTpTe between patients with and without arrhythmicdeath who received amiodarone. However, our findingof significantly longer TpTe intervals (at higher heartrates) in patients with arrhythmic death who receivedplacebo suggests that under some circumstances thismeasure is related to arrhythmic risk. In other words,as is with QT interval, there might be both a “bene-ficial” and “bad” prolongation of the TpTe interval.Our findings might also possibly suggest that insofaras QTp and TpTe intervals are prolonged, amiodaronetreatment is proportionally beneficial. However, whenTpTe/QT is increased, arrhythmic risk is enhanced.Because the TpTe interval is influenced by inaccu-racies in both determination of the peak and the end of the T wave, its reliability might be questioned. How-ever, in this study, automatic measurements werecarefully visually validated to minimize this problem.The analysis was performed on an intention-to-treat basis at randomization. It is likely that some of the patients receiving amiodarone discontinued thestudy medication during follow-up. However, becausewe found few differences in patients receiving pla-cebo, the exclusion of patients who discontinued thestudy medication would only make our findings evenmore striking.Despite the convincing in vitro concept and goodaccessibility of the TpTe interval as a measure of transmural repolarization heterogeneity, the inconsis-tencies addressed in this study suggest that extrapola-tion of results of experimental studies of myocardialtissue models to human surface electrocardiograms isproblematic. More appropriate surrogates of the invitro measured TpTe interval (e.g., the spatial mor-phology of the T wave) should be investigated. 1.  Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophys-iological properties in the deep subepicardium of the canine ventricle. The M cell. Circ Res  1991;68:1729–1741. 2.  Yan GX, Antzelevitch C. Cellular basis for the normal T wave and theelectrocardiographic manifestations of the long-QT syndrome.  Circulation  1998;98:1928–1936. 3.  Sicouri S, Moro S, Litovsky S, Elizari MV, Antzelevitch C. Chronic amioda-rone reduces transmural dispersion of repolarization in the canine heart.  J Car-diovasc Electrophysiol  1997;8:1269–1279. 4.  Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, Simon P.Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. EuropeanMyocardial Infarct Amiodarone Trial Investigators.  Lancet   1997;349:667–674. 5.  Pueyo E, Smetana P, Hnatkova K, Malik M. Optimum RR window length forestimation of the QT/RR regression model from continuous 24-hour Holterrecordings.  Proc Annu Conference Comput Cardiol  2002;565–568. 6.  Batchvarov VN, Ghuran A, Smetana P, Hnatkova K, Harries M, Dilaveris P,Camm AJ, Malik M. QT-RR relationship in healthy subjects exhibits substantialintersubject variability and high intrasubject stability.  Am J Physiol Heart CircPhysiol  2002;282:H2356–2363. 7.  Iwata H, Kodama I, Suzuki R, Kamiya K, Toyama J. Effects of long-term oraladministration of amiodarone on the ventricular repolarization of rabbit hearts.  Jpn Circ J   1996;60:662–672. 8.  Zabel M, Hohnloser SH, Behrens S, Woosley RL, Franz MR. Differentialeffects of D-sotalol, quinidine, and amiodarone on dispersion ventricular repo-larization in the isolated rabbit heart.  J Cardiovasc Electrophysiol  1997;8:1239–1245. 9.  Autenrieth G, Surawicz B, Kuo CS. Sequence of repolarization on the ven-tricular surface in the dog.  