Noninvasive ultrasound measurements of aortic intima-media thickness: Implications for in vivo study of aortic wall stress

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1 Noninvasive ultrasound measurements of aortic intima-media thickness: Implications for in vivo study of aortic wall stress Håkan Åstrand, MD, a Thomas Sandgren, MD, PhD, b Åsa Rydén Ahlgren, MD, PhD, c and Toste Länne, MD, PhD, a Jönköping, Helsingborg, and Malmö, Sweden Object: The abdominal aorta (AA) has a predilection for aneurysm formation. An etiologic factor may be underlying aortic wall stress. The purpose of this study was to examine whether the intima-media thickness (IMT) of the AA, as a surrogate to arterial wall thickness, can be measured noninvasively with satisfactory results to calculate circumferential wall stress, and to evaluate regional and gender differences in wall stress. Methods: Sixty-five middle-aged healthy subjects were examined with B-mode ultrasound to determine the diameter and IMT in the infrarenal AA, common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA). Blood pressure was measured noninvasively in the brachial artery. Wall stress was calculated according to the law of LaPlace. Results: Intraobserver variability for the IMT in the AA showed a coefficient of variation of 11%. IMT was thickest in the AA compared with the CCA, CFA, and PA (P <.001). There was a gender difference in IMT in the CFA (P <.05) and PA (P <.01) but not in the AA. Greater wall stress was found in the AA than in the CCA (P <.001) and PA (P <.001), with men having greater wall stress in all studied arterial regions. Conclusions: Aortic IMT can be satisfactorily studied in vivo with noninvasive B-mode ultrasound. There are gender differences in IMT and wall stress, and the largest wall stress is found in the AA in men, which might be important in aneurysm development. (J Vasc Surg 2003;37: ) The abdominal aorta (AA) has a predilection for aneurysm formation. One factor of importance may be that the aorta is the largest artery in the body, and wall stress is related to arterial diameter. Furthermore, the AA dilates 25% between the age of 25 and 70 years. 1 Remodeling and degeneration of the wall is accompanied by altered composition of the vessel wall, with increasing collagen-elastin ratio. 2,3 The possible importance of wall stress is emphasised in that there is a relation between blood pressure and increasing aneurysm diameter, as well as aneurysm diameter and risk for rupture. 4,5 A direct relation between wall stress in vivo and risk for aneurysm rupture has been proposed. 6 The law of LaPlace is used to calculate wall tension; it must be emphasized, however, that this equation originally was designed to study spheres with infinitely thin walls. This means that to study the circumferential arterial wall stress, the thickness of the wall must be added to the calculation. During the last decade a noninvasive ultrasound technique From the Department of Medicine and Care, University of Linköping, Division of Vascular Surgery, Jönköping Hospital, a Department of Surgery, Helsingborg Hospital, b and Department of Clinical Physiology, Malmö University Hospital. c Supported by grants from the Medical Faculty of Linköping University; the Swedish Research Council Grant 12661; and funding from Jönköping Hospital and the Swedish Heart-Lung Foundation. Competition of interest: none. Reprint requests: Håkan Åstrand, University of Linköping Division of Vascular Surgery, Jönköping Hospital, S , Jönköping, Sweden ( hakan.astrand@ltjkpg.se). Copyright 2003 by The Society for Vascular Surgery and The American Association for Vascular Surgery /2003/$ doi: /s (02) has been developed that makes it possible to study the intima-media thickness (IMT) of arteries in vivo, as a surrogate to arterial wall thickness, 7-11 which accordingly has been used to calculate circumferential wall stress. 