Preferential macrovasculopathy in systemic sclerosis detected by

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Arthritis Care & Research Vol. 63, No. 4, April 2011, pp 579 –587 DOI 10.1002/acr.20306 © 2011, American College of Rheumatology

SPECIAL THEME ARTICLE: VASCULAR COMORBIDITY IN THE RHEUMATIC DISEASES

Preferential Macrovasculopathy in Systemic Sclerosis Detected by Regional Pulse Wave Velocity From Wave Intensity Analysis: Comparisons of Local and Regional Arterial Stiffness Parameters in Cases and Controls JIE LIU, YAN ZHANG, TIE-SHENG CAO, YUN-YOU DUAN, LI-JUN YUAN, YI-LIN YANG, YU LI, AND LI YAO

Objective. To study the extent and severity of macrovasculopathy in systemic sclerosis (SSc; scleroderma) patients by comparing both local and regional arterial stiffness parameters. Methods. The local arterial stiffness indices of the right common carotid artery, right brachial artery, right radial artery, right superficial femoral artery, and right posterior tibial artery were measured in 25 SSc patients and strictly matched healthy controls. The regional pulse wave velocity (PWV) of each arterial segment was also calculated from wave intensity analysis. Results. There were no differences between the two groups in the stiffness index (␤), Peterson’s pressure modulus, arterial compliance, and local PWV derived from ␤ (PWV␤) of all vessels except the right brachial artery, of which ␤, Peterson’s pressure modulus, and PWV␤ were markedly lower and arterial compliance was higher in SSc patients compared with controls (P < 0.05). The forearm (brachial–radial) and arm (carotid–radial) PWVs were significantly higher in SSc patients than in controls (mean ⴞ SD 12.1 ⴞ 7.1 meters/second versus 8.3 ⴞ 3.5 meters/second and mean ⴞ SD 7.9 ⴞ 1.9 meters/second versus 6.9 ⴞ 1.5 meters/second, respectively; P < 0.05), whereas the upper arm (carotid– brachial), aortic (carotid–femoral), and leg (femoral–ankle) PWVs were not different between groups. The aortic PWV was also higher in the diffuse cutaneous SSc subgroup than in controls (mean 6.2, 95% confidence interval [95% CI] 5.4 – 6.9 meters/second versus mean 5.1, 95% CI 4.7–5.6 meters/second; P < 0.05) after adjusting for potentially influential variables. Conclusion. The macrovasculopathy occurs preferentially at the forearm and aorta in SSc, which can be sensitively and reliably detected by regional PWVs rather than commonly used local arterial stiffness indices.

INTRODUCTION Systemic sclerosis (SSc; scleroderma) is a generalized connective tissue disorder of unknown etiology characterized by thickening and fibrosis of the skin and distinctive visceral involvement associated with vascular damage (1). Its Supported by a grant from the National Natural Science Foundation of China (30770783). Jie Liu, MD, Yan Zhang, MD, Tie-Sheng Cao, MD, YunYou Duan, MD, Li-Jun Yuan, MD, Yi-Lin Yang, MD, Yu Li, MD, Li Yao, MD: Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China. Address correspondence to Tie-Sheng Cao, MD, Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, Shaanxi Province, China. E-mail: [email protected]. Submitted for publication March 25, 2010; accepted in revised form July 21, 2010.

most typical early manifestation is Raynaud’s phenomenon (RP), which occurs in more than 90% of patients with SSc (2). Traditionally, the vasculopathy of SSc has been considered mainly to affect small arteries and capillaries (3); however, there is recent evidence showing that SSc is associated with the prevalence of large vessel disease (4), endothelial dysfunction, and increased arterial wall stiffness (5). Although a number of studies were available regarding the increasing arterial stiffness of SSc patients in general, their results still remained discrepant in detail (6); furthermore, most of their parameters used for analyses were only restricted to the stiffness index (␤) of the common carotid artery, the aortic augmentation index, and the carotid–femoral pulse wave velocity (PWV), all of which mainly reflect the stiffness of large elastic arteries. In contrast, the stiffness of distal medium muscular arteries has not yet been well investigated. Additionally, the relation579

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Figure 1. A, simultaneous measurements of arterial diameter change and blood flow velocity in color Doppler/B (left) and M (right) modes, B, the output display of wave intensity (WI) and arterial stiffness indices, and C, calculation of regional pulse wave velocity (PWV) from WI and synchronous electrocardiogram waveform. The carotid–femoral transit distance (cfTD) was estimated by taking the difference of the distance from the suprasternal notch (SSN) to the carotid site (SSN-C) and the distance from the SSN to the femoral site (SSN-F) into account for parallel transmission along the brachiocephalic and carotid arteries and around the aortic arch (red shading). Note that the carotid–femoral PWV (cfPWV) and carotid– brachial PWV fails to assess the stiffness of the proximal aorta (red shading). The carotid– femoral transit time (cfTT) was calculated by subtracting the interval between the R wave of electrocardiogram and the first peak of WI (R ⫺ W1) of the right common carotid artery (RCCA) from that of the right superficial femoral artery (RSFA), and a similar procedure was used to compute other TTs. RBA ⫽ right brachial artery; RRA ⫽ right radial artery; RPTA ⫽ right posterior tibial artery; § ⫽ SSN; br ⫽ brachial–radial; fa ⫽ femoral–ankle. ␤ ⫽ stiffness index; Ep ⫽ Peterson’s pressure modulus; AC ⫽ arterial compliance; PWV␤ ⫽ local PWV derived from ␤; W1 ⫽ first peak of WI; W2 ⫽ second peak of WI; NA ⫽ negative area between W1 and W2; R-1st ⫽ R ⫺ W1; 1st-2nd ⫽ W1 ⫺ W2.

ships between arterial stiffness parameters and the macrovascular stiffening per se in SSc patients still remain to be fully explored. Recently, wave intensity analysis has become a useful method for evaluating traveling pressure and flow waves in the aorta and larger arteries. Some in-depth overviews of wave intensity analysis and its application were published previously (7,8). The wave intensity and arterial stiffness indices now can be obtained simultaneously and immediately through the wave intensity analysis ultrasound system, which is based on the Doppler and echotracking technique. Using this novel technique, the present study was designed to investigate the systemic macrovascular impairment in a Chinese SSc cohort, which has rarely been performed before, by examining the arterial stiffness parameters of both central elastic and peripheral muscular arteries. This study therefore offered an

opportunity to test which arterial stiffness parameters are more suitable for detecting the early macrovascular stiffening per se in SSc patients and which arteries are apt to be involved in the macrovasculopathy.