Am Heart J   1975;89:463–469. TABLE 2  QT, QTp, and TpTe Intervals and TpTe/QT Ratio at Different RR Interval Bins in Patients With and Without ArrhythmicDeath Receiving Amiodarone or Placebo Intervals/Ratio RR bin Amiodarone Placebo p Value*QT550–560 Arrhythmic death † 334  14 330  14 0.259No arrhythmic death † 334  17 327  19 0.002p ‡ 0.474 0.3051140–1150 Arrhythmic death † 431  23 452  27 0.112No arrhythmic death † 476  39 450  40 2.3  10  8 p ‡ 0.005 0.455QTp550–560 Arrhythmic death † 255  8 258  17 0.337No arrhythmic death † 262  17 261  19 0.437p ‡ 0.181 0.2731140–1150 Arrhythmic death † 323  19 367  31 0.013No arrhythmic death † 374  33 360  32 0.0004p ‡ 0.0004 0.330TpTe550–560 Arrhythmic death † 79  6 71  3 0.126No arrhythmic death † 73  2 66  1 0.00005p ‡ 0.169 0.0411140–1150 Arrhythmic death † 108  13 85  5 0.003No arrhythmic death † 102  17 89  15 1.3  10  10 p ‡ 0.218 0.251TpTe/QT550–560 Arrhythmic death † 0.24  0.04 0.22  0.04 0.158No arrhythmic death † 0.22  0.04 0.20  0.03 0.001p ‡ 0.151 0.0451140–1150 Arrhythmic death † 0.25  0.03 0.19  0.02 0.001No arrhythmic death † 0.21  0.03 0.20  0.03 2.3  10  6 p ‡ 0.005 0.198 *p Value refers to comparison between amiodarone group and placebo group. † Mean  SD. ‡ p Value refers to comparison between patients with and without arrhythmic death. BRIEF REPORTS  745  10.  Anyukhovsky EP, Sosunov EA, Rosen MR. Regional differences in electro-physiological properties of epicardium, midmyocardium, and endocardium. Invitro and in vivo correlations.  Circulation  1996;94:1981–1988. 11.  Weissenburger J, Nesterenko VV, Antzelevitch C. Transmural heterogeneityof ventricular repolarization under baseline and long QT conditions in the canineheart in vivo: Torsades de pointes develops with halothane but not pentobarbitalanesthesia.  J Cardiovasc Electrophysiol  2000;11:290–304. 12.  Akar FG, Yan GX, Antzelevitch C, Rosenbaum DS. Unique topographicaldistribution of M cells underlies reentrant mechanism of Torsade de pointes in thelong-QT syndrome.  Circulation  2002;105:1247–1253. 13.  Franz MR, Bargheer K, Rafflenbeul W, Haverich A, Lichtlen PR. Monopha-sic action potential mapping in human subjects with normal electrocardiograms:direct evidence for the genesis of the T-wave.  Circulation  1987;75:379–386. 14.  Rosenbaum DS, Kaplan DT, Kanai A, Jackson L, Garan H, Cohen RJ, SalamaG. Repolarization inhomogeneities in ventricular myocardium change dynami-cally with abrupt cycle length shortening.  Circulation  1991;84:1333–1345. 15.  Lubinski A, Lewicka-Nowak E, Kempa M, Baczynska AM, Romanowska I,Swiatecka G. New insight into repolarization abnormalities in patients withcongenital long QT syndrome: the increased transmural dispersion of repolariza-tion.  Pacing Clin Electrophysiol  1998;21:172–175. 16.  Viitasalo M, Oikarinen L, Swan H, Vaananen H, Glatter K, Laitinen PJ,Kontula K, Barron HV, Toivonen L, Scheinman MM. Ambulatory electrocar-diographic evidence of transmural dispersion of repolarization in patients withlong-QT syndrome type 1 and 2.  Circulation  2002;106:2473–2478. 17.  Savelieva I, Yap YG, Yi G, Guo X, Camm AJ, Malik M. Comparativereproducibility of QT, QT peak, and T peak-T end intervals and dispersion innormal subjects, patients with myocardial infarction, and patients with hypertro-phic cardiomyopathy.  Pacing Clin Electrophysiol  1998;21:2376–2381. 18.  Lubinski A, Kornacewicz-Jach Z, Wnuk-Wojnar AM, Adamus J, Kempa M,Krolak T, Lewicka-Nowak E, Radomski M, Swiatecka G. The terminal portion of the T wave: a new electrocardiographic marker of risk of ventricular arrhythmias. Pacing Clin Electrophysiol  2000;23:1957–1959. 19.  Mason JW. Amiodarone.  N Engl J Med   1987;316:455–466. 20.  van Opstal JM, Schoenmakers M, Verduyn SC, de Groot SH, Leunissen JD,van Der Hulst FF, Molenschot MM, Wellens HJ, Vos MA. Chronic amiodaroneevokes no Torsade de pointes arrhythmias despite QT lengthening in an animalmodel of acquired long-QT syndrome.  