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Cardiovascular ResponsesDuring Static Exercise

Studies in Patients With Complete Heart Block and DualChamber Pacemakers

Thomas Alexander, MD; Daniel B. Friedman, MD; Benjamin D. Levine, MD;James A. Pawelczyk, PhD; Jere H. Mitchell, MD

Background During static exercise in normal subjects, themean arterial pressure increases as a result of an increase inheart rate and thereby cardiac output with no significantchange in stroke volume or systemic vascular resistance. Wehypothesized that if one component of the blood pressureresponse to static exercise, ie, heart rate, were fixed, plasticityof the neural control mechanisms during exercise would allowfor preservation of the blood pressure response by alternativemechanisms.Methods and Results Thirteen patients 20 to 68 years old

with structurally normal hearts, complete heart block, and dualchamber pacemakers performed static exercise during threeconditions: (1) normal dual chamber sensing and pacing mode,(2) heart rate fixed at the resting value obtained in the DDDmode of 78±4 beats per minute, and (3) heart rate fixed at thepeak value obtained during exercise in the DDD mode of94±4 beats per minute. Heart rate, blood pressure, andcardiac output were measured and stroke volume and systemicvascular resistance were calculated at rest and at 1 and 5minutes during static one-leg extension at 20% of maximalvoluntary contraction. The mean arterial pressures at rest and

S ustained static exercise causes an increase inblood pressure because of an increase in cardiacoutput secondary to an increase in the heart

rate, whereas stroke volume and systemic vascular re-sistance do not change.1-5 Parasympathetic withdrawalis the efferent mechanism for the early heart rateresponse noted during static exercise.6-8 As static exer-cise is continued, the sympathetic nervous system playsan increasing role in maintaining the blood pressureresponse. Sympathetic nerve activity to resting muscle,assessed by microneurography, shows an increase onlyafter the first minute of static handgrip exercise,9-11although sympathetic activation of the cardiac responsemay occur as early as 30 seconds.6A number of experimental models have been used to

investigate the role of heart rate in the blood pressureresponse to static exercise. Studies using autonomicblockade to prevent an increase in heart rate duringstatic exercise did not inhibit the increase in bloodpressure.2,6,8,12 The blood pressure responses in these

Received August 4, 1993; revision accepted December 15, 1993.From the Harry S. Moss Heart Center, Departments of Internal

Medicine and Physiology, University of Texas Southwestern Med-ical Center, Dallas.Correspondence to Jere H. Mitchell, MD, 5323 Harry Hines

Blvd, Dallas, TX 75235-9034.

at 5 minutes were higher when the heart rate was fixed at thefaster peak exercise heart rate. In the DDD mode, heart rateincreased by 16 beats per minute and cardiac output by 1.1L/min, with a resultant 25 mm Hg increase in mean arterialpressure at 5 minutes with no change in the stroke volume orsystemic vascular resistance. In both fixed heart rate pacingmodes, mean arterial pressure increased by 24 mm Hg whenthe heart rate was fixed at the resting heart rate and by 25mm Hg when the heart rate was fixed at the faster peakexercise heart rate pacing modes associated with an increase instroke volume, with similar increases in cardiac output. Duringstatic exercise there was no change in systemic vascularresistance from the resting value in any pacing mode.

Conclusions When heart rate is fixed in the presence ofnormal left ventricular function, the mean arterial pressureincreases normally during static exercise because of an in-crease in stroke volume with no change in the systemicvascular resistance. (Circulation. 1994;89:1643-1647.)Key Words * cardiac output * heart block * pacing .

exercise

studies were caused by an increase in the systemicvascular resistance, with no change in heart rate orstroke volume. Patients with Chagas' heart disease13and evidence of cardiac parasympathetic denervation,as demonstrated by the lack of a heart rate response toatropine, also have an appropriate blood pressure re-sponse during static exercise because of an increase inthe systemic vascular resistance. Their blood pressureresponse is similar to Chagas' heart disease patientswith a normal parasympathetic nervous system, thelatter increasing their heart rate and thereby cardiacoutput appropriately. The constancy of the blood pres-sure response to isometric exercise is similar to that ofpatients with orthotopic heart transplants.14 However,in subjects with autonomic blockade and in patientswith Chagas' disease, cardiac function, in addition toheart rate, is affected.