PATIENTS AND METHODS Patients and controls. Twenty-five consecutive patients with an established SSc diagnosis according to the American College of Rheumatology criteria (9) were recruited from the Department of Rheumatology in Tangdu Hospital for the investigation, which had been approved by the ethics committee of the hospital and conformed to the principles of the Declaration of Helsinki. The disease duration was defined based on the onset of RP. Twenty-five strictly matched healthy subjects were randomly selected

Macrovasculopathy in SSc Detected by Regional PWVs as controls. All of the participants, including both patients and controls, were of the same ethnicity, i.e., Han nationality. None of the participants were smokers or had evidence of concomitant hypertension, arrhythmia, diabetes mellitus, dyslipidemia, known cardiovascular disease, vasculitis, and infection. Measurements. All of the measurements were performed by a single trained sonographer (JL) unaware of the participants’ status in the morning after they had fasted overnight and abstained from alcohol and caffeine. Participants rested supine in a quiet, air-conditioned room (22– 24°C) for at least 10 minutes before undergoing the following measurements. Blood pressure was measured 3 times in 5-minute intervals by an electronic sphygmomanometer (Omron HEM-7052) at the right upper arm, which was also the dominant arm, and the mean value was used in the study. Five arteries, including the right common carotid artery (RCCA), right brachial artery (RBA), right radial artery (RRA), right superficial femoral artery (RSFA), and right posterior tibial artery (RPTA), were studied at the following sites: 3 cm proximal to the bifurcation of the common carotid artery, 3 cm above the antecubital fossa, 3 cm above the wrist, 3 cm distal to the bifurcation of the common femoral artery, and 3 cm above the medial ankle, respectively. In addition, the intima-media thickness (IMT) of the posterior wall of each artery was determined by B-mode ultrasonography of high resolution at the sampling site. All of the arteries were examined thoroughly at full length in order to exclude regional hemodynamically relevant stenosis. Participants with such stenosis were not found in the study. Wave intensity and local arterial stiffness indices. This wave intensity analysis system is incorporated in ultrasonic diagnostic equipment (ProSound ␣10), which has a color Doppler system for blood flow velocity measurements and an echo-tracking subsystem for diameter change measurements with a 5–13 MHz linear array transducer. The details of this system were described elsewhere (10). Briefly, after setting the tracking positions, displayed as two small dotted bars along the anterior and posterior arterial walls perpendicular to the ultrasound beam line (line a in Figure 1A), the echo-tracking subsystem automatically starts measurements of arterial diameter change. The blood flow velocity averaged along the Doppler beam (line b in Figure 1A) crossing the artery is measured using range-gated color Doppler signals. At least 5 consecutive beats were ensemble averaged to obtain a representative waveform. After the measured blood pressure data were inputted for calibration, the wave intensity and local arterial stiffness indices were calculated automatically and displayed on the monitor (Figure 1B). Wave intensity is computed as (dP/dt) ⫻ (dU/dt), where dP and dU ⫽ changes in blood pressure and velocity, respectively, during constant short time intervals (dt). The wave intensity indices here include two intensive indices (the first peak [W1] and the second peak [W2]), two temporal indices (the interval between the R wave of electrocardiogram and W1 [R ⫺ W1] and the interval between W1

581 and W2 [W1 ⫺ W2]), and the negative area between W1 and W2 (NA), which indicates the effects of reflected waves. The local arterial stiffness indices, including ␤, Peterson’s pressure modulus, arterial compliance, and local PWV derived from ␤ (PWV␤), can be calculated by the echo-tracking subsystem according to the following formulas: ␤ ⫽ ln(Ps/Pd)/[(Ds ⫺ Dd)/Dd], Peterson’s pressure modulus ⫽ (Ps ⫺ Pd)/[(Ds ⫺ Dd)/Dd], arterial compliance ⫽ ␲(Ds ⫻ Ds ⫺ Dd ⫻ Dd)/[4 (Ps ⫺ Pd)], and PWV␤ ⫽ 冑␤ ⫻ Pd/2␳(11), where Ps ⫽ end systolic pressure; Pd ⫽ end diastolic pressure; Ds ⫽ maximum arterial diameter and Dd ⫽ minimum arterial diameter, measured by wall tracking of the medial–adventitial borders of the arteries; and ␳ ⫽ blood density (␳ ⫽ 1,050 kg ⫻ m⫺3). Regional arterial stiffness parameter: regional PWV. Regional PWV was calculated for each arterial segment as the pulse wave transit distance (TD) between two sampling sites divided by the corresponding pulse wave transit time (TT) delay: PWV ⫽ TD/TT (meters/second). The aortic (carotid–femoral), upper arm (carotid– brachial), and arm (carotid–radial) TDs were measured by subtraction method (12), while the leg (femoral–ankle) and forearm (brachial–radial) TDs were measured by direct site-tosite method, i.e., superficial measurement of the distance between the two sampling sites. The TT on the arterial segment was calculated by subtracting R ⫺ W1 of the proximal artery from that of the distal artery (Figure 1C). Intraobserver reproducibility for repeated measurements of arterial stiffness parameters. Fifteen subjects from the control group were randomly selected for assessment of the intraobserver intersession variability in repeated measurements of each arterial stiffness parameter. Both measurements were performed in the same condition with an interval of 1 day. The variability was calculated using Bland-Altman analyses (13) and expressed as percentages of 95% confidence limits of the difference (calculated as 冑2 SDs) from the mean value of the paired measurements (10). Statistical analysis. Data are expressed as the mean ⫾ SD for normally distributed continuous variables (including age, disease duration, diameter, IMT, R ⫺ W1, ␤, Peterson’s pressure modulus, arterial compliance, PWV␤, and regional PWVs) or as the median (interquartile range) for non–normally distributed continuous variables (including creatinine level and Medsger severity score), unless otherwise indicated. Differences between variables that assumed normal distributions were investigated by means of an unpaired t-test, while variables that did not assume normal distributions were investigated using the nonparametric Mann-Whitney U test. Pearson’s correlation was used to investigate the correlations between the normally distributed variables. A general linear model was applied to estimate differences in means of the regional PWVs between the SSc subgroups and control group after adjustment for possible confounding factors. All of the data were analyzed using the statistical software SPSS, version 15.0. For all tests, P values less than 0.05 (2-tailed) were considered statistically significant.