Circulation  2001;104:2722–2727. Syncope in Children and Adolescents and theCongenital Long QT Syndrome Anant Khositseth,  MD , Matthew W. Martinez,  MD , David J. Driscoll,  MD , andMichael J. Ackerman,  MD ,  PhD From a population-based epidemiologic cohort of chil-dren and adolescents who sought medical attention forsyncope (n    151), screening 12-lead electrocardio-grams were obtained from 118 patients (79 female) todetermine the frequency of significant QT prolongation.The distribution of heart rate corrected QT intervals(QTc) was compared with age- and sex-matched con-trols. Only one patient had QTc > 470 ms.   2003 by Excerpta Medica, Inc.(Am J Cardiol 2003;92:746–749) I t is generally recommended that an electrocardio-gram (ECG) be part of the current evaluation of syncope occurring in children and adolescents. 1,2 Theprevalence of long QT syndrome (LQTS) in syncopeis unknown. Before the molecular breakthroughs inLQTS, a QT interval corrected for heart rate (QTc),according to Bazett’s formula,  440 ms was consid-ered prolonged, and a QTc  420 ms was considerednormal. However, more recent genotype–phenotypecorrelations have indicated that 25% to 40% of carri-ers of LQT1 and LQT2 mutations show QTc values(420 to 470 ms) that overlap with those of noncarri-ers. 3,4 In contrast, the prevalence of “fainters” havinga nondiagnostic ECG with a QTc falling in this samerange (420 to 470 ms) as patients with “incompletepenetrant” or “concealed” LQTS also is unknown.Such information is critical for proper interpretation of the screening ECG when evaluating a young personwith syncope. Thus, the objectives of this study wereto identify the frequency of significant and diagnosticQT prolongation (QTc   470 ms) as well as the fre-quency of a nondiagnostic ECG in a community-basedpopulation of fainters who sought medical attentioncompared with age- and sex-matched controls. • • • Using data from the Rochester EpidemiologyProject, 151 children and adolescents  21 years old,of whom 98 were female and 131 white, who lived inRochester, Minnesota, were identified as havingsought medical attention for an initial syncopal epi-sode between 1987 and 1991. 5 The medical records of each patient were reviewed, and those without docu-mentation of a screening ECG were contacted forparticipation in this Institutional Review Board-ap-proved study. A 12-lead ECG was obtained from 118(78%) patients (79 female) from this cohort. The QTcwas computed both automatically using the MarquetteMAC8 (GE Marquette Medical Systems, Inc., Mil-waukee, Wisconsin) and manually. Manual determi-nation of the QT interval was performed using guide-lines similar to those reviewed by Moss. 6 Oneinvestigator (MWM) performed all manual QTc de-terminations using lead II and the standard Bazett’sformula (QTc  QT/square root of RR interval). Di-agnostically significant QT prolongation was definedas corrected QTc interval  470 ms. 7 ECGs from 118 age- and sex-matched controlswere obtained from Mayo Clinic’s electrocardiogra-phy database. The age of controls was matched to thepatient age at time of ECG rather than age at syncope, From the Department of Pediatric and Adolescent Medicine/Divisionof Pediatric Cardiology; the Department of Medicine/Division ofCardiovascular Diseases; and the Department of Molecular Pharma-cology and Experimental Therapeutics, Mayo Clinic/Mayo Founda-tion, Rochester, Minnesota. Dr. Ackerman is supported by the DorisDuke Charitable Foundation, New York, New York, and the NationalInstitutes of Health, Bethesda, Maryland (grant No. HD42569). Dr.Ackerman’s address is: Long QT Syndrome Clinic and Sudden DeathGenomics Laboratory, Guggenheim 501, Mayo Clinic/MayoFoundation, Rochester, Minnesota 55905. E-mail: ackerman.michael@mayo.edu. Manuscript received March 20, 2003; revisedmanuscript received and accepted May 27, 2003. 746  ©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/03/$–see front matterThe American Journal of Cardiology Vol. 92 September 15, 2003 doi:10.1016/S0002-9149(03)00846-4
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