9,12-16 This has only been performed systematically in the superficial arteries, because it has been argued that the depth of the aorta from the skin surface makes it beyond reach with this technique. The purposes of this study were to investigate whether the IMT of the AA can be satisfactorily examined noninvasively with ultrasound, with superficial arteries as reference data; to evaluate wall stress in different locations of the vascular tree; and to assess the influence of gender on wall stress. MATERIAL AND METHODS Sixty-five healthy white subjects participated in the study. All were nonsmokers, without hereditary factors for aneurysmal disease. They had no history of cardiopulmonary or cerebrovascular disease. Ankle brachial index was 1 or higher, and no subject had a history of peripheral vascular disease. The women were receiving no hormonal replacement therapy. Mean weight was kg for the men and kg for the women. Mean body mass index was kg/m 2 for the men and kg/m 2 for the women. Fifty-four subjects were examined twice consecutively by one experienced ultrasonographer. In 4 subjects it was not possible to evaluate IMT in the infrarenal AA because of bowel gas, plaque formation at the site of interest, or other problem in visualising the vessel. Thus in 25 men (age, ) and 25 women (age, ) the

2 JOURNAL OF VASCULAR SURGERY Volume 37, Number 6 Åstrand et al 1271 Fig 1. Ultrasonic longitudinal image of abdominal aorta imaged with a 5 MHz transducer. Upper arrowhead, luminal-intimal interface of aortic far wall; lower arrowhead, corresponding medial-adventitial interface. Intima-media thickness was defined as measured distance between these interfaces. infrarenal AA, common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA) were studied. The IMT of the CCA was visualized in all subjects. In 1 man and 1 woman the IMT of the PA could not be measured, and in 4 men and 1 woman the IMT of the CFA could not be measured, because of plaque formation at the site of interest. The readings from the 50 subjects were used to calculate intraindividual variability and to describe differences between gender and arterial regions. The aorta was examined at the midpoint between the renal arteries and the aortic bifurcation; the right CCA was examined 1 cm proximal to the bifurcation; the right CFA was examined at the site of the inguinal fossa, with the hip joint as a landmark; and the right popliteal artery was examined at the site of the popliteal fossa, with the patient prone and the patella as a landmark. All examinations were performed after at least 15 minutes of rest with the subjects supine, except for examination of the popliteal artery. At the beginning of the study, noninvasive pressure was measured in both arms with a sphygmomanometer. Since no significant difference in pressure between the arms was found, the right arm was used because of the location of the ultrasound equipment in the examining room. For measuring IMT and lumen diameter (LD), we used a Philips P700 ultrasound device (Philips Ultrasound, Santa Ana, Calif) with a 7.5 MHz linear transducer to scan the superficial vessels. For aortic imaging either a 5 or 3.5 MHz transducer was used. A longitudinal perpendicular image of the vessel was insonated and recorded on a video monitor (Panasonic Ag-7350l; Matsushita Electric Industrial Co, Osaka, Japan). The analyzing system was composed of a personal computer (Intel 486, Santa Clara, Calif), a video monitor (Panasonic H1450; Matsushita Electric Industrial Co), and a video recorder (Panasonic NV-HS1000; Matsushita Electric Industrial Co) linked to a text monitor and a digitizer (Summagraphics Summa Sketch III; GTCO CalComp, Scottsdale, Ariz). The longitudinal image was frozen in diastole, according to the prevailing standard of IMT measurement (Fig 1). Although tilting the transducer away from the transverse axis will falsely decrease the measured diameter and increase the IMT, this error is minimized because the echoes representing the IMT will not be clear enough unless the transducer is positioned in the midline of the vessel. The image was recorded on videotape, then measured manually by tracing a cursor along the echo edges on a 10 mm section with the

3 1272 Åstrand et al JOURNAL OF VASCULAR SURGERY June 2003 Fig 2. Intraobserver variability of intima-media thickness (IMT) measurements in infrarenal abdominal aorta according to method of Bland and Altman. 19 Difference between measurements 1 and 2 is denoted on vertical axis, and mean of measurements 1 and 2 on horizontal axis. aid of the digitizer. 10 The 10 mm longitudinal image provides approximately 100 boundary points between the echo edges where the IMT is measured, and the mean value of IMT is automatically calculated with a computerized system (VAP version 2.0). The software was written in Microsoft Pascal under MS-DOS operating system. The analyzing system was developed by the Department of Applied Electronics, Chalmers University of Technology, Gothenburg, Sweden. IMT was measured on the far wall, from the interface between blood and intima and the interface between media and adventitia. 