Significance of QRS prolongation during diagnostic ajmaline test in patients with suspected Brugada syndrome

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Significance of QRS prolongation during diagnostic ajmaline test in patients with suspected Brugada syndrome
  Significance of QRS prolongation during diagnostic ajmaline testin patients with suspected Brugada syndrome Velislav N. Batchvarov, MD, Malini Govindan, BMed, FRACP,A. John Camm, MD, FRCP, FESC, FAHA, FHRS, Elijah R. Behr, MD, MRCP From the Division of Cardiac and Vascular Sciences, St. George’s University of London, London, England. BACKGROUND  Current consensus documents on Brugada syn-drome recommend the diagnostic intravenous administration of aNa-channel blocker to be stopped when the QRS prolongs to  130% of baseline, presumably because of increased arrhythmicrisk. OBJECTIVE  This study sought to assess QRS prolongation duringajmaline testing and its relation to arrhythmic risk. METHODS  We analyzed an electrocardiographic (ECG) databasecollected during ajmaline testing in 148 patients (92 men, age 36  15 years). The QRS was measured at baseline and during the 1st to7th, 10th, and 15th minute after the beginning of ajmaline admin-istration. RESULTS  The average QRS prolongation was 36%    16% (range9% to 88%), not significantly different between positive (n  30)and negative (n  118) tests. QRS prolonged to  130% during 16(55%) positive and 71 (61%) negative tests ( P     .50), with noclinical side effects. The incidence of ventricular arrhythmias wasnot significantly different between patients with and without QRSprolongation. Short runs (3 to 8 complexes) of nonsustainedventricular tachycardia occurred in 3 patients with QRS prolonga-tion   130%. In 40% of positive tests, prolongation   130% oc-curred earlier by  1 minute than diagnostic Brugada ECG changes,i.e., early termination of the test could possibly have resulted infalse-negative outcomes. CONCLUSION  QRS prolongation   130% occurs in   50% of all tests. In 40% of positive tests it occurs before diagnostic ECGchanges. Always terminating the test when QRS prolongs  130%could possibly result in loss of important diagnostic information.It is appropriate to adjust the criteria for early termination of thetest to the baseline QRS and possibly other factors. KEYWORDS  Brugada syndrome; Ajmaline test; QRS prolongation;Proarrhythmia; Class I drugs; Ventricular arrhythmias; Conductiondefects(Heart Rhythm 2009;6:625–631) © 2009 Heart Rhythm Society. All rights reserved. Introduction The First 1 and Second 2 Consensus Report on Brugada syn-drome (BS) recommend that the diagnostic test with intra-venous administration of a sodium channel blocker (ajma-line, flecainide, procainamide, pilsicainide) in patients withsuspected BS should be terminated when the QRS of thestandard electrocardiogram (ECG) broadens to   130% of baseline, presumably because of increased risk of ventricu-lar arrhythmias. This risk, however, has not been systemat-ically assessed. In addition, prolonged QRS on a restingECG 3 or QRS prolongation during a diagnostic test with asodium channel blocker test can be an important sign of SCN5A mutation-related conduction disease 4,5 and can alsohave prognostic value. 6 Recently, it was reported thatamong BS probands, SCN5A mutation carriers had signif-icantly longer QRS (e.g., lead V2: 135  15 ms vs. 110  13,  P    .001) and showed significantly greater QRS pro-longation during an average follow-up of 10 years (22  20ms vs. 6  11 ms,  P  .003) compared with those withoutmutations. 3 It is also possible, at least theoretically, thatQRS broadening during the test can occur before the devel-opment of diagnostic Brugada type 1 ECG pattern and thusearly termination of the test could possibly result in afalse-negative outcome. Finally, it is difficult to assess pre-cisely and rapidly the QRS duration on paper ECG printoutsrecorded while the test progresses. Hence it is easy for QRSprolongation  130% of baseline to occur.We retrospectively analyzed a digital ECG database col-lected during diagnostic ajmaline tests in 148 patients withsuspected BS to assess the relationship between QRS pro-longation and the presence of symptoms, arrhythmias, anddrug-induced diagnostic ECG changes. Methods Between August 2003 and September 2008, a diagnosticajmaline test was performed in 148 patients (92 men, 56women, ages 36    15 years) as part of their standardclinical management. Indications for the test included: (1)aborted cardiac arrest (n    19) or documented sustainedventricular tachycardia (n    3), (2) syncope of unknown Supported in part by the British Heart Foundation.  