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Assessment of quantitative indices of artertial stenosis derived from intravenous digital subtraction angiography
Assessment of quantitatike indices of arterial stenosis derived from intravenous digital subtraction angiography Wallace W. Peck, M.D., Robert A. Slutsky, M.D., Folke Brahme, Charles B. Higgins, M.D. Sun Diego, Calif,
The use of intravenous digital subtraction angiography (DSA) for the evaluation of cardiac and vascular disease has been found both clinically practical and useful.‘-6 The capability of using intravenous DSA to assess the hemodynamic significance of a wellvisualized stenosis has not been systematically analyzed. Radiographic methods for evaluating flow in peripheral vascular disease have been introduced and verified using videodensitometric methods after intraarterial injections.7 A method of semiquantitation of flow in association with intraarterial DSA has also been introduced.E The use of intravenous DSA to compare the relative flows in different vessels has been suggested,4 but a systematic evaluation of the relationship between flow reduction and digital image data in stenotic vessels has not been previously reported. Moreover, determining a simple method for evaluating the resting hemodynamic significance of a vascular stenosis using simple image processing of intravenous DSA would have immediate clinical utility. Thus, the purpose of this study was to assess various parameters of flow curves generated from intravenous DSA for detecting and quantitating reductions in arterial blood flow in the presence of graded aortic stenoses in an experimental canine model. METHODOLOGY Experimental preparation. The study population was seven mongrel dogs (mean weight 24 f 2 kg). All were premeditated with 3 mg/kg of morphine sulfate given subcutaneously 30 minutes prior to the study. The animals were then anesthetized with 25 mg/kg of sodium pentobarbital administered intra-
From the Department Medical Center; and Received Reprint Radiology
for publication requests: H-755,
of Radiology, University Veterans Administration Oct.
13. 1983;
accepted
of California Hospital.
San
Diego
Dec. 20, 1983.
Robert A. Slutsky, M.D., University Hospital, 225 Dickinson St., San Diego, CA 92103.
Dept.
of
M.D., and
venously. Each animal was ventilated through a cuffed endotracheal tube using a Harvard respirator at a rate of 14 to 16 breaths/min (tidal volume 15 cc/kg). Through a midline abdominal incision the abdominal aorta was exposed and the inferior mesenteric artery was ligated. An electromagnetic flow probe connected to a pulsed-logic electromagnetic flowmeter (Biotronex Laboratory, Inc., Silver Spring, Md.) was placed around the aorta 1 to 2 cm distal to the renal arteries, allowing continuous monitoring of aortic blood flow. A snare occluder fashioned out of umbilical tape was placed around the aorta 3 cm distal to the flow probe. Through the right femoral vein a No. 7F NIH catheter was positioned in the right atrium for the injection of contrast media. Through the left carotid and right femoral arteries, No. 7F single-lumen catheters were placed approximately 4 cm proximal and distal to the snare ligature, respectively, for pressure monitoring. The positions of the catheters were monitored fluoroscopically and were confirmed at postmortem examination. All pressures (proximal and distal aortic) were measured through the fluid-filled catheters using Statham P23db transducers, and were recorded along with mean aortic blood flow on a four-channel (Gould 2400) strip-chart recorder. The transducers were recalibrated prior to each experiment. Drift in the blood flow measurement was minimized by frequent occlusive re-zeroing during the study. Study protocol. Mean aortic blood flow, mean proximal aortic pressure, and mean distal aortic pressure were recorded during the control period, 1 to 2 minutes after the production of two levels of stenosis sufficient to result in approximately a 25% and 75% reduction of flow and then during complete aortic occlusion. All flows were characterized as percent reduction from the control flow. After each level of stenosis, a delay of 15 to 30 minutes was 591
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Peck et al.
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1984 Journal
Fig. 1. Digital fluoroscopic imagesof the contrast-filled aorta during the control state and following 257; flow reduction. Proximal and distal regions-of-interest are shown.
used to insure recovery to control values. Fluoroscopic data were acquired after the injection of 2 cc/kg of sodium meglumine diatrizoate (Renografin 76) injected over 2 seconds. Respiration was suspended at end-inspiration during all studies. Fluoroscopy was performed using a Philips 6-inch (15.24 cm) cesium iodide image intensifier and a Vidicon television camera. Fluoroscopic factors were set at 60 kV(peak) and 3mA; data were obtained in the posteroanterior projection and were then recorded on analogue videotape (JVC, G-inch high-performance videocassette recorder HR6060Y with a signal-to-noise ratio of 48 dB). Data were obtained prior to each contrast injection and were later used as a mask. DSA of the abdominal aorta was performed in the control state, in the presence of two levels of subtotal stenosis, and with total aortic occlusion. The subtotal occlusions were created by gradually tightening the occluder until new stable reductions in blood flow were produced. The first level of stenosis reduced the control flow by 25% + 6% and the second level reduced the flow 75 % f 5 % below the control values. Data analysis. The videotaped fluoroscopic data (both mask and contrast images) were digitized off-line onto an image processing computer (MDS AZ, Ann Arbor, Mich.) at a rate of 3 frames/set. Digital acquisition was controlled by the operator to coincide with the onset of the intravenous injection of contrast media. Mask mode images were then obtained as previously described.g Data were recorded in a 256 X 256 matrix which yielded a pixel resolution of 0.43 mm/pixel (taking into account the magnification factor).
Each set of digital data was assigned two regionsof-interest (one proximal and one distal to the stenosis), from which x-ray density-time curves were generated. The regions-of-interest contained 36 square pixels (6 X 6 pixels) and were carefully selected to be within the walls of the aorta (Fig. 1). All curves underwent a two-point curve smoothing. Measurements obtained from each curve included: peak density, time to peak density (TTP), the slope of a linear fit applied to the wash-in (or upslope) portion of the curve, and the slope of a monoexponential fit to the wash-out portion of the curve. The TTP was defined as the time from the initiation of the rapid upslope of the x-ray density curve to the time of peak density. The exact time at the onset of the wash-in portion of the proximal curve (defined by the frame number) was also used as the starting point for the TTP calculation from the distal curve. The slope (m from y = mx + b) of the wash-in portion of the curve was derived with a least squares fit using a linear regression analysis on 9 -+ 2 (&SD) data points (r > 0.95 for all linear fits). The slope (k from y = eekx) of the wash-out portion of the curve was determined using a monoexponential curve fitting program on 7 IL 3 data points (r > 0.95 for all exponential fits). The range for the exponential fit was determined for the data between a 10% to 50% reduction in peak intensity on the wash-out portion of the curve. The ratio of the distal value to the proximal value was calculated for peak intensity, TTP, and upslope of the x-ray density curves. No curves demonstrated pixel saturation, as would be evidenced by a plateau shape of the curve (“flattopping”). Statistics. All data are given as the group mean i
Volume
108
Number
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Quantification of arterial stenosis by DSA
DOG 4 4220.
