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Probucol quantitative regression Swedish trial: New angiographic technique to measure atheroma volume of the femoral artery
Probucol Quantitative Regression Swedish Trial: New Angiographic Technique to Measure Atheroma Volume of the Femoral Artery Uno Erikson, MD, PhD, Sven Nilsson, MD, and GOran Stenport, MD
The Probucol Quantitative Regression Swedish Trial is studying the development of atherosclerosis in hyperiipidemic patients through the use of digitized femoral arteriographic examinations. In a 20-cm segment of the femoral artery, cross-sectional areas are calculated using an algorithm that was introduced by Hilal and Crawford. Changes in atheroma volume are measured in repeat arteriographic examinations. This report describes the radiologic technique, the scanning procedure and the image analysis. (Am J Cardiol 1988;62:44B-47B)
From the Department of Diagnostic Radiology, University Hospital, Uppsala, Sweden, and the Department of Diagnostic Radiology, Regional Hospital, Link6ping, Sweden. Address for reprints: Uno Erikson, MD, PhD, Department of Diagnostic Radiology, University Hospital, S-751 85 Uppsala, Sweden.
44B
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62
he measurement of lipids has been a well-known technique for years. However, the radiologic measurement of atherosclerosis is relatively new. Developing a technique that is reliable enough to compare with the chemical methods of lipid measurement represents a challenge. The aim of the Probucol Quantitative Regression Swedish Trial is to evaluate the extent to which development of atherosclerosis can be retarded by serum lipid alterations induced by administration of probucol, together with cholestyramine and dietary modification. It is well known that the growth of atherosclerotic plaques can not only be retarded but also reversed. I In an earlier study, I we performed femoral arteriography in 62 patients with significant hyperlipidemia. Sixty of them were asymptomatic, whereas 2 had intermittent claudication. The goal of the study was to determine whether lowering serum lipid levels through drug therapy could influence the development of atheromatous disease in the femoral artery. Half of the patients were treated with fenofibrate (Laboratoires Fournier, Dijon, France) and nicotinic acid, and the other half served as a control group. Arteriography was repeated up to 4 times in these patients without complications. Atherosclerotic lesions were found in 46 of the 62 patients (74%). Most patients had only small or moderate atheromatous deposits in the femoral artery at the initial examination. In most cases, there was no change during the 18 months of the study. Regression, as judged by visual gradation, was documented in 5 patients in the treated group but in none of the control patients (p <0.001). The primary end point of the Probucol Quantitative Regression Swedish Trial will be to measure changes in atheroma volume in the femoral artery. This volume will be calculated through quantitative densitometry of femoral arteriograms. Arteriography will be performed at the Departments of Diagnostic Radiology at the University Hospital in Uppsala and the Regional Hospital in Link6ping.
T
ANGIOGRAPHIC TECHNIQUES Repeat arteriography has an extremely low risk of adverse effects if it is performed carefully by experienced operators under controlled conditions. In our previous study, ] we repeated arteriography up to 4 times to evalu-
ate the adverse effects of the procedure (Table I). The only adverse effect was a single allergic reaction. We use an identical technique in Uppsala and Link6ping. Focal spot size is 0.2 mm, focus film distance is 105 cm and magnification rate is 0.31. We use a film changer with a coal-fiber top. The exposures can be electrocardiography-gated. No grid is used because the grid pattern in the image would disturb the densitometry. The contrast agent is ioxaglate (Hexabrix®), which has an iodine content of 320 mg/ml. The catheter is introduced under local anesthesia. No other medication is given. Overview arteriography covers the arterial tree from the distal aorta to the middle of the calves. It is performed according to the routine used for many years in both of our departments, ensuring good visualization of the distal abdominal aorta, the aortoiliac bifurcation, the pelvic arteries including the oblique projection of the profound femoral arteries, the femoral and popliteal arteries, and the fibular, anterior and posterior tibial arteries. This overview arteriography is performed at the first and last evaluation at year 0 and year 3. Special arteriography of 