Determination of Diastolic Function by Radionuclide Ventriculography

Subject Review Determination of Diastolic Function by Radionuclide Ventriculography

IAN P . CLEMENTS, M.D., LAWRENCE J . SINAK, M.D., RAYMOND J. GIBBONS, M.D., Division of Cardiovascular Diseases and Internal Medicine; MANUEL L. BROWN, M.D,, MICHAEL K. O'CONNOR, Ph.D., Section of Diagnostic Nuclear Medicine

Diastolic filling c a n b e m e a s u r e d b y r a d i o n u c l i d e v e n t r i c u l o g r a p h y w i t h u s e of s e v e r a l t e c h n i q u e s i n c l u d i n g t h o s e b a s e d o n g a t e d a n d list-mode acquisitions, t h e first-pass m e t h o d , a n d t h e n u c l e a r probe. R a d i o n u c l i d e v e n t r i c u l o g r a p h y specifically a s s e s s e s v o l u m e s , r a t e s of v o l u m e c h a n g e , a n d intervals d u r i n g ventricular filling. Normal v a l u e s for diastolic filling m e a s u r e m e n t vary d e p e n d i n g o n t h e individual r a d i o n u c l i d e m e t h o d s u s e d a n d t h e a g e of t h e patient. Comparative s t u d i e s of t h e r a d i o n u c l i d e m e t h o d w i t h contrast a n g i o g r a p h i c a n d D o p p l e r e c h o c a r d i o g r a p h i c t e c h n i q u e s for m e a s u r i n g d i a s t o l e a r e d i s c u s s e d , a n d t h e a d v a n t a g e s a n d disadvan­ t a g e s of t h e r a d i o n u c l i d e t e c h n i q u e s are explored. T h e role of r a d i o n u c l i d e assess­ m e n t of diastolic f u n c t i o n i n specific clinical e x a m p l e s of h y p e r t r o p h i c cardiomyopa­ thy, h y p e r t e n s i o n , a n t h r a c y c l i n e - i n d u c e d c a r d i o m y o p a t h y , a n d coronary artery d i s e a s e is r e v i e w e d . R a d i o n u c l i d e v e n t r i c u l o g r a p h y is a n a c c u r a t e a n d easily appli­ c a b l e p r o c e d u r e for s t u d y i n g left v e n t r i c u l a r v o l u m e c h a n g e s i n diastole.

DiastoHc function is abnormal in m a n y pathologic cardiac conditions.'''' Abnormal diastolic function h a s been described a s a clinically important feature of some conditions.^'"*'" Diastole is t h e period during the cardiac cycle that involves (1) reversal of the cellular mechan i s m s leading to contraction, (2) activation ofthe cellular m e c h a n i s m s leading to relaxation of the myocardium, and (3) occurrence o f t h e mechanical processes leading to filling of t h e ventricle, Of t h e s e three processes, t h e first t w o can be considered ventricular relaxation, and t h e third is ventricular filling. T h e relationship of these processes to left ventricular pressure a n d volu m e changes during ventricular filling is shown in Figure 1. Address reprint requests to Dr. I. P. Clements, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc β.'ίιΙΟΟΤ-ΙΟΙΘ, 1990

Brutsaert and associates'^ reviewed the control of relaxation of the left ventricle and proposed a tripartite theory involving ventricular loading conditions in systole, cellular processe s leading to inactivation of contraction and active relaxation, and temporal and spatial distribution of t h e s e t w o determinants of relaxation. Alterations in load influence relaxation, A n increase in ventricular load early in the process of emptying delays relaxation. This outcome is thought to be due to a n increase in t h e number of contractile sites a s a result of the increased load; therefore, more time is needed for the contractile sites to relax after emptying. A n increase in load late in ventricular emptying shortens t h e ejection period and has­ t e n s early filling. Thus, loading conditions in­ fluence the rate of inactivation of contractile Sites.

1007

1008 RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

S 1

s IC

., •-:-:-:':-:-:-:·:::ί::ί-:ί:>:-ί-:·:-:-^:-:·:-:->:-:: WKKltRS

^:-:^^:-;-S^:-J^^::^::l·:::::::^:-:---^-:--•:

!

EJECTION

IR

RFP

S C ontraetfllyH omraetfllyH

i DIASTASIS

SUCTION

C O N T R H CONTRβ

-- CLIMtC«L

FASIIVE

1 III

FILLING

...

...

