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Clinical methods and pathophysiology
Evaluation of the ambulatory arterial stiffness index in patients with rheumatoid arthritis Ugur Nadir Karakulaka, Levent Sahinera, Naresh Maharjana, Sercan Okutucua, Banu Evranosa, Elifcan Aladagb, Levent Kılıcb, Ali Akdoganb, Ergun Baris Kayaa, Giray Kabakcia and Kudret Aytemira Objective Patients with rheumatoid arthritis (RA) are at a higher risk of arterial disease, endothelial dysfunction, and vascular inflammation than the general population. Therefore, these patients are prone to decreased arterial compliance and increased arterial stiffness. Ambulatory arterial stiffness index (AASI) was introduced as an index that predicts cardiovascular risk. In this study, the AASI was evaluated in RA patients. Method Thirty-three RA patients and 33 healthy agematched and sex-matched individuals were evaluated according to the 24 h blood pressure (BP) profiles. The regression slope of diastolic over systolic BP was computed for each participant. AASI was defined as 1 − regression slope.
significantly higher in nondippers compared with dippers in the entire group and the RA group, but not in the control group. Independent predictors that were found to affect AASI in RA patients were age, nondipper status, VAS score, DAS28 score, and rheumatoid factor positivity. Conclusion AASI is higher in RA patients compared with healthy individuals. When the prognostic significance of AASI is considered, RA patients with higher AASI should be followed closely for future adverse cardiovascular outcomes. Blood Press Monit 20:254–259 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Blood Pressure Monitoring 2015, 20:254–259 Keywords: ambulatory arterial stiffness index, blood pressure, rheumatoid arthritis
Results There was no significant difference in terms of the basic demographic characteristics, and average day, average night, and total average BP profiles as well as dipper status among the two groups. AASI was 0.45 ± 0.12 and 0.38 ± 0.10 in the RA patients and the healthy controls, respectively (P = 0.019). AASI was not significantly different in women and men in both the groups. AASI was
Departments of aCardiology and bInternal Medicine, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey
Introduction
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease and cardiovascular disease is the single most common cause of death in these patients [10]. Patients with RA are at a higher risk of arterial disease, microvascular and macrovascular endothelial dysfunction (ED), and vascular inflammation than the general population [11,12]. ED and vascular inflammation increases vascular fibrosis of large arteries, resulting in a decrease in arterial compliance. All of these factors result in increased arterial stiffness [13]. The aim of this study was to investigate the relationship between AASI, which is a clinically applicable and easily obtainable predictor of cardiovascular outcomes, and the presence and clinical and laboratory features of RA in patients without cardiovascular diseases compared with the healthy participants [14].
The pathophysiological role of large arteries in functionally coupling the left ventricle with peripheral vessels has been the focus of interest in recent years [1]. Arterial stiffness is recognized as an important measure of functional properties of large arteries and it has been shown to be a predictor for increased risk of cardiovascular organ damage and future cardiovascular events [2,3]. There are several studies in the literature that measure arterial stiffness, but in these studies, measurements of arterial stiffness require the use of complex, costly equipment and well-trained and highly qualified operators [4–6]. As a novel technique, the ambulatory arterial stiffness index (AASI) derived from ambulatory blood pressure monitoring (ABPM), obtained over 24 h in a given individual, was introduced as an index that predicts cardiovascular risk [7,8]. AASI provides valuable information on arterial stiffness by analysis of relationship between systolic and diastolic blood pressures (BP). The regression slope of diastolic BP over systolic BP from 24 h ABPM and quantification of increase in diastolic BP for a given systolic BP change correspond to AASI, which in turn reflects arterial stiffness [9]. 1359-5237 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Correspondence to Ugur Nadir Karakulak, MD, Department of Cardiology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara 061000, Turkey Tel: + 90 312 305 17 82; fax: + 90 312 310 05 80; e-mail: [email protected] Received 26 November 2014 Revised 5 April 2015 Accepted 7 April 2015
Materials and methods Study population
Fifty-six patients, who were diagnosed with RA according to the American College of Rheumatology criteria, at the Department of Rheumatology of Hacettepe University, DOI: 10.1097/MBP.0000000000000130
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Arterial stiffness in rheumatoid arthritis Karakulak et al. 255