3493
coNlRoL
3748 x IO'
cl 000
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3802
OCCL I
OCCL 2
006 4 4092 .-
3511
0.000
3748 x 10'
x 101 4.10
x 10' 420
\ 1.00
200
3.00
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DISTAL(D)
OCCL 3
b
3748 x lcr
PROXIYAL(P)
3550 @ 0 000
3.663 Xl(r
x 10' 3.95 3.85
400
3.90
3.90
3.80
375
3.80
3.70
3.65
3.70
3.60 4.00 1& 3.50 0.0
3.60 0.0
1.00
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Fig. 2. Computer-generated flow curves from the regions-of-interest depicted in Fig. 1. Control curves are shown on the left and curves with 25% flow reduction are shownon the right. The top panel contains both proximal and distal curves. The middle panel showsthe proximal curve alone, and the bottom panel showsthe distal curve alone. Units of the Y axis are arbitrary density units and units of the X axis are arbitrary time units where 852 units = 1 second.
one standard deviation. Proximal and distal values after flow reduction were compared to control and with each other using the paired Student’s t test. Significant differences were assumed to be present if p < 0.05. The correlation of peak intensity, TTP, upslope, and wash-out slope with the degree of reduction in flow were obtained with a least squares fit using a standard linear regression analysis. OBSERVATIONS
Composite DSA images representing control and the first level of stenosis are shown in Fig. 1. Typical x-ray density-time curves with linear and monoexponential fits are depicted in Figs. ‘2 and 3 for control and for each level of stenosis. The (mean) proximal aortic pressure (AoP) increased slightly compared to control with each level of stenosis, but was significantly increased only with total occlusion (Table I). Distal AoP decreased in proportion with the amount of flow reduction (r = 0.92, p < 0.01).
3.55 b 0.0
100
Fig. 3. Computer-generated flow curves, as described in
Fig. 2, for 75% flow reduction on the left, and total occlusion on the right.
During each level of occlusion proximal and distal AoP differed significantly (p < 0.05 proximal vs distal). In the presence of total aortic occlusion distal AoP fell to 32 + 7 mm Hg. Proximal and distal TTP were significantly different for each level of stenosis (Table I). Compared to the control value, proximal TTP tended to increase with greater flow reductions, although not significantly. Compared to the control value, distal TTP increased as the occlusion was increased, but was significantly increased only during total occlusion. Otherwise, peak intensity (arbitrary density units) decreased with progressive flow reduction but was not significantly decreased until total occlusion. Upslopes of both the proximal and distal x-ray density-time transmission curves are shown in Fig. 4. The proximal upslope curve changed minimally during the first two levels of aortic flow reduction and then decreased significantly with total aortic occlusion. Distal upslope decreased significantly with all three levels of stenosis and correlated well with flow reduction (r = 0.82, p < 0.01). Proximal and distal upslopes compared to each other were significantly different for each level of aortic flow reduction (Table I, Fig. 4).
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Peck et al.
Table
I. Aortic occlusion indices
American
Stenosis 1
Contra/
Aortic pressure (mm Hg) TTP (see) Peak (DU) (DU/sec) Washout slope (X
Proximal
Distal
Proximal
126 t 11
126 _+ 11
130 -t 9
3.52 k 0.98
3.62 i 0.97 4061 t 281
3.24 + 0.69 $ 3.86 k 0.94 4026 + 538 1) 3873 +- 492
85.2
86.1
4098 k 284 86.1
Upslope
Stenosis 2
? 23.9
9.2 t 3.9
? 15.3
8.8 2 4.4
Distal s
ztz 18.7
8.9 k 7.8
Proximal
113 i 13t
/I 57.9
tr 12.81
4.1 2 2.2%
130i
9
Journal
Total occlusion
Distal #
1984
Heart
Proximal 138
73 + 25$
Distal
+ 9*
3
32 I
7i
3.67 t 0.98 11 4.43 -+ 1.18
3.86 _t 0.42
I/ 5.62 t 0.80
3915 72.4
3595 48.6
r 751 2 “1.31
I( 3406 )/ 11.1
2 ‘,.5X -<
2.7
I i
706 18.7
II3733 /I 47.7
6.5 i 2.9
+ 677 I 18.71
4.0
5.6 + 1.5
+ 7lOt F “1.2 A 2.4
10-J
DU/sec) *p < 0.1Xi vs DU = arbitrary
Table
control; density
Pp < 0.02 YS control; tp < 0.01 vs
control;
$p < 0.05 proximal vs distal;
lip < 0.01
proximal
vs distal:
T’I’P
= time
to peak;
units.
II. Aortic occlusion indices
-~~_Stenosis I
Control TTP,,,,,,/TTP,,,,,,,,
1.03 f 0.05
1.19
Stenosis 2
+ 0.14*
--.
0.99 + 0.02
1.02 +- 0.19
Total occlusion
0.96 + 0.02* L---N,S,
0.70 t 0.18t
~~-
~-
0.95 i P.-i
$ -~.-.~.
0.02* L-.-
.._
-~_!
