Semiquantitation of regional myocardial blood flow in normal human subjects by first-pass magnetic resonance imaging

Semiquantitation of regional myocardial blood flow in normal human subjects by first-pass magnetic resonance imaging J a n T. Keijer, MD, a Albert C. van Rossum, MD, a Machiel J. van Eenige, PhD, a Arend J. P. Karreman, BSc, a Mark B.M. Hofman, PhD, b J a a p Valk, MD, c and Cees A. Visser, MD a Amsterdam, The Netherlands

Several established imaging techniques have been applied in pursuit of quantitation of regional myocardial blood flow. Recognizing the value of positronemission tomography, focus has also turned towards clinically more available methods, such as twodimensional echocardiography, 1,2 ultrafast computed tomography, 3, 4 and digital subtraction angiography.5, 6 Their common approach on this issue is imaging the first pass of a contrast medium through the myocardium after a rapid bolus injection. Consecutively, flow parameters such as mean transit time (MTT) can be derived from curves of signal intensity (SI) versus time. According to indicator-dilution theory, 7, 8 flow (F) can be calculated as F = V/MTT, where V is the distribution volume of the indicator and MTT is the average time it takes the indicator to traverse the tissue. Thus, assuming a constant distribution volume, inverse MTT is a parameter linearly related to flow. Application of the first-pass approach to ultrafast magnetic resonance (MR) imaging techniques 9 offers the benefit of high spatial resolution and the possibility of imaging any desired imaging plane with little invasiveness and without ionizing radiation. Manning et al.10 used MR imaging to assess myocardial perfusion abnormalities in patients with coronary artery disease. They measured peak SI at the first pass of the contrast agent gadolinium diethyle-

From the Departments of aCardiology, bClinical Physics and Engineering, and CRadiology, Free University Hospital; Interuniversity Cardiology Institute; and Institute for Cardiovascular Research Vrije Universiteit. Received for publication Nov. 21, 1994; accepted Jan. 3, 1995. Reprint requests: Jan T. Keijer, Department of Cardiology, Free University Hospital, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. AM HEARTJ 1995;130:893-901. Copyright © 1995 by Mosby-Year Book, Inc. 0002-8703/95/$5.00 + 0 4/1/65308

netriamine pentaacetic acid (Gd-DTPA) before and after revascularization. Schaefer et al. 11 and Klein et al. 12 also measured first-pass SI changes after pharmacologic stress and related them to scintigraphic perfusion defects. Wilke et al. 13 validated the firstpass method in an animal model with perfusion measurements by radiolabeled microspheres as the gold standard. They assessed coronary flow reserve by using dipyridamole as a pharmacologic stressor and found a good correlation between inverse MTT and coronary flow. However, the true quantitative assessment of absolute coronary flow or flow reserve in h u m a n beings by first-pass MR imaging is subject to theoretical and practical limitations, several of which are directly related to the input of indicator into the myocardium. Reliable derivation of MTT requires a brief myocardial input, which results in a discrete first and second pass. Injecting a bolus of Gd-DTPA into a peripheral vein means considerable dispersion of the bolus before it reaches the myocardium. TM To obtain more adequate first-pass conditions, we pursued right atrial injection of Gd-DTPA in this study. The aim of the study was to assess the feasibility of firstpass MRI for semiquantitation of myocardial perfusion in human beings. Possible determinants of the myocardial input, including indicator injection site, indicator concentration, and hemodynamic parameters, were investigated. METHODOLOGY Study population. The study group consisted of 12 healthy volunteers (6 men and 6 women, mean age 27 [range 25 to 33] years). All subjects gave informed consent for participation in the study. In each subject an intravenous catheter (CavafLx Certodyn SD, Braun AG, Germany) was introduced through an antecubital vein and advanced to the right atrial po893

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Fig. 1. Washout curves of GD-DTPA from normal myocardium after central bolus injection. Open circles, Bolus concentration of 0.03 mmol/kg; solid circles, bolus concentration of 0.02 mmol/kg.

