Xenon studies of myocardial blood flow: Theoretical, technical, and practical aspects

Xenon Studies of Myocardial Blood Flow: Theoretical, Technical, and Practical Aspects A n t o n i o L ' A b b a t e and Attilio Maseri External detection by a single collimator of the washout curve of l ~ X e following its intracoronary injection was used in humans following its validation in animals. ~ However, additional experimental studies showed that the straightforward application of the theoretical principles on which the technique should be based resulted in uncorrected values. Special empirical modifications in the analysis of the washout curves were required in order to obtain a fair agreement between calculated and experimental flow values. 3 Furthermore, studies in humans 4"s indicate that reappearance of indicator into the

counting field due to recirculation and diffusion retention of the tracer in epicardial fat alter the precordial washout curve leading to underestimation of coronary blood flow. This method has found a second wave of applicatin in humans for the study of regional myocardial perfusion using a gamma camera, e-14 The amount of new information on regional myocardial perfusion provided by this approach is quite considerable; h o w e v e r , the interpretation of the values obtained in these studies requires particular attention in v i e w of the limitations outlined above.

THEORY, MODEL SIMULATIONS, A N D

monoexponential washout curve and W is the space of distribution of the tracer. Space W is not necessarily equal to the volume of the organ (V) depending on whether or not the tracer reaches the same concentration in the blood and in the tissue at equilibrium. When this occurs (i.e. blood and tissue behave as a single compartment of volume V) W equals V, otherwise the two volumes are different being related by a coefficient ~,, which depends on the characteristics of both the tracer and the biologic composition of V. This coefficient, currently defined as the "diffusion partition coefficient," is X = W / V and corresponds to the ratio between the concentration of the tracer in 1 ml of tissue (including intravascular blood) and the concentration in 1 ml of blood. It derives from above that when ~, is known, the estimate of K allows the definition of the specific flow (flow per unit volume or, when corrected for the specific gravity, flow per unit mass). Note that, apart from the general assumption of the tracer dilution method (i.e., the stationarity and linearity of the system), knowledge of the injected dose, the concentration of the tracer in the organ, and the counting efficiency are not required. Note also that this is a particular application of the general formula of the tracer dilution theory according to which F / V = l / t , where t is the mean transit time of the tracer through the organ. In fact for a monocompartimental model the disappearance rate of the tracer K is the inverse of t. The simplicity of this approach, joined to the possibility of detecting the time activity course by external counting, justifies the wide interest

EXPERIMENTAL VALIDATION

E BASIC T H E O R Y behind the use of T Hdiffusible indicators for measuring flow through an organ has been developed by Kety 15 and by Zierler.~6 In essence, following the instantaneous injection of a free diffusible indicator* into the organ (by direct intratissue depot or by arterial injection), flow can be assessed by measuring the disappearance rate (washout rate) of the indicator from the organ. By the use of gamma rays emitting tracers, the washout rate can be detected by external scintillation counting. The relationship between tracer washout rate and flow derives from a single compartment. Tracer is washed out according to a monoexponential function e -Kt whose value of K is proportional to flow. This flow (F) can be computed as F = K 9 W where K is the rate constant of the *Free diffusible indicator means the one that instantaneously diffuses from blood to surrounding tissue and vice versa. This does not imply that the concentration in blood and tissue is the same even in a static situation.

From the Coronary Research Group, Consiglio Nazionale Delle Ricerche Antonio L'Abbate, M.D.: Head of the Coronary Research Group, C.1V.R. Clinical Physiology Laboratory, Pisa, Italy; and Attilio Maseri, M.D.: Professor of Cardiovascular Medicine, Royal Postgraduate Medical School, University of London, and Director, Cardiovascular Research Unit, Hammersmith Hospital, London, United Kindon. Address reprint requests to Dr. Antonio L'Abbate, C.N.R. Clinical Physiology Laboratory, Via Savi 8, 56100 Pisa, Italy. 9 1980 by Grune & Stratton, Inc. 0001-2998/80/1001 ~)001 $02.00/0

2

Seminars in Nuclear Medicine, Vol. ;~, No. 1 (January), 1980

XENON STUDIES OF MYOCARDIAL BLOOD FLOW

for this technique both for clinical and research purposes. However, the practical application of the method is limited by the following assumptions: (1) knowledge of the partition coefficient ~; (2) removal of the tracer from the tissue in proportion to flow; (3) absence of tracer reappearance in the counting field; and (4) homogeneity of flow. Partition Coefficient

The myodcardial-blood partition coefficient for Xenon has been estimated in vitro to be 0.72/7 It is ten times higher for the adipose tissue. Thus the presence of fat in the composition of the organ will heavily affect the ratio F/V as the actual ~, will be somewhere in between 0.72 and 7, depending on which fraction of V is fat. Practically, this fraction cannot be determined and so remains an unknown. Removal o f the Tracer in Proportion to Flow

In the specific case of the heart, the presence of various amounts of adipose tissue on the surface of the heart leads to the problem of tracer exchange between muscle and fat. 18 Xenon accumulates in the epicardial fat because of a sort of tonometer effect by which the partial pressure of Xenon in the muscle tends to equilibrate by molecular diffusion with that in the adjacent epicardial fat, where the gas accumulates until the gradient is reversed. This phenomenon begins immediately after the injection and appreciably reduces the overall washout rate of ~33Xe from the very beginning, although the effects are clearly more significant at the tail of the curve. This has been shown in simultaneous washout curves of mXe and ~2SI-antipyrine generated from the whole heart, s In agreement with the data obtained in humans, animal experiments have shown that initial extrapolation of the washout curves leads to an underestimate of flow when the measurements include the basal regions of the heart with appreciable epicardial fat. 3 This problem, as well as the unknown of the partition coefficient, might be circumvented by the use of tracers that are not retained in fat more than in muscle. Tracer Recirculation

The tracer that reappears in the counting field following its washout from the myocardium, contributes to the recorded counting rate, lead-

3

ing to a slower external washout curve and an underestimate of flow. Since 90%--95% of Xenon is eliminated into the expired air at each passage through the lung, the 10%-5% that recirculates is generally thought to be small enough to not significantly affect the slope of the washout curve. However, studies performed in humans s and in animals ~9demonstrate that this is not the case. The crucial effect of reappearance of tracer in the counting field on the Xenon clearance curve is illustrated in Fig. 1, where two successive mXe washout curves, obtained in the openchest dog are shown. Tracer was injected in the bypassed left anterior coronary artery, and activity was detected from the anterior wall of the ventricle. The two injections were performed at the same pump flow but with a different collimation. When the solid angle of the collimator included a part of the left lung (B), a marked deviation from the initial slope was observed. In such a case, the curve cannot be described by a single-term exponential (i.e. one that is not linear on a semilogarithmic plot); thus, K remains indefinite. Monoexponential fitting of arbitrary proportion of the curve is not justified by theory and leads in any case to an underestimate of K. Even when we reduced the reappearance of the tracer to a m i n i m u m in the open-chest dog, by including in the counting field, in addition to the labeled myocardium, only a small proportion of the left ventricular cavity, a 15% systematic underestimate of flow leO, :~

?. 4

lo

.":i.?;..

