CASE REPORTS

Pilsicainide-Induced ST Segment Elevation and STSegment Depression in Two Patients with Variant Formsof Brugada-Type Electrocardiographic AbnormalitiesMASAOMI CHINUSHI, M.D.,* MINORU TAGAWA, M.D.,† DAISUKE IZUMI, M.D.,†HIROSHI FURUSHIMA, M.D.,† and YOSHIFUSA AIZAWA, M.D.†From the *School of Health Science and †First Department of Internal Medicine, Niigata University School ofMedicine, Niigata, Japan

In two patients with variant forms of Brugada electrocardiographic abnormalities, ST segment elevation,and reciprocal ST segment depression developed during intravenous administration of pilsicainide. Inone patient, pilsicainide accentuated the ST segment elevation in leads I, aVL, and V1–V3 and caused STsegment depression in leads II, III, and aVF. Coronary angiograms at the time of ST segment elevation werenormal. In the other patient, pilsicainide accentuated the coved-type ST segment elevation in leads II, III,and aVF and caused ST segment depression in leads I, aVL, and V2–V5. Frequent premature ventricularcomplexes (PVCs) with two different left bundle branch block patterns developed during ST segmentelevation. Intravenous isoproterenol returned the ST segment to baseline in both patients and suppressedthe PVCs in the second patient. We hypothesize that a wide area of epicardial myocardium with largeIto current might explain the reciprocal ST segment depression observed at the time of accentuated STsegment elevation. (PACE 2009; 32:811–815)

Brugada syndrome, ST segment deviation, pilsicainide

IntroductionST segment elevation on the surface elec-

trocardiogram (ECG) and fatal ventricular tach-yarrhythmias are manifestations shared by bothacute myocardial ischemia and Brugada syn-drome. During ST segment elevation associatedwith acute myocardial ischemia, one might expectpatients to complain of chest pain and recipro-cal ST segment depression to be present on theECG. In contrast, patients with Brugada syndromeare asymptomatic, and ST segment depression israrely recorded on the ECG. We observed twopatients with variant forms of Brugada ECG ab-normalities in whom ST segment depression de-veloped during the accentuation of ST segmentelevation by intravenous pilsicainide.

Case ReportsCase 1

A 34-year-old man was referred to ourhospital for investigation of ECG abnormalitiesdetected at the time of health maintenance exami-nation. The patient had no personal or family his-

Address for reprints: Masaomi Chinushi, M.D., School ofHealth Science, Niigata University School of Medicine, 2-746Asahimachi, Niigata 951-8518, Japan. Fax: 81-25-227-0774;e-mail: masaomi@clg.niigata-u.ac.jp

Received June 22, 2008; revised July 28, 2008; accepted August12, 2008.

tory of syncope or sudden death, was apparentlyhealthy, and offered no complaint, and the exami-nation of his cardiovascular system was normal.A standard 12-lead ECG showed sinus rhythm,and saddle-back (type 2) ST segment elevationwas intermittently recorded in leads V1–V3.1 Latepotentials were present on a signal-averaged ECG.The intravenous administration of 60 mg of pil-sicainide over 5 minutes amplified the ST seg-ment elevation, which resulted in a coved-typemorphology (type 1) in lead aVL. On the otherhand, in leads I and V1–V3, ST segment eleva-tion approached a coved appearance followingthe higher concentration of pilsicainide, thoughit did not quite achieve the coved-type morphol-ogy (Fig. 1).1 As the ST segment elevation becamemore prominent, ST segment depression appearedin leads II, III, and aVF. The ST segment returnedto baseline during the intravenous administrationof isoproterenol, 0.1 μg/min. Neither chest painnor ventricular tachyarrhythmias developed dur-ing the pilsicainide test.

Cardiac catheterization and electrophysio-logic studies were performed with the patient’sinformed consent. The His-ventricular (HV) inter-val during sinus rhythm was 50 ms. Our stimula-tion protocol for patients with Brugada-type ECGabnormalities includes up to three extrastimuli de-livered during pacing at drive cycle lengths of 600and 400 ms and rapid pacing down to a cyclelength of 286 ms from the right ventricular (RV)

C©2009, The Authors. Journal compilation C©2009 Wiley Periodicals, Inc.