sition. An electrocardiograph (ECG) electrode in the tip of the catheter was used to confirm the right atrial position. Three external leads served as a reference for the catheter lead. If no unequivocal P-wave changes could be observed while the catheter was slightly withdrawn, the position was estimated from the remaining catheter length and termed "central" (introduction 40 to 60 cm), "intermediate" (20 to 40 cm), or "peripheral" (<20 cm). The catheter was connected to a hand injector (Cordis, Miami, Fla.) through a tube system for administration of the contrast agent. The injection time was 2.5 seconds. J u s t before each imaging sequence, blood pressure and heart rate were measured with an automatic sphygmomanometer. MR imaging technique. MR image acquisitions were performed on a 1.5 T MR imaging system (Magnetom 63 SP, Siemens AG, Erlangen, Germany) with a Helmholtz receiver coil. A double-oblique short-axis plane was located at the mid-papillary muscle level. The inversion time was adjusted to null the signal from the myocardium (inversion time 25 to 175 msec). A turbo-fast low-angle-shot (FLASH) sequence 9 with a 180-degree inversion pulse was applied (repetition time 4.8 msec, echo time 2 msec, e x citation angle 10 degrees, field of view 2502 to 3002 mm 2, slice thickness 10 mm, matrix 90 × 128, voxel 2.8 x 2.0 × 10 mm 3, and acquisition time 432 msec). With the subject in the supine position, 64 ECG triggered images were obtained, 1 per heartbeat. Subjects were asked to hold their breath as long as possible and, if necessary, to take one quick breath. Adequacy of triggering and regularity of heart rhythm were verified by simultaneously recording ECG sig-

nal and MR pulse (Gould, Cleveland, Ohio). A bolus of Gd-DTPA (0.03 mmol/kg, Schering AG, Berlin, Germany) was injected at the eighth heartbeat after the start of imaging to allow imaging of Steady-state baseline conditions. Contrast agent, The paramagnetic compound GdDTPA 15 increases the relaxation rate of surrounding protons. This change results in the shortening of T1 and T2 relaxation times and hence increased SI on MR images. In concentrations <2 mmol/L, Gd-DTPA displays a linear relation with MR SI with use of a turbo-FLASH sequence. 13, 16 About 50% of injected Gd-DTPA is cleared from the capillaries during its first pass through the body. 17 Fig. 1 shows two washout curves of GD-DTPA from myocardium. From these curves, it follows that bolus injections can be repeated under approximately the same baseline conditions when sufficient washout time is allowed (about 15 minutes). To investigate the effect of bolus concentration on the myocardial input, different bolus concentrations (0.015 to 0.06 mmol/kg) were used in some subjects. Bolus volume w a s kept constant within every subject and was negligible (approximately 7.5 ml) compared with the central volume. Data analysis. MR images were analyzed off-line on a workstation (SUN Microsystems, Mountain View, Calif.). For every Gd-DTPA injection, 10 curves of SI versus time were obtained by measuring SI in regions of interest (ROI) in right ventricular (RV) and left ventricular (LV) cavities and in eight contiguous ROI in myocardium. Images resulting from inadequate triggering or irregular heartbeats were rejected from analysis. ~-Variate curve fitting. According to indicator-dilution theory, 7 MTT can be calculated as -

0O

f tC(t)dt MTT =

o

f C(t)dt o

where C(t) is the indicator concentration at time t. A nonlinear least-squares curve fit was applied to the data points of the SI-time curves according to a ~/-variate function, is described by t m t C(t) = Cp (~-~) e -m % - 1~ where Cp is the peak concentration of the indicator; tp is the time from the start of the upslope to peak concentration; and m is a factor that accounts for the shape of the curve. In practice, SI was imaged

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Fig. 2. SI-time curves of ascending aorta and LV were similar. Data points of ascending aorta and LV were obtained from same acquisitions. Solid lines, Curves fitted to first-pass data points only.

Fig, 3, Typical ventricular SI-time curves. SI first rises in RV cavity before rising in LV cavity. Both curves are followed by second '~hump,"caused by recirculating indicator. Solid lines, Fitted curves.

instead of concentration, and there was always a certain baseline level before the upslope of the SI-time curve, so the formula becomes

