Exercise Electrophysiology Testing: The Effectof Exercise on the Induction of VentricularArrhythmias hy Programmed VentricularStimulation

GREGORY S. THOMAS, HASAN GARAN, MICHAEL ].E. DAVIS,GREGORY D. GURFMAN. G. WILLIAM DEC, CHARLES A. BOUGHER.WILLIAM R. SLATER, BRIAN MCGOVERN, and ]EREMY N. RUSKINFrom the Cardiac Unit, Massachusetts General Hospital, Boston, Massachusetts

THOMAS, G.S., ET AL.: Exercise Electrophysiology Testing: The Effect of Exercise on the Induction ofVentricular Arrhythmias by Programmed Ventricular Stimulation. In order to assess fhe effect of acute,reversible myocardial ischemia on (he outcome of programmed ventricular sfimulation (PVSJ, ventricularstimulation was performed at rest, during exercise, and during recovery in 10 patients with coronary arterydisease. Of these ten patients, four were tested while off nntiarrhythmic drugs and six were tested onantiarrhythmic drug therapy. Nine of the ten patients developed acute myocardial ischemia duringexercise PVS. However, in only two of these ten patients ventricular arrhythmia could be induced by PVS,one during exercise and one during recovery. (PACE, Vol. 13, January 1990}

programmed ventricular stimulation, exercise, ventricular tachycardia, ventricular jibrillation, myocar-dial ischemia

Introduction

Acute myocardial ischemia remains an un-tested variable in electrophysiological testing.While many patients presenting with clinicalventricular arrhythmias and undergoing electro-physiological studies have significant coronaryartery disease ""* and exercise-induced ischemia,^standard programmed ventricular stimulation(PVS) is routinely performed at rest and it is notknown whether the conditions of physical stresscould alter the outcome of PVS.

The purpose of this preliminary, prospectivestudy was to test the safety, feasibility, and diag-nostic potential of a technique in which PVS wasperformed during acute myocardial ischemia in-

Dr. Garan is the recipient of an Established Invesligatorship(No. 84209) from the American Heart Association. Dallas,Texas.

Address for reprints: Hasan Garan, M.D.. Gardiac Unil, Massa-chusetts General Hospital, Fruit Street. Boston, MA 02114.

Received June 21, 1989: accepted August 30, 1989.

duced hy vigorous supine bicycle exercise. Thispreliminary study, performed in a homogenousgroup of patients, addresses two goals: (1) to in-crease the yield of PVS in prehospital cardiac ar-rest survivors in whom baseline PVS performed atrest and in the absence of myocardial ischemiainduces no ventricular arrhythmia; and (2) to findout whether the efficacy of an antiarrhythmicdrug therapy that has been found to suppress theventricular arrhythmia induced hy standard PVSat rest constitutes still adequate protection duringepisodic myocardial ischemia, representative ofthe living and working conditions of a patientwith coronary artery disease and a history of out-of-hospital cardiac arrest.

Methods

Patient Population

The study population consisted of 10 non-consecutive men referred to the MassachusettsGeneral Hospital for electrophysiological evalua-

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THOMAS, ET AL.

tion for documented sustained ventricular ar-rhythmias associated with hemodynamic col-lapse. The presenting clinical arrhythmia wassustained ventricular tachycardia (VT) in sevenpatients (exercise-induced in one of these) andventricular fibrillation [VF) in the remainingthree patients. All ten had significant coronaryartery disease [> 70% reduction in diameter ingreater than one major epicardial vessel) docu-mented by coronary angiography. All 10 had aclinical history of myocardial infarction and ven-tricular wall motion abnormalities consistentwith a previous myocardial infarct. The mean leftventricular ejection fraction was 31 + 7%. Themean age was 57 ± 7 years and ranged from 46 to69 years. Written consent was obtained from eachpatient prior to entry into the study. The protocolwas approved by the Human Studies Subcommit-tee of the Massachusetts General Hospital's Com-mittee on Research. For safety reasons, patientswith left main coronary artery stenosis, unstahleangina, or aortic stenosis were excluded.

Eiectrophysioiogicai Studies at Rest

In order to assess the usefulness of this tech-nique to increase the yield of resting PVS, onlypatients who did not have sustained VT or VFduring resting PVS through the use of two extra-stimuli were included in the protocol. Patientswere prospectively tested either during their ini-tial electrophysiology study while off antiarrhyth-mic drugs (four subjects) or during a follow-upstudy performed to assess the efficacy of an anti-arrhythmic drug (six suhjects). PVS was thus per-formed during rest, exercise, and recovery in foursubjects off antiarrhythmic drugs and six suhjectson an antiarrhythmic drug regimen. Exercise wasperformed on a stationary bicycle in the supineposition as described subsequently.

