Clinical Rheumatology

, Volume 27, Issue 12, pp 1517–1522

The impact of systemic sclerosis on arterial wall stiffness parameters and endothelial function

  • Alma Cypienė
  • Aleksandras Laucevicius
  • Algirdas Venalis
  • Jolanta Dadonienė
  • Ligita Ryliskytė
  • Zaneta Petrulionienė
  • Milda Kovaitė
  • Jonas Gintautas
Original Article

DOI: 10.1007/s10067-008-0958-1

Cite this article as:
Cypienė, A., Laucevicius, A., Venalis, A. et al. Clin Rheumatol (2008) 27: 1517. doi:10.1007/s10067-008-0958-1


Systemic sclerosis (SSc) is characterized by thickening and fibrosis of skin and internal organs that is associated with vascular damage. SSc may lead to arterial dysfunction and premature aging of the arteries. However, its relationship with parameters of arterial wall dysfunction has not been fully explored. To determine if carotid–radial pulse wave velocity (PWV), aortic augmentation index (AIx) and endothelial function are altered in SSc patients, 17 consecutive patients with SSc and 34 age- and gender-matched controls were included in our study. PWV and AIx were assessed non-invasively by applanation tonometry. The endothelium-dependent flow-mediated dilatation (FMD) test in a brachial artery was performed by the ultrasound system. The blood investigations included serum lipid profile, glucose, and high-sensitivity CRP (hsCRP) measurements. As compared to controls, SSc patients had significantly higher medians of the AIx (p = 0.002) and the PWV (p = 0.04) and the median of the FMD was significantly lower (p = 0.001). Stepwise linear regression including comorbid factors showed that SSc was a significant independent predictor of all arterial wall parameters measures. SSc patients have increased AIx and PWV and lower FMD as compared to control subjects. The relationship between SSc and measures of arterial wall parameters still remains unclear. Though replication of the results presented here is required, we conclude that SSc has a great impact on large and conduit arteries damage.


Arterial stiffness Atherosclerosis C-reactive protein Endothelial function Systemic sclerosis 


Systemic sclerosis (SSc; scleroderma) is a generalized disorder of the connective tissue characterized by thickening and fibrosis of skin and internal organs associated with vascular damage. Raynaud’s phenomenon is a prominent feature in SSc and significant structural abnormalities in terminal arteries are often present [1]. Traditionally, the vascular involvement of SSc has been considered to be mainly microvascular. There is recent evidence, however, that shows that SSc is associated with the prevalence of large vessel disease [2, 3], endothelial dysfunction [4] and increased arterial wall stiffness [5]; but the underlying mechanisms of these abnormalities remain unclear. The aim of this study was to determine if endothelial function and arterial wall stiffness parameters carotid–radial pulse wave velocity (PWV) and a surrogate marker of arterial wall dysfunction, namely—augmentation index (AIx) from applanation tonometry—were altered in SSc patients and describe the independent risk factors possibly affecting them.

Materials and methods

Study population

Seventeen consecutive patients with an established SSc diagnosis, defined according to the American Rheumatism Association criteria [6], were recruited from the Department of Rheumatology and examined in the Department of Cardiology and Angiology of Vilnius University Hospital Santariškių Klinikos, Lithuania. All seventeen patients had diffuse cutaneous SSc (dcSSc) [7]. Thirty-four age- and sex-matched healthy control subjects (aged 45.1 ± 5.4) were involved in the study when they were undergoing the preventive inspection at the Department of Cardiology and Angiology of the same hospital.

Subjects were excluded from the study in cases of cardiovascular disease, hypertension (blood pressure >140/90 mmHg), diabetes mellitus, total cholesterol >6.2 mmol/l, renal disease and current smokers. Approval was obtained from the Lithuanian Bioethics Committee, and a written informed consent was obtained from each participant.

Non-invasive assessment of arterial stiffness

Subjects were refrained from eating and drinking alcohol, coffee, or tea for at least 12 h prior to the study. The test of arterial stiffness was performed in the supine position in a quiet, temperature-controlled room (22–24°C) in the early morning hours. Pulse wave velocity (PWV) was determined by measuring the carotid-to-radial pulse wave transit time. Carotid and radial pulse waves were obtained non-invasively by applanation tonometry using high-fidelity micromanometer (Sphygmocor (v.7.01) AtCor Medical Pty. Ltd 1999–2002, Sydney, Australia). Pulse waves obtained consecutively from the radial and carotid arteries were referenced to a simultaneously recorded ECG, and transit time was computed from the time difference between the carotid and radial waveforms. The distance between the surface markings of the sternal notch and the radial artery was used to estimate the difference in path length between the carotid and radial arteries, and PWV adjusted for mean blood pressure was calculated. Aortic augmentation index (AIx adjusted for heart rate 75 bpm) was calculated from radial pulse waves of non-dominant arm [8, 9]. Validated transfer function from peripheral pulse wave analysis was used to generate a corresponding central waveform. From this, aortic AIx was calculated by using the integrated software. The systolic part of the central arterial waveform is characterized by two pressure peaks. The first peak is caused by left ventricular ejection, whereas the second peak is a result of pulse wave reflection. The difference between both pressure peaks reflects the degree to which central arterial pressure is augmented by wave reflection. AIx, a measure of systemic arterial stiffness, is calculated as the difference between the second and first systolic peaks expressed as a percentage of the pulse pressure [10]. Blood pressure was recorded in the left arm using an automatic blood pressure monitor (HEM-757; Omron Corporation, Kyoto, Japan).