..:... 9 :'=5 ... .'...

1

2

1

2 uJ.

Fig. 1. Two successive lZZXe washout curves obtained a t constant coronary pump flow b u t w i t h d i f f e r e n t collimat o r orientation in t h e open-chest dog. Inclusion in the counting field of a proportion of the left lung and a relatively larger portion of t h e l e f t ventricle markedly affected the shape of the washout curve (right).

4

L'ABBATE AND MASERI

10(]

%'~ 9

\

-experimental 9 corrected

"~

h., ..

"j.

.'..

"2.

'+2:,.. -,2.

+.

+ . .+.

.... 22:22

..'.. 9 .

1

2

3 ,,,

1

2

.'.

9 9

3

,,,

Fig. 2. Example of correction for recirculation of t w o curves obtained at low (left) and high (right) f l o w in the same animal. The effect of recirculation is higher at high flow. Note t h a t deviation of t h e curve at low f l o w is not due to tracer recirculation.

relative to the reference flow per gram of perfused tissue (obtained by the pump flow and the microsphere method) was observed at flow rates higher than 2.5 ml/min/gm. 19 The limiting effect of tracer recirculation can be obviated by a method of correction2~that has been satisfactorily employed in humans5 and animals. 19In essence, the amount of tracer reappearing in the counting field at each time, which has to be subtracted from the precordial curve, can be obtained by convoluting the decremental fractions of the precordial washout curve (i.e., the tracer washed out from the myocardium at each time) into the function describing the reappearance of the tracer in the counting field following its washout from the myocardium. This latter function can be assessed in vivo by detecting the time-activity curve of a known amount of the indicator injected as a bolus at the

outlet of the coronary system, i.e., into the right atrium. This method of correction assumes that a steady state is maintained throughout the duration of the measurement and that both the recirculating tracer and the tracer into the myocardium are seen, on the average, with comparable counting efficiency. Figure 2 shows a Xenon clearance curve obtained in the same experimental condition as Fig. 1 and its correction for recirculation. Experimentally, when correction for recirculation is applied, and in absence of other limiting factors, a correct estimation of actual flow can be obtained by the Xenon technique. ]9 Correction is essential, especially in the presence of a high ratio of myocardial blood flow to cardiac output (as can be produced by pacing or coronary vasodilating drugs). In fact, the amount of tracer reappearing in the counting field will depend on the relation between the washout rate from the myocardium and the permanence of the tracer into the heart cavities, pulmonary circulation, and systemic circulation.

Flow Nonhomogeneity When flow through the organs is not homogeneous, that is, when varying proportions of the organ have different flows per unit mass, the general basis of the method still applies when the organ is considered as composed of single homogeneous compartments and when F/V = f] + t"2... + f. = (K~ + K 2 . . . + K,) where f is the specific flow of each compartment. As shown in Fig. 3, the overall washout curve

Fig. 3. Model simulation of the effect of flow nonhomogeneity on the Z~Xe washout curve. (left) The monoexponential washout curves from 15 compartments of equal size but different flows ( h i g h / l o w f l o w ratio = 4). (right) The resulting overall washout curve (thick curve) deviates from a monoexponential course. Average flow, computed by monoexponential fitting of the curve down to 50% or 30% of the peak overestimates actual flow.

XENON STUDIES OF MYOCARDIAL BLOOD FLOW

resulting from a series of compartments of equal size but different flow cannot be described by a single exponential. Note that for each compartment, both the washout rate and the initial content of tracer (the activity at time zero) are proportional to flow. Deviation of the curve from a monoexponentiai is proportional to the nonhomogeneity of flow in the initial portion of the curve influenced by the higher flow rates, the final portion by the low ones. This implies that monoexponential fitting of the initial slope will overestimate the average flow. Model simulation shows that, using the monoexponential fitting down to 30% of the peak, the overestimate of mean flow is greater than 10% when, in a three-compartmental model, the ratio of the highest to lowest flow is greater than three. Obviously, the overestimate becomes larger and larger as the difference between the extreme flows increases. Thus, transmural differences in flow of the magnitude of those experimentally observed in ischemic segments, would not per se significantly affect a correct estimate of average wall flow. However, if greater differences exist between myocardial zones within the same solid angle of the collimator, such as anterior and posterior wall, average flow would be overestimated to a variable extent, depending on the magnitude of the differences and the spatial location of the areas with high and low flows relative to the detector. To overcome the limiting effect of flow nonhomogeneity on the computation of average flow, Zierler proposed a different analysis of the washout curve, i.e., the stochastic analysis or area/peak method? 6 Briefly, the mean transit time ([) of the tracer through the organ can be derived from the ratio between the area under the washout curve and its peak, so that F/V = H/A, where H is the peak of the curve and A the area. As long as the curve is recorded down to zero or at least to 1% of the peak, this method does not require the washout curve to have a monoexponential course, thus avoiding any arbitrary or empirical segmental monoexponential fitting of the curve. In spite of the theoretical advantages, the practical use of the area/peak method is limited by the following: 1. the curve has to be recorded down to background level (incomplete recording requires

