Response of Left Ventricular Volume to Exercise in Man Assessed by Radionuclide Equilibrium Angiography ROBERT SLUTSKY, M.D., JOEL KARLINER, M.D., DONALD RICCI, M.D., GERHARD SCHULER, M.D., MATTHIAS PFISTERER, M.D., KIRK PETERSON, M.D., AND WILLIAM ASHBURN, M.D. SUMMARY To assess the effects of exercise on left ventricular volumes we studied 10 normal men, 15 pa- tients with coronary disease who developed angina pectoris during exercise, and 10 patients with known coro- nary disease who did not develop angina during exercise. Each subject performed supine bicycle exercise under a mobile, single-crystal scintillation camera until angina or fatigue occurred. Technetium-99m bound to human serum albumin was the imaging agent. Data were collected at rest and during the last 2 minutes of each 3-minute stage of exercise and for 10 minutes after exercise. Volumes were calculated by a new radionuclide technique that correlates well with cineangiography and is expressed in nondimensional units. In normal sub- jects, the end-diastolic volume (EDV) at rest was not different from that at peak exercise: 15.8 ± 6.1 (SD) vs 15.2 ± 7 (NS). The end-systolic volume (ESV) decreased from 5.6 ± 2.9 to 2.6 ± 1.6 at peak exercise (p < 0.01). ESV decreased progressively in all but two of 30 exercise periods. Angina patients had a larger EDV (p < 0.01) at rest and during chest pain (p < 0.01) than normals. Angina patients increased their ESV from 10.9 ± 6.7 to 14.2 ± 7.5 during chest pain (p < 0.001), resulting in a decreased ejection fraction (EF) (0.57 ± 0.15 to 0.45 ± 0.16, p < 0.001). All angina patients had a higher ESV during chest pain than during the exercise stage before chest pain. As a group, patients who did not develop angina had a lower EDV at rest and peak exercise than those who did develop angina: 14.8 vs 23.5 (p < 0.01) and 13.7 vs 23.5 (p < 0.01), respectively. The ESV went from 8.1 ± 4.1 at rest to 7.3 ± 5.3 at peak exercise, and the EF from 0.45 ± 0.12 to 0.50 ± 0.16 (all NS). We conclude: that the EF increases during exercise due to a decrease in ESV; that the EF in patients with angina decreases because of an increase in ESV; and that the EF in coronary disease pa- tients without angina shows no change because there is no significant change in the ESV. Radionuclide equilib- rium angiography may prove useful for assessing EF and volume changes in patients with coronary artery dis- ease. RECENT DATA SUGGEST that assessment of left ventricular function during exercise may be a useful method of evaluating patients with coronary artery disease (CAD). 1-3 The response to exercise of left ven- tricular chamber size both in normal subjects and in patients with heart disease is of considerable physio- logic interest. However, few reliable nontraumatic methods of assessing this response are available. Therefore, we compared the volumetric response to exercise in normals, patients with CAD who develop angina and patients with coronary disease who do not develop angina with exercise. To do this we used graded supine bicycle exercise and a newly described method4 for assessing left ventricular volume by radio- nuclide equilibrium angiography that does not require geometric assumptions of left ventricular shape. Subjects Group 1 consisted of 10 normal male volunteers who had no known illnesses and were taking no From the Divisions of Nuclear Medicine and Cardiology, Univer- sity of California, San Diego, School of Medicine, San Diego, Cali- fornia. Supported by SCOR in Ischemic Heart Disease research grant HL-17682, awarded by the NHLBI, NIH. Address for reprints: Robert Slutsky, M.D., University of California Medical Center, 225 West Dickinson Street, San Diego, California 92103. Received August 24, 1978; revision accepted March 7, 1979. Circulation 60, No. 3, 1979. medications. These subjects ranged in age from 24 -43 years (mean 32 years). All of these subjects had nor- mal resting and stress ECGs, as well as a normal clinical examination. None underwent contrast angiography. Group 2 consisted of 15 patients who were studied in the cardiac catheterization laboratory before angiography. All had obstructive CAD (at least one stenotic lesion > 70% of the diameter in a major cor- onary artery) and all developed classic angina pec- toris during supine bicycle exercise. Seven had one- vessel; four had two-vessel