Application of digital techniques to selective coronary arteriography: Use of myocardial contrast...

Application of digital techniques to selective coronary arteriography: Use of myocardial contrast appearance time to measure coronary flow reserve

Robert Vogel, M.D., Michael LeFree, B.S., Eric Bates, M.D., William O’Neill, M.D., Richard Foster, M.D., Philip Kirlin, M.D., David Smith, B.S., and Bertram Pitt, M.D. Ann Arbor, Mich.

For more than 20 years, selective coronary arteriography has remained virtually the only clinical technique for visualizing the coronary arteries. Only recently have echocardiography’ and computerized radiography” 3 and tomography made modest con- tributions to evaluating the anatomy of the proximal portions of the coronary arteries and saphenous vein bypass grafts. Increasing evidence suggests, however, that visual estimation of arterial narrowing is often inaccurate and unreproducible5,6 and is poorly predictive of the hemodynamic consequences of the narrowings.7ps Arteriography, itself, has been only occasionally used for determinations of coronary blood flow, although densitometric measurements of absolute coronary flog-l2 and coronary flow reserve13 have been reported. More widely used clinical and experimental techniques for measuring coronary flow and myocardial perfusion include use of arterial electromagnetic flow meters,14 coronary sinus thermodilution catheters,15 directly applied and catheter-tipped velocity probes,16p l7 inert gas washout analysis,18 left heart and intracoronary administered labeled particles,1gp 2o and myocardium-avid radionu- clides.21 All of these, except the latter category of which thallium-201 is an example, yield quantitative information. Resultant regional and global flow information can be classified by whether it is relative or absolute in nature. With the use of any of these methods, full clinical evaluation often includes

From the Division of Cardiology, Veterans Administration Medical Cen- ter.

Supported in part by research funds of the Veterans Administration.

Received for publication Aug. 12,1982; revised Nov. 1,1982; accepted Dec. 20, 1982.

Reprint requests: Robert Vogel, M.D., Division of Cardiology, Veterans Administration Medical Center, 2215 Fuller Rd., Ann Arbor, MI 48105.

use of hyperemia-inducing stimuli so as to obtain data on coronary flow reserve in addition to basal data?’

In recent years, significant advances have been made in the application of computer technology to radiographic imaging. This combined technique, termed digital radiography, has resulted in the visualization of intravascular structures by means of intravenously injected contrast media23,24 or directly injected contrast media in reduced volume.25 These applications have in common the enhanced imaging of low concentrations of contrast media. Image enhancement of selective coronary arteriography for the purposes of measuring blood flow and distribution has also been suggested.% Our article describes a new technique for performing image enhancement of selective coronary arteriography with the purpose of fulfilling these goals. With the use of this digital approach, the spatial distribution and timing of contrast medium appearance through its arterial, myocardial, and venous phases are depicted in functional images with the use of simultaneous modula- tion of intensity and color. One parameter derivable by this technique, myocardial contrast appearance time, was investigated as a measure of relative regional blood flow. The reproducibility of this parameter was determined and its inverse propor- tionality to coronary blood flow with the use of coronary sinus and great cardiac vein thermodilution was correlated. Coronary flow reservet2 by means of contrast media-induced hyperemia, was explored with the use of this technique in patients with and without coronary artery disease. Results suggest that selective coronary arteriography can yield information on relative regional blood flow as well as anatomy.

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154 Vogel et al. January, 1984

American Heart Journal

Fig. 1. Digital enhancement of selective coronary arteriography. Six consecutive pre-P wave end- diastolic cinearteriographic frames digitized into 256 X 256 eight-bit pixel matrices are shown in the top row (CA). These were obtained in the left anterior oblique projection from a patient with total left anterior descending coronary artery obstruction. In this early study, CA-O was obtained just following contrast medium injection. The middle row (G10) demonstrates application of the gated-interval differencing process to the CA frames. This is performed by subtraction of consecutive CA frames (e.g., CA-4 minus CA-3 yields GID-4). The bottom row (MM) demonstrates application of the mask-mode enhancement process using CA-O as the mask (e.g., CA-4 minus CA-O yields MM-4). It should be noted that the myocardial (GID-3) and venous (GID-5) phases of contrast transit are seen in considerably greater isolated fashion when gated-interval differfencing is used rather than mask-mode enhancement. The ability to determine the temporal sequence of regional contrast appearance serves as the basis for using digital processing to assess relative coronary blood flow.

