Published online before print September 4, 2006, doi: 10.1161/CIRCULATIONAHA.105.601641
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(Circulation. 2006;114:1185-1192.)
© 2006 American Heart Association, Inc.
Vascular Medicine |
Rheumatoid Arthritis Is Associated With Increased Aortic Pulse-Wave Velocity, Which Is Reduced by Anti–Tumor Necrosis Factor-
Therapy
From the Clinical Pharmacology Unit (K.M.M.-P., A.D.B., S.M.L.W., Y., C.M.M., I.B.W.) and Department of Clinical Medicine (F.C.H., A.F.), University of Cambridge; Department of Radiology (P.W.P.B., S.H.), Addenbrooke’s Hospital; and Trinity College (J.B.), University of Cambridge, Cambridge, United Kingdom.
Correspondence to Dr Ian B. Wilkinson, Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Box 110, Cambridge CB2 2QQ, United Kingdom. E-mail ibw20{at}cam.ac.uk
Received November 14, 2005; revision received May 23, 2006; accepted June 8, 2006.
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Abstract |
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Background— Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, which is not explained by traditional cardiovascular risk factors but may be due in part to increased aortic stiffness, an independent predictor of cardiovascular mortality. In the present study, our aim was to establish whether aortic stiffness is increased in RA and to investigate the relationship between inflammation and aortic stiffness. In addition, we tested the hypothesis that aortic stiffness could be reduced with anti–tumor necrosis factor-
(TNF-) therapy.
Methods and Results— Aortic pulse-wave velocity (PWV), augmentation index, and blood pressure were measured in 77 patients with RA and in 142 healthy individuals. Both acute and chronic inflammatory measures and disease activity were determined. The effect of anti-TNF- therapy on PWV and endothelial function was measured in 9 RA patients at 0, 4, and 12 weeks. Median (interquartile range) aortic PWV was significantly higher in subjects with RA than in control subjects (8.35 [7.14 to 10.24] versus 7.52 [6.56 to 9.18] m/s, respectively; P=0.005). In multiple regression analyses, aortic PWV correlated independently with age, mean arterial pressure, and log-transformed C-reactive protein (R2=0.701; P<0.0001). Aortic PWV was reduced significantly by anti-TNF- therapy (8.82±2.04 versus 7.94±1.86 versus 7.68±1.56 m/s at weeks 0, 4, and 12, respectively; P<0.001); concomitantly, endothelial function improved.
Conclusions— RA is associated with increased aortic stiffness, which correlates with current but not historical measures of inflammation, suggesting that increased aortic stiffness may be reversible. Indeed, anti-TNF- therapy reduced aortic stiffness to a level comparable to that of healthy individuals. Therefore, effective control of inflammation may be of benefit in reducing cardiovascular risk in patients with RA.
Key Words: tumor necrosis factor- • inflammation • arthritis, rheumatoid arthritis
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Introduction |
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Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease. It is associated with increased mortality, mostly due to an excess of cardiovascular disease.1,2 Indeed, the average lifespan of individuals with RA is shortened by 3 to 18 years.3 Even after adjustment for traditional cardiovascular risk factors, there is a higher rate of cardiovascular events in subjects with RA than in healthy subjects,4 which suggests that additional mechanisms are responsible for the excess cardiovascular risk observed in RA.
Editorial p 1137
Clinical Perspective p 1192
Aortic stiffness, wave-reflection intensity, and endothelial function are independent predictors of cardiovascular risk in various patient groups5–9 and may also directly accelerate the atherosclerotic process.10 In previous studies, RA has been associated with endothelial dysfunction,11–14 which can be reversed with immunomodulatory therapy.13,15,16 Although increased arterial stiffness has also been reported in RA, existing studies have been small,17–21 and none has assessed aortic pulse-wave velocity (PWV), the current "gold standard" measure of arterial stiffness. It is also unclear whether arterial stiffness correlates better with markers of current inflammation,19 historical inflammation,18,20 or disease duration.21 Furthermore, none of the existing studies examined the relationship between changes in endothelial function and aortic stiffness or whether increased vessel stiffness can be reversed by antiinflammatory therapy.
