Differentiation of Primary and Secondary Raynaud's Disease by Carotid Arterial Stiffness

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1 Eur J Vasc Endovasc Surg 25, 336±341 (2003) doi: /ejvs , available online at on Differentiation of Primary and Secondary Disease by Carotid Arterial Stiffness K.-S. Cheng 1, A. Tiwari 1, A. Boutin 1, C. P. Denton 2, C. M. Black 2, R. Morris 3, A. M. Seifalian 1 and G. Hamilton 1 1 Cardiovascular Haemodynamic Unit, University Department of Surgery, 2 University Department of Rheumatology and 3 University 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, U.K. Introduction: primary disease may be difficult to differentiate clinically from the secondary form with an underlying connective tissue, haematological, neurovascular or drug-induced disorder. We undertook a study to determine the elastic carotid and muscular femoral arterial biomechanical properties and intima-media thickness (IMT) in subjects with primary and secondary disease, to assess whether these parameters could differentiate the two conditions. Methods: twenty patients with primary disease and 53 subjects with secondary associated with scleroderma (systemic sclerosis, SSc) had measurements of their carotid and femoral wall mechanics with 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, plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations were also measured. Results: the carotid elastic properties [mean (SD): elastic modulus: 560 (180) vs 1204 (558) mmhg, p and stiffness index: 5.69 (1.35) vs (6.4), p for primary and secondary respectively] were significantly impaired in patients with secondary disease even after adjustment for potentially influencing physiological and biochemical variables. There were no statistical differences in the femoral elastic properties or the carotid and femoral IMTs between the two groups. Conclusion: Duplex determination of the carotid elasticity or stiffness is different in primary phenomenon compared with secondary associated with SSc. This may be a useful non-invasive tool, in addition to autoantibody markers and nail-fold capillaroscopy, to differentiate between the two forms of phenomenon. Key Words: ; Scleroderma; Carotid artery; Compliance; Stiffness. Introduction syndrome was first described in 1862 by the French physician, Maurice Raynaud. It is characterized by spasm of the small arteries of the fingers and toes, causing the skin to turn pale and dusky blue. Estimates of its prevalence range from 5 to 30% of the population. It is five times commoner in women, particularly between the ages of 18 and 30 years. It is thought that 25±30% of cases occur in healthy women. Primary disease has no known cause. However, a multi-centre observation study has shown that 48% of primary showed one Please address all correspondence to: A. M. Seifalian, University Department of Surgery, Royal Free and University College Medical School, University College London, The Royal Free Hospital, Pond Street, London NW3 2QG, U.K. A.Seifalian@rfc.ucl.ac.uk or more clinical features, indicating a high risk of evolving into scleroderma (systemic sclerosis, SSc). 1 Secondary is associated with an underlying connective tissue, neurovascular, haematological or drug-induced disorder. The same study has shown that secondary was most frequently associated with SSc and was often the first presenting symptom of SSc, often preceding the connective tissue disorder by months to years. 1 It is sometimes difficult to distinguish primary disease from the secondary form. Nailfold capillaroscopy may be able to diagnose secondary to SSc. As SSc is a generalized connective tissue disease affecting other organs of the body apart from the skin, we may expect to see changes in the connective tissue matrix and hence, the wall mechanics of large arteries. There has been no study we could find in the literature looking at the carotid and femoral 1078±5884/03/ $35.00/0 # 2003 Elsevier Science Ltd. All rights reserved.

