- Email: [email protected]
Radionuclide determination of myocardial blood flow
Radionuclide Determination of Myocardial Blood Flow F. J, Bonte, R. W. Parkey, E. M. S t o k e l y , S. E. Lewis, L. D. H o r w i t z , a n d G. C. C u r r y The diffusible-indicator method of determining tissue blood flow was devised by Kety and his associates, 1-3 who observed the washout of an intraarterially injected tracer from the tissue of interest, and found that it was proportional to tissue blood flow. Kety's original tracer was nitrous oxide, but he soon adapted his method to the use of 24Na. Other investigators developed Kety's method further, substituting SSKr, and ultimately, 133Xe as diffusible indicators. It has been found that if 133Xe is injected directly into a coronary artery and its washout from myocardium is observed with a scintillation probe over the precordium, the resulting determination, mean myocardial blood flow, is of limited application. Since coronary artery disease is a regional process, the most useful determination ~s one that yields regional myocardial blood flow. This may be determined by one of the original Kety methods, 3 i.e., observing the washout of tracer injected directly into the myocardium, but since it requires thoracotomy this method is not widely applicable. Several groups have assembled instrument systems based on the use of scintillation camera-computer combinations with which they can enter the image of the passage of a bolus of intracornoary arterially injected
I
tracer, and by means of image data quantification derive regional myocardial blood flow values'by Kety's method. The authors have studied more than 130 dogs before and after experimental coronary embolization and have described a complete method of deriving regional myocardial blood flows with an Anger camera-small computer system. Analysis of flow curves thus generated has suggested the existence of more than one compartment within myocardial blood flow. These compartments might be related to primary/collateral flow or to the volume of perfused tissue incorporated in the region of interest. Cannon et al. 2s-27 have employed a multicrystal camera of the autofluoroscope type and an IBM 360/91 computer, in which the camera functions as 294 isolated detectors for the purpose of identifying as many regions of myocardial bTood flow. Cannon et al. have studied both normal human subjects and patients with radiographically demonstrable coronary artery disease and have found regional flow to be a valid method both for identifying the myocardial flow inhomogeneities expected with coronary artery disease and for evaluating the results of reparative surgery.
N 1945, Kety and Schmidt devised their n o w classic m e t h o d of measuring cerebral blood flow with a diffusible indicator, 1 and in 1948 Kety and his
From the Departments of Radiology and Internal Medicine, The University of Texas Southwestern Medical School at Dallas, Dallas, Tex. 75235. Supported in part by Research Grants HLO518Z and HLI3625, and Training Grant CA05136 from the ational Institute of Health, USPHS, and in part by a Grant from the Southwestern Medical Foundation. F. J. Bonte, M.D.: Professor and Chairman, Department of Radiology; R. W. Parkey, M.D.: Assistant Professor, Department of Radiology; E. M. Stokely, M.D.: Instructor, Department of Radiology; S. E. Lewis, M.S.E.E., Department of Radiology; L. D. Horwitz, M.D.: Assistant Professor, Department of Internal Medicine; G. C. Curry, M.D.: Assistant Professor, Department of Radiology, University of Texas Southwestern Medical School at Dallas, Dallas, Tex. 75235. Dr. Parkey is a Scholar in Radiological Research, James Picker Foundation, NAS-NRC. Dr. Curry is a former Scholar in Radiological Research, ]ames Picker Foundation, NAS-NRC. 9 1973 by Grune & Stratton, Inc. Seminars in Nuclear Medicine, VoL 3, No. 2 (April), 1973
153
154
BONTE ET AL.
associates applied this new technique to the estimation of blood flow in the myocardium.2 In these initial experiments they employed nitrous oxide as their indicator, but in 1949 Kety substituted ~4Na and described the first practical method of blood flow measurement using a radionuclide tracer. 3 In succeeding years several groups 4-11 elaborated further on Kety's work and developed alternative techniques for myocardial blood flow measurement in which the investigator either injected a diffusible tracer into a coronary artery or into the substance of the myocardium itself. In each case a radiation detection system was used to measure the disappearance, or "washout" of radiocativity, because Kety had shown that the rate of washout was a function of tissue blood flow. 1-3 Radiosodium and several other cation tracers soon gave way to the radioactive noble gases 85Kr and 133Xe for the two distinct advantages the latter provides (1) The fat-soluble gases are capable of diffusing much more rapidly through capillary endothelium into surrounding tissues, and thus can be used to measure far higher rates of blood flow than is possible with water-soluble cations, and (2) approximately 95% of a noble gas tracer bolus enters alveolar air at the first circulation through the lungs. Blood flow washout curves (see Fig. 1) are thus free of secondary peaks due to recirculation of tracer. Also, one can inject successive doses of tracer with very little build-up in background radioactivity. The tracer of choice has become l~3Xe, and most of the work described herein will have been done with this radionuclide. (183Xe: physical half-life = 5.27 days; 3' = 0.08 MeV; E~ = 0.1 MeV). Let us examine a representative procedure and see how blood flow is derived from radionuclide washout. Let us assume that a catheter has been placed in a coronary artery and a bolus of 133Xe dissolved in normal saline is injected through it. A scintillation detector, such as a probe or a scintillation camera, is in place over the precordiurn. Radioactivity observed by the detector will be plotted as in Fig. 1, with counts recorded on a logarithmic scale along the ordinate, and time on an ordinary scale along the abscissa. As the bolus of 133Xe appears within view of the detector there is a sharp rise in recorded radioactivity (the A limb of the curve in Fig. 1). When the bolus reaches the capillary bed of the myocardium, the freely diffusible
B
== 8
TIME
Fig. 1. Curve recorded after intra-coronary-arterial injection of a diffusible indicator, such as 133Xe. Data are plotted on a semi-logarithmic scale showing counts (amount of radioactivity) as a function of time after injection. A designates the limb of the curve which represents the arrival of tracer in the vascular bed of interest. B represents blood clearance of indicator from tissue, or "washout." C, the "tail" of the curve, represents washout of tracer from epicardial fat, and other functions which are discussed in the text.
RADIONUCLIDE DETERMINATION
155
c! Iz Fig. 2. Method of deriving k, the rate constant, from the straight-line portion of the washout curve. Times T1 and T2 are selected so that the curve between them is as close as possible to a straight line. C, and C2 are counts at times T1 and T2
8 %
..... L ....
