Journal of Human Hypertension (2001) 15, 685–691 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Progressive arterial wall stiffening in patients with increasing diastolic blood pressure FWPJ van den Berkmortel1, M van der Steen1, H Hoogenboom, H Wollersheim1, H van Langen2, and Th Thien1 1 Department of Medicine, Division of General Internal Medicine, 2Clinical Vascular Laboratory of the University Hospital Nijmegen, The Netherlands Background: Hypertension is an established risk factor for cardiovascular disease. Risk factor patterns for various cardiovascular complications are different. We studied the relationship between increasing diastolic blood pressure and arterial wall dynamics of various peripheral arteries in hypertensives to increase insight in the variability of properties within the arterial tree. Methods: Eighty-six untreated hypertensives participated in this cross-sectional study. The study-population was divided into quartiles with increasing diastolic office blood pressure. Cross-sectional compliance and distensibility coefficients of the carotid and femoral arteries were determined, using a vessel wall movement detector system (Wall Track System). Results: Diameters of both common carotid arteries enlarged (right: from 7.4 ⴞ 0.2 to 7.9 ⴞ 0.2 mm) while cross-sectional compliance (right: from 0.61 ⴞ 0.04 to 0.42 ⴞ 0.04 mm2/kPa) and distensibility coefficients (right: from 14.2 ⴞ 1.0 to 9.0 ⴞ 1.0 10−3/kPa) gradually dropped with increasing diastolic blood pressure. Cross-sectional compliance and diameter of the right common femoral artery remained unchanged while distensibility coefficient decreased although less gradually when compared with the carotid arteries. Conclusions: In untreated hypertensives gradual arterial wall stiffening of the carotid arteries occurred with increasing diastolic blood pressure. Gradual changes were less clear in the common femoral artery which points to the heterogeneity of the arterial tree. Journal of Human Hypertension (2001) 15, 685–691 Keywords: cross-sectional compliance coefficient; distensibility coefficient; arterial wall stiffening; carotid artery; femoral artery Introduction Hypertension is one of the most important cardiovascular risk factors. Risk factor patterns for various cardiovascular complications are different. For stroke, hypertension is the most important risk factor whereas, for intermittent claudication, smoking appears to be the number one risk.1 These differences in risk patterns suggest heterogeneity of the arterial tree. Ultrasonographic determinations of arterial wall stiffness are used to estimate the cardiovascular risk in groups of subjects. Recently, Blacher et al2–4 provided evidence for the use of dynamic vessel wall properties to estimate cardiovascular risk in patients with end-stage renal disease and hypertension. Correspondence: FWPJ van den Berkmortel, MD; Department of Medicine, Division of General Internal Medicine 541, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: F.Vandenberkmortel얀aig.azn.nl Received 10 September 2000; revised 19 April 2001; accepted 30 April 2001 Cross-sectional compliance (CC) and distensibility coefficient (DC) are two parameters which describe arterial wall dynamics and can be calculated from ultrasonographically measured (changes in) diameters of peripheral arteries.5,6 Results of studies which compared CC and DC of the common carotid (elastic arteries) and common femoral arteries (muscular arteries) between normotensive and hypertensive patients revealed decreased CC and DC in hypertensives.7–9 The elastic properties of muscular arteries are variable in the short-term which is partly due to influences of both vasoactive substances and the central nervous system.10 Whether CC and DC gradually decline with increasing blood pressure and whether the relationship between blood pressure and arterial wall dynamics is different at the various sites of the arterial tree (which is possibly reflected in differences in risk factor patterns of cardiovascular complications) was the subject of this study. Therefore, we determined CC and DC of both the right (rCCA) and left (lCCA) common carotid artery and of the right common femoral artery (rCFA) in untreated