METHODOLOGY

Arteriography. Investigation involving patients was reviewed and approved by the Committee on Human Studies. Participating patients, following informed consent, underwent selective coronary arteriography and left ventriculography for clinical indications. Standard technique multiple-view arteriography was accomplished with the use of a biplane cineangiographic unit (Philips Corp., Eind- hoven, the Netherlands, Optimus M200). Arteriog- raphy for subsequent digital processing was obtained in the left anterior oblique projection by means of fixed kV, mA, and pulse width x-ray exposure at 30 frames/set. During this type of imaging, patients were required to hold their breath at moderate inspiration, and no table panning was permitted. Sodium meglumine diatrizoate (Squibb & Sons, Inc., Princeton, NJ, Renografin-76), 4 to 6 cc, was hand injected over a three-cardiac cycle interval for opacification of the right coronary artery and 6 to 8 cc over the same interval was used for the left coronary artery. Individual rates of injection

were chosen so as to produce a small amount of reflux into the sinuses of Valsalva. Multiple studies of individual coronary arteries were performed with the use of the same injection rate and volume. The coronary catheter was not withdrawn following contrast medium administration, and its position was not varied between repeated studies. Care was taken to begin film exposure at least one cardiac cycle prior to contrast medium injection, which was initi- ated as close to the QRS complex as possible. All arteriography was recorded on 35 mm tine film (Kodak Corp., Rochester, NY, CFR), along with the patient’s ECG.

Digital processing. Digital processing of the 35 mm tine films required three general operations: digitization, gated interval differencing, and functional image generation. Selective coronary arteriograms undergoing computer processing were displayed on a projector (Vanguard Corp., Melville, NY, XR-35) equipped with a primary beam splitter coupled to a fixed-gain video camera. Six consecutive cardiac cycle pre-P wave end-diastolic frames were chosen,

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Number 1 Coronary reserve by digital contrast-enhanced arteriography 155

beginning just prior to contrast medium injection, by means of the combined criteria of ECG core- spondence and duplication of arterial posit on. These six frames were digitized into 256 X 256 eight- bit (256 gray shades) pixel matrices by averaging eight video digitizationa of each chosen frame so as to reduce video noise (Colorado Video Corp., Boul- der, CO, model 274). Video amplifier gain and projector light levels were adjusted to provide a linear correspondence between contrast x-ray absorption and digital scale. The digital images were stored in the disk memory and subsequent processing was performed on a minicomputer (Digital Equipment Corp., Maynard, MA, PDP 11/34). Image enhancement was then performed by means of gated-interval differencing of the six digitized frames. This technique, first reported by this laboratory for enhancement of intravenous contrast injection left ventriculography,27-2g utilizes subtraction of consecutive ECG-gated frames, each separated by a single cardiac cycle. These corresponding frames can be chosen from any portion of the cardiac cycle, pre-P wave end-diastolic timing being chosen for coronary artery enhancement because of the mini- mal cardiac motion present during this period. This technique differs from mask mode enhancement3*26 which employs subtraction of a single frame obtained prior to contrast administration from the series of frames obtained following contrast injection. Examples of application of gated-interval differencing and gated mask mode subtraction to a series of six digitized selective coronary arteriograms are shown in Fig. 1.

