Effect of Amiodarone on the Descending Limb of the
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-
enrolled patients were survivors of acute myocardial tion with amiodarone or with placebo, we found a
infarction (aged 18 to 75 years) who had left ventric- significant rate-dependent prolongation of TpTe inter-
ular ejection fraction Յ40% as assessed by multiple- val in patients who received amiodarone. Patients
gated nuclear angiography between days 5 and 21 who had arrhythmic death had significantly longer
after the index infarction. The median follow-up of the TpTe intervals than others on placebo but not on
trial was 21 months. A total of 866 3-lead Holter amiodarone. Assuming that TpTe reflects transmural
recordings (462 from patients receiving amiodarone repolarization heterogeneity, our findings suggest
and 404 from patients receiving placebo) obtained 1 that heterogeneity and arrhythmic risk are increased
month after treatment randomization were available by amiodarone. This contradicts the finding of de-
for this study. Clinical characteristics of the studypopulation are listed in creased transmural repolarization heterogeneity by
RR, QT, and QTp intervals in all 24-hour record- amiodarone and the appreciated antiarrhythmic effi-
ings were automatically measured on a beat-to-beat cacy of this drug. 2003 by Excerpta Medica, Inc.
basis by a commercial Holter system (Pathfinder, Del (Am J Cardiol 2003;92:742–746)
Mar Reynolds Medical, Irvine, California). TpTe in- Therearesubstantialdifferencesintheelectricalprop- tervals were computed as the difference of QT and
erties between different layers of the ventricular QTp intervals. The automatic measurement was per- Based on in vitro experiments, the interval formed under careful visual control, and artifacts were between the peak and the end of the T wave (TpTe) was eliminated manually. Only beats with accepted QT proposed to quantify transmural heterogeneity in action and RR intervals were considered. In each recording, potential duration Also based on in vitro exper- the analysis was performed using the lead with most iments, the antiarrhythmic effect of amiodarone was partly attributed to decreased transmural repolarization Instead of using only the RR interval preceding each beat, weighted averages of RR intervals (RR) drug has this effect in the clinical setting. We therefore within a window preceding each beat were consid- examined the following assumptions. (1) If TpTe ex- presses transmural repolarization heterogeneity and if diac cycles in a window previous to the QT measure- amiodarone decreases this heterogeneity, will the TpTe ment were weighted for their impact on its rate intervals in patients receiving placebo after infarction be adaptation. For each cardiac beat, the corresponding longer than in those receiving amiodarone? (2) If the numeric representation of the RR interval history and antiarrhythmic effect of amiodarone is at least in part the corresponding RR interval value was derived. The achieved by the decrease of transmural repolarization optimum averaging window was identified individu- heterogeneity, will patients who experience arrhythmic ally in each patient by best-fitting QT/RR data to a set death while receiving amiodarone have longer TpTe of 10 a priori defined regression models designed to intervals than those who do not? We therefore investi- cover a physiologic variety of QT/RR In this gated QT, Q to T peak (QTp), and TpTe intervals in way, the influence of QT/RR hysteresis on the assess- Holter recordings of patients who were enrolled into the ment of the QT/RR relation was eliminated.
European Myocardial Infarction Amiodarone (i.e., Because transmural repolarization heterogeneity is patients randomized to placebo and amiodarone after known to be influenced by cycle uncorrected QT, QTp, and TpTe intervals and TpTe/QT ratios were averaged in each recording across 10-ms RR The study used data collected during the European interval bins ranging from 550 to 1,150 ms.
Myocardial Infarction Amiodarone In short, Statistical analysis was based on the intention to treat at randomization. Arrhythmic death was used asthe outcome event. The classification of the mode of From the Department of Cardiological Sciences, St. George’s HospitalMedical School, London, United Kingdom. This study was supported death originally performed by the event committee of in part by the Primara¨rzteverein des Wilhelminenspitals, Vienna, Aus- the trial was used. A comparison was also performed tria; and the Wellcome Trust and the British Heart Foundation, London, between patients who did and did not have arrhythmic United Kingdom. Dr. Malik’s address is: Department of Cardiological death. Averaged values of QT, QTp, and TpTe in Sciences, St. George’s Hospital Medical School, Cranmer Terrace, individual RR bins were pooled together in amioda- London SW17 0RE, United Kingdom. E-mail: [email protected].
