Carotid and femoral arterial wall mechanics in scleroderma

K.-S. Cheng, A. Tiwari, A. Boutin, C. P. Denton1, C. M. Black1, R. Morris2, G. Hamilton and A. M. Seifalian

Cardiovascular Haemodynamic Unit, University Department of Surgery, 1Centre for Rheumatology and 2University Department of Primary Care and Population Sciences, Royal Free and University College Medical School, University College London and The Royal Free Hospital, London NW3 2QG, UK.

Correspondence to: A. M. Seifalian, University Department of Surgery, Royal Free and University College Medical School, UCL, Royal Free Hospital, Pond Street, London NW3 2QG, UK. E-mail: A.Seifalian{at}RFC.UCL.AC.UK


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. Large-vessel arterial disease is increasingly recognized as a major cause of morbidity in autoimmune rheumatic disorders. Recent evidence suggests that scleroderma (systemic sclerosis, SSc) may be linked to altered fibrillin-1 metabolism associated with a defect in chromosome 15q. If this is the case, we may expect to see changes in the arterial wall mechanics of large vessels not clinically involved in the disease process. We undertook a study to determine whether the biomechanical properties and intima–media thickness (IMT) of the elastic carotid artery and the muscular femoral artery are altered in subjects with limited (lcSSc) and diffuse (dcSSc) cutaneous SSc.

Methods. Measurements of carotid and femoral wall mechanics were made in 33 patients with lcSSc, 19 patients with dcSSc and 21 control subjects, using a duplex scanner coupled to a Wall Track system. Their age, gender, body mass index, heart rate, systolic and diastolic blood pressures, presumed cardiovascular load, and plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations were also measured.

Results. There was a progressive and significant reduction (P < 0.001) in the elastic properties of the carotid artery from the control group (compliance, 16.24 ± 4.39 %mmHg–1 x 10–2) to the lcSSc group (10.89 ± 2.43 %mmHg–1 x 10–2) to the dcSSc group (7.65 ± 2.08 %mmHg–1 x 10–2), even after adjustment for the systemic physiological and biochemical variables studied, which are known to influence the mechanics of arterial walls. There was no apparent difference between the groups in the mean elastic indices of the femoral artery and the IMT of the carotid and femoral arteries.

Conclusion. The elastic properties of the carotid artery are significantly altered in SSc, and the two major subsets of SSc may be distinguished by their carotid artery biomechanics. This suggests that connective tissue abnormality occurs at sites not previously assessed.

KEY WORDS: Pathophysiology, Haemodynamics, Scleroderma, Limited cutaneous, Diffuse cutaneous, Systemic sclerosis, Carotid, Compliance, Stiffness.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Scleroderma [systemic sclerosis (SSc)] is a systemic disorder of unknown aetiology characterized by sclerosis or hardening of the connective tissues. Early features include Raynaud's phenomenon and induration and contraction of the skin of the fingers and hands. It is classified according to the extent of skin involvement into a limited cutaneous form (lcSSc), affecting the skin of the head, neck and hands and not extending proximally beyond the elbow or knee joint, and a diffuse cutaneous subset (dcSSc) with proximal limb or truncal involvement. Approximately two-thirds of cases can be classified into the limited subset.

Vascular abnormalities of the small- and medium-sized vessels are a hallmark of almost all scleroderma patients. More than 95% have secondary Raynaud's disease. It is relevant that recent studies suggest that scleroderma may be linked to fibrillin gene defects, and hence may represent a generalized connective tissue disorder [1]. Recent studies suggest that skin biomechanics are also altered in SSc (this may occur even at sites that are not clinically involved) and that lcSSc and dcSSc show significant differences [2]. If this is the case, we may expect to see changes in the wall mechanics of large elastic arteries in scleroderma patients rather than in the more muscular femoral artery.

The aim of this study was to determine the biomechanical properties and intima–media thickness (IMT) of the elastic carotid artery and the muscular femoral artery in subjects with lcSSc and dcSSc to assess whether we could use these parameters to differentiate these conditions.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Elastic indices
The arterial elastic properties and indices are well described [35]. Petersen's elastic modulus (Ep) describes the elasticity of the vessel. It was first described in 1960 [6] and has been used in many studies. The diametrical compliance/arterial distensibility (C) describes the relative change in arterial diameter for a given change in pressure and allows comparison between vessels of different sizes. However, both these indices are highly dependent on blood pressure. Conversely, the stiffness index (ß) is claimed to be less pressure-dependent [7]. In this study, we use all three indices to assess the mechanics of the common carotid and femoral wall to avoid bias towards any of the parameters.

