The presence of considerable wall thickening in all

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1 Ill Evidence for In Vivo Carotid and Femoral Wall Thickening in Human Hypertension Jerome Gariepy, Marc Massonneau, Jaime Levenson, Didier Heudes, Alain Simon, and the Groupe de Prevention Cardio-vasculaire en Medecine du Travail Little is known of the in vivo structural changes of large arteries in uncomplicated hypertension. Therefore, we measured the intima-media thickness and lumen diameter of common carotid and femoral arteries by a computerized ultrasonographic technique in 25 normotensive and 25 never treated hypertensive men of similar age (from 25 to 72 years). The intraobserver variability of carotid and femoral wall thicknesses was 4.3% and 5.6%, respectively. Moreover, an in vitro study of 13 human arterial segments removed at autopsy demonstrated a strong correlation (r=.989, P<.001) between computerized ultrasonic and histological intima-media thickness measurements. Compared with control subjects, hypertensive patients had similar arterial diameters but higher carotid and femoral intima-media thicknesses (P<.001) as well as higher ratios of carotid and femoral intima-media thickness to lumen (/ > <.001, P<.01). The carotid thickness was correlated with age in control subjects (r=.48, P<.05) but not in hypertensive patients. The femoral thickness was correlated with age both in control subjects (r=.55, P<.01) and in hypertensive patients (r=.46, P<.05). Thus, carotid and femoral arterial walls of hypertensive patients were thickened. This thickening was not due to age, although aging also thickened both vessels in control subjects and the femoral artery only in hypertensive patients. Such a wall thickening associated with a normal diameter provides direct evidence of vascular growth and represents a new target to monitor noninvasively in vivo for large artery changes in human hypertension. (Hypertension 1993;22: ) KEY WORDS ultrasonography tunica intima tunica media hypertension, essential The presence of considerable wall thickening in all high-pressure sections of blood vessels has been well documented in chronic hypertension both in experimental animals and in human subjects at autopsy. 16 This wall thickening is physiologically important because it can fundamentally alter resistance vessel behavior 1 as well as the compliance of large conduit arteries, 7 two key factors that participate in the biomechanical regulation of arterial circulation. 37 Nevertheless, such a vascular hypertrophy has remained difficult to evaluate directly in vivo in human hypertension because of technical limitations. Recently, the thickening of small arteries isolated from subcutaneous biopsy specimens with patients under local anesthesia was demonstrated in patients with untreated moderate to severe essential hypertension. 8 For large arteries, direct in vivo measurement has not yet been reported in hypertensive patients. Because high-resolution B-mode ultrasonography currently allows for direct noninvasive measurement of large artery wall thickness, 9 " 12 we coupled the technique with an original automatic comput- Received October 19, 1992; accepted in revised form March 10, From the Centre de Medecine Preventive Cardio-vasculaire (J. Gariepy, M. Massonneau, J. Levenson, A. Simon) and Laboratoire d'anatomie Pathologique (D. Heudes), INSERM U 28, Paris, and the Groupe de Prevention Cardio-vasculaire en Medecine du Travail (PCVMETRA Group), Boulogne, France. Reprint requests to Centre de Medecine Preventive Cardiovasculaire, Hopital Broussais, 96 Rue Didot, Paris Cedex 14, France (Pr Simon). er-assisted image analysis to investigate the common carotid and femoral arteries of men with sustained essential hypertension never treated with any antihypertensive drug. The data were compared with those of normotensive men of similar age. Methods Twenty-five control normotensive men (29 to 72 years) with a supine diastolic blood pressure less than 90 mm Hg (KorotkofF phase V) and 25 ambulatory male patients (25 to 68 years) with sustained hypertension defined as a supine diastolic blood pressure more than 95 mm Hg on an average of three outpatient visits entered the study (Table 1). Control subjects and patients were selected at their worksites by a group of occupational health physicians (PCVMETRA Group) conducting a cardiovascular risk factor screening program for employees of several companies within the Paris area. 13 All patients had essential hypertension documented by appropriate laboratory tests, and none had ever taken any antihypertensive treatment. Hypertension was uncomplicated in all patients, and none had neurological, cardiac, or renal involvement or arteriopathy of the legs. All study subjects underwent an evaluation of traditional cardiovascular risk factors (Table 1). Body mass index (weight per height squared) was used to measure excess of weight. Blood lipids including total and high-density lipoprotein cholesterol and triglyceride levels were measured by classic enzymatic methods after subjects had fasted for 14 hours Those who had total cholesterol levels greater than 7.2