0.95 i 0.02t N,S. ..---,'
0.66 + 0.17t
*p < 0.05
vs control;
+,ZI < 0.02 vs control;
$p < 0.01
vs control;
§p < 0.05 total
Washout slopes of the x-ray density-time curves both proximal and distal to the stenosis are also depicted in Fig. 4. The proximal and distal wash-out slopes were somewhat variable but tended to decrease with increasing stenosis, and the difference compared to control was statistically significant at the first level of stenosis as well as total occlusion. The ratio of distal to proximal TTP, the ratio of distal to proximal peak intensity, and the ratio of distal to proximal upslope are shown in Table II. The ratio for TTP increased significantly as aortic flow decreased (r = 0.66, p < 0.01) (Table II). When the largest ratio of TI’P from the control values was used as the normal cutoff value, 19 of 21 (91% ) data points representing significant stenoses had values greater than this arbitrary cutoff (Fig. 5). One TTP ratio from the first level of stenosis group and one from the total occlusion group fell below this cutoff value. The peak intensity ratios also decreased with reduced flow (r = 0.62, p < 0.011, although the differences were less distinct (Table II). The upslope ratios decreased with increasing stenosis, reaching
oedusion
vs stenosis
1 or “; TTP
= time
to peak.
statistical significance at the first level of stenosis (r = 0.72, p < 0.01) (Table II). When the smallest upslope ratio from the control group was used as the normal cutoff value, 17 of 21 (81% ) data points from the significantly occluded vessels had values lower than this arbitrary cutoff (Fig. 6). Two of these data points were from the first level and two were from the second level of stenosis. COMMENTS
This study provides some quantitative parameters for evaluating the significance of vascular stenotic lesions using computer-generated flow curves (x-ray density curves) obtained from intravenous DSA. We found the upslope and TTP to be the most valuable parameters of the x-ray density-time curves for assessing blood flow reduction. Although these parameters were different proximally and distally for each level of stenosis, these parameters may be influenced by a number of factors, including: the vessel studied, framing rate, the equipment, the size of the region-of-interest, amount of soft tissue
Volume
108
Number
3, Part I
r
Quantification T
of arterial
stenosis
by DSA
2.0 F 1.8 -
85 z %
88-
2 0 -
51-
595
* ~~0.05 $e+c pCO.01
3 z %
1x-
E2
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: . a***
. . :l e *
ci
2 f
vs CONTROL vs CONTROL
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.
A.
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-
00 &Lb m-
8.8 -
ax s
-
3.4 clCONTROL
25% FLOW REOUCTION
75% FLOW REDUCTION
vs CONTROL vs CONTROL PROX vs DISTAL
Proximal and distal upslope (top) and washout slope (bottom) at control and at each level of stenosis. DU = arbitrary density units. Fig.
4.
I
CONTROL
25% FLOW REDUCTION
I
75% FLOW REDUCTION
I
TOTAL OCCLUSION
Fig. 5. The ratios of the TTP (time to peak density) of the distal region-of-interest to the TTP of the proximal region-of-interest on the aorta are shown in the control state and at each level of stenosis. The dashed line denotes arbitrary cutoff for the range of normals.
** iikl COMPLETE OCCLUSION
I
I-
1.2 -
1.0 -
0.8 -----
l
. . .* . . -.-----
-X- p ~0.05 -1~s ~~0.01
. ---.-------. -09 m
0.6 -
0
0 ---------------. . . G-X.*
“s CONTROL vs CONTROL
0
.
0.4 -
0.2 r ,
scatter and attenuation, cardiac output, and vascular resistance. Distal-to-proximal ratios of these parameters were examined in order to have an internal control. This resulted in a range of normals for the dog aorta. Using this range of normal values, we found 81% of the upslope ratios and 91% of the TTP ratios fell outside this range when a reduction in blood flow was present. The range of normals would need to be reestablished for humans and possibly for individual vessels. Alternatively, a stenotic vessel could be compared with a normal (and most likely matched) vessel in the field of view. In the present study a normal control vessel was not available because of the small field of view afforded by our system. The role of collaterals in altering the characteristics of the density-time curves was not evaluated. Nonetheless, density changes below the occlusion occurred with contrast injection, presuming some collateral flow. When a vessel is totally occluded there is dilatation of available anastomotic channels.‘O Hessel et all’ found that limb blood flow declined to 35% of resting flow following sudden
1
CONTROL
I
25% FLOW REDUCTION
1
75% FLOW REOUCTION
I
TOTAL OCCLUSION
Fig. 6. The ratios of the linear upslope (of the timetransmissioncurves) from the distal region-of-interest to proximal region-of-interest on the aorta are shown in the control state and at each level of stenosis.The dashed line denotes arbitrary cutoff for the range of normals.
occlusion of the common femoral artery, with rapid recovery of femoral flow to 60% of the control value within 2 hours, presumably due to dilatation of collateral vessels. Others12 have noted the importance of collateral recruitment for improving regional blood flow after 90 minutes of occlusion. Since our data were gathered within the first few minutes following blood flow reduction, collaterals probably played only a small part in the production of our results. The correlation between flow reduction and digital data was only fair and may be attributed to the lack of control of collaterals, the variability of neuromuscular and humoral controls on peripheral vascular resistance, and the changes in cardiac out-
September,
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Peck et al.