Factors shaping ventricular S I - t i m e curves. Under standard conditions of bolus administration, with administration of identical bolus volumes in the same injection time, several factors appeared to have influence on ventricular SI-time curves, as follows. Catheter location: A more peripheral catheter position was found to prolong the LV and RV SI-time curves. Fig. 4 shows the effect of catheter position on ventricular curve shape. Bolus concentration: In another indicator-dilution study, 19 peak SI increased with increasing bolus concentration, but the width of resultant SI-time curves remained constant. However, in this study, bolus concentration appeared to have a widening effect on ventricular SI-time curves, thus prolonging MTT. Fig. 5 shows the effect of increasing bolus concentration on RV and LV curves in one subject. Myocardial SI-time curves. Fig. 6 shows a typical SI-time curve obtained from myocardial and LV ROI in a healthy volunteer. Myocardial SI rises about 1 second after LV SI. Myocardial recirculation follows LV recirculation and is visible as a second upslope, commencing before SI has returned to baseline. Curve-fitting procedure. The first steady-state baseline point of the SI-time curve was assigned the starting point for the curve-fitting ofventricular and myocardial SI-time curves. The curve-fitting algorithm automatically assigned a data point as the starting point of the upslope of the LV and myocardial SI-time curves. If this data point preceded the LV upslope in the case of myocardial SI-time curves

Y(t) = Ys for t < ts and ÷

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Y(t) = Yp ~-y~-) ~ ,m e -m(--=--~p 1) + Ys for t -> ts where Y(t) is the SI at time t; Yp is peak SI; ts is the first time point of the upslope of the SI-time curve; and Ys is the initial baseline SI. Apart from MTT, the time to peak SI and the width (arbitrarily defined as width between data points at 0.1 peak amplitude) of the SI-time curves were also derived from the fitted SI-time curve. Average values of MTT and the other parameters were expressed as means _+ SD. OBSERVATIONS

A central venous position of the catheter was achieved in 7 (58%) of 12 subjects, an intermediate position in 2 (17%), and a peripheral position in 3 (25%). Catheter introduction was tolerated well in all subjects, and no complications occurred. Input to the myocardium: Ventricular SI-time curves. SI-time curves of the ascending aorta were almost identical to LV SI-time curves (Fig. 2). Lacking SItime curves from the coronary arteries, we considered the LV SI-time curves as myocardial input. Fig. 3 shows typical SI-time curves obtained from the ventricular cavities.

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Fig. 4. Effect of catheter position on RV and LV SI-time curves. SI-time curves were obtained by injecting identical boluses at different catheter positions. Within one subjeet, catheter was withdrawn from right atrial to intermediate and peripheral position, respectively. For clarity, only fitted data are shown. Heart rate and blood pressure were constant.

Fig. 5. Effect of different bolus concentrations on LV and RV SI-time curves within one subject with right atrial catheter. Concentrations were 0.00375 (curve 1), 0.0075 (curve 2), 0.015 (curve 3), and 0.03 mmol/kg (curve 4). For clarity, only fitted curves are shown. Heart rate and blood pressure were constant during consecutive imaging sequences.

(because of noise), t h e n a correction w a s m a d e b y i m p o s i n g on t h e a l g o r i t h m t h e first d a t a point a f t e r t h e LV u p s l o p e (accounting for t h e t i m e r e q u i r e d for t h e indicator to t r a v e l f r o m t h e L V to t h e aortic root, t h r o u g h t h e c o r o n a r y arteries, a n d into t h e myocardium). T h e l a s t p o i n t (the cutoffpoint) w a s d e t e r m i n e d b y v i s u a l e s t i m a t i o n of t h e o n s e t of recirculation. F o r t h e v e n t r i c u l a r S I - t i m e curves, t h e cutoff point w a s set a t six d a t a points or m o r e a f t e r t h e point w i t h p e a k SI. A f t e r this point, c u r v e p a r a m e t e r s w e r e not significantly affected b y selection of a l a t e r t i m e point as long as t h e point w a s s i t u a t e d on t h e downslope of t h e v e n t r i c u l a r curve. T h i s finding implies t h a t t h e effect of recirculation on v e n t r i c u l a r M T T is negligible. F o r t h e LV curves, this finding is s h o w n in Fig. 7, A. T h e effect of t h e cutoff p o i n t on m y o c a r d i a l c u r v e p a r a m e t e r s is s h o w n in Fig. 7, B. M T T r e a c h e d m i n -

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Fig. 6. Typical LV and myocardial SI-time curve. Solid line, Fitted myocardial SI-time curve.