2 112 Hypertension Vol 22, No 1 My 1993 TABLE 1. Parameter Clinical Parameters Age (y) Body mass index (kg/m 2 ) Blood pressure (mm Hg) Systolic Diastolic Heart rate (bpm) Blood lipids (mmol/l) Total cholesterol HDL cholesterol Triglyce rides Blood glucose (mmol/l) Smoking status Lifelong dose (pack-years) Current smoker (%) Normotensive control subjects (n=25) 47±8 24±2 122±8 78±7 68± ± ± ± ±13 32 Hypertensive patients (n=25) 48±9 26±3* 162±llt 103±6t 72± ± ± ± ± ±11 24 bpm, Beats per minute; HDL, high-density lipoprotein. Values are mean±sd or percentage of subjects. *P<.05, t/ J <-001. mmol/l, triglyceride levels greater than 2 mmol/l, or both, were excluded to make the study groups as homogeneous as possible on a main risk factor and to avoid possible interactions between hypertension and marked lipid abnormalities on atherosclerotic process in the analysis. 14 Blood glucose level was measured after an overnight fast, and subjects with diabetes mellitus were excluded for the above reason. 14 Smoking was defined by the following criteria, carefully assessed by questioning the subjects 1314 : (1) A current daily smoker was defined as someone who had regularly smoked at least five cigarettes per day for the previous 3 months. Subjects who smoked fewer than five cigarettes per day were not included in the study. (2) Lifelong smoking dose was calculated by multiplying the mean number of cigarettes smoked daily by the number of years of smoking and was expressed in pack-years (ie, smoking of one pack each day during a year). Control subjects and patients were matched to total cholesterol level and smoking habits to avoid possible influences of these two major risk factors on the comparison between normotensive and hypertensive subjects (Table 1). After giving informed consent, subjects were referred to the vascular laboratory for noninvasive arterial investigations. Arterial Measurements Studies were performed with a real-time, B-mode ultrasound imager (Ultramark 4, Advanced Technologies Laboratories, Les Ulis, France). The right common carotid artery 3 cm proximal to the bifurcation and the right common femoral artery 3 cm proximal to the bifurcation were examined with a 7.5-MHz probe. Scanning of the carotid artery was performed in the anteroposterior projection, with the patient lying on his back with the head in axis. Scanning of the femoral artery was also performed in the anteroposterior projection, with the patient lying on his back with the lower limb in slight external rotation. The same physician made all measurements throughout the study. The ultrasonic image of the vessel was projected in real time on a television monitor. During the scanning, the sonographic physician tried to adjust the sound beam perpendicularly to the arterial surface of the far wall of the vessel to obtain two parallel echogenic lines corresponding to the lumen-intima and media-adventitia interfaces. These two lines defined the intima-media complex (IMC). 911 If a plaque, defined as a focal echogenic structure encroaching into the lumen vessel, 1314 was present in the arterial segment of measure, the subject was excluded from the study, because such an echogenic encroachment on the vascular lumen disrupts the double line arterial pattern. Once the two parallel echogenic lines of the far wall were clearly visible on the television monitor along at least 1 cm of the segment of measure, the "frozen" end-diastolic (electrocardiographic R-triggering) image was transferred on a computer (Apple Macintosh, Cupertino, Calif). After digitalization into 640x580 peak cells with 256 gray levels, this image was stored in a memory mass system and analyzed off-line. The total procedure time for investigating the two arterial sites exclusive of the off-line analysis averaged 15 minutes per subject. Analysis of Intima-Media Complex Thickness and Arterial Diameter An appropriate program (Iotec system, 16 Data Processing Co, Paris, France) performed off-line image treatment without the investigator knowing the blood pressure status of the subject. The program was based on the analysis of gray level density and on specific tissular recognition algorithms. 