5

extrapolation of the final portion of the curve, with possible error in computation of the area). 2. the contribution to the external counting of the tracer content in different parts of the organ should not be affected by different counting efficiency. 3. The peak of the curve should represent the total activity into the organ. Experimental studies show that the observed peak may underestimate the injected dose in spite of an apparent instantaneous injection. 19 Actually, the instantaneous delivery of the input at the capillary level is hardly achieveable even with a rapid and small intracoronary bolus, thus the dispersion in time of the input produces a reduction of the height of the peak. When corrected for the dispersion of the arrival times of the input by a mathematical convolution procedure, the peak can be correctly estimated. 19 4. Accuracy in determining the tail of the curve. Experimental studies indicate that errors due to poor counting statistics, background subtraction, and correction for recirculation, which mainly affect the final portion of the curve, prevent an accurate estimate of flow by the stochastic analysis in many instances. SURVEY OF THE EXPERIMENTAL RESULTS

Experimental validations of the Xenon method have been carried out in several studies with inconsistent results likely related to methodologic differences, such as the amount of tracer recirculating, the method used for measuring the reference flow and the tissue mass perfused, and the type of analysis applied to the Xenon curves. Measurements based on initial slope extrapolation showed good agreement between relative changes of Xenon flow and absolute total coronary flow in a range from 60 to 140 ml/min 1 but a progressive underestimate when flow, as measured by electromagnetic flow meter on the coronary sinus, was higher than 100 ml/minfl~Comparison between Xenon flows and reference flows per gram of tissue, as obtained by flow-meter values and the mass of the selectively perfused myocardium, showed a good agreement, although the difficulty in estimating the mass of tissue perfused poses some reservations to these conclusions. More recently, reference flow was obtained by the microsphere tech-

6

nique, and an excellent correlation was found in the closed-chest dog in the range of 0.4-2.0 ml/min/gm, z2 However, our results in the openchest dog, using microsphere flow as reference, show a 15% underestimate of flow by the Xenon method in the range of 2.5-10.0 ml/min/gm. Although in this study reappearance of the tracer in the counting field was minimized; only after correction for recirculation did we obtain an excellent correlation up to the higher values of flow~9 ruling out the possibility of a barrier diffusion of Xenon at high flow rates suggested to account for the progressive underestimates at high flows.2~ The amount of tracer reappearing in the counting field becomes more important at high flow rates. This fact explains the different results obtained in studies exploring different ranges of flow. Reported differences can also be accounted for by the modality of changes of coronary flow (whether in proportion to cardiac output and ventilation). Furthermore, the use of a closed-chest or open-chest preparation introduces another considerable variable, because in open-chest dogs an appropriate collimation, limiting the presence of lung and pericardiac tissues in the counting field, can minimize reappearance of tracer. Monoexponential extrapolation of the portion of the curve recorded during the initial 30 sec., as proposed by Cannon,7's does not overcome this problem of tracer reappearing in the counting field, as the tracer washed out from the myocardium over this time immediately reappears in the heart cavities and in the lung. Thus, it immediately affects the slope of the washout curve to an extent proportional to the myocardial washout rate relative to cardiac output and lung ventilation. Certainly, estimates of flow based on the initial washout can be assumed to be correct when regional flow nonhomogeneity lower than about 3 is present and when recirculation is corrected for. In fact, the presence of a tonometer effect between myocardium and fat should have little influence on the initial portion of the curve, as in this period the tracer accumulation in fat is still relatively small. In conclusion, in contrast to the straightforward theory, the practical use of the method for measuring flow is seriously limited by the difficulty of meeting all the necessary assumptions. As discussed, the "limiting" factors can be over-

L'ABBATE AND MASERI

come by a series of corrections and expedients that, however, markedly complicate the application of the method. In spite of these problems, the use of precordial washout method in patients can give useful qualitative and semiquantitative information on regional myocardial perfusion, even independently of the quantification of myocardial blood flow under a rather restricted set of circumstances, which will be described in detail below. REGIONAL MYOCARDIAL PERFUSION

The development of instrumentation for detection by imaging devices has opened new perspectives for the evaluation of myocardial perfusion on a regional basis. Indeed, the possibility of detecting regional differences in perfusion independent of the absolute values of myocardial blood flow is of particular interest in coronary heart disease, a patchy disease in which the physiological meaning of an average value of myocardial blood flow is questionable because ischemia of one part of the myocardium may be compensated for by a variable increase of flow in the remaining healthy muscle. Xenon-133 has the advantage over potassium analogues of being able to give information on the direction of the changes of flow in different areas. In fact, while, a cold area in a 2~ or 43K scintigram cannot be ascribed to an inadequate regional increase of flow or to an actual reduction of flow, the two conditions can be easily distinguished by the washout method. Although the results obtained in humans and animals with 133Xetechnique clearly indicate that quantitative estimates are not warranted because of the unacceptable deviations from the theoretical assumptions, it may provide useful semiquantitative information on regional myocardial perfusion, as long as appropriate care is taken in the collection and interpretation of the data.

Technique Following intracoronary injection of 133Xe, regional myocardial perfusion can be evaluated by external techniques, according to two approaches: (1) static imaging of both the initial distribution and the residual activity at later times, and (2) dynamic recording of the time course of the regional washout curves.

XENON STUDIES OF MYOCARDIAL BLOOD FLOW

Static imaging by scinticamera allows the detection of the myocardial distribution of the indicator in the myocardium. When its distribution is flow-dependent (uniform mixing at the coronary inlet), information on the distribution of myocardial perfusion may be obtained under appropriate circumstances. With the imaging devices commonly available, the three-dimensional distribution of the isotope is condensed into a two-dimensional one that constitutes the myocardial scintigram in a given projection. The detected activity for any area of the scintigram depends on (1) the amount of muscle in the solid angle outlined by each area; (2) the geometrical efficiency with which it is seen by the detecting system; and (3) its flow per unit mass (if the myocardium is perfused only by the injected vessel). The first two factors cannot be determined experimentally with sufficient accuracy, but if they are assumed to remain constant in successive measurements, changes in the distribution of activity on repeated scintigrams should reflect proportionate average changes of the regional flow, if poor mixing at the injection site, resulting in preferential streaming of the indicator, can be excluded. Thus, static imaging can be applied to the study of the relative change of the distribution of regional myocardial perfusion in successive measurements when the myocardial distribution of the indicator is flow-dependent. Furthermore, if geometry remains constant, comparison between the regional initial activity and the residual activity at any given time provides information on the fraction washed out from each region up to that time. Moreover, the amount of tracer removed from each region can be related to regional capillary perfusion if tracer accumulation in extracardiac tissues or epicardial fat can be excluded or taken into account. Areas that include epicardial fat may be identified on scintigrams taken 15-20 min after 133Xe injection, when the flow-dependent tracer washout from the myocardium should be complete (Fig. 4). Dynamic recording of ]33Xe washout provides direct information on regional perfusion per unit mass of myocardium when the assumptions outlined above are met. Because of the interest in detecting areas of reduced flow, we consider it