A single-intensity and color-modulated functional image was then generated from each set of five enhanced images. Five colors, each corresponding to one of the five postcontrast injection cardiac cycles analyzed, were used to display the cycle in which contrast medium appeared in each pixel. Two hun- dred fifty-six intensity levels were used to depict the relative amount of the increase in contrast medium that occurred in each pixel during its appearance cycle. This form of dual functional arteriographic image was termed a contrast medium appearance picture (CMAP), major steps in the generation of which are displayed in Fig. 2 using the data presented in Fig. 1.

image analysis. Myocardial contrast appearance time (MCAT), defined as the time from the onset of contrast injection to its appearance within a region of myocardium, was investigated aa an index of relative regional coronary blood flow. Regional MCATs were determined from the CMAPs by means of averaging of the appearance times of all

Table I. Results of repeat regional MCAT determinations

Pair Arterial MCAT, MCAT, MCAT,/ NO. distribution fsec) (see) MCAT,

1 LAD 2.46 2.63 0.94 2 LAD 1.92 2.08 0.92 3 LAD 2.09 1.82 1.15 4 CIRC 2.36 2.64 0.89 5 CIRC 3.19 2.68 1.19

6 CIRC 2.44 2.56 0.95 7 RCA 2.34 2.17 1.08 8 RCA 2.53 2.32 1.09

9 RCA 2.13 2.50 0.85 Group mean k 1 SD 1.01 * 0.12

Abbreviations: MCAT = myocardial contrast appearance time (subscripts

refer to first of second determination); LAD = left anterior descending coronary artery; CIRC = circumflex coronary artery; RCA = right coronary artery.

the pixels within an operator-defined region of interest. These regions were chosen to correspond to individual arterial distributions with exclusion of the artery itself. Repeated individual analyses used equivalent regions of interest. Averaged regional CMAP values are the same as ostium to myocardium transit times (MCATs) due to the initiation of the CMAP formation process simultaneous with the onset of contrast medium injection, as noted previously. Computer data generated as part of each regional MCAT analysis included: mean and standard deviation of appearance time (in cardiac cycles), total number of pixels in the region of interest, and number of pixels in the region within which contrast appeared (Fig. 3).

The relationship between regional coronary blood flow and the transit time index MCAT can be expressed as follows. Equation 1: Regional blood flow = regional distributional volume/MCAT. Un- der the circumstance that the regional distributional volume remains unknown, MCAT cannot be used to determine absolute coronary flow. During conditions when regional flow varies, but distributional volume does not, the following relationship within a single region holds true. Equation 2: Regional blood AowJregional blood flow, = MCATJMCAT,. This formula, based on the assumption that regional distributional volume remained constant, was used to calculate relative flow changes from the variations in MCAT in individual coronary regions of interest. As part of its application, MCAT change was corrected for alterations in cycle length. Due to the individual patient variability in regional distributional volumes, only MCAT ratios (not MCAT values) were compared between different regions

156 Vogel et al.

and patients. In doing this, each individual patient region served as its own control.

Patient studies. Investigation into the use of the MCAT ratio as an index of relative regional coronary blood flow was divided into studies of reproducibility, correlation with directly measured blood flow changes, and hyperemic change as a function of associated coronary artery disease. Thirty male patients, ages 27 to 61, had CMAP analysis of at least one major arterial distribution as part of their coronary arteriography. Fifty-seven of 70 attempted regional MCAT ratio determinations were included in the study. Thirteen were excluded due to patient motion which caused excessive arterial misalign- ment. Major arterial distribution analyses were lim- ited to regions associated with normal or hypokinetic wall motion on biplane left ventriculography. Akinetic and dyskinetic segments were excluded so as to reduce the effect of the unknown hyperemic capacity of myocardial scar on these initial studies.

To measure reproducibility, nine arterial distributions were each analyzed on two occasions under similar control conditions. All 18 arteriograms were obtained at least 3 minutes following any prior contrast medium administration. Each arteriogram was subjected to CMAP formation and histographi- tally analyzed MCAT determination for matching major arterial distribution regions of interest. Intrinsic MCAT reproducibility was reported as the standard deviation of the ratios of the pairs of values.

Validation of MCAT ratio correlation with changes in regional blood flow was performed by means of coronary sinus and great cardiac vein thermodilution determinations of blood flow as the

January. 1984


standard.15 Overall left coronary artery perfusion regional MCAT ratios were compared in 12 instances with changes in coronary sinus flow, and left anterior descending regional MCAT ratios were compared in eight instances with great cardiac vein flow changes. In four instances, both coronary sinus and great cardiac vein flows could not be reliably measured as manifest by respiratory variation of the thermodilution tracings. Coronary blood flow was varied by atrial pacing, with measurements being compared between control (nonpaced) and one of 80, 100, or 120 paced heart rates. The linear regression equation and correlation coefficient were calculated for the flow ratios as determined by angiography versus thermodilution.