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Table 1. Demographic characteristics of the SSc patients and healthy controls*

Age, years Sex, male/female Height, cm Weight, kg BMI, kg/m2 Heart rate, beats/minute Systolic BP, mm Hg Diastolic BP, mm Hg Pulse pressure, mm Hg LVEF, % Plasma glucose, mmoles/liter Creatinine, median (IQR) ␮moles/liter Total cholesterol, mmoles/liter Triglycerides, mmoles/liter Medsger severity scale score, median (IQR) Echo PASP, no. ⬍35 mm Hg 35–65 mm Hg ⬎65 mm Hg

Controls (n ⴝ 25)

SSc (n ⴝ 25)

P

46.2 ⫾ 11.2 3/22 159.5 ⫾ 5.8 54.6 ⫾ 5.6 21.45 ⫾ 1.92 71.6 ⫾ 8.4 117.6 ⫾ 12.7 72.1 ⫾ 7.7 45.5 ⫾ 6.3 66 ⫾ 7 4.62 ⫾ 0.39 57.0 (49.5–63.5) 4.48 ⫾ 0.60 0.99 ⫾ 0.28 0

47.2 ⫾ 10.1 3/22 158.6 ⫾ 5.7 55.3 ⫾ 7.4 21.98 ⫾ 2.61 75.0 ⫾ 14.9 112.9 ⫾ 11.3 69.8 ⫾ 6.2 43.1 ⫾ 7.4 68 ⫾ 5 4.51 ⫾ 0.59 60.0 (53.0–65.0)† 4.33 ⫾ 0.73 0.91 ⫾ 0.39 7.0 (5.0–9.5)

NS NS NS NS NS NS NS NS NS NS NS NS NS NS

25 0 0

4 18 3

* Values are the mean ⫾ SD unless otherwise indicated. 1 mm Hg ⫽ 0.133 kPa. SSc ⫽ systemic sclerosis; NS ⫽ not significant; BMI ⫽ body mass index; BP ⫽ blood pressure; LVEF ⫽ left ventricular ejection fraction; IQR ⫽ interquartile range; PASP ⫽ pulmonary artery systolic pressure. † Two patients with SSc, but no controls, had a serum creatinine level above 117 ␮moles/liter.

RESULTS Characteristics of the study population. All of the patients (mean ⫾ SD disease duration 4.9 ⫾ 5.6 years) had RP, and only 3 (12%) had digital ulcers. Seventeen patients (68%) had limited cutaneous systemic sclerosis (lcSSc) and the other 8 (32%) had diffuse cutaneous systemic sclerosis (dcSSc) (14). Twenty-one patients (84%) had pulmonary fibrosis or pulmonary arterial hypertension, where pulmonary artery systolic pressures of ⬎35 mm Hg on echocardiogram were used as a screening cutoff point. Cardiac abnormalities were observed in 12 patients (48%). Nine patients (36%) had gastrointestinal and 2 patients (8%) had renal manifestations. Four patients (16%) had musculoskeletal involvement and 3 patients (12%) had Sicca symptoms. Common characteristics of the SSc patients and healthy controls as well as the Medsger severity score (15,16) and pulmonary arterial hypertension degree of the SSc patients are described in Table 1. The two groups were well matched with respect to age, sex, size, body mass index (BMI), blood pressure, left ventricular ejection fraction, and metabolic profile. Regarding SSc patients’ current therapy within 24 hours, the drugs used were: proton-pump inhibitors (80%), steroids (32%), immunosuppressive agents (16%), alfacalcidol (48%), nonsteroidal antiinflammatory drugs (12%), diuretics (8%), penicillamine (12%), aspirin (68%), dipyridamole (64%), beta-blockers (8%), angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (8%), calcium-channel blockers (12%), as well as traditional Chinese medicine, including sodium tanshinone IIA sulfonate (STS; 84%) and scutellarin (60%).