7

INITIAL

15 rain

Xe

/) Tc

Tc

Fig. 4. l ~ X e scintigram immediately after the injection (left) and 15 rain after the injection (right). The initial scintigram reflects flow distribution while the latter scintigram shows l~Xe accumulation in epicardial fat. Reference scintigram obtained by m"Tc microspheres.

essential to not confine the analysis of the washout curve to its initial portion. Both for static imaging and for dynamic recording, the constancy of the spatial relation between the detecting device and the heart during the course of the measure is essential. With static imaging, changes in geometry make the qualitative interpretation of successive scintigrams difficult and a quantitative evaluation impossible. With dynamic recording, the cyclic changes of the volume of the heart contribute to the blurring of the image but do not hamper measurement, because the time constant of the cardiac cycle is short compared with the course of the washout curve. 23Changes in the pattern of breathing (and hence of heart position) and movements of the patient may significantly distort the washout curve by altering the relation between the heart and the detector. Thus, the use of an indicator capable of providing a continuous reference of the spatial position of the myocardium appears desirable both for successive static imaging and for prolonged dynamic regional washout studies. As a continuous reference of the spatial position of the myocardium during the injection and washout of 133Xe, we

8

L'ABBATE AND MASERI

....,.,....]

...-:...

: ..,,

-.

&. ' : - ' Z ' " " . . ' - . - - ' - . , , .

.'..

57 26% 0

,.

". 1

56 <10% 2 min

0

. '... 1

'..

46 16% 0 I

100-

] / 10 /

-

"

..,

42 ,. 36% 2 min. ......... 0 I

-.

44 ".. 48% ".. 0 1 2into

2 rnin ..........

. .. 2 min i

--

._

9

47 " 30% 0 I 2 min. ..........

"

iiiii'i

~50

44 ".. | :34% " . x'lO ........ 0 1 2 m i a ............ r, ( : il i(ii*~iiii*~i

Fig. 5. Simultaneous t i m e - a c t i v i t y curves of m"Tc and ~=Xe in semilogarithmic scale for the nine areas of interest at rest. Each dot represents the activity in a 5-sec interval. A c t i v i t y of SSmTc remains constant over the whole time of the *=Xe washout. The washout is slower at the base, w h e r e the greater final *~Xe accumulation was observed.

used 9 9 m T c human albumin microspheres injected into the left coronary artery at the beginning of the study (Fig. 5). Patients with a long coronary main stem (in whom uniform mixing of indicator with blood is likely) with only one stenosis in the left anterior descending or circumflex coronary artery, are ideal candidates for assessing the potentiality of this technique. In fact, they represent experimental models designed by nature in whom, in each circumstance, an area perfused by normal vessels serves as a internal control relative to the poststenotic area.

Protocol At the beginning of the study, the patient is positioned in our laboratory under the gamma camera, and about 1 mCi of 99mTc labeled human albumin microspheres (15 #m average

diameter) is injected into the left coronary artery through a Judkins catheter. The microspheres, which remain fixed in the myocardium, are used as a marker for the spatial position of the myocardium and as a reference during the successive mXe static and dynamic regional studies. About 5 mCi of mXe, dissolved in 1 m saline and preloaded in the coronary catheter, is flushed with 5 m of blood in about 2-3 sec. The injection is made after the induction of hemodynamic changes when the intention is to study the changes in initial distribution, and it is performed just before the hemodynamic changes when the intention is to evaluate the effect of hemodynamic changes on the washout curve during the actual transient. These two approaches provide complementary information, which is essential when the changes of perfusion affect, to a considerably variable extent, different zones of myocardium included in the same areas of interest. Data acquisition is continued for about 15 min following the first mXe injection to locate areas with pericardiac Xenon fat accumulation and for 3-5 min for successive injections.

Data Processing The scintigram of the entire heart is automatically subdivided by the computer into nine areas of interest. The regional myocardial distribution of 133Xe is determined, after background subtraction, at three times: for 10 sec following the peak counting rate; for 15 sec at 10% residual activity, and for 60 sec about 15 min after the first injection. The mXe washout curves, after integrating the count rate over 5-sec intervals, are evaluated as follows: The half-time (t~/2) of the monoexponential that fits the washout curve from the peak down to 50% is calculated. The slope of this monoexponential is obtained by the least-squares method and is indicated as: bl = (0.693/h/2). In the cases in which, between 50% and 20% of the peak of the curve, there is a significant deviation from the initial exponential slope, a second exponential (b2) is calculated, which fits the curve from the point where the significant deviation begins down to the 10% point. The deviation is considered significant when the Chi-square, calculated between the experimental points and the

XENON STUDIES OF MYOCARDIAL BLOOD FLOW

monoexponential fit, systematically exceeds by three times the average value in the initial 50%. Recording over the initial 30 sec of the washout for the evaluation of regional differences of clearance rate, as performed by Cannon and co-workers7'8 is adequate when differences in flow within each area of interest do not exceed three but may altogether miss areas of severe ischemia that may be localized to only one segment of the myocardial wall during angina within any area of interest.

Limitations of the Technique Site of injection. For washout studies, selective injection of ~33Xe is to be preferred to the aortic injection used by Korhola, 1~ which, although providing better mixing for initial distribution studies, results in significant recirculation of the indicator and requires a very large dose. Furthermore, the simultaneous labeling of right and left ventricular myocardium complicates the interpretation of the washout curves in the areas of the scintigram that also include right ventricular myocardium, which is known to have a much lower flow per unit weight than the left. Counting geometry. 99mTchuman albumin microspheres, which are commonly used for myocardial scintigraphy, )4 are a suitable reference indicator for the identification and monitoring of the myocardial position during the course of ~33Xe study. In fact, when injected into a coronary artery, they remain fixed in the myocardium until biodegraded. The separation of the 99mTCand ~33Xegamma emission is good, and the contribution of 99mTc results in only a small rise in the 133Xe background level. We have observed significant variations in 99raTeactivity during the course of the washout curve in 5 instances out of 36 measurements. Constancy of geometrical relations is particularly required during hemodynamic measurements performed in different situations and when transients are induced during the course of the washout curve. The counting efficiency for 133Xedecreases by about 50% for every 5 cm of depth within the body. Also, the resolution is appreciably worse at 8 em depth than at 3 era. Thus, there is a greater possibility of observing regional differences in tracer behavior in the heart wall, which is closer