15 The image was transferred from the storage memory mass system to the television monitor of the computer and represented a 3.63-fold magnification of the anatomic structure examined. The observer chose a field of measure that included the IMC and automatically drew a rectangle at least 1 cm long in the longitudinal axis of the vessel and at least 0.3 cm high in the direction perpendicular to the wall (Fig 1). The computer located the two interfaces (lumen-intima and media-adventitia) by discriminating changes in gray levels inside the sample area and drew the two parallel lines, visualizing these interfaces on the computer monitor (Fig 1). The average thickness of the IMC obtained along the length of the sample area represented the mean value of at least 100 successive local measures. The IMC thickness was measured every 10 fim along 1 cm of the length of artery. The internal lumen diameter of the artery was averaged along the same distance as the IMC, between the near and far lumen-intima interfaces (Fig 1). The IMC-to-lumen ratio was calculated as the ratio between IMC thickness and lumen diameter and was expressed as a percentage of the diameter. The tension per unit wall layer was calculated according to Laplace's law as the ratio between diastolic blood pressure and twice the IMC-tolumen ratio. 1 The total procedure time for computerassisted measurement of IMC thickness and diameter was less than 1 minute per vessel. Histological Validation of Computerized Intima-Media Complex Measurements To provide histological validation of our computerized ultrasonographic IMC measurement, we performed an additional experimental study of 13 arterial segments on two human arterial specimens (one carotid

3 Gariepy et al Large Artery Growth in Hypertension 113 common carotid artery NEAR WALL lumen-intima interface FAR WALL media -adventitia interface common femoral artery NEAR WALL lumen-intima interface media-adventitia interface FAR WALL FIG 1. Computer-assisted off-line analysis ofb-mode imaging of common carotid artery (top panel) and common femoral artery (bottom panel). White rectangle on far arterial wall indicates the field of automatic measure of intima-media complex thickness. Blue and red parallel lines drawn by the computer inside the rectangle visualize the lumen-intima and media-adventitia interfaces. Blue line drawn by the computer on the near arterial wall visualizes the near lumen-intima interface. artery and one brachial artery) removed at autopsy. The specimens were fixed with a 10% Formalin solution before ultrasonic and histological IMC measurements. The 13 arterial segments to be studied (7 on the carotid and 6 on the brachial artery specimens) were determined with metallic pins. The ultrasonic examination of these 13 arterial segments was performed first, while the arterial specimens were placed in a box with water at room temperature. The same B-mode echographic apparatus as in the clinical study was used, and the longitudinal intimal surface of the far wall of each segment to be examined was exposed to the incident incoming pulse after optimal positioning of the probe was obtained. Once the double line arterial pattern defining the IMC could be individualized, the image was digitized, stored in the computer, and analyzed off-line by the computerized image-analysis system described above. Histological measurements were performed on all arterial segments submitted to ultrasonic examination. Each arterial segment was cut transversely and embedded in paraffin. Three nonadjacent 5-/Ltm sections were cut from each segment, and the slices were stained by orcein. Computer-assisted morphometry16 was done using an analyzer with 256 gray levels and a 512x512-pixel grid connected to a microcomputer (NS model 1500, Microvision Nachet, Evry, France). This provided automatic calculation of the intima+media thickness of the wall submitted to previous ultrasonic investigation. The IMC thickness of the 13 arterial segments measured by ultrasonography was 0.65 ±0.22

4 114 Hypertension Vol 22, No 1 July 1993 TABLE 2. Differences Between Repeated Measurements of Intima-Media Complex Thickness and Lumen Diameter Patient Common carotid artery AIMC thickness ALumen diameter mm % mm % Common femoral artery AIMC thickness ALumen diameter mm % mm % Mean SD IMC, intima-media complex. Data are expressed as absolute value or percentage of first measure (SD) mm, and the intima+media thickness of the same segments measured by histological examination was 0.85 ±0.34 mm. The absolute difference between ultrasonic and histological measurements was 0.21 ±0.13 mm. The ultrasonic IMC thickness (y) correlated significantly with the histological intima+media thickness (x) of the 13 arterial segments (y=0.63*+0.11, r=.98, Reproducibility of Measurements To assess the