Increased Stiffness of Radial Artery Wall Material in End-Stage Renal Disease
Abstract The incremental elastic modulus (Einc), which is the slope of the relationship between stress and strain of arteries, is a marker of vascular wall material stiffness. Isobaric Einc is reduced at the site of the radial artery in patients with essential hypertension and increased at the site of the common carotid artery in subjects with end-stage renal disease (ESRD). Whether the changes in Einc are influenced by the topography of the vessels, the composition of the arterial wall, and/or by the presence of ESRD is largely ignored. Radial artery Einc was measured in 19 patients with ESRD and compared with the Einc of 89 subjects with essential hypertension and 20 normotensive control subjects. Transcutaneous measurements of radial artery internal diameter and wall thickness (echo-tracking device) and digital pulse pressure (Finapres) were allowed to calculate Einc under operational (ie, at the mean arterial pressure of each group) and isobaric (100 mm Hg) conditions, as well as for a given wall stress. Internal diameter and pulsatile changes in diameter were identical in the three groups. Wall thickness and mean blood pressure were significantly elevated in subjects with hypertension but not in ESRD patients. Circumferential wall stress was identical in the three groups. For the same operational wall stress, and therefore at the operational mean arterial pressure of each group, Einc (kPa · 103) was increased in patients with ESRD (5.53±4.0 versus 3.3±2.4 in control subjects; P<.05) and normal in subjects with essential hypertension (3.87±4.0). Under isobaric conditions, Einc was also significantly lower in subjects with hypertension and elevated in patients with ESRD. Thus, at the site of a medium-sized muscular artery constantly devoid of atherosclerosis, the stiffness of wall material is increased in patients with ESRD. The demonstrated alterations of the arterial wall are independent of the level of blood pressure and tensile stress and should be related to the status ESRD.
The compliance and the distensibility of the whole arterial tree are reduced in subjects with essential hypertension (see reviews in Reference 11 ). These findings are constantly observed when compliance and distensibility are measured under operational conditions, ie, at the mean arterial pressure of hypertensive subjects, and compared with those of normotensive control subjects measured at their own mean arterial pressures. However, recent studies have shown important discrepancies in the compliance and distensibilities of central and peripheral arteries.2 3 4 In subjects with essential hypertension, although the operational carotid compliance is reduced,2 it remains normal at the site of a peripheral muscular artery as the radial artery.3 4 High-resolution echo-tracking techniques2 3 4 5 have been recently developed, allowing compliance and distensibility to be evaluated for the same pressure in normotensive and hypertensive subjects. It has been reported that the isobaric distensibility of the carotid artery is normal in subjects with essential hypertension2 and that of the radial artery is normal or even higher than in normotensives subjects.4 6 Because in hypertensive humans arterial hypertrophy is constantly present at the site of these arteries,7 attention has focused on the mechanisms by which the mechanical properties of the arterial wall material may contribute themselves to the maintenance of isobaric compliance and distensibility.6 Thus, it is important to determine in vivo the stiffness of the wall material of the carotid and the radial arteries, ie, the slope of the stress-strain relationship of these vessels, also called Einc.8
Laurent et al4 found that radial artery isobaric Einc was reduced in subjects with essential hypertension, indicating a decrease in the stiffness of the wall material on peripheral muscular arteries of medium size. In such hypertensive subjects, the study of a central artery like the carotid elastic artery showed that normal isobaric distensibility was associated with increased wall thickness, a finding that points also to a decrease in the stiffness of wall material.4 6 In contrast, in a population of normotensive and hypertensive subjects with ESRD, London et al9 demonstrated an increase in Einc measured at the site of the common carotid artery for a similar BP level as control subjects. Thus, major discrepancies may be observed in the value of Einc in hypertensive subjects. There is, as yet, no evidence to indicate whether the decreased isobaric Einc in subjects with essential hypertension and the increased isobaric Einc in subjects with ESRD result from the particular topography and structure of the vessel studied (carotid or radial artery) or to the presence or absence of ESRD.