Diameter, IMT, R ⴚ W1, and local arterial stiffness indices. No significant differences were found between the two groups in terms of the vessel diameter, IMT, and R ⫺ W1, except for the R ⫺ W1 of the RRA, which was markedly shortened in the SSc patients compared with the controls (mean ⫾ SD 162.6 ⫾ 20.1 msec versus 175.2 ⫾ 17.6 msec; P ⬍ 0.05), as shown in Table 2. Because the other wave intensity indices, including W1, W2, W1 ⫺ W2, and NA, were not related to the arterial stiffness or were reported to lack reproducibility (e.g., W2 and NA) (10), the data for them were not included here for discussion, although they also showed no differences between the two groups. There were no significant differences between the two groups in the local arterial stiffness indices of all arteries except the RBA, of which the ␤, Peterson’s pressure modulus, and PWV␤ were markedly lower and the arterial compliance was apparently higher in SSc patients than in healthy controls (P ⬍ 0.05). Regional PWVs. The forearm and arm PWVs in SSc patients were significantly higher than that observed in the controls (mean ⫾ SD 12.1 ⫾ 7.1 meters/second versus 8.3 ⫾ 3.5 meters/second and 7.9 ⫾ 1.9 meters/second versus 6.9 ⫾ 1.5 meters/second, respectively; P ⬍ 0.05), whereas the upper arm, aortic, and leg PWVs showed no difference between the SSc and control groups (mean ⫾ SD 6.7 ⫾ 1.8 meters/second versus 6.5 ⫾ 2.1 meters/ second, 5.6 ⫾ 1.3 meters/second versus 5.2 ⫾ 1.3 meters/ second, and 11.7 ⫾ 4.1 meters/second versus 11.4 ⫾ 3.7 meters/second, respectively; P ⬎ 0.05), as shown in Figure 2. The subgroup analyses showed that in addition to the forearm and arm PWVs, the aortic PWV was also higher in dcSSc patients as compared with controls after adjustment

96.6 ⫾ 22.7 139.1 ⫾ 21.8 162.6 ⫾ 20.1§ 186.3 ⫾ 28.9 244.0 ⫾ 27.5 99.5 ⫾ 11.2 144.5 ⫾ 12.7 175.2 ⫾ 17.6 197.5 ⫾ 27.8 256.0 ⫾ 24.5 0.447 ⫾ 0.086 0.280 ⫾ 0.037 0.223 ⫾ 0.029 0.419 ⫾ 0.026 0.258 ⫾ 0.034 7.35 ⫾ 0.91 3.92 ⫾ 0.56 2.27 ⫾ 0.39 5.39 ⫾ 0.63 2.12 ⫾ 0.39 RCCA RBA RRA RSFA RPTA

7.40 ⫾ 0.61 3.92 ⫾ 0.60 2.32 ⫾ 0.49 5.62 ⫾ 0.71 2.01 ⫾ 0.34

0.466 ⫾ 0.069 0.286 ⫾ 0.033 0.226 ⫾ 0.026 0.420 ⫾ 0.054 0.260 ⫾ 0.041

SSc Control SSc Control SSc Control Vessel

* Values are the mean ⫾ SD. IMT ⫽ intima-media thickness; R ⫺ W1 ⫽ interval between the R wave of electrocardiogram and the first peak; SSc ⫽ systemic sclerosis; ␤ ⫽ stiffness index; PWV␤ ⫽ local pulse wave velocity derived from ␤; RCCA ⫽ right common carotid artery; RBA ⫽ right brachial artery; RRA ⫽ right radial artery; RSFA ⫽ right superficial femoral artery; RPTA ⫽ right posterior tibial artery. † Diameter here indicates the maximum diameter that was automatically measured by echo tracking and does not refer to the real maximum inner diameter but an approximation of the maximum inner diameter plus the posterior and anterior IMT of the examined vessel. ‡ P ⬍ 0.01 versus the control group. § P ⬍ 0.05 versus the control group.

0.775 ⫾ 0.225 6.36 ⫾ 0.91 6.38 ⫾ 1.15 0.159 ⫾ 0.098§ 9.76 ⫾ 1.75 8.22 ⫾ 1.84‡ 0.034 ⫾ 0.039 10.68 ⫾ 1.87 11.24 ⫾ 2.94 0.264 ⫾ 0.186 8.32 ⫾ 1.68 8.73 ⫾ 1.29 0.023 ⫾ 0.012 10.12 ⫾ 1.61 10.55 ⫾ 1.98 113.4 ⫾ 44.8 191.4 ⫾ 81.6‡ 364.4 ⫾ 167.1 211.2 ⫾ 56.6 310.8 ⫾ 111.3 9.44 ⫾ 3.42 15.80 ⫾ 6.03‡ 30.80 ⫾ 13.94 17.88 ⫾ 4.99 26.03 ⫾ 8.74 8.93 ⫾ 2.02 21.42 ⫾ 6.90 25.83 ⫾ 8.95 15.67 ⫾ 5.94 22.88 ⫾ 6.40

111.6 ⫾ 32.3 265.3 ⫾ 91.5 320.3 ⫾ 115.9 194.3 ⫾ 78.6 284.2 ⫾ 88.1

0.744 ⫾ 0.208 0.098 ⫾ 0.044 0.026 ⫾ 0.011 0.260 ⫾ 0.111 0.025 ⫾ 0.008

SSc Control SSc Control SSc Control SSc Control

Arterial compliance, mm2/kPa Peterson’s pressure modulus, kPa

␤ R ⴚ W1, msec IMT, mm Diameter, mm†

Table 2. Diameter, IMT, R ⴚ W1, and local arterial stiffness indices in the SSc and control groups*

PWV␤, meters/second

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Figure 2. Regional pulse wave velocity in the systemic sclerosis (SSc; n ⫽ 25) and control (n ⫽ 25) groups. Values are the mean ⫾ SD. Forearm ⫽ brachial–radial; upper arm ⫽ carotid– brachial; arm ⫽ carotid–radial; aortic ⫽ carotid–femoral; leg ⫽ femoral– ankle; m/s ⫽ meters/second; ** ⫽ P ⬍ 0.01 versus the control group; NS ⫽ not significant versus the control group; * ⫽ P ⬍ 0.05 versus the control group.

for age, sex, BMI, heart rate, and systolic and diastolic blood pressure; however, none of the regional PWVs showed statistical differences between the lcSSc subgroup and control group before and after adjustment (Table 3). Correlations of arterial stiffness parameters with age and disease duration. Only the ␤, Peterson’s pressure modulus, PWV␤ of the RCCA, and aortic PWV displayed significant positive correlations to age in the control group, with the aortic PWV being of the highest correlation coefficient (r ⫽ 0.733, P ⬍ 0.001), as shown in Table 4. No significant correlations were found between the measured arterial stiffness parameters and disease duration in the SSc group (data not shown). Intraobserver reproducibility. The intraobserver intersession variabilities were apparently lower in regional PWVs than in most of the local arterial stiffness parameters. The variabilities of local and regional arterial stiffness parameters appeared to be reversely related to the caliber of the sampling arteries and the distance of the arterial segments, respectively (Table 4), due to a larger variation in tone of smaller muscular arteries, which are under permanent neurohumoral control.