T!
k T2
TIME
xenon leaves the capillary vascular space to enter muscle and fat cells, which compose the heart wall. The exchange takes place in relation to Solubility of 133Xe in myocardial muscle (or fat) ~A. Solubility of laaXe in blood The partition coefficient is X. For 13aXe in myocardium it is usually given as 0.72, lz while for fat it is very high, 8.0.11 After the crest of the bolus passes, the blood which follows it contains less tracer than do the tissues surrounding capillary vessels, and the tracer begins to diffuse from tissues back into the vascular space at a rate proportional to blood flow. You wil lnote that the early portion of the curve describes a nearly straight line on the semilogarithmic scale on which it has been plotted (B limb, Fig. 1). It is this portion of the curve most investigators believe to represent myocardial blood flow. Blood flow may be calculated from the washout curve by one of several methods. The original one is the Kety-Schmidt equation
r = (k) (x) (zo0)/p, where F is blood flow, and ~ is the partition coefficient (see above). The rate constant k is derived from the washout curve in the manner described below. The Kety-Schmidt equation is based upon a known volume of tissue perfused, but inasmuch as the volume of myocardium perfused in any individual determination is not known, blood flow is expressed in terms of an arbitrary 100 g of tissue, which is converted to volume by dividing by p, the specific gravity of myocardiurn (volume -- mass/specific gravity). The value of p is 1.05. Therefore the units in which blood flow (F) is expressed will be milliliters/minute/100 g of myocardium. The rate constant k is the slope of the washout curve. It is derived from the semilogarithmic data plots as in Fig. 2, using the equation k - - log C 1 - 1 o g 0.434 ( T 9 ~
Cz T 1)
'
where times T 1 and T ~ (see Fig. 2) are selected so that the curve between them is as close as possible to a straight line. C i and C ~ are counts at times T 1 and T ~, respectively (Fig. 2). The factor 0.434 must be used to convert
156
BONTE ET AL.
r lz O o
B2
\ TIME
Fig. 3. Mathematical treatment of some myocardial blood flow c u r v e s suggests two different flow rates or "compartments" in the myocardial washout (B, Fig. 1) portion of the curve. These are represented by tangents drawn parallel to appropriate segments of the curve, and identified as B1 end B2.
logarithm-to-the-base-10 data so that they may be used in a log-to-the-base-e equation. It represents logl0e. It is evident from examination of the curve in Fig. 1 that several functions are expressed. The steep portion of the washout curve (B limb) is assumed to represent myocardial blood flow, but the origin of the long tail (C limb, Fig. 1) has not been completely solved. It is believed to reflect, in part, washout of tracer from epicardial and body wall fat, and clearance of Xe from the lungs. Although 95% of the tracer bolus of 133Xe leaves blood and enters alveolar air on its first passage throgh the lungs, it is cleared from the lungs at a much slower rate. We have measured the x3SXe pulmonary clearance half-time in dogs as 108 - 35 sec. It is quite likely that there are other factors, as yet unknown, that participate in the formation of the tail of the washout curve. If the data comprising the myocardial blood flow curve are treated by a mathematical process known as compartmental analysis, 13 flow "'compartments" can be found corresponding to the B and C limbs. However, under some circumstances the B limb itself can be resolved into two different slopes yielding two different flow rates, or compartments. 14"1s This situation, which is analogous to renal blood flow measured with diffusible indicators, le is illustrated in Fig. 3, where B1 and B2 represent mathematically identifiable compartments within myocardial blood flow. This phenomeonon will be discussed further in a later section. An alternative method of flow curve data treatment is that of Zierler. 18 In this method the area under the washout curve is divided by its height. This scheme has been applied successfully to the calculation of cerebral blood flow but it has as yet been little used in myocardial flow calculations. Excellent discussions of the available methods of flow curve data treatment are to be found in the papers of Bassingthwaighte and his associates. 1~176A detailed discussion of some of the problems in the methods can be found in the article by Pachinger and Bing in this issue. Let us now consider several methods presently used to determine myocardial blood flow. MEAN MYOCARDIAL BLOOD FLOW
If a bolus of a diffusible indicator, such as 183Xe, is injected through a catheter into a coronary artery, a disappearance curve can be recorded with a scintillation probe placed over the precordium. Flow measurements calcu-
RADIONUCLIDE DETERMINATION
157
lated from curves of this sort have been termed total or mean myocardial blood flow. The resultg Of mean flow determinations have been disappointing, since they often yield overlapping flow values and thus fail to distinguish between patients with radiographically demonstrable coronary artery disease and individuals with radiographically normal coronary vessels. The best explanation seems to be that coronary artery disease in relatively small areas of myocardium may Cause severe symptoms and disability even though flow is normal throughout the remainder of the myocardium. However, since most of the indicator washout is occuring in the undamaged areas, mean myocardial flow may still be within the normal range. It has therefore become clear to most investigators that a method must be devised that will permit sensitive measurement of regional myocardial blood flow. Under specific circumstances, however, mean myocardial blood flow measurements may be made to furnish useful information. Horwitz, Curry, Parkey, and Bonte, of this institution, utilii~ed a mean flow technique to study eight individuals with riormal coronary vessels and 15 patients with coronary artery disease. After selective coronary angiograms were obtained, a bolus of laaXe in normal saline was injected into the main left or right coronary artery, and a washout curve was measured with a scintillation proble especially designed to detect and record laaXe energies (1 X 1/4 = in. T1-NaI crystal). An intravenous infusion of isoproterenol was then given in order to produce Cardiac stress by elevating heart rate and cardiac output. A second bolus of radioxenon was injected into the same artery, and mean myocardial flows were calculated before and after isoproterenol stress. H0rwitz and his associates found that mean myocardial flow rose during isoproterenol infusion in most subjects, but when the change in mean flow was compared with the changes in cardiac output it was apparent that in individuals with obstructive coronary artery disease the increment in coronary flow was low compared with the increment in total cardiac output. Many patients with coronary artery disease were unable to respond to isoproterenol stress with an appropriate increase in mean flow, and therefore the ability to distinguish between normal and abnormal coronary vasculatures using mean flow was greatly enhanced. This study will be published in detail in the near future. Although measurement of mean myocardial blood flow may have value in determinations in which an individual is allowed to serve as his own control, even in these circumstances mean blood flow may be a variable which is dependent upon another, such as cardiac output. REGIONAL MYOCARDIAL BLOOD FLOW
Since mean myocardial blood flow is not always a useful index, investigators have attempted to devise methods that would reflect regional changes in the flow patterns of hearts with impaired vasculature. Early workers applied KeW's technique, a employing intramyocardial injection of radiosodium, but this agent was ultimately replaced, first with SSKr, and later with lagXe. Using intramyocardial tracer injection Sullivan et al. s found a relatively uniform flow rate in various sites about the myocardium of normal human subjects, but noted convincing inhomogeneity of flow in individuals with disease which
158
A
BONTE ET AL.