1 of the femoral arteries is performed at all 4 evaluations. The catheter tip is placed in the external iliac artery at the lower border of the sacroiliac joint. Two injections are made, one 10 minutes after the other. The exposures are electrocardiographygated. Calculation of atheroma volume is based on computerized analysis of the arteriograms from the 2 angiographic series, in which the analyzed segment is always 26.2 cm long. COMPUTERIZED I M A G E PROCESSING AND ANALYSIS A Sigma Scanner (IMTEC, Uppsala, Sweden) is used in an Epsilon Image Processing work station (IMTEC). The principle of the digiEzing unit in the scanner is that of a line camera; in other words, the image is digitized line by line. The camera has a charge-coupled device array with 2,048 light-sensitive elements. The smallest pixel size possible is 37.5 #m. In the Probucol Quantitative Regression Swedish Trial we are using a pixel size of 75 #; after digitizing the image, the size of the image matrix is between 1 and 2 Mb. A fundamental step in the image analysis is finding the edges of the scanned artery segment. To ensure that we can do so, the standard image processing computer program in the Epsilon has been combined and extended with some special purpose routines into a semiautomatic procedure. When a contrast-filled small artery overlaps the artery segment to be studied, the cross-sectional areas intersecting the overlap region would be overestimated if no correction were made. To overcome this difficulty, a special procedure has been developed to eliminate overlapping vessels. This procedure is necessary to avoid large errors in volume calculation. However, this correction results in the loss of some information, since minor wall irregularities at the intersection of 2 vessels will not be
TABLE I Adverse Reactions During Arteriography (173 Interventions)
No. of patients Allergic reaction Hematoma Embolus Arterial damage
1
2
53 1 0 0 0
52 0 0 0 0
Examination 3 21 0 0 0 0
4 47 0 0 0 0
(ik) FIGURE 1. Lambda (j,k) is the length of the chord that the radiaUon has passed through the artery before reaching the film in the pixel with coordinate j,k. By using the method of Crawford et al, 4,s lambda (j,k) can be calculated from the film density at (j,k), the background densities near the artery, and 2 film constants.
detected. Therefore, after correcting for crossing arteries, the edge detection program is repeated. VOLUME CALCULATIONS The cross-sectional areas along the artery can be calculated by the formula first used by Hilal 2 in 1966 (Fig. 1). Hilal used the formula to measure flow velocities in arteries that he assumed to be circular. In the late 1970s, Crawford and Blankenhorn used Hilal's formula to calculate cross-sectional areas in arteriograms. 3-5 In our study, a longitudinal plot of the cross-sectional area is made for every 20-cm segment of the femoral artery (Fig. 2). The straight line above the curve represents a rough estimate of the cross-sectional areas in the healthy artery. The area between this line and the curve represents the atheroma volume. REPRODUCIBILITY The reproducibility in repeated estimations has been very high in our work. In a calculation based on 12 patients, the Pearson correlation coefficient was 0.992 and the coefficient of variation 0.072.
THE AMERICAN JOURNAL OF CARDIOLOGY JULY25, 1988
45B
A SYMPOSIUM: HYPERCHOLESTEROLEMIA
O
0
so"
I-oo
"
150 '
'
"
20O
mm
FIGURE 2. Longitudinal plot of the cross-seeUonal area along an arterial segment. The area between the curve and the horizon. tal line above it represents the estimated atheroma volume.
V A L I D I T Y IN A M O D E L The validity of this method was investigated by Ruhn et al, 6 using a plexiglass plate with 6 longitudinal holes simulating blood vessels. Various amounts of a hardening plastic material were injected into the holes to simulate atherosclerotic plaques (Fig. 3). A circulating contrast medium mixture was then pumped through the system,
Volume 250
20C
15C
lOG
50
s
,o
is
2"0
2"s
Densitometric volume FIGURE 3. PlexJglass phantom with cylindrical holes to simulate blood vessels. The volumes of small arUflcial plaques within Ihe holes were calculated by using the densitome~ic method described. (Reprinted with permission from Acta Radial [Oiasn] [Stockh].s)
46B
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62
FIGURE 4. Correlation between real volume and donsitometric volume (r 0.987). (Reprinted with permission from Acta Radiol [I)iagn] (Stockh). s) =
and the volume was calculated by the method described here. Figure 4 illustrates the relation between the densitometric volume and the real volume. The correlation coefficient was 0.987.