Tho stimulation protocol consisted of PVS atthe right ventricular apex with an electrode cath-eter placed percutaneously via either the subcla-vian or the internal jugular vein. At rest, progres-sively premature single and double ventricularextrastimuli were introduced following eight-beat drive trains of ventricular pacing at cyclelengths of 600 and 400 msec in all patients. PVSincluded triple extrastimuli at the right ventricu-lar apex during baseline resting electrophysiologi-cal study off antiarrhythmic drugs in all four pa-tients in whom PVS was also performed during

exercise and recovery off antiarrhythmic drugs.The end point of stimulation was the induction ofsustained VT, VF, or completion of the stimula-tion protocol including three extrastimuli. In thesix patients undergoing follow-up studies on anti-arrhythmic drug therapy, the stimulation proto-col at rest included up to double extrastimuliduring ventricular pacing if this was the mode ofstimulation which induced sustained arrhythmiaduring the basehne drug-free study. Otherwise itincluded PVS through three extrastimuli.

A sustained ventricular arrhythmia was de-fined as any ventricular arrhythmia lasting morethan 30 seconds, causing hemodynamic collapse,or requiring intervention for termination. Theother details of our standard stimulation protocolhave been described elsewhere.^

Electrophysiological Studies During Exerciseand Recovery

During the first stage of exercise (see below),ventricular stimulation consisted of single anddouble extrastimuli during ventricular pacing at acycle length of 400 msec. If a second or third stageof exercise was used, only douhle extrastimuliwere introduced during ventricular pacing at 400msec. Stimulation during immediate recoveryalso consisted of double extrastimuli during ven-tricular pacing at 400 msec. The reason for the useof this abbreviated stimulation protocol was theneed to overdrive exercise-related sinus tachy-cardia during ventricular trains of PVS and tocomplete programmed stimulation within thelimited period of time that a patient could exer-cise at near maximal capacity. Triple extrastimuhwere not used during exercise PVS because ofsimilar time constraints.

The right ventricular effective refractory pe-riod was measured during ventricular pacing at acycle length of 400 msec. The effective refractoryperiod was defined as the longest S -S couplinginterval at which S2 failed to depolarize the ven-tricle.

Exercise Protocol

The exercise workload was individualizedfor each patient with the goal of achieving nearmaximal exercise capacity during the final stageof exercise. Programmed ventricular stimulationwas hegun 1 minute after the start of each stage of

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exercise. Completion of the programmed ventric-ular stimulation protocol during each stage re-quired approximately 4 minutes. During the firstminute of each stage the exercise workload wasgradually increased to bring the patient to the de-sired intensity level. The goal during the firststage of exercise was a subjective intensity levelof "somewhat hard", a level of 13 on the Borgscale.^ The goal of the second stage of exercisewas to hring the patient to a workload near hismaximal intensity, but which he could performfor 4-5 minutes in order to complete the stimula-tion protocol. If the investigators judged that thepatient did not reach near maximal capacity dur-ing the second stage of exercise, a third stage at ahigher workload was performed at near maximalcapacity. During recovery, programmed ventricu-lar stimulation was hegun immediately upon thecessation of exercise.

Thalliuni-201 Imaging

Supine bicycle thalUum-201 exercise testingwas performed subsequently in 8 of the 10 pa-tients with coronary artery disease. Exercise wasperformed to the same exercise workload thatwas attained during the electrophysiology study.Ischemia occurring during exercise was definedas either angina or diagnostic electrocardio-graphic changes seen during the exercise segmentof the electrophysiology study or hy thallium re-distribution on the follow-up thallium exercisetest. Of the ten patients, nine developed ischemiaduring exercise. Thallium-201 imaging was per-formed according to the technique described else-where.^

Statistical Analysis

The left ventricular ejection fractions, ages,and right ventricular effective refractory periodsare reported as mean values ± standard deviation.Differences between means were determinedusing Student's t-test. A two-tailed t-test with theBonferroni correction for multiple comparisonswas used to determine the level of significance.

Results

Programmed Ventricular Stimulation at Rest

Of the four patients undergoing PVS at rest inthe absence of entiarrhythmic drugs, none had

sustained VT or VF in response to two extrastim-uli and only one of the four had sustained VTinduced by three extrastimuli during rest PVS(Table I).