Manuscript received March 25, 2003; revised manuscript received rone- and placebo-treated patients. Student’s t test for unpaired samples was used for the comparison. A p 2003 by Excerpta Medica, Inc. All rights reserved.
The American Journal of Cardiology Vol. 92 September 15, 2003 TABLE 1 Baseline Characteristics of Patients*
*Values in parentheses represent the percentage of the total number in each arm.
† p Value refers to comparison between amiodarone group and placebo group.
TpTe interval in patients who receivedamiodarone after infarction who didnot have arrhythmic death. Although value Ͻ0.05 was considered statistically significant.
patients who received placebo who had arrhythmic death had significantly longer TpTe intervals than those who The rate relations of the QT and QTp intervals are did not have arrhythmic death, there was no significant shown in and the rate relation of the TpTe difference among patients who received amiodarone.
interval and TpTe/QT ratio in the investigated groups is Assuming that TpTe reflects transmural repolariza- shown in Because it is obvious from these tion heterogeneity, these findings suggest that this figures that the difference between the groups is rate heterogeneity is increased by amiodarone. This con- dependent, shows the statistical evaluation of the tradicts the finding of decreased transmural repolar- QT, QTp, and TpTe intervals and the TpTe/QT ratio at ization heterogeneity by amiodarone in cardiac tissue 2 different RR interval bins (i.e., 550 to 560 ms and Although direct in vivo evidence of this drug effect is missing, 2 other studies that investigated the QTp and QT intervals were longer in patients with- electrophysiologic effects of amiodarone in isolated out arrhythmic death who received amiodarone. The Langendorff-perfused rabbit also described difference was rate dependent as evidenced by being no changes in dispersion of APD across the epicardi- more marked at long RR intervals. However, patients or between various right and left ventricular endo- with arrhythmic death who received amiodarone had cardial and epicardial Thus, a marked increase shorter QTp intervals than did patients who received in transmural repolarization heterogeneity by amioda- placebo. Although this was less obvious at short RR intervals, it became increasingly more marked at It seems therefore questionable whether the TpTe interval measured in clinical Holter recordings reflects amiodarone vs no arrhythmic death on placebo: 550 to transmural repolarization heterogeneity. Using a ca- 560 ms, p ϭ 0.216, and 1,140 to 1,150 ms, p ϭ 0.005, respectively). For patients receiving placebo, there that the inscription of the T wave of the electrocar- was no significant difference between those with and diogram stems mainly from differences in APD in without arrhythmic death at any RR interval bin.
different layers of the ventricular wall. It was shown Among patients receiving amiodarone, the TpTe that the peak of the T wave marks full repolarization interval did not significantly differ between those who of the epicardium, whereas the end of the T wave did and did not have arrhythmic death. However, marks full repolarization of the M region. Therefore, irrespective of the arrhythmic outcome, TpTe was in vitro TpTe interval was shown to measure trans- significantly longer in patients receiving amiodarone mural dispersion of By recording epicardial monophasic action potentials fromdifferent areas of the heart in open-chested dogs simultaneously with 2surface electrocardiographic leads,an earlier also suggested thatTpTe interval bear a certain relationto the dispersion of repolarization inthe entire heart.
in humans is missing, and the extentof transmural gradients of APD invivo remains to be Additionally, recent evidence sug-gests that transmural heterogeneitiesmight be even more variable thanConsidering the 3-di-mensional structure of the intactheart and the multitude of gradientspreviously (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 the 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.
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 creased TpTe values in various high-risk suggest that in-creased circumstances, 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 effiand lowof 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 riskfactor.
scribed increased TpTe intervals inpatients with long QT syndrome 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.
TABLE 2 QT, QTp, and TpTe Intervals and TpTe/QT Ratio at Different RR Interval Bins in Patients With and Without Arrhythmic
Death Receiving Amiodarone or Placebo
*p Value refers to comparison between amiodarone group and placebo group.
†Mean Ϯ SD.
‡p Value refers to comparison between patients with and without arrhythmic death.