put with contrast injection. Even with these limitations, the technique has proved useful for detecting blood flow reduction across a stenosis. Current radiographic methods used for evaluating arterial blood flow involve videodensitometric methods during arteriography. Link et aL7s13and Lantz et a1.14 have demonstrated the accuracy of this technique for quantitating relative blood flow in multiple arteries in canines and in patients with peripheral vascular disease. This technique involves an intraarterial injection because of the need to know accurately the amount of contrast media delivered to the region-of-interest. Intravenous injections of contrast would be more desirable but introduce more problems when one is employing videodilution techniques. Despite rapid pressure injection of contrast media, concentration in the arterial circulation is inconsistent and is dependent on a relatively passive transit from the injection site to the right heart and intermittent active injection into the arterial circulation, moderated by the central blood volume and cardiac output in individual patients3 Thus, the major drawback of this type of technique is the inability to estimate the amount of contrast media (indicator) reaching the vessel under investigation. By using the shape of the curve rather than the area under the curve, some (though not all) of the problems are minimized. Kruger et a1.4 demonstrated the utility of intravenous injections for comparing relative blood flow between two companion vessels, but if flow is altered in the “normal” companion vessel then all comparisons are meaningless (a not uncommon occurrence in peripheral vascular disease). The method presented in this study is not dependent upon other vessels, though normal companion vessels could also be used for internal reference purposes. The conversion of fluoroscopic x-ray data into a digital format not only permits contrast enhancement of the images but also facilitates computerassisted quantitative and functional analysis of the data. We believe this will be particularly useful for evaluating the significance of vascular lesions in atherosclerotic disease. Blood flow across a stenosed vessel at rest does not diminish until 60 5%to 90 % of the vessel’s luminal area has been reduced.15-lR Depending on the size of the vessel and the resolution of the particular imaging system, visual interpretation of a significant stenosis based on critical luminal area differences may be difficult. Thus, quantitative analysis may aid in assessing blood flow across stenotic lesions and the importance of the observed luminal narrowing. Finally, this technique may be helpful in evaluating peripheral vascular
American
Heart
1984 Journal
disease following interventions such as angioplasty.‘j We thus conclude that the use of density-time curve parameters proximal and distal to a stenosis may prove important in evaluating the significance of peripheral vascular disease and warrants further investigation. CONCLUSIONS
Quantitative evaluation of vascular flow dynamics using intravenous DSA to assess the significance of a vascular stenosis would be a major advance in the noninvasive evaluation of atherosclerotic disease. To evaluate DSA data during changes in vascular flow, we studied seven mongrel dogs using DSA of the aorta at a control stage and then during three levels of stenosis (24 + 6%) 75 f 5%) and 100% reductions in flow). X-ray density-time curves were generated using manually assigned regions-of-interest both proximal and distal to the stenosis. From both density-time curves we determined the time to peak x-ray density (TTP), the linear upslope of the curves, and the monoexponential wash-out slope of the curves. The ratio of distal to proximal: (1) peak x-ray density, (2) TTP, and (3) linear upslope were also examined and were correlated with flow dynamics. Although the post-stenotic upslope correlated best with the severity of aortic flow reduction (r = 0.82, p < 0.05), the ratios of distal to proximal TTP and upslope proved to be reliable for detecting a reduction in blood flow. Nonetheless, the ability of this technique to determine the absolute reduction in flow was not ideal, probably in large part due to the nonlinear relationship between regional blood flow and regional blood volume. Thus, we conclude that quantitative analysis of density versus time flow curves derived from intravenous DSA is a simple method for evaluating the hemodynamic significance (i.e., reduction in blood flow) of a stenotic vascular lesion. Digital subtraction techniques with the application of simple region assignment, curve generation, and digital curve manipulation may prove useful in evaluating the significance of vascular lesions at rest. REFERENCES
1. Kruger RA, Mistretta CA, Houk TL, Kubal W, Riederer SJ, Ergun DL, Shaw CG, Lancaster JC, Rowe GG: Computerized fluoroscopy techniques for intravenous study of cardiac chamber dynamics. Invest Radio1 14:279, 1979. 2. Crummy AB, Strother CM, Sackett JF, Eraun DL. Shaw CC. Kruger RA, Mistretta CA, Turnipseed WD, Lieberman RP; Myerowitz PD. Ruzicka FF: Comouterized fIuoroscoov: Digital subtraction for intravenous angiocardiography and arteriography. AJR 135:1131,1980. :3. Meaney TF, Weinstein MA, Buonocore E, Pavelicek W, Borkowski GP. Gallagher JH, Sufka B, MacIntyre W,J:
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4.
5.
6.
7.
8.
9.
Digital subtraction angiography of the human cardiovascular system. AJR 135:1153, 1980. Kruger RA, Anderson RE, Koehler R, Nelson JA, Sorenson JA, Morgan T: A method for the noninvasive evaluation of cardiovascular dynamics using a radiographic device. Radiology 139:301, 1981. Higgins CB, Norris SL, Gerber KH, Slutsky RA, Ashburn WL, Baily N: Quantitation of left ventricular dimensions and function by digital video subtraction angiography. Radiology 144:461, 1982. Gerber KH, Slutsky RA, Bhargava V, Ashburn WL, Higgins CB: Detection and assessment of severity of regional ischemic left ventricular dysfunction by digital fluoroscopy. AM HEART J lO4:27, 1982. Link DP, Foerster JM, Lantz BMT, Holcroft JW: Assessment of DeriDheral blood flow in man bv video dilution techniaue: A A preliminary report. Invest Radio1 16:298, 1981. Bursch JH, Hahne HJ, Brennecke R, Gronemeier D, Heintzen PH: Assessment of arterial blood flow measurements by digital angiography. Radiology 141:39, 1981. Norris SL. Slutskv RA. Mancini GBJ. Ashburn WL. Greeoratos G, Peterson -KL,’ Higgins CB: ‘Comparison of digital intravenous ventriculography with direct left ventriculography for quantitation of left ventricular volume and ejection fractions. Am J Cardiol 51:1399, 1983.
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10. Abrams HL: Caldwell lecture. The collateral circulation: Response to ischemia. AJR 140:1051, 1983. 11. Hessel SJ, Gerson DE, Bass A, Hollenberg NK, Dowgialo IT, Abrams HL: Renal collateral blood supply after acute unilateral renal artery occlusion. Invest Radio1 l&490, 1975. 12. John HT, Warren R: The stimulus to collateral circulation. Surgery 49:14, 1961. 13. Link DP, Lantz BMT, Foerster JM, Holcroft JW, Reid MH: New videodensitometric method for measuring renal arterv blood flow at routine arteriography: Validation-in the canine model. Invest Radio1 14:464. 1979. 14. Lantz BMT, Foerster JM, Link DP, Holcroft JW: Determination of relative blood flow in single arteries: New video dilution technique. AJR 134:1161, 1981. 15. Levin DC, Beckmann CF, Serur JR: Vascular resistance changes distal to progressive arterial stenosis: A critical re-evaluation of the concept of vasodilator reserve. Invest Radio1 15:120, 1980. 16. Shipley RE, Gregg DE: The effect of external constriction of a blood vessel on blood flow. Am J Physiol 141:289, 1944. 17. Fiddian RV, Byar D, Edwards EA: Factors affecting flow through a stenosed vessel. Arch Surg 68:83, 1964. 18. Logan SE: On the fluid mechanics of human coronary artery stenosis. IEEE Trans Biomed Eng 22:327, 1975.