10,11 The means of the IMT and LD were calculated from the first two good quality images. The cross-sectional intima-media area (IMA) was also calculated according to the formula IMA (LD/2 IMT) 2 (LD/2) 2, where IMT is intima-media thickness (mm) and LD is lumen diameter (mm). Wall stress was calculated according to the law of LaPlace. Wall thickness is not included in its classic form: Wall tension pressure radius. We used the extended formula, sometimes also named Lamé 17 or Frank, 18 to calculate circumferential wall stress (dyne/cm 2 ): Wall stress DP (LD/2)/IMT, where DP is diastolic pressure (dyne/cm 2 ) (used because IMT measurements were performed in diastole; 1 mm Hg equals 1333 dyne/cm 2 ), LD is lumen diameter (cm), and IMT is intima-media thickness (cm). Eleven healthy subjects were included in an interobserver variability study performed by two different sonographers (AA examination in 11 subjects, and analysis of both the right and left CCA in 5 subjects). Each examiner performed three consecutive recordings of the 11 AA and the 10 CCA. The first recording of each examiner was compared, as were the second and third recordings. This resulted in three different coefficients of variation (CV) from the aorta and from the CCA, and the means of these were calculated. Informed consent was obtained from each patient; the ethics committee in Lund, Sweden, approved the study. Statistical analysis. Variability calculations between observations and observers were performed with the method described by Bland and Altman. 19 The coefficient of variation (CV) was calculated with the formula CV (%) s 100/X. The formula s SD/ 2 was used to calculate the standard deviation of the intraobserver error (s). 10 Comparisons were made with the Student t test. Software used was Statistica 5.0. * and denote significant differences at the level of P.05. RESULTS Reproducibility. Intraindividual reproducibility of IMT measurements in the AA are shown in Fig 2. CV was calculated to 11%. CV of the CCA, CFA, and PA were 6%, 8%, and 10%, respectively. IMA showed similar results, with CV of 12%, 6%, 8%, and 10% for the AA, CCA, CFA, and PA, respectively. When measuring LD, CV was lower: 4%, 2%, 2%, and 2% in the AA, CCA, CFA, and PA, respectively (Table I). Interindividual variability in the examined aortas was 10% for IMT. CV of the IMA was 14%, and CV of the LD was 6%. The CCA had a CV of 8% for IMT, 8% for IMA, and 3% for LD. LD, IMT, IMA, and wall stress. Table II shows the LD in the four investigated arterial segments. Fig 3 shows IMT in the four arterial regions. The aorta had thicker IMT than did the other vessels (P.001). IMT was thicker in men than in women in both the CFA (P.05) and PA (P.01). In the CCA there was a tendency for thicker IMT in men than in women, but the difference was not significant. In the AA no difference in IMT was noted between men and women. The AA had greater IMA than the other vessels did (P.001). IMA was greater in men than in women in the CFA and PA (P.001) as well as the CCA (P.05). IMA in

4 JOURNAL OF VASCULAR SURGERY Volume 37, Number 6 Åstrand et al 1273 Table I. Coefficients of variation for four vascular regions studied Intima-media thickness Intima-media area Lumen diameter CV (%) CV (%) CV (%) AA (n 50) CCA (n 50) CFA (n 45) PA (n 48) CV, Coefficient of variation; AA, abdominal aorta; CCA, common carotid artery; CFA, common femoral artery; PA, popliteal artery. the AA tended to be greater in men than in women, but the difference was not significant (P.07) (Table II). Fig 4 shows the wall stress in the four arterial regions. The AA had greater wall stress than did the CCA (P.001) and PA (P.001), but not significantly greater then the CFA. However, there was a gender difference for AA (P.001), PA (P.001), CCA (P.01), and CFA (P.01), with men having greater wall stress in all regions. DISCUSSION It is possible with noninvasive ultrasound to study IMT, with good reproducibility, not only in superficial arteries but also in the much deeper lying infrarenal AA. This makes it possible to calculate aortic wall stress in vivo. In a middle-aged population of healthy men and women, wall stress is greater in the AA than in the CCA and PA. Further, arterial wall stress is greater in men than in women in all studied arterial regions. IMT has been extensively studied and validated in superficial arteries, initially with CV around 10%. 