Evaluation of Left-Ventricular Function in

Assessment of left-ventricular function is usuallybased on contrast ventriculography. Ultrasonographyand gamma-imaging techniques are simpler and havebeen proposed as possible means of “noninvasive―evaluation of ventricular function (1—7). We havederived systolic and diastolic time intervals, ejectionfractions, and the rates of left-ventricular ejectionfrom left-ventricular time-activity curves acquiredafter equilibration of intravenously injected Tc-99malbumin, by synchronizing the scintillation camera

with the electrocardiogram. The resulting timeactivity curves describe the changes of radioactivitywithin the left ventricle in relation to the electrocardiographic R-R cycle. Systolic time intervals werealso obtained from 30 patients by combined carotid

Received Aug. 1, 1977; revision accepted Oct. 10, 1977.For reprints contact: Henry N. Wagner, Jr., Div. of Nu

clear Medicine, The Johns Hopkins Medical Institutions,Baltimore, MD 21205.

Volume 19, Number 2 135

Normal Persons and Patients

With Heart Disease

Saeeda Qureshi, Henry N. Wagner, Jr., Philip 0. Alderson, Daniel F. Housholder,KennethH.Douglass,MattheusG. Loffer,Edward1.Nickoloff,

MasatadaTanabe,and LloydG. Knowles

The Johns Hopkins Medical Institutions, Baltimore, Maryland

After equilibration o/ Tc-99m albumin in the vascular compartment, leftventricular time-activity curves were obtained by synchroniwtion of thescintillation camera with the electrocardiogram from normal persona andpatients with heart disease. These curves were divided into various inter.vds, and the following indices were obtained: pre-ejection period (PEP),PEP/R-R; left-ventricular ejection time (LVET), LJ'ET/R.R; left-ventricular rapid-filling time (LVFT1), LVFT1/R-R; left-ventricular diastasis including atrial systole (LVFT), LVFT/R.R, PEP/LVET; ejection fradion(EF) and EF/LVET. The relative systolic time intervals derived from timeactivity curves were compared with those obtained in 30 patients by carotidpulse tracing, phonocardiography and ECG. Significant correlations (p <0.001) were found (r = 0.89 for LVET/R-R, r = 0.77 for PEP/L VET).In addition, the time-activity curve indices obtained from 27 patients witheither essential hypertension, myocardial infarction, idiopathic cardiomyopathy or congestive heart failure were compared with indices obtained fromeight normal volunteers. Patients with congestive heart failure and cardiomy

opathy showed prolongation of PEP/R-R and an increased PEP/LVET. Inhypertensive patients, prolongation of LVFT1/R-R and shortening ofLVFT/R.R were found. Ejection fraction remained normal in hypertensivepatients, was slightly decreased in myocardial infarction patients, andmarkedly reduced in patients with congestive heart failure and cardiomyopathy. These initial results suggest that display and analysis of synchronized left-ventricular time-activity curves may be of value in the studyof patients with certain types of heart disease.

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QURESHI, WAGNER, ALDERSON, HOUSHOLDER,DOUGLASS, LOTTER, NICKOLOFF, TANABE, AND KNOWLES

red. Care was taken to avoid the right ventricle, leftatrium, and pulmonary vasculature (Fig. 1 ). In anindependent study we found that interobserver vanability in selection of this area was approximately5% (coefficient of variation).

In order to obtain the background (extraventnicular) activity an area of interest was selected immediately lateral to the left ventricle, but not overlapping the pulmonary artery or the left ventricle.Overlapping the pulmonary artery resulted in a riseof the background activity during systole. If a partof the left ventricle was included in the backgroundarea, background activity was observed to decreaseduring ventricular systole. Both these conditions crcated errors in true background estimation, and wereavoided.Curvesof net count rate over the left yentricule and the background area were generated bycomputer. The average background activity was thensubtracted from the left ventricular curve (Fig. 2).

Indices of ventricular function. The following indices were obtained from the net left-yentnculartime-activity curves (Fig. 3):

1. Ejection fraction (EF):

End-diastolic counts —End-systoliccounts

End-diastolic counts

2. Pre-ejection period (PEP) : period of electromechanical delay and isovolumic contraction.

3. Left-ventricular ejection time (LVET)@ periodof ventricular emptying.

4. Left-yentricular rapid inflow time (LVFT1):phase of rapid ventricular filling after closureof the aortic yalye.

5. Left-yentnicular diastasis including atrial systole (LVFT2) : slow phase of ventricular fillingbefore the next systole.