Patients with complete heart block and otherwisefunctionally normal hearts who have dual chamberpacing and sensing pacemakers are uniquely suitable forexamining the role of heart rate in the cardiovascularresponses during static exercise in the absence of theconfounding effects of drugs or of abnormal cardiacfunction. A preliminary report of these findings hasbeen presented.15

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1644 Circulation Vol 89, No 4 April 1994

MethodsSubjectsThe subjects used in this study were 13 patients (2 men and

11 women) with programmable dual chamber pacing andsensing (DDD) pacemakers placed for complete atrioventric-ular conduction block. The mean age was 34 years (range, 22to 68 years), mean height was 161 cm (range, 152 to 168 cm),and mean weight was 64 kg (range, 44 to 101 kg). Thepathogenesis of the complete atrioventricular conductionblock was congenital in 8 patients, secondary to successfulatrioventricular nodal ablation for atrial tachyarrhythmias in 4,and idiopathic conduction disease in 1. None of the patientshad evidence for coronary artery disease, and none weretaking cardiovascular medications.The research protocol was approved by the Institutional

Review Board of the University of Texas Southwestern Med-ical Center. All subjects gave written informed consent. Anormal cardiovascular and neurological status was ascertainedby evaluating past medical records and after a careful historyand physical examination. None of the patients had activemedical problems at the time of the study. Two patients wereexcluded from participating in the study because they failed tomeet the entry criteria; one had ventricular preexcitationresulting from a bypass tract, and the other had intact atrio-ventricular conduction. A total of 13 subjects participated andcompleted all three phases of the exercise protocol.

ProceduresDDD pacemakers have leads in both the atria and ventricles

with the capability to sense and to track intrinsic cardiacelectrical activity. In patients with normal sinus node functionand complete heart block, the intrinsic sinus rhythm is sensedand the ventricle is sequentially paced, thus simulating thenormal physiological heart rate responses to static exercise.The heart rate can be fixed by programming the DDDpacemakers to the DOO mode, in which the pacemaker doesnot sense any intrinsic electrical activity and paces the atriaand, after an appropriate delay, the ventricle. In the presenceof a faster competing intrinsic sinus activity, successful atrialpacing may not occur because of failure to capture. Ventricu-lar pacing would still occur at the programmed heart rate,since the presence of complete heart block would preventconduction of any atrial activity. The effects of fixed heart ratepacing during static exercise in the absence of confoundingdrug effects or cardiac disease were examined in patients withDDD pacemakers. Heart rate was fixed either at the slowerresting heart rate or at the peak exercise heart rate for thesame exercise protocol to determine whether the cardiovascu-lar responses would differ at either end of this spectrum.

All patients abstained from smoking and drinking caffeine-containing beverages on the day of the study and were told toavoid strenuous exercise in the preceding 24 hours. They wereseated on a straight-back chair and asked to perform staticknee extension using their dominant leg with the knee flexed at900. The generated force was measured with a strain gauge.Maximal voluntary contraction was determined as the maximalforce generated during three separate attempts sustained for aperiod of 2 seconds. The 20% maximal voluntary contractionwas calculated and displayed on an oscilloscope for visualfeedback to the patient so that force could be maintainedconstant throughout the 5-minute exercise period. Heart ratewas monitored continuously with limb leads from the ECG(Siemans, Mingograph 7). Mean arterial pressure was mea-sured by photoplethysmography (Finapres, Ohmeda).16 Car-diac output was measured by a modified acetylene rebreathingsystem that has been described in detail previously.'7 For thismethod the patients breathed a mixture of 0.60% acetylene,45.00% oxygen, 9.50% helium, and the rest nitrogen from arebreathing bag for a period of 20 seconds. Gas concentrationsduring rebreathing were analyzed by a mass spectrometer

(model MGA 1100, Perkin-Elmer, Pomona, Calif), and theanalog output was sampled at 50 Hz with a minicomputer(PDP 11-23, Digital Equipment, Maynard, Mass). Duringrebreathing there is an exponential decline in the exhaledacetylene concentration because of its uptake by the pulmo-nary capillary blood. The slope of this line was used tocalculate cardiac output as described by Triebwasser et al.The stroke volume (SV=CO/HR, where CO is cardiac outputand HR is heart rate) and systemic vascular resistance(SVR=MAP/COx80, where MAP is mean arterial pressure)were then calculated and reported in milliliters anddynes. cm` * s-5 , respectively.