ATRIAL CONTR MUSCLt PUMP

RELAXATION Load Oapandanc*

Compllanc*

Fig. 1. Diagram showing relationship of ventricular relax­ ation and filling to pressure (P) and volume (V) changes as a function of time. Contr = contraction; D = diastole; IC = isovolumic contraction; IR = isovolumic relaxation; RFP = rapid filling phase; S = systole. (From Brutsaert and associates.'^ By permission of Grune & Stratton.)

The cellular milieu also influences the rate of inactivation of contractile sites. This milieu includes such variables as cellular pH, me­ tabolites, and concentrations of circulating cat­ echolamines. During the initial portion of ventricular fill­ ing, cellular m e c h a n i s m s are paramount in determining diastolic filling, although the influ­ ence of mechanical effects cannot be ignored. In subsequent portions of ventricular filling, how­ ever, the physical properties of the ventricle are dominant. The a s s e s s m e n t of the mechanical nature of ventricular filling is based on the interrelation­

Mayo Clin Proc, J u l y 1990, Vol 65

ships of left ventricular pressure, volume, and wall thickness or m a s s . The left ventricular pressure-volume loop (Fig. 2) contains a consid­ erable portion of the information necessary to define and characterize diastole. During the period of isovolumic relaxation, primarily pres­ sure-related variables are used to measure dia­ stolic function because left ventricular volume is considered to be constant. Subsequent to the isovolumic phase, pressure and volume changes with time are used conjointly to define ventricu­ lar filling. Brutsaert and colleagues'^ listed the various pressure, volume, wall thickness, and time m e a s u r e m e n t s that have been used to m e a s u r e diastolic function—particularly relax­ ation—and indicated how each factor may be influenced. Gaasch and co-workers'^ similarly reviewed the interaction of pressure and volume during the passive phase of ventricular filling, in both normal and diseased states, and indicated which variables were useful in measuring dia­ stolic function. In this review, we will focus on the ability of radionuclide angiography to provide informa­ tion about diastolic function. Other noninvasive techniques that m e a s u r e diastolic function are available. Echocardiography can a s s e s s left ventricular dimension changes during ventricu­ lar filling.'" In addition, Doppler echocardiogra­ phy can be used to measure the blood flow velocity across the mitral valve throughout the period of diastole."* Noninvasive techniques, however, provide on­ ly a portion of the information necessary for a complete understanding of diastolic function. For example, no information is available about left atrial or left ventricular pressure. Without knowledge of cardiac pressures, changes in dia­ stolic function measured noninvasively, in patho­ logic s t a t e s and with therapeutic interventions, m u s t be interpreted cautiously. Thus, one can­ not substantiate that a change in a diastolic m e a s u r e m e n t obtained noninvasively reflects an actual change in the relaxation and filling processes or occurs because of a change in an associated unmeasured variable such as left atrial pressure. Despite this limitation, one aspect of left ventricular diastole that can be

RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION 1009

Mayo Clin Proc, J u l y 1990, Vol 65

EJECTION Volume ES-

IVC

EJECTION S V S T O L E—

RDF DIASTASIS

AS

-LV V O L U M E - -

-

D A IS T O L E

-TIME-

Fig. 2. Left ventricular (LV) pressure-volume relationships. Left, Simultaneous pressure-time and volume-time curves during cardiac cycle. Right, Instantaneous pressure-volume relationships. AS = atrial systole; ED = end-diastole; ES = end-systole; tVC = isovolumic contraction; IVR = isovolumic relaxation; RDF = rapid diastolic filling. (From Bonow RO: Effects of calcium-channel blocking agents on left ventricular diastolic function in hypertrophic cardiomyopathy and in coronary artery disease. Am J Cardiol 55:172B-178B, 1985. By permission of Reed Publishing USA.)

a s s e s s e d noninvasively is ventricular volume. In this review, we describe the use of radionu­ clide ventriculography to study volume changes in the left ventricle during diastole. We also illustrate some of the diastolic abnormalities found in patients with use of this method. DEFINITIONS Left ventricular filling can be a s s e s s e d with several radionuclide techniques, such as firstpass ventriculography," gated equilibrium ven­ triculography (with both frame-mode and listmode acquisition),'''^"^^ and the n o n i m a g i n g nuclear probe.'^^' Any method of radionuclide ventriculography generates a background-corrected time-activity curve for the left ventricle. This curve is used to determine the left ventricular ejection fraction, but it also can be analyzed in more detail to provide rates of filling and time intervals. Be­ cause activity in the left ventricle is proportional to volume, the rate of left ventricular activity change with time is proportional to the rate of