6. PEP/LVET ratio.7. EF/LVET ratio: rate of left-ventricularemp

tying.When the slope of the initial plateau (PEP)

FIG.1. H.artimagein40°LAOviewwithleftventricularareaof interest and background area marked. Original images were incolor, with area above left ventricle clearly visible as left atriumbecauseof its green color. Basedon count levels,end-systolicimageis shownroutinely in green, end-diastolic image in red, and theseare superimposedin a final compositeimage.

pulse tracing (C), phonocardiography (P), and dcctrocardiography (E), and were compared with thosederived from time-activity curves. The combinedstudy is referred to as CPE. The indices obtainedfrom the patients with various heart disease werethen compared with the indices of eight normal volunteers to determine whether certain heart diseases

were associated with characteristic changes.

METHODS

All patients received a 25 mCi i.v. injection ofTc-99m albumin while lying supine beneath a scmtillation camera fitted with a high-resolution, lowenergy, parallel-hole collimator. An electrocardiographic gate was used to monitor the R waves of eachpatient's ECG. Camera images synchronized with theECGwere obtainedfor 64 intervalsduringa cardiaccycle, with the patient lying in a 40—50°LAO position. Eight million counts were obtained in approximately 15 mm.

Selectionof regions of interest. The left-ventriculararea of interest was selected from a color-coded image where systole was shown in green and diastole in

X100.

A B

FIG.2. Leftventriculartime-activitycurve with background Is shown (A). (B) isthe same ventricularcurvewith backgroundsubtracted and vertical scale expanded.

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CLINICAL SCIENCESDIAGNOSTICNUCLEAR MEDICINE

and electrocardiography (CPE) (9) employing a mu!tichannel photographic system*. A microphone wasplaced over the upper part of the precordium in aposition optimum for the recording of the initialhigh-frequency vibrations of the second heart sound.The pulsations within the carotid artery were recorded with a small plastic funnel attached by polyethylene tubing to a strain gauge. The recordingswere obtained at a paper speed of 100 mm/sec. The

total electromechanical systole (QS2) was measuredfrom the onset of the QRS complex to the first highfrequency vibrations of the aortic component of thesecond heart sound, and the left-ventricular ejectiontime (LVET) was measured from the beginning ofupstroke to the trough of the incisura of the carotidarterial pulse tracing. LVET was then subtractedfrom the total systole (QS2) to obtain the pre

ejection period (PEP). All intervals were calculatedfrom the mean of measurements made on six to tenconsecutive beats, each read to the nearest 5 msec.The heart rate was again used to express these resultsas relative time intervals (e.g., PEP/R-R), and theserelative time intervals were compared with those obtamed from ventricular time-activity curves.

Clinical comparison. Left-ventricular time-activitycurves were obtained in 104 patients and eight norma! volunteers. The volunteers were young malesaged 22—34 (mean 26) who had normal electrocardiograms and no signs, symptoms, or history of cardiovascular disease. The patients were classified as

follows:

1. Essential hypertension (n = 10) : Patients witha longstanding (range 5—12 yr) history of hypertension, but no history of myocardial infarction or congestive heart failure. All weretaking antihypertensive medication (e.g., diuretics, hydralazine, a-methyldopa) . The bloodpressures (mean ± SD) of these patients atthe time of the current study were: Systolic =175 ± 37; diastolic = 104 ± 13.

2. Recent myocardial infarction (n = 4) : Patients without hypertension or congestive heartfailure who had a documented (clinical, ECG,enzymes) myocardial infarction, not more than4 wk before the blood-pool study.

3. Congestive heart failure (n = 10) : Patientswhose primary illness was hypertension, ormyocardial infarction (not within 4 wk) orboth together with clinical and radiographicevidence of congestive heart failure. These patients were being treated with digitalis anddiuretics.

4. Idiopathic cardiomyopathy (n = 3) : Patientsdiagnosed as having primary cardiomyopathy,with no evidence of hypertension or myocardial

T@ NE

FIG.3. Time-activitycurvewIthsystolicanddiastolicintervalsmarked.

changed and the count rate began to fall, a cursorposition was recorded and that point was designatedas the beginning of LVET. Similarly when the slopewent through zero at the nadir of the curve, thatpoint was chosen as the end of LVET. This LVETperiod does not include protodiastole, the periodwhen the aortic valve is still open but the ventriclehas ceased ejection (8).