B
C
D
Fig. 4. Representative regional myocardial blood flow experiment. (A) Polaroid scintiphoto of camera oscilloscope shows maximum distribution of a bolus of 20-mCi 133Xe injected into the anterior descending artery of a 20-kg dog. (B) Second injection of 133Xe following embolization of distal branches of the anterior descending artery (same animal as in A). (C and D) Dotted lines enclose "areas of interest," or myocardial regions from which computer will be asked to derive regional myocardial blood values. Region 1 is selected to contain presumably "normal" myocardial flow, and region 2 embraces the area of ischemia and infarction. Images were made with multichannel, convergent-hole "magnifying" collimator, which provides 2:1 image magnification.28
had been demonstrated by cine-coronary-arteriography. Intramyocardial injection, which was also used by other investigators 9'14 obviously requires thoracotomy, however, and therefore cannot be used in the general workup of patients thought to have coronary artrery disease. The development of scintillation cameras and of computer image data processing suggested a new instrumentational approach to several groups 15"29'-~7. Two principal systems have been evolved: That which the authors employ 15'~2-24 features a large crystal scintillation camera (NuclearChicago Pho/Gamma) and a dedicated PDP 8/I computer with both tape and disk storage cap'abilities. Data are stored by the computer in a 64 X 64 matrix (they are not sufficiently numerous to support a finer matrix), and are recorded in the f o r m of consecutive images, or "frames," of arbitrary time duration, In most studies performed with this system we have used a frame length of 3.6 sec, and have recorded the washout curve for a total of 300 sec. However, Stokely, of this institution, has shown that 10-sec frames will provide sufficient curve detail, and a total recording time of 90 sec after the curve peak will convey sufficient information concerning the B-limb to permit flow calculation with 90% accuracy. 24 After the passage of the bolus has been recorded, the computer is asked to display the content of each frame serially upon an oscilloscope. Polaroid films of these frames, or Polaroid films made from one of the camera's oscilloscopes during the passage of the bolus, are used to determine the boundaries of "areas of interest" within which regional myocardial flow curves are to be generated. An illustrative experiment is shown in Fig. 4. The subject was a 20-kg dog, one of a series of 130 dogs in which we have studied regional myocardial blood flow before and after experimental coronary embolization with either metallic mercury or a specially shaped intraarterial metal plug. Figure 4A is a camera scintiphoto of a laSXe bolus at its maximum distribu-
RADiONUCLIDE DETERMINATION Fig. 5. t33xe washout curves obtained from animal whose scintiphotos are seen in Fig. 4. They are derived from regions 1 and 2 before (Pre) and after (Post) embolization of distal branches of the anterior descending artery. Note that the slopes of the curves in Region 1 are essentially unchanged, but that there is considerable diminution in slope after embolization (Post) in Region 2:
159
Pre
Post
REGION 1
REGION 2
tion following injection of a 20-mCi dose through a catheter in place in the anterior descending artery. Figure 4B represents a second injection in the same animal made after embolization of several distal Branches of the anterior descending artery. Using these images we elected to determine regional myocardial blood flows in the areas designated I and 2 in Figs, 4C and D. The boundaries of these areas were described to the computer which totaled, frame by frame, only those counts which were recorded within the two areas of interest. The computer was then instructed to display histograms of counts recorded as a function of observation time. Figure 5 shows tracings of curves obtained in each of the regions of interest before (Pre, Fig. 5) and after (Post, Fig. 5) arterial embolization. Finally, the computer was caused to derive myocardial blood flows from slopes selected along the B limbs of the washout curves for each area of interest. Values obtained, expressed in milliliters/ minute/100 g are seen in Table 1. Note considerable depression, but not complete abolition, of measurable flow in Region 2. In some subjects, regional blood flow curves, when treated by compartmental analysis, yielded two separate flow rates, or compartments, as in B1 and B2 in Fig. 3. As was mentioned earlier, such a situation is analagous to that found when renal blood flow is determined from the washout of a diffusible indicator injected into a renal artery. Thorburn et al. 16 observed three renal compartments in addition to the usual tail and, by performing autoradiography of kidney sections obtained at intervals following injection, obtained data suggesting that the first compartment represented superficial renal cortical, the second deep cortical, and that the third represented medullary, flow. (They related the tail of the curve to flow through perirenal fat.) Table 1. Myocardial Blood Flow Obtained in Dog Pre- and Postembolization of Coronary Artery (milliliters/minute/100 g)
Region 1 Region 2
Pre
Post
118 139
109 61
160
BONTE ET AL.
Various explanations have been advanced for the possible existence of two compartments in the myocardial washout curve. The first is that, physiologically, myocardial flow may be separated into subepicardial and subendocardial components, which have been found to yield different flow rates with intramyocardial injection techniques. 9 A second possibility is that of primary and collateral flow, 14"15'17 especially in myocardial regions containing infarcts. We therefore applied the technique of Thorburn et al. 16 to myocardial blood flow. Animals were sacrified at intervals of from 10 to 90 sec after intracoronary-arterial injection of 133Xe. Hearts were removed and immediately frozen, and full-thickness myocardial sections were prepared for autoradiography, Thus far, however, we have been unable to correlate geographic Xe distribution with calculated flow compartments. Further observations on this matter have been made by Stokely et al., ~4 who have observed dual-compartment myocardial washout curves in a number Of dogs, both before and after embolization. These curves were, however, derived from relatively large myocardial regions. Stokley et al. have reprocessed the same data, successively reducing the areas of the regions in question. As regions became smaller, the tendency toward multicompartmentation disappeared, even though counting statistics remained satisfactory. This finding suggests that the tendency to form several flow compartments is in some way related to the geometric distribution of both vessels and myocardium in the region being studied. Although we have frequently observed multicompartrnent curves in dogs, we only occasionally see them in mean flow studies in humans, usually in patients with radiographically demonstrable disease whose flow routes are presumably abnormal. The second principal instrument system for deriving regional myocardial blood flow is that of Cannon et al. 2~-2~ These researchers have selected as their detector a multi-crystal camera, the Bender Camera (Baird-Atomic Autofluoroscope) as their detector and have, in effect, isolated each of the 294 crystals
I~1~11~ [ 39 ~24~:~
/
"4/ 64
Q
h 78
~
q
3"
73
81
68
59
Fig. 6. Computer printout showing myocardial blood flow rates in ml/min/100g in different regions of the heart. Flow rates were calculated from individual zs3Xe washout curves generated by individual camera crystals functioning as separate detectoi's. The subject, a human volunteer, was thought to be normal. A tracing of his normal left coronary arteriogram is superimposed upon the display of regional blood flow values. With permission. 27
RADIONUCLIDE DETERMINATION
161
-<
Fig. 7. Regional myocardial blood flow values are low, demonstrating reduced tissue perfusion in the region of the myocardium normally supplied by the occluded circumflex branch of the left coronary artery. With permission. 27
,
46
47
70
67
~ 1
47
26
34
27
27
56 " ~ 7
20
24
32
22
30
48
,5
IS
25
28
37
34/
~8"/"~
J r
19
17
15
24
I
28
/
~,:,'~6
into separate recording entities ~ith the aid of an IBM 360/91 computer. Cannon et al., ~8 who have carried out their studies largely in man, record for only 39 sec following the peak of the curve, since they wish to use only that portion of the washout curve that is apt to form a straight line in a semilogarithmic plot (B limb, Fig. 1), and which does not contain the tail of the curve. Flow studies are performed as an adjunct to coronary arteriography, and coronary arteriograms are used to select those crystals from which flow values are to be evoked. Figure 6 shows a printout utilized by Cannon et al., ~6 in which the patient's coronary arteriorgram has been traced upon a grid containing individual regional myocardial flow values. Cannon et al. have noted that there is a degree of inhomogeneity in the myocardial flow values obtained in normal individuals which is greater than that observed by investigators who used intramyocardial tracer injection to study regional flow. They have also observed that flow rates for left ventricular myocardium exceeded those of right ventricle and atrium.