DISCUSSION The IMTs in SSc patients have been studied by several researchers. Mourad et al (17) found that the radial artery internal diameter of SSc patients was significantly decreased, whereas the IMT and mean arterial pressure were closely similar to the controls. The carotid, femoral, and brachial IMTs in SSc patients also showed no differences from the controls (18 –20). In accordance with previous studies, the IMTs measured at 5 different arteries in SSc

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Table 3. Regional PWVs of the SSc subgroups versus the control group after adjustment for age, sex, body mass index, heart rate, and systolic and diastolic blood pressure* Control (n ⴝ 25)

lcSSc (n ⴝ 17)

dcSSc (n ⴝ 8)

9.0 (7.0–10.9) 6.5 (5.7–7.2) 7.0 (6.4–7.6) 5.1 (4.7–5.6) 12.1 (10.6–13.6)

8.9 (6.6–11.3) 6.5 (5.5–7.4) 7.1 (6.4–7.8) 5.4 (4.9–5.9) 11.8 (10.1–13.6)

16.5 (13.0–19.9)† 7.3 (5.9–8.7) 9.1 (8.0–10.2)† 6.2 (5.4–6.9)‡ 9.2 (6.6–11.8)

Forearm PWV, meters/second Upper arm PWV, meters/second Arm PWV, meters/second Aortic PWV, meters/second Leg PWV, meters/second

* Values are the mean (95% confidence interval). PWV ⫽ pulse wave velocity; SSc ⫽ systemic sclerosis; lcSSc ⫽ limited cutaneous SSc; dcSSc ⫽ diffuse cutaneous SSc; forearm ⫽ brachial–radial; upper arm ⫽ carotid– brachial; arm ⫽ carotid–radial; aortic ⫽ carotid–femoral; leg ⫽ femoral–ankle. † P ⬍ 0.01 versus the control group. ‡ P ⬍ 0.05 versus the control group.

patients showed no differences from the controls in the present study (Table 2). The mean value of the common carotid IMT here was somewhat lower than those reported previously, probably due to the ethnic or other differences in the studied populations. This finding confirmed that SSc is not associated with an increased prevalence of early signs of atherosclerosis. Four different local arterial stiffness indices (␤, Peterson’s pressure modulus, arterial compliance, and PWV␤) were selected for analyses in the study to avoid bias toward any of the parameters. Curiously, only the local arterial stiffness indices of the RBA in SSc patients showed differences compared with controls, which appeared to indicate a decrease in brachial arterial stiffness of SSc patients. However, as we know, the stiffness of most arteries in SSc patients has been demonstrated to be increased in many reports, without any arteries in these patients reported to have decreased stiffness. The elastic properties of the carotid artery were reported to be de-

creased in SSc patients, whereas those of the femoral artery did not change (18). Andersen et al (21) found that radial artery wall stiffness was significantly greater in SSc patients than in controls. The stiffness of the brachial artery was seldom studied before, whereas its endothelial function was evaluated by a number of researchers but still with conflicting reports. Most of the reports indicated that the flow-mediated dilation (FMD%) was impaired while the nitroglycerin-mediated dilation was often preserved (22–24), but there were still at least two reports showing that the FMD% was also preserved in SSc (19,21). The whole large-vessel stiffness in patients with SSc was also proven to be worsened by increasing in the augmentation index and PWV of the aorta (25). So the decreasing in local arterial stiffness indices of the RBA observed here could not be explained except for taking the effects of current medications of SSc patients into consideration. At the time of this study, vasoactive drugs that could potentially influence arterial stiffness included aspirin (26), dipyridam-

Table 4. Age-correlated coefficients (n ⴝ 25) and intraobserver intersession variabilities (n ⴝ 15) of arterial stiffness parameters in the control group* Peterson’s pressure modulus, kPa



Arterial compliance, mm2/kPa

PWV␤, meters/second

Vessel

r

V, %

r

V, %

r

V, %

r

V, %

RCCA RBA RRA RSFA RPTA Forearm PWV Upper arm PWV Arm PWV Aortic PWV Leg PWV

0.429† ⫺0.137 ⫺0.061 ⫺0.074 0.026

15.4 23.6 19.8 13.7 22.3

0.525‡ 0.045 0.248 0.094 0.194

16.6 23.5 19.9 13.4 22.4

⫺0.182 0.086 0.086 0.032 0.125

8.9 21.6 23.3 8.4 32.3

0.504† 0.025 0.204 0.096 0.150

7.3 11.1 10.0 6.4 11.1

Regional PWVs, meters/second r

V, %

0.213 0.184 0.272 0.733§ ⫺0.271

9.3 7.0 3.4 3.2 5.9

* ␤ ⫽ stiffness index; PWV␤ ⫽ local pulse wave velocity derived from ␤; PWV ⫽ pulse wave velocity; r ⫽ correlation coefficient to age; V ⫽ intraobserver intersession variability; RCCA ⫽ right common carotid artery; RBA ⫽ right brachial artery; RRA ⫽ right radial artery; RSFA ⫽ right superficial femoral artery; RPTA ⫽ right posterior tibial artery; forearm ⫽ brachial–radial; upper arm ⫽ carotid– brachial; arm ⫽ carotid–radial; aortic ⫽ carotid–femoral; leg ⫽ femoral–ankle. † P ⬍ 0.05. ‡ P ⬍ 0.01. § P ⬍ 0.001.