Faculty of Medicine, were included in this cross-sectional study. To evaluate the effect of the presence of RA on arterial stiffness, patients with the following were excluded from the study: coronary artery disease, hypertension, diabetes mellitus, hyperlipidemia, obesity (BMI > 30 kg/m2), cerebrovascular event, smokers, renal or hepatic disease, and diseases characterized by chronic inflammation. Accordingly, 33 of the 56 patients were evaluated. All patients were currently receiving disease-modifying antirheumatic drugs. Twenty-eight patients were under the methotrexate and leflunomide combination, three patients were under the methotrexate, sulfasalazine, and hydroxychloroquine combination, and the last two patients were under the methotrexate and adalimumab combination. Thirty-three healthy individuals with a similar age and sex profile were included as a control group. Healthy individuals were recruited from among the staff of Hacettepe University Faculty of Medicine Department of Cardiology, Rheumatology and Coronary Care Unit. The study was approved by the local ethics committee and patients provided written informed consent. General assessment
Participants were assessed for baseline demographic characteristics, disease duration, body weight, height, and current medication. BMI was calculated as weight in kilograms divided by height in meters squared. Clinical assessment included evaluation of patient-derived visual analogue scale (VAS) of current disease activity (0–100 mm, 0 signifying best and 100 signifying worst possible health) and the modified disease activity score (DAS28), a validated composite score calculated from 28 tender and 28 swollen joints [15,16]. Venous blood was analyzed for erythrocyte sedimentation rate (ESR), highsensitive C reactive protein (hs-CRP), and rheumatoid factor (RF). Ambulatory blood pressure monitoring
ABMP studies were carried out using a Tracker NIBP2 (Del Mar Reynolds Medical Ltd, Hertford, UK) monitoring device. The device was applied to the nondominant arm for 24 h. The first hour was discarded from analysis. BP readings were obtained automatically at 15-min intervals during the daytime and 30-min intervals during the nighttime. Recordings were accepted only if more than 85% of the raw data were valid. Time in bed was defined on the basis of the patient-kept diary that documented the exact time of getting into and arising from bed. The average BP for this time in bed was calculated from the ambulatory monitoring data (termed nighttime BP). Daytime BP was defined as the average BP during the rest of the 24-h period. The mean BP was calculated as the diastolic pressure plus one-third of the pulse pressure. A regression slope of diastolic over systolic BP was computed for each participant [7,9]. Regression line was not forced through the origin (intercept 0) because during diastole when flow
decreases to 0, such a phenomenon does not occur for BP. We defined AASI as 1 − regression slope. The stiffer the arterial tree, the closer the regression slope and AASI are to 0 and 1, respectively. Nocturnal dipping (%) was defined as percentage decrease in nocturnal systolic BP compared with daytime systolic BP. When patients showed nocturnal dipping of less than 10%, they were defined as nondippers. Statistical analysis
Statistical evaluation was carried out using the statistical package for social sciences for Windows 20 (IBM SPSS Inc., Chicago, Illinois, USA) program. Variables with a normal distribution were analyzed using the Kolmogorov–Smirnov test. Variables with a normal distribution were shown as mean ± SD whereas those without a normal distribution were shown as median. Categorical variables were shown as number and percentage. Comparison between groups of continuous variables was performed using a t-test for independent variables showing a normal distribution and the Mann–Whitney U-test for those not showing a normal distribution. The Pearson χ2-test was used to compare categorical variables. Pearson correlation analysis was used to test normal variables considered to be associated with AASI, whereas Spearman correlation analysis was used for variables not showing a normal distribution. Multiple linear regression analysis was used to determine predictors among risk factors considered to be related to AASI both in the entire population and in the RA population. In the RA population, logarithmic conversion was used for linear regression for variables that were not distributed normally (BMI, CRP). P less than 0.05 was considered statistically significant.
Results Table 1 shows the basic demographic characteristics including age, sex, and BMI and ABPM profiles of the RA patients (n = 33) and the healthy control group (n = 33) included in the study. The mean age of the entire population was 53.4 ± 10.9 years, that of the RA patients was 54.2 ± 12.3 years, and that of the control group was 52.6 ± 9.4 years. There was no significant difference in terms of age, sex, BMI, and average day, average night, and total average BP profiles as well as dipper status among the two groups (P > 0.05). The same table also shows the disease period, and VAS and DAS48 scores as well as the levels of inflammatory parameters hs-CRP and ESR and RF positivity of RA patients. The mean disease duration was 120.7 ± 98.6 months. The mean VAS score of the patients was 32.3 ± 21.1 mm and the mean DAS48 score was 3.1 ± 1.1. RF was positive in 75.8% of the RA patients, whereas levels of hs-CRP and ESR were normal or near normal. AASI was found to be 0.42 ± 0.12 in the entire population. AASI was 0.45 ± 0.12 and 0.38 ± 0.10 in RA patients and