123 133
h 0
J
91 Y
j!
Fig. 8. Patient with coronary artery disease who had received an internal mammary artery implant, indicated by open arrows on the superimposed arteriogram, made by injection through the implant. Note high flow rates (milliliters/minute/100g) along the course of the implant (compare with values in Fig. 6). Note also that anterior descending artery is obstructed (solid arrow) and fills retrograde from the implant. With permission. 27
162
BONTE ET AL.
C a n n o n et al. h a v e r e p o r t e d studies of 24 patients with h e a r t disease w h o s e c o r o n a r y a r t e r i o g r a m s were abnormal. 2v In patients w i t h diffuse c o r o n a r y artery disease regional blood flow rates w e r e o f t e n r a t h e r u n i f o r m l y depressed t h r o u g h o u t the m y o c a r d i u m , while in several patients w i t h localized occlusive disease localized reductions in regional flow were n o t e d (see Fig. 7, a n d c o m p a r e to Fig. 6). These o f t e n c o r r e s p o n d e d to r a d i o g r a p h i c a l l y d e m o n s t r a t e d arterial lesions. C a n n o n et a l Y h a v e also a t t e m p t e d to appraise the success of reparative s u r g e r y such as internal m a m m a r y i m p l a n t a t i o n , as in Fig. 8. N o t e t h a t the anterior descending artery is completely occluded near its origin (solid arrow, Fig. 8), and t h a t it is a p p a r e n t l y filling r e t r o g r a d e f r o m the internal m a m m a r y a r t e r y i m p l a n t (open arrows, Fig. 8). G o o d regional m y o c a r d i a l b l o o d flows 9are p r e s e n t t h r o u g h o u t m u c h of the area served b y the implant. Because of their short o b s e r v a t i o n time (39 sec) C a n n o n et al. h a v e n o t h a d the o p p o r t u n i t y to test the possible existence of t w o or m o r e c o m p a r t m e n t s in the m y o c a r d i a l flow curve. T h e s e two g r o u p s o f investigators h a v e s h o w n the feasibility of d e t e r m i n i n g regional m y o c a r d i a l b l o o d flow b y scintillation c a m e r a / c o m p u t e r combinations. This technique m a y find wide clinical application in the near future. REFERENCES
1. Kety, S. S., and Schmidt, C. F.: The determination of cerebral blood flow in man by use of nitrous oxide in low concentrations. Am. J. Physiol. 144:53, 1945. 2. Eckenhoff, J. E., Hafkenschiel, J. H., Harmel, M. H., Goodale, W. T., Lubin, M., Bing, R. J., and Kety, S. S.: Measurement of coronary blood flow by nitrous oxid.e method. Am. J. Physiol. 152:356, 1948. 3. Kety, S. S.: Measurement of regional circulation by the local clearance of radioactive sodium. Am. Heart J. 38:321, 1949. 4. Herd, J. A., Hollenberg, M., Thorburn, G. D., Kovald, H. H., and Barger, A. C.: Myocardial blood flow determined with krypton-85 in unanesthetized dogs. Am. J. Physiol. 203:122, 1962. 5. Ross, R. S., Ueda, K., Lichtlen, P. R., and Rees, J. R.: Measurement of myocardial blood flow in animals and man by selective injection of radioactive inert gas into the coronary arteries. Circ. Res. 15:28, 1964. 6. Cohen, L. S., Elliott, W. C., and Gorlin, R.: Measurement of myocardial blood flow using krypton-85. Am. J. Physiol. 206:997, 1964. 7. Cullen, M. L., and Reese, H. L.: Myocardial circulatory changes measured by the clearance of 24Na. J. Appl. Physiol. 5:281, 1952. 8. Sullivan, J. M,, Taylor, W. J., Elliott,
W. C., and Gorlin, R. : Regional myocardial blood flow. J. Clin. Invest. 46:1402, 1967. 9. Brandi, G., Fam, W. M., and McGregor, M.: Measurement of coronary blood flow in local areas of myocardium using Xenon-133. J. Appl. Physiol. 24:446, 1968. 10. Rees, J. R., and Redding, V. J.: Experimental myocardial infarction in the dog; comparison of myocardial blood flow within, near, and distant from the infarct. Circ. Res. 25:161, 1969. 11. Wagner, H. N., Jr.: Regional bloodflow measurements with krypton-85 and xenon-133. In Kniseley, R. M., and Tauxe, W. N. (Eds.): Dynamic Clinical Studies with Radioisotopes. Oak Ridge, Atomic Energy Commission, 1964. 12. Conn, H. L., Jr.: Equilibrium distribution of radioxenon in tissue: xenon-hemoglobin association curve. J. Appl. Physiol. 16:1065, 1961. 13. Hoedt-Rasmussen, K., Sveinsdottir, E., and Lassen, N. E.: Regional cerebral blood flow in man determined by intra-arterial injection of inert gas. Circ. Res. 18:237, 1966. 14. Horwitz, L. D., Gorlin, R., Taylor, W. J., and Kemp, H. G.: Effects of nitroglycerin on regional myocardial blood flow in coronary artery disease. J. Clin. Invest. 50:1578, 1971.
RADIONUCLIDE DETERMINATION
15. Parkey, R. W., Lewis, S. E., Stokely, E. M., and Bonte, F. J.: Compartmental analysis of the Xe-133 regional myocardial blood-flow curve. Radiology 104:425, 1972. 16. Thorburn, G. D., Kopald, H. H., Herd, 1. A., Hollenberg, M., O'Morchoe, C. C. C., and Barger, A. C.: Intrarenal distribution of nutrient blood flow determined with krypton-85 in the unaesthetized dog. Circ. Res. 13:290, 1963. 17. Winbury, M. M.: Redistribution of left ventricular blood flow produced by nitroglycerin. An example of integration of the macro- and microcirculation. Circ. Res. (Suppl. 1) 28:140, 1971. 18. Zierler, K. L. Equations for measuring blood flow by external monitoring of radioisotopes. Circ. Res. 16:309, 1965. 19. Bassingthwaighte, J. B., Strandell, T., and Donald, D. S.: Estimation of coronary blood flow by washout of diffusible indicators. Circ. Res. 23:259, 1968. 20. Bassingthwaighte, J. B.: Blood flow and diffusion through mammalian organs. Science 167:1347, 1970. 21. Baltaxe, H. A., Formanek, G., Loken, M., and Amplatz, K.: Clinical limitations to use of xenon for measurement of myocardial blood flow. Invest. Radiol. 4:317, 1969.
