© 1996 American Heart Association, Inc.
Articles |
Atherosclerotic Disease in the Femoral Artery in Hypertensive Patients at High Cardiovascular Risk
The Value of Ultrasonographic Assessment of Intima-Media Thickness and Plaque Occurrence
the Department of Clinical Physiology (M.S.), Wallenberg Laboratory for Cardiovascular Research (I.W., J.W.), and the Department of Medicine (B.F., S.A.), Göteborg University, Sahlgrenska University Hospital, Gothenburg, Sweden.
Correspondence to Björn Fagerberg, MD, Department of Medicine, Göteborg University, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden.
Abstract
The aim of the present investigation was to examine the occurrence of ultrasound-assessed morphological changes in the right common femoral artery and relate these findings to the ankle-arm index and to symptoms of lower-extremity arterial disease in hypertensive men at high cardiovascular risk (n=143). Comparisons were made with a healthy reference group consisting of age-matched men at low risk (n=46). The results showed that it was possible to obtain high-quality measurements of intima-media thickness in about 80% of all men and that the intraobserver variability was satisfactory (14%). A normal mean intima-media thickness was defined, using data from the low-risk group. Plaque occurrence and mean intima-media thickness in the right common femoral artery were significantly associated with ankle-arm index both in the right and left leg. There were more and larger plaques, as well as thicker mean and maximum intima-media complexes, in the high-risk group than in the low-risk group. In the high-risk group, 11% suffered from symptoms of right lower-extremity artery disease, 20% had an ankle-arm index 
0.9, 62% had moderate or large plaques (compared with 28% in the low-risk group, P<.001), and 77% had an enlarged intima-media complex. The cumulative frequency of signs of atherosclerosis in the right leg was 81% among the 110 patients in whom complete results from all examinations were available. Our conclusion is that ultrasound measurement of the intima-media thickness of the common femoral artery is a valuable method to evaluate morphological changes related to atherosclerotic disease in the lower extremity.
Key Words: ultrasonography • intima-media thickness • atherosclerosis • femoral artery • intermittent claudication
Atherosclerosis is a systemic disease with a segmental distribution. One of the major manifestations of this pathological process is lower-extremity arterial disease, which increases in prevalence in parallel with increasing age and occurrence of risk factors such as smoking, diabetes mellitus, and hypertension.1 2 3 4
A better knowledge of underlying pathophysiological mechanisms, as well as the development of strategies to prevent and treat arterial disease in this vascular region, requires methods to study early subclinical stages of the atherosclerotic process in the vessel wall. With high-resolution B-mode ultrasound it is possible to study wall morphology in superficially located arteries, such as the carotid arteries. A growing body of evidence resulting from a large number of ultrasonographic studies of this arterial territory indicates that the intima-media complex in the vessel wall seems to be related to both the atherosclerotic process and clinical manifest disease.5 6 7 8 9 10 11
There is a paucity of data as regards the utility of ultrasonography as a method to assess atherosclerotic changes in the femoral artery. Some studies have used this technique to evaluate plaque occurrence or different degrees of stenosis, but very few have addressed the possibility of measuring the intima-media thickness.4 12 13 Our group has reported that the femoral artery intima-media complex was thicker in patients with familial hypercholesterolemia in comparison with healthy age-matched controls.13
In the present study we have recruited a group of patients at high risk of cardiovascular disease and compared them with a healthy, age-matched low-risk group. The aim was to examine the occurrence of ultrasound-assessed morphological changes in the common femoral artery vessel wall and relate these findings to the ankle-arm index and to symptoms of lower-extremity arterial disease.
Methods
The study groups and the design of the study have been described in several previous reports.14 15 16
Study Groups
High-Risk Group
At the Hypertension Unit, Sahlgrenska Hospital, Göteborg University, Sweden, a group of hypertensive men (n=508) at high risk for cardiovascular disease was recruited to an open, randomized, parallel-group study of the feasibility and effects of a comprehensive multiple-risk-factor-modification program.15 From this group, one third (n=169) of the patients were randomly selected to take part in an ultrasound study of the carotid artery.16 The randomization procedure was based on a computer-generated allocation to one of the two treatment groups after stratification for serum cholesterol, smoking habits, and organ damage secondary to hypertension or atherosclerosis.15
All patients had long-standing treated hypertension diagnosed according to previously reported criteria and routines.15 These men were representative of high-risk hypertensive patients in Gothenburg, since the majority (>90%) were recruited earlier by screening a random third of all men in their age groups in the Göteborg Primary Prevention Trial.17
The inclusion criteria were male sex, age 50 to 72 years (at randomization), and one or more of the following: serum cholesterol level 
6.5 mmol/L, tobacco smoking corresponding to one cigarette or more per day, or diabetes mellitus defined according to WHO criteria.18 The exclusion criteria were unwillingness to participate or serious chronic disease that might interfere with compliance or the interpretation of results.