The present study was therefore carried out to evaluate the Einc of the radial artery, a vessel constantly devoid of atherosclerosis,10 in patients with ESRD and to compare the findings with those observed in a population of subjects with essential hypertension. Einc was determined in vivo using high-resolution ultrasound techniques, thus enabling us to measure transcutaneously radial artery diameter and wall thickness.
The study was carried out on 128 men, including 19 patients with ESRD, 89 patients with essential hypertension (HT) and 20 normotensive control subjects (CT). The causes of renal failure were glomerulonephritis (11 patients), nephroangiosclerosis (5 patients), interstitial nephritis (2 patients), and polycystic renal disease (1 patient). ESRD patients were treated by hemodialysis (mean duration of dialysis, 8.2±6.3 years; ±1SD) with a well-functioning AVF established at least 3 months previously on the nondominant arm.9 The median predialysis BP for the 6 months preceding their inclusion was 132±22/76±13 mm Hg. Inclusion criteria included absence of present or prior cardiovascular complications (acute myocardial infarction, valvular heart disease, cerebrovascular disease, or decompensated heart failure) and a normalized BP for the 6 months preceding the study. Among the 19 ESRD patients, 12 were on antihypertensive therapy that included calcium antagonists (n=9), angiotensin-converting enzyme (n=8), and beta-blocking agent (n=6), alone or in combination. Eleven patients received recombinant human erythropoietin.
The hypertensive population included 89 never-treated subjects referred to the Hypertensive Unit of Broussais Hospital. The diagnosis of essential hypertension was established by the presence of a sustained increase in BP (>140 mm Hg systolic and/or >90 mm Hg diastolic pressure on the basis of sphygmomanometer measurements) and the absence of clinical or laboratory evidence, suggesting secondary forms of hypertension, as detailed previously.2 4 Twenty normotensives control subjects free of clinical evidence of coronary artery or cerebrovascular disease, valvular heart disease, or renal disease were included. The study was approved by the Ethics Committee of Broussais Hospital, and all patients gave their written consent.
The investigation was performed at 3 pm in a controlled environment at 22±2°C. For ESRD patients, the hemodynamic study was performed 24 hours after their midweek hemodialysis.9 Patients were dialyzed three times per week on AN 69 membranes (Hospal) for 4 to 5 hours. Dialysate was delivered by a system that included bicarbonate delivery, adjustable sodium concentration, and controlled ultrafiltration. Each patient was studied in the supine position after at least 10 minutes of rest. Before the arterial measurements, systolic and diastolic pressures were determined automatically every 5 minutes at the non-AVF arm with a Dinamap 845 oscillometric BP recorder. Systolic and diastolic pressures were determined as the average of five measurements. Blood samples were taken for routine biochemical parameters as well as plasma levels of parathormone and homocysteine, as previously described.9 11 Then the radial artery parameters were measured on the non-AVF arm of the ESRD patients. In patients with essential hypertension and in control subjects, all the radial artery measurements were performed on their right arms. The 20 subjects with essential hypertension were checked to ensure that there was no difference between the measurements made on the right and the left radial arteries. In the three groups of subjects, continuous measurements of the finger BP on the non-AVF arm were obtained during the overall investigation using the Finapres device (Ohmeda, BOC Group Inc).3 4
Measurements of Arterial Parameters
The ultrasound system used in the present study (NIUS 02,SMH) has been previously described and validated for measurement of radial artery internal diameter and its systolic-diastolic variations and determination of radial artery wall thickness in humans.3 4 12 13 14 Briefly, a high-resolution pulse echo-tracking device was used to acquire backscattered radiofrequency data from the radial artery at the wrist. The transducer was positioned so that its focal zone was in the center of the artery, and the backscattered echoes from both the anterior and posterior walls could be visualized. A typical radiofrequency signal was then displayed on a computer monitor interfaced to the transducer system. Arterial diameter and posterior wall thickness were measured when a “double peak” radiofrequency ultrasound signal of the anterior and posterior walls was obtained, as previously published and validated.13 