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256 Blood Pressure Monitoring 2015, Vol 20 No 5
Basic demographic and clinical characteristics and blood pressure of all participants and disease-related characteristics of rheumatoid arthritis patients
Table 1
Age (years) Sex (male) [n (%)] BMI (kg/m2) AASI Average day SBP (mmHg) Average day DBP (mmHg) Average day MBP (mmHg) Average night SBP (mmHg) Average night DBP (mmHg) Average night MBP (mmHg) Total average SBP (mmHg) Total average DBP (mmHg) Total average MBP (mmHg) Nondipper [n (%)] Duration of RA (months) VAS (mm) DAS28 RF positivity [n (%)] hs-CRP (mg/l) ESR (mm/h)
All patients (n = 66)
Rheumatoid arthritis (n = 33)
Control group (n = 33)
P
53.4 ± 10.9 45 (68.2) 26.9 ± 3.5 0.42 ± 0.12 119.6 ± 10.9 71.03 ± 8.1 88.36 ± 9.0 110.24 ± 13.3 62.3 ± 8.6 79.45 ± 10.2 117.03 ± 11.19 68.76 ± 8.03 85.89 ± 9.0 25 (37.9) – – – – – –
54.2 ± 12.3 24 (72.7) 27.25 ± 3.5 0.45 ± 0.12 118.76 ± 12.4 69.5 ± 7.2 87.24 ± 8.6 110.5 ± 15.2 61.5 ± 7.8 79.2 ± 10.2 116.3 ± 12.7 67.3 ± 7.0 84.8 ± 8.6 12 (63.6) 120.7 ± 98.6 32.3 ± 21.1 3.18 ± 1.17 25 (75.8) 0.48 22.85 ± 15.78
52.6 ± 9.4 21 (63.6) 26.59 ± 3.48 0.38 ± 0.10 120.42 ± 9.5 72.5 ± 8.7 89.5 ± 9.3 109.9 ± 11.4 63.1 ± 9.3 79.6 ± 10.4 117.8 ± 9.6 70.1 ± 8.7 86.9 ± 9.4 13 (60.6) – – – – – –
0.554 0.428 0.447 0.019* 0.542 0.130 0.315 0.855 0.453 0.887 0.601 0.160 0.352 0.800 – – – – – –
AASI, ambulatory arterial stiffness index; DBP, diastolic blood pressure; ESR, erythrocyte sedimentation rate; hs-CRP, high-sensitive C-reactive protein; MBP, mean blood pressure; RA, rheumatoid arthritis; RF, rheumatoid factor; SBP, systolic blood pressure; VAS, visual analogue scale. *P< 0.05.
AASI according to sex are shown in Table 2. In the entire population, AASI was calculated to be 0.41 ± 0.11 in women and 0.43 ± 0.14 in men. In the RA group, AASI was found to be 0.45 ± 0.09 in women and 0.48 ± 0.18 in men. AASI was not significantly different in women and men both in the entire population and in the RA group Fig. 1
140
DBP= 0.41×SBP+28.7
130
(P values of 0.556 and 0.526, respectively). The same was also true for the control group. Figure 3 shows the difference between the control group and the RA patients in Fig. 2
110 DBP = 0.65×SBP−0.67 100 DBP (mmHg)
healthy controls, respectively, and this difference was statistically significant (P = 0.019). Figures 1 and 2 show regression slope samples and AASI calculated from diastolic and systolic BP values derived from 24-h ABPM records. Figure 1 belongs to an RA patient with an AASI of 0.59 and Fig. 2 belongs to a healthy individual with an AASI of 0.59.
90 80 70 60
DBP (mmHg)
120 50
110
90
100
100
110
120
130
140
150
160
170
SBP (mmHg)
90 Regression slope sample of a healthy individual. AASI was calculated to be 0.35. AASI, ambulatory arterial stiffness index; DBP, diastolic blood pressure; SBP, systolic blood pressure.
80 70 60 50 100
120
140
160
180
Table 2 Distribution of ambulatory arterial stiffness index according to sex
SBP (mmHg) Regression slope sample of a rheumatoid arthritis patient. AASI was calculated to be 0.59. AASI, ambulatory arterial stiffness index; DBP, diastolic blood pressure; SBP, systolic blood pressure.
Female (n = 45)
Male (n = 21)
P
0.41 ± 0.11 0.45 ± 0.09 0.38 ± 0.12
0.43 ± 0.14 0.48 ± 0.18 0.40 ± 0.09
0.556 0.526 0.580
All patients RA Control RA, rheumatoid arthritis.
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Arterial stiffness in rheumatoid arthritis Karakulak et al. 257
terms of AASI as well as the difference in women and men in both groups. Table 3 shows AASI according to dipper/nondipper status. In the entire population, AASI was significantly higher in nondippers compared with dippers (0.45 ± 0.12 vs. 0.37 ± 0.10, P = 0.008). Similarly, in the RA group also, AASI was significantly higher in nondippers compared with dippers (0.50 ± 0.12 vs. 0.37 ± 0.07, P = 0.003). In the control group, however, AASI was not significantly different in dippers and nondippers (P = 0.433). In terms of RF positivity in the RA group, AASI was found to be 0.41 ± 0.07 in RF − patients and 0.48 ± 0.13 in RF + patients and this difference was also statistically significant (P = 0.011). When the effects of age, sex, and BMI were not taken into account, multivariable linear regression analysis in the entire population showed the presence of RA (β = 0.304, P = 0.010) and nondipper status (β = 0.316, P = 0.007) to be independent predictors affecting AASI (Table 4). In the multivariate linear regression model created from risk factors associated with AASI in RA patients (age, BMI, nondipper status, duration of RA, VAS and DAS28 scores, hs-CRP, ESR, and RF), independent predictors affecting AASI were found to be age (β = 0.485, P = 0.01), nondipper status (β = 0,554, P = 0,002), VAS score (β = 0.671, P = 0.011), DAS28 score (β = 0.796, P = 0.014), Fig. 3
Female Male
P = 0.019
0.80
and RF positivity (β = 0.422, P = 0.025). The effects of BMI, sex, RA duration, and ESR and hs-CRP levels on AASI were not present in multivariate linear regression analysis (P > 0.05) (Table 5).