Twenty-eight major arterial distributions were subjected to CMAP formation and histographically analyzed MCAT determination under control conditions (no contrast medium administration during the prior 3 minutes). In each instance, the same data were also obtained under hyperemic conditions induced by 4 to 8 cc of intracoronary contrast medium administered 10 seconds previously. In the two instances in which significant bradycardia resulted from the hyperemia-inducing injection of contrast medium, demand right atrial pacing was employed to prevent heart rate from dropping more than 20%. By means of the standard multiple-view angiography performed on each of the arterial distributions, maximal coronary stenosis (percentage of normal diameter) was calculated by means of hand tracings of the projected arterial silhouette of the view in which the coronary stenosis appeared to be of the highest grade. Caliper measurements of the stenotic and normal arterial diameters were obtained, and maximal diameter stenosis was calcu-

Fig. 2. Contrast medium appearance picture (CMAP) formation. The maximal value of each corresponding pixel location within the five gated-interval differenced frames (Fig. 1, GID 1-5) is determined and depicted in the upper left panel. The GID frame numbers of each of these maximal value pixels are then color coded and displayed in the upper right panel. The specific color sequence used is shown in the small bar in the lower left panel. For example, red pixels denote locations in which contrast medium increase was maximum (i.e., contrast appeared) during the first cardiac cycle following contrast injection; yellow pixels denote contrast appearance during the second cardiac cycle, etc. The final CMAP (lower left) is both intensity and color modulated to simultaneously depict both the amount and timing of regional contrast appearance. The arterial phase, alone, is shown in the lower right panel. Fig. 3. Histographic determination of mean myocardial contrast appearance time. The process of averaging the contrast medium appearance time over the many pixels within an operator-defined region of interest (outlined in pink in the lower left panel and displayed in isolated fashion in the upper left panel) is illustrated. In this example, a distal circumflex coronary artery region of perfusion was chosen. The appearance time histogram is displayed in the upper right panel. Final data (lower right panel) include mean and standard deviation of regional contrast medium appearance time, the number of pixels in the entire region, and the number of pixels in the region within which contrast appeared. This process increases the temporal precision for regional determinations beyond the individual pixel five-sampling point limitation.

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See legend on opposite page.



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Fig. 4. Validation of relative blood flow changes. Region- al changes in blood flow determined arteriographically (AQA) are compared with correspondent changes in flow measured by thermodilution (AQr). Left coronary regional flow changes were compared with coronary sinus changes (solid dots) and left anterior descending regional flow changes were compared with great cardiac vein flow changes (open dots). The lines of identity (solid) and linear regression between these parameters (broken) are shown. Variations in regional flow were induced with atria1 pacing. The regression line (% change) can be expressed as y = 0.79x + 5.3 (F = 0.90, p < 0.0001).

lated to the nearest 5%. Regional coronary flow reserves were determined as cycle length-corrected MCAT ratios. Values obtained from normal (<20% stenosis) regions were statistically compared with those distal to >70% stenoses by means of the unpaired t test.

OBSERVATIONS

No untoward reactions occurred in any of the patient studies. Specifically, repeat contrast medium injection, at an interval of 10 seconds, which was required for hyperemic arteriography, was well tol- erated in all cases. The results of the nine repeated MCAT determinations performed to measure their reproducibility are listed in Table I. The reproducibility of this parameter was found to be 12%. Subsequently, MCAT ratios were judged to represent statistically significant alterations in regional flow if they were outside of the range 0.76 to 1.24 (1.00 z!z 2 SD).

A 0.90 correlation coefficient was found between regional blood flow ratios determined by the CMAP arteriographic and the thermodilution techniques (p < 0.0001). These data are plotted in Fig. 4.