volume change with time. Left ventricular ac­ tivity change is usually normalized by dividing by the activity in the left ventricle at the onset of ventricular contraction. This calculation yields a rate of change of volume in the left ventricle that is expressed in end-diastolic volumes per second. Figure 3, a left ventricular activity or volumeversus-time curve, shows timing points from which the various left ventricular filling vari­ ables can be calculated. From radionuclide studies, the following diastolic features have been determined. Peak Filling Rate.—The most rapid change in ventricular volume with time is called the peak filling rate. It usually occurs in the initial period of fast filling—the rapid filling phase. Most nuclear cardiology computers can calcu­ late the first derivative of the time-activity curve; the maximal value of this derivative during diastole is considered the peak filling rate and is expressed in end-diastolic volumes per second (EDV/s). (It m a y also be expressed in stroke

1010 RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

1.0

•

....·•

• • >

•

-

0.31

•

·

• 4

Β

A

ι

0

1,000

0

Msec Fig. 3. Smoothed raw data of activity (y-axis) plotted against time in milliseconds (x-axis) to show important points on filling curve. A = onset of filling; Β = end of isovolumic period; C = point of peak filling rate; D = end of rapid filling phase; Ε = end of slow filling phase; F = end of atrial filling phase. (From Sinak and Clements.^' By permission of Reed Publishing USA.)

volumes per second or in milliliters per second.) It is important to inspect both the time-activity curve and the point identified as the most rapid filling rate because occasionally the most rapid filling rate occurs during the atrial filling phase and not during the initial rapid filling phase. In our experience, this occurrence h a s been noted in patients with hypertensive cardiomyopathy. Time to Peak Filling Rate.—The interval, in milliseconds, b e t w e e n the point of minimal ventricular volume and the point at which the peak filling rate occurs is labeled as the time to peak filling rate. First-Half Filling Fraction.—The firsthalf filling fraction is the proportion of stroke volume that is filled in t h e first half of the dia­ stolic filling period. Other investigators have also derived the first-third filling fraction,*''^'' the proportion of stroke volume t h a t is filled in the first third of the diastolic filling period. Because the diastolic filling period shortens with increas­ ing heart rate, first-half and first-third filling fractions are highly dependent on heart rate. Rapid, Slow, and Atrial Filling Mea­ surements.—The peak filling rate, time to peak

Mayo Clin Proc, J u l y 1990, Vol 65

filling rate, and first-half filling fraction have been u s e d most commonly to characterize filling by radionuclide ventriculography. Several other variables are available from time-activity curves. With suitable acquisition and processing proto­ cols, the entire filling phase can be graphed and the rapid, slow, and atrial filling p h a s e s can be defined; the fraction of stroke volume or filling duration contained or occupied, respectively, by t h e s e discrete p h a s e s can be determined. In patients with or without cardiac disease, a brief period of slow filling at the onset of the initial rapid filling phase can be identified. Betocchi and colleagues^'* equated this period with the isovolumic phase of ventricular filling. TECHNIQUES FOR ACQUISITION AND PROCESSING Left ventricular time-activity curves generated by techniques based on list-mode or gated acqui­ sition can be used to study left ventricular fill­ ing. Curve-fitting techniques have subsequently been applied by some investigators^'^" to deter­ mine filling measurements. Time-activity curves produced by conventional consecutive R-wave gating, including list-mode acquired data refor­ m a t t e d forward from the R wave by using the stored consecutive R w a v e s as gating signals, have an artifact in the later part of the curve. ^" Consequently, the later frames of such acquisi­ tions contain l e s s activity t h a n might be antici­ pated (Fig. 4 A). This outcome is a result of in­ trinsic variability of heart rate, predominantly sinus arrhythmia. The artifact h a s little, if any, effect on the early m e a s u r e m e n t s of diastole, such as time to peak filling rate and peak filling rate. Nevertheless, first-half filling fraction m a y be affected because the end of the diastolic filling period cannot be determined from the time-activity curves. Methods based on consecu­ tive R-wave gating have considerable difficulty in generating information about atrial filling because the artifact occupies a substantial por­ tion of atrial filling. Thus, neither the propor­ tion of stroke volume contributed by atrial filling nor the proportion of the filling period occupied by atrial filling can be calculated accurately by u s i n g consecutive R-wave gated acquisition.

RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION 1011

Mayo Clin Proc, J u l y 1990, Vol 65

B. 100

43h

-I

.08

0.4

1.1

U

C.

E.F. = .57

E.F. = .60

40 h

L

2.0

.08 0.4

.04

0.4

2.0

Time, sec

Fig. 4. Blood-pool time-activity curves obtained sequentially from the same patient by consecutive R-wave gating (A), list-mode acquisition and gated reformatting with an "artificial" cycle length in excess of the actual cycle length entered into the reformatting sequence (B), and alternate R-wave gating (C). Curves were obtained by three-point smoothing of the raw data. E.F. = ejection fraction. (From Clements and associates."*' By permission of C. V. Mosby Company.)

Several available methods can surmount this problem. Betocchi and colleagues^'' reformatted the list-mode acquired data by using 10-ms frame durations and advocated producing a composite curve by g a t i n g both forward and backward from the R wave. At the Mayo Clinic, a technique based on a frame-mode acquisition method^' that involves alternate R-wave gating generates a composite time-activity curve (Fig. 4 C) that includes infor­ mation from a series of pairs of cardiac cycles. The first of t h e s e two composite cycles contains a complete diastolic filling curve and can be used for analj'^.is of all p h a s e s of ventricular filling. Bacharach and co-workers^**'^-'detailed the tech­ nical requirements for generating adequate timeactivity curves; Juni and Chen "* recently quan­ tified errors in several acquisition protocols. The nonimaging nuclear probe can be used for investigation of diastole." This technique h a s the advantage of a small sampling interval (10 ms) and s e e m s to provide good time-activity curves throughout diastole. Some investigators, however, have found that the nuclear probe re­ sults correlate only moderately well with those of contrast angiography in determining systolic function (ejection fraction), and concern h a s been expressed that this result m a y be due to posi­ tioning difficulties.^' Because the nuclear probe

does not sample the entire ventricle, ejection fraction could be overestimated or underesti­ mated, depending on the regional function of the ventricle. This imprecision might be expected to cause problems also in a s s e s s i n g diastolic func­ tion, although studies have suggested that dias­ tole a s s e s s e d by the nuclear probe method is better correlated with contrast angiographic es­ timations t h a n w h e n a s s e s s e d by conventional gated radionuclide ventriculography.^' Clearly, more comparative studies of all modalities of a s s e s s i n g left ventricular diastolic function are needed. Time-activity curves have been generated from first-pass acquired data, but questions have been raised about the accuracy of this method in studying the diastolic portion of the curve,-*'^ inasmuch as activity in the left ventricle is not constant during diastole in the first-pass method. This situation is a consequence of a variable dilution of activity in the left ventricle because of ventricular filling with blood that contains no radioactivity. Left ventricular time-activity curves have been acquired in conjunction with left ventricular pressure curves.''' '''' This method allows deter­ mination of left ventricular pressure-volume loops and t h u s the integration of pressure and volume changes in diastole.

1012 RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

NORMAL VALUES FOR DIASTOLIC FUNCTION A S S E S S E D BY RADIO­ NUCLIDE VENTRICULOGRAPHY Table 1 s u m m a r i z e s normal v a l u e s for diastolic m e a s u r e m e n t s found in numerous studies by various radionuclide techniques, including nor­ mal values for the alternate R-wave method. From the data of the Mayo normal population,^'* the 10th and 90th percentiles of peak filling rate are 2.4 and 3.6 EDV/s, respectively. Corre­ sponding v a l u e s for time to peak filling rate and first-half filling fraction are 135 and 2 1 2 m s and 0.58 and 0.84, respectively. Studies have b e g u n to show t h a t age influ­ ences diastolic function. In t h e Mayo study of 4 2 normal patients,^'* rapid filling fraction w a s neg­ atively correlated with age (r = -0.58; P<0.001); atrial filling fraction and filling duration in­ creased with advancing age (r = 0.56 and 0.55; P<0.001). Other radionuclide studies have dem­ onstrated a dependence of rapid filling rate and atrial filling on age,'*^''" and echocardiographic studies support the greater role of the atrial phase of diastole with increasing age.'"''^ Thus, as Miller and co-workers^° emphasized, the age of the patient m u s t be considered w h e n diastolic m e a s u r e m e n t s are assessed. COMPARISON WITH OTHER TECHNIQUES F e w reported studies h a v e compared contrast angiographic m e t h o d s and radionuclide m e t h ­ ods of m e a s u r i n g diastolic volume changes with time. Magorien and colleagues'"' found that peak filling rate and time to peak filling rate were similar w h e n m e a s u r e d by contrast ven­ triculography and blood-pool radionuclide ven­ triculography. In a provocative study. S e a l s and co-workers^' compared m e a s u r e m e n t s of peak filling rate by two radionuclide methods (con­ ventional gated radionuclide angiography and nuclear cardiac probe) with contrast angiogra­ phy; although each method yielded similar group m e a n values, correlation coefficients between the methods depended on specific m e a s u r e m e n t s and varied considerably b e t w e e n 0.08 and 0.83. The best correlation w a s between nuclear probe and contrast angiographic m e a s u r e m e n t s of peak