Initially, baseline resting measurements (Rest) of cardiacoutput, heart rate, and blood pressure were obtained in allsubjects before exercise. Measurements of the cardiac output,heart rate, and mean arterial pressure were repeated at 1minute and 5 minutes during static leg extension. All patientsexercised first in the rate-responsive dual chamber sensing andpacing mode (DDD), which tracked the intrinsic atrial rateand after an appropriate atrioventricular delay paced theventricle. The subjects then repeated the exercise in randomorder, either with heart rate fixed at the resting rate (DOO-Rest) or with the heart rate fixed at the peak exercise rate(DOO-Ex). During the latter two exercises, the sensing featureof the dual chamber pacemakers was turned off (DOO mode).No other pacemaker parameters were altered throughout thestudy. A 20-minute rest period was allowed between thedifferent static exercise conditions.

Data AnalysisTwo-factor repeated-measures ANOVA (mode x time) was

used to analyze and compare changes in the hemodynamicvariables (cardiac output, mean arterial pressure, stroke vol-ume, systemic vascular resistance, heart rate) during sustainedstatic one-leg extension among the three pacing modes (DDD,DOO-Rest, and DOO-Ex). However, because the cardiacoutput data were not normally distributed, these data weretransformed logarithmically for statistical analysis. Statisticalsignificance was established at P<.05. Probabilities wereadjusted by use of the Huynh-Feldt method to account fordepartures from the assumption of sphericity. When signifi-cant differences were found among pacemaker modes or withtime, contrasts were formed to test the difference betweeneach set of measurements. Statistical significance was estab-lished with a Bonferroni-adjusted value of P=.017. An addi-tional repeated-measures ANOVA was used to compare themean response across exercise in the different pacemakermodes to ascertain whether the order of exercise (ie, whetherthe DOO-Rest or DOO-Ex were done second or third afterthe DDD mode) affected comparisons among pacemakermodes.

ResultsHemodynamic Data During RestDuring rest, heart rate and mean arterial pressure

were higher in the DOO-Ex pacing mode (Table; Fig 1).The cardiac output was decreased in the DOO-Restmode secondary to intermittent loss of atrioventricularsynchrony (Table; Fig 2). This decrease was secondaryto a decrease in the stroke volume, since heart rate wasnot different between DDD and DOO-Rest pacingmodes. Mean arterial pressure was maintained in theDOO-Rest mode despite a drop in cardiac output by anassociated increase in the systemic vascular resistancecompared with the DDD pacing mode (Table; Fig 2).The cardiac output in the DOO-Ex mode was notdifferent from the DDD mode at rest (Table; Fig 2).With the elevated heart rate in DOO-Ex mode, stroke

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Alexander et al Static Exercise in Pacemaker-Dependent Patients 1645

Hemodynamic Values in the Different Pacing Modes at Rest and During Exercise

DDD DOO-Rest DOO-Ex

Rest Ex-1 Ex-5 Rest Ex-1 Ex-5 Rest Ex-1 Ex-5Heartrate, bpm 79±4 86±4* 94+5* 78±4 78±4 78±4 94±4 94±4 94±5Mean arterialpressure, mm Hg 92±4 101 ±4*

Cardiac output,L min-'

115±5* 95±3 106±4* 119±6* 97±3t 11 1±5*t 121±5*

4.50+0.27 5.13±0.41 * 5.58±0.50* 4.07±0.23t 4.72±0.42*t 5.29±0.44* 4.36+0.40 4.79+0.34* 5.33±0.41 *

Stroke volume, mL 59±5 62±6 62+7 54±4t 63±7 70+7*t 44+13t 52+4*t 58±5*Systemic vascularresistance,dynes. s-1 * cm-5 1702±114 1652±103 1777±136 1924±109t 1911±130t 1909±134t 1879±112 1944±136t 1925+139tDDD indicates dual chamber sensing and pacing mode; DOO-Rest, heart rate fixed at resting rate; DOO-Ex, heart rate fixed at peak

exercise rate; Ex-1, exercise after 1 minute; Ex-5, exercise after 5 minutes; and bpm, beats per minute. Signficance P<.017. *Comparedwith rest in same pacing mode. tCompared with DDD pacing mode.

volume was reduced, resulting in no change in thecardiac output at rest (Table; Fig 2).