We have already shown that patients with active systemic vasculitis have increased aortic PWV compared with those in remission and with healthy control subjects.22 This earlier study suggests first, that arterial stiffness may correlate with the degree of active inflammation rather than historical inflammation, and second, that vessel stiffness may be reversed with successful immunomodulatory therapy. The aim of the present study was to establish whether RA is associated with increased aortic PWV in a large cohort of patients and to investigate the relationship between inflammation and arterial stiffness, particularly whether stiffness in RA better relates to current inflammation or historical inflammation. In addition, we wished to test the hypothesis that increased aortic stiffness and endothelial dysfunction are reversible with anti–tumor necrosis factor- (TNF-) therapy.
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Methods |
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Study Population
Study 1
Sequential patients with an established diagnosis of RA (1987 American Rheumatism Association criteria),23 aged between 26 and 83 years and with at least 5 years of follow-up data, were recruited from the Rheumatology Clinics at Addenbrooke’s Hospital, Cambridge, United Kingdom, over a 12-month period. Concomitantly, age-, gender-, height-, and body mass index–matched healthy volunteers (ratio of 2 controls per RA patient) were randomly selected from a local community database and invited to take part in the study. Individuals with cardiovascular disease, untreated hypertension (blood pressure
140/90 mm Hg), diabetes mellitus, total cholesterol 6.5 mmol/L, or renal disease and current smokers were excluded, because these conditions are associated with endothelial dysfunction and arterial stiffening.24 Approval was obtained from the Local Research Ethics Committee, and written informed consent was obtained from each participant.
Study 2
All subjects eligible for etanercept therapy (British Society for Rheumatology and National Institute of Clinical Excellence guidelines) at Addenbrooke’s hospital over a 6-month period were invited to participate in the study providing they met study criteria as for study 1. A separate group of control subjects, matched for age and gender (ratio of 3 controls to 1 patient), were again recruited concomitantly from a community database.
Arterial Stiffness and Wave-Reflection Measurements
All studies were conducted in a quiet, temperature-controlled room. After 15 minutes of supine rest, peripheral blood pressure was recorded in the brachial artery (OMRON-705CP; Omron Corp, Kyoto, Japan).25 Radial artery waveforms were obtained with a high-fidelity micromanometer (SPC-301; Millar Instruments, Houston, Tex) from the wrist, and a corresponding central waveform was generated with a validated transfer function (Sphygmocor; AtCor Medical, Sydney, Australia)26,27 as previously described in detail.28 Augmentation index (AIx), a composite measure of systemic arterial stiffness and wave-reflection amplitude or intensity, and heart rate were determined with the integrated software. Aortic (carotid to femoral) and brachial (carotid to radial) PWV were measured as described previously.28 All measurements were made in duplicate and mean values used in the subsequent analysis.
Endothelial Function Measurements
Endothelial function was assessed in the brachial artery of the nondominant arm with the technique of flow-mediated dilatation (FMD).29 Vessel diameter was measured with high-resolution vascular ultrasound (Acuson 128XP/10; Siemens AG, Germany) with a 10.0-MHz linear-array transducer, continuously for 1 minute at baseline and for a further 5 minutes after release of a cuff inflated to 200 mm Hg, placed distal to the ultrasound probe. After return to baseline, vessel diameter was again measured continuously for 5 minutes after administration of 25 µg of sublingual nitroglycerin (NTG). FMD was defined as the maximum percentage increase in vessel diameter during reactive hyperemia; NTG-mediated dilatation was defined as the maximum percentage increase in vessel diameter after sublingual NTG.
