because of its unique channel-blocking properties.9 As aclass I antiarrhythmic drug, aprindine blocks the sodiumchannel mainly in the inactivated channel state.10 Bepri-dil enhances the sodium channel-blocking effect ofaprindine on atrial tissue because it prolongs the actionpotential duration and the duration of the inactivatedstate of the sodium channel in the atrium. In addition toclass I antiarrhythmic drug action, aprindine causes amoderate reduction in calcium current, in the delayedrectifier K current, and in the hyperpolarization-activatedinward current.9,11 Although the precise mechanism ofAF termination with a combination of bepridil withaprindine was not clear, it can reverse remodeling of theatrial substrate.

1. Singh BN. Bepridil therapy: guidelines for patient selection and monitoring oftherapy. Am J Cardiol 1992;69(suppl):79D–85D.2. Kato R, Singh BN. Effects of bepridil on the electrophysiologic properties ofisolated canine and rabbit myocardial fibers. Am Heart J 1986;111:271–279.3. Wang JC, Kiyose T, Kiriyama K, Arita M. Bepridil differentially inhibits two

delayed rectifier K currents, Ikr and Iks, in guinea-pig ventricular myocytes. Br JPharmacol 1999;128:1733–1738.4. Kobayashi S, Reien Y, Ogura T, Saito T, Masuda Y, Nakaya H. Inhibitoryeffect of bepridil on hKv1.5 channel current: comparison with amiodarone andE-4031. Eur J Pharmacol 2001;430:149–157.5. Fujiki A, Sakabe M, Nishida K, Mizumaki K, Inoue H. Role of fibrillationcycle length in spontaneous and drug-induced termination of human atrial fibril-lation: spectral analysis of fibrillation waves from surface electrocardiogram. CircJ 2003;67:391–395.6. Hara Y, Nakaya H. SD-3212, a new class I and IV antiarrhythmic drug: apotent inhibitor of the muscarinic acetylcholine-receptor-operated potassium cur-rent in guinea-pig atrial cells. Br J Pharmacol 1995;116:2750–2756.7. Li Y, Sato T, Arita M. Bepridil blunts the shortening of action potentialduration caused by metabolic inhibition via blockade of ATP-sensitive K chan-nels and Na-activated K channels. J Pharmacol Exp Ther 1999;291:562–568.8. Perelman MS, Mckenna WJ, Rowland E, Krikler DM. A comparison ofbepridil with amiodarone in the treatment of established atrial fibrillation. BrHeart J 1987;58:339–344.9. Kodama I, Ogawa S, Inoue H, Kasanuki H, Kato T, Mitamura H, Hiraoka M,Sugimoto T. Profile of aprindine, cibenzoline, pilsicainide and pirmenol in theframework of the Sicilian gambit. Jpn Circ J 1999;63:1–12.10. Kodama I, Honjo H, Kamiya K, Toyama J. Two types of sodium channelblock by class-I antiarrhythmic drugs studied by using Vmax of action potentialin single ventricular myocytes. J Mol Cell Cardiol 1990;22:1–12.11. Ohtomo-Sekine Y, Uemura H, Tamagawa M, Nakaya H. Inhibitory effects ofaprindine on the delayed rectifier K current and the muscarinic acetylcholinereceptor-operated K current in guinea-pig atrial cells. Br J Pharmacol 1999;126:751–761.

Safety and Feasibility of Dobutamine StressEchocardiography in Patients With Implantable

Cardioverter Defibrillators

Abdou Elhendy, MD, PhD, John Windle, MD, and Thomas R. Porter, MD

Coronary artery disease is the underlying etiology ofleft ventricular dysfunction and arrhythmias in mostpatients who receive implantable cardioverter defi-brillators (ICDs). The aim of this study was to assessthe safety and feasibility of dobutamine stress echo-cardiography (DSE) in patients with an ICD. DSE (do-butamine up to 50 �g/kg/min, atropine up to 2 mg)was performed in 87 patients with an ICD and knownor suspected coronary artery disease. The ICD wasinactivated before the stress test and reactivated afterthe study; no serious complications occured. DSE is asafe and feasible method for evaluating myocardialischemia in patients with an ICD. �2003 by Ex-cerpta Medica, Inc.

(Am J Cardiol 2003;92:475–477)

Dobutamine stress echocardiography (DSE) is auseful alternative to exercise stress testing in

patients with limited exercise capacity. However,most laboratories consider the test contraindicated inpatients at high risk of severe ventricular arrhyth-mias.1,2 The aim of this study was to assess the safetyand feasibility of DSE for evaluation of myocardial

ischemia in patients with implantable cardioverter de-fibrillators (ICDs).