Hemodynamic Data During Static ExerciseIn the dual chamber DDD pacing mode the mean

arterial pressure increased from rest at 1 and at 5minutes of sustained static one-leg extension (Table; Fig1). This was a result of an increase in cardiac outputsecondary to an increase in the heart rate. The strokevolume and systemic vascular resistance did not changeduring the exercise protocol (Table; Fig 2).When heart rate was fixed at the resting level (DOO-

Rest), the mean arterial pressure increased from rest at1 minute and at 5 minutes during static exercise (Table;Fig 1). The mean arterial pressures at 1 and 5 minutes

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FIG 1. Graphs showing mean arterial pressure (mm Hg) andheart rate (beats per minute) at rest and during 5 minutes ofstatic leg extension at 20% maximal voluntary contraction. -indicates DDD (dual chamber sensing and pacing); A, DOO-Rest(heart rate fixed at the resting value); and o, DOO-Ex (heart ratefixed at peak exercise value). *Significant group difference; seeTable for specific comparisons.

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FIG 2. Graphs showing cardiac output (liters per minute), strokevolume (milliliters), and systemic vascular resistance(dynes * s-1 * cm-5) at rest and during 5 minutes of static legextension at 20% maximal voluntary contraction. * indicatesDDD (dual chamber sensing and pacing); A, DOO-Rest (heartrate fixed at the resting value); and o, DOO-Ex (heart rate fixed atpeak exercise value). *Significant group difference; see Table forspecific comparisons.

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1646 Circulation Vol 89, No 4 April 1994

differ at 1 minute, and at 5 minutes it was higher than inthe DDD mode. The stroke volume in the DOO-Restpacing mode was also greater than that seen in theDOO-Ex pacing mode at 5 minutes (Table; Fig 2). Inthe DOO-Rest mode the systemic vascular resistance(Table; Fig 2) did not change from the control restingvalues during the exercise protocol, although the valuesobtained were greater at 1 and 5 minutes than those inthe DDD pacing mode.When heart rate was fixed at the peak exercise level

(DOO-Ex), the mean arterial pressure increased fromrest at 1 minute and at 5 minutes during static exercise(Table; Fig 1). At 5 minutes the mean arterial pressurewas greater than that obtained in the DDD mode. At 1minute, however, the mean arterial pressure in theDOO-Ex pacing mode was not different from thoseobtained in either the DDD or the DOO-Rest pacingmode. The mean arterial pressure response was due toan increase in cardiac output brought about by anincrease in the stroke volume, since heart rate was fixedby pacing. The stroke volume (Table; Fig 2) increasedfrom rest after 1 and 5 minutes of exercise. As duringrest, the stroke volume at 1 minute was lower comparedwith the DDD mode and the DOO-Rest mode. At 5minutes the stroke volume (Table; Fig 2) was notdifferent from that in the DDD pacing mode butremained lower than in the DOO-Rest mode. Thesystemic vascular resistance did not change from restduring exercise in the DOO-Ex mode, as was seen withthe other two pacing modes. However, the systemicvascular resistance was higher in the DOO-Ex modethan in the DDD mode at 1 and 5 minutes of staticexercise.

DiscussionThe important finding of this study is that mean

arterial pressure increases normally during static exer-cise despite a fixed heart rate and, further, that thisincrease occurs by an increase in the stroke volume(hence cardiac output) without significant changes insystemic vascular resistance. The present study showsthat stroke volume can compensate for a fixed heart rateto elicit a normal blood pressure response to staticexercise. This observation is different from studies inwhich heart rate was not allowed to increase by use ofautonomic blockade and the increase in blood pressurewas due to an increase in systemic vascular resis-tance.26'12 However, autonomic blockade, in addition topreventing an increase in the heart rate, may havedecreased cardiac contractility and prevented an in-crease in contractility from occurring during exercise.Similarly, studies in patients with Chagas' disease, whohave cardiac parasympathetic denervation, found thatan increase in the systemic vascular resistance ac-counted for the blood pressure response when the heartrate did not change.'3 Also, ventricular function mayhave been abnormal in these patients, and evaluation ofthe sympathetic nervous system was not performed.Thus, in previous studies stroke volume was unlikely tochange because the heart itself was affected.