REFERENCES 1. Erikson U, Helmius G, Hemmingsson A, Ruhn G, Olsson AG. Repeat femoral arteriography in hyperlipidemic patients. Acta Radiol [Diagn] (Stockh) 1988; 29.'303-309. 2, Hilal SK. Determination of the blood flow by a radiographic technique. PhD Dissertation, University of Minnesota, 1966.
3, Blankenhorn DH, BrooksSH, Seizer RH, Barndt R. The rate ofatherosclerosis change during treatment of hyperlipoproteinemia. Circulation 1978;57:355361. 4. Crawford DE, Brooks SH, Selver RH, Barn& R, Beckenbach ES, Blankenhorn DH. Computer densitometry for angiographic assessment of arterial cho-
lesterol content and gross pathology in human atherosclerosis. J Lab Clin Med 1977;89:378. 5. Crawford DE, Blankenhorn DH. Measurement of atherosclerotic luminal irregularity and obstruction by radiographic densitometry. Invest Radiol 1977; 12.'307-313. 6. Ruhn G, Erikson U, Helmius G, Hemmingsson A. Computerized quantitation of atherosclerosis in an experimental model. Acta Radiol [Diagn] [Stockh] 1982;23:621-624.
Discussion Question." Obviously this is an important study and, by its very nature, one not likely to be repeated. Why didn't you include cardioangiography as an end point? I would think that would be your primary end point. Dr. Erikson." Of course, it is a major problem to repeat coronary angiograms during a 3-year study in which the patient is exposed on 4 occasions to extensive peripheral angiography. Since many of these patients are symptomfree, we decided that it was not ethical. Furthermore, we think that the techniques described for quantitative coronary angiography are not exactly controlled. Many of the arteriograms that have been exposed and evaluated in other studies have minor, and sometimes major, problems because the heart is moving. One could actually create
artifacts by taking the picture in the wrong phase of the heart cycle. The advantage of the femoral arteriogram is that we have a control for that. Question." I think it is disappointing that you are not going to get cardioangiograms. I don't think you will have the opportunity to do this type of study again. Dr. Erikson." We hope that our study can influence other complementary angiographic studies. In addition, we do have another ongoing study of about 100 patients on diet in whom we have performed repeated coronary angiography. In that study, however, we use a visual comparison between the 2 coronary arteriograms. The radiologic work is finished and a correlation to different lipids and other factors is under way.
THE AMERICAN JOURNAL OF CARDIOLOGY JULY25, 1988 4 7 B
The Probucol Quantitative Regression Swedish Trial is studying the development of atherosclerosis in hyperiipidemic patients through the use of digitized femoral arteriographic examinations. In a 20-cm segment of the femoral artery, cross-sectional areas are calculated using an algorithm that was introduced by Hilal and Crawford. Changes in atheroma volume are measured in repeat arteriographic examinations. This report describes the radiologic technique, the scanning procedure and the image analysis. (Am J Cardiol 1988;62:44B-47B)
From the Department of Diagnostic Radiology, University Hospital, Uppsala, Sweden, and the Department of Diagnostic Radiology, Regional Hospital, Link6ping, Sweden. Address for reprints: Uno Erikson, MD, PhD, Department of Diagnostic Radiology, University Hospital, S-751 85 Uppsala, Sweden.
44B
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62
he measurement of lipids has been a well-known technique for years. However, the radiologic measurement of atherosclerosis is relatively new. Developing a technique that is reliable enough to compare with the chemical methods of lipid measurement represents a challenge. The aim of the Probucol Quantitative Regression Swedish Trial is to evaluate the extent to which development of atherosclerosis can be retarded by serum lipid alterations induced by administration of probucol, together with cholestyramine and dietary modification. It is well known that the growth of atherosclerotic plaques can not only be retarded but also reversed. I In an earlier study, I we performed femoral arteriography in 62 patients with significant hyperlipidemia. Sixty of them were asymptomatic, whereas 2 had intermittent claudication. The goal of the study was to determine whether lowering serum lipid levels through drug therapy could influence the development of atheromatous disease in the femoral artery. Half of the patients were treated with fenofibrate (Laboratoires Fournier, Dijon, France) and nicotinic acid, and the other half served as a control group. Arteriography was repeated up to 4 times in these patients without complications. Atherosclerotic lesions were found in 46 of the 62 patients (74%). Most patients had only small or moderate atheromatous deposits in the femoral artery at the initial examination. In most cases, there was no change during the 18 months of the study. Regression, as judged by visual gradation, was documented in 5 patients in the treated group but in none of the control patients (p <0.001). The primary end point of the Probucol Quantitative Regression Swedish Trial will be to measure changes in atheroma volume in the femoral artery. This volume will be calculated through quantitative densitometry of femoral arteriograms. Arteriography will be performed at the Departments of Diagnostic Radiology at the University Hospital in Uppsala and the Regional Hospital in Link6ping.