Of the original group of 169 patients randomized to the ultrasound examination, 164 men agreed to take part in the examination at baseline. After 3 years 11 patients had died, 3 patients were so handicapped by disease that they could not be reexamined, 1 patient had moved to another area, and 5 men were unwilling to participate in the follow-up study. Thus, 144 men underwent the reexamination, which also included ultrasonography of the right common femoral artery not performed at the baseline study. Readable ultrasound examinations were obtained in 143 patients.
Low-Risk Group
An age-matched low-risk group was recruited from a representative population sample in Göteborg. Fifty-four subjects were initially included, fulfilling the following criteria: diastolic blood pressure <95 mm Hg, no antihypertensive treatment, no smoking during the last 3 years, serum cholesterol 6.5 mmol/L, normal fasting blood glucose, and sinus rhythm at an electrocardiographic examination. Seven subjects were later excluded owing to signs of silent myocardial infarction (2 men), silent myocardial ischemia (2 men), or transient ischemic attacks (3 men). One subject refused to participate. Hence, 46 subjects were finally included in the low-risk control group.
For technical reasons it was not possible to obtain high-quality ultrasound images from all men. The numbers of men included in the different analyses are presented in Table 1
.
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All subjects gave informed consent after written and oral information, and the study was approved by the ethical committee of the Faculty of Medicine, Göteborg University.
Anthropometry
Body weight, body mass index, and waist:hip circumference ratio were measured according to recommended principles.15
Blood Pressure
Resting blood pressure was measured phonographically (Korotkoff sounds recorded on electrocardiographic paper) in the right arm in connection with the ultrasound examination as earlier described.19 Blood pressure was calculated to the nearest 1 mm Hg and the mean of two recordings was used.
Ankle systolic pressure was measured just before the ultrasound examination by trained technicians using a standardized protocol. A standard blood pressure cuff was placed around the ankle, and the blood flow in the posterior tibial artery and the dorsalis pedis artery was monitored with a Doppler flow detector at the lower edge of the cuff. The cuff was inflated until the arterial flow signal disappeared. The cuff pressure was then gradually lowered. The pressure at which the arterial flow signal returned indicated the systolic blood pressure level in the artery under examination. Ankle systolic pressures were measured in both legs. Duplicate measurements were done, followed by an auscultatory measurement of the arm systolic pressure. The means of duplicate measurements were used in the calculation of the ankle-arm index, and the lower of the two indices calculated in each leg was used in the following analyses. An abnormal ankle-arm index was defined as a value 0.9. This cutoff point has been defined from angiographic studies and is strongly predictive of atherosclerotic obstruction.20
Cardiovascular Disease and Smoking
Established criteria for stroke, myocardial infarction, and angina pectoris were used.15 Symptomatic lower-extremity arterial disease was defined as a history of burning pain in the calf or the whole leg provoked by walking exercise and relieved within minutes after rest, or after surgery for such disease.
Information on smoking habits was obtained by a self-administered questionnaire.15 The total number of years of smoking was multiplied by the average number of cigarettes smoked daily. The product was called "cigarette-years."
Biochemical Analysis
Venous blood was drawn after an overnight fast and after 5 minutes of supine rest for determination of blood glucose, serum triglycerides, and total serum cholesterol by use of established methods.21 22
Ultrasonography
The scanning procedure has been described in detail earlier.13 In short, the examination was performed with an ultrasound scanner (Acuson 128) equipped with a linear 7-MHz transducer. The theoretical axial resolution was 0.3 mm. Subjects were examined in supine position.13 The right femoral artery was scanned distal to the inguinal ligament along a section 
4 cm proximal and 1 cm distal to the flow divider (the site where the artery divides into the superficial and profound femoral arteries) to detect and image plaques. The pulsed Doppler signal was carefully watched for changes (velocity, turbulence) to avoid overlooking poorly visible plaques. Further, a more pronounced local increase in flow velocity, compatible with stenosis, was used to classify large plaques (see below).