In the dual chamber atrial and ventricular sensingand pacing mode (DDD mode), the pacemaker tracksthe intrinsic sinus rate and paces the ventricle after anappropriate atrioventricular delay. During sustained

mode, the heart rate increases in a normal fashion andaccounts for the increase in cardiac output and meanarterial pressure with no change in stroke volume andsystemic vascular resistance from the resting values.This cardiovascular response was identical to that ob-tained with normal subjects.-3 When heart rate wasfixed at either the slower resting rate (DOO-Rest) or atthe faster peak exercise rate (DOO-Ex), the increase inmean arterial pressure during exercise was the same. Inboth pacing modes, an increase in cardiac output ac-counted for the increase in mean arterial pressureduring static exercise without a change in systemicvascular resistance. With heart rate held constant, anincrease in stroke volume accounted for the increase incardiac output and, thereby, an increase in mean arte-rial pressure.The constancy of stroke volume observed during

static exercise in the DDD mode is consistent with thegeneral consensus that cardiac output, but not strokevolume, increases during static exercise.',245 However,the observation that stroke volume changes accountsolely for the blood pressure response when heart rate isfixed has not been reported previously. From a similarinvestigation, Bergenwald et al18 found that systemicvascular resistance increased slightly during static hand-grip exercise but increased dramatically from baselinewith sustained atrial pacing at 109 beats per minute.The difference between that investigation and the pre-sent one may be explained by the fact that the pacingrate was beyond the heart rate measured during exer-cise without pacing, resulting in a 32% increase incardiac output but only an 18% reduction in baselinestroke volume. Systemic vascular resistance decreased20% at rest, perhaps as an arterial baroreflex-mediatedcompensatory response to the large increase in flow andblood pressure associated with relatively high-rate pac-ing. Thus, an increase in systemic vascular resistancewith high-rate pacing was unmasked by the relativelylow initial value of systemic vascular resistance. Thepresent study reveals that when heart rate is matchedclosely with physiological states, the compensatory he-modynamic change occurs exclusively with strokevolume.The increase in stroke volume that occurs with static

exercise when the heart rate is fixed at the resting orpeak exercise level can be explained by an increase inthe end-diastolic volume (Frank-Starling mechanism),by an increase in contractility (caused by decreasedparasympathetic and increased sympathetic nerve activ-ity) or by both mechanisms. Such autonomic changeswould result in a decreased end-systolic volume. Sinceno measurement of left ventricular volumes was made inthis study, one can only speculate about which mecha-nism was important in increasing the stroke volume inthe present study.

In the present study, systemic vascular resistanceincreased when fixed-rate pacing in the DOO-Rest orDOO-Ex pacing mode was initiated (Table; Fig 2). Inthe DOO-Rest pacing mode, the decrease in cardiacoutput caused by loss of atrioventricular synchrony mayhave triggered a baroreflex-mediated increase in sys-temic vascular resistance to maintain mean arterialpressure. Also, the blood pressure response to staticexercise was accelerated during pacing at the faster

static one-leg exercise with the pacemaker in the DDD peak exercise heart rate (DOO-Ex) compared with the

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Alexander et al Static Exercise in Pacemaker-Dependent Patients 1647

DDD pacing mode. At 5 minutes the mean arterialpressures were no different in either mode after a steadystate was achieved.

In summary, the blood pressure response is maintainedduring static one-leg exercise in patients with normal leftventricular function and dual chamber pacemakers whenthe heart rate is fixed at the resting or peak exercise rate.Further, this response is caused by an increase in strokevolume and not by an increase in systemic vascular resis-tance. Additional studies are needed to determine themechanisms for this increase in stroke volume. It could becaused by an increase in end-diastolic volume (Frank-Starling mechanism), by an increase in the contractilestate of the left ventricle with a decrease in end-systolicvolume, or by both mechanisms.

AcknowledgmentsThis research was supported by National Heart, Lung, and

Blood Institute training grant HL-07360 (Drs Alexander andPawelczyk), the Lawson and Rogers Lacy Research Fund inCardiovascular Diseases, and the Frank M. Ryburn, Jr, Chairin Heart Research. We would like to acknowledge Jim Harper,Pamela Maass, and David Maass for their help in completingthe study and typing the manuscript. We would also like tothank Murugappan Ramanathan, PhD, for his technical helpin setting up our apparatus and computer program for nonin-vasive cardiac output determination. Finally, we would like tothank Ronald Victor, MD, and A.A. Bove, MD, for their helpand suggestions.