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Fig. 7. A, Effect of curve fit cutoff point on LV-curve amplitude, width, and MTT in 12 normal subjects. Selection of cutoff point later than sixth data point after peak SI did not significantly affect these curve parameters. B, Effects ofcutoffpoint on myocardial SI-time-curve parameters in seven subjects with central and two subjects with intermediate catheter position. Solid circles, Recirculation points. In general, optimal cutoff point was data point preceding recirculation point.

imum values when choosing a point before the recirculation point (the inflection point between first circulation and recirculation). This observation implies that when choosing this point as cutoffpoint, the effect of recirculation on the myocardial curve fit is minimized. Usefulness of peripheral injections. In general, the quality of myocardial SI-time curves resulting from a peripheral bolus injection (of equal concentration, 0.03 mmol/kg) was poor, making adequate curve-fitting impossible. Myocardial MTT in normal subjects and patients. Absolute values of myocardial MTT in different regions in healthy subjects were quite similar (Fig. 8). Table I shows the values (means _+ SD) of MTT and of other curve parameters. As expected, myocardial MTT was related to LV MTT (Fig. 9). COMMENTS

In this study we evaluated methodologic aspects of first-pass MR imaging in human subjects, in pursuit of clinical application of the method.

Dependence of myocardial MTT on input. The dependence of myocardial MTT on the input is a practical problem that needs to be solved when clinical application of first-pass MR imaging is the objective. The myocardial input, in casu the ventricular SI-time curve, appeared to depend on injection site and bolus concentration. Administration of a central venous bolus is the best possible low-invasive way to obtain a sharp bolus. Myocardial SI-time curves originating from a central bolus injection of 0.03 mmol/kg Gd-DTPA allow adequate curve-fitting, unlike those from peripheral injections. Our results indicate that analysis with MTT becomes difficult if not impossible when a peripheral bolus (with the same concentration) is given. A peripheral bolus results in wider and lower ventricular SI-time curves (Fig. 4). Differentiation between the first and second passes becomes troublesome because the input continues while recirculating indicator has already returned to the myocardium. Increasing the bolus concentration leads to greater Sis, improving the signal-to-noise ratio.

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Fig. 8. MTT in seven normal subjects with central catheter position. Regions 1 to 8 refer to clockwise contiguous ROI, starting from anterior insertion of the right to the left ventricle.

Table I. Mean curve parameters averaged over eight my-

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ocardial ROI in seven normal subjects with central catheter position

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Fig. 9. Relation between mean myocardial MTT and LV MTT in 7 subjects from Fig. 8. Line of linear regression is shown.

However, the concentration of Gd-DTPA studied had a marked effect on ventricular SI-time curves (Fig. 5). From work in the indicator dilution technique, a rise in amplitude with increasing concentration is expected, 19 but in theory the width of the curve should be independent of bolus concentration. After scaling up the different curves to the maximum SI at the greatest concentration used, these differences in curve width were still apparent. This result means t h a t the phenomenon cannot be explained by the nonlinear relation between contrast agent and SI or by the accuracy of the measuring system. It suggests t h a t Gd-DTPA has longer residence in the heart when the bolus concentration is greater. Even if bolus injection site and concentration are standardized, variations in cardiac output would still influence the myocardial input. Hence, to compare myocardial MTT in serial measurements or to make interindividual comparisons, deconvolution of

•

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Values are expressed as means -+ SD. Width, Width of myocardial SI-time curve at 0.1 peak amplitude; tp, time from upslope of myocardial SI-time curve to peak amplitude.

the myocardial input is necessary. 2° In theory, deconvolution' is possible when the input function (i.e., the LV SI-time curve) is known. The nonlinear behavior of Gd-DTPA in the ventricles is a complicating factor in this matter. MTT as a flow parameter. The first-pass MR imaging technique has been applied by several investigators.lO, 13 In MR and other imaging studies, m a n y physical parameters have been derived from first circulation SI-time curves and related to myocardial blood flow. 1-6, 10, 13 MTT (the average of all of the various times it takes different indicator particles to traverse the organ of study) and regional blood volume are parameters with a physiologic meaning, m The work of Meier and Zierler 7 established the use of these parameters on a solid theoretical basis. Wilke et al. 13 validated the use of MTT as a parameter for myocardial blood flow by using the first-pass MR imaging method. The importance of MTT lies in