For the measurement of intima-media thickness, the scanning focused on a 15-mm-long section proximal to the bifurcation. The vessel was scanned both longitudinally and transversely to determine the optimal longitudinal projection in which the ultrasound beam crossed the thickest part of the vessel wall perpendicularly. In this position, with the aid of a simultaneously recorded electrocardiographic signal, three separate images were captured, synchronized to the top of the R wave (end diastole), and recorded on videotape. A short sequence of real-time images was also recorded on videotape. Nearly all recordings (>90%) were performed by one technologist, who also read all images in a blinded fashion.
Measurements of Intima-Media Thickness
The ultrasound images from the videotapes were analyzed in a computerized analyzing system.23 Measurement of intima-media thickness was done along a 15-mm-long section of the common femoral artery, defined by two reference lines in the analyzing program. The distal line was set manually at the point where the far wall of the common femoral artery started to bend and form the profound femoral artery. The intima-media thickness of the far wall was defined as the distance from the leading edge of the lumen-intima interface to the leading edge of the media-adventitia interface. These interfaces were manually traced, as shown in Fig 1. The computer program measured and calculated the mean and maximum intima-media thickness between the reference lines. Three separate frozen images from the same section of the artery were measured, and the mean of these measurements was used in the analyses.23
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The definition of the upper limit for a normal mean intima-media thickness in the femoral artery was based on the following calculations in the low-risk group: only subjects who had never smoked were accepted as a healthy reference group, as there was a significant association between smoking (expressed as cigarette-years) and mean femoral artery intima-media thickness in the total low-risk group (r=.36, P=.035). In the group with subjects who had never smoked and who had no detectable plaque, the mean femoral artery intima-media thickness was 0.84 (SD 0.14) mm. The upper limit for a normal intima-media thickness was arbitrarily defined as the sum of the mean value and twice the SD in this subgroup, resulting in a value of 1.12 mm.24
Assessment of Plaque Occurrence
A semiquantitative subjective scale (visual scoring) was used to grade the size of plaques.13 This analysis included plaques in the near as well as the far wall of the vessel. A plaque was defined as a distinct area with an intima-media thickness >50% thicker than neighboring sites judged visually. Grade 0 designated no plaque; grade 1, one or more small plaques (each <20 mm2); and grade 2, moderately sized plaques. The differentiation between grades 1 and 2 was made subjectively in most cases, and quantitative measurements of the area were made in the computerized analyzing system only when the correct classification was not obvious to the observer.25 Grade 3 indicated large plaques that cause a change in blood flow as defined by the pulsed Doppler curve: a 100% increase in peak systolic velocity at the site of the plaque in relation to the segment proximal to the plaque, concomitant with a loss of reverse flow.
Intraobserver Variability
Twenty-nine men, 16 high-risk patients and 13 low-risk subjects, were examined on two different occasions within 7 to 14 days to estimate the intraobserver variability of recording and measurement of intima-media thickness. The two recordings and measurements were performed by the same technologist, who was blinded with regard to the results of the first examination. The coefficient of variation (CV) was 14% for mean intima-media thickness (r=.89). Plaque scoring differed in 17%, ie, in 5 of 29 cases (small plaques versus no plaque or moderate plaque in 4 cases and no plaque versus moderate plaque in 1 case).
Statistical Analysis
Results are presented as means and SDs of the mean. The values for ankle-arm index and intima-media thickness were skewed, and the results are given as median values and the range between the 50th and 75th percentiles (interquartile range).
In the variability study, Pearson's correlation coefficient (r), means, and SDs for differences between the two examinations were calculated. The intraobserver error(s) was calculated according to the formula 
. The CV describes the difference as a percentage of the pooled mean values (
) and was calculated according to the formula CV=[(s·100)/]%.
The Mann-Whitney U test was used to compare continuous variables. Categorical variables were analyzed by 
2 test or Fisher's exact test. Spearman's rank correlation (rs) was used in the correlation analyses (except in the variability study). A test for trend (Mantel-Haenszel 2) was used to analyze the relationship between a quantitative variable (ie, ankle-arm index) and a qualitative variable (ie, plaque status).
A two-sided value of P<.05 was considered statistically significant.