Address reprintrequests and correspondence:  Dr. Velislav N. Batchvarov, Division of Cardiac and Vascular Sciences, St. George’s University of London, Cran-mer Terrace, London SW17 0RE, United Kingdom. E-mail . (Received December 12, 2008; accepted January31, 2009.)1547-5271/$ -see front matter © 2009 Heart Rhythm Society. All rights reserved. doi:10.1016/j.hrthm.2009.01.038  srcin (n  40), (3) family history of BS (n  45) or suddencardiac death (SCD) (n    60), and (4) ECG changes sus-picious for but not diagnostic of BS discovered during ECGexamination performed for other reasons (n  8). More than1 indication was present in some patients. Ajmaline wasadministered intravenously in a dose of 1 mg/kg for 5minutes under constant ECG monitoring in a hospital set-ting. 2,7 The test was considered positive (and drug admin-istration terminated) if a type 1 Brugada pattern developedin any 2 or more of leads V1 to V3 and V1 to V3 recordedfrom 1 intercostal space higher, i.e., 3rd space for V1 andV2 (high V1 to V3 leads, V1h to V3h). 1,2,7 Digital 10-second ECGs (MAC 5000, GE Medical, Mil-waukee, Wisconsin, 500 Hz, 4.88-  V resolution) were ac-quired before, at short intervals (3 to 5 per minute) during,and up to 10 minutes after the end of drug administration incase of a negative test, and until the ECG changes com-pletely subsided in case of a positive test. In the first 42patients, standard 12-lead readings were acquired. FromMarch 2006, the high V1h to V3h leads were also routinelyrecorded (15-lead ECGs). 8-10 All ECGs were subsequentlyexported to a custom-made software program that allowsthe ECG to be displayed on screen in various formats withhigh magnification and amplitudes and intervals to be ac-curately measured with on-screen calipers. For each ajma-line test, we analyzed three 10-second ECGs recorded atbaseline and 2 ECGs recorded during each minute from the1st to the 7th, and during the 10th and 15th minute afterbeginning of ajmaline administration (21 ECGs per test).Visibly noisy ECGs were not included in analysis. In eachECG, the PR, QRS, and QT interval were measured man-ually on-screen on the 12 (or 15) superimposed leads fromthe earliest PR or QRS onset to the latest QRS offset (for theQRS) or return of the T-wave to baseline (for the QTinterval) in any lead. In each ECG, 3 consecutive QRS-Tcomplexes were measured and the results were averaged.The QTc interval was calculated using the Fridericia for-mula and the average heart rate over the 10-second ECG.Data are presented as mean  standard deviation. Nom-inal and categorical values were compared between studygroups using paired and unpaired 2-tailed student  t   test andchi-square test, respectively. A 2-tailed  P  value of   .05 wasconsidered statistically significant. Results Of 148 tests, 30 (20.3%) were positive and 118 (79.7%)were negative. The clinical and ECG characteristics of thepatients are presented in Table 1. Patients with positive tests were on average older ( P  .05), were more likely to havea family history of BS (43% vs. 21%,  P    .013), and Table 1  Clinical characteristics of the patientsPositive test (n  30) Negative test (n  118)  P   valueAge (yrs) 41  17 35  15 .050Men (n, %) 18 (60%) 74 (63.5) .78Aborted cardiac arrest (n, %) 2 (6.7) 17 (14.4%) .26Syncope (n, %) 4 (13.3%) 20 (16.9%) .63Family history of BS (n, %) 13 (43.3%) 25 (21.2%) .013Family history of SCD (n, %) 7 (23.3%) 39 (33.1%) .30VA during the testAll VA 8 (26.7%) 14 (11.9%) .042Single VPBs 5 (16.7%) 7 (5.9%) .054Complex VPBs* 2 (6.7%) 5 (4.2%) .57NSVT† 1 (3.3%) 2 (1.7%) .57Heart rate (beats/min)Baseline 72  14 68  14 .15During the test 83  15‡ 81  12‡ .39Difference 11  6 13  9 .30PR interval (ms)Baseline 172  26 160  25 .03During the test 224  32‡ 215  31‡ .18Difference 52  19 55  16 .45QRS (ms)Baseline 102  17 98  14 .12During the test 136  19‡ 132  22‡ .40Difference 34  14 35  16 .76Difference (%) 34  15 36  16 .60QTc interval (Fridericia, ms)Baseline 407  22 408  19 .82During the test 458  32‡ 449  27‡ .12Difference 51  25 41  19 .02 BS    Brugada syndrome; NSVT    3 or more consecutive VPBs at a rate of 120 beats/min or higher; SCD    sudden cardiac death; VA    ventriculararrhythmia; VPB  ventricular premature beat.