Laboratory Measurements
Fasting lipid profile, blood glucose, and C-reactive protein (CRP) were determined in patients and control subjects by standard methodology. In the RA group, erythrocyte sedimentation rate (ESR) and rheumatoid factor were also measured. Historical inflammation was measured by calculating cumulative ESR over 5 years (2 readings per year, 6 months apart) by the area under the curve method.30
DAS28 Score and van der Heijde–Modified Sharp Method
For subjects with RA, the validated composite disease activity score (DAS28) was calculated. This utilizes the ESR, visual analogue score (VAS) of well being, and the number of tender and swollen joints, from a total of 28 joints assessed, in the following equation.31,32 equation
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The van der Heijde modification of the Sharp method of scoring hand radiographs in RA was used to score the radiological changes (erosions and joint space narrowing); this provided a further marker of chronic inflammation.33 Two radiologists scored the films independently, having conferred previously on a training set of films taken from patients not in the study. The correlation coefficient between the scores from the 2 observers was 0.99. Total scores of the 2 observers were averaged and used in subsequent data analysis.
Experimental Protocols
Study 1
Blood pressure (peripheral and central), aortic AIx, PWV (aortic and brachial), fasting lipids, blood glucose, and CRP were measured in both patients and control subjects. In the RA cohort, the DAS28, ESR, and rheumatoid factor were recorded, and the van der Heijde–modified Sharp score and cumulative ESR were calculated as measures of chronic disease activity. As previously reported,34 RA patients were divided into 2 subgroups according to their current inflammatory status (high or low) with a threshold CRP level of 10 mg/L, which divided patients into 2 equally sized subgroups.
Study 2
Study 2 was an open-label study. Blood pressure (peripheral and central), aortic AIx, PWV (aortic and brachial), FMD, fasting lipids, blood glucose, CRP, and DAS28 were measured at baseline and again at 4 and 12 weeks after twice-weekly subcutaneous administration of 25 mg of etanercept, a soluble decoy TNF- receptor.
Statistical Analysis
Data were analyzed with SPSS software (version 12; SPSS Inc, Chicago, Ill). In study 1, unpaired 2-tailed Student t tests were used to compare group differences, except when the distributions were not similar across the groups (CRP, ESR, and PWV), in which case a Mann-Whitney test of medians was performed. In the subsequent analysis, logarithmic transformations were used for the skewed variables. Multiple regression analysis (stepwise method with forward selection procedure) was performed for the RA patients to determine the independent predictors of PWV. Factors for the stepwise model were considered either because they were established or putative determinants of stiffness or were based on an initial regression analysis with an "enter" model, whereby factors were included if they achieved a significance value of <0.4. In study 2, Greenhouse-Geisser–corrected probability values were used if Mauchly’s test revealed a violation of sphericity. The 1-way repeated-measures ANOVA was used to investigate the effect of etanercept, where the element of time was given as discrete time points. Within-subject contrasts were tested for significance with custom hypothesis tests (simple). Unpaired 2-tailed Student t tests were used to compare differences between cases and controls. Values are represented as mean±SD or medians (interquartile range). A probability of <0.05 was considered significant.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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Study 1
A total of 77 patients with RA and 142 matched control subjects were studied. The mean age of the RA group was 57±13 years, and mean disease duration was 13±10 years. The demographic variables and biochemical and hemodynamic characteristics of patients and control subjects are shown in Table 1. There were no significant differences in mean arterial pressure (MAP), heart rate, lipid profile, or blood glucose levels between the groups. Median CRP was significantly higher in the RA group than in control subjects (6.00 [3.00 to 16.00] versus 1.67 [0.86 to 3.45] mg/L; P<0.001). Current therapy for the RA patients included anti-TNF-
therapy (n=13), methotrexate (n=45), other disease-modifying drugs (n=28), nonsteroidal antiinflammatory drugs (n=57), and prednisolone (n=30, mean dose 7.0±2.9 mg). Most patients were taking 2 or more drugs concomitantly (n=68), and none were free from medication. Twenty-eight patients were treated for hypertension.