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Figure 1. Electrocardiographic recordings during pilsicainide test in patient 1. (A) Subtle ST segment elevation ispresent in leads V2–V3 at baseline. (B, C) Accentuation of the ST segment elevation in leads V2–V3, I, and aVL bypilsicainide, with development of ST segment depression in leads II, III, and aVF. (D) Return of the ST segmentelevation to baseline during isoproterenol infusion.

apex and outflow tract. In this case, ventricularfibrillation (VF) was induced by triple extrastimulidelivered at the RV outflow tract. The intracardiacpressures, coronary angiograms, and left ventricu-logram were normal, and coronary vasospasm wasnot induced by 50 μg of ergonovine maleate, in-jected into each of the left and right coronary ar-teries. After injection of isosorbide dinitrate, a sec-ond intravenous pilsicainide test was performed,which reproduced the ST segment deviation ob-served a few days earlier. However, simultaneouscoronary angiograms revealed no stenosis of eitherthe left or the right coronary artery. The patient de-clined to undergo implantation of a cardioverterdefibrillator and genetic analyses. He has sufferedno adverse cardiac event over a 6-month follow-up.

Case 2

Similar ECG observations were made in a 17-year-old man whom we have previously describedas having a variant form of Brugada syndrome.2His 12-lead ECG at rest showed sinus rhythm

and subtle ST segment elevation in leads II, III,and aVF. The intravenous administration of pil-sicainide, 40 mg over 4 minutes, induced type 1ST segment elevation in leads II, III, and aVF. AsST segment elevation became more prominent, STsegment depression appeared in leads I, aVL, andV2–V5 (Fig. 2), along with frequent premature ven-tricular complexes (PVCs) and runs of up to threeconsecutive premature ventricular cycles (Fig. 3).The left bundle branch block QRS morphology ofthe PVCs was associated with left axis deviationor with a normal axis. The intravenous adminis-tration of isoproterenol, 0.1 μg/min, returned theST segment to baseline and suppressed the PVCs.The patient remained asymptomatic throughoutthe test.

After informed consent was obtained from thepatient and his family, cardiac catheterization andelectrophysiologic studies were performed, whichrevealed the presence of normal coronary arteriesand left ventricular function and an HV intervalprolonged to 65 ms during sinus rhythm. VF wastwice induced by triple extrastimuli delivered at

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Figure 2. Electrocardiographic recordings during pilsicainide test in patient 2. (A) Subtle ST segment elevation ispresent in leads II, III, and aVF at baseline. (B–D) Accentuation of the ST segment elevation in leads II, III, and aVF,by pilsicainide, with development of ST segment depression in leads I, aVL, and V2–V5. (E) Return of the ST segmentelevation to baseline during isoproterenol infusion.

the RV apex. The patient and his family refusedimplantation of a cardioverter defibrillator and ge-netic analyses. He has remained free of adversecardiac event over a 50-month follow-up.

DiscussionIn patients without structural heart disease,

coved ST segment elevation in leads V1–V3 ofthe surface ECG is a diagnostic sign of Brugadasyndrome.1,3 Some studies have suggested thatST segment elevation and initiation of VF in pa-tients with Brugada syndrome are associated withmarked RV transmural dispersion of repolariza-tion, which facilitates phase 2 reentry between twoRV epicardial regions or between RV endocardiumand epicardium.4,5 The ST segment is usually el-evated in leads V1–V3 of the ECG, although ithas also been observed in leads II, III, and aVF(variant form).2,6,7 This is attributed to the promi-nent distribution of the large Ito current in the epi-cardium of the RV outflow tract,4,8 and the marked

shortening of myocardial action potential durationby several factors, including class I antiarrhyth-mic drugs.1,9 However, since the amount of my-ocardium represented by the RV outflow tract isrelatively small, reciprocal ST segment depressionis rarely observed in Brugada syndrome.