All of the six patients who underwent exer-cise PVS while receiving antiarrhythmic drugshad undergone a previous baseline electrophysio-logical study off antiarrhythmic drugs duringwhich sustained VT or VF had been induced atrest. Double extrastimuli induced this drug-freehaseline VT or VF in five of the patients and threeextrastimuli induced VT in the other patient. An-tiarrhythmic drug therapy was instituted and asubsequent electrophysiological study showedthat in the presence of antiarrhythmic drugs, noVT or VF was inducible by PVS in any of thepatients (Table I).

Programmed Ventricular Stimulation DuringExercise and Recovery

The first column of Table I demonstrates theresults of PVS in the four patients who were stud-ied while not receiving antiarrhythmic drugs.PVS during exercise and recovery failed to inducea sustained arrhythmia in any of these patients,despite the presence of exercise-induced myocar-dial ischemia in all four patients.

The results of PVS performed in the six pa-

Table I.

Results of Programmed Ventricular Stimulation Off andOn Antiarrhythmic Drugs

Off AAD On AAD

VT/VF Induced with 2 ES (Rest)VT/VF Induced with 3 ES (Rest)VT/VF Induced with 2 ES (Exercise)VT/VF Induced with 2 ES (Recovery)

Results of Programmed Ventricular Stimulation On and Off Antiar-rhythmic Drugs: in this Tabie the first column represents the re-sults of the 4 patients studied off antiarrhythmic drugs (AAD) andthe second coiumn, the 6 patients studied on antiarrhythmicdrugs. The 4 rows represent the 4 study conditions, rest pro-grammed ventricular stimulation (PVS) using 2 extrastimuli (ES),rest PVS using 3 ES, PVS during exercise using 2 ES. and PVSduring recovery using 2 ES. The numerators represent the num-ber of patients in whom ventricular tachycardia (VT) or ventricularfibrillation (VF) was induced during that study condition and thedenominator, the number of patients \NUO were tested. Triple ex-trastimuli at rest was only performed in 1 of the 6 patients on AADsince in the remaining 5 patients, 2 ES was all that was required toprovoke VT or VF during their baseline drug-free PVS.

0/41/4

0/4

0/4

0/60/1

1/6

1/6

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THOMAS, ET AL.

tients who were studied while receiving antiar-rhythmic drugs are shown in the second columnof Table I. None developed sustained VT or VFduring PVS at rest using up to two extrastimuli(five patients) or three extrastimuli (one patient)while receiving antiarrhythmic drugs and five ofthe six had exercise-induced myocardial isch-emia. Ventricular tachycardia was induced byPVS during exercise only in one patient and dur-ing recovery only in another patient (Table 1). Theother four patients did not develop sustained VTor VF during rest, exercise, or recovery.

Thus, on antiarrhythmic drugs or off. despitedocumented exercise-induced acute myocardialischemia in nine of the ten patients exercise failedto alter the outcome of PVS using up to two ven-tricular extrastimuli in 90% of the patients; theresults were similar for PVS performed during therecovery period.

Exercise

The mean perceived rate of exertionachieved at peak exercise was 16 ± 2 on the Borgscale. This is equivalent to a subjective rating of"hard" exertion. The mean peak heart rate was108 ± 22 beats/min and mean rate-pressure prod-uct 15,241 ± 5,539. The mean peak workload was42 ± 25 watts.

Exercise-induced myocardial ischemia wasdocumented in nine of the 10 patients. Eight of 10patients underwent thallium-201 testing to thesame workload attained during the exercise com-ponent of the electrophysiology test, and only oneof these patients did not have exercise-inducedischemia by either angina, ECG changes, or thal-lium-201 redistribution. The other seven patientswho underwent thallium-201 testing had thal-lium-201 redistribution consistent with ischemia,three of these also had angina during Ihe exercisecomponent of the electrophysiology test. In theremaining two patients who did not participate inthallium-201 testing, each had exercise-inducedischemia, one documented by angina and ECGchanges and the other documented by EGGchanges without angina. Both of these patientshad> 1.5 mm of down sloping ST depression withexercise.

Right Ventricular Effective Refractory Period

The comparison of right ventricular effectiverefractory periods during ventricular pacing at a

iOO,

250^

2001-

150

REST EXERCISE RECOVERY

P<005P<005

Figure 1, Right Ventricular Effective Refractory Pe-riods During Ventricular Pacing at a Cycle Length of 400msec: Each connected set of squares represents (he rightventricular effective refractory period (ERP) during ven-tricular pacing of an indiWduaJ patient during each ofthe three study conditions. The short bold horizontallines represent the group mean ERP during each studycondition. Both the reductions in the mean ERP betweenrest and exercise, and rest and recovery were signi/Jcant(P < 0.05).

cycle length of 400 msec at rest, during exercise,and during recovery is shown in Figure 1. Themean effective refractory period was 241 ± 22msec at rest, 225 ± 26 msec during exercise, and220 ± 19 msec during recovery. The differencesbetween the effective refractory periods at restand during exercise and between rest and recov-ery were significant (P < 0.05).