Discussion This study is the first to show that AASI, which is an indicator of arterial stiffness, is higher in RA patients compared with healthy individuals. In addition, this study also shows the presence of RA to be an independent risk factor of high AASI. There is a very close relationship between systolic and diastolic BP in the arterial system. In a healthy, compliant artery, the increase in diastolic BP is higher than systolic BP whereas in a stiff artery, the tendency for diastolic BP to increase compared with systolic BP decreases. The higher increase in diastolic BP compared with systolic BP is known as a regression slope and it can be derived from 24-h ABPM. AASI, however, is expressed as 1 − regression slope and is a parameter reflecting arterial stiffness. The regression slope approaches ‘1’ whereas the AASI value approaches ‘0’ when there is a higher unit increase in diastolic BP compared with a unit increase in systolic BP. The opposite is true for a stiffer artery and AASI will approach ‘1’ [9]. In this study, the average AASI of RA patients was found to be significantly higher than that of the control group, that is AASI was found to be close to ‘1’. The increase in arterial stiffness is a consequence of vascular fibrosis and elastic fiber degradation of large arteries, resulting in a decrease in arterial compliance. Decreased arterial compliance, which is a major determinant of an increase in systolic BP, is an independent risk factor for stroke, coronary heart disease, and heart Distribution of ambulatory arterial stiffness index according to dipper status
Table 3
AASI
0.60
All patients RA Control
0.40
Dipper (n = 25)
Nondipper (n = 41)
P
0.37 ± 0.10 0.37 ± 0.07 0.36 ± 0.11
0.45 ± 0.12 0.50 ± 0.12 0.39 ± 0.09
0.008* 0.003* 0.433
RA, Rheumatoid arthritis. *P< 0.05.
Determination of independent predictors of ambulatory arterial stiffness index by multiple linear regressiona analysis
Table 4
0.20
P > 0.05 Variables
P > 0.05 0.00 Control
95% CI
RA
The difference between the control group and the rheumatoid arthritis patients in terms of AASI as well as the difference in women and men in both the groups. AASI, ambulatory arterial stiffness index; RA, rheumatoid arthritis.
RA Age BMI Sex Dipper
B
SE
β
P
Lower
Upper
0.072 0.001 –0.006 0.039 0.077
0.027 0.001 0.004 0.030 0.028
0.304 0.088 –0.187 0.155 0.316
0.010* 0.456 0.116 0.188 0.007*
0.018 –0.002 –0.014 –0.020 0.022
0.126 0.004 0.002 0.098 0.132
B, unstandardized coefficient; CI, confidence interval; RA, rheumatoid arthritis; β, standardized coefficient. a RA and dipper status were found to be independent predictors in analysis after adjustment of age, sex, and BMI. *P< 0.05.
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258 Blood Pressure Monitoring 2015, Vol 20 No 5
Predictors of ambulatory arterial stiffness index in the rheumatoid arthritis population
Table 5
95% CI Variables Age BMI Nondipper Duration of RA VAS score DAS28 score RF hs-CRP ESR
B ± SE
β
P
Lower
Upper
0.048 ± 0.017 0.060 ± 0.058 1.374 ± 0.381 0.002 ± 0.002 0.384 ± 0.138 0.825 ± 0.312 1.176 ± 0.169 0.199 ± 0.169 0.005 ± 0.16
0.485 0.174 0.554 0.174 0.671 0.796 0.422 0.205 0.067
0.010* 0.314 0.002* 0.279 0.011* 0.014* 0.025* 0.251 0.757
0.013 –0.060 0.585 –0.002 0.097 0.180 0.159 –0.151 –0.029
0.083 0.180 2.162 0.006 0.670 1.470 2.192 0.549 0.039
B, unstandardized coefficient; CI, confidence interval; ESR, erythrocyte sedimentation rate; hs-CRP, high-sensitive C-reactive protein; RA, rheumatoid arthritis; RF, rheumatoid factor; VAS, visual analogue scale; β, standardized coefficient. *P< 0.05.