reliability of arterial measurements, we invited 11 randomly selected participants to a repeated ultrasonographic assessment by the same physician 6 hours after the original assessment. During the first examination, an anatomic mask of the artery examined and of its surrounding structure was automatically generated by the computer software and stored in the memory mass system. This mask allowed the sonographic physician to adjust the probe in the same position at the second examination as at the first. Using this procedure, we found that the reproducibility of measures defined by the variation coefficient between the two repeated examinations was on average 4.3±3.5% and 5.6±3.8% for the carotid and femoral IMC thicknesses and 3.0±2.6% and 3.6±2.7% for the carotid and femoral diameters, respectively (Table 2). Statistical Analysis Group data are expressed as mean±sd. Comparisons of parameters between normotensive and hypertensive groups were made by the Student's t test. Differences were considered significant at a value of P<.05. Correlations were performed by least-squares regression. Results Compared with control subjects, hypertensive patients had a higher IMC thickness at both the carotid site (P<.001) and femoral site (P<.001) (Table 3). Nineteen of the 25 hypertensive patients had a carotid IMC thickness above the upper limit of the control group, defined by the mean control value of carotid thickness+1 SD (Fig 2). Twelve hypertensive patients had a femoral IMC thickness above the upper limit of the control group (Fig 2). No significant differences in carotid and femoral lumen diameters existed between the groups (Table 3). In contrast, hypertensive patients had a higher IMC-tolumen ratio than control subjects at both the carotid site (P<.001) and femoral site (P<.01) (Table 3). In addition, the tangential tension was higher in hypertensive patients than in control subjects at the carotid site (P<.05) but was not different at the femoral site (Table 3). Table 4 shows the correlations existing in the normotensive and hypertensive groups between IMC thickness of the carotid and femoral arteries and cardiovascular risk factors. Age was significantly correlated to carotid IMC thickness in the normotensive group (P<.05) but not in the hypertensive group. Age was significantly correlated to femoral IMC thickness in the normotensive (P<.01) and in the hypertensive (P<.05) groups. Among the other variables, only diastolic blood pressure was correlated to carotid IMC thickness in the TABLE 3. Arterial Parameters Normotensive control subjects Parameter (n=25) Common carotid artery IMC thickness (mm) 0.51 ± Lumen diameter (mm) 6.30±0.64 IMC-to-lumen ratio (%) 8.20±1.20 Tangential tension (kpa) 64.93±9.18 Common femoral artery IMC thickness (mm) 0.53±0.10 Lumen diameter (mm) 8.73±1.21 IMC-to-lumen ratio (%) 6.20±1.40 Tangential tension (kpa) 88.74±23.14 IMC, intima-media complex. Values are mean±sd. *P<.001, tp<05, y<.01. Hypertensive patients (n=25) 0.63±0.10* 6.49± ±1.60* 72.36±12.40t 0.69±0.19* 8.88± ±2.20* 95.13±28.62

5 Gariepy et al Large Artery Growth in Hypertension 115 (A Ul 1.2-r O CAROTID ARTERY *- -8" FEMORAL ARTERY 0.3-L FiG 2. Scatterplot shows distribution of intima-media complex (IMC) thickness of common carotid and femoral arteries in normotensive control subjects ( ) and hypertensive patients (o). Bars indicate mean±sd. normotensive group (P<.05). Such correlations did not exist for lumen diameter. Discussion Recently, efforts have been made to develop atraumatic techniques capable of detecting structural changes of human arteries and their relation to cardiovascular risk factors In the present work, we used :: oo o a noninvasive ultrasonographic computer-assisted technique for quantifying wall thickness and for assessing its modification in sustained essential hypertension. We investigated the carotid and femoral arteries, which are both highly exposed to atherosclerosis but might have some difference in their reactivity to cardiovascular risk factors. 13 ' 14 The thickness of the arterial wall is a parameter particularly important to measure in hypertension, in which vascular hypertrophy can be considered to be the hallmark. 17 The IMC thickness of the far wall of the common carotid artery can be measured very accurately when ultrasonic measurements are compared with histological measurements. 