Complications

The only minor complication occurred in a46-year-old man with three-vessel coronary ar-tery disease who was tested 8 days following sin-gle vessel angioplasty which effectively con-trolled his resting angina. This patient experi-enced prolonged angina following exercise butmyocardial infarction did not occur,

Discussion

The use of programmed atrial, and in somecases, ventricular, stimulation during exercise inpatients suspected of having supraventricular ar-rhythmias has been reported before,^ However,

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the effects of exercise and recovery on the resultsof PVS in patients with out-of-hospital cardiac ar-rest have not been previously described. In ourstudy population of ten patients with coronaryartery disease presenting with either hemody-namically intolerable sustained VT or VF, wefound the addition of an exercise component tothe eiectrophysioiogicai evaluation with PVS tobe feasible and safe. However, in this patient pop-ulation with either no or drug-suppressed induc-ible ventricular arrhythmia at rest, we found thatPVS during exercise did not increase the yield ofeiectrophysioiogicai testing and added very little,if any, clinically useful information to the out-come of the rest PVS despite achievement of vig-orous exercise in all patients, and development ofmyocardial ischemia in all but one. Because only10 patients underwent testing, any observationscomparing tbe results of rest PVS to PVS duringexercise or recovery must be regarded as prelimi-nary.

Two potential applications for the techniquewere outlined in the introduction: (1) as an at-tempt to increase the yield of eiectrophysioiogicaitesting in patients who have no inducible ar-rhythmias during resting PVS; or (2) as a tech-nique to confirm the persistent efficacy of a par-ticular antiarrhythmic drug regimen, previouslyshown to suppress an arrhythmia induced at rest,when myocardial ischemia develops in tbe pa-tient with coronary artery disease under livingand working conditions of a physically active life-style. Regarding the first question, we found thattbe sensitivity of PVS using two extrastimuli wasnot increased during exercise and two extrastim-uli during exercise did not appear superior to PVSusing tbree extrastimuli at rest. Regarding thesecond question, our results suggest that PVSduring exercise might induce VT previously sup-pressed by drugs during PVS at rest. However, tbeincidence of this phenomenon was very low, 16%(1/6) for exercise and also 16% (1/6) for recovery,and many more cases are required to demonstrateconvincingly that this incidence is statisticallyhigher than the incidence of short-term nonre-producibility in response to PVS during antiar-rhythmic drug therapy, which is 6% in our labo-ratory.^"

Davis and his colleagues have examined theeifect of myocardial ischemia induced hy rightatrial pacing on the results of PVS in a different

group of patients presenting with ventricular ar-rhythmias occurring either during exertion orchest pain." Double extrastimuli during ischemiaresulted in a sustained arrbytbmia in two of 12patients. By contrast, tbree extrastimuli at restresulted in a sustained arrhythmia in 10 of 12patients." Our data agree with their resultsshowing a similar low yield for PVS with doubleextrastimuli during episodic myocardial isch-emia.

The role of ischemia during arrhythmia in-duction has recently been studied by Morady andco-workers.'^ These investigators demonstratedevidence of myocardial ischemia, as reflected bynet myocardial lactate production, during a stan-dard PVS protocol in a small group of patients,presumably resulting from the hemodynamicchanges precipitated by PVS. They found an asso-ciation between net lactate production and VTinduction in a few patients even when myocar-dial ischemia was not clinically obvious. By con-trast, our study demonstrated little if any correla-tion between PVS during iscbemia and inducibleVT. This occurred even when ischemia was clini-cally obvious and, therefore, presumably moresevere than the ischemia induced by PVS alone.The apparently discordant results can perhaps beexplained by small numbers of patients studiedand differences in patient selection and stimula-tion protocol. Unlike ours, tbe majority of patientsstudied by Morady and bis co-workers bad in-duced VT during their PVS protocol which usedtriple extrastimuli for most of tbe inductions.^^

A different approach to enhancing tbe yieldof eiectrophysioiogicai testing and PVS is the useof isoproterenol. Higgins investigated the effect ofisoproterenol in a group of 12 young adults with-out evidence of coronary artery disease who hadVT during exercise testing.^^ While baseline PVSwas negative in all 12 patients, infusion of isopro-terenol alone without PVS resulted in the induc-tion of VT in each subject. However, tbe patients,studied by Higgins, are different from our patientsall of wbom had coronary artery disease. Further-more, important differences may exist betweenthe physiological effects of exercise and isopro-terenol infusion. Isoproterenol results in beta 1and 2 adrenergic receptor stimulation which initself modifies electropbysiological parameters.Beta adrenergic stimulation witbout ischemiamay be an important mechanism in the develop-

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THOMAS, ET AL.

ment of exercise-induced arrhythmias in patientswithout coronary artery disease, but effort-in-duced ischemia is a common finding in older pa-tients with coronary artery disease. In such pa-tients, we considered exercise to he a more physi-ological provocation than isoproterenol infusion,and this consideration was one of the major rea-sons for our particular design.