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The results of the hemodynamic measurements are displayed in Table 2. The median aortic PWV was significantly higher in RA patients than in control subjects (8.35 [7.14 to 10.24] versus 7.52 [6.56 to 9.18] m/s, respectively; P=0.005). Median brachial PWV was also slightly but significantly raised in the RA group compared with controls (8.60 [7.75 to 9.75] versus 8.15 [7.34 to 9.38] m/s, P=0.02). There were no significant differences, however, in augmentation pressure, AIx, or MAP. Patients with RA were then subdivided into 2 groups according to their inflammatory status. Mean age, gender distribution, and MAP were not significantly different between these 2 subgroups. Patients with serum CRP 10 mg/L (n=36) had significantly higher median aortic PWV than patients with CRP levels <10 mg/L (n=41; 9.15 [7.90 to 10.72] versus 7.80 [6.30 to 9.71] m/s, respectively; P=0.004), but there was no significant difference in aortic PWV between RA patients with serum levels of CRP <10 mg/L and control subjects (7.80 [6.30 to 9.71] versus 7.52 [6.56 to 9.18] m/s, respectively; P=0.7). Brachial PWV did not differ between the high- and low-CRP groups (8.70 [8.10 to 9.90] versus 8.33 [7.60 to 9.54] m/s, respectively; P=0.3). In a post hoc analysis, RA subjects were divided into treated hypertensive or normotensive groups. There were no significant differences in any of the hemodynamic measurements between groups, and this division did not meaningfully alter the control comparisons.
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In a stepwise regression analysis (Table 3), MAP, age, and logCRP were independently associated with aortic PWV (R2=0.701; P<0.0001). Neither cumulative ESR, logESR, DAS28, Sharp/van der Heijde score, disease duration, total cholesterol, blood glucose, presence of hypertension, drug treatment, gender, body mass index, heart rate, or rheumatoid factor entered the final model. In a stepwise regression model for brachial PWV, only MAP was found to be an independent predictor (R2=0.474; P=0.003).
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Study 2
Nine RA patients, mean age 54±19 years, with active disease (DAS28 6.08±1.63) received subcutaneous injections of etanercept in addition to existing therapy, which was not altered during the study. One of the patients was free from any medication at the start of the study, whereas treatment of the other 8 patients consisted of prednisolone (n=6, mean dose 7.5±4.2 mg), methotrexate (n=3), sulfasalazine (n=1), and nonsteroidal antiinflammatory drugs (n=5). Table 4 shows the effect of etanercept on disease activity, inflammatory markers, and hemodynamics at 0, 4, and 12 weeks after the initiation of the therapy and gives details of individual time point comparisons. Disease activity was reduced significantly by etanercept (DAS28 scores 6.08±1.27, 4.07±1.22, and 3.84±0.98, respectively; P<0.0001), and both markers of inflammation (CRP and ESR) were significantly reduced (P=0.011 and P=0.009, respectively). Neither MAP nor AIx was significantly affected by therapy (P=0.2 and P=0.6, respectively). However, aortic PWV was significantly reduced by etanercept from 8.82±2.04 m/s at baseline to 7.94±1.86 and 7.68±1.56 m/s at 4 and 12 weeks, respectively (P=0.0003; Figure 1). In contrast, brachial PWV was not reduced by etanercept (P=0.8). Age, gender, and MAP of matched control subjects (n=24) were compared with RA patients at baseline and 12 weeks after initiation of etanercept therapy. Baseline aortic PWV was significantly higher in patients than in control subjects (8.82±2.04 versus 7.67±1.53 m/s, respectively; P=0.04), but after 12 weeks of treatment, aortic PWV did not differ significantly between patients and control subjects (7.68±1.86 versus 7.67±1.53 m/s, respectively; P=0.98).