10 The same accuracy of measurement can be extrapolated to the far wall of the common femoral artery, which presents measurement conditions similar to those of the common carotid artery. Nevertheless, the accuracy of IMC measurements required the same careful procedure for both vessels. At first, we performed our experiments on the far wall only, because with the ultrasonographic apparatus used in this study the far wall could be more constantly and repeatably visualized than the near wall even if reliable measurements of the near wall could be sometimes obtained. The reason was due to the different order in which the interfaces of the intima-lumen and media-adventitia are exposed to the incoming ultrasound beam, which generates different B-mode images of the near and far walls. 10 Furthermore, it was rarely possible to obtain double line arterial patterns of both the near and far walls simultaneously. Indeed, a scanning plane perpendicular to both walls is required to obtain an image, and this is difficult because of pulsatile arterial movements. 10 Secondly, we measured the IMC thickness of subjects without atherosclerotic plaque at the site of measure because the plaque encroachment on arterial lumen disrupts the double line arterial pattern. Nevertheless, because our measurements were performed very locally in the same arterial segment (3 cm proximal to the carotid and femoral bifurcation) in all the study subjects, we did not deal with the wall IMC thickness in other arterial TABLE 4. Correlation Coefficients Between Carotid and Femoral Intima-Media Complex Thickness and Cardiovascular Risk Factor in Normotensive and Hypertensive Groups Carotid IMC thickness Femoral IMC thickness Parameter Age (y) Body mass index (kg/m 2 ) Blood pressure (mm Hg) Systolic Diastolic Pulse Heart rate (bpm) Blood lipids (mmol/l) Cholesterol HDL cholesterol Triglyce rides Fasting glucose (mmol/l) Lifelong smoking (pack-years) Normotensive 0.48* * 0.19 Hypertensive Normotensive 0.55T Hypertensive 0.46* IMC, intima-media complex; bpm, beats per minute; HDL, high-density lipoprotein. *P<.05, t/ > <01.

6 116 Hypertension Vol 22, No 1 July 1993 segments. Lastly, we used a special off-line computerassisted image-analysis system to minimize observer bias. This procedure allowed excellent reproducibility for both IMC thickness and lumen diameter at the two arterial sites examined. Additional reasons explained our high reproducibility rate. The sonographer was the same physician and was especially trained in vascular investigation. Moreover, a large number of IMC thickness and lumen diameter measures were performed by the computer every 10 /j,m along at least 1 cm of vessel, and the real value of thickness and diameter was calculated as the average of 100 measures. Furthermore, the use of an anatomic mask of the artery and of its surrounding structures in the memory system of the computer allowed for the adjustment of the probe in the same position at different examinations. Although the methodology of IMC measurement by ultrasonography has been previously validated histologically, 10 we have tested the validity of our original computerized imageanalysis technique by performing a series of in vitro measures on several segments of human arterial specimens and comparing ultrasonographic and histological measurements. 16 As already reported, 10 a constant difference existed between ultrasonic IMC thickness and that measured by histology because of artifacts introduced during tissue processing for histological evaluation. 10 Nevertheless, the highly significant linear relation between the two methods indicates that the computerized ultrasonic technique could be used to estimate the IMC thickness of peripheral conduit artery walls. Our data demonstrate that sustained high blood pressure, in the absence of any preceding antihypertensive medication, was associated with an in vivo increase in the IMC thickness of the far wall of the two large arteries examined. Nevertheless, the IMC values show noticeably more scatter in the femoral than in the carotid arteries in both the control and hypertensive groups. This may be a function of deeper vessels with lesser resolution of the IMC image. However, the possibility of poorer resolution of the femoral wall is not supported by the observation of stronger correlations of age with the femoral IMC compared with carotid arteries. It is also possible that the larger variance of femoral IMC measurements may express a more heterogeneous sensitivity of the femoral wall to hypertension. This hypothesis agrees with the difference of sensitivity to atherogenesis and risk factors previously suggested between carotid and femoral sites The IMC thickening found in our hypertensive patients is in accordance with previous observations in animals and in humans at autopsy, showing that large arteries of hypertensive patients were thicker than normal vessels These observations also indicated that this arterial thickening could be mainly due to a medial hypertrophy, although an adaptive intimal thickening has been described in response to the elevation of blood pressure. 