middle-aged Arterial wall stiffening in hypertension FWPJ van den Berkmortel et al 686 hypertensive subjects who were divided into quartiles on the basis of their increasing diastolic office blood pressures (OBP). automated oscillometric device (Dinamap, Critikon Inc, Tampa, FL, USA). CC and DC were calculated from D, ⌬D and pulse pressure (⌬P), according to the following equations: Materials and methods CC = D(⌬D/2⌬P) expressed in mm2/kPa Subjects DC = (2⌬D/D)/⌬P expressed in 10−3/kPa A total of 101 hypertensive subjects who visited the outpatient clinic of our university hospital in the period between November 1995 and October 1998 for the first time because of hypertension, were asked to participate in this study. Subjects only joined the study if, in their own physicians opinion, it was safe to stop all antihypertensive drugs or if they did not use antihypertensive medication at all. After informed consent, current antihypertensive drugs were stopped or tapered off in case of betaadrenoceptor blocking drugs. Two weeks after stopping the medication the patients were seen at least twice for OBP measurements with a mercury sphygmomanometer. These were performed according to protocol: at least two times after a 10 min rest, in a supine position and with an appropriate cuff attached to the right upper arm. Patients were defined hypertensive when the average of the two office sessions systolic OBP exceeded 160 mm Hg or if the diastolic OBP amounted to over 90 mm Hg. Fifteen subjects were excluded because they did not fulfill the inclusion criteria. The remaining 86 patients were divided into quartiles (Q) according to their mean diastolic OBP. The first (QI) and last quartile (QIV) consisted of 22 subjects; in the other two quartiles 21 patients were assigned to each. Materials Compliance and distensibility are vessel wall properties which describe arterial wall stiffness. Compliance and distensibility are defined as respectively the absolute and relative change in volume for a given change in pressure. Arterial volume cannot be measured directly. Therefore it is assumed that arteries have a circular shape and that the arterial length does not change during the cardiac cycle. With this assumption it is possible to estimate compliance and distensibility by calculating the cross-sectional compliance (CC) and distensibility coefficient (DC). CC and DC can be assessed by measuring diameters (D) and diameter changes (⌬D) ultrasonographically. The vessel wall movement detector (Wall Track System, Maastricht, The Netherlands) has extensively been described by the group of Hoeks and Reneman.5,6 Briefly, with this system arterial D and ⌬D were measured during the cardiac cycle for about 4 s. The system used in this study consisted of an ultrasound device with a 7.5 MHz transducer (Scanner 200, Pie Medical) and a data acquisition system, coupled to a personal computer. Blood pressures were measured at the left upper arm every 3 min with a semiJournal of Human Hypertension Pulse pressures (⌬P = systolic − diastolic blood pressure) were calculated out of all blood pressure recordings which were registered during the measurements of the particular artery. In our laboratory reproducibility figures for CC and DC varied between 10 and 15–20% respectively for the common carotid and common femoral artery.11 Study design The study design was approved by the Medical Ethics Committee of the University Hospital of Nijmegen. All participants gave informed consent before entering the study. Preparation Participants were not allowed to drink caffeinecontaining beverages for at least 10 h before measurement. They were also requested to stop smoking 1 h before dynamic vessel wall properties were assessed. Measurement conditions Measurements were started after 10 min of supine rest. Special attention was given to perform the tracings at the end of a normal expiration to avoid movement artefacts. All measurements were performed by the same investigator (FvdB) to aim at maximal accuracy. The CCA was measured after turning the head of the subject 45 degrees contralateral from midline position. The rCFA was measured in supine position with the legs parallel to each other. Measurement sites Both CCA and the