*Polymorphic VPBs, bigeminy, couplets.†There was no sustained ventricular arrhythmia.‡ P   .001 vs. baseline. 626 Heart Rhythm, Vol 6, No 5, May 2009  showed significantly greater baseline PR interval and QTcinterval prolongation during the test compared with thosewith negative tests. The incidence of all ventricular arrhyth-mias (27% vs. 12%,  P    .042) and single ventricular pre-mature beats (VPBs) (17% vs. 6%,  P    .054) were alsosignificantly higher in patients with positive tests (Table 1). There were 3 cases of short runs of ventricular tachycardia(VT), one of them (3.3%) during a positive test and 2 (1.7%)during negative tests ( P    .57). However, during 1 of thenegative cases, a type 1 Brugada pattern developed in theinferior leads (inferior form of BS, see later). If we considerthis test positive, the incidence of nonsustained VT wouldalso be significantly higher in patients with positive than inthose with negative tests (6.7% vs. 0.8%,  P    .04). Therewere no sustained ventricular arrhythmias.The average QRS prolongation was 35  15 ms (36%  16%,median33%,range9%to88%)andwasnotsignificantlydifferent among patients with positive and negative tests(Table 1). The QRS prolonged to   130% of baseline in 16(55%) of patients with positive and 71 (61%) of those withnegative tests ( P    .50). No clinical side effects were notedduring any test.There were no significant differences in the incidence of all ventricular arrhythmias, single VPBs, or complex ar-rhythmias between patients with QRS prolongation to  130% compared with those without. However, all 3 casesof short runs of VT occurred in patients with QRS prolon-gation of   130% of baseline, albeit without statistical sig-nificance ( P  .14) (Table 2). Among patient with QRS prolongation  130% of base-line, the incidence of nonsustained VT was not significantlygreater in those with positive tests compared with those withnegative tests (6.3% vs. 2.8%,  P  .50) (Table 2). However,if the test with Brugada-type changes in the inferior leads isconsidered positive instead of negative, patients with bothQRS prolongation  130% and a positive test had a signif-icantly higher rate of nonsustained VT during the test thanthose with QRS prolongation   130% and a negative test(12.6% vs. 1.4%,  P  .028).The first case of nonsustained VT occurred in a 50-year-old man with no symptoms and normal baseline ECG whowas studied subsequent to the sudden and unexpected deathof his 18-year-old son in his sleep. A single short run (8beats) of polymorphic VT occurred at the moment when atype 1 Brugada pattern first developed in lead V1 and V2and the QRS was prolonged from 95 ms at baseline to 134ms (41%) (Table 3). Had drug administration stopped 1minute, 30 seconds earlier when the QRS was first pro-longed to 126 ms (31%), the test may have been interpretedas negative or inconclusive.The second case was of a 40-year-old woman with anormal baseline ECG and negative ajmaline test who sev-eral months earlier had had an episode of cardiac arrestcaused by polymorphic ventricular tachycardia with subse-quent implantation of an ICD (Table 3). A run of 6 beats of  polymorphic VT triggered by an early ventricular extrasys-tole occurred during the 4th minute of the test, when the Table 2  Ventricular arrhythmias in patients with and withoutQRS prolongationGroup QRS  130% QRS  130%  P   valueAll patients (n  148) n  61 n  87All VA 10 (16%) 12 (13.8%) .66Single VPBs 6 (9.8%) 6 (6.9%) .52Complex VPBs* 4 (6.6%) 3 (3.4%) .38NSVT† 0 (0%) 3 (3.4%) .14Positive tests (n  30) n  14 n  16All VA 5 (35.7%) 3 (18.8%) .29Single VPBs 4 (28.6%) 1 (6.3%) .10Complex VPBs* 1 (7.1%) 1 (6.3%) .92NSVT† 0 (0%) 1 (6.3%) .34Negative tests (n  118) n  47 n  71All VA 5 (10.6%) 9 (12.7%) .74Single VPBs 2 (4.3%) 5 (7.0%) .53Complex VPBs* 3 (6.4%) 2 (2.8%) .35NSVT† 0 (0%) 2 (2.8%) .25 NSVT    3 or more consecutive VPBs at a rate of 120 beats/min orhigher; VA  ventricular arrhythmia; VPB  ventricular premature beat.