Flow-mediated dilatation (FMD) measurement

The endothelium-dependent flow-mediated dilatation test in a brachial artery was performed according to the method described by Celermajer et al. and adapted according to international recommendations [11, 12] and technical equipment of our department [13]. The brachial artery diameter was measured on B-mode imaging by the ultrasound system (Logiq 7, General Electric, Solingen, Germany) with a high-resolution 12-MHz linear-array transducer.

The computerized software program for image acquisition (CVI Acquisition) and semi-automatic analysis software were used (Vascular Analysis Tools, Vascular Converter CVI and Brachial Analyzer, Medical Imaging Application, 1998–2003 LLC Iowa City, IA 52246 USA). The arterial diameter was measured between the intima/lumen interfaces of the anterior and posterior wall at the end of diastole (synchronized with the beginning of the R wave on the continuously recorded ECG). Scans were taken in the longitudinal plane 1–8 cm above the antecubital fossa. Measurements were done at rest and during reactive hyperemia. Ten to 15 resting scans were obtained and resting arterial flow velocity was measured by means of a pulsed Doppler signal at the 60° angle to the vessel, with the range gate in the centre of the artery. Increased flow was induced by the inflation of a pneumatic tourniquet to a 100-mmHg suprasystolic pressure for 5 min. A second scan was taken continuously for 3 min after cuff deflation, including a repeated flow velocity measurement within the first 15s after cuff release. During image acquisition a stereotactic probe-holding device was used.

To assess endothelium-independent vasodilatation, subjects received sublingual nitroglycerin (25 µg). Brachial artery images were acquired for the next 5 min after administration of sublingual nitroglycerin. Blood pressure, heart rate, height, and weight were measured for all patients. Blood samples were obtained in the morning after a 12-h fasting for the following tests: erythrocyte sedimentation rate, high-sensitivity C-reactive protein (hsCRP) by means of immunonephelometry (BN* Systems, Marburg, Germany), total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), serum glucose, and creatinine.

Statistical analysis

Analyses were conducted using SPSS (version 15.0 for Windows). Mann–Whitney U and chi-square tests were performed for comparing demographic and clinical characteristics between groups with a two-sided significance level of 0.05. In order to evaluate the relationship between measures of arterial stiffness and SSc while taking into account other potentially relevant variables, stepwise linear regression was employed (variables entry probability = 0.05, removal probability = 0.10). Three separate linear regressions were performed, one for each measures of arterial stiffness. The independent variables included in the model were: body mass index (BMI), mean blood pressure (MBP), HDL, LDL, TG, log (CRP), log(creatinine), and presence of SSc. Total cholesterol was excluded from analysis to avoid multicollinearity. For the model assessing FMD, diameter of blood vessel was also included in the analysis.


Demographic, clinical, and arterial wall parameters characteristics of 17 SSc patients and 34 controls are presented in Table 1. There were no statistically significant differences between groups in terms of age, body mass index, blood pressure, total cholesterol, high density lipoprotein, and creatinine; C-reactive protein and triglycerides were significantly higher in patients with SSc. Low density lipoprotein was slightly higher in control group. Mann–Whitney U and chi-square analyses showed that all measures of arterial wall parameters were significantly different in the SSc group (Fig. 1), with AIx and PWV significantly elevated and FMD significantly decreased in SSc patients. Endothelium-independent dilatation did not differ between the two groups.
Fig. 1

Differences between groups in terms of augmentation index, pulse wave velocity, and flow-mediated dilation

Table 1

Clinical characteristics and arterial wall parameters between SSc and control groups


SSc group (n = 17)

Controls (n = 34)

p value

Age (years)

48 [42; 53]

45 [43; 47]

Height (cm)

164 [162; 168]

167 [163; 171]


BMI (kg/m2)

26.5 [20.0; 28.3]

24.5 [23.0; 26.7]


Systolic blood pressure (mmHg)

122 [117; 124]

118 [112; 123]

Diastolic blood pressure (mmHg)

80 [74; 84]

76 [71; 83]


Mean blood pressure (mmHg)

94 [91; 98]

93 [85; 99]