These signals were visible only as the ultrasound beam crosses the axis (center) of the vessel. Due to the resolution of the method, the intima and the media of the vessels could not be differentiated, so that wall thickness, as previously reported,7 13 14 represents intima-media thickness. Data were determined by computing the analytic signal according to methods previously described13 14 and based on Fourier transformation. From determination of pulsatile changes in diameter (echo-tracking) and pressure (Finapres), the pressure-diameter, compliance-pressure, and distensibility pressure curves were established within the systolodiastolic range of operational pressures using a Langewouters model.3 6 14 15 All measurements were performed by the same observer (X.G.). Short-term intraobserver repeatability was 2.8% and 5.1%, respectively, for internal diameter (Di) and intima-media wall thickness (h) measurements.14
For calculated parameters, the lumen cross-sectional area (LCSA) was defined as LCSA (mm2)=3.14Di2/4, and the wall cross-sectional area (WCSA) as WCSA (mm2)=(3.14De2/4)−(3.14Di2/4), where De is the external diameter. The radius-thickness ratio was calculated as Di/(h · 2). The mean circumferential wall stress (kilopascals) was calculated as MAP · Di/2 hours, where MAP is the mean arterial pressure. CC, a marker of the exchange capacities of the vessel (Windkessel effect), was defined as ΔLCSA/PP, where ΔLCSA is the systolodiastolic difference in LCSA and PP is the pulse pressure. CD, which is CC normalized to diastolic LCSA, provided information about the ‘elasticity’ of the artery as a hollow structure.4 6 Finally, Einc provides direct information on the elastic properties of the wall material, independently of the vessel geometry.4 8 By definition, for a cylindrical vessel with isotropic wall, the incremental modulus of elasticity is the slope of the stress-strain curve and can be defined by: Einc=Δs/Δe, where Δs represents change in stress and Δe change in strain. Usually, strain is defined by e=(d−d0)/d0, with d0 the diameter at zero transmural pressure. For in vivo measurements, d0 is in general unknown. Therefore, we used Hooke’s law, which refers to thick-walled tubes, and adapted it for continuous determination of the pressure-diameter relationship and its derivation.3 4 16 17 This procedure does not require the knowledge of the unloaded (unstretched) state dimension for the calculation of strain.18 Einc was calculated according to the formula4 : Einc=3 · (1+LCSA/WCSA) 1/CD. Finally, CC, CD, and Einc were calculated under two different conditions. First, under operational conditions, CC, CD, and Einc were determined for the same circumferential wall stress, ie, at the operational MAP of each group. Second, under isobaric conditions, CC, CD, and Einc were calculated at a reference pressure of 100 mm Hg, thus allowing comparisons of groups at the same level of pressure.
The statistical analyses were performed using Statview SE 1.03 software on a Macintosh computer. A two-factor ANOVA, followed by the Newman-Keuls test, was used to compare the three groups under consideration. Independence of association was assessed by multiple regression. Results are presented as mean±1 SD. A value of P<.05 was considered significant.
The characteristics of the populations are presented in Table 1⇓. When control subjects and ESRD patients were compared, BP was significantly higher in hypertensives. Compared with the HT group, pulse pressure was significantly lower in control subjects. However, this parameter was quite similar in HT and ESRD patients. Age was significantly lower in control subjects compared with the HT and ESRD groups. In this latter group, body mass index was significantly lower compared with control subjects and hypertensive patients. The three groups had similar heart rates. Serum total cholesterol and calcium levels were comparable (Table 1⇓). In ESRD patients, plasma levels of parathormone (256±206 pg/mL) and plasma homocysteine (42.3±16.1 μmol/L) were elevated, as previously published.9 11
Radial Artery Structure
The results of radial artery measurements are shown in Table 2⇓. Whereas internal artery diameter was similar in the three groups, the wall of the radial artery was significantly thicker in essential hypertensive patients than in control subjects and ESRD patients. In patients with essential hypertension, the thickness/radius ratio was increased compared with control subjects but not the ESRD group. The wall cross-sectional area of HT group was increased, but it remained within the normal range in ESRD patients. The circumferential wall stress was quite similar in the three groups (Table 2⇓ and Fig 1⇓).