A preliminary experiment was done to evaluatethe method of selecting the end of LVET. Three different lengths of LVET were chosen by selecting theend of LVET as: point A, where the down-slope suddenly changed to a horizontal position (Fig. 3); pointC, where the activitystarted rising again;and point B,the mid-point between points A and C. These threevalues of LVET were correlated with the LVETobtained by carotid pulse tracing, phonocardiography, and electrocardiogram in eight normal volunteers and eight patients with various heart diseases.The correlation coefficient was found to be 0.78 forpoint A, 0.70 for point B, and 0.54 for point C.Point A was therefore selected as the end of LVETin this study. LVFT1 was defined as starting at thispoint and ending at the transition point where therapid rise suddenly slowed. From this point to theend of a cardiac cycle was defined as the LVVF2period (Fig. 3).

Reproducibility of the selection of these time intervals was determined by a study in which six observers independently derived systolic and diastolictime intervals in 20 randomly selected left-ventriculartime-activity curves. The data are described underresults. The heart rate was used to calculate theventricular function indices as a fraction of the R-Rinterval (e.g., PEP/R-R) , and it is these relativeindices which are described in this paper.

Comparison with independenfly measured systolictime intervals. Immediately after the radionuclidestudies of 30 patients, the durations of the systolictime intervals (PEP, LVET) were measured by simultaneous carotid pulse tracing, phonocardiography

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SSS

QURESHI, WAGNER, ALDERSON, HOUSHOLDER,DOUGLASS, LOTTER, NICKOLOFF, TANABE, AND KNOWLES

infarction. These patients showed biventriculardilatation, had no perfusion defects on Tl-201studies and had diffuse myocardial hypokinesis.They were also being treated with digitalis anddiuretics.

5. Others (n = 77) : Patients with combinationsof the problems cited above.

The clinical comparisons in this paper will beconcerned with patients in groups 1—4only (agerange 38—84,mean age 58, 60% males) and thenormal volunteers (total N = 35) . The data frompatients with multiple cardiac problems will not bereported because the complexity of their disease prevented clear-cut analysis. The relative indices ohtamed from the curves of these patients were compared to the indices derived from the curves ofnormal volunteers. The mean heart rate of the normal volunteers (59 ± 12/mm) was similar to thatof the patients with hypertension (68 ± 14) andrecent myocardial infarction (72 ± 11 ), and wasslightly slower than that of the patients with congestive failure (79 ± 14) and cardiomyopathy (87± 13) . Statistical analyses were performed usingthe t-test.

RESULTS

Reproducibility among six observers in selectingsystolic and diastolic time intervals was good, with acoefficient of variation of 10.7% for PEP, 6.3%for LVET, 20.0% for LVFT1 and 5.6% for LVFT2.The mean indices ( ±1 s.d.) derived from the curvesof eight normal volunteers were: PEP/R-R 0.10 ±

0.02, LVET/R-R 0.26 ±0.04, LVVF1/R-R 0.25± 0.03, LVFT2/R-R 0.39 ± 0.07, PEP/LVET0.38 ±0.08, EF 0.56 ±0.08, EF/LVET 2.11 ±0.40. A close relationship was found in 30 patientsbetween systolic time intervals obtained by CPEand those derived from the time-activity curves. Thecorrelation coefficientwas 0.78 for PEP/R-R, 0.89for LVET/R-R, and 0.77 for PEP/LVET. The regression lines for the LVET/R-R and the PEP/LVET ratios are shown in Fig. 4. The correlationwas also good between PEP/LVET and ejectionfraction in 27 patients with various heart diseasesand eight normal volunteers (Fig. 5). The PEP/LVET ratio increases as the ejection fraction falls(r = 0.77, p < 0.001).

The indices of left ventricular function obtained inpatients are compared with those of the normal volunteers in Fig. 6. In patients with hypertension therewas prolongation of LVFT1/R-R and shortening ofLVFT2/R-R, whereas PEP/R-R and PEP/LVETremained normal (Fig. 6a) . Patients with congestiveheart failure showed prolongation of PEP/R-R andan increase in the PEP/LVET ratio (Fig. 6b). Pa

LVET'@R

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n= 30r=@.77p< .o@i

A

0.7

0.6

0.5

@ 0.4

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0.1

n30r =0.89p( .001

0.1 0.2 0.3 0.4

PHONO.

U 0.1 G2 0.3 04 G5 0.6 0@7PHONO.