9

to the detector. For these reasons, large changes of perfusion occurring in a myocardial region far from the counter may be obscured by much smaller opposite changes in the wall closer to the detector. With the resolution of our instrumentation, the dimensions of the nine areas in which myocardial scintigrams are subdivided provide significant interference among adjacent areas. However, activity in one area is not appreciably affected by that of nonadjacent areas. Therefore, in the left anterior oblique projection, the activity in the myocardial territories perfused by the anterior descending and circumflex arteries can be adequately separated. Effect of tissue mass in the area of interest. Assuming that extracardiac activity during the course of the washout is more or less uniformly distributed, it will reduce the slope of the washout curve in the areas with little myocardial tissue (and hence a low initial activity) to a much greater extent than in the areas with a larger amount of myocardium (and hence a high peak activity). This is the case in scarred or aneurismatic areas of the heart wall, in which the washout slope will be artificially slowed down by the relatively important contribution of tracer reappearing in the containing field. Analysis of the data. Initial washout was chosen because it can be considered predominantly representative of tracer and is washed out faster. Residual activity in each area, when ~33Xe activity in the whole scintigrams has decreased to 10% of its peak value, was taken as representative of tracer behavior in poorly perfused myocardium. Indeed, this dual approach appears to provide the best separation of the washout behaviour in areas distal to a critical stenosis, as compared with those perfused by normal vessels, for a comparable degree of ~33Xe accumulation in the 15-min scintigram, t2 The evaluation of the regional t33Xe washout curves over a fixed percentage of the peak (the slope down to 50% of the peak) rather than at a fixed time, as performed by Cannon and colleagues, 7'8 presents the advantage of normalizing the individual variability of myocardial blood flow, which is quite large in relation to the large variability of factors that determine myocardial oxygen demandsY The level at which the curve deviates from the monoexponential fit, of the initial 50% of the

10

curve and the slope of the exponential that fits the second part of the curve are calculated only with the intention of providing a semiquantitative estimate of the nonuniformity of the washout in each selected area. Multicompartimental analysis 9 does not seem warranted because mXe exchange with epicardial fat takes place in two temporally separated phases (away from and back to the myocardium) according to the direction of net tracer flux, and accumulation of 133Xeinto extracardiac tissues (especially the lung) contributes less to the initial than to the final part of the curve. 5 On the other hand, stochastic analysis cannot be applied, because these washout curves can in no instances be followed down to zero nor to 1% of the peak (which, according to model simulations 4"~9could be considered adequate for this purpose) because of tracer recirculation and retention in epicardial fat.

Effects of nonmixing and/or collateral flow. When there is inadequate mixing of the tracer with blood in the coronary before the first branching point or when there is significant collateral flow, the initial tracer distribution no longer reflects the distribution of blood flow. The regional washout curves reflect correctly myocardial blood flow only when perfusion of each area is homogeneous. In the presence of significant differences in perfusion in the myocardium included in the solid angle of each area, the initial slope of the washout curve will predominantly reflect the flow to the tissue to which the tracer was preferentially distributed. Interpretation of the results. For areas in which the 15-min 133Xeresidue is negligible, the initial slope of the washout curve may allow the estimation of average flow per gram of myocardium when perfusion is h o m o g e n o u s or uniformly distributed in a range of 1-3. However, also in this case, recirculation of the tracer will lead to a systematic underestimation of flow, which will be greater with higher flow. Flow can be considered homogeneous or uniformly distributed about a mean value with a rather small dispersion when the washout follows a monoexponential course down to 1% of the peak. The presence of a deviation from a monoexponential course in the intermediate part of the curve is suggestive of a markedly skewed or bimodal distribution of flow and/or of appreciable tracer

L'ABBATE AND MASERI

recirculation or fat retention. When flow is markedly nonhomogeneous, 27"28the initial monoexponential extrapolation overestimates average flow because the indicator, injected as a bolus, is predominantly distributed to the well-perfused tissue. The extent of the overestimate depends on the magnitude of the flow difference to the various parts of the myocardium included in each zone and on their relative size. The values obtained in normal subjects by the Xenon washout and the initial slope method approximate 60 m l / m i n / 1 0 0 gm, 1'5'28 which is a lower figure than those reported with nitrous oxide (85 m l / m i n / 1 0 0 gm I) and much lower than those reported with tritiated water (111 and 97 ml/min/100 gm 29"3~ and antipyrine (128 m l / m i n / 1 0 0 gmS). In our findings, correction for tracer reappearing in the counting field increased flow values from 74 to 85 m l / m i n / 1 0 0 gm. 5 In initial reports, the values obtained in patients with coronary artery disease showed quite a considerable scatter without any consistent difference from normals at rest. ~'31-34 Also, the results obtained during pacing-induced tachycardia were discordant. 35'36 Lower values were obtained in patients with cardiomyopathy and normal coronary angiograms in proportion to the reduced contractility, but flow did increase during pacing. 37 These findings suggest that a low basal flow value can be related to a reduced contractility. Flow values were also considerably lower in patients with severe aortic stenosis and heart failure) 8 Thus, it is difficult to interpret whether the relatively low values obtained in some patients with C H D 39 are related to the extent of coronary obstruction per se limiting resting flow or to reduced myocardial demands. In fact, we found that the values obtained in patients with ventricular failure from myocardiopathy and from CHD were comparable and showed a similar smaller increase than normals during pacing, suggesting that in both cases the myocardial demand, rather than the coronary supply, was reduced. 4~ Preliminary data indicate that in some patients with normal coronary arteries and angina, flow increases considerably less during pacing relative to controls 4~ suggesting the possible cause of functional factors impairing perfusion in the genesis of angina besides the traditional cause of

XENON STUDIES OF MYOCARDIAL BLOOD FLOW

11

severe organic lesions of the large arterial branches preventing the increase of flow. This may represent a fruitful field for application of the technique.

patients. Thus, a reduction of myocardial oxygen demand in these areas might be responsible for the decreased flow. Our findings, obtained in a very selected population under strictly controlled circumstances, indicate that, at rest, only minor areas of markedly reduced clearance can be found distal to a critical stenosis. This conclusion can be inferred from the fact that, while the initial slopes in normal and poststenotic areas were not significantly different, the residual activity at 90% washout in areas with comparable final fat accumulation of Xenon was often higher in poststenotic regions of interest, indicating the presence of a compartment of small dimensions with markedly slower washout (Fig. 6). The interpretation of these findings is once more difficult without independent information on the characteristics of the tissue in these regions of interest.