Total cholesterol (mmol/l)

5.6 [4.1; 5.8]

5.2 [4.6; 6.0]


High density lipoprotein (mmol/l)

1.4 [1.1; 2.0]

1.6 [1.3; 1.8]


Low density lipoprotein (mmol/l)

2.7 [2.1; 3.3]

3.4 [2.6; 3.8]


Triglycerides (mmol/l)

1.3 [1.1; 2.0]

0.8 [0.7; 1.3]


C-reactive protein (mg/l)

3.1 [3.1; 5.7]

0.6 [0.3; 1.5]


Creatinine (mmol/l)

70 [65; 78]

71 [63; 79]


Disease duration (years)

6 [4; 12]


Aortic augmentation index %

29 [22; 33]

19 [13; 24]


Pulse wave velocity (m/s)

9.1 [8.5; 9.8]

8.3 [7.4; 9.4]


Flow mediated dilatation %

3.7 [2.1; 8.6]

9.2 [6.8;11.0]


Endothelium-independent dilatation %

13.3 [10.0; 16.1]

14.4 [11.1; 16.5]


Descriptives for continuous variables are presented as median [25% quantile; 75% quantile]; Mann–Whitney test’s p values are reported.

The final step in the linear regressions is presented in Table 2. The only significant predictor in the Alx and PWV models at the last step was SSc, indicating that it was a better, independent predictor than all other variables entered into the models. For the FMD model, both SSc and blood vessel diameter were significant, independent predictors, indicating that each, on its own, contributed to the variance in the outcome measure.
Table 2

Last step of stepwise linear regression for arterial wall parameters

Dependent variable

Model R2

Model adjusted R2


Independent variable

Regression Coefficient





































SSc coding: 0 absent, 1 present.

AIx Augmentation index, PWV pulse wave velocity, FMD flow mediated dilatation


This study showed that markers of arterial wall dysfunction, namely aortic AIx and carotid–radial PWV, were higher in SSc patients as opposed to control subjects. In addition, FMD was impaired in SSc patients with no history of cardiovascular disease. Our findings build on those reported by Andersen and colleagues [14], who found that radial artery wall stiffness was significantly greater in SSc patients than in controls. The demonstrated increase in artery stiffness in SSc patients is consistent with findings of macroangiopathy, as demonstrated angiographically, in the ulnar and radial arteries of SSc patients [15]. In the present study we have shown that regional carotid–radial PWV from applanation tonometry is increased in SSc patients. AIx, which we found to be increased in SSc patients, is not only marker of systemic arterial stiffness but is also related to intensity of pulse wave reflections, which in turn depends on the geometry and vasomotor tone of the arterial system [16]. Moreover, AIx could be related to endothelial function [17]. Both arterial stiffness and endothelial function may be reversible conditions [18].

In one study, endothelial-dependent and endothelial-independent vasodilation [11] was used in patients with SSc [19]; the study concluded that both endothelial-dependent (flow-mediated) and endothelial-independent (nitrate-mediated) vasodilation are significantly impaired in patients with dcSSc as compared to healthy controls. In addition, the ratio of flow-mediated to nitrate-mediated vasodilation was lower in patients, although this finding did not reach statistical significance. Lastly, the authors concluded that carotid intima plus media thickness was increased in the SSc group. In further studies, the same research group examined the acute [19] and chronic (over 28 days) [20] effects of estrogen on endothelial-dependent and on not endothelial-independent vasodilation. Taking into account all of the groups research [19, 20], the authors concluded that patients with SSc have impairment of both endothelial and smooth muscle function in the brachial artery and that these abnormalities, taken together with the increase in the carotid and intima media thickness, the findings point to both structural and functional problems in the large vessels. In our study we did not find significant differences between endothelium-independent dilatation in either investigative group, though endothelium-independent dilatation in SSc group was slightly lower as compared to the control group. Because of the small sample size assessed in the current study, further research needs to be conducted to clarify the relationships between these variables.

It has been shown that treatment with the oral endothelin receptor antagonist bosentan might improve damaged vascular endothelial function in SSc patients [21]. The results of our study were consistent with findings of previous studies [19, 20, 21, 22] that showed lower FMD SSc patients. At least one study, however, showed no differences in FMD between SSc patients and controls [14]. The discrepancy between the data provided in the previous study [14] and our study may be explained by the age of the patients: the SSc patients were about 58 years in the previous study whereas our patients were about 47 years. Age influences the cardiovascular structure and function as an individual due to the normal “aging process“[23].