rCFA were measured. The CCA were measured 2 cm proximal of the bulb. The rCFA was measured at least 1 cm proximal of the bifurcation into the deep and superficial femoral artery. We only measured the CFA at one side as this measurement is time consuming and measurements only reach high quality if subjects lie down motionless. Data analysis At least three recordings were obtained to gather information over about 12–15 cardiac cycles. A tracing was rejected if a standard deviation of more than 10% of ⌬D was present in one recording of 4 s which mostly contains three to five consecutive heart- Arterial wall stiffening in hypertension FWPJ van den Berkmortel et al beats.11 For each heart cycle, and therefore each determination of D and ⌬D of the artery under investigation, CC and DC were calculated. The average of all 12–15 single calculated CC’s and DC’s was used as the final result. Initially Kruskal–Wallis tests were used for overall testing over the four groups. In case of statistical significant differences a Mann–Whitney U test was used for between group analysis. P values less than 0.05 (two-sided) were considered significant. We also calculated moving averages of CC and DC of both CCA according to Chau.12 Therefore, the 86 hypertensive subjects were classified by increasing diastolic OBP and designated by an index. Overlapping subgroups of 20 subjects each were formed by grouping subjects one up to 20, then subjects two up to 21, and so on, until subgroup 67 comprising patients 67 up to 86. In each subgroup the mean DC was calculated and plotted against the mean diastolic OBP. In addition, stepwise regression analysis was performed (SPSS Inc, Chicago, IL, USA) with D, CC and DC of rCCA, lCCA and rCFA as dependent variables and age, gender, systolic OBP, diastolic OBP, smoking habit, previous antihypertensive treatment, heart rate, length, weight, plasma cholesterol and glucose as independent variables. Results In Table 1 the baseline characteristics of the studypopulation divided in quartiles (Q) are shown. Less than three patients were not included because in their own physicians opinion it was not safe to stop antihypertensive medication (mainly due to recent cerebrovascular events). Each Q consisted of 21–22 subjects with mean diastolic OBP increasing from 95 ⫾ 0.7 mm Hg in QI to 118 ⫾ 1.7 mm Hg in QIV. There were no significant differences in main baseline characteristics (age, weight and plasma cholesterol levels). Pulse pressures were not significantly different in all quartiles. The number of males in QII (7 (33%)) was smaller compared with values in the other quartiles (QI: 11 (50%), QIII: 10 (48%) and QIV: 12 (55%)). The number of smokers was not different between the quartiles. Subjects with higher diastolic OBP more often used antihypertensive drugs and combinations of antihypertensives at the first visit to our hospital. Moreover, symptomatic atherosclerotic disease was present more frequently in the higher quartiles. Overall testing over the four quartiles was statistically significant for all measured vessel wall parameters except for the diameter (P = 0.06) and crosssectional compliance of the rCFA. In Figure 1 diameters (D; Figure 1a), cross-sectional compliance (CC; Figure 1b) and distensibility coefficients (DC; Figure 1c) of the rCFA and of both CCA are shown for the whole group divided into quartiles with increasing diastolic OBP. Results of comparisons between the quartiles (Mann–Whitney U test) are shown if Kruskal–Wallis tests were statistically significant. Figure 1a shows that D of both CCA were significantly enlarged in subjects with more severe hyper- 687 Table 1 Baseline characteristics of quartiles (Q) with increasing mean diastolic office blood pressure (OBP) Group/Parameter QI (n = 22) QII (n = 21) QIII (n = 21) QIV (n = 22) Age (years)a† Male/femaleb Smokerb 47.7 ± 2.9 11/11 6 44.8 ± 2.6 7/14 5 47.6 ± 2.8 10/11 7 49.0 ± 2.6 12/10 6 Length (m)a Weight (kg)a BMI (kg/m2)a OBP systolica,‡ OBP diastolica,‡ Pulse pressure (mm Hg) Heart rate (beats/mina) Plasma glucose (mmol/L)a Plasma cholesterol (mmol/L)a Alcohol intake (units/week)a Number of antihypertensive drugs at inclusion: 0 (not treated pharmacologically)b 1† 2† ⬎2b Diabetes Mellitus (type 2)b Symptomatic atherosclerotic diseaseb Orally treated hypercholesterolaemiab 1.72 ± 0.02 78.2 ± 3.4 26.2 ± 0.8 161 ± 4 95 ± 1 66 ± 2 73 ± 1 5.13 ± 0.12 6.0 ± 0.3 6±2 1.68 ± 0.02 79.1 ± 4.1 27.8 ± 1.3 163 ± 4 103 ± 0*** 63 ± 3 77 ± 2 5.07 ± 0.12 6.0 ± 0.3 6±2 1.68 ± 0.03 80.9 ± 4.4 28.8 ± 1.4 174 ± 3*,§ 107 ± 0***,§§ 72 ± 4 74 ± 3 5.89 ± 0.50 5.8 ± 0.2 6±2 1.71 ± 0.02 81.3 ± 3.9 27.6 ± 1.0 189 ± 5***,얏 118 ± 2***,§§,얏얏 70 ± 4 82 ± 2 5.57 ± 0.25 5.7 ± 0.2 11 ± 3 11 8 2 1 0 5 2 6 10 1 4 0 2 0 0 8 7 6 1 4 1 4 7 9 2 3 7 2 Data are presented as mean ± s.e. †P ⬍ 0.05, ‡P ⬍ 0.001 overall testing over the four quartiles (Kruskal–Wallis); bData are presented as absolute numbers; *P ⬍ 0.05, ***P ⬍ 0.001 compared with QI; §P ⬍ 0.05, 얏P ⬍ 0.01, §§P ⬍ 0.001 compared with QII; 얏얏P ⬍ 0.001 compared with QIII (Mann–Whitney U test). a Journal of Human Hypertension Arterial wall stiffening in hypertension FWPJ van den Berkmortel et al 688 tension (rCCA: 7.9 ⫾ 0.2 (QIII) and 7.9 ⫾ 0.2 (QIV) mm; lCCA: 7.8 ⫾ 0.2 (QIII) and 7.7 ⫾ 0.2 (QIV) mm) compared with subjects of QII with less severe hypertension (rCCA: 7.3 ⫾ 0.2 and lCCA: 7.2 ⫾ 0.1 mm). D of the rCFA also showed a tendency to increment although no significance was reached. Figure 1b shows that CC of both CCA decreased gradually with increasing diastolic OBP (r/lCCA: 0.61 ⫾ 0.04/0.55 ⫾ 0.05(QI), 0.54 ⫾ 0.04/0.47 ⫾ 0.03(QII), 0.53 ⫾ 0.05/0.45 ⫾ 0.02(QIII), 0.42 ⫾ 0.04/0.39 ⫾ 0.04(QVI) mm2/kPa). CC of the rCFA was not significantly different between all quartiles. Figure 1c presents data on DC. DC of both CCA decreased gradually with increasing diastolic OBP. Although DC of the rCFA changed significantly between the quartiles (P = 0.001 Kruskal–Wallis; P ⬍ 0.05 when QI and QII were compared with QIII and QIV) a gradual decrease was less obvious. Additionally, DC of both CCA were analysed according to the moving average method of Chau.12 Results of this analysis for the rCCA are shown in Figure 2. This figure shows a gradual decline in DC of the rCCA with increasing diastolic OBP. A similar graph was obtained from data of the lCCA (not shown). In Table 2 the results of stepwise regression analysis to study the influence of the independent factors: age, gender, systolic OBP, diastolic OBP, smoking habit, previous use of antihypertensive drugs, heart rate, length, weight, total cholesterol and glucose on the dependent variables: D, CC and DC of all investigated arteries are presented. Age and diastolic OBP were important factors mainly contributing to DC of both carotid arteries (age: R2: 0.278 (rCCA) and 0.410 (lCCA); diastolic OBP: R2: 0.125 (rCCA) and 0.123 (lCCA)). Dynamic vessel wall properties of the right common femoral artery were not influenced significantly by age and diastolic OBP. Other factors contributing to the dynamic vessel wall properties of the investigated arteries are shown in Table 2. Discussion In this study a gradual decline in cross-sectional compliance and distensibility coefficient with increasing diastolic OBP was seen at the carotid artery (both sides). This relation was less clear at the femoral artery. The study population was divided into quartiles with increasing diastolic OBP. The main baseline characteristics were similar between the quartiles. In QIII and QIV a larger number of subjects used at least two antihypertensive drugs before inclusion and suffered more frequently from symptomatic atherosclerotic disease. These data demonstrate the presence of more severe hypertension and therefore higher cardiovascular risk in the upper quartiles. Figure 1 Diameters (a), cross-sectional compliance (b) and distensibility coefficients (c) of both common carotid arteries and of the right common femoral artery of the quartiles (Q) based on increasing diastolic office blood pressure (QI: white bars, QII: light grey bars, QIII: dark grey bars, QIV: black bars). Mean ± s.e.m. are given. Further abbreviations; r, right; 1l left; CCA, common carotid artery; CFA, common femoral artery; CC, cross-sectional compliance; DC, distensibility coefficient. *P ⬍ 0.05, **P ⬍ 0.01 (Mann–Whitney U test). Journal of Human Hypertension Arterial wall stiffening in hypertension FWPJ van den Berkmortel et al carotid arteries, this parameter