Operational Functional Parameters
The operational compliance and operational distensibility of the three groups were quite similar. Compared with hypertensive patients and control subjects, and for the same wall stress, ESRD patients had a higher operational elastic modulus, but the difference was significant only when compared with control subjects (Fig 1⇑).
Isobaric Functional Parameters
The values for CC, CD, and Einc at a reference pressure of 100 mm Hg are presented in Table 3⇓. Isobaric CC and CD were significantly higher in hypertensive subjects, compared with control subjects and ESRD patients. Fig 2⇓ shows the curves that relate Einc to BP in the three groups. Compared with ESRD patients, isobaric Einc was significantly lower in hypertensive patients and normotensive subjects. In ESRD patients, the isobaric (100 mm Hg) Einc values were identical whether the subjects were untreated (6.58±6.8 kPa · 103) or treated for hypertension (6.38±13 kPa · 103).
Relationships Among Einc, Clinical Characteristics, and Radial Artery Structure
Multivariate analyses, which included age, mean and pulse pressures, body mass index, intima-media thickness, and group status were performed. The isobaric elastic modulus of the radial artery was independently predicted by the group status (P<.0089) (Table 4⇓). Age, body mass index, and BP were not related to isobaric Einc. Similar findings were obtained when operational Einc was studied instead of isobaric Einc.
The radial artery wall thickness was independently predicted by the mean BP and pulse pressure and to a lesser extent by age (Table 5⇓). Group status had no influence on wall thickness.
The main finding of this study is that the stiffness of the radial artery wall material (Einc) was significantly elevated in patients with ESRD compared with normotensive subjects or patients with essential hypertension, whether the result was expressed at mean operational arterial pressure (and therefore at similar wall stress; Fig 1⇑) or at a given BP, ie, 100 mm Hg (Table 3⇑). In contrast, the stiffness of wall material in patients with essential hypertension was either normal at a given wall stress or tended to be lower at a given BP (100 mm Hg). Moreover, operational compliance was comparable in the three groups. Taken together, these findings suggest that at the site of the radial artery of patients with essential hypertension or ESRD, the exchange capacities of the vessel may be largely preserved despite substantial differences in the elasticity of arterial wall material.
In the past, the mechanical properties of arteries were evaluated from the Moens-Korteweg equation, which usually assumed a thin arterial wall.8 Thus, wall thickness was neglected in the calculation and the results were presented mainly in terms of distensibility. The present study clearly shows that using high-resolution echo-tracking techniques2 3 4 5 substantial differences in wall thickness may be observed. First, vascular hypertrophy was present in subjects with essential hypertension but not in patients with ESRD. Second, the degree of vascular hypertrophy was proportional to the level of BP according to the classic Laplace law. Mostly the finding was highly dependent of group status (Table 4⇑), namely the presence or absence of ESRD. Thus, it is relevant to characterize the mechanical properties of wall material in patients with ESRD.
At first approximation, the specificity of the increased Einc in patients with ESRD could be discussed. Indeed, in the present investigation, the normal individuals were younger and the hypertensive group by definition had a higher BP than ESRD patients. Thus, because Einc is the slope of the stress-strain relationship of the radial artery, it was important to evaluate Einc for the same mean value of wall stress in the three populations of subjects. Fig 1⇑ shows that wall stress was quite similar in patients with ESRD, essential hypertension, and normotensive control subjects and that Einc at this value of wall stress was likely elevated in patients with ESRD. On the other hand, using the Einc-pressure curves provided by echo-tracking techniques, we demonstrated that Einc was increased in patients with ESRD for the same BP (100 mm Hg) (Table 3⇑) as for the control population and the subjects with essential hypertension. Finally, on the basis of multiple regression analysis, we showed that the increased Einc was influenced neither by the presence of antihypertensive therapy nor by age (Table 4⇑), but was strongly influenced by the presence of kidney disease and/or advanced renal failure. Thus, the increased Einc should be related to the status of the kidney independently on the level of BP and tensile stress.