Subjects
A total of 73 subjects were recruited prospectively in this study, which was approved by the local hospital ethics committee and conformed to the principles of the Declaration of Helsinki. They were divided into three groups: patients with lcSSc (33), patients with dcSSc (19) and control participants (21). Patients were recruited consecutively from rheumatology and general surgical clinics. No other exclusion criteria were applied. SSc was diagnosed clinically by an experienced rheumatologist and followed the classification criteria of the American College of Rheumatology. Ninety-five per cent of cases carried antinuclear antibodies and in 70% these included hallmark SSc-associated reactivity (anti-topoisomerase-1, anticentromere, anti-RNA polymerase I/III and anti-fibrillarin antibodies) [8, 9].

The control subjects included patients with varicose veins, gallstones and lumps and bumps and excluded patients with significant cardiovascular disease. All subjects had their measurements performed in the clinics and were therefore preoperative and not influenced by surgical trauma.

Measurements
The age, gender and the body mass index (BMI) of the patients were recorded. The presumed cardiovascular load, assessed on the basis of the cumulative total vascular risk score (TVRS), was calculated for all subjects [1012]. This was based on a study by Lehmann et al. [10], which showed a significant inverse relation between aortic compliance, assessed by non-invasive duplex measurement, and the number of cardiovascular risk factors/events. We believed that this was a significant finding and an appropriate method of adjustment for all factors that may potentially influence arterial elastic properties, particularly in studies with a small sample size. We have modified the TVRS in previous published studies to include hypercholesterolaemia and renal impairment [11, 12], as these factors can also influence arterial biomechanics [1316]. These risk factors and events were as follows: (i) current cigarette-smoking or having smoked within the last 12 months; (ii) a history of hypertension on medication; (iii) a history of hypercholesterolaemia on medication; (iv) a history of diabetes mellitus; (v) a history of ischaemic heart disease; (vi) a history of stroke, transient ischaemic attack or known carotid stenosis of >50%; (vii) known renal impairment; and (viii) peripheral vascular disease. Although we have not formally assessed the modified scoring system, we believed that this is one method that allows equal adjustment of the cardiovascular load in our groups of subjects. The subjects also had measurements made of plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations, because these could affect arterial wall mechanics and the IMT.

The subjects were rested for 10 min in the supine position to allow the pulse and blood pressure to stabilize before any form of ultrasonic measurement was performed. Heart rate and blood pressure were recorded non-invasively from the right brachial artery using an automated pressure monitor (Dynamap Compact TS; Johnson & Johnson Medical, Newport, UK).

Real-time B-mode and M-mode images of the motion of the arterial wall and IMT were recorded using a 7.5 MHz linear array probe. Measurements were made in the sagittal plane at 90° to the long axis of the artery, using a specially adapted duplex scanning system (Pie 350; Pie Medical Systems, Maastricht, The Netherlands) with signal output to a high-resolution, echo-locked wall tracking system (Wall Track; Pie Medical Systems) [11, 1719]. The IMT of the far wall and the change in the arterial luminal diameter with respect to each cardiac cycle were measured at discrete points within 3 cm proximal to the bifurcation of the common carotid and common femoral arteries. The far wall was chosen as its IMT has been shown to be more accurate than the near-wall IMT [20]. The IMT was recognized by the double-line pattern corresponding to the lumen–intima and media–adventitia interfaces. The distance between these two interfaces is the IMT [21, 22]. The side of the recording was chosen such that it was the asymptomatic side or the side with the lowest degree of stenosis. The site was chosen such that no visible atheroma could be visualized on the duplex scanner. The elastic indices were subsequently calculated from the given equations. The IMTs were automatically computed by the Wall Track system.