was not changed in the right common femoral artery with higher diastolic OBP (Figure 1). Similar results were obtained in the stepwise regression analysis. Thus, diastolic blood pressure seems to affect arterial wall dynamics of various arteries differently which is in accordance with the results of others.7,14 One possible explanation for the heterogeneity between the elastic carotid and the muscular femoral artery may be the fact that elastic properties in muscular arteries can be modified by vasoactive substances (such as angiotensin, noradrenaline and atrial natriuretic factor) or the central nervous system.10 There were small nonsignificant differences in dynamic vessel wall properties of the right compared with the left common carotid artery. Significant differences between the left and the right common carotid artery have not been described in literature. One possible explanation for this is the right-handedness of the single observer, who performed all measurements. We used brachial artery pulse pressures to calculate dynamic vessel wall properties of the carotid as well as of the femoral artery. The assumption that pulse pressure is identical at different sites of the arterial tree is incorrect, thereby creating a deviation from the real cross-sectional compliance and distensibility coefficient. As we compared between groups we feel this inaccuracy has not affected our results. There were differences in mean heart rate although these were not significant when tested with Kruskal–Wallis analysis. In anaesthetised rats acute increases in heart rate are accompanied by reductions in arterial compliance and distensibility.15 Differences in mean heart rate, of similar magnitude, did not influence arterial wall dynamics in smokers.16 To exclude the influence of heart rate on our results we analysed the current data with stepwise regression and found that heart rate was only of significance for the cross-sectional compliance of the right common femoral artery. Figure 2 Moving means (according to method of Chau12) for changes in distensibility coefficients of the right common carotid artery with increasing diastolic office blood pressure. Considering the whole study population, there were differences in dynamic vessel wall properties between the various arteries. The common femoral artery diameter was larger than the carotid artery diameter. Cross-sectional compliance and distensibility coefficients were lower in the muscular femoral artery compared with the elastic carotid artery. This is in accordance with earlier findings13 that dynamic vessel wall properties such as CC and DC decrease from the proximal elastic to the distal muscular arteries. Although distensibility coefficients of all investigated arteries were lower in the higher diastolic OBP groups, gradual changes with diastolic blood pressure increase were most clearly seen in the carotid arteries (Figures 1 and 2). In contrast with the gradual decrease of cross-sectional compliance in both 689 Table 2 Results of stepwise regression analysis with diameter (D), cross-sectional compliance (CC) and distensibility coefficients (DC) of both common carotid (CCA) and the right common femoral (CFA) as dependent variables. Numbers represent the value of R2, the coefficient of determination. Only variables with at least a single significance are given. (+), (−) and gender (m ⬎ f) indicate the sense of the relation Artery dependent variables: Independent variables: Age Gender (m⬎f) Diastolic OBP Systolic OBP Heart rate Weight Cholesterol Glucose Previous drug therapy Right CCA D CC Left CCA DC 0.286 (+) 0.057 (−) 0.278 (−) 0.073 (m⬎f) — — — 0.122 (−) 0.125 (−) 0.049 (−) — — — — — — — 0.042 (−) — — — — — — — 0.068 (+) — D CC 0.049 (+) 0.105 (−) 0.291 (m⬎f) 0.049 (m⬎f) — 0.114 (−) — — — — — — 0.073 (−) — — — — — Right CFA DC 0.410 (−) — 0.123 (−) — — 0.029 (−) — — — D CC DC — — — 0.186 (m⬎f) — — — — — — — 0.165 (−) — 0.067 (−) — — — — — — — — — 0.079 (−) — — 0.079 (−) Journal of Human Hypertension Arterial wall stiffening in hypertension FWPJ van den Berkmortel et al 690 In our study age was the strongest contributor to dynamic vessel wall properties of the carotid artery but not for arterial wall function of the femoral