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Concomitantly, FMD was significantly increased after etanercept (2.91±1.37, 3.86±1.32, and 4.00±1.22% at 0, 4, and 12 weeks, respectively; P=0.003; Figure 2), but there were no significant change in the NTG response (P=0.8) or the baseline diameter (P=0.6). There was no significant difference in the FMD (4.26±1.00% versus 4.00±1.22%, respectively; P=0.5) or NTG response (P=0.8) between the matched control subjects and RA patients after 12 weeks of etanercept therapy.
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Discussion |
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The present study supports the hypothesis that systemic inflammation in RA is associated with increased aortic stiffness and that stiffness may potentially be reversed with successful immunomodulatory therapy. We have demonstrated for the first time that aortic PWV is increased in patients with RA compared with healthy control subjects. This correlated with current CRP, a marker of inflammation, but not with disease duration, historical inflammation, or the extent of radiological damage. Aortic stiffness was reduced, and concomitantly, endothelial function was normalized with anti-TNF-
therapy. Systemic inflammation may contribute to the increased incidence of cardiovascular disease in RA, because inflammation is known to play a pivotal role in the pathogenesis of cardiovascular disease.35 Indeed, serum levels of CRP, an acute-phase reactant, predict cardiovascular events in healthy individuals36 and in patients with preexisting cardiovascular disease.37 Potentially, systemic inflammation could cause an excess of cardiovascular disease in RA by either accelerating atherosclerosis directly38 or destabilizing plaques.39 Alternatively, inflammation may impair endothelial function13,14,40,41 or cause premature arterial stiffening, both of which may also promote atheroma formation. Although previous studies have assessed arterial stiffness in RA, the results of these mostly small studies are confusing.17–21 Various parameters and techniques have been used, and none of the studies measured aortic PWV, the "stiffness parameter" with the most outcome data.
A further discrepancy between these studies is the relative importance of current versus historical inflammation and the relationship between cumulative articular damage and arterial stiffness. Some studies have suggested that historical or cumulative inflammation or disease duration correlate best with arterial stiffness,18,20,21 whereas others have shown a correlation with current measures of inflammation or disease activity.17,19
In the present study, median aortic PWV was &10% higher in RA patients than in matched controls. Although this may appear to be a relatively small difference, it is likely to be clinically important, because aortic PWV increases by only &6% per decade in healthy individuals,42 which suggests that subjects with RA have arteries &20 years older than chronological control subjects. Contrary to findings by Klocke et al,20 we did not find a significant difference in AIx between the RA and control groups. This could be due to the fact that the population in the present study was older (mean age 57 years compared with 42 years). Indeed, we have recently shown that AIx is not as sensitive a measure of arterial stiffness as aortic PWV in individuals over 50 years of age.43 Moreover, Klocke et al did not match subjects for MAP, which we have previously demonstrated confounds AIx,44 as well as other indices of stiffness; thus their findings may relate to the higher MAP in the RA subjects. Conversely, our data from a larger cohort of patients with RA indicate that RA is primarily associated with aortic stiffening, as indicated by the higher aortic (carotid to femoral) PWV, rather than enhanced wave reflection, because AIx did not differ from that in control subjects. AIx is a composite measure that depends on wave velocity, the site of reflection, and the amplitude of the reflected wave. The normal AIx in the RA group, despite faster wave speed, may therefore indicate reduced wave reflection, possibly because of reduced impedance mismatch at the point of reflection due to peripheral vasodilatation. Although brachial PWV was higher in the RA group, it does not appear to be influenced by inflammation per se, because brachial PWV was not higher in RA patients with CRP 
10 mg/L than in patients with CRP <10 mg/L, and it was not independently related to CRP in regression analyses.