*Polymorphic VPBs, bigeminy, couplets.†There was no sustained ventricular arrhythmia. Table 3  Characteristics of the patients with nonsustained VT during the testPatientno.Age (yrs),sexSymptoms/indicationfor the testStructural heartdiseaseTestoutcome Pretest ECG VT QRS (ms)*QTc interval (ms)*1 50, male Asymptomatic, strongfamily history of SCDNone Positive Normal Long-coupledpolymorphicVT, 8 beats95–134 (41%) 387–4832 40, female Aborted cardiac arrest dueto polymorphic VT, ICDimplanted before the testNone Negative Normal Short-coupledpolymorphicVT, 6 beats76–100 (39%) 400–4093 57, male Asymptomatic, strongfamily history of BS andSCDNone Negative NonspecificIVCDShort-coupledpolymorphicVT, 3 beats128–203 (59%) 426–511 BS  Brugada syndrome; ICD  implantable cardioverter-defibrillator; IVCD  indeterminate ventricular conduction defect; SCD  sudden cardiac death;VT  ventricular tachycardia.*Pre-test duration is the duration at the moment of occurrence of VT, prolongation from baseline (%). 627Batchvarov et al QRS Prolongation During Ajmaline Test  QRS complex was prolonged from 76 ms at baseline to 100ms (39%).The third case was of a 58-year-old asymptomatic manwho was studied because 2 members of his family had beendiagnosed with BS (Table 3, Figure 1). His resting ECG showed a nonspecific intraventricular conduction defect(QRS  128 ms) and type 3 Brugada pattern in the inferiorleads. During the test, the QRS prolonged to 204 ms (59%)with development of a type 1 Brugada pattern in lead III andlead AVF and type 2 in lead II (possibly an inferior form of BS). A run of 3 ventricular ectopic beats occurred after theadministration of the drug was finished, and the QRS com-plex was still prolonged to 196 ms (53%). Two other mem-bers of this family showed an indeterminate intraventricularconduction defect at baseline with further QRS prolongationduring the test, from 110 to 150 msec (36%) and from 115to 180 msec (57%), respectively. Another relative had com-plete left bundle branch block with left axis deviation and aQRS duration of 130 ms at baseline, which further pro-longed to 190 ms (46%) during the test. A known SCN5Amutation (G1743E) was later identified in this family. Thus,the substantial QRS prolongation of 4 members of thisfamily with BS may be a sign of SCN5A mutation-relatedventricular conduction defects. Although it may be arguedthat the ajmaline test subjected this patient to an undue risk of arrhythmias because of the markedly prolonged baselineQRS, it also provided clinically important evidence of anatypical form of BS.In 12 patients with positive tests (40%), the QRS pro-longed to 130% of baseline earlier than the appearance of clear diagnostic criteria for a positive test by an average of approximately 90 seconds (the exact time difference couldnot be estimated because the ECGs were not acquired atstrictly equal time intervals). Had these tests terminated atthe moment of QRS prolongation by 30%, some couldpossibly have been interpreted as negative or borderline.There were no significant differences between symptom-atic (n    10, 8 with syncope and 2 with aborted cardiacarrest) and asymptomatic (n    20) patients with positivetests with respect to their age, gender, baseline, and maxi-mum PR and QTc intervals and the PR and QTc incrementsduring the test (Table 4). Patients with symptoms had sig- nificantly longer baseline (112  24 vs. 98  10,  P  .03)but not maximum QRS interval (139    26 vs. 135    15, P  .55) compared with those without symptoms. Accord-ingly, the QRS prolongation during the test was signifi-cantly greater in asymptomatic than symptomatic patients(38%  14% vs. 26%  15%,  P  .03) (Table 4). There were no significant differences between