and four had three-vessel CAD. Seven patients had contraction abnormalities at rest. Four had one or more resting hypokinetic areas and three had one or more akinetic areas. In six pa- tients, propranolol was stopped at least 48 hours be- fore exercise. Six patients were taking digoxin and diuretics. There were three women and 12 men, rang- ing in age from 36-72 years (mean 52 ± 14 years). Group 3 consisted of 10 patients with known CAD who did not develop angina pectoris during supine ex- ercise. They were attending a rehabilitation or research clinic for patients who had suffered a well- documented myocardial infarction. Four patients were taking propranolol, which was discontinued at least 48 hours before the study. Five patients were tak- ing digoxin and diuretics, and four patients had used nitroglycerin for rare angina in the past. Six patients had not had angina since suffering a myocardial in- farction. All were men, ranging in age from 42-59 years (mean 51 ± 6 years). No patient in this group 565 by guest on May 21, 2018 http://circ.ahajournals.org/ Downloaded from
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Response of Left Ventricular Volume to Exercisein Man Assessed by Radionuclide Equilibrium Angiography
ROBERT SLUTSKY, M.D., JOEL KARLINER, M.D., DONALD RICCI, M.D.,
GERHARD SCHULER, M.D., MATTHIAS PFISTERER, M.D.,
KIRK PETERSON, M.D., AND WILLIAM ASHBURN, M.D.
SUMMARY To assess the effects of exercise on left ventricular volumes we studied 10 normal men, 15 pa-
tients with coronary disease who developed angina pectoris during exercise, and 10 patients with known coro-
nary disease who did not develop angina during exercise. Each subject performed supine bicycle exercise undera mobile, single-crystal scintillation camera until angina or fatigue occurred. Technetium-99m bound tohuman serum albumin was the imaging agent. Data were collected at rest and during the last 2 minutes of each3-minute stage of exercise and for 10 minutes after exercise. Volumes were calculated by a new radionuclidetechnique that correlates well with cineangiography and is expressed in nondimensional units. In normal sub-jects, the end-diastolic volume (EDV) at rest was not different from that at peak exercise: 15.8 ± 6.1 (SD) vs
15.2 ± 7 (NS). The end-systolic volume (ESV) decreased from 5.6 ± 2.9 to 2.6 ± 1.6 at peak exercise(p < 0.01). ESV decreased progressively in all but two of 30 exercise periods. Angina patients had a largerEDV (p < 0.01) at rest and during chest pain (p < 0.01) than normals. Angina patients increased their ESVfrom 10.9 ± 6.7 to 14.2 ± 7.5 during chest pain (p < 0.001), resulting in a decreased ejection fraction (EF)(0.57 ± 0.15 to 0.45 ± 0.16, p < 0.001). All angina patients had a higher ESV during chest pain than duringthe exercise stage before chest pain. As a group, patients who did not develop angina had a lower EDV at restand peak exercise than those who did develop angina: 14.8 vs 23.5 (p < 0.01) and 13.7 vs 23.5 (p < 0.01),respectively. The ESV went from 8.1 ± 4.1 at rest to 7.3 ± 5.3 at peak exercise, and the EF from 0.45 ± 0.12to 0.50 ± 0.16 (all NS). We conclude: that the EF increases during exercise due to a decrease in ESV; that theEF in patients with angina decreases because of an increase in ESV; and that the EF in coronary disease pa-
tients without angina shows no change because there is no significant change in the ESV. Radionuclide equilib-rium angiography may prove useful for assessing EF and volume changes in patients with coronary artery dis-ease.
RECENT DATA SUGGEST that assessment of leftventricular function during exercise may be a usefulmethod of evaluating patients with coronary arterydisease (CAD).1-3 The response to exercise of left ven-tricular chamber size both in normal subjects and inpatients with heart disease is of considerable physio-logic interest. However, few reliable nontraumaticmethods of assessing this response are available.Therefore, we compared the volumetric response toexercise in normals, patients with CAD who developangina and patients with coronary disease who do notdevelop angina with exercise. To do this we usedgraded supine bicycle exercise and a newly describedmethod4 for assessing left ventricular volume by radio-nuclide equilibrium angiography that does not requiregeometric assumptions of left ventricular shape.