% CORONARY ARTERY STENOSIS

Fig. 5. Coronary flow reserve compared with degree of coronary stenosis. The hyperemia-to-control flow ratio measured regionally by means of contrast-induced hyperemia is shown plotted against the percentage diameter stenosis of the perfusing coronary artery. Regional flow ratios were determined by using the assumption that flow was inversely proportional to myocardial contrast appearance time and were evaluated in regions distal to stenoses, if present. Based upon reproducibility studies, a ratio of 1.0 f 0.24 is statistically unchanged (stippled area). All of the 12 normal and none of the seven high-grade stenosis regions of perfusion demonstrated significant hyperemic flow increases. The regions distal to the nine intermediate-grade stenoses (25% to 74%) demonstrated variable responses.

The linear regression equation was found to be y = 0.79x + 5.3, where y and x represent CMAP and thermodilution percentage flow changes, respectively. The CMAP technique tended to underestimate large increases in flow, although in a linear man- ner.

Data on the 28 coronary flow reserve determinations are given in Table II. Their hyperemia-to- control flow ratios are plotted against the degree of stenosis of the supplying artery in Fig. 5. All patients with normal coronary arteries, four of nine patients with 20 % to 65 % coronary stenoses, and no patients with >70% coronary stenoses had significant hyper- emit changes following contrast medium challenge. The group mean ratio for those with normal arteries was 1.82 -t 0.33, whereas the group mean for those with >70% stenoses was 1.01 + 0.12. These two groups differed significantly in their responses to hyperemic challenge 0, < 0.01). Examples of CMAPs obtained from a patient with normal right and left coronary arteries are shown in Fig. 6.

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Fig. 6. Arteriographic determination of coronary flow reserve. Left anterior oblique projection left coronary (top panels) and right coronary (bottom panels) artery contrast medium appearance pictures obtained during baseline (left panels) and hyperemic (right panels) conditions from a patient with normal coronary arteries are shown. Faster coronary artery blood flow under hyperemic conditions can be appreciated by the greater distance the contrast bolus travels along the arteries during the first cardiac cycle following injection (red color) compared with the baseline studies. The regions perfused by these arteries demonstrate earlier contrast appearance (yellow and white vs green and blue) during hyperemia suggesting increased regional flow. The ratio of appearance times (corrected for heart rate changes) is used to determine the regional coronary flow reserve. In these studies, hyperemia was induced by a lo-second prior injection of contrast medium.

COMMENTS

Previous techniques. The arteriographic assessment of coronary blood flow has been previously accomplished by Rutishauser et al.gvlo and Smith et al. 11* l2 with the use of intracoronary and aortic root contrast media injection, respectively. Both of these similar approaches used densitometric determinations of the mean transit time of the contrast medium through a measured length and diameter of arterial segment to calculate absolute coronary flow. Good correlations were reported between angiographic and flow meter determinations. In general, however, their determinations can be applied only to proximal, nonbranching coronary arteries whose courses need to be perpendicular to the x-ray beam. This, coupled with the requirement for precise

arterial diameter determination, makes these techniques invalid for circuitous, distal, or branched arterial distributions. They do suggest, however, that coronary flow can be measured by means of some form of contrast medium distributional transit time.

More recently, Foerster et all3 described a technique to measure coronary reactive hyperemia with the use of selective coronary arteriography. This parameter of relative coronary flow was determined by means of comparative densitometric analysis of a known amount of injected contrast medium as it traversed a selected coronary artery region. This technique does not require measurement of either coronary artery diameter or arterial segment absolute length. It does require, however, that the entire

160 Vogel et al. January. 1984


Table II. Patient arteriographic, ventriculographic, and control and hyperemic MCAT data

Patient

Cloronary artery stenosis (5%)

LAD, CIRC, RCA Left ventriculography MCAT HR, HR, MCAT, MCAT, Flow AP,ANT,POST,INF distribution fbpm) @pm) (set) Csec) ratio