163
22. Christensen, E. E., and Bonte, F. J.: Radionuclide coronary angiography and myocardial blood flow. Radiology 95:497, 1970. 23. Bonte, F. J., and Christensen, E. E.: Regional myocardial blood flow after experimental myocardial embolization. J. Nuclear Med. 11:302, 1970. 24. Stokely, E. M., Nardizzi, L. R., Parkey, R. W., and Bonte, T. J. : Regional myocardial perfusion data with spatial and temporal quantization. J. Nuclear Med. (In press). 25. Cannon, P. J., Haft, J. I., and Johnson, P. M.: Visual assessment of regional myocardial perfusion utilizing radioactive xenon and scintillation photography. Circulation 40:277, 1969. 26. Cannon, P. J., Dell, R. B., and Dwyer, E. M., Jr.: Measurement of regional myocardial perfusion in man with 133-xenon and a scintillation camera. J. Clin. Invest. 51:964, 1972. 27. - - , - - , - - : Regional myocardial perfusion rates in patients with coronary artery disease. J. Clin. Invest. 51:978, 1972. 28. Dowdey, J. E., and Bonte, r. J.: Principles of scintillation camera image magnification with convergent multichannel collimators. Radiology 104:89, 1972.
I
tracer, and by means of image data quantification derive regional myocardial blood flow values'by Kety's method. The authors have studied more than 130 dogs before and after experimental coronary embolization and have described a complete method of deriving regional myocardial blood flows with an Anger camera-small computer system. Analysis of flow curves thus generated has suggested the existence of more than one compartment within myocardial blood flow. These compartments might be related to primary/collateral flow or to the volume of perfused tissue incorporated in the region of interest. Cannon et al. 2s-27 have employed a multicrystal camera of the autofluoroscope type and an IBM 360/91 computer, in which the camera functions as 294 isolated detectors for the purpose of identifying as many regions of myocardial bTood flow. Cannon et al. have studied both normal human subjects and patients with radiographically demonstrable coronary artery disease and have found regional flow to be a valid method both for identifying the myocardial flow inhomogeneities expected with coronary artery disease and for evaluating the results of reparative surgery.
N 1945, Kety and Schmidt devised their n o w classic m e t h o d of measuring cerebral blood flow with a diffusible indicator, 1 and in 1948 Kety and his
From the Departments of Radiology and Internal Medicine, The University of Texas Southwestern Medical School at Dallas, Dallas, Tex. 75235. Supported in part by Research Grants HLO518Z and HLI3625, and Training Grant CA05136 from the ational Institute of Health, USPHS, and in part by a Grant from the Southwestern Medical Foundation. F. J. Bonte, M.D.: Professor and Chairman, Department of Radiology; R. W. Parkey, M.D.: Assistant Professor, Department of Radiology; E. M. Stokely, M.D.: Instructor, Department of Radiology; S. E. Lewis, M.S.E.E., Department of Radiology; L. D. Horwitz, M.D.: Assistant Professor, Department of Internal Medicine; G. C. Curry, M.D.: Assistant Professor, Department of Radiology, University of Texas Southwestern Medical School at Dallas, Dallas, Tex. 75235. Dr. Parkey is a Scholar in Radiological Research, James Picker Foundation, NAS-NRC. Dr. Curry is a former Scholar in Radiological Research, ]ames Picker Foundation, NAS-NRC. 9 1973 by Grune & Stratton, Inc. Seminars in Nuclear Medicine, VoL 3, No. 2 (April), 1973
153
154
BONTE ET AL.
associates applied this new technique to the estimation of blood flow in the myocardium.2 In these initial experiments they employed nitrous oxide as their indicator, but in 1949 Kety substituted ~4Na and described the first practical method of blood flow measurement using a radionuclide tracer. 3 In succeeding years several groups 4-11 elaborated further on Kety's work and developed alternative techniques for myocardial blood flow measurement in which the investigator either injected a diffusible tracer into a coronary artery or into the substance of the myocardium itself. In each case a radiation detection system was used to measure the disappearance, or "washout" of radiocativity, because Kety had shown that the rate of washout was a function of tissue blood flow. 1-3 Radiosodium and several other cation tracers soon gave way to the radioactive noble gases 85Kr and 133Xe for the two distinct advantages the latter provides (1) The fat-soluble gases are capable of diffusing much more rapidly through capillary endothelium into surrounding tissues, and thus can be used to measure far higher rates of blood flow than is possible with water-soluble cations, and (2) approximately 95% of a noble gas tracer bolus enters alveolar air at the first circulation through the lungs. Blood flow washout curves (see Fig. 1) are thus free of secondary peaks due to recirculation of tracer. Also, one can inject successive doses of tracer with very little build-up in background radioactivity. The tracer of choice has become l~3Xe, and most of the work described herein will have been done with this radionuclide. (183Xe: physical half-life = 5.27 days; 3' = 0.08 MeV; E~ = 0.1 MeV). Let us examine a representative procedure and see how blood flow is derived from radionuclide washout. Let us assume that a catheter has been placed in a coronary artery and a bolus of 133Xe dissolved in normal saline is injected through it. A scintillation detector, such as a probe or a scintillation camera, is in place over the precordiurn. Radioactivity observed by the detector will be plotted as in Fig. 1, with counts recorded on a logarithmic scale along the ordinate, and time on an ordinary scale along the abscissa. As the bolus of 133Xe appears within view of the detector there is a sharp rise in recorded radioactivity (the A limb of the curve in Fig. 1). When the bolus reaches the capillary bed of the myocardium, the freely diffusible
B
== 8
TIME
Fig. 1. Curve recorded after intra-coronary-arterial injection of a diffusible indicator, such as 133Xe. Data are plotted on a semi-logarithmic scale showing counts (amount of radioactivity) as a function of time after injection. A designates the limb of the curve which represents the arrival of tracer in the vascular bed of interest. B represents blood clearance of indicator from tissue, or "washout." C, the "tail" of the curve, represents washout of tracer from epicardial fat, and other functions which are discussed in the text.
RADIONUCLIDE DETERMINATION
155
c! Iz Fig. 2. Method of deriving k, the rate constant, from the straight-line portion of the washout curve. Times T1 and T2 are selected so that the curve between them is as close as possible to a straight line. C, and C2 are counts at times T1 and T2
8 %
..... L ....
T!
k T2
TIME
xenon leaves the capillary vascular space to enter muscle and fat cells, which compose the heart wall. The exchange takes place in relation to Solubility of 133Xe in myocardial muscle (or fat) ~A. Solubility of laaXe in blood The partition coefficient is X. For 13aXe in myocardium it is usually given as 0.72, lz while for fat it is very high, 8.0.11 After the crest of the bolus passes, the blood which follows it contains less tracer than do the tissues surrounding capillary vessels, and the tracer begins to diffuse from tissues back into the vascular space at a rate proportional to blood flow. You wil lnote that the early portion of the curve describes a nearly straight line on the semilogarithmic scale on which it has been plotted (B limb, Fig. 1). It is this portion of the curve most investigators believe to represent myocardial blood flow. Blood flow may be calculated from the washout curve by one of several methods. The original one is the Kety-Schmidt equation
r = (k) (x) (zo0)/p, where F is blood flow, and ~ is the partition coefficient (see above). The rate constant k is derived from the washout curve in the manner described below. The Kety-Schmidt equation is based upon a known volume of tissue perfused, but inasmuch as the volume of myocardium perfused in any individual determination is not known, blood flow is expressed in terms of an arbitrary 100 g of tissue, which is converted to volume by dividing by p, the specific gravity of myocardiurn (volume -- mass/specific gravity). The value of p is 1.05. Therefore the units in which blood flow (F) is expressed will be milliliters/minute/100 g of myocardium. The rate constant k is the slope of the washout curve. It is derived from the semilogarithmic data plots as in Fig. 2, using the equation k - - log C 1 - 1 o g 0.434 ( T 9 ~
Cz T 1)
'
where times T 1 and T ~ (see Fig. 2) are selected so that the curve between them is as close as possible to a straight line. C i and C ~ are counts at times T 1 and T ~, respectively (Fig. 2). The factor 0.434 must be used to convert
156
BONTE ET AL.