SubjectsGroup 1 consisted of 10 normal male volunteers
who had no known illnesses and were taking no
From the Divisions of Nuclear Medicine and Cardiology, Univer-sity of California, San Diego, School of Medicine, San Diego, Cali-fornia.
Supported by SCOR in Ischemic Heart Disease research grantHL-17682, awarded by the NHLBI, NIH.Address for reprints: Robert Slutsky, M.D., University of
California Medical Center, 225 West Dickinson Street, San Diego,California 92103.
Received August 24, 1978; revision accepted March 7, 1979.Circulation 60, No. 3, 1979.
medications. These subjects ranged in age from 24 -43years (mean 32 years). All of these subjects had nor-mal resting and stress ECGs, as well as a normalclinical examination. None underwent contrastangiography.Group 2 consisted of 15 patients who were studied
in the cardiac catheterization laboratory beforeangiography. All had obstructive CAD (at least onestenotic lesion > 70% of the diameter in a major cor-onary artery) and all developed classic angina pec-toris during supine bicycle exercise. Seven had one-vessel; four had two-vessel and four had three-vesselCAD. Seven patients had contraction abnormalities atrest. Four had one or more resting hypokinetic areasand three had one or more akinetic areas. In six pa-tients, propranolol was stopped at least 48 hours be-fore exercise. Six patients were taking digoxin anddiuretics. There were three women and 12 men, rang-ing in age from 36-72 years (mean 52 ± 14 years).Group 3 consisted of 10 patients with known CAD
who did not develop angina pectoris during supine ex-ercise. They were attending a rehabilitation orresearch clinic for patients who had suffered a well-documented myocardial infarction. Four patientswere taking propranolol, which was discontinued atleast 48 hours before the study. Five patients were tak-ing digoxin and diuretics, and four patients had usednitroglycerin for rare angina in the past. Six patientshad not had angina since suffering a myocardial in-farction. All were men, ranging in age from 42-59years (mean 51 ± 6 years). No patient in this group
had undergone contrast ventriculography within 1year of the radionuclide study. However all 10 had un-dergone contrast angiography previously (mean 2.1 ±0.8 years before the study). Seven patients had three-vessel CAD and three had two-vessel CAD at the timeof the study. All patients had at least one akinetic seg-ment by ventriculography (see table 1 for angio-graphic data from groups 2 and 3).
MethodsAll subjects were studied in the nuclear medicine
laboratory except those in group 2, who were studiedin the cardiac catheterization laboratory immediatelybefore contrast angiography. Each patient had an in-travenous catheter placed in a forearm vein for the in-jection of 15-25 mCi 99mTc bound to human serumalbumin. Studies were performed with the patient inthe supine position under a mobile, single-crystal scin-tillation camera in the left anterior oblique position.
All patients in each group were studied within 10
TABLE 1. Contrast Angiography Results
Site of coronary Wall motion abnormalitiesPatient artery lesions Location Severity
minutes of injection to minimize count rate decay andyet allow mixing throughout the blood pool. Tenminutes of ECG gated scintillation camera data werecollected at rest; additional data were collected in allsubjects during the last 2 minutes of each subsequent3-minute stage of progressively more strenuous supinebicycle exercise. After each 3-minute stage was com-pleted, an additional workload was added until fatigueor pain resulted. Data were also collected for 10minutes after exercise.