The most important limitation of this prelim-inary study is the small and selected patient pop-ulation in whom it was conducted. Our resultsmust not be generalized to patients with otherunderlying cardiac diseases (e.g., nonischemiccardiomyopathy) who suffer out-of-hospital car-diac arrest. Furthermore, in order to draw morecertain conclusions about the role of exerciseduring PVS, our preliminary observations shouldbe confirmed in a larger group of patients. A sec-ond limitation is the requirement for rigorous ex-ercise, commonly unfulfilled, in patients withcoronary artery disease with poor ventricularfunction and ventricular arrhj/thmias. Such ashortcoming would limit the wide applicahility ofthis technique. Finally the use of an abbreviated

References

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2. Myerburg R], Kessler KM. Estes D, et al. Long-termsurvival after prehospital cardiac arrest: Analysisof outcome during an 8 year study. Circulation1984; 70:538-546.

3. Ruskin JN, Di Marco IP, Garan H. Out-of-hospitalcardiac arrest: EiRctrophysiologic observationsand selection of long-term antiarrhythmic ther-apy. N Engl J Med 1980; 303:607-613.

4. Roy D, Waxman HL. Kienzle MG, et al. Glinicalcharacteristics and long-term follow-up in 119survivors of out-of-hospilal cardiac arrest: Rela-tion to inducibility at electrophysiologic testing.Am J Gardiol 1983; 52:969-974.

5. Ritchie |L, Hallstrom AP, Troubaugh BG, et al.Out-of-hospital sudden coronary death: Rest andexercise radionuclide left ventricular function insurvivors. Am J Gardiol 1985; 55:645-651.

6. Wilber D|. Garan H, Finkelstein D. et al. Out-of-hospital cardiac arrest: Use of electrophysiologictesting in the prediction of long-term outcome. NEngl J Med 1988: 318:19-24.

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protocol, necessitated by the inability of the pa-tients to exercise at near peak level long enoughto undergo PVS at multiple cycle lengths and alsowith the use of three extrastimuli, further Umitsthe sensitivity and the usefulness of this noveltechnique.

In summary, PVS during exercise and recov-ery can be performed with a low complicationrate. However, due to the inahility of most of thepatients to sustain maximal exertion for a suffi-ciently long time, an extensive, rigorous stimula-tion protocol including three extrastimuli is notpractical during exercise. Given this limitation, ina selected group of patients with coronary arterydisease presenting with sustained ventricular ar-rhythmias and collapse, the increase in yield ofelectrophysiological testing was negligible evenwhen nine of ten patients had exercise-inducedmyocardial ischemia. Whether the results woulddiffer using a hroader range of patients, a morerigorous but selective stimulation protocol, oreven higher exercise workloads is unknown andrequires further investigation.

8. Wilson RA. Okada RD, Boucher GA, et ai. Radio-nuclide-determined changes in pulmonary bloodvolume and thallium uptake in patients with coro-nary artery disease. Am | Gardiol 1983; 51{3]:741-748.

9. Crick J. Holt P, Bucknall C, et al. Exercise-en-hanced programmed stimuiation study, (abstract)PACE 1985:8:303.

10. Garan H. Stavens GS. McGovern B. et al. Repro-ducibility of ventricular tachycardia suppressionby antiarrhythmic drug therapy during serialelectrophysiologic testing in coronary artery dis-ease. Am I Gardiol 1986; 58;959-963.

11. Davis MIE, Boucher GA, Garan H. et al. Pro-grammed ventricular stimulation during myocar-dial ischemia induced by rapid atrial pacing, (ab-stract) J Am Coll Gardiol 1987; 9(2):107A.

12. Morady F. DiGarlo LA. Krol RB. et al. Role ofmyocardial ischemia during programmed stimula-tion in survivors of cardiac arrest with coronaryartery disease. | Am Goll Gardiol 1987; 9:1004-1012.

13. Higgins JR. Exercise-induced sustained ventricu-lar tachycardia in young healthy adults: Glinical.electropbysiologic findings, and treatment, (ab-stract) I Am Coll Cardiol 1986; 7(2):223A.

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