r lz O o
B2
\ TIME
Fig. 3. Mathematical treatment of some myocardial blood flow c u r v e s suggests two different flow rates or "compartments" in the myocardial washout (B, Fig. 1) portion of the curve. These are represented by tangents drawn parallel to appropriate segments of the curve, and identified as B1 end B2.
logarithm-to-the-base-10 data so that they may be used in a log-to-the-base-e equation. It represents logl0e. It is evident from examination of the curve in Fig. 1 that several functions are expressed. The steep portion of the washout curve (B limb) is assumed to represent myocardial blood flow, but the origin of the long tail (C limb, Fig. 1) has not been completely solved. It is believed to reflect, in part, washout of tracer from epicardial and body wall fat, and clearance of Xe from the lungs. Although 95% of the tracer bolus of 133Xe leaves blood and enters alveolar air on its first passage throgh the lungs, it is cleared from the lungs at a much slower rate. We have measured the x3SXe pulmonary clearance half-time in dogs as 108 - 35 sec. It is quite likely that there are other factors, as yet unknown, that participate in the formation of the tail of the washout curve. If the data comprising the myocardial blood flow curve are treated by a mathematical process known as compartmental analysis, 13 flow "'compartments" can be found corresponding to the B and C limbs. However, under some circumstances the B limb itself can be resolved into two different slopes yielding two different flow rates, or compartments. 14"1s This situation, which is analogous to renal blood flow measured with diffusible indicators, le is illustrated in Fig. 3, where B1 and B2 represent mathematically identifiable compartments within myocardial blood flow. This phenomeonon will be discussed further in a later section. An alternative method of flow curve data treatment is that of Zierler. 18 In this method the area under the washout curve is divided by its height. This scheme has been applied successfully to the calculation of cerebral blood flow but it has as yet been little used in myocardial flow calculations. Excellent discussions of the available methods of flow curve data treatment are to be found in the papers of Bassingthwaighte and his associates. 1~176A detailed discussion of some of the problems in the methods can be found in the article by Pachinger and Bing in this issue. Let us now consider several methods presently used to determine myocardial blood flow. MEAN MYOCARDIAL BLOOD FLOW
If a bolus of a diffusible indicator, such as 183Xe, is injected through a catheter into a coronary artery, a disappearance curve can be recorded with a scintillation probe placed over the precordium. Flow measurements calcu-
RADIONUCLIDE DETERMINATION
157
lated from curves of this sort have been termed total or mean myocardial blood flow. The resultg Of mean flow determinations have been disappointing, since they often yield overlapping flow values and thus fail to distinguish between patients with radiographically demonstrable coronary artery disease and individuals with radiographically normal coronary vessels. The best explanation seems to be that coronary artery disease in relatively small areas of myocardium may Cause severe symptoms and disability even though flow is normal throughout the remainder of the myocardium. However, since most of the indicator washout is occuring in the undamaged areas, mean myocardial flow may still be within the normal range. It has therefore become clear to most investigators that a method must be devised that will permit sensitive measurement of regional myocardial blood flow. Under specific circumstances, however, mean myocardial blood flow measurements may be made to furnish useful information. Horwitz, Curry, Parkey, and Bonte, of this institution, utilii~ed a mean flow technique to study eight individuals with riormal coronary vessels and 15 patients with coronary artery disease. After selective coronary angiograms were obtained, a bolus of laaXe in normal saline was injected into the main left or right coronary artery, and a washout curve was measured with a scintillation proble especially designed to detect and record laaXe energies (1 X 1/4 = in. T1-NaI crystal). An intravenous infusion of isoproterenol was then given in order to produce Cardiac stress by elevating heart rate and cardiac output. A second bolus of radioxenon was injected into the same artery, and mean myocardial flows were calculated before and after isoproterenol stress. H0rwitz and his associates found that mean myocardial flow rose during isoproterenol infusion in most subjects, but when the change in mean flow was compared with the changes in cardiac output it was apparent that in individuals with obstructive coronary artery disease the increment in coronary flow was low compared with the increment in total cardiac output. Many patients with coronary artery disease were unable to respond to isoproterenol stress with an appropriate increase in mean flow, and therefore the ability to distinguish between normal and abnormal coronary vasculatures using mean flow was greatly enhanced. This study will be published in detail in the near future. Although measurement of mean myocardial blood flow may have value in determinations in which an individual is allowed to serve as his own control, even in these circumstances mean blood flow may be a variable which is dependent upon another, such as cardiac output. REGIONAL MYOCARDIAL BLOOD FLOW
Since mean myocardial blood flow is not always a useful index, investigators have attempted to devise methods that would reflect regional changes in the flow patterns of hearts with impaired vasculature. Early workers applied KeW's technique, a employing intramyocardial injection of radiosodium, but this agent was ultimately replaced, first with SSKr, and later with lagXe. Using intramyocardial tracer injection Sullivan et al. s found a relatively uniform flow rate in various sites about the myocardium of normal human subjects, but noted convincing inhomogeneity of flow in individuals with disease which
158
A
BONTE ET AL.