22 Unfortunately, our current ultrasonic B-mode imaging, even with the assistance of our computerized imageanalysis system, did not allow us to discriminate the part of the media from that of the intima in the IMC thickening process The lack of pathological evaluation of arteries of the subjects also did not allow us to correlate the IMC thickness with any histological pattern. Among the mechanisms that could explain such a vascular hypertrophy, pressure elevation certainly has a mechanical influence but does not seem sufficient to produce hypertrophy. Indeed, 24% and 52% of hypertensive patients had a carotid and femoral thickness, respectively, within the confidence limits of the control group because of the large variance of the IMC measurements in the hypertensive group. This IMC scatter could have some clinical usefulness by allowing one to separate patients with vascular hypertrophy from those without and so to better individualize the arterial status within the hypertensive population. Furthermore, the little evidence of correlation between IMC thickness and blood pressure within the hypertensive group as well as the control group constitutes an additional argument that the increased IMC thickness in the hypertensive patients may not just be a response to the increased pressure. In this respect, it is interesting to observe the lack of correlation between IMC thickness and pulse pressure. This does not confirm, at least in conduit arteries, the hypothesis currently debated that pulse pressure correlates with vascular structure better than systolic, diastolic, or mean blood pressure. 23 Another mechanical cause of hypertrophy could be a reduction in wall shear stress, which was experimentally demonstrated to be closely linked with intimal thickening and was clinically observed in the brachial artery of hypertensive patients compared with normotensive control subjects. 26 However, there is no evidence that shear stress was reduced in the present study, because lumen diameter was normal in femoral and carotid arteries. Finally, the influence of growth factors on intimal or medial thickening or both remains an important mechanism that could explain the increased IMC thickness of hypertensive patients. 27 High blood pressure was not the only cardiovascular risk factor capable of altering the arterial wall thickness. In accordance with previous reports, we found that in the normotensive control subjects, age was positively related to the IMC thickness of the two vessels examined. This relation did not exist at the carotid site in hypertensive patients, indicating that the elevation of blood pressure probably outweighed the effect of aging on the carotid wall. In contrast, the femoral thickness remained correlated to age in hypertensive patients, suggesting an important sensitivity of this vessel to the aging process. 13 We did not find that other risk factors such as weight, lipid levels, and smoking affected the wall thickness of the two vessels examined. The lack of influence of lipids, in either the normotensive or hypertensive group, was surprising with respect to a previous observation of an increased carotid wall thickness in hypercholesterolemic subjects compared with normocholesterolemic control subjects. 11 However, contrary to the patients investigated in this previous study, our subjects in the present study had cholesterol levels somewhat higher than normal. Furthermore, the present work minimized a possible influence of cholesterol on wall thickness by comparing the normotensive and hypertensive groups at a similar level of blood cholesterol. The lack of influence of smoking on wall thickness in any group at any site was also noticeable with respect to previous reports showing associations between large artery atherosclerosis and smoking habits Nevertheless, in these reports, atherosclerosis was defined as

7 a plaque whose presence was by definition excluded from our work. Contrary to the IMC thickness, the lumen diameter was not different between control subjects and hypertensive patients at the two sites examined. We have already reported that hypertension did not affect the carotid artery diameter in the same way as the brachial artery diameter As previously discussed, 30 the lack of carotid and femoral dilatation in hypertensive patients in spite of the elevation in their distending blood pressure was in favor of a reduced arterial distensibility or of higher vasomotor tone. This decreased distensibility could be due in part to arterial wall thickening, which is a well-known determinant of arterial stiffness. 