Macrovasculopathy in SSc Detected by Regional PWVs ole, beta-blockers, ACE inhibitors or angiotensin II receptor blockers, calcium-channel blockers, as well as traditional Chinese medicine (STS and scutellarin). Pharmacologic studies indicate that the effects of long-term treatment with ACE inhibitors, calcium-channel antagonists, and some beta-blockers on arterial stiffness are generally similar (27), and they can all improve the arterial stiffening (28,29). The STS (30) and scutellarin (31) have also been demonstrated to have vasorelaxant effects. These vasoactive drugs have little direct effect on large central elastic arteries, but can markedly change the PWV from the periphery to the heart by altering the stiffness of the peripheral medium-sized muscular arteries, which is modulated by the vasomotor tone, either depending on the endothelial function or sympathetic nervous system (32) or the renin–angiotensin system (33). Because most of the prescribed drugs for SSc patients had vasodilatory effects, it was also explicable that the local arterial stiffness indices of the other 4 arteries (RCCA, RRA, RSFA, and RPTA) in SSc patients showed no statistical differences as compared to controls, although with a tendency to increase arterial stiffness in these arteries. The results also implied that the brachial artery might be less damaged by SSc or that its local arterial stiffness indices are affected more by pharmacologic treatments than by the other arteries (34). On the other hand, it must be admitted that random variation in the measurements of small muscular arteries was rather large (Table 4). Moreover, histologic work has described the structural differences between elastic and muscular arteries (35), and the noninvasive work further confirmed that the elastic moduli of the brachial and radial arteries are different from that of the common carotid artery (36). Therefore, the local arterial stiffness indices are not appropriate for evaluating the stiffness of a relatively small muscular artery, such as the radial or tibial artery, when considering the accuracy and reproducibility. Therefore, we took the regional PWVs for further analyses on segmental arterial stiffness. In our study, the forearm PWV increased apparently in the SSc group, and furthermore, the aortic PWV was also shown to be increased in the dcSSc subgroup as compared with the control group. The difference between the results of local and regional stiffness parameters may be due to the different influence of vasoactive therapy, which is going to be our next study. The normal values of regional PWVs in the study appeared to be lower than those in the previous reports (37), probably due to the age, ethnic, or other differences in the studied populations and different methods used to measure the regional PWVs. In order to evaluate the validity of the abovementioned arterial stiffness parameters in reflecting the arterial stiffness per se, these parameters were made correlative analyses with age in the control group, because age is identified as a significant independent determinant of stiffness in elastic arteries. Among these parameters, only the ␤, Peterson’s pressure modulus, PWV␤ of the RCCA, and aortic PWV showed significant positive correlations to age, while only the RCCA is the elastic artery among the investigated vessels in this study. This result conformed to the previous reports showing that the stiffness parameters of the peripheral muscular arteries are modified appreciably

585 by vasoactive stimuli, and the mechanical properties of the deeper elastic arteries provide sufficiently reliable information about changes caused by aging (38). Agerelated stiffening affects predominantly the aorta and proximal elastic arteries, and to a lesser degree the peripheral medium-sized muscular arteries (39). Among the arterial stiffness parameters that could detect the age-related changes in the stiffness of elastic arteries caused by medial calcification and loss of elasticity, the aortic PWV had the highest correlation with age in the study; moreover, only the regional PWVs other than the corresponding local arterial stiffness indices showed abnormality due to the macroangiopathy in SSc patents, which also implied that the local arterial stiffness indices may be more susceptible to vasoactive drugs than regional PWVs. Both results here confirmed that the regional PWV is a powerful independent indicator (gold standard index) of the arterial stiffening in both elastic and muscular arteries, and can be applied to detect the pathology prior to the appearance of morphologic changes of the vasculature (40). With no differences found in the caliber and IMT of each artery between the SSc and control groups (Table 2), we conclude that this regional PWV method can easily quantify the alteration of arterial wall mechanics, perhaps due to the fibrosis of the arterial media and adventitia reflected by the increased integrated backscatter values (41), which precede the morphologic and geometric changes under high-resolution B-mode ultrasound in SSc patients. Taken together, this study suggests that the stiffening initially and predominantly affects the muscular arteries of the forearm in SSc patients, and as the disease develops it will be involved in the aorta and the proximal elastic arteries, whereas the muscular arteries of the leg and upper arm are less commonly affected. The result is in line with some epidemiologic evidence and previous reports that the radial artery wall stiffness was significantly greater in SSc patients than in controls (21), and the findings of macrovasculopathy in the ulnar and radial arteries of the SSc patients were also demonstrated by angiography (42). Macrovascular occlusion proximal to the digits seemed to be more frequent in the upper extremity than in the lower extremity (43). Therefore, patients with SSc may have preferential targets for the macrovasculopathy just as their skin involvements are of heterogeneity. We speculate that the preferential stiffening in muscular arteries of the forearm may be related to the high incidence of RP in the hands, which might lead inflammatory injury to their adjacent arteries, while the stiffening in elastic arteries might be relevant to the alteration of fibrillin 1 metabolism in SSc patients (44). The underlying mechanisms and the clinical implications of this phenomenon should be studied further. To our knowledge, this is the first study to examine segmental macrovasculopathy throughout the entire arterial tree except cerebral arteries in patients with SSc, and to provide evidence of heterogeneity in their macrovascular complications. The major strength of our study is a design that allowed the concomitant measurements of both local and regional arterial stiffness parameters in a simple, objective, and time-saving way. Our study also had