The use of intravenous digital subtraction angiography (DSA) for the evaluation of cardiac and vascular disease has been found both clinically practical and useful.‘-6 The capability of using intravenous DSA to assess the hemodynamic significance of a wellvisualized stenosis has not been systematically analyzed. Radiographic methods for evaluating flow in peripheral vascular disease have been introduced and verified using videodensitometric methods after intraarterial injections.7 A method of semiquantitation of flow in association with intraarterial DSA has also been introduced.E The use of intravenous DSA to compare the relative flows in different vessels has been suggested,4 but a systematic evaluation of the relationship between flow reduction and digital image data in stenotic vessels has not been previously reported. Moreover, determining a simple method for evaluating the resting hemodynamic significance of a vascular stenosis using simple image processing of intravenous DSA would have immediate clinical utility. Thus, the purpose of this study was to assess various parameters of flow curves generated from intravenous DSA for detecting and quantitating reductions in arterial blood flow in the presence of graded aortic stenoses in an experimental canine model. METHODOLOGY Experimental preparation. The study population was seven mongrel dogs (mean weight 24 f 2 kg). All were premeditated with 3 mg/kg of morphine sulfate given subcutaneously 30 minutes prior to the study. The animals were then anesthetized with 25 mg/kg of sodium pentobarbital administered intra-
From the Department Medical Center; and Received Reprint Radiology
for publication requests: H-755,
of Radiology, University Veterans Administration Oct.
13. 1983;
accepted
of California Hospital.
San
Diego
Dec. 20, 1983.
Robert A. Slutsky, M.D., University Hospital, 225 Dickinson St., San Diego, CA 92103.
Dept.
of
M.D., and
venously. Each animal was ventilated through a cuffed endotracheal tube using a Harvard respirator at a rate of 14 to 16 breaths/min (tidal volume 15 cc/kg). Through a midline abdominal incision the abdominal aorta was exposed and the inferior mesenteric artery was ligated. An electromagnetic flow probe connected to a pulsed-logic electromagnetic flowmeter (Biotronex Laboratory, Inc., Silver Spring, Md.) was placed around the aorta 1 to 2 cm distal to the renal arteries, allowing continuous monitoring of aortic blood flow. A snare occluder fashioned out of umbilical tape was placed around the aorta 3 cm distal to the flow probe. Through the right femoral vein a No. 7F NIH catheter was positioned in the right atrium for the injection of contrast media. Through the left carotid and right femoral arteries, No. 7F single-lumen catheters were placed approximately 4 cm proximal and distal to the snare ligature, respectively, for pressure monitoring. The positions of the catheters were monitored fluoroscopically and were confirmed at postmortem examination. All pressures (proximal and distal aortic) were measured through the fluid-filled catheters using Statham P23db transducers, and were recorded along with mean aortic blood flow on a four-channel (Gould 2400) strip-chart recorder. The transducers were recalibrated prior to each experiment. Drift in the blood flow measurement was minimized by frequent occlusive re-zeroing during the study. Study protocol. Mean aortic blood flow, mean proximal aortic pressure, and mean distal aortic pressure were recorded during the control period, 1 to 2 minutes after the production of two levels of stenosis sufficient to result in approximately a 25% and 75% reduction of flow and then during complete aortic occlusion. All flows were characterized as percent reduction from the control flow. After each level of stenosis, a delay of 15 to 30 minutes was 591
September,
592
Peck et al.
American
Heart
1984 Journal
Fig. 1. Digital fluoroscopic imagesof the contrast-filled aorta during the control state and following 257; flow reduction. Proximal and distal regions-of-interest are shown.
used to insure recovery to control values. Fluoroscopic data were acquired after the injection of 2 cc/kg of sodium meglumine diatrizoate (Renografin 76) injected over 2 seconds. Respiration was suspended at end-inspiration during all studies. Fluoroscopy was performed using a Philips 6-inch (15.24 cm) cesium iodide image intensifier and a Vidicon television camera. Fluoroscopic factors were set at 60 kV(peak) and 3mA; data were obtained in the posteroanterior projection and were then recorded on analogue videotape (JVC, G-inch high-performance videocassette recorder HR6060Y with a signal-to-noise ratio of 48 dB). Data were obtained prior to each contrast injection and were later used as a mask. DSA of the abdominal aorta was performed in the control state, in the presence of two levels of subtotal stenosis, and with total aortic occlusion. The subtotal occlusions were created by gradually tightening the occluder until new stable reductions in blood flow were produced. The first level of stenosis reduced the control flow by 25% + 6% and the second level reduced the flow 75 % f 5 % below the control values. Data analysis. The videotaped fluoroscopic data (both mask and contrast images) were digitized off-line onto an image processing computer (MDS AZ, Ann Arbor, Mich.) at a rate of 3 frames/set. Digital acquisition was controlled by the operator to coincide with the onset of the intravenous injection of contrast media. Mask mode images were then obtained as previously described.g Data were recorded in a 256 X 256 matrix which yielded a pixel resolution of 0.43 mm/pixel (taking into account the magnification factor).
Each set of digital data was assigned two regionsof-interest (one proximal and one distal to the stenosis), from which x-ray density-time curves were generated. The regions-of-interest contained 36 square pixels (6 X 6 pixels) and were carefully selected to be within the walls of the aorta (Fig. 1). All curves underwent a two-point curve smoothing. Measurements obtained from each curve included: peak density, time to peak density (TTP), the slope of a linear fit applied to the wash-in (or upslope) portion of the curve, and the slope of a monoexponential fit to the wash-out portion of the curve. The TTP was defined as the time from the initiation of the rapid upslope of the x-ray density curve to the time of peak density. The exact time at the onset of the wash-in portion of the proximal curve (defined by the frame number) was also used as the starting point for the TTP calculation from the distal curve. The slope (m from y = mx + b) of the wash-in portion of the curve was derived with a least squares fit using a linear regression analysis on 9 -+ 2 (&SD) data points (r > 0.95 for all linear fits). The slope (k from y = eekx) of the wash-out portion of the curve was determined using a monoexponential curve fitting program on 7 IL 3 data points (r > 0.95 for all exponential fits). The range for the exponential fit was determined for the data between a 10% to 50% reduction in peak intensity on the wash-out portion of the curve. The ratio of the distal value to the proximal value was calculated for peak intensity, TTP, and upslope of the x-ray density curves. No curves demonstrated pixel saturation, as would be evidenced by a plateau shape of the curve (“flattopping”). Statistics. All data are given as the group mean i
Volume
108
Number
3, Part1
Quantification of arterial stenosis by DSA
DOG 4 4220.