To investigate further the role of acute inflammation in arterial stiffening, we subdivided RA patients into 2 groups according to their serum levels of CRP and found that patients with a serum CRP 10 mg/L had a significantly higher aortic PWV than patients with CRP levels <10 mg/L, in whom aortic PWV did not differ from that of control subjects. Importantly, age, gender distribution, and MAP did not differ between the RA subgroups. These findings support our earlier findings in patients with antineutrophil antibody–associated systemic vasculitis,22 where the levels of acute inflammation were found to positively correlated with aortic PWV.
Although aortic PWV is a robust measure of aortic stiffness, it is influenced by a number of factors, such as MAP and age. To control for confounding factors and to establish which factors predicted aortic PWV, we constructed a stepwise regression model for aortic PWV. As expected, MAP and age entered the model, but logCRP also remained an independent predictor of aortic PWV, explaining 5% of the variance in aortic PWV. Chronic inflammation, measured by cumulative ESR over 5 years or modified Sharp score, which is a measure of cumulative radiological damage of joints due to chronic inflammation, did not correlate with aortic PWV. Our findings are interesting because they suggest that the aortic stiffness may be modifiable with a successful immunomodulatory therapy. Although we and others have shown that endothelial function can be improved in patients with RA13,15,16 and anti-neutrophil antibody–associated systemic vasculitis45 with successful immunomodulatory therapy, no studies have shown that arterial stiffness can be reduced with immunomodulatory therapy in RA. On the contrary, van Doornum et al46 reported that anti-TNF- therapy did not reduce arterial stiffness; however, they assessed arterial stiffness by measuring AIx rather than aortic PWV.
In the present study, we have shown that anti-TNF- therapy with etanercept not only reduces the levels of acute inflammatory markers (ESR and CRP) and disease activity (DAS28) but also decreases aortic PWV and concomitantly improves endothelial function, without altering NTG response or baseline diameter of the brachial artery. This indicates that both arterial stiffness and endothelial function are potentially reversible in RA. It also suggests that endothelial dysfunction may be the underlying cause of arterial stiffness in RA and supports our findings in the ovine and human iliac artery, in which we have shown that nitric oxide regulates local arterial distensibility.47,48
Potential Limitations
We studied RA patients with established disease rather than conducting a prospective study in patients with early disease because one of our main aims for the study was to establish whether arterial stiffness in RA is associated with acute or chronic inflammatory load. Such an approach may introduce bias from the treatment and survival effects that can only be addressed by much longer-term follow-up of incident cases. The data concerning etanercept were collected from a relatively small, open-label study. This reflects the fact that it was considered unethical to conduct a double-blind, randomized trial of etanercept in RA patients with a DAS28 5.1. Nevertheless, a similar open-label study design has been adopted previously by others.16,45,46 We attempted to minimize bias by using anonymized, blinded, offline analysis of the FMD recordings and an operator unfamiliar with the study. PWV values were calculated by the SphygmoCor system directly, and the readings were made by a person unaware of the clinical status of the subject or other investigations. Nevertheless, due to the nonrandomized design of the present study, we cannot exclude the possibility of a non–drug-related reduction in PWV.
Summary
We have shown that RA is associated with increased aortic stiffness in comparison with healthy control subjects. Aortic stiffness correlated with current but not historical measures of inflammation or disease score, which suggests that arterial stiffness may be modifiable. Indeed, anti-TNF- therapy reduced aortic stiffness and concomitantly improved endothelial function to a level comparable to that of healthy individuals. This suggests that effective control of inflammation may reduce cardiovascular risk in patients with RA as it improves arterial stiffness and endothelial function, both of which are established surrogate measures of risk. Also, RA may provide a useful model to investigate the effects of other immunomodulatory agents such as HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors on arterial stiffness and endothelial function.
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Acknowledgments |
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Sources of Funding
Kaisa Mäki-Petäjä is currently a GlaxoSmithKline-funded PhD student. This work was performed in the British Heart Foundation–sponsored vascular research laboratory at Addenbrooke’s Hospital, Cambridge, United Kingdom.
Disclosures
None.
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