• • •The study group consisted of 87 consecutive pa-

tients with limited exercise capacity who received anICD for secondary or primary prevention of suddencardiac arrest, and who underwent dobutamine–atro-pine stress echocardiography for evaluating myocar-dial ischemia between 1996 and 2002 at the Univer-sity of Nebraska Medical Center. Exclusion criteriawere unstable chest pain and New York Heart Asso-cation functional class IV congestive heart failure. Allpatients gave informed consent to undergo the dobut-amine stress test. The institute’s review board ap-proved the study protocol.

The ICD was set at an inactive mode immediatelybefore starting the dobutamine stress test. Dobutaminewas infused at a starting dose of 5 �g/kg/min for 3minutes, followed by 10 �g/kg/min for 3 minutes(low-dose stage). The dobutamine dose was increasedby 10 �g/kg/min every 3 minutes up to a maximumdose of 50 �g/kg/min. Atropine (up to 2 mg) wasadministered intravenously if 85% of maximal pre-dicted heart rate (220 � age) could not be achieved.End points of the test were achievement of target heartrate, maximal dose of dobutamine and atropine, ex-tensive new wall motion abnormalities, �2 mV ofdownsloping ST-segment depression measured 80 msfrom the J point compared with that at baseline, hy-pertension (blood pressure �240/120 mm Hg), symp-

From the Department of Cardiology and Internal Medicine, Universityof Nebraska Medical Center, Omaha, Nebraska. Dr. Elhendy’s ad-dress is: 982265 Nebraska Medical Center, Omaha, Nebraska68198-2265. E-mail: Aelhendy@unmc.edu. Manuscript receivedMarch 7, 2003; revised manuscript received and accepted May 8,2003.

475©2003 by Excerpta Medica, Inc. All rights reserved. 0002-9149/03/$–see front matterThe American Journal of Cardiology Vol. 92 August 15, 2003 doi:10.1016/S0002-9149(03)00673-8

tomatic decrease in systolic blood pressure, symptom-atic or sustained ventricular or supraventriculartachycardia, or any intolerable adverse effect due toadministration of dobutamine or atropine. Metoprolol(1 to 5 mg) was used intravenously to reverse the sideeffects of dobutamine if these did not revert quicklyafter termination of dobutamine infusion. The ICDwas reactivated 6 minutes after the stress test. DSEwas considered feasible if the patient achieved thetarget heart rate (85% of maximal heart rate predictedfor age) and or an ischemic end point (new or wors-ening wall motion abnormalities, angina, or ST-seg-ment depression).

Images were acquired at rest, continuously duringthe test, and during recovery. Images were recordedon videotapes and, in addition, the baseline, low-dose,peak-stress, and recovery images were recorded in aquad-screen format. For analysis of left ventricularfunction, a 16-segment model was used.3 Each seg-ment was scored using a 5-point scale, with 1 �normal, 2 � mild hypokinesia, 3 � severe hypokine-sia, 4 � akinesia, and 5 � dyskinesia. Ischemia was

defined as new or worsening wall motion abnormali-ties during stress, indicated by an increase in wallmotion score of �1 grade in �1 segment. A biphasicresponse in an akinetic or severely hypokinetic seg-ment was considered as an ischemic response.4 Isch-emia was not considered present when akinetic seg-ments at rest became dyskinetic during stress.4Ejection fraction was measured using the validatedmodification of the method of Dujardin et al5 or byvisual estimation.6

Continuous data are presented as mean values �SD and were compared by the Student’s t test. Thechi-square test was used to compare differences be-tween proportions. Logistic regression models wereused to identify predictors of tachyarrhythmias andhypotension during dobutamine stress. Variables in-cluded in the multivariate model were the variablesthat showed a significant difference or a trend to adifference (p �0.1) in the univariate analysis. Differ-ences were considered significant if the null hypoth-esis could be rejected at the 0.05 probability level.

Clinical features of the study patients are listed inTable 1. Electrophysiologic studies were performed inall patients before ICD placement. The studies showedinducible sustained monomorphic ventricular tachy-cardia in 61 patients (70%). The ICD was placed in theremaining patients without inducible ventriculartachycardia because of a history of sudden cardiacarrest with left ventricular dysfunction, or recurrentsymptomatic ventricular tachycardia in patients whowere unable to tolerate or to respond to antiarrhythmictherapy. Twelve patients (14%) had atrial fibrillation.The stress test was performed 3.6 � 2.1 years afterICD implantation.

There were no incidences of death, myocardialinfarction, ventricular fibrillation, or sustained ventric-ular tachycardia during or shortly after the stress test.Hemodynamic data and incidence of arrhythmias dur-ing DSE are presented in Table 2. Nonsustained ven-tricular tachycardia occurred in 6 patients (7%). Ven-tricular and supraventricular tachycardias wereterminated in all patients spontaneously by discontinu-ing dobutamine infusion or by administration of meto-prolol. The target heart rate was reached in 75 patients(86%). Reasons for test termination in other patientswere angina in 3 patients, hypotension in 1 patient,ventricular arrhythmias in 1 patient, and maximal doseof dobutamine and atropine in 8 patients. Of the 12patients who failed to achieve the target heart rate, thetest was still feasible in 7 patients due to the occur-rence of an ischemic end point. The study was con-sidered feasible in 82 patients (94%).