10,20 Recent studies have shown improved results, with CV that varies around 5% in the carotid artery and 5% to 8% in the radial artery. 9,21,22 The femoral artery is more difficult to examine 23 ; however, a recent study reported CV less than 5%. 24 Increased carotid IMT has been associated with most cardiovascular risk factors, eg, age, male sex, smoking, serum low-density lipoprotein cholesterol, hypertension, and diabetes. 7,25-28 IMT in the AA is considered more difficult to study because it lies deep, and optimal images are more difficult to obtain because of bowel gas and abdominal fat. Thus, resolution is less sharp because transducers with lower frequency must be used, compared with those used to study superficial arteries. To our knowledge, no studies have measured IMT in vivo in the AA. IMT measurements in the AA showed a CV of 10% to 11 % (Table I), comparable with the early results in superficial arteries by Wendelhag et al. 10 In their study of the CCA they were unable to obtain readings in 3 of 50 subjects, compared with 4 of 54 in our study of the AA. However, CV for CCA and CFA in our study was 6% and 8%, respectively, comparable with recent studies of superficial vessels. 29 The somewhat higher variability of IMT measurements in the AA compared with superficial arteries is probably due to a combination of depth and lower resolution of the transducers. Calculations of IMA showed similar results as for IMT, with intraobserver variability of 12% in the aorta. Thus IMT of the AA can be measured with satisfactory reproducibility, although it is evident that the AA is somewhat more difficult to examine compared with superficial arteries. Reproducibility of IMT measurements for the PA was somewhat lower than for the CCA, with CV of 10% and 6%, respectively. The PA in 2 of 50 subjects and the CFA in 5 of 50 subjects could not be examined because of technical reasons. This indicates that superficial muscular arteries, eg, CFA and PA, are more difficult to examine than superficial elastic arteries, possibly because of short-term changes in smooth muscle tone in the arterial wall. 30,31 In the AA, no gender difference in IMT was found in our middle-aged men and women examined. Because arterial wall thickness affects pulsatile wall motion in response to changes in arterial pressure, this finding is somewhat surprising, because a significant gender difference in aortic wall stiffness has been reported. 1,17 A factor that might have greater effect on gender differences in aortic wall motion is the relation between elastin and collagen within the arterial wall. Hormonal factors might contribute; hormone replacement therapy in women reduces arterial wall stiffness and intima-media thickening That no gender difference in IMT was found in the AA is in contrast with most studies of superficial arteries, in which male sex seems to be a risk factor for intima-media thickening. 26,35 Both in vitro and in vivo, increased transmural pressure and circumferential stress lead to medial thickening via increased smooth muscle cell production of connective tissue components The arterial wall stress hypothesis postulates that an increase in diameter or blood pressure leads to increased wall stress, which in turn activates smooth muscle cells, with an increase in wall matrix and wall thickness. 39 This means that wall stress is restored, according to the law of LaPlace. Thus IMT of the radial artery in patients with hypertension increases to a thickness where the wall stress is stabilized at a normal level. 9 Furthermore, wall stress is greatest along the inner surface of the wall, and decreases towards the outer layers. 40 Wall stress rather than shear stress has been suggested to be responsible for the distribution of atherosclerosis in the vascular tree. 41 This hypothesis fits well with our data for wall stress in various arterial regions, which show that wall stress is greater in men than in women and that the greatest stress is in the aortic region (Fig 4). Autopsy studies of atherosclerotic lesions confirm a higher degree of atherosclerotic manifestations in men, 42,43 with the aorta the site of predilection. The influence of aneurysm size and blood pressure on increasing diameter and rupture of abdominal aortic aneurysm (AAA) indicate that aortic wall stress may be important. 4-6 Hall et al 6 discussed aortic wall stress as a predictive factor for AAA rupture. In this retrospective study they used CT scans to assess aortic wall thickness and radius. They found that increased wall stress was correlated with