7 The fact that the lumen diameters are not different between control subjects and hypertensive patients also suggests the possibility of an enlargement of the carotid and femoral arteries. The arteries must indeed be larger in hypertensive patients because the lumen diameters are equal but the IMC thickness is greater than in control subjects. Such a phenomenon provides direct evidence that essential hypertension is associated with large artery growth. 32 This is in contrast to observations from smaller arteries that have suggested that hypertension is not associated with growth but with a rearrangement of material. 33 The larger conduit arteries in hypertension also evoke the compensatory enlargement of large arteries, which has been emphasized in patients with atherosclerosis. 34 ' 35 The mechanisms by which IMC thickening and lumen diameter could be mutually adjusted in hypertension are likely to be complex and remain to be identified. 34 In addition, because carotid and femoral lumen diameters were unchanged in hypertension, the IMC-to-lumen ratio of these vessels was found to be greater in hypertensive patients than in control subjects. Such an increase in the IMC-to-lumen ratio could contribute to keeping the tension per unit wall layer of artery relatively unchanged in hypertension. 1 The calculation of the tangential tension showed that it was effectively not different between hypertensive and control groups at the femoral site but was higher in hypertensive patients at the carotid site. This latter observation is difficult to explain on the basis of the present data, but it could participate in the abnormal baroreceptor reflex sensitivity described in human hypertension. 36 In conclusion, the large artery wall IMC thickening of hypertensive patients constitutes an in vivo diffuse structural change, which affects the vessels of the upper part as well as those of the lower part of the body. As a normal diameter and a thicker IMC presumably give a greater IMC cross-sectional area, our findings provide direct evidence that essential hypertension is associated with vascular growth, at least in conduit arteries. However, further investigations will be needed to analyze more precisely the physiopathological mechanisms of this vascular growth and to examine whether it may be reversible during antihypertensive treatment, as well as whether such a reversibility may have implications for the benefits to be gained from blood pressure reduction on the progression of cardiovascular disease. 37 Acknowledgments We thank the Banque Nationale de Paris, l'oreal-paris, Matra SA, and Procter & Gamble France, for sponsoring the PCVMETRA Group. Gariepy et al Large Artery Growth in Hypertension 117 We also thank Vania Gerard and Christine Beuzet for their excellent secretarial assistance and Muriel Del Pino for her excellent technical assistance. Lastly, we thank the PCVMETRA Group (Patrick Segond, MD, Chairman) and Chantal Delmotte, MD; Thierry Drumare, MD; Anne Marie Giard, MD; Franchise Kiesgen, MD; and Elizabeth Lamothe, MD, who recruited normotensive control subjects. References 1. Folkow B. Structural factors: the vascular wall. Consequences of treatment. Hypertension. 1983;5(suppl III):III-58-III Johnson G. On certain points in the anatomy and pathology of Blight's disease of the kidney: II. On the influence of the minute blood-vessels upon the circulation. Trans R Med ChirSoc. 1868;51: Folkow B, Grimby G, Thulesius O. Adaptative structural changes of the vascular walls in hypertension and their relation to the control of the peripheral resistance. Ada Physiol Scand. 1958;44: Wolinsky H. Effects of hypertension and its reversal on the thoracic aorta of male and female rats: morphological and chemical studies. Circ Res. 1971;28: Karsner HT. Thickness of aortic media in hypertension. Trans AssocAm Physicians. 1938;53: Greene MA, Friedlander R, Boltax AJ, Hadjigeorge CC, Lustic GA. Distensibility of arteries in human hypertension. Proc R Soc Exp Biol. 1966;121: Simon A, O'Rourke M, Levenson J. Arterial distensibility and its effects on wave reflection and cardiac loading in cardiovascular disease. Coronary Artery Disease. 1991;2:llll Aalkjaer C, Heagerty AM, Petersen KK, Swales JD, Mulvany MJ. Evidence for increased media thickness, increased neuronal amine uptake, and depressed excitation-contraction coupling in isolated resistance vessels from essential hypertensives. Circ Res. 1987;61: Pignoli P. Ultrasound B-mode imaging for arterial wall thickness measurement. Atheroscler Rev. 1984;12: Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation. 1986;74: Poli A, Tremoli E, Colombo A, Sirtori M, Pignoli P, Paoletti R. Ultrasonographic measurement of the common carotid artery wall thickness in hypercholesterolemic patients. Atherosclerosis. 