References1. Lind AR, Taylor SH, Humphreys PW, Kennely BM. The circu-

latory effects of sustained voluntary contraction. Clin Sci. 1964;27:229-244.

2. Lewis SF, Taylor WF, Bastian BC, Graham RM, Pettinger WA,Blomqvist CG. Hemodynamic response to static and dynamichandgrip before and after autonomic blockade. Clin Sci. 1983;64:593-599.

3. Mitchell JH, Wildenthal K. Static (isometric) exercise and theheart: physiological and clinical considerations. Annu Rev Med.1974;25:369-381.

4. Kilbom A, Persson J. Circulatory response to static muscle con-tractions in three different muscle groups. Clin Physiol. 1981;1:215-225.

5. Lewis SF, Snell PG, Taylor WF, Hamra M, Graham RM, PettingerWA, Blomqvist CG. Role of muscle mass and mode of contractionin circulatory responses to exercise. J Appl Physiol. 1985;58:146-151.

6. Martin CE, Shaver JA, Leon DF, Thompson ME, Reddy PS,Leonard JJ. Autonomic mechanisms in hemodynamic responses toisometric exercise. J Clin Invest. 1974;54:104-115.

7. Diepstra G, Gonyea W, Mitchell JH. Cardiovascular response tostatic exercise during selective autonomic blockade in the con-scious cat. Circ Res. 1980;47:530-535.

8. Mitchell JH, Reeves DR Jr, Rogers HB, Secher NH, Victor RG.Autonomic blockade and cardiovascular responses to staticexercise in partially curarized man. J Physiol. 1989;413:433-445.

9. Mark AL, Victor RG, Nerhed C, Wallin BG. Microneurographicstudies of the mechanisms of sympathetic nerve responses to staticexercise in humans. Circ Res. 1985;57:461-469.

10. Victor RG, Pryor SL, Secher NH, Mitchell JH. Effects of partialneuromuscular blockade on sympathetic nerve responses to staticexercise in humans. Circ Res. 1989;65:468-476.

11. Vissing SF, Scherrer U, Victor RG. Stimulation of skin sympa-thetic nerve discharge by central command: differential control ofsympathetic outflow to skin and skeletal muscle during staticexercise. Circ Res. 1991;69:228-238.

12. Macdonald HR, Sapru RP, Taylor SH, Donald KW. Effect ofintravenous propanol on system circulating to sustained handgrip.Am J Cardiol. 1966;18:333-343.

13. Martin-Neto JA, Maciel BC, Gallo L Jr, Junqueira LF Jr, AmorinDS. Effect of parasympathetic impairment on the hemodynamicresponse to handgrip in Chagas heart disease. Br Heart J. 1986;55:204-210.

14. Robson SC, Furniss SS, Heads A, Boys RJ, McGregor C, BextonRS. Isometric exercise in the denervated heart: a Doppler echo-cardiographic study. Br Heart J. 1989;61:223-230.

15. Alexander T, Friedman DB, Levine BD, Pawelczyk JA, MitchellJH. Cardiovascular responses during static exercise: studies inpatients with complete atrioventricular block. Circulation. 1991;84:1261. Abstract.

16. Friedman DB, Jensen FB, Matzen S, Secher NH. Non-invasiveblood pressure monitoring during head-up tilt using the Penazprinciple. Acta Anaesthesiol Scand. 1990;34:519-522.

17. Triebwasser JH, Johnson RL, Burpo RP, Campbell JC, ReardonWC, Blomqvist CG. Non invasive determination of cardiac outputby a modified acetylene rebreathing procedure utilizing mass spec-trometer measurements. Aviat Space Environ Med. 1977;48:203-220.

18. Bergenwald L, Elkund B, Freyschuss U. Circulatory effects inhealthy young men of atrial pacing at rest and during isometrichandgrip. J Physiol. 1981;318:445-453.

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T Alexander, D B Friedman, B D Levine, J A Pawelczyk and J H Mitchellblock and dual chamber pacemakers.

Cardiovascular responses during static exercise. Studies in patients with complete heart

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1994 American Heart Association, Inc. All rights reserved.

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