T
ANGIOGRAPHIC TECHNIQUES Repeat arteriography has an extremely low risk of adverse effects if it is performed carefully by experienced operators under controlled conditions. In our previous study, ] we repeated arteriography up to 4 times to evalu-
ate the adverse effects of the procedure (Table I). The only adverse effect was a single allergic reaction. We use an identical technique in Uppsala and Link6ping. Focal spot size is 0.2 mm, focus film distance is 105 cm and magnification rate is 0.31. We use a film changer with a coal-fiber top. The exposures can be electrocardiography-gated. No grid is used because the grid pattern in the image would disturb the densitometry. The contrast agent is ioxaglate (Hexabrix®), which has an iodine content of 320 mg/ml. The catheter is introduced under local anesthesia. No other medication is given. Overview arteriography covers the arterial tree from the distal aorta to the middle of the calves. It is performed according to the routine used for many years in both of our departments, ensuring good visualization of the distal abdominal aorta, the aortoiliac bifurcation, the pelvic arteries including the oblique projection of the profound femoral arteries, the femoral and popliteal arteries, and the fibular, anterior and posterior tibial arteries. This overview arteriography is performed at the first and last evaluation at year 0 and year 3. Special arteriography of 1 of the femoral arteries is performed at all 4 evaluations. The catheter tip is placed in the external iliac artery at the lower border of the sacroiliac joint. Two injections are made, one 10 minutes after the other. The exposures are electrocardiographygated. Calculation of atheroma volume is based on computerized analysis of the arteriograms from the 2 angiographic series, in which the analyzed segment is always 26.2 cm long. COMPUTERIZED I M A G E PROCESSING AND ANALYSIS A Sigma Scanner (IMTEC, Uppsala, Sweden) is used in an Epsilon Image Processing work station (IMTEC). The principle of the digiEzing unit in the scanner is that of a line camera; in other words, the image is digitized line by line. The camera has a charge-coupled device array with 2,048 light-sensitive elements. The smallest pixel size possible is 37.5 #m. In the Probucol Quantitative Regression Swedish Trial we are using a pixel size of 75 #; after digitizing the image, the size of the image matrix is between 1 and 2 Mb. A fundamental step in the image analysis is finding the edges of the scanned artery segment. To ensure that we can do so, the standard image processing computer program in the Epsilon has been combined and extended with some special purpose routines into a semiautomatic procedure. When a contrast-filled small artery overlaps the artery segment to be studied, the cross-sectional areas intersecting the overlap region would be overestimated if no correction were made. To overcome this difficulty, a special procedure has been developed to eliminate overlapping vessels. This procedure is necessary to avoid large errors in volume calculation. However, this correction results in the loss of some information, since minor wall irregularities at the intersection of 2 vessels will not be
TABLE I Adverse Reactions During Arteriography (173 Interventions)
No. of patients Allergic reaction Hematoma Embolus Arterial damage
1
2
53 1 0 0 0
52 0 0 0 0
Examination 3 21 0 0 0 0
4 47 0 0 0 0
(ik) FIGURE 1. Lambda (j,k) is the length of the chord that the radiaUon has passed through the artery before reaching the film in the pixel with coordinate j,k. By using the method of Crawford et al, 4,s lambda (j,k) can be calculated from the film density at (j,k), the background densities near the artery, and 2 film constants.
detected. Therefore, after correcting for crossing arteries, the edge detection program is repeated. VOLUME CALCULATIONS The cross-sectional areas along the artery can be calculated by the formula first used by Hilal 2 in 1966 (Fig. 1). Hilal used the formula to measure flow velocities in arteries that he assumed to be circular. In the late 1970s, Crawford and Blankenhorn used Hilal's formula to calculate cross-sectional areas in arteriograms. 3-5 In our study, a longitudinal plot of the cross-sectional area is made for every 20-cm segment of the femoral artery (Fig. 2). The straight line above the curve represents a rough estimate of the cross-sectional areas in the healthy artery. The area between this line and the curve represents the atheroma volume. REPRODUCIBILITY The reproducibility in repeated estimations has been very high in our work. In a calculation based on 12 patients, the Pearson correlation coefficient was 0.992 and the coefficient of variation 0.072.