REGIONAL MYOCARDIAL PERFUSION: SURVEY OF RESULTS IN HUMANS

Results at Rest Regional estimates of perfusion are essential in patients with CHD because of the patchy nature of the disease. The regional variability of Xenon clearance rates was found to be greater in the presence of severe CA s t e n o s i s 12'42'43 in agreement with data obtained from outflow detection methods.26.44 However, at rest and in patients without previous myocardial infarctions, the reduction of regional myocardial perfusion was not necessarily correlated to the location of the stenosis. In the presence of an old myocardial infarction, the activity will be reduced in the region of interest, including the infarcted area, because of the loss of myocardial tissue. Therefore, the contribution of tracer reappearing in the counting field will reduce the slope to a greater extent than in normal regions. In the absence of myocardial infarction, a reduction of flow was commonly observed relative to control regions only distal to occluded vessels in the presence of dyskinesia. The interpretation of this finding is again difficult: If flow is already reduced in resting conditions because of insufficient collaterals, ischemia should ensue for any minimal level of exertion, but this is not supported by the increase of flow observed in the same regions during pacing and by the frequent finding of a good exercise tolerance in these

Results During Hemodynamic Stimulations During pacing-induced angina, regional differences in perfusion between poststenotic and normal regions of interest become apparent. These differences can be detected both as regional deficits in the initial distribution of t h e tracer when the injection is made after the induction of ischemia, and as changes in the regional washout slopes when ischemia is produced just after the injection of the tracer (Figs. 7 and 8). 12'13 It appears obvious that, when the injection is performed during the period of established ischemia, the relatively small amount of tracer in the cold areas as evidenced in the initial scintigram, cannot contribute adequately to the washout when the differences

t.5 INITIAL W A S H O U T

REGIONAL RESIDUAL ACTIVITY

SLOPES

sec:

%

60

14 O O

=o

40 Fig. 6. Comparison of the washout rate of ~ X e from Control and poststenotic areas at rest. While no appreciable difference is present in the tl/2 of the initial slope, in four cases a higher residual activity is present in the poststenOtic areas in comparison with the control areas.

g 20

6

'

2b

'

4b

'

6'o,..,

CONTROL AREA

'

I()

'

I~$

%

CONTROL AREA

12

L'ABBATE AND MASERI

9"...'"..'...'.'....."

I!

........'"~

...'...

"'.

.-'..,.-....

II

ill

Ill

i 9

1

-.

9

, I Illll

j#iifiiiiifiii~ii~i~iiiiiii{~i

1

, ~iliiiiiiiillJlljJiljiiiJiiiji

II rain

!iiili!11t llI'llil!!llflllllli

.'.'..'3".'"3...'..+..'. 9

,.,.." '....../.."."...

!!

II 41'~

IIs

, lJJ#iJJiJJJJJJJJJiJJJliiJJijjJ 9...

9

:!::lI l:=~i~l:lt:!l~l::illiil|l

9

f #i!!!!!!!ii!!JiiiJiJiil!!!!i!ii

,.-

....

........'%..

II

"'.

14 I1~

"'.,.

i

O

.

1

9

0

tmle

5 - "

!JJJJJiiiJi!JlJiJiiJfiJJiJJiiii

.. l||Jl.Jl.'Jl-JJiill~lJiJJiJiil

..

t roll

....

iJ~iiiiiJ|!.~!!ii|lii~lJiii~llii

".'.'"

"--'....'-,...

:III

118:

Wl

""

14

""

II

41% o

1

.

I

ml~

!! ! !! !! !1.!t !.-'.!-t_l!I !l( - i..-'i.{l..'.l{

o

-. 1

!

mia

iiiiii!liii!!!iiiili~ilili!iiii

in flow within the region of interest exceed a factor of about three, which is quite likely considering the tridimensional structure of the heart walls. Thus the lower washout rates found in poststenotic areas in these conditions are likely to underestimate the differences in flow from control regions. Indeed, in studies in which ischemia was induced immediately after the tracer was distributed to the myocardium (presumably uniformly, as the injection was performed in

Fig. 7. Regional washout curves obtained during pacing-induced angina in a patient with critical stenosis of the left anterior descending artery. In the anterior apical and center areas, the washout is fitted by a monoexponential down to 2 0 % of the peak, and it is clearly slower than the initial washout in the circumflex areas 9 In all areas, the washout was faster than during control 9 (Reproduced with permission from Cardiovascular Research. 13)

resting conditions) the washout slope in the poststenotic regions actually became slower than in the preischemic period, sometimes to a remarkable extent. ]2'~3This applies also to studies based on the injection of vasodilator drugs. Our studies showed that the response to intracoronary carbochromer in patients with one single stenosis could be interpreted differently according to whether the injection was performed during the Xenon washout or before and whether or not the tails of the curves were analyzed. 45 Xenon injec-

XENON STUDIES OF MYOCARDIAL BLOOD FLOW

13

9 ....

'.

9 ". 9149 '. 9149149

.' 9 9 ..

". 9149 ".""

9 .9

........'.,

9

9

",j

"0

1

'.2...'.- 3min-0

1 -+ 2

3min

I ~+m...++.++++..+++.+.++iii+r,"+i i~+!+!!!!!+!!!!+!!!++!!!+++'+'!++++!+++++++! , iiiijJJflJJJJJ.ijjmJJJJJiilliiiJilliJJiiii: IInltt!!!!t!!!Jll!!!ml!!illllllUllt(!!

9 .'...

- . 9149 . 9149149149149149,..'.'"

5'"1

.... 9 ' , 9149149149

... 9

LAP.

G

%..

.1

~

%

~ 90

1

2

..

..

1

0

" "3-min

|iiiijiiijiii~iiiiiiiiiiiiiiiiiiiiiiiiiii

! mii~iii++~7+mm!+iii+mi.mmiiiiii .,. 9149149

9

-.. " 9

{ .,,..'""....".".'..-.""