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some limitations. First of all, ideally, the blood pressure used for calculating local arterial stiffness indices should be measured at the corresponding artery; however, we chose to use the external brachial artery pressure as the source because it was more accessible than other arteries, which would hinder precise measurements of the indices at these arteries, as mentioned previously. Second, the status of SSc patients (most of them were women) was heterogeneous with regard to menstrual cycle (45,46), menopause status (47), and type of ongoing medical treatment (48), all of which were shown to affect the arterial stiffness parameters. Finally, the small sample size did not permit multivariant analyses for comparing arterial stiffness parameters in SSc patients with a different status. In summary, the macrovasculopathy of SSc patients, characterized by arterial stiffening with no significant change in IMT, predominantly affects the muscular arteries of the forearm and the proximal elastic arteries, whereas the muscular arteries of the leg and upper arm are less commonly affected. Regional PWV is a sensitive and reliable noninvasive index for quantifying the extent and degree of macrovascular stiffening in SSc patients, which might be occult in local arterial stiffness indices due to the pharmacologic effects or other influential factors in the clinic setting. The regional PWV autocalculation function should be integrated into the ultrasound system for routine screening of segmental macrovasculopathy. The medication withdrawal is ethically unacceptable in clinics, which inevitably introduces potential sources of error for examining arterial stiffness. Therefore, large-scale clinical trials are needed to examine the therapeutic intervention on the arterial stiffness parameters during the management of SSc. Further studies are needed to clarify whether the macrovascular abnormalities indicated by regional PWVs are correlated with skin sclerosis or internal organ manifestations and have an impact on the prognosis and treatment strategy. The macrovascular involvement stratification in SSc patients might act as a valuable guide in assessing the efficacy of therapeutic interventions in addition to the local microcirculation and blood pressure.

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11. 12.

13. 14.

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AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Cao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Liu, Cao. Acquisition of data. Liu, Zhang, Yang, Li, Yao. Analysis and interpretation of data. Liu, Cao, Duan, Yuan, Yang.

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REFERENCES 1. Walmsley D, Goodfield MJ. Evidence for an abnormal peripherally mediated vascular response to temperature in Raynaud’s phenomenon. Br J Rheumatol 1990;29:181– 4. 2. Koenig M, Joyal F, Fritzler MJ, Roussin A, Abrahamowicz M, Boire G, et al. Autoantibodies and microvascular damage are independent predictive factors for the progression of Raynaud’s phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients, with validation of proposed

21.

22.

criteria for early systemic sclerosis. Arthritis Rheum 2008;58: 3902–12. Ho M, Veale D, Eastmond C, Nuki G, Belch J. Macrovascular disease and systemic sclerosis. Ann Rheum Dis 2000;59:39 – 43. Veale DJ, Collidge TA, Belch JJ. Increased prevalence of symptomatic macrovascular disease in systemic sclerosis. Ann Rheum Dis 1995;54:853–5. Gosse P, Taillard J, Constans J, and the ERAMS Study Investigators. Evolution of ambulatory measurement of blood pressure and parameters of arterial stiffness over a 1-year period in patients with systemic sclerosis: ERAMS study. J Hum Hypertens 2002;16:627–30. Hettema ME, Bootsma H, Kallenberg CG. Macrovascular disease and atherosclerosis in SSc. Rheumatology (Oxford) 2008; 47:578 – 83. Parker KH. An introduction to wave intensity analysis. Med Biol Eng Comput 2009;47:175– 88. Sugawara M, Niki K, Ohte N, Okada T, Harada A. Clinical usefulness of wave intensity analysis. Med Biol Eng Comput 2009;47:197–206. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581– 90. Niki K, Sugawara M, Chang D, Harada A, Okada T, Sakai R, et al. A new noninvasive measurement system for wave intensity: evaluation of carotid arterial wave intensity and reproducibility. Heart Vessels 2002;17:12–21. Harada A, Okada T, Niki K, Chang D, Sugawara M. On-line noninvasive one-point measurements of pulse wave velocity. Heart Vessels 2002;17:61– 8. Mitchell GF, Izzo JL Jr, Lacourciere Y, Ouellet JP, Neutel J, Qian C, et al. Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the Conduit Hemodynamics of Omapatrilat International Research Study. Circulation 2002;105:2955– 61. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307–10. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15: 202–5. Medsger TA Jr, Silman AJ, Steen VD, Black CM, Akesson A, Bacon PA, et al. A disease severity scale for systemic sclerosis: development and testing. J Rheumatol 1999;26: 2159 – 67. Medsger TA Jr. Assessment of damage and activity in systemic sclerosis. Curr Opin Rheumatol 2000;12:545– 8. Mourad JJ, Priollet P, Girerd X, Safar M, Lazareth I, Laurent S. The wall to lumen ratio of the radial artery in patients with Raynaud’s phenomenon. J Vasc Res 1997;34:298 –305. Cheng KS, Tiwari A, Boutin A, Denton CP, Black CM, Morris R, et al. Carotid and femoral arterial wall mechanics in scleroderma. Rheumatology (Oxford) 2003;42:1299 –305. Roustit M, Simmons GH, Baguet JP, Carpentier P, Cracowski JL. Discrepancy between simultaneous digital skin microvascular and brachial artery macrovascular post-occlusive hyperemia in systemic sclerosis. J Rheumatol 2008;35:1576 – 83. Hettema ME, Zhang D, de Leeuw K, Stienstra Y, Smit AJ, Kallenberg CG, et al. Early atherosclerosis in systemic sclerosis and its relation to disease or traditional risk factors. Arthritis Res Ther 2008;10:R49. Andersen GN, Mincheva-Nilsson L, Kazzam E, Nyberg G, Klintland N, Petersson AS, et al. Assessment of vascular function in systemic sclerosis: indications of the development of nitrate tolerance as a result of enhanced endothelial nitric oxide production. Arthritis Rheum 2002;46:1324 –32. Sfikakis PP, Papamichael C, Stamatelopoulos KS, Tousoulis D, Fragiadaki KG, Katsichti P, et al. Improvement of vascular endothelial function using the oral endothelin receptor antag-

Macrovasculopathy in SSc Detected by Regional PWVs

23.