5 1274 Åstrand et al JOURNAL OF VASCULAR SURGERY June 2003 Table II. Intima-media area and lumen diameter in four vascular regions studied IMA (mm 2 ) LD (mm) Men Women Men Women AA NS *** CCA * ** CFA *** *** PA *** *** IMA, Intima-media area; LD, lumen diameter; AA, abdominal aorta; CCA, common carotid artery; CFA, common femoral artery; PA, popliteal artery; NS, not significant. *Significant difference between gender, P.05. **Significant difference between gender, P.01. ***Significant difference between gender, P.001. Significant difference between the marked vessel and the aorta, P.001. Fig 3. Regional and gender differences in intima-media thickness (IMT) in four arterial regions: infrarenal abdominal aorta (AA), common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA). Bars, Mean SD. *Significant difference between gender, P.05. **Significant difference between gender, P.01. ***Significant difference between gender, P.001. Significant difference between arterial regions, P.001. Fig 4. Regional and gender differences in circumferential wall stress in four arterial regions: infrarenal abdominal aorta (AA), common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA). Bars, Mean SD. *Significant difference between gender, P.05. **Significant difference between gender, P.01. ***Significant difference between gender, P.001. Significant difference between arterial regions, P.001. AAA rupture. However, CT demonstrates great variability in arterial diameter. 44,45 Furthermore, no validation of wall thickness measurements was performed, making the stress values uncertain. In studying arterial wall stress it is important that wall thickness be included in the equation, inasmuch as the original law of LaPlace was based on an infinitely thin and homogeneous wall. Coexistence of greater diameter and IMT in the aorta compared with the other vessels supports the vessel protection theory, with increasing IMT reducing wall stress (Figs 3 and 4; Table II). However, wall stress is not fully compensated for, because the aorta still tends to have greater stress compared with the other investigated arteries, which was most apparent in the men (Fig 4). It may be speculated whether these findings form an etiologic background as to why the infrarenal aorta is a predilection site for aneurysm and why there is a male preponderance for aneurysm development. 46,47 No significant difference in wall stress was found between the aorta and the CFA in the healthy subjects studied. There are, however, large differences in architectural arrangement of the arterial wall in central elastic and peripheral muscular arteries, which makes the effect of wall stress on the integrity of the femoral artery not easily compared with the aorta, as indicated by differences in mechanical properties. 48,49 A limitation to the study of wall stress is that only IMT was measured and the adventitial layer was excluded. However, the major part of total wall thickness is included in IMT measurements. 50,51 Further, the relation between adventitial thickness and IMT is not affected by sex or age. 52 Accordingly, IMT has during recent years been used as a surrogate for arterial wall thickness in the calculation of wall stress. 9,12-16

6 JOURNAL OF VASCULAR SURGERY Volume 37, Number 6 Åstrand et al 1275 In conclusion, it is possible to study IMT with good reproducibility, not only in superficial arteries but also in the much deeper lying infrarenal AA. This makes it possible to calculate aortic wall stress in vivo with noninvasive ultrasonic techniques. In a middle-aged population of healthy men and women, aortic wall stress was greater than in the CCA and PA. Further, arterial wall stress was greater in men than in women in all studied arterial regions. That IMT of the abdominal aortic wall may be investigated with reproducible results in vivo opens new possibilities in the study of the aging process and pathologic changes in the aortic wall. REFERENCES 1. Sonesson B, Hansen F, Stale H, Länne T. Compliance and diameter in the human abdominal aorta: The influence of age and sex. Eur J Vasc Surg 1993;7: Schlattmann TJM, Becker AE. 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