2 Differentiation of Primary and Secondary Disease 337 wall mechanics in primary and secondary disease. The aim of this study is to determine the elastic carotid and muscular femoral biomechanical properties and intima-media thickness (IMT) in subjects with primary and secondary disease to assess whether we could use these parameters to differentiate the two forms. Methods Elastic indices The arterial biomechanical properties are well described. 2±5 In this study, we use the diametrical compliance (C), Petersen's elastic modulus (Ep) and stiffness index (b) to assess the common carotid and femoral wall mechanics to avoid bias towards any of the parameters. Both C and Ep are dependent on blood pressure but b is claimed by some authors to be less pressure dependent. 6 Subjects A total of 73 subjects were recruited prospectively in this study, which has been approved by the local hospital Ethics Committee and conformed to the principles of the Declaration of Helsinki. Twenty had primary disease and 53 had thermographically confirmed secondary disease associated with SSc. disease was diagnosed by the classical colour changes, which occurred in the digits of the hands or/and feet. Primary was defined by the Allen and Brown's criteria of negative nail-fold capillaroscopy and normal serological study (sera screened on Hep 2 cells at 1:100). SSc was diagnosed clinically by an experienced rheumatologist and broadly followed the classification criteria of the American College of Rheumatology. Ninety-five percentage of cases carried antinuclear antibodies and in 70% these included a hallmark SSc associated reactivity. Patients were recruited consecutively from the rheumatology and general surgical clinics. No other exclusion criteria were applied. Measurements The age, gender, body mass index (BMI), heart rate, systolic and diastolic blood pressures were recorded for all subjects. In addition, the plasma creatinine, fasting cholesterol, triglyceride and glucose were measured. The presumed cardiovascular load assessed on the basis of a cumulative total vascular risk score (TVRS) was calculated for all subjects. 5,7 This was based on Lehmann's study, which showed a significant inverse relation between the aortic compliance and the number of cardiovascular risk factors. 7 We believed that this was a significant finding and has modified the TVRS to include hypercholesterolaemia, peripheral vascular disease and renal impairment. 5 These risk factors and events were as follows: (1) current cigarette smoking or ex-smoker within the last 12 months; (2) history of hypertension on medication; (3) history of hypercholesterolaemia on medication; (4) history of diabetes mellitus; (5) history of ischaemic heart disease; (6) history of stroke, transient ischaemic attack or known carotid stenosis 450%; (7) known renal impairment and (8) peripheral vascular disease. Although we have not formally assessed the modified scoring system, we believed that this is one method, which allowed equal adjustment of the cardiovascular load in our groups of subjects. The subjects were rested for 10 min in the supine position to allow resting pulse rate and blood pressure to be achieved before any form of 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, U.K.). Real-time B-mode and M-mode images of the arterial wall motion and IMT were recorded using a 7.5 MHz linear array probe 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 Track system (Wall Track, Pie Medical Systems, Maastricht, The Netherlands). 5,8±11 This system tracked the anterior and posterior walls of the vessel over a cardiac cycle. 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. It also automatically measured the far wall IMT of the vessel. The far wall was chosen because it has been shown to be more accurate than the near wall IMT. 12,13 The IMT was recognized by the double line pattern corresponding to the lumen-intima and media adventitia interfaces. 12 The distance between these two interfaces is the IMT. 12,14,15 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

3 338 K.-S. Cheng et al. visible atheroma could be visualized on the duplex scanner. Measurements were taken within 3 cm proximal to the bifurcation of the common carotid or common femoral artery. Vessel wall motion and IMT were each recorded for three times from the common carotid and common femoral arteries. 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 elastic indices were subsequently calculated from the given equations. 5 Data analysis and statistical methods The chi-squared test was used to compare the gender ratio between the two groups. The remaining physiological and biochemical variables were compared between the two groups using unpaired (independent) t-test. A general linear model was applied to estimate differences in means in the carotid and femoral elastic indices and IMT between the two groups of subjects, after adjusting for potentially influential variables, including age, BMI, heart rate, systolic and diastolic pressures, TVRS, plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations. The intra-observer variations were quantified from the three readings using the intra-class correlation coefficients (ICCs): V b ICC ˆ V b V w where V b is the between subject variance and V w is the within subject variance. The inter-observer errors in our unit has been determined from our previous study with the ICCs between 0.88 and 0.91 for carotid and femoral distensions and 0.89 for carotid and femoral IMT measurements. 5 All statistical tests were performed with SPSS version for Windows. Results The physiological and biochemical parameters between primary and secondary are shown in Table 1. Patients with secondary were significantly older and had significantly higher heart rate and systolic blood pressure than those with primary. Both primary and secondary were commoner in female subjects. Patients with secondary disease caused by SSc have significantly impaired carotid elastic Table 1. Physiological and biochemical parameters between primary and secondary. Primary Secondary Number M:F 4:16 10:43 Age (years) (15.58) (11.35) <0.001 BMI (kg/m 2 ) (3.35) (3.71) 0.85 Heart rate (6.60) (7.83) 0.04 (beats/min) Systolic BP (15.60) (17.7) <0.001 Diastolic BP (12.86) 76.7 (11.38) 0.64 TVRS (number) 0.35 (0.75) 0.57 (0.8) 0.3 Creatinine (10.86) (59.27) 0.11 Cholesterol 4.77 (1.26) 5.01 (1.02) 0.55 Triglyceride 1.89 (1.02) 1.78 (0.79) 0.73 Glucose 5.02 (2.62) 4.87 (1.83) 0.81 Data are mean (SD). M denotes male and F denotes female. BMI is the body mass index. TVRS is the total vascular risk score. Table 2. The elastic indices and IMT of primary and secondary subjects. Carotid C (% mmhg 10 2 ) Carotid Ep Carotid b (dimensionless) Femoral C (% mmhg 10 2 ) Femoral Ep Femoral b (dimensionless) Carotid IMT (mm) Femoral IMT (mm) Primary Secondary (5.71) 9.50 (3.01) < (180.56) (558.23) < (1.35) (6.4) < (4.29) 5.55 (3.93) (993.82) ( ) (9.85) (13.21) (0.19) 0.65 (0.24) (0.19) 0.74 (0.31) 0.2 Data in mean (SD). C denotes diametrical compliance, Ep the Petersen's elastic modulus and b is the stiffness index. properties [mean (SD): C: 9.5 (3.01) vs (5.71) % mmhg , p ; Ep: 1204 (558) vs 560 (180) mmhg; b: (6.4) vs 5.69 (1.35) for secondary and primary respectively] (Table 2). This highly significant finding exists even after adjustment for potentially influencing physiological and biochemical variables (Table 3). There are no statistical differences in terms of the femoral elastic indices, the carotid and the femoral IMTs between the two groups (Table 3).

4 Differentiation of Primary and Secondary Disease 339 Table 3. Unadjusted and adjusted (for age, heart rate and systolic blood pressure) for the differences in mean and 95% confidence intervals between the primary and secondary groups. Variable Unadjusted difference (95% CI) (n ˆ 73) Adjusted difference (95% CI) (n ˆ 42) Carotid C (%mmhg 10 2 ) (7.99 to 12.09) < (4.85 to 9.26) <0.001 Carotid Ep ( to 389.9) < ( to 37.8) Carotid b (dimensionless) 6.22 ( 9.11 to 3.34) < ( 7.37 to 0.49) Femoral C (%mmhg 10 2 ) 0.80 ( 1.50 to 3.10) ( 1.92 to 3.64) 0.54 Femoral Ep ( to 295.2) ( to 522.4) 0.40 Femoral b (dimensionless) 3.04 ( to 4.14) ( to 3.99) 0.28 Carotid IMT (mm) 0.02 ( 0.14 to 0.09) ( 0.11 to 0.16) 0.72 Femoral IMT (mm) 0.10 ( 0.27 to 0.06) ( 0.26 to 0.13) 0.52 The intra-observer ICCs for the carotid and femoral distension and IMT measurements varied from 0.92 to 0.96, indicating a high level of reproducibility. Discussion The theoretical accuracy of the Wall-Track system is in the region of three microns for distension and ten microns for arterial diameter. 16 The reproducibility of the duplex-wall Track system is good with errors of between 8 and 12% for the carotid compliance 17±20 and well below 20% for the IMT. 21±25 Our study has shown intra-observer errors of no more than 8%. The blood pressure should ideally be measured from the same segment of artery under investigation. However, the brachial pressure is used because it is more accessible than either the carotid or femoral artery and it has been used as the reference point in many published research. 26±31 The validity of this approach has also been verified by several groups. 32±35 The problem associated with this method of measurement of blood pressure arises in the young or healthy patients because the pulse pressure increases by around 18±31% between the aorta and the brachial artery. 36,37 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. 38,39 However, with increasing age the pulse wave velocity increases so that the augmentation phenomenon also occurs in the central arteries. 40,41 Thus the differences in the pulse pressure between central and peripheral arteries disappear in the middle-aged and elderly subjects. 38 Since our subjects were on the whole in the middle ages, we could therefore assume that the brachial pressure reflected the carotid and femoral pressures. There is the first study we know of the effects of disease on the carotid and femoral wall elastic properties and IMT. Secondary disease with underlying SSc is significantly associated with increased carotid stiffness and elasticity or reduced carotid compliance. This impaired carotid biomechanical behaviour may be the result of altered fibrillin-1 metabolism. It may be relevant that fibrillin-1 (FBN-1) metabolism has been reported to be altered in SSc fibroblasts cultured from noninvolved sites. 42 Defective fibrillin function leads to aortic abnormalities in humans with Marfan syndrome and in a haplo-insufficiency mouse model. 43,44 Abnormalities in uninvolved skin fibroblasts are consistent with a genetically based alteration in fibrillin biochemisty in SSc. Another explanation is the result of increased vascular tone secondary to repeated reperfusion injury associated with the severe form of digital vasospasm seen in secondary. The last explanation may be due to increased cardiovascular load in subjects with secondary. The carotid elastic properties are recognized as good markers of cardiovascular risk and events. 3,4 Indeed, subjects with secondary caused by SSc have higher risk of hypertensive crisis and pulmonary hypertension. The femoral artery is not similarly affected because it is a muscular rather than an elastic artery. It is interesting that fibrillin-1 regulates elastin fibre assembly and elastin is expressed most commonly in the elastic arteries. 45,46 Ultrasonic measurement of the carotid elastic properties is an invaluable clinical tool in the assessment of disease and provides further complementary information in addition to tests such as antinuclear antibodies and nail-fold capillary microscopy. 47 This method is non-invasive, accurate and reproducible. It is quick and easy to perform by a trained vascular technician with the available hardware and software and should be readily available in a vascular unit with easily accessible vascular laboratory. References 1 Grassi W, De Angelis R, Lapadula G, Leardini G, Scarpa R. Clinical diagnosis found in patients with phenomenon: a multicentre study. Rheumatol Int 1998; 18: 17±20.

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