24.

25.

26.

27. 28. 29. 30.

31. 32. 33.

34. 35. 36.

onist bosentan in patients with systemic sclerosis. Arthritis Rheum 2007;56:1985–93. Szucs G, Timar O, Szekanecz Z, Der H, Kerekes G, Szamosi S, et al. Endothelial dysfunction precedes atherosclerosis in systemic sclerosis: relevance for prevention of vascular complications. Rheumatology (Oxford) 2007;46:759 – 62. Cypiene A, Laucevicius A, Venalis A, Dadoniene J, Ryliskyte L, Petrulioniene Z, et al. The impact of systemic sclerosis on arterial wall stiffness parameters and endothelial function. Clin Rheumatol 2008;27:1517–22. Timar O, Soltesz P, Szamosi S, Der H, Szanto S, Szekanecz Z, et al. Increased arterial stiffness as the marker of vascular involvement in systemic sclerosis. J Rheumatol 2008;35: 1329 –33. Meune C, Mahe I, Mourad JJ, Cohen-Solal A, Levy B, Kevorkian JP, et al. Aspirin alters arterial function in patients with chronic heart failure treated with ACE inhibitors: a dosemediated deleterious effect. Eur J Heart Fail 2003;5:271–9. Asmar R. Effect of antihypertensive agents on arterial stiffness as evaluated by pulse wave velocity: clinical implications. Am J Cardiovasc Drugs 2001;1:387–97. London GM, Marchais SJ, Guerin AP, Pannier B. Arterial stiffness: pathophysiology and clinical impact. Clin Exp Hypertens 2004;26:689 –99. Takami T, Shigemasa M. Efficacy of various antihypertensive agents as evaluated by indices of vascular stiffness in elderly hypertensive patients. Hypertens Res 2003;26:609 –14. Liu J, Morton J, Miedzyblocki M, Lee TF, Bigam DL, Fok TF, et al. Sodium tanshinone IIA sulfonate increased intestinal hemodynamics without systemic circulatory changes in healthy newborn piglets. Am J Physiol Heart Circ Physiol 2009;297:H1217–24. Pan Z, Feng T, Shan L, Cai B, Chu W, Niu H, et al. Scutellarininduced endothelium-independent relaxation in rat aorta. Phytother Res 2008;22:1428 –33. Boutouyrie P, Lacolley P, Girerd X, Beck L, Safar M, Laurent S. Sympathetic activation decreases medium-sized arterial compliance in humans. Am J Physiol 1994;267:H1368 –76. Giannattasio C, Failla M, Stella ML, Mangoni AA, Turrini D, Carugo S, et al. Angiotensin-converting enzyme inhibition and radial artery compliance in patients with congestive heart failure. Hypertension 1995;26:491– 6. Van Bortel LM, Kool MJ, Boudier HA, Struijker Boudier HA. Effects of antihypertensive agents on local arterial distensibility and compliance. Hypertension 1995;26:531– 4. Fischer GM, Llaurado JG. Collagen and elastin content in canine arteries selected from functionally different vascular beds. Circ Res 1966;19:394 –9. Shau YW, Wang CL, Shieh JY, Hsu TC. Noninvasive assess-

587

37. 38.

39.

40.

41.

42. 43. 44.

45.

46.

47. 48.

ment of the viscoelasticity of peripheral arteries. Ultrasound Med Biol 1999;25:1377– 88. O’Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE. Clinical applications of arterial stiffness: definitions and reference values. Am J Hypertens 2002;15:426 – 44. Kawasaki T, Sasayama S, Yagi S, Asakawa T, Hirai T. Noninvasive assessment of the age related changes in stiffness of major branches of the human arteries. Cardiovasc Res 1987; 21:678 – 87. Benetos A, Laurent S, Hoeks AP, Boutouyrie PH, Safar ME. Arterial alterations with aging and high blood pressure: a noninvasive study of carotid and femoral arteries. Arterioscler Thromb 1993;13:90 –7. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006;27:2588 – 605. Kawasaki M, Ito Y, Yokoyama H, Arai M, Takemura G, Hara A, et al. Assessment of arterial medial characteristics in human carotid arteries using integrated backscatter ultrasound and its histological implications. Atherosclerosis 2005;180: 145–54. Dick EA, Aviv R, Francis I, Hamilton G, Baker D, Black C, et al. Catheter angiography and angioplasty in patients with scleroderma. Br J Radiol 2001;74:1091– 6. Hasegawa M, Nagai Y, Tamura A, Ishikawa O. Arteriographic evaluation of vascular changes of the extremities in patients with systemic sclerosis. Br J Dermatol 2006;155:1159 – 64. Wallis DD, Tan FK, Kielty CM, Kimball MD, Arnett FC, Milewicz DM. Abnormalities in fibrillin 1– containing microfibrils in dermal fibroblast cultures from patients with systemic sclerosis (scleroderma). Arthritis Rheum 2001;44:1855– 64. Hayashi K, Miyachi M, Seno N, Takahashi K, Yamazaki K, Sugawara J, et al. Variations in carotid arterial compliance during the menstrual cycle in young women. Exp Physiol 2006;91:465–72. Giannattasio C, Failla M, Grappiolo A, Stella ML, Del Bo A, Colombo M, et al. Fluctuations of radial artery distensibility throughout the menstrual cycle. Arterioscler Thromb Vasc Biol 1999;19:1925–9. Tanaka H, DeSouza CA, Seals DR. Absence of age-related increase in central arterial stiffness in physically active women. Arterioscler Thromb Vasc Biol 1998;18:127–32. Asmar RG, London GM, O’Rourke ME, Safar ME, for the REASON Project Coordinators and Investigators. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension 2001;38:922– 6.