TpTe prolongation with arrhythmic risk. Consistent tencies addressed in this study suggest that extrapola- with this finding, we did not observe any difference in tion of results of experimental studies of myocardial TpTe between patients with and without arrhythmic tissue models to human surface electrocardiograms is death who received amiodarone. However, our finding problematic. More appropriate surrogates of the in of significantly longer TpTe intervals (at higher heart vitro measured TpTe interval (e.g., the spatial mor- rates) in patients with arrhythmic death who received phology of the T wave) should be investigated.
placebo 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- 1. Sicouri S, Antzelevitch C. A subpopulation of cells with unique electrophys-
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iological properties in the deep subepicardium of the canine ventricle. The M cell.
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Syncope in Children and Adolescents and the
Congenital Long QT Syndrome
Anant Khositseth, MD, Matthew W. Martinez, MD, David J. Driscoll, MD, and From a population-based epidemiologic cohort of chil-
range (420 to 470 ms) as patients with “incomplete dren and adolescents who sought medical attention for
penetrant” or “concealed” LQTS also is unknown.
syncope (n ؍ 151), screening 12-lead electrocardio- Such information is critical for proper interpretation of
grams were obtained from 118 patients (79 female) to
the screening ECG when evaluating a young person determine the frequency of significant QT prolongation.
with syncope. Thus, the objectives of this study were The distribution of heart rate corrected QT intervals
to identify the frequency of significant and diagnostic (QTc) was compared with age- and sex-matched con-
QT prolongation (QTc Ͼ470 ms) as well as the fre- trols. Only one patient had QTc >470 ms. 2003 by quency of a nondiagnostic ECG in a community-based
Excerpta Medica, Inc.
population of fainters who sought medical attention (Am J Cardiol 2003;92:746–749)
compared with age- and sex-matched controls.
It is generally recommended that an electrocardio-
Using data from the Rochester Epidemiology gram (ECG) be part of the current evaluation of Project, 151 children and adolescents Ͻ21 years old, of whom 98 were female and 131 white, who lived in prevalence of long QT syndrome (LQTS) in syncope Rochester, Minnesota, were identified as having is unknown. Before the molecular breakthroughs in sought medical attention for an initial syncopal epi- LQTS, a QT interval corrected for heart rate (QTc), sode between 1987 and The medical records of according to Bazett’s formula, Ն440 ms was consid- each patient were reviewed, and those without docu- ered prolonged, and a QTc Ͻ420 ms was considered mentation of a screening ECG were contacted for normal. However, more recent genotype–phenotype participation in this Institutional Review Board-ap- correlations have indicated that 25% to 40% of carri- proved study. A 12-lead ECG was obtained from 118 ers of LQT1 and LQT2 mutations show QTc values (78%) patients (79 female) from this cohort. The QTc (420 to 470 ms) that overlap with those of noncarri- was computed both automatically using the Marquette In contrast, the prevalence of “fainters” having MAC8 (GE Marquette Medical Systems, Inc., Mil- a nondiagnostic ECG with a QTc falling in this same waukee, Wisconsin) and manually. Manual determi-nation of the QT interval was performed using guide- From the Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology; the Department of Medicine/Division of investigator (MWM) performed all manual QTc de- Cardiovascular Diseases; and the Department of Molecular Pharma- terminations using lead II and the standard Bazett’s cology and Experimental Therapeutics, Mayo Clinic/Mayo Founda- tion, Rochester, Minnesota. Dr. Ackerman is supported by the Doris Duke Charitable Foundation, New York, New York, and the National agnostically significant QT prolongation was defined Institutes of Health, Bethesda, Maryland (grant No. HD42569). Dr.
Ackerman’s address is: Long QT Syndrome Clinic and Sudden Death ECGs from 118 age- and sex-matched controls Genomics Laboratory, Guggenheim 501, Mayo Clinic/Mayo were obtained from Mayo Clinic’s electrocardiogra- Foundation, Rochester, Minnesota 55905. E-mail: ackerman.
phy database. The age of controls was matched to the [email protected]. Manuscript received March 20, 2003; revisedmanuscript received and accepted May 27, 2003.
patient age at time of ECG rather than age at syncope, 2003 by Excerpta Medica, Inc. All rights reserved.
The American Journal of Cardiology Vol. 92 September 15, 2003


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