FIG. 4. CorrelatIonbetweenLVET/R-Ras derivedfromtimeactivity curves and CPE Is shown (A). (B) shows correlation betweenPEP/LVETderived by some procedures.

tients with myocardial infarction showed prolonga.tion of LVFT1/R-R (Fig. 6c). Primary cardio-.myopathy produced prolongation of PEP/R-R,shortening of LVFT2/R-R and an increased PEP!LVET (Fig. 6d).

Ejection fraction was normal in hypertensive patients, slightly diminished in patients with myocardial infarction, and markedly decreased in patientswith cardiomyopathy or congestive heart failure. The

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* *

CLINICAL SCIENCESDIAGNOSTICNUCLEAR MEDICINE

0.07) remained relatively constant even when thePEP/LVET ratio changed significantly.

Figure 7 illustrates a normal time-activity curve(Fig. 7a) and curves in patients with various heartdiseases. The time-activity curve from a hypertensive patient (Fig. 7b) shows relative prolongation ofthe fast-filling time (LVFT1) and shortening of thediastasis plus atrial systole (LVFT2). The curvesof patients with congestive heart failure (Fig. 7c)and cardiomyopathy (Fig. 7d) showed relative prolongation of PEP and an increased PEP/LVETratio. An application of these curves is demonstrated

by pre- and postoperative studies from a patient withaortic stenosis (Fig. 8). The LVET/R-R ratio waselevated preoperatively (0.40), but decreased aftersurgery (0.27). Ejection fraction increased from39% to 69% and the rate of left-ventricular ejectionmore than doubled postoperatively (3.29 against1.24 preoperatively).

DISCUSSION

Synchronized blood-pool imaging of the heartwith Tc-99m albumin provides information about

PEP/IVET

FIG. 5. CorrelationbetweenPEP/LVETandejectionfractionobtamed from left ventricular time-activity curves in 27 patients and8 normal volunteers.

rate of ejection of blood from the left ventricle (EF/LVET) was diminished in all patients except thosewith hypertension. In the normal volunteers and patients with heart disease the total duration of electromechanical systole per R-R interval (0.39 ±

a b

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61

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FIG.6. Comparisonofventricularfunctionindicesinnormalvolunteersand in patients with various heart diseases.Star appearsbeneath data columnswhere function indices of normals and pa

Hents were significantly different (p < 0.05). Statistical analysis isnot shownin (C) and (D) due to small sample size. Ml myocardialinfarction; CHF = congestiveheart failure.

Volume 19, Number 2 139

.— NORMAL(8)

@@@ELtLItE

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QURESHI, WAGNER, ALDERSON, HOUSHOLDER, DOUGLASS, LOTTER, NICKOLOFF, TANABE, AND KNOWLES

C COPIBESTIVE FAILURE

15

a NORMAL

853

6'40

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FIG.7. Representativeventriculartime-activity curves are shown for a normalcontrol (a), and patients with hypertension(b), congestive heart failure (c) and cardiomyopathy(d).

PRE@OPERATIVE POST-OPERArIyE

FIG.8. P,*-andpostoperativecurvesfrom patient with aortic stenosis.S

both regional and overall ventricular function. Thecurrent study demonstrates that systolic and diastolic time intervals, ejection fraction, and the rateof ejection of blood from left ventricle can be ohtamed from left-ventricular time-activity curves. Acharacteristic shape for this curve was found in eightnormal volunteers and shapes of the curves werealtered (as were the derived ventricular indices)in patients with various types of heart disease.There was no single parameter that determinedcharacteristics of the curve for a specific disease,but multiple parameters considered in combinationsuggested certain diseases—e.g., hypertensive heartdisease. Drugs alone (particularly those with motropic effects) may alter these ventricularfunctionindices. Several patients reported in this study were

being treated with digitalis. However, these patientswere in congestive heart failure at the time of theirstudy and the alterations in their function curves arefelt to represent primarily those of ventricular failure.In this preliminary reviewof patients, left-ventricularfailure, regardless of its cause, resulted in an elevation of the PEP/LVET ratio, a decreased rate ofejection, and a diminished ejection fraction.

The relative ventricular time intervals obtainedfrom time-activity curves correlate closely with thoseobtained by CPE, but they are not identical. TheLVET derived from time-activitycurves in this studyspecifically denotes the period of left-ventricularejection, without including the short, isovolumicphase (protodiaStole) that precedes closure of theaortic valve. The PEP is also slightly shorter than

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that determined by CPE, since it is measured fromthe upstroke of the R wave, not the downstroke ofthe 0 wave. Since both the PEP and LVET ohtamed from time-activity curves are shortened (compared with CPE measurements), the PEP-LVETratio is relatively unchanged. An advantage of thetime-activity curve method over CPE is its abilityto provide diastolic indices of left-ventricular function, ejection fraction, and the rate of ventricularejection, in addition to systolic time intervals.