failure [6,17]. AASI, which is an indicator of arterial stiffness, has been associated with an increased risk of cardiovascular mortality in hypertensive patients and stroke in the general population [7,18]. Arterial stiffness is affected by a number of clinical factors including advanced age, hypertension, diabetes mellitus, hyperlipidemia, and obesity [19]. In our study, individuals with these clinical risk factors have been excluded and participants with similar profiles in terms of age, sex, and BMI have been included. Therefore, the objective of this study was to evaluate the effect of RA on arterial stiffness independent of other risk factors. Rheumatic arthritis is a disease in which chronic inflammatory processes play an important role. Inflammation in the vascular bed results in extracellular matrix deposition, vascular smooth muscle cell hyperplasia, T-lymphocyte and macrophage infiltration, ED, and fibrosis [20,21]. These changes are very similar to atherosclerosis in the arterial system. Moreover, there is evidence of early atherosclerosis in RA patients without any cardiovascular disease or risk factors [22]. All these processes lead to arterial stiffness in RA. In this study, AASI was not found to be associated with disease duration whereas a significant relation was found between parameters of disease severity such as VAS, DAS28, and RF and AASI. In contrast, a study evaluating arterial stiffness in RA patients by PW analysis and augmentation index has shown a significant relation with disease duration and not with disease severity parameters, and this has been attributed to arterial stiffness being related to cumulative inflammatory disease rather than acute systemic inflammation [5]. The association between AASI and RA disease scores and inflammatory markers and the lack of significance between disease duration and the AASI value as shown by this study supports the hypothesis that ‘severity of activity of disease/inflammation’ affects the arterial system more than ‘the time spent with the disease’. High titer of RF is a marker of severe clinical course. Those RA patients who are RF positive are at a higher risk for more aggressive disease, including
inflammation outside the joints [23]. In contrast, the lack of association with ESR and hs-CRP, both of which are important inflammatory markers, may be because of the small number of patients. It is known that nondipper status is closely related to cardiac autonomic dysregulation, target organ damage, and ventricular repolarization [24,25]. Besides, studies have shown cardiac autonomic function to be affected in RA patients compared with normal individuals [26,27]. In this study, AASI of nondippers was significantly higher than that of dippers in the RA group. In addition, nondipper status was found to be a predictor of high AASI in the entire population as well as the RA group. Similar to this result, Lee et al. [28] showed nondipper status to be an independent predictor of high AASI and the authors concluded that AASI is affected by autonomic dysregulation. However, although the proportion of nondipper individuals was similar in the two groups (63.6% in the RA group vs. 60.6% in the control group, P = 0.800), a significant association between AASI and nondippers was not found in the control group. The significant relation between AASI and nondipper status found in the entire population may be because of the strong association between AASI and nondipper status in the RA patient group. Therefore, AASI as a composite parameter not only indicates arterial compliance and stiffness but also provides valuable information on cardiac autonomic function because of its association with the diurnal cycle and nondipper status [29,30]. The limitations of our study include the small sample size in the patient as well as the control group, no use of electrographic, echocardiographic, or other imaging techniques, and the lack of analysis of different laboratory values. The fact that only patients without any cardiovascular risk factors were included may bring into question the results of this study because in the real world, most RA patients have several cardiovascular risk factors. Nevertheless, it should be kept in mind that the possible confounding factors described above as exclusion criteria might have diluted the true association between AASI and RA. All patients in this study were under one of the three combination therapies of diseasemodifying antirheumatic drugs and most of the patients were receiving methotrexate and leflunomide. Although these drugs are considered in similar groups, the possible effects of every drug and combinations on the results have not been evaluated in this study. Finally, this study is cross-sectional in design and the patients were not followed up in terms of cardiovascular end-points; thus, the possible association between AASI and these endpoints has not been evaluated. The findings of this study will need confirmation in larger studies. As a conclusion, our study showed that AASI, which is an indicator of arterial stiffness, is higher in RA patients
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Arterial stiffness in rheumatoid arthritis Karakulak et al. 259
compared with healthy individuals. As shown in this study, the presence of RA is a predictor of higher AASI as is nondipper status, which has also been shown in other studies. In addition, in the RA group, indicators of disease activity including severity scores and inflammatory and autoimmune markers were found to be predictors of high AASI independent of disease duration. When the prognostic significance of AASI is considered, RA patients with higher AASI should be followed closely for future adverse cardiovascular outcomes. Therefore, AASI should be studied more frequently in a larger RA population as well in other diseases involving both the cardiac and the arterial systems.
12
13 14
15
16
17
Acknowledgements The authors thank Hakan Cakir for his statistical analyses in this study.
18
19
Conflicts of interest
There are no conflicts of interest.