artery. This is in accordance with the literature.17,18 Studies that investigated the influence of gender on arterial wall stiffness parameters have revealed conflicting results.19–21 We found that gender had little effect on cross-sectional compliance and distensibility coefficient of the carotid as well as of the femoral artery. Gender did contribute to diameters of the carotid as well as of the femoral artery which could have influenced the results in QII as in this quartile gender distribution differed from that in other quartiles. As in our study previously treated hypertensives as well as never treated hypertensives participated, the effect of former treatment on arterial wall dynamics was investigated. Stepwise regression analysis showed that there was a small contribution of former treatment to the distensibility coefficient of only the right common carotid artery. Therefore, former treatment was not a major contributor to our results concerning arterial wall dynamics. Smokers refrained from smoking only 1 h before measurement. As in stepwise regression analysis smoking was not a contributor to dynamic vessel wall properties, it is unlikely that this has affected our results. Moreover our results are in accordance with a study16 in which arterial wall dynamics between smokers and non-smokers were compared. The results of dynamic vessel wall measurements in hypertensives are difficult to interpret because of their pressure dependency. Pulse pressures are used in the calculation of cross-sectional compliance and distensibility coefficient. As pulse pressures were not significantly different between the quartiles it is unlikely that they accounted for the differences in cross-sectional compliance and distensibility coefficients with increasing diastolic OBP. In contrast with a comparable study performed by Duprez et al22 the contribution of office systolic blood pressure to dynamic vessel wall properties was of minor importance in our group which is probably due to the stronger influence of office diastolic blood pressure. Arterial wall stiffening in hypertension is not necessarily associated with an increase in atherosclerotic damage but may merely be a reflection of the elevated mean arterial pressure. Therefore individual distensibility–pressure curves were made by others7,23,24 to compare arterial wall dynamics at a standardised pressure. At 100 mm Hg enhanced arterial wall stiffening was only present at the femoral artery which suggests structural alterations at this site.7 Individual distensibility–pressure curves show a logarithmic relationship between pressure and distensibility with only minimal changes in distensibility in the presence of high pressure.7,23,24 We showed gradual changes in cross-sectional compliance and distensibility coefficients of the carotid arteries throughout a wide range of hypertension Journal of Human Hypertension (systolic OBP range: 120–237 mm Hg, diastolic OBP range: 90–140 mm Hg). If we assume that the relationship between pressure and arterial wall stiffness in groups can be described by a similar logarithmic curve we can conclude from our data that we remain in the middle part of the curve over a wide range of hypertension. Although it is not clear whether progressive arterial wall stiffening in hypertension is associated with structural changes, a recent study provides evidence for the value of pulse wave velocity as a powerful predictor of cardiovascular risk in hypertension.3 Our data support this study as dynamic vessel wall function was affected most in the upper quartiles which consisted of subjects with severe hypertension and probably highest cardiovascular risk. Pulse wave velocity provides information regarding arterial stiffness over a certain distance of the arterial tree. We advise cautiousness to use data on arterial wall dynamics of isolated arteries as heterogeneity exists within the arterial tree. In conclusion we found enhanced arterial wall stiffening with increasing diastolic OBP. Gradual stiffening was obvious at the common carotid artery and less clear at the common femoral artery which illustrates the heterogenic vessel wall behaviour of the arterial tree. 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