3493
coNlRoL
3748 x IO'
cl 000
x 10' 4.25 4.10 4.00 3.90 3.80 3.70 3.60 3.50 k 0.0
PROXIMAL (PI
3802
OCCL I
OCCL 2
006 4 4092 .-
3511
0.000
3748 x 10'
x 101 4.10
x 10' 420
\ 1.00
200
3.00
4.00 XIV
DISTAL(D)
OCCL 3
b
3748 x lcr
PROXIYAL(P)
3550 @ 0 000
3.663 Xl(r
x 10' 3.95 3.85
400
3.90
3.90
3.80
375
3.80
3.70
3.65
3.70
3.60 4.00 1& 3.50 0.0
3.60 0.0
1.00
2.00
3.00
4.00 x l[r
x 10' 4.20
x 10’
4.10
4.10 4.00 3.90 3.80
DOG 4 3931 ,P
410
I 10' 4.25
3.70 3.60 3.50 b 00
,P /p 0’ il LIii!34 LB4 0.000
OOG 4 4162.
593
1.00
2.00
3.00
4.00 XlW
DtSlAl(D)
3.55 l!Y!!Il 0.0 1.00
2.00
3.00
4.00 XIV
200
3.00
400 Xl[r
x 101 3.95 385 375 3.65
g/ 1.00
2.00
3.00
4.00 x IIT
yy 0.0
1.00
2.00
3.00
4.00 xw
Fig. 2. Computer-generated flow curves from the regions-of-interest depicted in Fig. 1. Control curves are shown on the left and curves with 25% flow reduction are shownon the right. The top panel contains both proximal and distal curves. The middle panel showsthe proximal curve alone, and the bottom panel showsthe distal curve alone. Units of the Y axis are arbitrary density units and units of the X axis are arbitrary time units where 852 units = 1 second.
one standard deviation. Proximal and distal values after flow reduction were compared to control and with each other using the paired Student’s t test. Significant differences were assumed to be present if p < 0.05. The correlation of peak intensity, TTP, upslope, and wash-out slope with the degree of reduction in flow were obtained with a least squares fit using a standard linear regression analysis. OBSERVATIONS
Composite DSA images representing control and the first level of stenosis are shown in Fig. 1. Typical x-ray density-time curves with linear and monoexponential fits are depicted in Figs. ‘2 and 3 for control and for each level of stenosis. The (mean) proximal aortic pressure (AoP) increased slightly compared to control with each level of stenosis, but was significantly increased only with total occlusion (Table I). Distal AoP decreased in proportion with the amount of flow reduction (r = 0.92, p < 0.01).
3.55 b 0.0
100
Fig. 3. Computer-generated flow curves, as described in
Fig. 2, for 75% flow reduction on the left, and total occlusion on the right.
During each level of occlusion proximal and distal AoP differed significantly (p < 0.05 proximal vs distal). In the presence of total aortic occlusion distal AoP fell to 32 + 7 mm Hg. Proximal and distal TTP were significantly different for each level of stenosis (Table I). Compared to the control value, proximal TTP tended to increase with greater flow reductions, although not significantly. Compared to the control value, distal TTP increased as the occlusion was increased, but was significantly increased only during total occlusion. Otherwise, peak intensity (arbitrary density units) decreased with progressive flow reduction but was not significantly decreased until total occlusion. Upslopes of both the proximal and distal x-ray density-time transmission curves are shown in Fig. 4. The proximal upslope curve changed minimally during the first two levels of aortic flow reduction and then decreased significantly with total aortic occlusion. Distal upslope decreased significantly with all three levels of stenosis and correlated well with flow reduction (r = 0.82, p < 0.01). Proximal and distal upslopes compared to each other were significantly different for each level of aortic flow reduction (Table I, Fig. 4).
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Table
I. Aortic occlusion indices
American
Stenosis 1
Contra/
Aortic pressure (mm Hg) TTP (see) Peak (DU) (DU/sec) Washout slope (X
Proximal
Distal
Proximal
126 t 11
126 _+ 11
130 -t 9
3.52 k 0.98
3.62 i 0.97 4061 t 281
3.24 + 0.69 $ 3.86 k 0.94 4026 + 538 1) 3873 +- 492
85.2
86.1
4098 k 284 86.1
Upslope
Stenosis 2
? 23.9
9.2 t 3.9
? 15.3
8.8 2 4.4
Distal s
ztz 18.7
8.9 k 7.8
Proximal
113 i 13t
/I 57.9
tr 12.81
4.1 2 2.2%
130i
9
Journal
Total occlusion
Distal #
1984
Heart
Proximal 138
73 + 25$
Distal
+ 9*
3
32 I
7i
3.67 t 0.98 11 4.43 -+ 1.18
3.86 _t 0.42
I/ 5.62 t 0.80
3915 72.4
3595 48.6
r 751 2 “1.31
I( 3406 )/ 11.1
2 ‘,.5X -<
2.7
I i
706 18.7
II3733 /I 47.7
6.5 i 2.9
+ 677 I 18.71
4.0
5.6 + 1.5
+ 7lOt F “1.2 A 2.4
10-J
DU/sec) *p < 0.1Xi vs DU = arbitrary
Table
control; density
Pp < 0.02 YS control; tp < 0.01 vs
control;
$p < 0.05 proximal vs distal;
lip < 0.01
proximal
vs distal:
T’I’P
= time
to peak;
units.
II. Aortic occlusion indices
-~~_Stenosis I
Control TTP,,,,,,/TTP,,,,,,,,
1.03 f 0.05
1.19
Stenosis 2
+ 0.14*
--.
0.99 + 0.02
1.02 +- 0.19
Total occlusion
0.96 + 0.02* L---N,S,
0.70 t 0.18t
~~-
~-
0.95 i P.-i
$ -~.-.~.
0.02* L-.-
.._
-~_!