Adequate imaging was obtained in all patients.Mean ejection fraction was 32 � 10%. Regional wallmotion abnormalities were detected in 84 patients(97%) on the baseline echocardiogram. Ischemia wasdetected in 31 patients (36%). The incidence of echo-cardiographic ischemia was not different in patientswith versus without dobutamine-induced tachyar-rhythmias (43% vs 35%, respectively).

Univariate predictors of dobutamine-induced hy-potension (systolic pressure decrease �20 mm Hg)

TABLE 1 Clinical Features of the Study Patients (n � 87)

Clinical Features

Age (yrs) 67 � 11Men 61 (70%)Previous myocardial infarction 77 (89%)Previous coronary bypass 63 (72%)Previous percutaneous intervention 30 (34%)Diabetes mellitus 18 (21%)Systemic hypertension 61 (70%)Cigarette smoking 5 (6%)Hypercholesterolemia* 55 (63%)History of cardiac arrest 30 (34%)History of syncope 14 (16%)History of sustained ventricular tachycardia 55 (63%)Angina 20 (27%)Atypical chest pain 30 (34%)Heart failure 48 (55%)Medications

� blockers 31 (36%)Calcium channel blockers 28 (32%)Angiotensin-converting enzyme inhibitors 63 (72%)Antiarrhythmic medications 34 (39%)

*Fasting total cholesterol �200 mg/dl.

TABLE 2 Hemodynamic Data of the Study Patients (n � 87)

Dobutamine Stress Test Parameters

Heart rate at rest (beats/min) 70 � 15Heart rate at peak stress (beats/min) 135 � 17Achievement of target heart rate 75 (86%)Systolic blood pressure at rest (mm Hg) 143 � 26Systolic blood pressure at peak stress (mm Hg) 141 � 30Systolic blood pressure decrease �20 mm Hg 15 (17%)Maximal dobutamine dose (�g/kg/min) 36 � 8Atropine given (patients) 40 (46%)Mean atropine dose (mg) 1.1 � 0.4Horizontal or downsloping ST depression 14 (16%)Angina during stress 10 (11%)Arrhythmias during dobutamine stress

Nonsustained ventricular tachycardia 6 (7%)Supraventricular tachycardia 1 (1%)

476 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 92 AUGUST 15, 2003

were older age (p �0.01), higher baseline systolicblood pressure (p �0.05), higher dobutamine dose (p�0.05), and ejection fraction at rest (p �0.001). In-dependent predictors of hypotension in a multivariateanalysis were ejection fraction at rest (p �0.01, chi-square 5.1) and age (p �0.05, chi-square 3.3). Ejec-tion fraction at rest was the only univariate predictorof tachyarrhythmias (p �0.01, chi-square 2.1).

• • •In this study, we assessed the safety and feasibility

of DSE in 87 patients at high risk of severe ventriculararrhythmias and/or a history of sudden cardiac arrestwho were treated with ICDs. The test was tolerated inall patients without serious side effects. There were nodeaths or episodes of ventricular fibrillation or sus-tained tachycardia. Nonsustained ventricular tachycar-dia occurred in 7% of patients, which is slightly higherthan the average incidence of 4% reported in previousstudies in an unselected population.1 Nevertheless,episodes of ventricular tachycardia were terminatedspontaneously by discontinuation of dobutamine infu-sion or by administration of metoprolol. The studywas considered feasible (achievement of 85% of pre-dicted heart rate and/or an ischemic end point) in 94%of patients, which is comparable to previous stud-ies.1,2,7 Myocardial ischemia was detected in 36% ofpatients and was not associated with an increased riskof arrhythmias during the dobutamine stress test.Baseline ejection fraction was a predictor of tachyar-rhythmias during stress testing. This finding is consis-tent with previous studies that showed that the occur-rence of arrhythmias with dobutamine stress wasrelated to the extent of wall motion abnormalities atrest, and explains the relatively higher incidence ofventricular tachycardia in this study, because we in-cluded patients with more severe left ventricular dys-function.1,7–9 A decrease of �20 mm Hg in systolicblood pressure occurred in 17% of patients. This waswell tolerated and necessitated termination of the testin only 1 patient. Age and ejection fraction at rest wereindependent predictors of hypotension. Althoughsome studies found no correlation between the wallmotion score index at rest and dobutamine-inducedhypotension in a heterogenous population,10 studies ofpatients with previous myocardial infarction demon-strated an association between blood pressure re-sponse and the extent of wall motion abnormalities atrest.11,12 The association between age and hypotensioncan be explained by impaired compensatory mecha-nisms in hypotension with aging.13

The number of patients in this study was small.Further studies are needed to confirm our findings.Although this study demonstrated the safety of DSEusing sustained or symptomatic ventricular tachycar-dia as a test end point, it appears reasonable to dis-

continue the test if the patient develops ventriculartachycardia lasting �15 seconds.