Thus, scintillation camera data were collected at thefollowing times: 1) rest (5 minutes); 2) minutes 2 and 3of exercise; 3) minutes 5 and 6 of exercise; 4) maximalexercise (2 minutes) or angina; 5) minutes 2 and 3after exercise; 6) minutes 4 and 5 after exercise; and 7)minutes 9 and 10 after exercise
Exercise was discontinued if the patient complainedof angina, severe fatigue or if marked electro-cardiographic abnormalities (ST depression > 3 mm)occurred. A modified V5 lead was used to monitor theECG. The heart rate and blood pressure were alsorecorded at rest, at maximal exercise and duringrecovery. No patient had more than three ectopicbeats/min at rest or peak exercise, and only one pa-tient had more than one ectopic beat/min at rest orpeak exercise.Data were stored on videotape (in a digital format)
in real-time and transferred to a dedicated computer(Medical Data Systems), and a multiple imageprogram (MUGE) summed the information into onetime-activity (volume) curve, which was divided into20-28 equal time frames (depending on the heart rate)for analysis. The EF was then determined and end-diastolic and end-systolic volumes (EDVs and ESVs,respectively) were calculated, as previously described
FIGURE 1. Left ventricular volumes derived from contrastventriculography are compared with ventricular volumesderived by a radionuclide method (in nondimensional units).Using the regression equation, the SEE for end-diastolicvolume (EDV) is ± 21.1 ml andfor ESVis 13.4 ml. See textfor discussion of the method.
in detail.' Briefly, end-diastolic and end-systoliccounts were determined from the "volume curve."These counts were divided by the total number of pro-
cessed heart beats and then corrected for the ad-ministered dose and the time of each frame. Volumeswere expressed as nondimentional units and a regres-
sion analysis was developed in which the followingequation was used to calculate EDV or ESV units:
EDV or ESV =
counts X 10 miC/m2 X 0.04heart beats actual dose/m2 time/frame
When the EDV and ESV units derived by means ofthis radionuclide method were compared with left ven-tricular volumes calculated from contrast ventricu-lography, the correlation coefficients using the aboveequation were: EDV = 0.85 (n = 35); ESV = 0.87 (n= 35); all volumes = 0.90 (n = 70). The regressionequation was y = 0.14x + 3.12 (fig. 1).
All patients gave informed written consent for thisprotocol, which was approved by the Committee on
Investigations Involving Human Subjects/Volun-teers, University of California Medical Center, SanDiego.
All statistics were calculated by repeated measures
analysis of variance or paired t test.
Results
Group 1: Normal Subjects
Each patient in the group was able to exercise for atleast 9 minutes. The EDV was not significantlydifferent when resting and maximal exercise valueswere compared (15.8 ± 6.1 vs 15.2 i 7 units). Duringexercise, the ESV decreased from 5.7 ± 2.8 to 2.61.6 (p < 0.05), and the EF increased from 0.67 + 0.07to 0.80 0.05 (p < 0.01). Individual results are givenin tables 2 and 3. In general, the EDV remainedrelatively constant during exercise, while the ESV de-
TABLE 2. Normal SubjectsPatient Rest 2/3 Ex 5/6 Ex M Ex 2/3 PEx 4/5 PEx 9/10 PEx
Abbreviations: 2/3 Ex = minutes 2 and 3 of exercise; 5/6 Ex = minutes 5 and 6 of exercise; M Ex =maximal exercise; 2/3 PEx = minutes 2 and 3 after exercise; 4/5 PEx = minutes 4 and 5 after exercise; 9/10PEx = minutes 9 and 10 after exercise.
5/6 Ex 120 - 10M Ex 154= 19 180= 20 62 i 192/3 PEx 124 - 14
4/5 PEx 102 - 19
9/10 PEx 88 15 125 - 14 67 - 13
Values are - SD.Abbreviations: BP = blood pressure; 2/3 Ex = minutes 2
and 3 of exercise; 5/6 Ex = minutes 5 and 6 of exercise; M Ex= maximal exercise; 2/3 PEx = minutes 2 and 3 after exer-cise; 4/5 PEx = minutes 4 and a after exercise; 9/10 PEx= minutes 9 and 10 after exercise.
clined markedly, thus accounting for the increase inEF. These values returned to normal by 10 minutesafter exercise.