Macrovascular damage may occur in 50–60% of SSc patients [22]. Further evidence for large vessel dysfunction in SSc was proposed by Constans et al. [24], who reported lower brachial arterial distensibility in 18 patients with SSc compared with 18 healthy controls using a new technique involving monitoring the timing of Korotkoff sounds over 24 h. Another recent study assessed vasodilation (endothelial-dependent and endothelial-independent) and vasoconstriction by examining digital blood flow responses (by venous occlusion plethysmography) to intraarterial methacholine, sodium nitroprusside, and clonidine in SSc patients and controls [25]. Responses to methacholine and to the α 2-adrenergic agonist clonidine were found to be impaired in patients with SSc. In that study, the impairment of endothelial-dependent vasodilation in SSc also addressed the issue of adrenergic function by examining responses to clonidine.

Vasodilation and vasoconstriction are dependent upon both an intact endothelium and neural control mechanisms. It is likely that of both these elements are dysfunctional and/or damaged due to the SSc disease process [26]. In SSc, the balance between vasodilation and vasoconstriction is disturbed in favor of reduced vasodilation (perhaps as a result of a relative deficiency of nitric oxide or of vasodilatory neuropeptides such as calcitonin-gene-related peptide) or increased vasoconstriction (perhaps as a result of increased release of endothelin-1) [26, 27]. Endothelin-1, which stimulates the proliferation and contraction of vascular smooth muscle cells, is released in greater amounts from endothelial cells in contact with serum in SSc patients [28]. The increased endothelin activity inhibits NO synthesis [29]. Alteration of smooth muscle tone may change the mechanical properties of predominantly muscular arteries, where stiffness also seems to be affected by NO-inhibition. [30]. In a recent review, Kahaleh and LeRoy [31] highlighted possible etiologies of endothelial injury. They found that platelet activation and reduced red cell deformability can also contribute to impairment of blood flow in SSc.

Another important factor in vasodilation (endothelial-dependent and endothelial-independent) is nitric oxide, whose significance was outlined in a review by Herrick [2].

The vasodilation, which is dependent upon an intact endothelium (endothelial-dependent), is compromised at an earlier stage of disease than vasodilation, which does not require a functioning endothelium (endothelial-independent). The nitric oxide, produced by the endothelium, acts directly on vascular smooth muscle to produce vasodilation. Endothelial-dependent and endothelial-independent vasodilation in patients with SSc have been studied in both the dermal microvasculature and large peripheral vessels [2].

Recent studies lend support to the hypothesis that endothelial cell and neurogenic control mechanisms are dysregulated, disturbing the delicate balance between vasodilation and vasoconstriction in favor of vasoconstriction. Although some of the results are conflicting, possibly due to the heterogeneity of the underlying disease process as well as to methodological differences between studies, the majority of evidence supports that both endothelial-dependent and endothelial-independent vasodilation become impaired in SSc, but that the more pronounced deficit is usually endothelial-dependent [2].

In SSc, there are many factors that may be related to the status of the central elastic and the muscular conduit arteries, in particular, increased levels of hsCRP. In our study, we found that hsCRP is increased in SSc patients. However, multiple regression analysis in our study did not reveal dependence of hsCRP neither on AIx nor on PWV and on FMD in the SSc patients.


Our findings suggest that enhanced asymptomatic atherosclerosis, detected at an earlier stage by identification of abnormal arterial wall properties, such as aortic augmentation index, carotid–radial pulse wave velocity and flow-mediated dilatation, are more prevalent among SSc patients than in control subjects and cannot be predicted by the measurement of traditional risk factors. Nonetheless, inclusion of additional factors shows that AIx and PWV are better explained by SSc, as disease. Our results support the hypothesis that FMD appears to be a sensitive marker for detecting of enhanced development of atherosclerosis in SSc patients, and that it depends on vessel diameter and SSc, as disease. Further studies with larger sample sizes and that are matched on important risk factors are needed in order to build upon the results presented here.


Dr. Cypienė: none; Dr. Laucevicius: none; Dr. Venalis: none; Dr. Dadonienė: none; Dr. Ryliskytė: none; Dr. Petrulionienė: none; Dr. Kovaitė: none; Dr. Santucci: none; Dr. Gintautas: none.

Copyright information

© Clinical Rheumatology 2008

Authors and Affiliations

  • Alma Cypienė
    • 1
  • Aleksandras Laucevicius
    • 2
  • Algirdas Venalis
    • 1
  • Jolanta Dadonienė
    • 1
  • Ligita Ryliskytė
    • 2
  • Zaneta Petrulionienė
    • 2
  • Milda Kovaitė
    • 2
  • Jonas Gintautas
    • 3
  1. 1.Institute of Experimental and Clinical Medicine at Vilnius UniversityVilniusLithuania
  2. 2.Department of Cardiovascular Medicine, Vilnius University; Centre of Cardiology and AngiologyVilnius University Hospital Santariskiu KlinikosVilniusLithuania
  3. 3.Department of Clinical Research, MediSys Health Network: Jamaica Hospital Medical CenterBrookdale University Hospital and Medical Center, and Flushing Hospital Medical CenterNew YorkUSA

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