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its inverse relation to myocardial blood flow. If blood volume is known, blood flow can be calculated. Because it often is not known, at least the ratio of flow at two times or locations can be calculated, provided the blood volume is constant. Applying MTT as flow parameter has the advantage that all first-circulation data points are used for its calculation, whereas other parameters are derived from considerably fewer data points. Furthermore, MTT is not affected by spatial variations in MR signal magnitude, contrary to SI-dependent parameters such as peak amplitude and slope. An often encountered objection against the use of MTT is that extrapolation is necessary beyond the recirculation point. With use of the ~-variate function for fitting ventricular SI-time curves, the influence of recirculation was negligible. As for the myocardial SI-time curves, the influence of recirculation can be reduced to a minimum when fitting according to the proposed empirical rules. In practice, the first part of the curve usually matches very well with the ~-variate function. However, curve-fitting of the true first pass becomes impossible when the first pass of the myocardial input is slow and thus continues into recirculation. In general, the possibility to discern the first from the second pass depends on the sharpness of the bolus and the circulation in the organs responsible for initial recirculation, the heart and kidneys. 14 We have shown that myocardial MTT in normal subjects at rest is similar in all regions of the myocardial short-axis slice. Absolute values of myocardial MTT, depending on the input, are slightly higher than the resting values from first-pass studies in h u m a n beings with selective coronary or leftside heart injection. 22 Feasibility. Performing first-pass MR imaging on an outpatient basis is safe and relatively easy. Imaging a single short-axis level at first-pass (including catheter introduction) takes approximately 1 hour. Each additional level takes 10 minutes more. However, advancing the catheter to the intended central position may be a problem in some subjects. Limitations. As discussed earlier in this article, the relation between Gd-DTPA concentration and SI is positively linear for Gd-DTPA concentrations <2 mmol/L. Without direct blood sampling, there is no w a y of knowing whether conditions in the central circulation will yield linear data. However, as significant dilution and dispersion occurs between the right atrium and myocardium, we assume concentrations in myocardium to approach linear conditions. Use of a diffusible indicator such as Gd-DTPA has implications for the obtained LV and myocardial S I -

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time c u r v e s . 23' 24 The prolonging effect of lung passage (diffusion and dispersion) on LV MTT negatively affects the myocardial SI curves, making distinction between first and second circulation more difficult by broadening the input. Diffusion may also affect the myocardial SI-time curves. Tong et al. 25 showed that the effect of diffusion into canine myocardium is largest for lower ranges of flow (<0.5 ml/ min). Therefore we expect diffusion to have a prolonging effect on myocardial SI-time curves in the case of a critical coronary stenosis. This implies overestimation of the measured MTT, which does not necessarily hinder the detection of low flow but may even increase differences between normal and hypoperfused myocardium. According to indicator-dilution theory, curves of concentration versus time can be constructed 14when an indicator is sampled at the exit of an organ. Sampling by changes in imaging contrast density in the organ itself is a fundamentally different situation 26 The measured entity is the amount of indicator remaining in the organ instead of the amount leaving the organ. Because the former depends on the underlying vascular structure, in theory it is incorrect to use it for measuring absolute blood flow, but it allows a relative comparison between two situations with the same vascular structure. With respect to this problem, MTT in this study was compared only between myocardial regions in the same slice, assuming no major differences in regional vascular anatomic features. To avoid confusion, we followed previous nomenclature in the use of"MTT," although it would be more correct to speak of "mean residence time." In this study, subjects were studied at rest. For clinical application in patients with coronary artery disease, it would be preferable to rule out vascular volume as a variable by inducing maximal vasodilation. However, in the case of a severe stenosis, abnormalities in first-pass curves can also be expected at rest. 10 Furthermore, there is evidence that MTT at rest can predict vasodilatory capacity because of its dependence on vascular volume. 27 In all subjects we encountered concentric ringshaped structures of signal loss. Shortening the acquisition time window in the cardiac cycle reduced the intensity of these artifacts, supporting the hypothesis that they are associated with myocardial motion. Given the limitations of the scarming technique used, we used a minimal time window of 432 msec. The artifacts occurred mainly in conjunction with high signal intensities in the ventricular cavities and hence affected few (zero to four) points in the upslope of myocardial SI-time curves. Because the