Group 2: Patients Who Developed Angina During Exercise
The patients in this group exercised to variouslevels, but all, by design, were limited by angina. TheEDV in group 2 patients was larger at rest than in thenormal subjects (23.5 ± 8.8 vs 15.8 ± 6.1 units, p <0.05), and was not significantly different from theEDV at angina (23.5 ± 9). The ESV in group 2 pa-tients at angina increased by an average of 30% (14.2± 8.7 vs 10.9 ± 6.7 at rest, p < 0.001). Additionally,the ESV in all patients increased during the 2-minuteexercise stage before angina compared with controlvalues (13% increase, p < 0.01). The EF decreasedfrom 0.57 ± 0.15 at rest to 0.45 ± 0.16 (p < 0.001) atangina; this decrease was due to the rise in ESV andthe decrease in stroke volume. In table 4, the heartrate and blood pressure measurements are given at therespective exercise stages. Because duration of exer-cise varied, the stages preceding angina were not in-cluded.
Table 5 shows the volume and EF changes in allangina patients. The ESV was greater at angina than
TABLE 4. Heart Rate and Blood Pressure in Angina Patients
Heart rate Systolic BP Diastolic BP(beats/min) (mm Hg) (mm Hg)
Values are - SD. Blood pressures were assessed with cuffsphygmomanometers.
Abbreviations: 2/3 PEx = minutes 2 and 3 after exercise;4/5 PEx = minutes 4 and 5 after exercise; 9/10 PEx =minutes 9 and 10 after exercise; BP = blood pressure.
at rest in 14 of 15 patients (93.3%). The remaining pa-tient had isolated right coronary artery disease. Shehad an initial decrease in ESV, but showed an increasein ESV when the value at angina and the value 2 min-utes before angina were compared. The ESV increasedin all 15 patients during the exercise stage 2 minutesbefore angina. There was a rebound increase in EFafter angina, which was associated with a decrease inEDV and an even more precipitous decline in ESV.
Group 3: CAD Patients Who Did Not Develop AnginaThe work load and duration of exercise varied in
group 3 patients. In all 10 patients, exercise wasstopped because of fatigue. The blood pressure andheart rate results are shown in table 6.As shown in table 7, there was no change in either
the average EDV (14.8 + 4.7 at rest vs 13.7 ± 6 unitsat maximal exercise (NS), or the average EF (0.48 atrest vs 0.50 at maximal exercise (NS). However, infour of these 10 patients, the EF increased at least10%, and three had a decrease in ESV. Again, apostexercise early rebound in EF was seen, associatedwith a greater proportional reduction in ESV than inEDV (see figure 2 for comparative results).
DiscussionStudies of exercise have indicated that within cer-
tain limits, stroke volume remains relatively con-stant,5-7 although in severe exercise this may not be thecase.8 By use of silver-tantalum markers, decreases inboth the end-diastolic and end-systolic dimension dur-ing exercise have been observed.9-10 These studies wereperformed in patients who required cardiac surgeryfor either congestive heart failure or valvular lesions,thereby limiting patient selection. Using a thermodilu-tion technique in a series of patients with cardiac dis-ease, Bristow et al. reported no consistent changes inEDV with exercise." Similarly, Gorlin et al. found lit-tle change in EDV by angiography during supine exer-cise, while ESV decreased.12 Recently, Crawford etal.'3 examined left ventricular internal dimensions byechocardiography in exercising normal subjects andfound results similar to those of Gorlin et al.12Few studies have been designed to assess the change
in left ventricular volume in response to ischemia.Sharma et al. reported an increase in both EDV andESV with a decrease in EF during angina with con-trast ventriculography.2 His results for normals andpatients without angina are similar to ours. He foundan increase in EDV with angina, which may be due insmall part to the volume load of two contrast injec-tions and the added depressant effect of the dye. Joneset al. also describe a large increase in both EDV andESV in patients who develop angina pectoris.'4 Theyshow much more impressive changes in patients withmore severe coronary disease. Their patients exercisederect, which might explain why their volume responseresults differed from ours, which were obtained duringsupine exercise. Additionally, our angina patientstended to have fewer coronary lesions (with respect to
All volumes are given in nondimensional radionucide units (see text).Abbreviations: PTA = exercise stage preceding anginal exercise stage; A = exercise stage during which
angina occurred; PEx 2/3 = minutes 2 and 3 after exercise; PEx /45 = minutes 4 and 5 after exercise; PEx9/10 = minutes 9 and 10 after exercise.