20
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Clinical methods and pathophysiology
Evaluation of the ambulatory arterial stiffness index in patients with rheumatoid arthritis Ugur Nadir Karakulaka, Levent Sahinera, Naresh Maharjana, Sercan Okutucua, Banu Evranosa, Elifcan Aladagb, Levent Kılıcb, Ali Akdoganb, Ergun Baris Kayaa, Giray Kabakcia and Kudret Aytemira Objective Patients with rheumatoid arthritis (RA) are at a higher risk of arterial disease, endothelial dysfunction, and vascular inflammation than the general population. Therefore, these patients are prone to decreased arterial compliance and increased arterial stiffness. Ambulatory arterial stiffness index (AASI) was introduced as an index that predicts cardiovascular risk. In this study, the AASI was evaluated in RA patients. Method Thirty-three RA patients and 33 healthy agematched and sex-matched individuals were evaluated according to the 24 h blood pressure (BP) profiles. The regression slope of diastolic over systolic BP was computed for each participant. AASI was defined as 1 − regression slope.
significantly higher in nondippers compared with dippers in the entire group and the RA group, but not in the control group. Independent predictors that were found to affect AASI in RA patients were age, nondipper status, VAS score, DAS28 score, and rheumatoid factor positivity. Conclusion AASI is higher in RA patients compared with healthy individuals. When the prognostic significance of AASI is considered, RA patients with higher AASI should be followed closely for future adverse cardiovascular outcomes. Blood Press Monit 20:254–259 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Blood Pressure Monitoring 2015, 20:254–259 Keywords: ambulatory arterial stiffness index, blood pressure, rheumatoid arthritis
Results There was no significant difference in terms of the basic demographic characteristics, and average day, average night, and total average BP profiles as well as dipper status among the two groups. AASI was 0.45 ± 0.12 and 0.38 ± 0.10 in the RA patients and the healthy controls, respectively (P = 0.019). AASI was not significantly different in women and men in both the groups. AASI was
Departments of aCardiology and bInternal Medicine, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey
Introduction
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease and cardiovascular disease is the single most common cause of death in these patients [10]. Patients with RA are at a higher risk of arterial disease, microvascular and macrovascular endothelial dysfunction (ED), and vascular inflammation than the general population [11,12]. ED and vascular inflammation increases vascular fibrosis of large arteries, resulting in a decrease in arterial compliance. All of these factors result in increased arterial stiffness [13]. The aim of this study was to investigate the relationship between AASI, which is a clinically applicable and easily obtainable predictor of cardiovascular outcomes, and the presence and clinical and laboratory features of RA in patients without cardiovascular diseases compared with the healthy participants [14].
The pathophysiological role of large arteries in functionally coupling the left ventricle with peripheral vessels has been the focus of interest in recent years [1]. Arterial stiffness is recognized as an important measure of functional properties of large arteries and it has been shown to be a predictor for increased risk of cardiovascular organ damage and future cardiovascular events [2,3]. There are several studies in the literature that measure arterial stiffness, but in these studies, measurements of arterial stiffness require the use of complex, costly equipment and well-trained and highly qualified operators [4–6]. As a novel technique, the ambulatory arterial stiffness index (AASI) derived from ambulatory blood pressure monitoring (ABPM), obtained over 24 h in a given individual, was introduced as an index that predicts cardiovascular risk [7,8]. AASI provides valuable information on arterial stiffness by analysis of relationship between systolic and diastolic blood pressures (BP). The regression slope of diastolic BP over systolic BP from 24 h ABPM and quantification of increase in diastolic BP for a given systolic BP change correspond to AASI, which in turn reflects arterial stiffness [9]. 1359-5237 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Correspondence to Ugur Nadir Karakulak, MD, Department of Cardiology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara 061000, Turkey Tel: + 90 312 305 17 82; fax: + 90 312 310 05 80; e-mail: [email protected] Received 26 November 2014 Revised 5 April 2015 Accepted 7 April 2015
Materials and methods Study population
Fifty-six patients, who were diagnosed with RA according to the American College of Rheumatology criteria, at the Department of Rheumatology of Hacettepe University, DOI: 10.1097/MBP.0000000000000130
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Arterial stiffness in rheumatoid arthritis Karakulak et al. 255
Faculty of Medicine, were included in this cross-sectional study. To evaluate the effect of the presence of RA on arterial stiffness, patients with the following were excluded from the study: coronary artery disease, hypertension, diabetes mellitus, hyperlipidemia, obesity (BMI > 30 kg/m2), cerebrovascular event, smokers, renal or hepatic disease, and diseases characterized by chronic inflammation. Accordingly, 33 of the 56 patients were evaluated. All patients were currently receiving disease-modifying antirheumatic drugs. Twenty-eight patients were under the methotrexate and leflunomide combination, three patients were under the methotrexate, sulfasalazine, and hydroxychloroquine combination, and the last two patients were under the methotrexate and adalimumab combination. Thirty-three healthy individuals with a similar age and sex profile were included as a control group. Healthy individuals were recruited from among the staff of Hacettepe University Faculty of Medicine Department of Cardiology, Rheumatology and Coronary Care Unit. The study was approved by the local ethics committee and patients provided written informed consent. General assessment