Several technical factors require emphasis. Thebackground area must be selected with care. A background area overlying portions of the left ventricleor large pulmonary arteries gives erroneous values.Extra-systoles and other types of arrhythmia produce variable R-R intervals and cause distortion ofthe time-activity curves, particularly the diastoliccomponent. The ejection fraction in such patientstends to be spuriously low.

The correlation between ejection fraction andPEP/LVET derived from time-activitycurves (r =0.77) is in close agreement with that obtained byWeissler and others (10) who compared CPE withcontrast ventriculography. However, the PEP-LVETratio and ejection fraction cannot be used as synonymous terms, since we have observed appreciableabnormalities in PEP/LVET in some patients without alterations in ejection fraction. For example,patients with hypothyroidism may have a prolongedPEP and elevated PEP/LVET ratio without a diminished ejection fraction. In addition, patients witharterial hypertension (without congestive heart failure) had normal ejection fractions, whereas theirfilling time was significantly prolonged and diastasisshortened compared with the normal. It seems possible that in certain types of heart disease, indicesother than ejection fraction may be more sensitive inearly detection of ventricular dysfunction. Furtherstudies are needed to determine more precisely therelative utility of radionudide determination of ejec

tion fraction and other ventricular function indicesin assessment of cardiac dysfunction.

ACKNOWLEDGMENTThis work was aided in part by U. S. Public Health Serv

ice Grants #GM 10548, GM-01496, and HL-20674. Dr.Qureshi was an IAEA Fellow, on training leave from Pakistan Atomic Energy Nuclear Medicine Department, MayoHospital, Lahore, Pakistan.

FOOTNOTES Cambridge Scientific Instruments, Ltd., Cambridge, Eng

land.REFERENCES

1. ZARETBL, Sm@uss HW, HURLEY PJ, et al: A noninvasive scintiphotographic method for detecting regionalventricular dysfunction in man. N Engi I Med 284: 1165—1170,1971

2. Sm@qussHW, ZARETBL, HURLEY PJ, et al: A scmtiphotographic method for measuring left ventricular ejection fraction in man without cardiac catheterization. Am ICardiol 28: 575—580,1971

3. GREENMV, Osmow HG, DOUGLASMA, et al: Hightemporal resolution ECG-Gated scintigraphic angiocardiography. I Nuci Med 16: 95—98,1975

4. Pirr B, Si@uss HW: Evaluation of ventricular function by radioisotopic techniques. N Engi I Med 296: 1097—1099, 1977

5. Bosr.a JS, BACHARACHSL, GREEN MV, Ct al: Realtime radionuclide cineangiography in the noninvasive evaluation of global and regional left ventricular function at restand during exercise in patients with coronary-artery disease.NEnglJMed296: 839—844,1977

6. FORTUINNJ, HooD WP Jii, Ciuio E: Evaluation ofleft ventricular function by echocardiography.Circulation46: 26—35,1972

7. KISSLOJ, V@NRUMM OT, THURSTONEFL: Cardiacimaging using a phased array ultrasound system 11. Clinicaltechnique and application. Circulation 53: 262—267,1976

8. RUCHTC, PATTONHD: Events of the Cardiac Cycle.In Physiology and Biophysics, 19th edition. Philadelphia,WE Saunders,1965,pp 554—558

9. WEISSLERAM, HARRIsWS, SCHOENPELDCD: Systolictime intervals in heart failure in man. Circulation 37: 149—159, 1968

10. Lawis RP, LEIGHTONRF, FORESTERWF, et al: Systolic Time Intervals. In Noninvasive Cardiology, WeisslerAM, ed. New York, Grune and Stratton, 1974, pp. 30 1—368

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1978;19:135-141.J Nucl Med.   Lotter, Edward L. Nickoloff, Masatada Tanabe and Lloyd G. KnowlesSaeeda Qureshi, Henry N. Wagner, Jr., Philip O. Alderson, Daniel F. Housholder, Kenneth H. Douglass, Mattheus G.  DiseaseEvaluation of Left-Ventricular Function in Normal Persons and Patients With Heart

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