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starting point for the myocardial curve fit was assigned according to the upslope of the LV SI-time curve, curve-fitting usually was possible. Future developments. The distinct shape of firstpass SI-time curves may be improved by an intravascular contrast agent. Recent technical developments may accelerate the clinical application of first-pass MR imaging. Spatial resolutionwill benefit from faster scanning techniques, such as echoplanar imaging. 28, 29 A better signal-to-noise ratio can be achieved by using phased-array coilsP ° These developments offer perspectives for measurement of transmural differences in perfusion. Echo-planar imaging can improve temporal resolution. Because of its shorter acquisition time, this technique reduces motion artifacts and allows simultaneous imaging of different myocardial levels. Thus, information about regional perfusion in a major part of the myocardium may be obtained in a limited amount of time. SUMMARY

The purpose of this study was to investigate the feasibility of first-pass MR imaging for measurement of regional myocardial blood flow in human beings. The first pass of the contrast agent Gd-DTPA through the myocardium was imaged in 12 normal volunteers with an ECG-gated Turbo-Flash sequence. The MTT of the contrast agent through the myocardium after a bolus injection was derived from curves of SI versus time. The bolus was injected through an intravenous catheter, which was advanced to the central venous position (preferably the right atrium). To investigate myocardial input function, different bolus concentrations and catheter positions were compared. It is concluded that first-pass MR imaging is feasible in human subjects when a central injection of 0.03 mmol/kg of Gd-DTPA is applied. MTT values were similar throughout the myocardium of normal subjects at rest, reflecting normal perfusion. Absolute values of MTT were related to the myocardial input. W e t h a n k R. P r i n s z e n and K. v a n der V e g t for their assistance in scanning. REFERENCES

1. Kaul S, Kelly P, Oliner JD, Glasheen WP, Keller MW, Watson DD. Assessment of regional myocardial blood flow with myocardial contrast two-dimensional echocardiography. J Am CoU Cardiol !989;13:468-82. 2. Porter TA, D'Sa A, Turner C, Jones LA, Minisi AJ, Mohanty PI~ Vetrovec GW, Nixon JV. Myocardial contrast echocardiography for the assessment of coronary blood flow reserve: validation in humans. J Am Coll Cardiol 1993;21:349-55. 3. Rumberger JA, Feiring AJ, Lipton MJ, Higgins CB, En SR, Marcus ML. Use of ultrafast computed tomography to quantitate regional myocardial perfusion: a preliminary report. J Am Cell Cardiol 1987;9:59-69.