absolute number of lesions) than did either Sharma's
or Jones's patients. The method used in our study was
count-dependent and uncorrected for radiotracer de-cay. Thus, we might underestimate volumes withlonger studies. Variable individual count attenuation
and error estimates between the radionuclide and an-giographic methods might also enhance the differencesbetween our study and those of the previously men-tioned investigators. Borer and his co-workers havesuggested that gated equilibrium radionuclide
angiography can be used to separate patients withischemic heart disease from normal subjects.' Theyhave already shown that EF declines with the onset ofanginal symptoms.
In the present study we used the gated radionuclideapproach to assess left ventricular volumes during andafter supine bicycle exercise. We have previously vali-dated this method relative to standard contrastangiography.4 In normal subjects, the EDV does notchange significantly with exercise, while the ESVdeclines by an average of 56%, thereby accounting forthe rise in EF. In patients who develop angina, the EFdecreases because of an increase in the ESV, while theEDV remains unchanged. In patients with coronarydisease who do not develop angina, the changes involume tend to vary considerably, but the mean valuesfor this group show little change in EDV, ESV or EF.In this group of patients with infarcts and akinetic seg-ments there may be perfusion of fibrotic zones of myo-cardium rather than reversibly ischemic muscle. Thus,exercise-induced perfusion deficits might have littledirect effect on fibrotic zones, but may depress morenormal muscle. However, we cannot ascertain thisfrom our data.
In conclusion, the response of left ventricular vol-ume to supine bicycle exercise shows significant varia-tion between normal subjects and patients withvarious manifestations of ischemic heart disease. Thismethod may be useful in determining the origin ofatypical forms of chest pain and the response of theischemic myocardium to various interventions.
% rest
End-systolic volume
123456789
10Mean= SD
% rest
9.9 7.217.2 20.15.8 4.18.3 8.44.5 3.78.2 8.8
10.7 9.28.7 8.93 2.04.2 2.58.1 7.5
i4.1 -5.2
93
93 89 82 93
8.720.71.192.43.17.16.11.53.3
6.3
i5.878
8.813.61.88.72.94.87.85.11.94.6
6
3.7
74
917.25.78.435.7
10.872.33.87.3
4.4
90
Ejection fraction
123456789
10
0.400.260.620.490.440.510.340.470.580.66
0.450.210.640.460.500.490.350.520.650.71
Mean 0.48 0.50= SD =±0.12 i0.16Mean % 108
0.420.290.890.450.610.710.330.650.760.67
0.430.240.810.490.530.580.420.610.700.61
0.440.260.550.510.500.510.310.520.720.69
0.58 0.54 0.50-0.20 -0.16 -0.14
121 113 104
All ventricular volumes are expressed in nondimensionalradionuClide units.
Abbreviations: MEx = maximal exercise; PEx 2/3 =minutes 2 and 3 after exercise; PEx 4/5 = minutes 4 and 5after exercise; PEx 9/10 = minutes 9 and 10 after exercise.
References1. Borer JS, Bachrach SL, Green MV: Real-time radionuclide
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REST M Ex 2/3 5/6 9/10 REST ANGINA 2/3 5/6 9/10 REST M Ex 2/3 5/6 9/10vJ REST M Ex 2/3 5/6 9/10 REST ANGINA 2/3 5/6 9/10 REST M Ex 2/3 5/6 9/10
P Ex P Ex P Ex P Ex P Ex P Ex P Ex P Ex P Ex
FIGURE 2. Ejection fraction, end-diastolic volume and end-systolic volumeare plottedforall threegroups.Volumes are expressed in nondimensional units. M Ex = point ofmaximal exercise; Angina = the point atwhich angina developed; 2/3 P Ex = minutes 2 and 3 after exercise; 5/6 P Ex = minutes 5 and 6 after exer-
cise; 9/10 P Ex = minutes 9 and 10 after exercise; CAD = coronary artery disease. Angina was accom-
panied by new ST-segment depression > 0.1 m V.
I I I
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