B
C
D
Fig. 4. Representative regional myocardial blood flow experiment. (A) Polaroid scintiphoto of camera oscilloscope shows maximum distribution of a bolus of 20-mCi 133Xe injected into the anterior descending artery of a 20-kg dog. (B) Second injection of 133Xe following embolization of distal branches of the anterior descending artery (same animal as in A). (C and D) Dotted lines enclose "areas of interest," or myocardial regions from which computer will be asked to derive regional myocardial blood values. Region 1 is selected to contain presumably "normal" myocardial flow, and region 2 embraces the area of ischemia and infarction. Images were made with multichannel, convergent-hole "magnifying" collimator, which provides 2:1 image magnification.28
had been demonstrated by cine-coronary-arteriography. Intramyocardial injection, which was also used by other investigators 9'14 obviously requires thoracotomy, however, and therefore cannot be used in the general workup of patients thought to have coronary artrery disease. The development of scintillation cameras and of computer image data processing suggested a new instrumentational approach to several groups 15"29'-~7. Two principal systems have been evolved: That which the authors employ 15'~2-24 features a large crystal scintillation camera (NuclearChicago Pho/Gamma) and a dedicated PDP 8/I computer with both tape and disk storage cap'abilities. Data are stored by the computer in a 64 X 64 matrix (they are not sufficiently numerous to support a finer matrix), and are recorded in the f o r m of consecutive images, or "frames," of arbitrary time duration, In most studies performed with this system we have used a frame length of 3.6 sec, and have recorded the washout curve for a total of 300 sec. However, Stokely, of this institution, has shown that 10-sec frames will provide sufficient curve detail, and a total recording time of 90 sec after the curve peak will convey sufficient information concerning the B-limb to permit flow calculation with 90% accuracy. 24 After the passage of the bolus has been recorded, the computer is asked to display the content of each frame serially upon an oscilloscope. Polaroid films of these frames, or Polaroid films made from one of the camera's oscilloscopes during the passage of the bolus, are used to determine the boundaries of "areas of interest" within which regional myocardial flow curves are to be generated. An illustrative experiment is shown in Fig. 4. The subject was a 20-kg dog, one of a series of 130 dogs in which we have studied regional myocardial blood flow before and after experimental coronary embolization with either metallic mercury or a specially shaped intraarterial metal plug. Figure 4A is a camera scintiphoto of a laSXe bolus at its maximum distribu-
RADiONUCLIDE DETERMINATION Fig. 5. t33xe washout curves obtained from animal whose scintiphotos are seen in Fig. 4. They are derived from regions 1 and 2 before (Pre) and after (Post) embolization of distal branches of the anterior descending artery. Note that the slopes of the curves in Region 1 are essentially unchanged, but that there is considerable diminution in slope after embolization (Post) in Region 2:
159
Pre
Post
REGION 1
REGION 2
tion following injection of a 20-mCi dose through a catheter in place in the anterior descending artery. Figure 4B represents a second injection in the same animal made after embolization of several distal Branches of the anterior descending artery. Using these images we elected to determine regional myocardial blood flows in the areas designated I and 2 in Figs, 4C and D. The boundaries of these areas were described to the computer which totaled, frame by frame, only those counts which were recorded within the two areas of interest. The computer was then instructed to display histograms of counts recorded as a function of observation time. Figure 5 shows tracings of curves obtained in each of the regions of interest before (Pre, Fig. 5) and after (Post, Fig. 5) arterial embolization. Finally, the computer was caused to derive myocardial blood flows from slopes selected along the B limbs of the washout curves for each area of interest. Values obtained, expressed in milliliters/ minute/100 g are seen in Table 1. Note considerable depression, but not complete abolition, of measurable flow in Region 2. In some subjects, regional blood flow curves, when treated by compartmental analysis, yielded two separate flow rates, or compartments, as in B1 and B2 in Fig. 3. As was mentioned earlier, such a situation is analagous to that found when renal blood flow is determined from the washout of a diffusible indicator injected into a renal artery. Thorburn et al. 16 observed three renal compartments in addition to the usual tail and, by performing autoradiography of kidney sections obtained at intervals following injection, obtained data suggesting that the first compartment represented superficial renal cortical, the second deep cortical, and that the third represented medullary, flow. (They related the tail of the curve to flow through perirenal fat.) Table 1. Myocardial Blood Flow Obtained in Dog Pre- and Postembolization of Coronary Artery (milliliters/minute/100 g)
Region 1 Region 2
Pre
Post
118 139
109 61
160
BONTE ET AL.
Various explanations have been advanced for the possible existence of two compartments in the myocardial washout curve. The first is that, physiologically, myocardial flow may be separated into subepicardial and subendocardial components, which have been found to yield different flow rates with intramyocardial injection techniques. 9 A second possibility is that of primary and collateral flow, 14"15'17 especially in myocardial regions containing infarcts. We therefore applied the technique of Thorburn et al. 16 to myocardial blood flow. Animals were sacrified at intervals of from 10 to 90 sec after intracoronary-arterial injection of 133Xe. Hearts were removed and immediately frozen, and full-thickness myocardial sections were prepared for autoradiography, Thus far, however, we have been unable to correlate geographic Xe distribution with calculated flow compartments. Further observations on this matter have been made by Stokely et al., ~4 who have observed dual-compartment myocardial washout curves in a number Of dogs, both before and after embolization. These curves were, however, derived from relatively large myocardial regions. Stokley et al. have reprocessed the same data, successively reducing the areas of the regions in question. As regions became smaller, the tendency toward multicompartmentation disappeared, even though counting statistics remained satisfactory. This finding suggests that the tendency to form several flow compartments is in some way related to the geometric distribution of both vessels and myocardium in the region being studied. Although we have frequently observed multicompartrnent curves in dogs, we only occasionally see them in mean flow studies in humans, usually in patients with radiographically demonstrable disease whose flow routes are presumably abnormal. The second principal instrument system for deriving regional myocardial blood flow is that of Cannon et al. 2~-2~ These researchers have selected as their detector a multi-crystal camera, the Bender Camera (Baird-Atomic Autofluoroscope) as their detector and have, in effect, isolated each of the 294 crystals
I~1~11~ [ 39 ~24~:~
/
"4/ 64
Q
h 78
~
q
3"
73
81
68
59
Fig. 6. Computer printout showing myocardial blood flow rates in ml/min/100g in different regions of the heart. Flow rates were calculated from individual zs3Xe washout curves generated by individual camera crystals functioning as separate detectoi's. The subject, a human volunteer, was thought to be normal. A tracing of his normal left coronary arteriogram is superimposed upon the display of regional blood flow values. With permission. 27
RADIONUCLIDE DETERMINATION
161
-<
Fig. 7. Regional myocardial blood flow values are low, demonstrating reduced tissue perfusion in the region of the myocardium normally supplied by the occluded circumflex branch of the left coronary artery. With permission. 27
,
46
47
70
67
~ 1
47
26
34
27
27
56 " ~ 7
20
24
32
22
30
48
,5
IS
25
28
37
34/
~8"/"~
J r
19
17
15
24
I
28
/
~,:,'~6
into separate recording entities ~ith the aid of an IBM 360/91 computer. Cannon et al., ~8 who have carried out their studies largely in man, record for only 39 sec following the peak of the curve, since they wish to use only that portion of the washout curve that is apt to form a straight line in a semilogarithmic plot (B limb, Fig. 1), and which does not contain the tail of the curve. Flow studies are performed as an adjunct to coronary arteriography, and coronary arteriograms are used to select those crystals from which flow values are to be evoked. Figure 6 shows a printout utilized by Cannon et al., ~6 in which the patient's coronary arteriorgram has been traced upon a grid containing individual regional myocardial flow values. Cannon et al. have noted that there is a degree of inhomogeneity in the myocardial flow values obtained in normal individuals which is greater than that observed by investigators who used intramyocardial tracer injection to study regional flow. They have also observed that flow rates for left ventricular myocardium exceeded those of right ventricle and atrium.
123 133
h 0
J
91 Y
j!
Fig. 8. Patient with coronary artery disease who had received an internal mammary artery implant, indicated by open arrows on the superimposed arteriogram, made by injection through the implant. Note high flow rates (milliliters/minute/100g) along the course of the implant (compare with values in Fig. 6). Note also that anterior descending artery is obstructed (solid arrow) and fills retrograde from the implant. With permission. 27
162
BONTE ET AL.