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4. Weiss RM, Otoadese EA, Noel MP, DeJong SC, Heery S. Quantitation of absolute regional myocardial perfusion using cine computed tomography. J Am Coll Cardiol 1994;23:1186-93. 5. Pijls NHJ, Uijen GJH, Hoevelaken A, Arts T, Aengevaeren W, Bos HS, Fast JH, Van Leeuwen KL, Van der Werf T. Mean transit time for the assessment of myocardial perfusion by videodensitometry. Circulation 1990;81:1331-40. 6. Eigler NL, Schuelen H, Whiting JS, Pfaff JM, Zeiher A, Gu S. Digital angiographic impulse response analysis of regional myocardial perfusion: estimation of coronary flow, flow reserve, and distribution volume by compartment transit time measurement in a canine model. Circ Res 1991;68:870-80. 7. Meier P, Zierler KL. On the theory of the indicator-dilution method for measurement of blood flow and volume. J Appl Physio11954;6:731-44. 8. Bloomfield DA. Dye curves: the theory and practice of indicatordilution. Baltimore: University Park Press, 1974. 9. Frahm J, Merboldt KD, Bruhn H, Gyngell ML, Haenicke W, Chien D. 0.3-Second FLASH MRI of the h u m a n heart. Magn Res Med 1990;13:150-7. 10. Manning WJ, Atkinson DJ, Grossman W, Paulin S, Edelman RR. First-pass nuclear magnetic resonance imaging studies using gadolinInm-DTPA in patients with coronary artery disease. J Am Coll Cardiol 1991;18:959-65. 11. Schaefer S, VanTyenR, SalonerD. Evaluation ofmyocardialperfusion abnormalities with gadolinium-enhanced snapshot MR-imaging in humans. Radiology 1992;185:795-801. 12. Klein MA, Collier BD, Hellman RS, Bamrah VS. Detection of chronic coronary artery disease: value of pharmacologically stressed, dynamically enhanced turbo-fast low-angle shot MR images. AJR Am J Roentgenol 1993;161:257-63. 13. Wilke N, Simm C, Zhang J, Ellermarm J, Ya X, Merkle H, Luedemarm H, Bache RJ, Ugurbil tL Contrast-enhanced first-pass myocardial perfusion imaging: correlation between myocardial blood flow in dogs at rest and during hyperemia. Magn Res Med 1993;29:485-97. 14. Nichols KRK, Warner HR, Wood EH. A study of dispersion of an indicator in the circulation. Ann N Y Acad Sci 1964;115:721-37. 15. Weinmann HJ, Brasch RC, Press WR, Wesbey GE. Characteristics of gadolinium-DTPA complex: a potential NMR contrast agent. AJR Am J Roentgenol 1984;142:619-24. 16. Manning WJ, Atkinson DJ, Parker AJ, Edelman RE. Assessment of intracardiac shunts with gadolinium-enhanced ultrafast MR imaging. Radiology 1992;184:357-61. 17. Schmiedl U, Moseley ME, Ogan MD, Chew WM, Brasch RC. Comparison of initial biodistribution patterns of Gd-DTPA and albumin-(GdDTPA) using rapid spin-echo MR imaging. J Comput Assist Tomogr 1987;11:306-13. 18. Thompson HK, Starmer CF, Whalen RE, McIntosh HD. Indicator transit time considered as a gamma variate. Circ Res 1964;14:502-15. 19. Burbank FH, Brody WR, Bradley BR. Effect of volume and rate of contrast medium injection on intravenous digital subtraction angiographic contrast medium curves. J Am C011 Cardiol 1984;4:308-15. 20. Rosen BR, Belliveau JW, Chien D. Perfusion imaging by nuclear magnetic resonance. Maga Reson Q 1989;5:263-81. 21. Klingensmith WC. Regional blood flow with first circulation time-indicater curves: a simplified, physiologic method of interpretation. Radiology 1983;149:281-6. 22. Pijls NHJ, Uijen GJH, Pijnenburg T, Van Leeuwen KL, Aengevaeren W, Barth JD, Den Arend J, Hoeveiaken A, Van der Werf T. Reproducibility of mean transit time for maximal myocardial flow assessment by videodensitometry. Int J Card Imaging 1990/1991;6:101-8. 23. Chinard FP, Enns TE, Nolan MF. Indicator-dilution studies with diffusible indicators. Circ Res 1962;10:473-90. 24. Canty JM, Judd RM, Brody AS, Klocke F. First-pass entry of nonionic contrast agent into the myocardial extravascular space: effects on radiographic estimates of transit time and blood volume. Circulation 1991;84:2071-8. 25. Tong CY, Prato F, Wisenberg G, Lee TY, Carroll E, Sandler D, Wills J. Measurement of the extraction efficiency and distribution volume for Gd-DTPA in normal and diseased canine myocardium. Magn Resort Med 1993;30:337-46.

Volume 130, Number 4 American Heart Journal

26. WeiskoffRM, Chesler D, Boxerman JL, Rosen BR. Pitfalls in MR measurement of tissue blood flow with intravascular tracers: which mean transit time? Magn Res Med 1993;29:553-9. 27. Schuelen H, Eigler NL, Whiting JS. Digital angiographic impulse response analysis of regional myocardial perfusion: detection of autoregulatory changes in nonstenotic coronary arteries induced by collateral flow to adjacent coronary arteries. Circulation 1994;89:1004-12.

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ABIM ANNOUNCEMENT REGARDING BOARD ELIGIBILITY

The American Board of Internal Medicine is undertaking a complete review of its policies concerning Board Eligibility. The ABIM anticipates that revised Board Eligibility policies will be announced by December 31, 1996. In the interim, the rules concerning the duration and reestablishment of the Board Eligible status will be suspended. All candidates with this status will continue to be regarded as Board Eligible and therefore able to sit for the Certifying Examinations in internal medicine or the subspecialties. However, the Board's Qualifying Examination, developed to reestablish Board Eligibility, will not be offered. Candidates who have questions about this policy should contact the American Board of Internal Medicine, 3624 Market St., Philadelphia, PA 19104-2675 (800-441-2246).