In ESRD patients, the radial artery is important to investigate because this artery is constantly devoid of atherosclerosis.10 The increased isobaric Einc was associated with normal wall/lumen ratio and medial cross-sectional area, and there was no substantial alteration in isobaric compliance or distensibility. In such patients, the study of the common carotid artery,9 an artery in which atherosclerosis is frequent,19 showed that isobaric Einc was also increased. A normal common carotid artery wall-to-lumen ratio was observed, but was associated with an increased medial cross-sectional area; isobaric distensibility was reduced, whereas isobaric compliance was only slightly modified. In ESRD patients, the main difference between the radial and carotid arteries was in the value of artery diameter, which was increased at the site of the carotid but not of the radial artery. Thus, a eutrophic pattern with normal lumen diameter was observed for the radial artery and an outward hypertrophy for the carotid artery.20
The reasons for the increased radial artery Einc are difficult to elucidate. Vascular functional and structural factors may be involved. Increased cardiac output and forearm blood flow have been widely reported in patients with ESRD9 21 22 and might be responsible for arterial changes through a disturbed flow-dilation mechanism and endothelial dysfunction.23 However, increased shear stress, undoubtedly present in ESRD patients, is known to induce dilatation rather than hypertrophy of the arterial wall. Nevertheless, in ESRD patients, other endothelial factors may be involved, since at the site of the radial artery, not only does diameter not dilate adequately in response to an acute increase in flow but the release of nitric oxide is blunted also; however, the release of prostacyclin is not.24 Furthermore, in ESRD patients the accumulation of an endogenous inhibitor of nitric oxide synthesis has been noted.25 Nitric oxide donors are known to increase the elasticity of large vessels, and their blockade in turn might favor arterial rigidity.26
In the present investigation, it is important to note that the increased isobaric Einc in patients with ESRD contrasts with the decreased isobaric Einc observed in subjects with essential hypertension.4 In the latter case, the decreased Einc was associated with increased wall-to-lumen ratio and an increased value of medial cross-sectional area, isobaric compliance, and distensibility. Since the radial artery is a muscular medium-sized artery, it has been suggested that an increase in distensible muscular material might be responsible for the enhanced isobaric compliance and distensibility in subjects with essential hypertension.6 An opposite pattern for structural changes of the arterial wall may be suggested in ESRD patients. Studies in experimental uremia and in vitro in arteries of uremic patients have shown striking structural alterations involving an increase in wall thickness, cross-sectional media, total number of vascular smooth muscle cells, and volume of extracellular matrix (including collagen but not elastin).27 28 29 Calcifications of elastic lamellae may be present, suggesting the potential role of parathormone. Such structural changes are not similar to those observed in aging, atherosclerosis, and hypertension. Thus, the role of renal factors may be suggested, such as those related to water logging, the accumulation of advanced glycosylation end product, and oxidation damage.30
In conclusion, the present study has shown that the presence of kidney disease and/or advanced renal failure affects the stiffness of the wall material at the site of peripheral muscular medium-sized arteries. This change is unlikely to be due to atherosclerosis or to changes in tensile stress and is substantially different from that which occurs at the site of the carotid artery in ESRD patients and from that observed in subjects with essential hypertension. We therefore suggest that the kidney disease should be responsible per se for the changes in the arterial wall observed at the site of the conduit arteries of ESRD patients.
Selected Abbreviations and Acronyms
|CT||=||normotensive control subjects|
|Einc||=||incremental elastic modulus|
|ESRD||=||end-stage renal disease|
|HT||=||patients with essential hypertension|
This study was partly supported by funds from the Assistance Publique-Hôpitaux de Paris (appel d’offres Biologie du vieillissement projet 94.17.17), Société Française d’Hypertension artérielle, and grants from Institut National de la Santé et de la Recherche Médicale (INSERM) (Convention 494014).
- Received February 19, 1997.
- Revision received March 24, 1997.
- Accepted June 23, 1997.
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