Mayo Clin Proc, J u l y 1990, Vol 65

filling rate, and the worst correlation w a s be­ t w e e n nuclear probe and gated radionuclide m e a s u r e m e n t s of peak filling rate. Radionuclide determinations of diastolic fill­ ing and Doppler echocardiographic a s s e s s m e n t of diastolic function have been compared.''"''^ Such comparisons are difficult because several approximations m u s t be made to generate, from the Doppler echocardiographic data, a variable comparable to radionuclide peak filling rate. Thus, the poor correlation between Doppler and radionuclide peak filling rates is not surprising, although it m a y be improved by normalizing for mitral stroke v o l u m e . T h e ratios of early to atrial filling by the two methods s e e m compa­ rable.'"* Also, w h e n intervals are measured, investigators should realize that radionuclide ventriculography includes t h e isovolumic phase in the duration of the initial period of rapid filling, w h e r e a s a Doppler m e a s u r e m e n t of this interval m a y exclude it.'"' Clearly, more comparative studies between radionuclide and Doppler echocardiographic methods are needed. Such combined studies m a y yield better w a y s to characterize diastolic abnormalities in pathologic states. In fact, the optimal noninvasive method for a s s e s s m e n t of diastole is not yet known. Radionuclide ventriculography has certain advantages because of its ability to measure relative volume changes with time, without the geometric assumptions necessary with contrast angiographic and echocardiographic techniques. Major a d v a n t a g e s of the radionuclide technique are its e a s e of performance, lack of dependence on patient anatomy, and production of data in a digitized format ready for computer processing and generation of the m e a s u r e m e n t s of diastol­ ic function. D i s a d v a n t a g e s of the radionuclide technique include dependence of acquisition on a regular cardiac rhj^hm (thus excluding patients with irregular rhythms) and inability to time, rela­ tive to the volume curve, important cardiac e v e n t s such as the opening of the mitral valve and the closing of the aortic valve. This ability would be helpful in defining the isovolumic phase of ventricular filling.

Mayo Clin Proc, J u l y 1990, Vol 65

RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

1013

Table 1.—Diastolic Filling: Normal V a l u e s ( M e a n t SD) From P u b l i s h e d Reports* Source Betocchi et al^"'

Technique

No. of subjects

PFR (EDV/s)

TPFR (ms)

33

3.5 ± 0 . 5 (>2.5)t

145 ± 20 (<180)t

32 12

3.13 ± 0 . 8 5 2.14 ± 0.63

151 ± 3 8

18 10

3.04 ± 1.06 3.1 ± 0 . 6

159 ± 65

11

2.63 ± 0.39

158 ± 27

'/2FF

Inouye et aP

List-mode; 10-20 ms/F; forward and reverse gating; curve fitting First-pass; 20 ms/F First-pass; 25 ms/F; curve fitting Gated Gated; 32 F/RR; curve fitting Gated; 32 F/RR

Lavine et aP"*

Gated; 32 F/RR

21

3.11 ±0.65

169 ± 36

Soufer etal'" Sinak & Clements^'

Nuclear probe; 10 ms/F Alternate cycle gating; 28 F/RR

14 42

4.04 ±0.77 2.9 ± 0 . 5

173 ± 3 1

0.72 ±0.11

2.4 3.6

135 212

0.58 0.84

Reduto et al'' Polak et al" Miller et al'" Poliner et aF^

10th percentile 90th percentile

(V:iFF, 0.60 ±0.07) (V.iFF, 0.46 ±0.13)

*EDV = end-diastolic volume; F = frame; '/2FF = first-half filling fraction; V.iFF = first-third filling fraction; PFR = peak filling rate; RR = RR interval; TPFR = time to peak filling rate. tDefined by Bonow et al."*