Results
Table 2 shows the characteristics of the high- and low-risk groups, respectively. Owing to selection criteria, the groups were of similar age but differed in blood pressure, smoking habits, previous tobacco consumption, serum lipid levels, prevalence of diabetes mellitus, and cardiovascular disease.
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Ankle-Arm Index
The distributions of the ankle-arm index are shown in Fig 2. The median values (and interquartile range) of the ankle-arm index in the right leg were 1.06 (0.10) and 1.18 (0.09) in the high- and low-risk groups, respectively (P<.0001). For the left leg, the corresponding values were 1.06 (0.07) and 1.15 (0.09), respectively (P<.0001). There were no significant differences between the values in the two legs in either group.
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Among the patients in the high-risk group, 15 suffered from symptomatic vascular disease in the right leg. Three of these 15 had an ankle-arm index above the cutoff point of 0.9. However, all 3 had atherosclerotic plaques and an enlarged intima-media thickness in the common femoral artery. One of the patients had undergone a revascularization operation.
In the left leg, 12 patients had symptoms or manifestations of vascular disease, and 2 of these patients had an ankle-arm index >0.9 in the left leg. None of these patients had undergone vascular surgery.
Plaque and Intima-Media Thickness
The occurrence of atherosclerotic plaques in the right femoral artery is depicted in Fig 3. There were more and larger plaques in the patient group than in the low-risk group (P<.0001). Most plaques were localized in the common femoral artery, although large plaques were observed in the superficial femoral artery in 3 cases and a small plaque in 1 case. One small plaque was found in the profound femoral artery in 1 patient. Fifteen of 16 patients with symptomatic vascular disease in the right leg had plaques of moderate or large size (94%).
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It was not possible to measure intima-media thickness in 41 (22%) of the men for technical reasons. However, this group did not show any significant differences in age, body mass index, cigarette-years, intermittent claudication, or number of moderate or large plaques in comparison with the patients with available data on intima-media thickness.
The distributions of mean intima-media thickness in the right femoral artery are shown in Fig 4. Median values (and interquartile range) were 1.57 (0.56) mm and 1.07 (0.39) mm in the patient and low-risk groups, respectively (P=.0009; the corresponding means±SDs were 1.65±0.66 mm and 1.34±0.79 mm, respectively). All except 1 of 11 patients with symptomatic vascular disease were found to have an intima-media thickness above the normal reference level as defined from the low-risk group.
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The median values (and interquartile range) of maximum intima-media thickness were 2.12 (0.63) mm in the high-risk group and 1.35 (0.78) mm in the low-risk group, respectively (P=.0035).
In high- and low-risk men taken together, intima-media thickness (expressed as median value and interquartile range) increased in parallel with the occurrence and severity of plaques in the common, superficial, or profound femoral arteries: no plaque, 0.90 (0.22) mm, n=40; small plaques, 1.14 (0.36) mm, n=27; and moderately sized or large plaques, 1.80 (0.48) mm, n=82, respectively (P<.0001).
Comparisons Between Ankle-Arm Index and Ultrasonography
As shown in Fig 5, the ankle-arm index in the right leg was significantly associated with both plaque status and mean intima-media thickness in the right common femoral artery.
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Comparison Between Left and Right Legs
In both groups taken together, there was a highly significant association between ankle-arm index in the right and left leg, respectively (rs=.80, P<.0001). An ankle-arm index below the cutoff point of 0.90 was found in both legs in 19 men, in the right leg only in 9 men, and unilaterally in the left leg in 11 men.
Measurements of mean intima-media thickness in the right femoral artery were available in 10 men with symptomatic vascular disease in the left leg. The intima-media complex was enlarged in all these cases. In a corresponding analysis, plaque data were available in 12 patients with symptoms or signs of disease in the left leg, and all these men were found to have moderate to large plaques in the right femoral artery.
In all men taken together, there was a highly significant association between plaque status in the right femoral artery and ankle-arm index in the left leg (P<.0001). Likewise, mean intima-media thickness in the right femoral artery was related to the left ankle-arm index (P=.0005).
Comparison of Diagnostic Methods
Complete results from the ankle-arm index measurements and the ultrasound examinations were obtained in 110 patients. The relationships between these different methods to diagnose peripheral artery disease in the right leg are presented in Fig 6. Among the 110 patients, 10 men had symptomatic disease in the right leg, including surgical treatment in 1 case. Among these patients with clinical manifestations, all had moderate or large atherosclerotic plaques and increased intima-media thickness (except 1 man, in whom ankle-arm index was low, however), whereas the ankle-arm index was 0.9 in 7 patients.