THE AMERICAN JOURNAL OF CARDIOLOGY JULY25, 1988
45B
A SYMPOSIUM: HYPERCHOLESTEROLEMIA
O
0
so"
I-oo
"
150 '
'
"
20O
mm
FIGURE 2. Longitudinal plot of the cross-seeUonal area along an arterial segment. The area between the curve and the horizon. tal line above it represents the estimated atheroma volume.
V A L I D I T Y IN A M O D E L The validity of this method was investigated by Ruhn et al, 6 using a plexiglass plate with 6 longitudinal holes simulating blood vessels. Various amounts of a hardening plastic material were injected into the holes to simulate atherosclerotic plaques (Fig. 3). A circulating contrast medium mixture was then pumped through the system,
Volume 250
20C
15C
lOG
50
s
,o
is
2"0
2"s
Densitometric volume FIGURE 3. PlexJglass phantom with cylindrical holes to simulate blood vessels. The volumes of small arUflcial plaques within Ihe holes were calculated by using the densitome~ic method described. (Reprinted with permission from Acta Radial [Oiasn] [Stockh].s)
46B
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62
FIGURE 4. Correlation between real volume and donsitometric volume (r 0.987). (Reprinted with permission from Acta Radiol [I)iagn] (Stockh). s) =
and the volume was calculated by the method described here. Figure 4 illustrates the relation between the densitometric volume and the real volume. The correlation coefficient was 0.987.
REFERENCES 1. Erikson U, Helmius G, Hemmingsson A, Ruhn G, Olsson AG. Repeat femoral arteriography in hyperlipidemic patients. Acta Radiol [Diagn] (Stockh) 1988; 29.'303-309. 2, Hilal SK. Determination of the blood flow by a radiographic technique. PhD Dissertation, University of Minnesota, 1966.
3, Blankenhorn DH, BrooksSH, Seizer RH, Barndt R. The rate ofatherosclerosis change during treatment of hyperlipoproteinemia. Circulation 1978;57:355361. 4. Crawford DE, Brooks SH, Selver RH, Barn& R, Beckenbach ES, Blankenhorn DH. Computer densitometry for angiographic assessment of arterial cho-
lesterol content and gross pathology in human atherosclerosis. J Lab Clin Med 1977;89:378. 5. Crawford DE, Blankenhorn DH. Measurement of atherosclerotic luminal irregularity and obstruction by radiographic densitometry. Invest Radiol 1977; 12.'307-313. 6. Ruhn G, Erikson U, Helmius G, Hemmingsson A. Computerized quantitation of atherosclerosis in an experimental model. Acta Radiol [Diagn] [Stockh] 1982;23:621-624.
Discussion Question." Obviously this is an important study and, by its very nature, one not likely to be repeated. Why didn't you include cardioangiography as an end point? I would think that would be your primary end point. Dr. Erikson." Of course, it is a major problem to repeat coronary angiograms during a 3-year study in which the patient is exposed on 4 occasions to extensive peripheral angiography. Since many of these patients are symptomfree, we decided that it was not ethical. Furthermore, we think that the techniques described for quantitative coronary angiography are not exactly controlled. Many of the arteriograms that have been exposed and evaluated in other studies have minor, and sometimes major, problems because the heart is moving. One could actually create
artifacts by taking the picture in the wrong phase of the heart cycle. The advantage of the femoral arteriogram is that we have a control for that. Question." I think it is disappointing that you are not going to get cardioangiograms. I don't think you will have the opportunity to do this type of study again. Dr. Erikson." We hope that our study can influence other complementary angiographic studies. In addition, we do have another ongoing study of about 100 patients on diet in whom we have performed repeated coronary angiography. In that study, however, we use a visual comparison between the 2 coronary arteriograms. The radiologic work is finished and a correlation to different lipids and other factors is under way.
THE AMERICAN JOURNAL OF CARDIOLOGY JULY25, 1988 4 7 B