CLINICAL ILLUSTRATIONS The following three cases illustrate abnormal­ ities of filling detected by blood-pool gated ra­ dionuclide ventriculography. The influence of therapy is demonstrated in all three cases. Case 1.—^A 74-year-old w o m a n w a s thought to have hypertrophic obstructive cardiomyopa­ thy, which had been diagnosed in 1979 on the basis of echocardiographic findings. In 1987, she complained of m i d c h e s t discomfort that ex­ tended to the j a w and w a s associated with ex­ ertion, which had been present for several years and w a s not relieved by sublingual doses of nitroglycerin. In January 1987, she h a d more severe chest pain associated with atrial fibril­ lation at a ventricular rate of 150 beats/min. She w a s admitted to her local hospital, where pulmonary edema w a s noted on a chest roent­ genogram. The current examination at the Mayo Clinic revealed a regular pulse at 72 beats/min and arterial pressure of 120/80 m m Hg. The carotid pulses were brisk, and grade 3 (on the basis of 1 to 6) midsystolic m u r m u r s were noted at the base and apex of the heart. These m u r m u r s did

not increase with the Valsalva maneuver. An electrocardiogram showed left-axis deviation with low anterior forces. Echocardiography (Mmode and two-dimensional) disclosed asymmet­ ric septal hypertrophy and systolic anterior motion of the mitral valve. Doppler examination indicated a resting maximal instantaneous gra­ dient of 36 to 50 m m H g in the left ventricular outflow tract and mild mitral regurgitation. A resting radionuclide ventriculogram showed a left ventricular ejection fraction of 0.79 in asso­ ciation with hypertrophy of the basal septum and normal wall motion. The filling curve (Fig. 5 β ) showed a delay in filling (peak filling rate, 1.82 EDV/s; time to peak filHng rate, 210 ms; first-half filling fraction, 0.46) compared with that in a normal patient (Fig. 5 A). Of note, the initial period of rapid filling w a s damped and prolonged; actually, the most rapid filling oc­ curred during the atrial phase. Verapamil therapy, 80 m g four times a day, w a s begun. One month later, the chest discom­ fort had decreased, and a resting radionuclide ventriculogram showed little change in left ventricular ejection fraction (0.78) but a striking

Mayo Clin Proc, J u l y 1990, Vol 65

1014 RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

Β 125 ρ

105 h

· Ρ β * emptying point • P e *fflNngpoint

125 105 k 85 65

125 105 ash 65h 45h

45

0 200 400 eOO 800 1,100 msec

EF PFR, EDV/sec TPFR, msec XFF

1 1 1 1 1 1 1 1 0 200 400 800 800 1,100 msec

I 11 11 1 1 1 1

11 0 200 400 600 800 msec

0.67

0.79

0.78

2.43

1.82

2.59

204 0.63

210 0.46

216 0.64

1 1 1

Fig. 5. Blood-pool time-activity curves. A, In normal patient (without cardiac disease). Β and C (case 1), In 74-year-old woman with hypertrophic cardiomyopathy before (S) and after iC) initiation of verapamil therapy, 320 mg/day. Despite normal left ventricular ejection fraction (EF), peak filling rate (PFR) was decreased, time to peak filling rate (TPFR) was delayed, and first-half filling fraction ('/-zFF) was decreased in comparison with these measurements in a normal patient with a similar cycle length. Treatment with verapamil tended to return the filling abnormalities to normal. EDV = end-diastolic volume.

improvement in filling (Fig. 5 C)—substantial increases in peak filling rate (to 2.59 EDV/s) and first-half filling fraction (to 0.64). Comment.—This case illustrates the pro­ nounced reduction in filling rate in hypertrophic obstructive cardiomyopathy and the remark­ able improvement in filling produced by vera­ pamil. This improvement in filling w a s associ­ ated with alleviation of symptoms. Impaired left ventricular filling has been identified in pa­ tients with hypertrophic obstructive cardiomy­ opathy.'''•^'"''^ A prolonged isovolumic period, decreased peak filling rate, prolonged time to peak filling rate, decreased amount of filling in the rapid filling period, and enhanced amount of filling in atrial systole in comparison with nor­ mal have been described.''*''' Administration of verapamil and nifedipine returns t h e s e mea­ sures of diastolic function to normal in patients with hypertrophic cardiomyopathy.^"^" In con­ trast, propranolol treatment w a s reported not to