Experience with stress testing in patients with anICD is very limited. Gioia et al14 studied 101 patientswith a history of ventricular arrhythmias (31 patientsafter ICD implantation) with exercise or vasodilatorsingle-photon emission computed tomographic imag-ing. The extent of fixed (but not reversible) perfusionabnormalities was predictive of mortality during afollow-up of 29 months. Further studies are needed todetermine the prognostic utility of stress echocardiog-raphy in patients with ICDs.

1. Geleijnse ML, Fioretti PM, Roelandt JRTC. Methodology, feasibility safetyand diagnostic accuracy of dobutamine stress echocardiography. J Am CollCardiol 1997;30:595–606.2. Picano E, Mathias W Jr, Pingitore A, Bigi R, Previtali M. Safety andtolerability of dobutamine-atropine stress echocardiography: a prospective, mul-ticentre study. Echo Dobutamine International Cooperative Study Group. Lancet1994;344:1190–1192.3. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H,Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommendations for quantifica-tion of the left ventricle by two-dimensional echocardiography: American Societyof Echocardiography Committee on Standards, Subcommittee on Quantificationof Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358–367.4. Elhendy A, Cornel JH, Roelandt JR, van Domburg RT, Nierop PR, GeleijnseML, El-Said GM, Fioretti PM. Relation between contractile response of akineticsegments during dobutamine stress echocardiography and myocardial ischemiaassessed by simultaneous thallium-201 single-photon emission computed tomog-raphy. Am J Cardiol 1996;77:955–959.5. Dujardin KS, Enriquez-Sarano M, Rossi A, Bailey KR, Seward JB. Echocar-diographic assessment of left ventricular remodeling: are left ventricular diame-ters suitable tools? J Am Coll Cardiol 1997;30:1534–1541.6. Stamm RB, Carabello BA, Mayers DL, Martin RP. Two-dimensional echo-cardiographic measurement of left ventricular ejection fraction: prospective anal-ysis of what constitutes an adequate determination. Am Heart J 1982;104:136–144.7. Poldermans D, Fioretti PM, Boersma E, Forster T, van Urk H, Cornel JH,Arnese M, Roelandt RT. Safety of dobutamine-atropine stress echocardiographyin patients with suspected or proven coronary artery disease. Am J Cardiol1994;73:456–459.8. Elhendy A, van Domburg RT, Bax JJ, Roelandt JR. Relation between theextent of coronary artery disease and tachyarrhythmias during dobutamine stressechocardiography. Am J Cardiol 1999;83:832–835.9. De Sutter J, Poldermans D, Vourvouri E, Van Donburg R, Elhendy A, Bax J,Sozzi F, Jordaens L, De Buyzere M, Roelandt J. Long-term prognostic signifi-cance of complex ventricular arrhythmias induced during dobutamine stressechocardiography. Am J Cardiol 2003;91:242–244.10. Marcovitz PA, Bach DS, Mathias W, Shayna V, Armstrong WF. Paradoxichypotension during dobutamine stress echocardiography: clinical and diagnosticimplications. J Am Coll Cardiol 1993;21:1080–1086.11. Wang CH, Cherng WJ, Hung MJ. Dobutamine-induced hypotension is anindependent predictor for mortality in patients with left ventricular dysfunctionfollowing myocardial infarction. Int J Cardiol 1999;68:297–302.12. Elhendy A, van Domburg RT, Nierop PR, Geleijnse ML, Bax JJ, KasprzakJD, Liqui-Lung AF, Ibrahim MM, Roelandt JR. Impaired systolic blood pressureresponse to dobutamine stress testing: a marker of more severe functionalabnormalities in patients with myocardial infarction. J Am Soc Echocardiogr1998;11:436–441.13. Elhendy A, van Domburg RT, Bax JJ, Valkema R, Reijs AE, Krenning EP,Roelandt JR. Safety, hemodynamic profile, and feasibility of dobutamine stresstechnetium myocardial perfusion single-photon emission CT imaging for evalu-ation of coronary artery disease in the elderly. Chest 2000;117:649–656.14. Gioia G, Bagheri B, Gottlieb CD, Schwartzman DS, Callans DJ, MarchlinskiFE, Heo J, Iskandrian AE. Prediction of outcome of patients with life-threateningventricular arrhythmias treated with automatic implantable cardioverter-defibril-lators using SPECT perfusion imaging. Circulation 1997;21:95:390–394.

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