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In the high-risk group the cumulative results of the different diagnostic methods indicated a prevalence of right-sided femoral atherosclerotic disease of 81%, as shown in Fig 6
.
Discussion
Middle-aged and older hypertensive men with at least one of the additional risk factors of hypercholesterolemia, smoking, and diabetes mellitus were compared with a healthy, age-matched low-risk group. The results showed lower ankle-arm indices, larger mean intima-media thickness, and more and larger atherosclerotic plaques in the common femoral artery in the high- than in the low-risk group. In the high-risk group, 11% suffered from symptoms of vascular disease in the right leg and 20% had an ankle-arm index below the cutoff point of 0.9, whereas moderate to large plaques were found in 62%, and an enlarged mean intima-media complex was observed in 77%.
In vitro experiments of arteries comparing ultrasound measurements with anatomic structure have formed the basis for how to interpret transcutaneous ultrasound examinations.23 26 27 28 As to the ultrasound assessment of intima-media thickness in the common carotid artery, there is a growing body of data supporting the concept that increased intima-media thickness is an indicator of local and generalized atherosclerosis.11 Whether this also holds true for the femoral artery has not yet been clarified.
From our experience, a strictly standardized protocol makes it possible to obtain results with an intraobserver variability of 14% for measurement of mean intima-media thickness in the common femoral artery, to be compared with a variability of 10% for the common carotid artery.13 The variability is also acceptable for evaluation of plaque occurrence in the femoral artery. In comparison to the carotid artery, the femoral artery is more difficult to examine, mainly owing to the curved form, leading to a higher proportion of missing images.13 Thus, intima-lumen interface of the near wall cannot always be clearly visualized, resulting in problems of measuring vessel size, which is expressed as lumen diameter. Similarly, it may be difficult to obtain readable images of the intima-media thickness of the far wall, which was the case in one fifth of the men in the present study. However, this minority did not differ from the majority of men with available data as regards other characteristics, indicating that there is no systematic bias that might jeopardize the conclusions. It is also promising that we have found that with more experience, the proportion of missing images decreases.29
A further aspect of developing new methods is to define limits for normal values. When establishing the occurrence of significant plaques in the common femoral artery, we excluded ultrasound findings of small plaques, as these may be difficult to separate from enlarged intima-media thickness. The upper limit for a normal mean intima-media thickness in the common femoral artery was based on observations in the age-matched low-risk men who had never smoked and in whom no atherosclerotic plaques were found. It is important to underline that this definition cannot be generalized, as it was based on a limited number of men with a mean age of 69 years.
An alternative method to examine the femoral artery is intravascular ultrasonography, but this method is invasive and therefore difficult to use in asymptomatic or healthy subjects.30
In our opinion, there are several observations which indicate that intima-media thickness in the femoral artery is an indicator of the atherosclerotic process.
First, there was an association between intima-media thickness in the far wall of the common femoral artery and plaque status in the far or near wall of the common, superficial, or profound femoral arteries in the present study.
Second, we found that the level of ankle-arm index was related not only to plaque status but also to the intima-media thickness of the femoral artery.
Third, current data, as well as previous studies, have demonstrated that femoral artery intima-media thickness seems to be related to well-known risk factors for cardiovascular disease, such as hypercholesterolemia,4 13 smoking,4 14 and high plasma fibrinogen levels.4 14 A noteworthy finding is that there was an association between mean intima-media thickness and total tobacco consumption among previous smokers in the present low-risk group, in spite of the fact that they had quit smoking more than three years before inclusion in this study.
The femoral artery as a target for ultrasonographic studies is unique in the sense that the findings of morphological changes in the vessel wall can be related to possible hemodynamic effects within the same arterial segment, as the ankle-arm index can easily be measured. However, in the resting state there will be no pressure gradient in the artery unless there is at least a stenosis of 50% of the vessel diameter. Therefore, many subjects with an increased intima-media thickness will have a normal ankle-arm index. Besides, severe femoral atherosclerosis may give rise to collateral circulatory routes, leading to a higher ankle-arm index than that truly representative of the actual degree of femoral atherosclerosis. A source of error is also that rigidity of the arterial walls in the lower legs may be associated with falsely high measurements of ankle systolic pressure, leading to overestimation of ankle-arm indices. Hence, the observation that the ankle-arm indices showed a large variability for a given level of mean intima-media thickness may have several explanations.