influence peak filling rate or time to peak filling rate in such patients."* Radionuclide ventriculography with diastolic filling m e a s u r e m e n t s may be a valuable nonin­ vasive method for monitoring the effects of ther­ apy in patients with hypertrophic obstructive cardiomyopathy. Case 2.—^A 73-year-old m a n had been on antihypertensive therapy for 15 years. In Sep­ tember 1986, he w a s taking prazosin (5 m g three t i m e s a day) and furosemide (60 mg/day); he indicated that in recent years he had experi­ enced progressive effort fatigue and nasal stuffi­ ness. Results of cardiac examination were nor­ mal; the arterial pressure was 150/84 m m Hg supine and 160/80 m m H g standing. Relevant laboratory data included the following: creatinine, 1.0 mg/dl; potassium, 4.1 meq/liter; blood urea, 34 mg/dl; and hemoglobin, 14.0 g/dl. A chest roentgenogram and electrocardiogram were normal. M-mode and two-dimensional

Mayo Clin Proc, J u l y 1990, Vol 65

RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

1015

Β 125

• Peak emptying point • Peak filling point

105

Ul

125 105 ;

β5Η

es -

e5h

65 -

45 -

45 -

25 -

25 •

0

•

'

200 400 600 800

1,100

0

I

I I J I 1 I I I

200 400 600 800

msec

I I

1,100

25 h 0

I

1 I I

I I

I I

200 400 600 800

1,100

msec msec

EF PFR, EDV/sec TPFR, msec

0.68

0.58 0.62 2.35

1.86 1.19

84 0.72

205 0.41

222 0.44

Fig. 6. Blood-pool time-activity curves. A, In normal patient (without cardiac disease). Β and C (case 2), In 73-year-old man with hypertensive cardiomyopathy before (B) and after (C) initiation of verapamil therapy, 360 mg/day. Despite normal left ventricular ejection fraction (EF), peak filling rate (PER) was decreased, time to peak filling rate (TPFR) was delayed, and first-half filling fraction O/2FF) was decreased in comparison with these measurements in a normal patient with a similar cycle length. Treatment with verapamil diminished the filling abnormalities. EDV = end-diastolic volume.

echocardiograms showed normal systolic func­ tion and moderate basal septal hypertrophy. A radionuclide ventriculogram during exer­ cise showed left ventricular ejection fractions of 0.59 at rest and 0.65 at 500 kg · m/min workload; no regional wall motion abnormality w a s seen during rest or m a x i m a l exercise. Unlike that in a normal patient (Fig. 6 A), the resting timeactivity curve showed a profoundly abnormal filling pattern (Fig. 6 B), with the initial period of filling being considerably slowed (maximal fining rate, 1.19 EDV/s), and a delay in onset of this maximal rate to 205 m s after the end of emptying. The first-half filling fraction w a s 0.41, considerably less t h a n normal. The most rapid period of filling in this patient occurred during the atrial phase. Therapy with vera­ pamil, 120 m g three t i m e s a day, w a s initiated, and the prazosin therapy w a s discontinued. Two m o n t h s later, the patient's effort fatigue had diminished substantially, and a repeat

radionuclide ventriculogram showed a resting left ventricular ejection fraction of 0.68. The filling curve had improved (Fig. 6 C), with an increase in peak filling rate to 1.86 EDV/s. Comment.—Striking abnormalities are seen in filling variables in patients with hyperten­ sion. Time to peak filling rate is prolonged, and peak filling rate and first-third ejection fraction are decreased in patients with mild to moderate hypertension and normal systolic function.^ These abnormalities have been reasonably well correlated with left ventricular mass.^ ** Dia­ stolic abnormalities of left ventricular function may be the first sign of early cardiac involve­ m e n t in hypertension. Pulmonary edema and angina m a y develop in patients who have hyper­ tension and normal systolic function." Treat­ m e n t of the hypertension with nitrendipine (a calcium channel blocker) h a s been associated with both reduction in left ventricular m a s s and return of diastolic abnormalities to normal.^**

1016 RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

This case demonstrates the typical diastolic abnormalities described in hypertension and shows that improvement in filling can occur with the use of verapamil. Case 3.—A 66-year-old w o m a n with malig­ nant histiocytoma of the right calf had under­ gone right above-knee amputation; subsequently, extensive m e t a s t a t i c lesions were noted. S h e had a history of insulin-dependent diabetes mellitus but had no cardiac pathologic condition or hypertension. Treatment w a s commenced with menogaril (200 mg/m^ per month, intrave­ nously), an anthracycline antitumor agent with less cardiotoxic effect than doxorubicin.''" Two m o n t h s after the onset of menogaril ther­ apy, a radionuclide ventriculogram (Fig. 7 B) showed a normal ejection fraction and a de­ creased peak filling rate (1.75 EDV/s). Four m o n t h s later, the ejection fraction remained normal; however, diastolic filling w a s notably abnormal (Fig. 7 C) in comparison with that in a