Data analysis and statistical methods
Vessel wall motion and IMT were each recorded three times from the common carotid and common femoral arteries. Each recording was programmed to last for 2 s in order to catch at least one R wave-trigger reading and also not to distort the results by prolonged tracking of the specific part of the vessel. The average of three recordings of the vessel distension was taken as the mean diastolic and systolic luminal diameters. The average of three IMT recordings was used as the mean IMT. The intra-observer variations were quantified from the three readings using the intra-class correlation coefficients (ICCs). The inter-observer errors in our unit were determined from our previous study, with ICCs between 0.88 and 0.91 for carotid and femoral distensions and 0.89 for carotid and femoral IMT measurements [11].

The {chi}2 test was used to compare the gender ratios of the three groups. The remaining physiological and biochemical variables were compared between the three groups using ANOVA (analysis of variance). A general linear model was applied to estimate differences in means in the elastic indices and IMT of the carotid and femoral arteries between the three groups of subjects, after adjusting for potentially influential variables, including age, gender, BMI, heart rate, systolic and diastolic pressures, cardiovascular load based on the TVRS, and plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations.

All statistical tests were performed with SPSS version 10.05 for Windows (SPSS, Chicago, IL, USA).


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The physiological and biochemical characteristics of the three groups are shown in Table 1. Subjects with SSc were significantly older than the control group. As expected, the majority of patients with SSc were females.


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TABLE 1. Physiological and biochemical parameters of the subjects in the three groups

 
The carotid and femoral elastic indices and IMT of the three groups are given in Table 2 and Figs 13. As the physiological and biochemical variables we studied could influence the arterial wall mechanics, adjustments were made in the estimation of the differences in means and confidence intervals for the carotid and femoral wall mechanics (Table 3). Despite the adjustments, there was a progressive and significant (P < 0.001) impairment of the carotid elastic properties from lcSSc [difference in means compared with normal controls (95% confidence interval)]: [C = –4.29 (–6.29, –2.28); Ep = 273 (104, 441); ß = 2.21 (–0.52, 4.94) compared with normal controls] to dcSSc [C = –7.45 (–10.20, –4.69); Ep = 760 (529, 991); ß = 8.13 (4.39, 11.87) compared with normal controls].


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TABLE 2. Elastic indices and IMT in the three groups

 


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FIG. 1. Scattergram of carotid compliance in the three groups. Horizontal bars represent the means.

 


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FIG. 3. Scattergram of the carotid stiffness in the three groups. Horizontal bars represent the means.

 

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TABLE 3. Differences in means and confidence intervals (in parentheses) for the carotid and femoral viscoelastic indices and IMT for the two groups vs the normal control subjects before and after adjustment for age, gender, BMI, heart rate, systolic and diastolic blood pressure, TVRS, creatinine, cholesterol, triglyceride and glucose

 


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FIG. 2. Scattergram of the carotid elastic modulus in the three groups. Horizontal bars represent the means.

 
With regard to the femoral elastic indices and the carotid and femoral IMTs, there were no significant differences between the groups after adjustments (Table 3).

The intra-observer ICCs were very high, being between 0.92 and 0.96 for carotid and femoral distensions and 0.94 for the carotid and femoral IMTs.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
So far, only one group has published work on the relationship between scleroderma and IMT [23]. However, this involved the medium-sized muscular radial artery, where no difference was found in IMT [23]. Likewise, only one group has attempted to study arterial compliance in scleroderma subjects [24]; these authors used the timing of Korotkoff's sounds to determine the 24-h ambulatory compliance of large arteries in scleroderma patients. Although they found a significant (P = 0.003) reduction in regional arterial distensibility in subjects with scleroderma, this method, in our view, is not an accurate or direct assessment of arterial elasticity. We believe that duplex measurement is a more direct assessment of arterial elastic properties, with the advantage that specific segments of an individual artery can be analysed.

The limitations of the duplex–Wall Track system are the ability to recognize the anterior and posterior walls, the reproducibility and the problem of obtaining accurate measurement of blood pressure from the segment of artery concerned. The theoretical accuracy of the Wall Track system is in the region of 3 µm for distension and 10 µm for arterial diameter [25]. The errors associated with duplex estimation are acceptably low [2629]. Liang et al. [27] have shown a coefficient of variation of 9.2% for carotid compliance and 10% for the distensibility coefficient. In the ARIC study [28], a high degree of correlation has been shown between three different visits (reliability coefficients of 0.66 and 0.77 for the carotid elastic modulus and compliance respectively). In another study, the reproducibility of the distensibility and compliance coefficients ranged from 8 to 12% for the carotid artery in subjects with variable cardiovascular risk [29]. In general, the inter- and intra-observer errors are low for IMT estimation; usually the coefficient of variation is well below 20% [3032]. The error is not significantly correlated with the presence of cardiovascular risk factors but appears to be proportional to wall thickness, although wall thickness is small [32]. Our study showed that the intra-observer errors were no more than 8%.

Ideally, blood pressure should be measured from the segment of the artery under investigation. However, we chose to use the external brachial artery pressure as the source because it is more accessible than either the carotid or the femoral artery. This method is subject to error, as the pulse pressure increases by around 18–31% between the aorta and the brachial artery [33, 34]. This is caused by reflected waves from the periphery leading to augmentation of the peak pressure wave in the peripheral arteries close to the reflection sites [35]. However, this phenomenon occurs mainly in healthy and young subjects. With increasing age, the pulse wave velocity increases so that the augmentation phenomenon also occurs in the central arteries [36]. Thus, the differences in pulse pressure between central and peripheral arteries disappear in middle-aged and elderly subjects [35]. Several groups have also shown the validity of this approach [3740] and this has been used in much published research [41, 42].

Our findings suggest that connective tissue abnormality occurs at sites not previously assessed, by demonstrating a significant reduction in the compliance of the elastic carotid artery in scleroderma sufferers. Furthermore, the degree of elevation of carotid stiffness seems to correspond to the degree of severity of the scleroderma process. The femoral artery was not similarly affected by scleroderma in our study. This may have been due to the fact that this is a muscular artery, whereas the carotid is an elastic artery. It may be relevant that fibrillin-1 (FBN-1) metabolism has been reported to be altered in SSc fibroblasts cultured from non-involved sites [1]. FBN-1 regulates elastin fibre assembly; it is highly expressed in elastic arteries and less so at other sites of the vasculature. Defective fibrillin function leads to aortic abnormalities in humans with Marfan syndrome and in a haploinsufficiency mouse model [43, 44]. Abnormalities in uninvolved skin fibroblasts are consistent with a genetically based alteration in fibrillin biochemistry in SSc.

Another possible mechanism of the impairment in wall mechanics may be through enhanced vascular tone [45]. The control of vascular tone is determined predominantly by three factors: neuropeptides, the vascular endothelium and platelet function. It has been suggested that repeated vasospasm could lead to endothelial damage and platelet activation from reperfusion injury [45]. This lead to a provasospastic state, particularly when the vasodilatory aspect of the sensory nervous system has failed. A third possibility for the impaired carotid compliance in scleroderma sufferers and in particular the dcSSc group may be a reflection of the increased cardiovascular risk. Arterial elastic properties, as mentioned previously, are good markers of early atherosclerosis [4, 5]. Patients with dcSSc are known to be at greater risk of hypertensive crisis, although this is usually an acute event, and they are also at higher risk of pulmonary hypertension, especially in the later stage of the illness.

In conclusion, this study suggests that there are significant differences in carotid biomechanics between non-SSc subjects and SSc sufferers and also between the two subsets of SSc. There seemed to be a progressive and highly significant increase in carotid stiffness from the control to the lcSSc and to the dcSSc group. Future investigations should address the clinical associations of altered vessel stiffness in SSc in greater detail, and particularly the relevance to vascular morbidity or mortality. Such studies may provide valuable further insight into the previously reported associations between lcSSc and macrovascular arterial disease [46, 47].

Ultrasonic measurement of the viscoelastic properties of the carotid artery is an invaluable clinical tool and provides further complementary data, in addition to tests such as antinuclear antibodies, nail-fold capillary microscopy and dynamic admittance measurement of the mechanical properties of the skin.


    Acknowledgments
 
This work was supported in part by Public Health grant M142 (for purchase of the ultrasound scanner), the Stanley Thomas Johnson Foundation, Switzerland, the Arthritis Research Campaign (CPD) and Tyco, USA in part financial support of KSC's salary.

Conflicts of interest

The authors have declared no conflicts of interest.


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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 4 November 2002; Accepted 25 March 2003