"39 ",

4.

9, "

"0 Fig. 8. Alterations of regional curves, in the same patient as in Fig. 7, during pacing-induced angina. Xenon-133 was injected in control conditions. A t the arrow, the heart rate was suddently increased to 150 and, after a f e w beats, S - T depression in leads V=-Ve appeared, followed by chest pain. A f t e r the initial sudden change, counting geometry remained stable 9 The slopes became faster in the circumflex areas and slower in the anterior apical and central areas. (Reproduced with permission from Cardiovascular Research, TM)

1

++...+,,

2

+'iiiiiiiiifl+ljiiiiij||liiiijiiJiiiifiii :i_!. ~--~--'~!!--Jlllm='l ....... IIIII

.......

9

. ......9

.- . ......-

.... ....

..

9

". 9

,...

3min

0

! ~it!!H..r162162

1

2

9

.,......'.'"'.'.'.,.-'...i

9

3minO

:i+iiiJiiiiiiiir162 ...,..+"

3min

*I11

, "+.

2

1

" 2

3min

! miiiiJJii+!ttiii!t+iiiiiildit .... 9 ..,...,

..

'.,.+...'.............

O0

.'.+'..

100:

~7f %

""J

50

~!

9149149

501

I "'-.%

+"., "'%'...

10 . . . . . . .

"0 J

tion during the washout produced a much lesser increase of the washout rates than did a subsequent Xenon injection performed later when vasodilatation was still present, as indicated by the typical persistent electrocardiographic S-T, T wave changes. In addition, in the latter injection, marked deviation from monoexponential course was apparent at the end of these curves. These findings suggest a selective vasodilatation of some layers of the myocardium, which, in the

1

2

|dlfl!!l||!liiflfl~!iii

3rain" 0

10 1

2""" " .3min

i~;i:;, ! ;~![r

injection following the vasodilatation, were preferentially tagged, thus contributing predominantly to the washout, whereas the layers with lower flow contributed to the observed slower washout when the drug was injected during the washout of Xenon. Therefore, the correct application of this method requires a sophisticated approach. When initial distribution studies are to be performed, adequate mixing at the injection site is essential

14

L'ABBATE AND MASERI

but cannot be verified. When only initial slopes are considered, differences in average flow among areas of interest may be largely underestimated when heterogeneity of flow within the same region of interest exceeds about three. When the tail of the curve or the alterations in the washout produced by an intervention immediately after the injection of the tracer have to be analyzed, it is essential to have an intramyocardial reference tracer such as technetium microspheres.

PERSPECTIVES

On the basis of the results of studies designed to reassess the possibilities and limitations of this technique, it seems fair to conclude that, due to the limitations discussed above, this technique will not have a place for routine use in the evaluation of the coronary patient, but it is valuable for the study of special research problems. It can be used to obtain measurements of myocardial blood flow only in specially designed experiments, when the assumptions of the

method are strictly met. Current studies in humans are valuable in the assessment of regional differences in flow from initial washout rates, when perfusion in each region of interest does not differ by more than a factor of three as long as the reappearance of indicator in the counting field is adequately corrected for. When a region of interest includes myocardial zones with widely different flow rates, the mean flow will be overestimated from measurements of the initial slope. It is suited for the study of changes in the regional distribution of perfusion, as long as the possible occurrence of large nonhomogeneities of flow within areas of interest is considered. When perfusion is reasonably uniform within the solid angle of each region of interest, flow changes can be estimated from changes in the initial washout slope. When perfusion is not uniform, it is necessary to also assess the changes in the initial regional distribution of the tracer (assuming adequate mixing at the injection site) and in its residual activity, because estimates from the initial washout slope reflect predominantly the flow to the better-perfused zones.

REFERENCES

1. Ross RS, Ueda J, Lichtlen PR, et al: Measurement of myocardial blood flow in man by selective injection of radioactive inert gas into the coronary arteries. Circ Res 15:28-41, 1964 2. Pitt A, Friesinger GC, Ross RS: Measurement of blood flow in the right and left coronary artery beds in humans and dogs using the t33Xenon technique. Cardiovasc Res 3:100106, 1969 3. Bassingthwaighte JB, Strandell T, Donald DE: Estimation of coronary blood flow by washout of diffusible indicators. Circ Res 23:259-278, 1968 4. Maseri A: Myocardial flow by precordial residue detection following intracoronary slug injection of radioactive diffusible indicators, in Maseri A (ed): Myocardial Blood Flow in Man. Methods and Significance in Coronary Disease. Torino, Minerva Medica, 1972, pp 145-156 5. Maseri A, Pesola A, L'Abbate A, et al: Contribution of recirculation and fat diffusion to myocardial washout curves obtained by external counting in man. Stochastic versus monoexponential analysis. Cire Res 35:826-834, 1974 6. Maseri A, Mancini P, L'Abbate A, et ak Methods for regional dynamic study of myocardial blood flow in man. J Nucl Biol Med 15:54-57, 1971 7. Cannon P, Dell RB, Dwyer EM Jr: Measurement of regional myocardial perfusion in man with 133 Xenon and a scintillation camera. J Clin Invest 51:964-977, 1972 8. Cannon P, Dell RB, Dwyer EM Jr: Regional myocardial perfusion rates in patients with coronary artery disease. J Clin Invest 51:978-994, 1972

9. Holman BL, Adams DR, Jewitt D, et al: Measuring regional myocardial blood flow with t33Xe and the Anger camera. Radiology I 12:99-107, 1974 10. Korhola O: Myocardial scintigraphy and estimation of regional blood flow with Xenon-133. Acta Radiol (Suppl) (Stock) 337: 3-63, 1974 I I. Cannon P J, Sciacca RR, Fowler DL, et al: Measurement of regional myocardial blood flow in man: Description and critique of the method using Xenon-133 and a scintillation camera. Am J Cardiol 36:783-792, 1975 12. Maseri A, L'Abbate A, Pesola A, et al: Regional myocardial perfusion in patients with atherosclerotic coronary disease at rest and during pacing induced angina. Circulation 56:423-433, 1977 13. Maseri A, L'Abbate A, Michelassi C, et al: Possibilities, limitations, and technique for the study of regional myocardial perfusion in man by Xenon-133. Cardiovasc Res 11:277-290, 1977 14. Lichtlen PR, Engel H J, Hundeshagen H: Regional myocardial blood flow in normal and poststenotic areas after nitroglycerin, beta blockade (atenolol), coronary dilation (dipyridamole) and calcium antagonism (nifedipine). Herz Kardiovask Erkrank 2:81-86, 1977 15. Kety SS: Theory and applications of exchange of inert gas at lungs and tissues. Pharmacol Rev 3:1-41, 1951 16. Zierler J L : Equations for measuring blood flow by external monitoring of radioisotopes. Circ Res 16:309-321, 1965