125 Γ

normal subject who had a similar heart rate (Fig. 7 A). The peak filling rate w a s further depressed (to 1.50 EDV/s), and the first-half filling fraction w a s considerably decreased (to 0.29). Comment.—Recently, p a t i e n t s receiving doxorubicin have been found to have filling abnormalities in the presence of normal systol­ ic function."*' Investigators have suggested t h a t t h e s e filling abnormalities may appear at a cumulative dose of doxorubicin that is less t h a n the dose that causes systolic dysfunction."*' This case suggests that menogaril, a new an­ thracycline, also m a y alter diastolic function in the absence of systolic dysfunction. Study of anthracycline-induced left ventricular filling abnormalities may provide a better understand­ ing of the role of ventricular filling in cardiac disease. The clinical implications of these fill­ ing abnormalities for patient m a n a g e m e n t are uncertain.

125 r 105 \-

1-

105

UJ

· P M k Mnptylng point

Mayo Clin Proc, J u l y 1990, Vol 65

β5Κ 65 45 1

0

200

1

1

1

400 600 msec

1

1

L_l

800

0

1

200

1

1

1

J

400 600 msec

1

1

800

_l

1 1 1 1 1 1 1 1 1 0 200 400 600 800 msec

EF

0.58

0.57

0.55

PFR, EDV/sec

2.62

1.75

1.50

TPFR. msec

198

224

210

0.71

0.47

0.29

XFF

Fig. 7. Blood-pool time-activity curves. A, In normal patient (without cardiac disease). Β and C (case 3), In 66-year-old woman who had received menogaril (200 mg/m^ per month) for 2 and 6 months, respectively. Left ventricular ejection fraction (EF) remained normal with menogaril treatment; however, peak filling rate (PFR) showed a progressive decline, time to peak filling rate (TPFR) was delayed, and first-half filling fraction (VzFF) decreased with continued menogaril use. EDV = end-diastolic volume.

Mayo Clin Proc, J u l y 1990, Vol 65

RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

OTHER CLINICAL A S P E C T S Radionuclide ventriculography h a s detected considerable abnormalities in left ventricular filling in patients with coronary artery dis­ ease.^·'·^^·'·^^·" In patients with relatively normal systolic function, diastolic filling, particularly the peak filling rate, h a s been found to decrease with an increase in the number of diseased coronary a r t e r i e s . A l s o , the increase in peak filling rate that normally occurs during exercise w a s observed to be blunted in patients with coronary artery disease.^^•''^ In patients with normal systolic function and single-vessel coro­ nary artery disease, the peak filling rate m a y be less t h a n normal and t h e n become normal after successful balloon dilation. Diastolic filling usually w a s abnormal in pa­ tients with decreased systolic function, no mat­ ter w h a t caused the decreased function. Inves­ tigators have noted that slightly more t h a n a third of patients with s y m p t o m s and clinical confirmation of left heart failure have a nor­ mal or near-normal left ventricular ejection fraction."*'" Diastolic filling m e a s u r e m e n t s were abnormal in t h e s e patients. Diastolic dys­ function is thought to be the primary patholog­ ic feature in t h e s e patients. Regional abnormal­ ities in diastolic filling have been demonstrated by radionuclide ventriculography in patients with coronary artery disease*^'' and hypertro­ phic cardiomyopathy.^^ Regional changes in the diastolic properties of the ventricle m a y contribute to the changes in filling seen with aging 4 0 CONCLUSION Radionuclide ventriculography accurately mea­ sures volume changes during left ventricular filling and can be used to study diastole in various pathologic cardiac conditions. Such studies m a y allow better understanding of the s y m p t o m s and the pathophysiologic features associated with cardiac diastole and m a y aid in the selection of specific therapy for t h e s e prob­ lems. Physicians should remember t h a t volume changes are only a part of the e v e n t s that occur in the heart in ventricular diastole and that, to characterize diastole fully and to a s s e s s the

1017

eflFect of interventions, additional information involving invasive t e s t i n g may be necessary.

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1018 RADIONUCLIDE ANGIOGRAPHY AND DIASTOLIC FUNCTION

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