0.95 i 0.02t N,S. ..---,'
0.66 + 0.17t
*p < 0.05
vs control;
+,ZI < 0.02 vs control;
$p < 0.01
vs control;
§p < 0.05 total
Washout slopes of the x-ray density-time curves both proximal and distal to the stenosis are also depicted in Fig. 4. The proximal and distal wash-out slopes were somewhat variable but tended to decrease with increasing stenosis, and the difference compared to control was statistically significant at the first level of stenosis as well as total occlusion. The ratio of distal to proximal TTP, the ratio of distal to proximal peak intensity, and the ratio of distal to proximal upslope are shown in Table II. The ratio for TTP increased significantly as aortic flow decreased (r = 0.66, p < 0.01) (Table II). When the largest ratio of TI’P from the control values was used as the normal cutoff value, 19 of 21 (91% ) data points representing significant stenoses had values greater than this arbitrary cutoff (Fig. 5). One TTP ratio from the first level of stenosis group and one from the total occlusion group fell below this cutoff value. The peak intensity ratios also decreased with reduced flow (r = 0.62, p < 0.011, although the differences were less distinct (Table II). The upslope ratios decreased with increasing stenosis, reaching
oedusion
vs stenosis
1 or “; TTP
= time
to peak.
statistical significance at the first level of stenosis (r = 0.72, p < 0.01) (Table II). When the smallest upslope ratio from the control group was used as the normal cutoff value, 17 of 21 (81% ) data points from the significantly occluded vessels had values lower than this arbitrary cutoff (Fig. 6). Two of these data points were from the first level and two were from the second level of stenosis. COMMENTS
This study provides some quantitative parameters for evaluating the significance of vascular stenotic lesions using computer-generated flow curves (x-ray density curves) obtained from intravenous DSA. We found the upslope and TTP to be the most valuable parameters of the x-ray density-time curves for assessing blood flow reduction. Although these parameters were different proximally and distally for each level of stenosis, these parameters may be influenced by a number of factors, including: the vessel studied, framing rate, the equipment, the size of the region-of-interest, amount of soft tissue
Volume
108
Number
3, Part I
r
Quantification T
of arterial
stenosis
by DSA
2.0 F 1.8 -
85 z %
88-
2 0 -
51-
595
* ~~0.05 $e+c pCO.01
3 z %
1x-
E2
1.4-
: . a***
. . :l e *
ci
2 f
vs CONTROL vs CONTROL
'.2 -____
A--
----__
. . ;0** B------
8 .-------.
1.0 c
.
A.
17.0 g'
13.8-
* ~405 W ~401 +* p
5% m 20 2
10.2
-
00 &Lb m-
8.8 -
ax s
-
3.4 clCONTROL
25% FLOW REOUCTION
75% FLOW REDUCTION
vs CONTROL vs CONTROL PROX vs DISTAL
Proximal and distal upslope (top) and washout slope (bottom) at control and at each level of stenosis. DU = arbitrary density units. Fig.
4.
I
CONTROL
25% FLOW REDUCTION
I
75% FLOW REDUCTION
I
TOTAL OCCLUSION
Fig. 5. The ratios of the TTP (time to peak density) of the distal region-of-interest to the TTP of the proximal region-of-interest on the aorta are shown in the control state and at each level of stenosis. The dashed line denotes arbitrary cutoff for the range of normals.
** iikl COMPLETE OCCLUSION
I
I-
1.2 -
1.0 -
0.8 -----
l
. . .* . . -.-----
-X- p ~0.05 -1~s ~~0.01
. ---.-------. -09 m
0.6 -
0
0 ---------------. . . G-X.*
“s CONTROL vs CONTROL
0
.
0.4 -
0.2 r ,
scatter and attenuation, cardiac output, and vascular resistance. Distal-to-proximal ratios of these parameters were examined in order to have an internal control. This resulted in a range of normals for the dog aorta. Using this range of normal values, we found 81% of the upslope ratios and 91% of the TTP ratios fell outside this range when a reduction in blood flow was present. The range of normals would need to be reestablished for humans and possibly for individual vessels. Alternatively, a stenotic vessel could be compared with a normal (and most likely matched) vessel in the field of view. In the present study a normal control vessel was not available because of the small field of view afforded by our system. The role of collaterals in altering the characteristics of the density-time curves was not evaluated. Nonetheless, density changes below the occlusion occurred with contrast injection, presuming some collateral flow. When a vessel is totally occluded there is dilatation of available anastomotic channels.‘O Hessel et all’ found that limb blood flow declined to 35% of resting flow following sudden
1
CONTROL
I
25% FLOW REDUCTION
1
75% FLOW REOUCTION
I
TOTAL OCCLUSION
Fig. 6. The ratios of the linear upslope (of the timetransmissioncurves) from the distal region-of-interest to proximal region-of-interest on the aorta are shown in the control state and at each level of stenosis.The dashed line denotes arbitrary cutoff for the range of normals.
occlusion of the common femoral artery, with rapid recovery of femoral flow to 60% of the control value within 2 hours, presumably due to dilatation of collateral vessels. Others12 have noted the importance of collateral recruitment for improving regional blood flow after 90 minutes of occlusion. Since our data were gathered within the first few minutes following blood flow reduction, collaterals probably played only a small part in the production of our results. The correlation between flow reduction and digital data was only fair and may be attributed to the lack of control of collaterals, the variability of neuromuscular and humoral controls on peripheral vascular resistance, and the changes in cardiac out-
September,
596
Peck et al.