The ECG characteristics of our two cases areconsistent with the variant forms of Brugada syn-drome,2,6,7 since (1) ST segment elevation in rightprecordial leads approached a coved appearancefollowing the higher concentration of the pilsi-cainide in case 1, and a coved-type ST segmentelevation was induced in the inferior leads by theintravenous administration of pilsicainide in case2, and (2) VF was induced by programmed elec-trical stimulation.1,3 Furthermore, the ST segmentelevation recorded, in case 1, in leads other thanthe right precordial leads, including I and aVL, andthe development of two forms of PVCs in case 2suggest that, in both cases, the myocardium withlarge Ito current was present in a wider area of

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Figure 3. Ventricular arrhythmia induced by pilsicainide (case 2). Frequent PVCs with left bundle branch blockpattern and left axis deviation (A, B) or left bundle branch block pattern and normal axis (B) were induced during STsegment elevation.

the heart than in typical cases. If our hypothe-sis is correct, a more prominent Ito may lead toa more extensive area in which the epicardial ac-tion potential notch is accentuated and in whichthe epicardial action potential dome may be lost,leading to a prominent transmural voltage gradi-ent that is manifested as a ST segment elevationin facing leads and as a reciprocal ST segment de-pression in opposing leads. It is noteworthy that,in both cases, ST segment depression became ap-parent when ST segment elevation became moreprominent, and that ST segment depression andST segment elevation were simultaneously accen-tuated by pilsicainide and attenuated by isopro-terenol. Alternatively, a myocardium with largeIto current might have been predominant in theventricular endocardial layers, although this hy-pothesis is not supported by previous studies.

Myocardial ischemia, including from coronaryvasospasm, seems unlikely in both cases, sinceboth patients were young, asymptomatic duringthe ECG changes, and had normal coronary an-giograms and left ventriculograms. A normal coro-nary circulation was also confirmed at the time ofST segment elevation in case 1. Furthermore, intra-venous pilsicainide is unlikely to induce coronaryvasospasm, since sodium channels are known tobe present neither in vascular smooth muscle norin endothelial cells. Although apparently rare, re-ciprocal ST segment depression may develop insome patients with Brugada syndrome. Since itmay indicate the presence of a greater amountof myocardium with large Ito current, these pa-tients might be at higher risk of long-term ar-rhythmic events, but this hypothesis remains to betested.

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Corrado D, Gussak I, et al. Brugada syndrome: Report of the sec-ond consensus conference: Endorsed by the Heart Rhythm Societyand the European Heart Rhythm Association. Circulation 2005; 111:659–670.

2. Chinushi M, Izumi D, Furushima H, Watanabe H, AizawaY. Multiple premature beats triggered ventricular arrhythmiasduring pilsicainide infusion in a patient with inferior ST-segment elevation. Pacing Clin Electrophysiol 2006; 29:1445–1448.

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3. Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Bru-gada P. Long-term follow-up of individuals with the electrocardio-graphic pattern of right bundle-branch block and ST-segment eleva-tion in precordial leads V1 to V3. Circulation 2002; 105:73–78.

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5. Aiba T, Shimizu W, Hidaka I, Uemura K, Noda T, Zheng C, KamiyaA, et al. Cellular basis for trigger and maintenance of ventricularfibrillation in the Brugada syndrome model: High-resolution opticalmapping study. J Am Coll Cardiol 2006; 47:2074–2085.

6. Kalla H, Yan GX, Marinchak R. Ventricular fibrillation in a patientwith prominent J (Osborn) waves and ST-segment elevation in theinferior electrocardiographic leads: A Brugada syndrome variant? JCardiovasc Electrophysiol 2000; 11:95–98.

7. Takagi M, Aihara N, Takaki H, Taguchi A, Shimizu W, Ku-rita T, Suyama K, et al. Clinical characteristics of patients withspontaneous or inducible ventricular fibrillation without appar-ent heart disease presenting with J wave and ST segment eleva-tion in inferior leads. J Cardiovasc Electrophysiol 2000; 11:844–848.

8. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome andother mechanisms of arrhythmogenesis associated with ST-segmentelevation. Circulation 1999; 100:1660–1666.

9. Brugada R, Brugada J, Antzelevitch C, Kirsch GE, Potenza D, Tow-bin JA, Brugada P. Sodium channel blockers identify risk for sud-den death in patients with ST-segment elevation and right bundlebranch block but structurally normal hearts. Circulation 2000; 101:510–515.

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