1988; 70: Persson J, Stavenow L, Wikstrand J, Israelsson B, Formgren J, Berglund G. Noninvasive quantification of atherosclerotic lesions. Arterioscler Thromb. 1992;12: Giral P, Pithois-Merli I, Filitti V, Levenson J, Plainfosse MC, Mainardi C, Simon A, and the PCVMETRA Group. Risk factors and early extracoronary atherosclerotic plaques detected by threesite ultrasound imaging in hypercholesterolemic men. Arch Intern Med. 1991;151: Megnien JL, Sene V, Jeannin S, Hernigou A, Plainfosse MC, Merli I, Atger V, Moatti N, Levenson J, Simon A, and the PCVMETRA Group. Coronary calcification and its relation to extracoronary atherosclerosis in asymptomatic hypercholesterolemic men. Circulation. 1992;85: Wered Z, Barzilai B, Mohr GA, Thomas LJ III, Genton R, Sobel BE, Shoup TA, Melton HE, Miller JG, Perez JE. Quantitative ultrasonic tissue characterization with real-time integrated backscatter imaging in normal human subjects and in patients with dilated cardiomyopathy. Circulation. 1987;76: Capron L, Heudes D, Chajara A, Bruneval P. Effect of ramipril, an inhibitor of angiotensin converting enzyme, on the response of rat thoracic aorta to injury with a balloon catheter. / Cardiovasc Pharmacol. 1991;18: Handa N, Matsumoto M, Maeda H, Hougaku H, Ogawa S, Fukunaga R, Yoneda S, Kimura K, Kamada T. Ultrasonic evaluation of early carotid atherosclerosis. Stroke. 1990;21: Aars H. Static load-length characteristics of aortic strips from hypertensive rabbits. Acta Physiol Scand. 1968;73: Feigl EO, Peterson LH, Jones HW. Mechanical and chemical properties of arteries in experimental hypertension. J Clin Invest. 1963;42: Carlier PG, Rorive GL, Barbason H. Kinetics of proliferation of rat aortic smooth muscle cells in Goldblatt one-kidney, one-clip hypertension. Clin SciMolMed. 1983;65:

8 118 Hypertension Vol 22, No 1 July Foidart JM, Rorive GL, Nusgens B, Lapiere C. The relationship between blood pressure and aortic collagen metabolism in hypertensive rats. Clin Sci Mol Med. 1978;55(suppl 4): Stary HC, Blankenhorn DH, Chandler AB, Glagow S, Insull W, Richardson M, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. A definition of the intima of human arteries and of its atherosclerosis-prone regions. Circulation. 1992;85: Baumbach GL. Is pulse pressure a stimulus for altered vascular structure in chronic hypertension? Hypertension. 1991;18: Ku DN, Giddens DP, Zarins CK, Glagow S. Pulsatile flow and atherosclerosis in the human carotid bifurcation: pulsatile correlation between plaque location and low oscillating wall shear stress. Arteriosclerosis. 1985;5: Friedman MH, Deters OJ, Bargeon CB, Hutchins BM, Mark FF. Shear dependent thickening of the human arterial intima. Atherosclerosis. 1986;60: Simon A, Levenson J, Flaud P. Pulsatile flow and oscillating wall shear stress in the brachial artery of normotensive and hypertensive subjects. Cardiovasc Res. 1991;6: Chobanian AV Corcoran lecture: Adaptive and maladaptive responses of the arterial wall to hypertension. Hypertension. 1990; 15: Nichols WW, O'Rourke MF. Aging, high blood pressure and diseases in humans. In: Nichols WW, O'Rourke MF, eds. Me Donald's Blood Flow in Arteries, 3rded. London/Melbourne/Auckland: Edward Arnold Publishers Ltd; 1990: Heiss G, Scharrett R, Barnes R, Chambless LE, Szklo M, Alzola C, and the ARIC Investigators. Carotid atherosclerosis measured by B-mode ultrasound in populations: associations with cardiovascular risk factors in the ARIC study. Am J Epidemiol. 1991; 134: Chau NP, Levenson J, Simon A. Chronic progressive changes in brachial and carotid artery circulation under the combined effects of aging and hypertension. J Hypertens. 1990;8: Armentano R, Simon A, Levenson J, Chau NP, Megnien JL, Pichel R. Mechanical pressure versus intrinsic effects of hypertension on large arteries in humans. Hypertension. 1991;18: Lever AF, Harrap SB. Essential hypertension: a disorder of growth with origins in childhood. J Hypertens. 1992;10: Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension. 1989;13: Glagow S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis CG. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316: McPherson DD, Sirna JJ, Hiratzaka LF, Thorpe L, Armstrong ML, Marcus ML, Kerber RE. Coronary arterial remodeling studied by high-frequency epicardial echocardiography: an early compensatory mechanism in patients with obstructive coronary atherosclerosis. J Am CollCardiol. 1991;17: Gribbin B, Pickering TG, Sleight P, Peto R. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res. 1971;29: Margitie SE, Bond MG, Crouse JR, Furberg CD, Probstfield JL. Progression and regression of carotid atherosclerosis in clinical trials. Arterioscler Thromb. 1991;11: