Aortic stiffness in systemic sclerosis is increased independently of the extent of skin involvement
I. Moyssakis,
E. Gialafos,
V. Vassiliou,
E. Taktikou1,
C. Katsiari2,
D. P. Papadopoulos and
P. P. Sfikakis2
Cardiology Department, 1 Pneumonology Department and 2 First Department of Propaedeutic and Internal Medicine, Laikon Hospital, Athens University Medical School, Athens, Greece.
Correspondence to: I. Moyssakis, Laikon Hospital, Department of Cardiology, 17 Agiou Thomas Street, GR-15727 Goudi, Athens, Greece. E-mail: jimpapdoc{at}yahoo.com
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Abstract
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Objective. To study the stiffness of large arteries in relation to the extent of skin and lung fibrosis, aortic distensibility was examined in patients with diffuse and limited systemic sclerosis (SSc).
Methods. Consecutive patients (55 with diffuse and 51 with limited SSc) without signs and symptoms of heart failure or a previous history of arterial hypertension underwent echocardiography and lung function tests. Aortic stiffness was determined non-invasively by aortic distensibility and aortic strain measurements in all patients and in 50 healthy subjects, matched for age and gender.
Results. Aortic distensibility in patients with either diffuse (2.03 ± 0.26 x 106 cm2 dyn1) or limited SSc (2.12 ± 0.33) was similarly decreased compared with controls (2.49 ± 0.36, P<0.001). Moreover, aortic strain was significantly reduced in both patient groups compared with controls, confirming that aortic stiffness is increased in SSc independently of the extent of skin involvement. Left ventricular performance was similar between patients and controls, while left ventricular mass and tricuspid systolic gradient were significantly increased in both SSc groups, the latter being associated with aortic stiffness in multivariate analysis. No association with serum levels of C-reactive protein or lung function abnormalities indicative of pulmonary fibrosis were found.
Conclusions. Stiffness of the aorta is increased in patients with established SSc regardless of the extent of the inflammatory fibrotic process in the skin and lungs, suggesting that additional pathogenetic mechanisms contribute to the compromise of large arteries.
KEY WORDS: Vasculopathy, Aortic distensibility, Systemic sclerosis, Fibrosis
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Introduction
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Systemic sclerosis (SSc) is a generalized disorder of the connective tissue characterized by skin inflammation and thickening and fibrosis of 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]. In addition, alterations in the physical properties of peripheral arteries, such as increased rigidity and impaired distensibility, i.e. increased arterial stiffness, have been reported [26]. Arterial stiffness is an independent risk factor for cardiovascular risk, and it is currently thought that both functional and structural changes in the vessel wall are the main contributing factors [7].
The pathogenetic mechanisms underlying the macrovascular pathology in SSc are thought to depend on the degree of the ongoing inflammatory fibrotic process, the hallmark of the disease [1, 4]. Whether vascular compromise extends to large arteries, such as the aorta, is not well known. We studied here the distensibility of the aorta in patients with diffuse and limited SSc, and looked for associations between such possible alterations and multiple clinical and laboratory parameters, including the extent of skin involvement and/or lung fibrosis.
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Patients and methods
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Patients
Consecutive patients with SSc, according to the American Rheumatism Association criteria [8], were studied. Patients with previous myocardial infarction or stroke, valvular or congenital heart disease, congestive heart failure, atrial fibrillation, diabetes mellitus, hypertrophic cardiomyopathy, a previous history of arterial hypertension (systolic or diastolic arterial pressure >140 and >90 mmHg, respectively, present before the diagnosis of SSc) or chronic obstructive pulmonary disease, renal disease (serum creatinine >1.4 mg/dl), as well as patients unable to perform lung function tests, were excluded. There were 55 patients with diffuse SSc (49 women, aged 54 ± 12 yr) and 51 patients with the limited form of SSc (47 women, aged 52.7 ± 14.5 yr) [9]. The disease duration varied from 4.9 to 14.7 yr. At the time of the study, medications that could potentially influence our findings included calcium-channel blockers (n = 81), angiotensin-converting enzyme inhibitors (n = 89), non-steroidal anti-inflammatory agents (NSAIDS, n = 7) and small daily doses of steroids (equivalent to or less than 7.5 mg of prednisolone, n = 19). Serum levels of creatinine, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and C-reactive protein (CRP) concentrations, measured by standard methods, were available for all patients during the preceding month. Fifty healthy subjects (45 women, aged 55 ± 13 yr) served as the control group. Body mass index (BMI), menopausal status, cigarette smoking and lipid levels were recorded for patients and controls. The study protocol was ethically approved and all subjects gave informed consent.
Echocardiography
Comprehensive echocardiographic examination with pulsed, continuous and colour Doppler was performed with a Hewlett Packard Sonos 1000 ultrasound system using a 2.5 MHz transducer, and all measurements were made non-blindly, at the time echocardiography. Left-ventricular (LV) end-systolic and end-diastolic diameter and interventricular septum and posterior wall thickness at end-diastole were measured for calculation of the fractional shortening and LV mass with the Penn convention formula [10, 11]. Measurements of LV mass were divided by body surface area to obtain LV mass index. Continuous wave Doppler echocardiogram recorded in the apical four-chamber or parasternal short-axis view was used to estimate the peak systolic pressure gradient across the tricuspid valve. A tricuspid gradient (TG) greater than 30 mmHg was considered indicative of pulmonary hypertension [12, 13]. Aortic distensibility was determined non-invasively based on the relationship between changes in aortic diameter and pressure with each cardiac pulse [14, 15]. Ascending aorta was recorded at a level 3 cm above the aortic valve in the M-mode tracing guided by the two-dimensional echocardiogram in the parasternal long-axis view. Internal aortic diameters were measured by means of a calliper in systole and diastole as the distance between the trailing edge of the anterior aortic wall and the leading edge of the posterior aortic wall. Systolic aortic diameter was measured as the maximal anterior motion of the aorta and diastolic diameter at the peak of the QRS complex on the simultaneously recorded electrocardiogram. Ten consecutive cardiac beats were measured routinely and averaged. Blood pressure was measured with an external sphygmomanometer. Aortic distensibility was calculated as 2
D/Dd(Ps Pd) 106 cm2 dyn1, where
D is the change in aortic diameter between systole and diastole, Dd is the aortic diameter in diastole, Ps is the systolic arterial blood pressure and Pd the diastolic arterial blood pressure [14, 15]. Aortic strain, expressed as a percentage change, was calculated as
D/Dd [15]. The intraobserver and interobserver mean percentage error (absolute difference between two observation divided by the mean) was determined for the aortic dimensions in 30 randomly selected subjects, and were 4.2 and 4.6% for the systolic and 4.1 and 4.4% for the diastolic dimensions, respectively.
Pulmonary evaluation
All patients underwent physical examination, chest radiography and pulmonary function tests, including spirometric assessment of forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO). Patients were classified as having normal lung function tests, a restrictive or obstructive pattern, or an isolated DLCO reduction, as described [16].
Statistical analysis
Continuous variables between subjected groups were compared using one-way analysis of variance followed by post hoc analysis with the Scheffe test, while the differences between percentages of subjects with pulmonary hypertension were assessed with the
2 test. Univariate and multivariate linear regression models were built to evaluate whether the aortic distensibility and strain were associated with patients and all subjects clinical and laboratory characteristics. Values are expressed as mean ± S.D. A P value less than 0.05 was considered significant.
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Results
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Demographic characteristics, heart rate and arterial pressure measurements are summarized in Table 1. There were no significant differences between patients with diffuse and limited SSc in terms of disease duration and current or previous treatment with steroids, NSAIDS, calcium-channel blockers and angiotensin-converting enzyme inhibitors. Also, there were no significant differences between patients and controls regarding obesity, menopausal status, cigarette smoking and lipid levels. Abnormalities in lung function tests were present in 58 patients (55%); a restrictive pattern was seen in 42 patients, 34 of whom had diffuse SSc, while an isolated reduction of DLCO was present in 11 patients (eight with diffuse disease). Of those patients with a restrictive ventilatory defect, 35 had also clinico-radiological evidence of pulmonary fibrosis.
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TABLE 1. Demographic and clinical characteristics and echocardiographic measurements in patients with diffuse or limited SSc and healthy controls
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Since patients with clinical evidence of cardiac involvement had been excluded, the fractional shortening was not different between the patient groups and controls. Echocardiographic evidence of pulmonary hypertension was found in 20% of patients with diffuse and in 17.6% of patients with limited SSc, while a greater LV mass index was observed in SSc, irrespective of the disease form (Table 1). Significantly decreased aortic distensibility was found not only in patients with diffuse SSc, but also in those with limited disease, compared with healthy subjects. Notably, no significant difference between the two SSc subsets was revealed. Moreover, aortic strain was similarly reduced in both groups of patients compared with controls, confirming that aortic stiffness is increased in SSc, regardless of the extent of skin involvement (Table 1).
Subsequently, data from all 106 SSc patients collectively and from the total of patients and controls (n = 156) were studied by univariate and multivariate linear regression analysis to search for possible associations between aortic distensibility/strain and arterial systolic, diastolic and pulse pressure, fractional shortening, TG, BMI, LV mass index, DLCO, FVC, disease duration, serum levels of CRP, creatinine, LDL and HDL cholesterol. Univariate linear regression analysis in the control group showed significant relationships between aortic distensibility and strain with systolic, diastolic and pulse pressure (P = 0.002, P = 0.04, P = 0.01 and P = 0.01, P = 0.05, P = 0.02, respectively). Different results were revealed when this analysis was performed in the SSc patients; both aortic distensibility and strain were associated with TG and LV mass index (P = 0.023, P = 0.008 and P = 0.032, P = 0.001, respectively). In the same analysis of the total study population, aortic distensibility and strain were associated with systolic, diastolic and pulse pressure, as well as with the presence of SSc (P = 0.006, P = 0.05, P = 0.05, P = 0.001 and P = 0.03, P = 0.05, P = 0.05, P = 0.005, respectively).
Furthermore, multivariate linear regression analysis performed in the control group showed that aortic distensibility and strain were associated only with systolic blood pressure (P = 0.01 and P = 0.03, respectively). As shown in Table 2, of all parameters analysed in the SSc group, only TG was significantly associated with both aortic distensibility and strain. The same analysis in the total study population demonstrated that the only parameter associated with aortic distensibility and strain measurements was the presence of SSc.
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TABLE 2. Multivariate linear regression analysis of aortic distensibility and aortic strain with clinical and laboratory characteristics in patients with SSc (n = 106, model 1) and in the total study population (n = 156, model 2)
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Discussion
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Increased stiffness of the peripheral arteries is a prominent feature of SSc, and it may predict the overall disease severity [26]. Using a non-invasive, reproducible method, we found impaired distensibility and strain of the aorta in two large groups of selected patients with diffuse and limited SSc of more than 4 yr duration, compared with healthy controls. Although aortic diameters were not measured invasively, previous studies have shown that aortic diameters can be obtained with a high degree of accuracy, correlating to those obtained invasively, in subjects whose cardiothoracic anatomy permits an echocardiographic signal of satisfactory quality [14], which was always the case in our subjects. The pulse pressure obtained with an external sphygmomanometer may introduce an error factor, but the final effect on the validity of the aortic distensibility calculation is very low [14]. Pulse pressure wave velocity has also been used to estimate the elastic arterial properties [17]. These measurements, however, do not provide a direct measurement of the elastic properties of the aortic wall at different levels, but rather an overall estimation of the impedance of the arterial tree [14].
In order to minimize the influence of other factors which could affect aortic distensibility, patients with overt cardiac disease, stroke and diabetes mellitus were not studied. It is well recognized that arterial hypertension and the associated accelerated atherosclerosis significantly affects the aortic distensibility; thus, patients with a history of arterial hypertension prior to the diagnosis of SSc were not studied. Moreover, no differences regarding other atherosclerosis risk factors were present between patients and controls, while no association was found between increased aortic stiffness and diastolic or systolic arterial pressures within the patient group. The inevitable fact that most of the SSc patients were on vasodilating therapy with calcium-channel blockers, and were therefore likely to have had higher blood pressures than those that were found, represents a minor limitation. However, despite the fact that calcium-channel blockers are known to increase aortic distensibility [15], both aortic distensibility and strain were found to be impaired, confirming that aortic stiffness is increased in SSc. This finding was confirmed in the multivariate linear regression analysis in the total study population, which demonstrated that the presence of SSc was the only significant and independent predictor of the impaired elastic properties of the aorta.
An increased LV mass index was found in both SSc subgroups, in accordance with previous reports [18]. Such an increase could be associated with arterial stiffness, as recently shown in haemodialysis patients [19]; however, multivariate analysis failed to reveal a significant relationship in our patients. Impaired vasa vasorum flow, which has been shown to contribute to the nutrition of the outer layers of the thoracic aorta [20], may cause deterioration of the elastic properties of the aorta in SSc. Moreover, increased plasma levels of endothelin-1, the most potent endothelium-derived vasoconstrictor, have been reported in patients with SSc, and may also have contributed to the increased aortic stiffness in our patients [21, 22].
Aortic stiffness was not different between patients with the diffuse and limited forms of SSc by the time the disease was established, i.e. after the initial inflammatory phase. This finding is surprising, since internal organ fibrosis tends to occur predominantly in diffuse SSc [8, 9]. The absence of any relationship with the clinical subtype of SSc suggests that the pathogenetic mechanisms which eventually lead to diffuse or limited skin involvement affect the aorta equally. Possible differences between the two SSc groups regarding the onset of aortic stiffness development could not be established, because patients with early SSc, i.e. of less than 4 yr duration, were not studied. Given that there were no differences regarding disease duration, aortic distensibility or aortic strain between patients with diffuse and limited disease, we then examined our patients collectively. Aortic stiffness was not associated with arterial systolic, diastolic and pulse pressure, fractional shortening, body mass index, LV mass index, disease duration or serum levels of creatinine, LDL or HDL cholesterol at any level. To our surprise, no association between aortic stiffness and the presence of pulmonary fibrosis was revealed. In contrast to recent findings associating arterial stiffness with serum CRP levels in patients with vasculitis [17], such a relationship was not found in our patients, as is also the case in patients with rheumatoid arthritis [23].
Taken together, these results suggest that the pathogenetic mechanisms underlying the compromise of large arteries do not depend on the ongoing inflammatory fibrotic process in patients with established SSc. Early detection of aortic stiffness may provide an opportunity for targeting mediators of vascular injury [21] to modify the course of the disease as a whole. Future studies should examine the impact of such vascular therapeutic approaches in SSc.
The authors have declared no conflicts of interest.
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References
|
---|
- Rodnan GP, Myerowitz RL, Justh GO. Morphologic changes in the digital arteries of patients with progressive systemic sclerosis (scleroderma) and Raynaud phenomenon. Medicine (Baltimore) 1980;59:393408.[ISI][Medline]
- Constans J, Gosse P, Pellegrin JL et al. Alteration of arterial distensibility in systemic sclerosis. J Intern Med 1997;241:1158.[ISI][Medline]
- Veale DJ, Collidge TA, Belch JJ. Increased prevalence of symptomatic macrovascular disease in systemic sclerosis. Ann Rheum Dis 1995;54:8535.[Abstract]
- Andersen GN, Nilson LM, Kazzam E et al. Assessment of vascular function in systemic sclerosis. Arthritis Rheum 2002;46:132432.[CrossRef][ISI][Medline]
- Spieker C, Barenbrok M, Zidek W. Stiffness of systemic arteries in patients with progressive systemic sclerosis. Hypertension 1995;25:196.
- Gosse P, Taillard J, Constans J on behalf of 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;16:62730.[CrossRef][ISI][Medline]
- Arnett DK, Evans GW, Riley WA. Arterial stiffness: a new cardiovascular risk factor? Am J Epidemiol 1994;140:66982.[ISI][Medline]
- 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;23:58190.[ISI][Medline]
- Leroy EC, Black C, Fleischmajer R et al. Scleroderma (systemic sclerosis) classification, subsets and pathogenesis [editorial]. J Rheumatol 1988;15:2025.[ISI][Medline]
- Tajik AJ, Seward JB, Hagler DJ, Mair DD, Lie JT. Two-dimensional real time ultrasonic imaging of the heart and great vessels: technique, image orientation, structure identification and validation. Mayo Clin Proc 1978;53:271303.[ISI][Medline]
- Devereux RB, Alonso DR, Lutas EM et al. Echocardiographic assessment of the left ventricular hypertrophy. Comparison to necropsy findings. Am J Cardiol 1986;57:4508.[CrossRef][ISI][Medline]
- Aessopos A, Farmakis D, Taktikou H, Loukopoulos D. Doppler-determined peak systolic tricuspid pressure gradient in persons with normal pulmonary function and tricuspid regurgitation. J Am Soc Echocardiogr 2000;13:6459.[CrossRef][ISI][Medline]
- Mukerjee D, St George D, Knight C et al. Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis. Rheumatology 2004;43:4616.[Abstract/Free Full Text]
- Stefanadis C, Stratos C, Boudoulas H, Kourouklis C, Toutouzas P. Distensibility of the ascending aorta: comparison of invasive and non-invasive techniques in healthy men and in men with arterial disease. Eur Heart J 1990;11:9906.[Abstract]
- Stratos C, Stefanadis C, Kallikazaros I, Boudoulas H, Toutouzas P. Ascending aorta distensibility abnormalities in hypertensive patients and response to nifedipine administration. Am J Med 1992;93:50512.[ISI][Medline]
- Sfikakis PP, Kyriakidis M, Vergos C et al. Diffusing capacity of the lung and nifedipine in systemic sclerosis. Arthritis Rheum 1990;33:16349.[ISI][Medline]
- Booth AD, Wallace S, McEniery CM et al. Inflammation and arterial stiffness in systemic vasculitis. Arthritis Rheum 2004;50:5818.[CrossRef][ISI][Medline]
- Toumanidis S, Papamichael C, Antoniades G et al. Cardiac involvement in collagen diseases. Eur Heart J 1995;16:25762.[Abstract]
- Nitta K, Akiba T, Uchida K et al. Left ventricular hypertrophy is associated with arterial stiffness and vascular calcification in hemodialysis patients. Hypertens Res 2004;27:4752.[CrossRef][ISI][Medline]
- Stefanadis C, Vlachopoulos C, Karayannakos P et al. Effect of vasa vasorum flow on structure and function of the aorta in experimental animals. Circulation 1995;91:266978.[Abstract/Free Full Text]
- Schachna L, Wigley FM. Targeting mediators of vascular injury in scleroderma. Curr Opin Rheumatol 2002;14:68693.[CrossRef][ISI][Medline]
- Kahalah MB. Endothelin and endothelial-dependent vasoconstrictor in scleroderma. Arthritis Rheum 1991;34:97883.[ISI][Medline]
- Klocke R, Cockroft JR, Taylor GJ, Hall IR, Blake DR. Arterial stiffness and central blood pressure, as determined by pulse wave analysis, in rheumatoid arthritis. Ann Rheum Dis 2003;62:4148.[Abstract/Free Full Text]
Submitted 11 April 2004;
revised version accepted 12 October 2004.