2 0, 0, 0 N, N, N, N

3 0, 0, 0 N, N, N, N

5 6

8 9

10

11

12

13 100, 80, 65* N, N, N, N

14 80, 80, 100 H, N, K H

15 80, 100, 90 H, N, A, H 16 100, 50, so A, N, A, A

0, 0, 0 N, N. N, N

0, 0, 0 N, N, N, N

0, 0, 0 N, N, N, N 100, 30, o* N, N, N, N

20, 100, 35 D, N, A, N 50, loo, 100 A, N, A I-I 65, 0, 95 N, N, H, A 40, 60, SO N, N, N N

20, 95, 25

30, 75, 100 A. N, H, A

N, N, N, N

LAD 66 63 4.20 2.51 1.67 CIRC 66 63 4.09 2.36 1.73 RCA 62 58 4.81 2.14 2.25 LAD 75 69 2.64 1.82 1.45 CIRC 75 69 2.84 1.92 1.48

RCA 72 62 2.90 1.92 1.51

LAD 55 53 4.07 2.50 1.63 CIRC 55 53 4.22 2.18 1.94

RCA 62 55 3.48 1.54 2.26 LAD 51 60 3.70 1.89 1.96 CIRC 51 60 2.94 1.82 1.62 RCA 72 67 4.73 1.99 2.38 CIRC 75 67 2.61 1.96 1.33 RCA 69 67 2.63 1.83 1.44 LAD 58 56 2.08 2.48 0.84 LAD 67 69 2.50 2.58 0.97 LAD 51 53 2.60 2.85 0.91 CIRC 51 53 3.33 3.42 0.97 LAD 78 78 3.01 1.85 1.63 CIRC 78 78 2.97 2.81 1.06

LAD 56 55 2.26 1.89 1.20 CIRC 56 55 2.35 3.33 0.71 CIRC 64 56 1.84 1.75 1.05 RCA 72 72 3.01 2.38 1.26 LAD 67 64 2.96 2.48 1.19 DIAG 67 64 2.30 2.13 1.08 RCA 72 86 2.40 2.22 1.08

LAD 60 64 2.99 3.35 0.89

Abbreviations: LAD = left anterior descending coronary artery; CIRC = circumflex coronary artery; RCA = right coronary artery; AP = apical segment; ANT = septal and anterior segments; POST = posterior segments; INF = inferior segment; N = normokinetic; H = hypokinetic; A = akin&c; D = dyskinetic; MCAT = myocardial contrast appearance time; HR = heart rate: subscripts C and H refer to control and hyperemic states, respectively. *Patent LAD saphenous vein graft.

contrast medium bolus be injected without reflux into the coronary artery. In opposition to the techniques described above, this method is applicable to more distal coronary locations and does not require the arterial segment to be perpendicular to the x-ray beam. These factors suggest that the measurement of relative rather than absolute flow is less technical- ly demanding as applied to the complex coronary circulation.

Although these techniques utilized varying degrees of computer processing, no true image enhancement was utilized. Robb et al.% demonstrated that the coronary microcirculation could be visualized by computer enhancement of selective arteriography and suggested that this ability could be used to obtain regional coronary flow information. They did point out, however, that absolute densitometric analysis of this phase of contrast medium transit could not be accomplished by means

of two-dimensional radiography. In keeping with these previously described factors, the technique described in this paper utilizes digital enhancement of myocardial phase contrast media to assess relative changes in regional blood flow.

Current methodology. In opposition to the ECG- gated mask mode subtraction method used by Robb et al., a new technique, gated-interval differencing, was employed for this study. As seen in Fig. 1, in differencing consecutive gated frames, this technique provides better temporal separation of the individual phases of contrast medium transit than does mask mode processing. This is due to the fact that the difference between consecutive frames is solely attributable to new regional contrast appearance. Although this form of time varying analysis is ideal for measuring the timing of regional contrast appearance, absolute densitometric data are not generated by its use. These factors provided the

Volume 107 Number 1 Coronary reserve by digital contrast-enhanced arteriography 161

basis for our investigation of transit time as an index of relative flow. A second important variation from previous work is our extension of the short proximal arterial segment analysis of Rutishauser et al. to a more comprehensive assessment of coronary ostia to multiregional myocardial appearance time.