men andwomen in the incidence of all ventricular arrhythmias(13.6% vs. 19.6%,  P  .20), single VPBs (5.4% vs. 12.5%, P    .13), complex VPBs (3.3% vs. 7.1%,  P    .28), ornonsustained VT (2.2% vs. 1.8%,  P    .87). The baselineQRS (103  14 vs. 92  12 ms,  P  .001) and maximumQRS during the test (138  21 vs. 126  20 ms,  P  .001)were longer in men, whereas the maximum QRS prolonga-tion (35  15% vs. 37  17%,  P  .33) and the percentageof patients with QRS prolongation to   130% (57.6% vs.62.5%,  P  .56) were not significantly different between the2 groups. Discussion Our results show that QRS prolongation to   130% of baseline occurs in more than half of all positive and nega-tive ajmaline tests in patients investigated for BS. Impor-tantly, in 40% of all positive tests, QRS prolongation of such magnitude occurred more than 1 minute before theappearance of a diagnostic Brugada ECG pattern. Hence, Table 4  Characteristics of patients with positive tests(n  30) according to symptomsWith symptoms*(n  10)No symptoms*(n  20)  P   valueAge (yrs) 42  16 41   18 .83Men (n, %) 6 (60%) 12 (60%) 1.00PR interval (ms)Baseline 175   26 170   27 .62After the test 222  34† 225   32† .80Difference 47  27 55   14 .26QRS (ms)Baseline 112   24 98   10 .028After the test 139  26† 135   15† .55Difference 27  13 37   13 .069Difference (%) 26  15 38   14 .033QTc interval (Fridericia, ms)Baseline 412   29 405   18 .41After the test 461  46† 457   22† .69Difference 49  30 52   23 .81 *Symptoms are syncope and/or prior cardiac arrest.† P   .001 vs. baseline. Figure 1  ECGs recorded at baseline (left panel) and 1 minute after theend of ajmaline administration (right panel) in a 58-year-old asymptomaticman who was studied because 2 members of his family have been diag-nosed with BS. The QRS prolonged from 128 ms at baseline to a maximumof 204 ms (59%) during the test. A run of 3 ventricular ectopics occurredafter the end of drug administration when the QRS complex was stillprolonged to 196 ms (right panel). See the text for details. 628 Heart Rhythm, Vol 6, No 5, May 2009  early termination of drug administration may have resultedin false-negative or borderline results in some of these tests.These results do not question the well-established link between marked QRS prolongation and increased risk of ventricular arrhythmias during administration of sodiumchannel blockers. They do suggest, however, that the rec-ommendation of the Consensus Reports 1,2 to terminate aj-maline administration when the QRS prolongs to  130% of baseline should not be applied blindly to all cases. Ourfindings and data from other published studies suggest thatthe decision to stop the test, as well as the overall assess-ment of the test-related arrhythmic risk, should also takeinto consideration other factors, in addition to the drug-induced QRS prolongation. Factors predicting occurrence of ventricular arrhythmias during pharmacologic testing for Brugada syndrome Statistical assessment of the factors predicting arrhythmiaoccurrence during pharmacologic testing for BS seems dif-ficult because of the rarity of such adverse events. The mainstudies addressing this problem are summarized in Table 5.In 3 studies, VT occurred in 18%, 11 6.2%, 12 and 10.7%, 13 respectively, during testing with flecainide or pilsicainide.The majority or all of the patients enrolled in these studies,however, had baseline ECGs that were diagnostic of BS.Two large studies with ajmaline 14 and flecainide, 15 in whichonly patients similar to ours with nondiagnostic baselineECGs were enrolled, the incidence of VT was 1.3 14 and0%, 15 respectively. Rolf et al 14 reported 2 cases of sustainedVT during 158 tests with ajmaline (1.3%), both havingoccurred in patients in whom the investigators have contin-ued drug administration after the appearance of diagnosticBrugada-type ECG changes. Our finding of a higher inci-dence of ventricular arrhythmias in patients with positivecompared with those with negative tests is in concert withthese data. QRS prolongation and arrhythmic risk inBrugada syndrome and during administrationof sodium channel blockers Morita et al. 12 reported