put with contrast injection. Even with these limitations, the technique has proved useful for detecting blood flow reduction across a stenosis. Current radiographic methods used for evaluating arterial blood flow involve videodensitometric methods during arteriography. Link et aL7s13and Lantz et a1.14 have demonstrated the accuracy of this technique for quantitating relative blood flow in multiple arteries in canines and in patients with peripheral vascular disease. This technique involves an intraarterial injection because of the need to know accurately the amount of contrast media delivered to the region-of-interest. Intravenous injections of contrast would be more desirable but introduce more problems when one is employing videodilution techniques. Despite rapid pressure injection of contrast media, concentration in the arterial circulation is inconsistent and is dependent on a relatively passive transit from the injection site to the right heart and intermittent active injection into the arterial circulation, moderated by the central blood volume and cardiac output in individual patients3 Thus, the major drawback of this type of technique is the inability to estimate the amount of contrast media (indicator) reaching the vessel under investigation. By using the shape of the curve rather than the area under the curve, some (though not all) of the problems are minimized. Kruger et a1.4 demonstrated the utility of intravenous injections for comparing relative blood flow between two companion vessels, but if flow is altered in the “normal” companion vessel then all comparisons are meaningless (a not uncommon occurrence in peripheral vascular disease). The method presented in this study is not dependent upon other vessels, though normal companion vessels could also be used for internal reference purposes. The conversion of fluoroscopic x-ray data into a digital format not only permits contrast enhancement of the images but also facilitates computerassisted quantitative and functional analysis of the data. We believe this will be particularly useful for evaluating the significance of vascular lesions in atherosclerotic disease. Blood flow across a stenosed vessel at rest does not diminish until 60 5%to 90 % of the vessel’s luminal area has been reduced.15-lR Depending on the size of the vessel and the resolution of the particular imaging system, visual interpretation of a significant stenosis based on critical luminal area differences may be difficult. Thus, quantitative analysis may aid in assessing blood flow across stenotic lesions and the importance of the observed luminal narrowing. Finally, this technique may be helpful in evaluating peripheral vascular
American
Heart
1984 Journal
disease following interventions such as angioplasty.‘j We thus conclude that the use of density-time curve parameters proximal and distal to a stenosis may prove important in evaluating the significance of peripheral vascular disease and warrants further investigation. CONCLUSIONS
Quantitative evaluation of vascular flow dynamics using intravenous DSA to assess the significance of a vascular stenosis would be a major advance in the noninvasive evaluation of atherosclerotic disease. To evaluate DSA data during changes in vascular flow, we studied seven mongrel dogs using DSA of the aorta at a control stage and then during three levels of stenosis (24 + 6%) 75 f 5%) and 100% reductions in flow). X-ray density-time curves were generated using manually assigned regions-of-interest both proximal and distal to the stenosis. From both density-time curves we determined the time to peak x-ray density (TTP), the linear upslope of the curves, and the monoexponential wash-out slope of the curves. The ratio of distal to proximal: (1) peak x-ray density, (2) TTP, and (3) linear upslope were also examined and were correlated with flow dynamics. Although the post-stenotic upslope correlated best with the severity of aortic flow reduction (r = 0.82, p < 0.05), the ratios of distal to proximal TTP and upslope proved to be reliable for detecting a reduction in blood flow. Nonetheless, the ability of this technique to determine the absolute reduction in flow was not ideal, probably in large part due to the nonlinear relationship between regional blood flow and regional blood volume. Thus, we conclude that quantitative analysis of density versus time flow curves derived from intravenous DSA is a simple method for evaluating the hemodynamic significance (i.e., reduction in blood flow) of a stenotic vascular lesion. Digital subtraction techniques with the application of simple region assignment, curve generation, and digital curve manipulation may prove useful in evaluating the significance of vascular lesions at rest. REFERENCES
1. Kruger RA, Mistretta CA, Houk TL, Kubal W, Riederer SJ, Ergun DL, Shaw CG, Lancaster JC, Rowe GG: Computerized fluoroscopy techniques for intravenous study of cardiac chamber dynamics. Invest Radio1 14:279, 1979. 2. Crummy AB, Strother CM, Sackett JF, Eraun DL. Shaw CC. Kruger RA, Mistretta CA, Turnipseed WD, Lieberman RP; Myerowitz PD. Ruzicka FF: Comouterized fIuoroscoov: Digital subtraction for intravenous angiocardiography and arteriography. AJR 135:1131,1980. :3. Meaney TF, Weinstein MA, Buonocore E, Pavelicek W, Borkowski GP. Gallagher JH, Sufka B, MacIntyre W,J:
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108
Number
3. Part I
4.
5.
6.
7.
8.
9.
Digital subtraction angiography of the human cardiovascular system. AJR 135:1153, 1980. Kruger RA, Anderson RE, Koehler R, Nelson JA, Sorenson JA, Morgan T: A method for the noninvasive evaluation of cardiovascular dynamics using a radiographic device. Radiology 139:301, 1981. Higgins CB, Norris SL, Gerber KH, Slutsky RA, Ashburn WL, Baily N: Quantitation of left ventricular dimensions and function by digital video subtraction angiography. Radiology 144:461, 1982. Gerber KH, Slutsky RA, Bhargava V, Ashburn WL, Higgins CB: Detection and assessment of severity of regional ischemic left ventricular dysfunction by digital fluoroscopy. AM HEART J lO4:27, 1982. Link DP, Foerster JM, Lantz BMT, Holcroft JW: Assessment of DeriDheral blood flow in man bv video dilution techniaue: A A preliminary report. Invest Radio1 16:298, 1981. Bursch JH, Hahne HJ, Brennecke R, Gronemeier D, Heintzen PH: Assessment of arterial blood flow measurements by digital angiography. Radiology 141:39, 1981. Norris SL. Slutskv RA. Mancini GBJ. Ashburn WL. Greeoratos G, Peterson -KL,’ Higgins CB: ‘Comparison of digital intravenous ventriculography with direct left ventriculography for quantitation of left ventricular volume and ejection fractions. Am J Cardiol 51:1399, 1983.
Quantification of arterial stenosisby DSA
597
10. Abrams HL: Caldwell lecture. The collateral circulation: Response to ischemia. AJR 140:1051, 1983. 11. Hessel SJ, Gerson DE, Bass A, Hollenberg NK, Dowgialo IT, Abrams HL: Renal collateral blood supply after acute unilateral renal artery occlusion. Invest Radio1 l&490, 1975. 12. John HT, Warren R: The stimulus to collateral circulation. Surgery 49:14, 1961. 13. Link DP, Lantz BMT, Foerster JM, Holcroft JW, Reid MH: New videodensitometric method for measuring renal arterv blood flow at routine arteriography: Validation-in the canine model. Invest Radio1 14:464. 1979. 14. Lantz BMT, Foerster JM, Link DP, Holcroft JW: Determination of relative blood flow in single arteries: New video dilution technique. AJR 134:1161, 1981. 15. Levin DC, Beckmann CF, Serur JR: Vascular resistance changes distal to progressive arterial stenosis: A critical re-evaluation of the concept of vasodilator reserve. Invest Radio1 15:120, 1980. 16. Shipley RE, Gregg DE: The effect of external constriction of a blood vessel on blood flow. Am J Physiol 141:289, 1944. 17. Fiddian RV, Byar D, Edwards EA: Factors affecting flow through a stenosed vessel. Arch Surg 68:83, 1964. 18. Logan SE: On the fluid mechanics of human coronary artery stenosis. IEEE Trans Biomed Eng 22:327, 1975.