Participants were assessed for baseline demographic characteristics, disease duration, body weight, height, and current medication. BMI was calculated as weight in kilograms divided by height in meters squared. Clinical assessment included evaluation of patient-derived visual analogue scale (VAS) of current disease activity (0–100 mm, 0 signifying best and 100 signifying worst possible health) and the modified disease activity score (DAS28), a validated composite score calculated from 28 tender and 28 swollen joints [15,16]. Venous blood was analyzed for erythrocyte sedimentation rate (ESR), highsensitive C reactive protein (hs-CRP), and rheumatoid factor (RF). Ambulatory blood pressure monitoring
ABMP studies were carried out using a Tracker NIBP2 (Del Mar Reynolds Medical Ltd, Hertford, UK) monitoring device. The device was applied to the nondominant arm for 24 h. The first hour was discarded from analysis. BP readings were obtained automatically at 15-min intervals during the daytime and 30-min intervals during the nighttime. Recordings were accepted only if more than 85% of the raw data were valid. Time in bed was defined on the basis of the patient-kept diary that documented the exact time of getting into and arising from bed. The average BP for this time in bed was calculated from the ambulatory monitoring data (termed nighttime BP). Daytime BP was defined as the average BP during the rest of the 24-h period. The mean BP was calculated as the diastolic pressure plus one-third of the pulse pressure. A regression slope of diastolic over systolic BP was computed for each participant [7,9]. Regression line was not forced through the origin (intercept 0) because during diastole when flow
decreases to 0, such a phenomenon does not occur for BP. We defined AASI as 1 − regression slope. The stiffer the arterial tree, the closer the regression slope and AASI are to 0 and 1, respectively. Nocturnal dipping (%) was defined as percentage decrease in nocturnal systolic BP compared with daytime systolic BP. When patients showed nocturnal dipping of less than 10%, they were defined as nondippers. Statistical analysis
Statistical evaluation was carried out using the statistical package for social sciences for Windows 20 (IBM SPSS Inc., Chicago, Illinois, USA) program. Variables with a normal distribution were analyzed using the Kolmogorov–Smirnov test. Variables with a normal distribution were shown as mean ± SD whereas those without a normal distribution were shown as median. Categorical variables were shown as number and percentage. Comparison between groups of continuous variables was performed using a t-test for independent variables showing a normal distribution and the Mann–Whitney U-test for those not showing a normal distribution. The Pearson χ2-test was used to compare categorical variables. Pearson correlation analysis was used to test normal variables considered to be associated with AASI, whereas Spearman correlation analysis was used for variables not showing a normal distribution. Multiple linear regression analysis was used to determine predictors among risk factors considered to be related to AASI both in the entire population and in the RA population. In the RA population, logarithmic conversion was used for linear regression for variables that were not distributed normally (BMI, CRP). P less than 0.05 was considered statistically significant.
Results Table 1 shows the basic demographic characteristics including age, sex, and BMI and ABPM profiles of the RA patients (n = 33) and the healthy control group (n = 33) included in the study. The mean age of the entire population was 53.4 ± 10.9 years, that of the RA patients was 54.2 ± 12.3 years, and that of the control group was 52.6 ± 9.4 years. There was no significant difference in terms of age, sex, BMI, and average day, average night, and total average BP profiles as well as dipper status among the two groups (P > 0.05). The same table also shows the disease period, and VAS and DAS48 scores as well as the levels of inflammatory parameters hs-CRP and ESR and RF positivity of RA patients. The mean disease duration was 120.7 ± 98.6 months. The mean VAS score of the patients was 32.3 ± 21.1 mm and the mean DAS48 score was 3.1 ± 1.1. RF was positive in 75.8% of the RA patients, whereas levels of hs-CRP and ESR were normal or near normal. AASI was found to be 0.42 ± 0.12 in the entire population. AASI was 0.45 ± 0.12 and 0.38 ± 0.10 in RA patients and
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256 Blood Pressure Monitoring 2015, Vol 20 No 5
Basic demographic and clinical characteristics and blood pressure of all participants and disease-related characteristics of rheumatoid arthritis patients
Table 1
Age (years) Sex (male) [n (%)] BMI (kg/m2) AASI Average day SBP (mmHg) Average day DBP (mmHg) Average day MBP (mmHg) Average night SBP (mmHg) Average night DBP (mmHg) Average night MBP (mmHg) Total average SBP (mmHg) Total average DBP (mmHg) Total average MBP (mmHg) Nondipper [n (%)] Duration of RA (months) VAS (mm) DAS28 RF positivity [n (%)] hs-CRP (mg/l) ESR (mm/h)
All patients (n = 66)
Rheumatoid arthritis (n = 33)
Control group (n = 33)
P
53.4 ± 10.9 45 (68.2) 26.9 ± 3.5 0.42 ± 0.12 119.6 ± 10.9 71.03 ± 8.1 88.36 ± 9.0 110.24 ± 13.3 62.3 ± 8.6 79.45 ± 10.2 117.03 ± 11.19 68.76 ± 8.03 85.89 ± 9.0 25 (37.9) – – – – – –
54.2 ± 12.3 24 (72.7) 27.25 ± 3.5 0.45 ± 0.12 118.76 ± 12.4 69.5 ± 7.2 87.24 ± 8.6 110.5 ± 15.2 61.5 ± 7.8 79.2 ± 10.2 116.3 ± 12.7 67.3 ± 7.0 84.8 ± 8.6 12 (63.6) 120.7 ± 98.6 32.3 ± 21.1 3.18 ± 1.17 25 (75.8) 0.48 22.85 ± 15.78
52.6 ± 9.4 21 (63.6) 26.59 ± 3.48 0.38 ± 0.10 120.42 ± 9.5 72.5 ± 8.7 89.5 ± 9.3 109.9 ± 11.4 63.1 ± 9.3 79.6 ± 10.4 117.8 ± 9.6 70.1 ± 8.7 86.9 ± 9.4 13 (60.6) – – – – – –
0.554 0.428 0.447 0.019* 0.542 0.130 0.315 0.855 0.453 0.887 0.601 0.160 0.352 0.800 – – – – – –
AASI, ambulatory arterial stiffness index; DBP, diastolic blood pressure; ESR, erythrocyte sedimentation rate; hs-CRP, high-sensitive C-reactive protein; MBP, mean blood pressure; RA, rheumatoid arthritis; RF, rheumatoid factor; SBP, systolic blood pressure; VAS, visual analogue scale. *P< 0.05.