As is demonstrated in equation 1 (Methods sec- tion), MCAT is an index of blood flow transit time rather than of flow volume. Use of this transit time index to determine relative regional blood flow changes depends on the distributional volume of the particular myocardial region remaining constant. Preliminary studies from our laboratory, performed to determine the feasibility of this technique, demonstrated no significant alterations in epicardial arterial diameter during arterial pacing or within 15 seconds following contrast medium administration. This, combined with the close relationship between the changes in MCAT and coronary sinus flow, suggests that distributional volume remains fairly constant under the described considerations. This relationship between MCAT and flow would be disturbed, however, if distributional volume were directly or indirectly varied under other circum- stances.

al vessels, cardiac imaging involves an organ which is in constant cyclical motion. Application of this technique to coronary arteriography, therefore, requires utilization of frames which are obtained from corresponding portions of the cardiac cycle so as to preclude motion-induced artifact. The pre- P-wave interval of late diastole was found to contain the least coronary artery motion and the greatest intercyclical arterial correspondence. Despite this, the injection of intracoronary contrast medium caused a minor degree of change in cardiac geometry irrespective of changes in intrinsic heart rate. With careful attention to arterial registration, this was not found to produce major CMAP artifact.

Another important methodologic consideration is the initial effect of selective contrast medium injection on intracoronary flow. Whereas injection of low-viscosity 5% dextrose results in a transient increase in coronary flow measured by electromagnetic flow meter,30 injection of sodium meglumine diatrizoate has been shown to cause a 20% to 50% decrease in coronary flow which lasts a few seconds.gz30 This initial blood flow reduction is not observed in the coronary sinus.30’3i In general, however, it is well accepted that contrast media injection in arteriographic doses does cause early alterations in coronary flow. Thus, it is unlikely that absolute coronary flow can be measured by standard selective arteriography. It is for this reason that this study attempted to assess coronary contrast flow as a relative parameter (i.e., flow ratios), proposing that relative changes in appearance time would vary generally inversely to changes in blood flow.

Another issue of importance is the use of only five temporal sampling points per pixel. This does not constitute an inherent limitation of the gated-interval differencing technique which can be performed At any phase in the cardiac cycle. As demonstrated in Fig. 3, statistical averaging of the many pixel values within an arterial segment was employed to increase MCAT temporal precision. Early investigation into this issue suggested that the temporal precision of using histographic averaging of only the end-diastolic appearance time pixel values was not improved by the use of both systolic and diastolic appearance data.

Another source of temporal sampling inaccuracy stems from the use of manual contrast injection. This necessitates giving great attention to initiating contrast injection as close to the QRS complex as possible and to using the same injection technique during repeated studies. Despite these current technical limitations, a reasonable intrinsic reproducibility for the technique of 12 % was found. This value is similar to the 10% reported for xenon-133 washout myocardial perfusion reproducibility.32 Following contrast medium injection, the catheter was not withdrawn from the coronary ostium as its presence in the ostium has been shown not to alter coronary blood Aow.~~, l7 To further improve reproducibility of the technique, we are currently using an ECG- synchronized power injector for contrast medium administration.

Technical considerations. Several technical issues Last, the use of 35 mm tine film initial data must be considered in the analysis of the CMAP storage with subsequent digitization requires com- formation process. First, as for all digital radio- ment, as this technique differs from the direct video graphic imaging, patients are required to remain digitization currently employed in standard digital motionless. Failure to accomplish this produces radiography. Coupled with the low degree of high- subtraction artifacts. In this initial investigation, 57 frequency noise inherently present on tine film, the of 70 studies were successfully completed, although use of multiple video digitization averaging for each great attention had to be applied to this issue. frame resulted in less enhanced image noise than the Additionally, unlike digital radiography of peripher- use of frame subtraction and video disk storage. No



logarithmic or other gray-scale transformation of the digital data was employed as a highly linear system response was found between the amount of added contrast medium and the resultant increment in digital value. This correlation existed for x-ray energies ranging from 60 to 95 kV over a wide range of tissue absorption and for up to 2.5 mm thickness of added full concentration contrast medium. We believe that this linear correlation resulted from our use of the logarithmic portion of the film sensito- metric curve. Overall, the technique’s validity is suggested by the close correlation found between relative flow changes measured by the arteriographic and thermodilution techniques.