17. Corm HL Jr: Equilibrium distribution of radioxenon

XENON STUDIES OF MYOCARDIAL BLOOD FLOW

in tissue: Xenon-hemoglobin association curve. J Appl Physiol 16:1065-1070, 1961 18. Shaw D J, Pitt A, Friesinger GC: Autoradiographic study of the mXenon disappearance method for measurement of myocardial blood flow. Cardiovasc Res 6:268-276, 1972 19. L'Abbate A, Maseri A, Ballestra AM, et ah Effect of inhomogeneous perfusion and recirculation on precordial measurements of myocardial blood flow by inert gases. Theoretical and experimental evaluation. (submitted for publication). 20. Maseri A: Correction of recirculation in regional blood flow studies by residue detection: J Appl Physiol 36:375-378, 1974 21. Hirzel HO, Krayenbuehl HP: Validity of the 133Xenon method for measuring coronary blood flow. Comparison with coronary sinus outflow determined by an electronic flowprobe. Pfliigers Arch 349:159-169, 1974 22. Seiacca RR, Weiss MB, Blood DK, et ah Comparison of regional myocardial blood flow measurements with ~33Xe and radioactive microspheres in dogs with coronary artery constrictions. Cardiovas Res 13:330-337, 1979 23. Zierler KL: Theory of measurement of myocardial blood flow in man by use of indicators and tracers, with consideration of assumptions and their violation in practical problem arising in special cases, in Maseri A (ed): Myocardial Blood Flow in Man. Methods and Significance in Coronary Disease. Torino, Minerva Medica, 1972, pp 89-119 24. Grames GM, Jansen (2, Gander MP, et al: Safety of the direct coronary injection of radiolabelled particles. J Nucl Med 15:2-6, 1974 25. Braunwald E: The determinants of myocardial oxygen consumption. Thirteenth Bowditch Lecture. Physiologist 12:65-93, 1969 26. Kloche F J, Wittenberg SM: Heterogeneity of coronary blood flow in human coronary artery disease and experimental myocardial infarction. Am J Cardiol 24:782790, 1969 27. McGregor M: Significance of myocardial flow measurements in the evaluation of the coronary patient, in Maseri A (ed): Myocardial Blood Flow in Man. Methods and Significance in Coronary Disease. Torino, Minerva Medica, 1972, pp 287-295 28. Lichtlen P, Nocetti I, Halter J: Myocardial blood flow in man as shown by the myocardial Xenon-clearancetechnique, in Maseri A (ed): Myocardial Blood Flow in Man. Methods and Significance in Coronary Disease. Torino, Minerva Medica, 1972, pp 310--320 29. Klassen GA, Agarwal JB, Jansen PH, et al: Blood flow and tissue space of left coronary artery in man. Circ Res 27:185-195, 1970 30. L'Abbate A, Biagini A, Michelassi C, et al: Myocardial kinetics of Thallium and Potassium in man. Circulation (in press).

15

31. Klein MD, Cohen LS, Gorlin R: Krypton 8s myocardial blood flow: Precordial scintillation versus coronary sinus sampling. Am J Physiol 209:705-710, 1965 32. Holmberg S, Paulin S, P[erovsk~, l, et al: Coronary blood flow in man and its relation to the coronary arteriogram. Am J Cardiol 19:486-491, 1967 33. Baltaxe HA, Formanek G, Loken M, et ah Clinical limitations to the use of Xenon for measurement of myocardial blood flow. Invest Radiol 4:317-322, 1969 34. Rudolph W, Hegemann M: Utility and limitations of myocardial perfusion measurements with radionuclides using a probe detector. J Nucl Biol Med 16:254-258, 1972 35. Conti CR, Pitt B, Gundel WD, et al: Myocardial blood flow in pacing-induced angina. Circulation 42:815825, 1970 36. Holmberg S, Varnauskas E: Coronary circulation during pacing-induced tachycardia. Acta Med Scand 190:481--490, 1971 37. Weiss MB, Ellis K, Sciacca RR, et al: Myocardial blood flow in congestive and hypertrophic cardiomyopathy: Relationship to peak wall stress and mean velocity of circumferential fiber shortening. Circulation 54:484-494, 1976 38. Johnson LL, Weiss MB, Ellis K, et ah Reduced myocardial blood flow in aortic stenosis. Circulation 52:II139, 1975 39. Cannon P J, Weiss MB, Sciacca RR: Myocardial blood flow in coronary artery disease: Studies at rest and during stress with inert gas washout techniques. Prog Cardiovasc Dis 20:95-120, 1977 40. Maseri A, L'Abbate A, Contini C, et al: Myocardial blood flow in ischemic heart disease, in Bartorelli C, Zanehetti A (eds): Cardiovascular Regulation in Health and Disease. Milan, Cardiovascular Research Institute, 1971, pp 225-234 41. Dwyer EM Jr, Dell RB, Cannon PJ: Regional myocardial blood flow in patients with angina and normal coronary arteries. Circulation 46!II-6, 1973 42. Cannon P J, Schmidt DH, Weiss MB, et al: The relationship between regional myocardial perfusion at rest and arteriographic lesions in patients with coronary atherosclerosis. J Clin Invest 56:1442-1454, 1975 43. Cannon P J, Dell RB, Dwyer EM Jr: Regional myocardial perfusion rates in patients with coronary artery disease. J Clin Invest 51:978-994, 1972 44. Klocke F J, Koberstein RC, Pittman DE, et ah Effects of heterogeneous myocardial perfusion on coronary venous H2 desaturation curves and calculations of coronary flow. J Clin Invest 47:2711-2724, 1968 45. Maseri A, Pesola A, Contini C, et ah Localized functional reduction of myocardial perfusion in angina pectoris. Possible role of a "steal effect." Acta Cardiol Suppl 19:135-146, 1974