C a n n o n et al. h a v e r e p o r t e d studies of 24 patients with h e a r t disease w h o s e c o r o n a r y a r t e r i o g r a m s were abnormal. 2v In patients w i t h diffuse c o r o n a r y artery disease regional blood flow rates w e r e o f t e n r a t h e r u n i f o r m l y depressed t h r o u g h o u t the m y o c a r d i u m , while in several patients w i t h localized occlusive disease localized reductions in regional flow were n o t e d (see Fig. 7, a n d c o m p a r e to Fig. 6). These o f t e n c o r r e s p o n d e d to r a d i o g r a p h i c a l l y d e m o n s t r a t e d arterial lesions. C a n n o n et a l Y h a v e also a t t e m p t e d to appraise the success of reparative s u r g e r y such as internal m a m m a r y i m p l a n t a t i o n , as in Fig. 8. N o t e t h a t the anterior descending artery is completely occluded near its origin (solid arrow, Fig. 8), and t h a t it is a p p a r e n t l y filling r e t r o g r a d e f r o m the internal m a m m a r y a r t e r y i m p l a n t (open arrows, Fig. 8). G o o d regional m y o c a r d i a l b l o o d flows 9are p r e s e n t t h r o u g h o u t m u c h of the area served b y the implant. Because of their short o b s e r v a t i o n time (39 sec) C a n n o n et al. h a v e n o t h a d the o p p o r t u n i t y to test the possible existence of t w o or m o r e c o m p a r t m e n t s in the m y o c a r d i a l flow curve. T h e s e two g r o u p s o f investigators h a v e s h o w n the feasibility of d e t e r m i n i n g regional m y o c a r d i a l b l o o d flow b y scintillation c a m e r a / c o m p u t e r combinations. This technique m a y find wide clinical application in the near future. REFERENCES
1. Kety, S. S., and Schmidt, C. F.: The determination of cerebral blood flow in man by use of nitrous oxide in low concentrations. Am. J. Physiol. 144:53, 1945. 2. Eckenhoff, J. E., Hafkenschiel, J. H., Harmel, M. H., Goodale, W. T., Lubin, M., Bing, R. J., and Kety, S. S.: Measurement of coronary blood flow by nitrous oxid.e method. Am. J. Physiol. 152:356, 1948. 3. Kety, S. S.: Measurement of regional circulation by the local clearance of radioactive sodium. Am. Heart J. 38:321, 1949. 4. Herd, J. A., Hollenberg, M., Thorburn, G. D., Kovald, H. H., and Barger, A. C.: Myocardial blood flow determined with krypton-85 in unanesthetized dogs. Am. J. Physiol. 203:122, 1962. 5. Ross, R. S., Ueda, K., Lichtlen, P. R., and Rees, J. R.: Measurement of myocardial blood flow in animals and man by selective injection of radioactive inert gas into the coronary arteries. Circ. Res. 15:28, 1964. 6. Cohen, L. S., Elliott, W. C., and Gorlin, R.: Measurement of myocardial blood flow using krypton-85. Am. J. Physiol. 206:997, 1964. 7. Cullen, M. L., and Reese, H. L.: Myocardial circulatory changes measured by the clearance of 24Na. J. Appl. Physiol. 5:281, 1952. 8. Sullivan, J. M,, Taylor, W. J., Elliott,
W. C., and Gorlin, R. : Regional myocardial blood flow. J. Clin. Invest. 46:1402, 1967. 9. Brandi, G., Fam, W. M., and McGregor, M.: Measurement of coronary blood flow in local areas of myocardium using Xenon-133. J. Appl. Physiol. 24:446, 1968. 10. Rees, J. R., and Redding, V. J.: Experimental myocardial infarction in the dog; comparison of myocardial blood flow within, near, and distant from the infarct. Circ. Res. 25:161, 1969. 11. Wagner, H. N., Jr.: Regional bloodflow measurements with krypton-85 and xenon-133. In Kniseley, R. M., and Tauxe, W. N. (Eds.): Dynamic Clinical Studies with Radioisotopes. Oak Ridge, Atomic Energy Commission, 1964. 12. Conn, H. L., Jr.: Equilibrium distribution of radioxenon in tissue: xenon-hemoglobin association curve. J. Appl. Physiol. 16:1065, 1961. 13. Hoedt-Rasmussen, K., Sveinsdottir, E., and Lassen, N. E.: Regional cerebral blood flow in man determined by intra-arterial injection of inert gas. Circ. Res. 18:237, 1966. 14. Horwitz, L. D., Gorlin, R., Taylor, W. J., and Kemp, H. G.: Effects of nitroglycerin on regional myocardial blood flow in coronary artery disease. J. Clin. Invest. 50:1578, 1971.
RADIONUCLIDE DETERMINATION
15. Parkey, R. W., Lewis, S. E., Stokely, E. M., and Bonte, F. J.: Compartmental analysis of the Xe-133 regional myocardial blood-flow curve. Radiology 104:425, 1972. 16. Thorburn, G. D., Kopald, H. H., Herd, 1. A., Hollenberg, M., O'Morchoe, C. C. C., and Barger, A. C.: Intrarenal distribution of nutrient blood flow determined with krypton-85 in the unaesthetized dog. Circ. Res. 13:290, 1963. 17. Winbury, M. M.: Redistribution of left ventricular blood flow produced by nitroglycerin. An example of integration of the macro- and microcirculation. Circ. Res. (Suppl. 1) 28:140, 1971. 18. Zierler, K. L. Equations for measuring blood flow by external monitoring of radioisotopes. Circ. Res. 16:309, 1965. 19. Bassingthwaighte, J. B., Strandell, T., and Donald, D. S.: Estimation of coronary blood flow by washout of diffusible indicators. Circ. Res. 23:259, 1968. 20. Bassingthwaighte, J. B.: Blood flow and diffusion through mammalian organs. Science 167:1347, 1970. 21. Baltaxe, H. A., Formanek, G., Loken, M., and Amplatz, K.: Clinical limitations to use of xenon for measurement of myocardial blood flow. Invest. Radiol. 4:317, 1969.
163
22. Christensen, E. E., and Bonte, F. J.: Radionuclide coronary angiography and myocardial blood flow. Radiology 95:497, 1970. 23. Bonte, F. J., and Christensen, E. E.: Regional myocardial blood flow after experimental myocardial embolization. J. Nuclear Med. 11:302, 1970. 24. Stokely, E. M., Nardizzi, L. R., Parkey, R. W., and Bonte, T. J. : Regional myocardial perfusion data with spatial and temporal quantization. J. Nuclear Med. (In press). 25. Cannon, P. J., Haft, J. I., and Johnson, P. M.: Visual assessment of regional myocardial perfusion utilizing radioactive xenon and scintillation photography. Circulation 40:277, 1969. 26. Cannon, P. J., Dell, R. B., and Dwyer, E. M., Jr.: Measurement of regional myocardial perfusion in man with 133-xenon and a scintillation camera. J. Clin. Invest. 51:964, 1972. 27. - - , - - , - - : Regional myocardial perfusion rates in patients with coronary artery disease. J. Clin. Invest. 51:978, 1972. 28. Dowdey, J. E., and Bonte, r. J.: Principles of scintillation camera image magnification with convergent multichannel collimators. Radiology 104:89, 1972.