In summary, available data consistently support the concept that ultrasonographic assessment of mean intima-media thickness in the common femoral artery is a valid indicator of the atherosclerotic disease process in the lower extremities. However, more studies addressing this issue are needed in the future, as intima-media thickening may have explanations other than atherosclerosis; eg, changes in flow and tension.31
Before evaluating the prevalence of atherosclerotic disease in the lower extremities, we had to define limits delineating abnormal from normal findings. As to ankle-arm index, we used the cutoff point 0.9, which has been validated with both angiography and Doppler examinations.20
In the total group of high-risk men, 13% had symptoms of occlusive arterial disease in one of the lower extremities. These findings can be compared with the results from the Edinburgh Artery Study showing a prevalence of 4.5% in a randomly selected population sample of subjects of age 55 to 74 years.32 This difference is naturally explained by the accumulation of risk factors for atherosclerotic disease in the present high-risk group.
In a recent survey of a large population sample of subjects 65 years old, 12% had an ankle-arm index <0.9.33 In the Edinburgh Artery Study, 18% of the subjects were found to have an ankle-arm index 0.9.32 In the present study, the corresponding figure was 28% of all patients in the high-risk group, taking both legs into account. Previous studies have shown prevalences of lower-extremity artery disease ranging from 3% to 20%, depending on the age of the subject studied and on how measurements of ankle-arm indices were applied.32
Ultrasound-assessed moderate and large plaques in the right femoral artery occurred in 62% of the men in the high-risk group. This result compares fairly well with data from other sonographic studies showing prevalences of atherosclerotic plaques in the femoral artery ranging from 53% to 58%.2 3 However, those studies differed in several aspects from the present study: The patients were younger than our patients, and other selection criteria were applied (cardiac disease or hypercholesterolemia); other definitions of plaque size were used; and ultrasound examinations were done in both legs, whereas we examined the right leg only. The last issue raises the question as to what degree the atherosclerotic disease process is bilaterally distributed in the lower extremities. In this respect we observed that both mean intima-media thickness and plaque occurrence in the right common femoral artery showed highly significant associations with ankle-arm indices on the contralateral side, ie, in the left leg.
Using a large intima-media thickness as a measure, we found that atherosclerosis occurred in 77% of the high-risk men. Among the patients with symptomatic lower-extremity artery disease in the right leg, 91% had enlarged intima-media thickness and 94% had moderate to large atherosclerotic plaques in part of the femoral artery examined by us.
The cumulative frequency of lower-extremity artery disease in the right leg was 81% in the high-risk group, using the results of the ankle-arm index measurements and the ultrasound examinations as diagnostic tools in the group of 110 patients in whom all data were available. As expected, most cases with silent atherosclerosis were found with the ultrasound technique.
In the present low-risk group, femoral artery plaques were found in 28% of the subjects, to be compared with a study of subjects >64 years old living in retirement houses demonstrating that plaques in the common femoral arteries were found in 11% of the subjects in one or both legs.34 However, a less sensitive ultrasound method was used in that study.
Our conclusion is that ultrasonographic measurement of the intima-media thickness in the femoral artery seems to be a valuable indicator of atherosclerotic disease in the lower-extremity arteries. The results show that subclinical atherosclerosis in the femoral artery is a more common finding in patients at high coronary risk than is generally known. Also, subjects at low risk have a high prevalence of subclinical atherosclerosis. Intensive training of the examination technique is necessary to obtain high-quality recordings. Future studies of large population samples are needed to establish sex- and age-specific limits for normal intima-media thickness.
Acknowledgments
This study was supported by grants from the Swedish Medical Research Council (B92-19X-09937-01A, B93-19X-09937-02B, B94-19X-09937-02B and 03A, B 95-19X-09937-04B), the Swedish Heart and Lung Foundation, the Swedish Hypertension Society, King Gustaf V and Queen Viktoria Foundation, Astra Hässle Cardiovascular Research Laboratories, Mölndal, Sweden. The RIS group also consists of Ove K. Andersson, Marianne Hartford, Thomas Hedner, Hans Herlitz, Susanne Ljungman, Bengt Persson, Ola Samuelsson, Bengt Widgren, and Marian Wysocki. We wish to thank Caroline Schmidt for excellent technical assistance.
Received August 17, 1995; revision received February 2, 1996; References
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