that the QRS was marginally longerat baseline (0.10    0.02 vs. 0.09    0.01,  P    .08) andbecame significantly longer after pilsicainide administration(0.13    0.03 vs. 0.11    0.01,  P    .04) in patients whodeveloped compared with those who did not develop ven-tricular arrhythmias during the test. However, the investi-gators mention that “QRS interval after administration of pilsicainide only showed slight prolongation in patients withpilsicainide-induced arrhythmia,” and it seems from theabove figures that this prolongation was likely within the30% of baseline. Gasparini et al 11 briefly mention that 1 of the 4 patients in their study developed polymorphic VTpreceded by ST-segment changes diagnostic of BS andprogressive QRS widening at the end of a flecainide test. Incontrast, Shimizu et al 16 reported that among 12 patientswith BS tested with flecainide (2 mg/kg intravenously for 10minutes), those who developed VPBs and couplets (n  3)tended to have narrower QRS (117    6 vs. 142    26 ms, P  .07) and smaller QRS prolongation (25  8 vs. 33  8,  P    .08), but greater ST-segment elevation after theinfusion of the drug compared with the rest of the patients(n  9) who did not develop arrhythmias during the test.Our results seem to indicate that the proarrhythmic effectof ajmaline is augmented in the presence of both a substratefor BS (i.e., a positive test) and marked QRS prolongation(  130% of baseline), although the small number of events(2 cases of nonsustained VT, 1 of them in a patient withinferior form of BS, 12.6%) precludes definite conclusions.Both the therapeutic as well as the toxic and proarrhyth-mic effects of all sodium channel blockers are manifestedon the ECG by a different degree of PR and QRS prolon-gation. 17 Although the average PR and QRS prolongationduring chronic treatment with therapeutic doses of flecain-ide has been reported to be 25%, 18 a substantially greaterdegree of QRS prolongation (up to 75%) has been observedin many patients without clinical effects. 18 The risk of toxicity and proarrhythmia with class I drugs likely dependson the presence of preexisting ventricular conduction de-fect. 17 The presence of SCN5A mutations, even in asymp-tomatic patients, also has been shown to increase the risk of ventricular arrhythmia during flecainide testing for BS. 11 Therefore, it seems illogical to apply the same criteria fordrug toxicity to all patients regardless of other factors, suchas their baseline QRS duration. It seems more appropriatethat criteria for test termination be adjusted to the baselineQRS duration in a similar fashion to those proposed forquinidine but with greater leeway (  50% in patients withnormal QRS duration and   25% in patients with majorintraventricular conduction disturbances 19 ). Other factorsthat could potentially augment the arrhythmic risk duringthe test, such as the presence of SCN5A mutation-relatedconduction disease, the appearance of microscopic T-wavealternans 12 and the development of both diagnostic BrugadaECG changes and marked QRS prolongation need furtherinvestigation. Ultimately, however, improving diagnosticyield requires the acceptance of a risk of ventricular arrhyth-mia, whether the QRS prolongs by more than 30% or not.For example, in our second case accompanied by nonsus-tained VT, the QRS prolonged from 75 to 100 ms (33%),which cannot be considered a major sign of increased ar-rhythmic risk.The degree of QRS prolongation during a sodium chan-nel blocking test can provide important diagnostic informa-tion as shown by Smits et al, 5 who reported significantlygreater QRS prolongation during the test in BS patients with(n    23) compared with those without (n   54) identifiedSCN5A mutations (142    31 vs. 118    21,  P    .05),whereas the baseline QRS was not significantly differentbetween the 2 groups (104  26 vs. 100  17,  P  NS).Our observation of longer pretest QRS duration in symp-tomatic compared with asymptomatic patients with positiveajmaline test is similar to the study of Junttila et al, 6 who 629Batchvarov et al QRS Prolongation During Ajmaline Test
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