Microcirculation arteriography. Although the visualization of contrast medium appearance in its myocardial phase is the focus of this technique, no data are presented on the exact nature of what is being imaged by this process. In angiographic terminology, it is likely that this enhancement technique visual- izes the “myocardial blush” visually observed at times on tine film directly. The effect of contrast media on the microcirculation has been demonstrated to produce capillary dilatation and local blood flow reduction,33 leading to the possibility that myocardial contrast medium visualization is associated with microcirculation contrast accumulation- This remains conjectural at this time, although the known effects of contrast media on the microcirculation suggest that relative densitometric and indicator-dilutional technique evaluations of myocardial flow, as opposed to transit time-based methods, are less likely feasible. Difficulty with application of relative densitometric analysis is supported by our observation that high-rate atria1 pacing produces less dense visualization of the myocardial contrast phase than does contrast-induced hyperemia, despite similar flow rates and MCATs. Arterio- graphic indicator-dilution analysis is perturbed by the effects of reactive hyperemia (see below) which occurs during the washout period, thus making evaluation of baseline flow difficult to perform. Additional problems associated with application of this technique include the contrast-induced system- ic hypotension that occurs during the washout period and the prolonged time during which patients are required to remain motionless. These factors, combined with the above-mentioned difficulties associated with obtaining absolute densitometric determinations, constitute the reasons for our selection of relative inflow transit time-based methodology.

Coronary flow reserve. Under experimental conditions, following an initial transient decrease in coro-

nary blood flow, sodium meglumine diatrizoate causes a more sustained increase in flow which disappears in 2 to 3 minutes.30 Maximal increase in dog arterial flow occurs at 10 to 12 seconds and is approximately 3 to 4 times control flow, although a lesser ratio of 1.68 has been reported for the coronary sinus flow response. 3o In humans, the consensus of available data’“, ‘?I 32, 95-87 suggests a contrast- induced coronary flow reserve ratio of 1.84 with the use of the mean of values established by various techniques (range 1.52 to 2.56). The mean ratio determined by the presented technique for the 12 normal arterial distributions studied is almost iden- tical to the consensus mean (1.82). Similarly, the hyperemia-to-control flow ratio in distributions sup- plied by high-grade stenotic coronary arteries ranges from 0.89 to 1.46 in other studies. For our group of patients with >70% coronary stenoses, the value determined was 1.01. Lesions ranging from 20% to 65% diameter stenosis showed hyperemia-to-control ratios intermediate between the normal and high-grade stenosis group values, both in the current and previously presented studies. Preliminary data reported on pressure gradients across coronary lesions of 25 % to 75 % severity demonstrated 8 of 22 to have >40 mm gradients.38 In the current study, five of nine patients with 20% to 65 % lesions had absent coronary reserve (no statistical increase in blood flow).

These close agreements with previous published data on coronary reserve in patients with and without coronary artery disease tend to reinforce the direct validation data presented. Together, they suggest that this or a similar technique can enable arteriography to provide useful clinical information on relative coronary blood flow and regional coronary flow reserve in addition to coronary anatomy.

CONCLUSIONS

Recently, substantial advances have been made in the field of digital radiography which have enabled the visualization of vascular structures containing low concentrations of contrast media. In this report, we describe a new technique which applies computer processing to selective coronary arteriography to extract temporal and spatial information on the appearance of contrast medium as it passes through the arterial, myocardial, and venous phases of the coronary circulation. These data are displayed in color- and intensity-modulated functional images. Relative changes in regional myocardial contrast appearance time, as measured by this technique, were found to correlate closely with changes in

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coronary blood flow measured by the coronary sinus and great cardiac vein thermodilution method. Cor- onary flow reserve, with the use of contrast medium- induced hyperemia, was assessed by this technique in 28 arterial perfusion regions in patients with and without coronary artery disease. The resultant data are quantitatively similar to those previously reported by other techniques. These findings suggest that selective arteriography can be used to assess regional coronary flow reserve as well as anatomy.

The authors thank Miss Diane Bauer for her expert secretarial assistance in the preparation of this manuscript.

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