AASI according to sex are shown in Table 2. In the entire population, AASI was calculated to be 0.41 ± 0.11 in women and 0.43 ± 0.14 in men. In the RA group, AASI was found to be 0.45 ± 0.09 in women and 0.48 ± 0.18 in men. AASI was not significantly different in women and men both in the entire population and in the RA group Fig. 1
140
DBP= 0.41×SBP+28.7
130
(P values of 0.556 and 0.526, respectively). The same was also true for the control group. Figure 3 shows the difference between the control group and the RA patients in Fig. 2
110 DBP = 0.65×SBP−0.67 100 DBP (mmHg)
healthy controls, respectively, and this difference was statistically significant (P = 0.019). Figures 1 and 2 show regression slope samples and AASI calculated from diastolic and systolic BP values derived from 24-h ABPM records. Figure 1 belongs to an RA patient with an AASI of 0.59 and Fig. 2 belongs to a healthy individual with an AASI of 0.59.
90 80 70 60
DBP (mmHg)
120 50
110
90
100
100
110
120
130
140
150
160
170
SBP (mmHg)
90 Regression slope sample of a healthy individual. AASI was calculated to be 0.35. AASI, ambulatory arterial stiffness index; DBP, diastolic blood pressure; SBP, systolic blood pressure.
80 70 60 50 100
120
140
160
180
Table 2 Distribution of ambulatory arterial stiffness index according to sex
SBP (mmHg) Regression slope sample of a rheumatoid arthritis patient. AASI was calculated to be 0.59. AASI, ambulatory arterial stiffness index; DBP, diastolic blood pressure; SBP, systolic blood pressure.
Female (n = 45)
Male (n = 21)
P
0.41 ± 0.11 0.45 ± 0.09 0.38 ± 0.12
0.43 ± 0.14 0.48 ± 0.18 0.40 ± 0.09
0.556 0.526 0.580
All patients RA Control RA, rheumatoid arthritis.
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Arterial stiffness in rheumatoid arthritis Karakulak et al. 257
terms of AASI as well as the difference in women and men in both groups. Table 3 shows AASI according to dipper/nondipper status. In the entire population, AASI was significantly higher in nondippers compared with dippers (0.45 ± 0.12 vs. 0.37 ± 0.10, P = 0.008). Similarly, in the RA group also, AASI was significantly higher in nondippers compared with dippers (0.50 ± 0.12 vs. 0.37 ± 0.07, P = 0.003). In the control group, however, AASI was not significantly different in dippers and nondippers (P = 0.433). In terms of RF positivity in the RA group, AASI was found to be 0.41 ± 0.07 in RF − patients and 0.48 ± 0.13 in RF + patients and this difference was also statistically significant (P = 0.011). When the effects of age, sex, and BMI were not taken into account, multivariable linear regression analysis in the entire population showed the presence of RA (β = 0.304, P = 0.010) and nondipper status (β = 0.316, P = 0.007) to be independent predictors affecting AASI (Table 4). In the multivariate linear regression model created from risk factors associated with AASI in RA patients (age, BMI, nondipper status, duration of RA, VAS and DAS28 scores, hs-CRP, ESR, and RF), independent predictors affecting AASI were found to be age (β = 0.485, P = 0.01), nondipper status (β = 0,554, P = 0,002), VAS score (β = 0.671, P = 0.011), DAS28 score (β = 0.796, P = 0.014), Fig. 3
Female Male
P = 0.019
0.80
and RF positivity (β = 0.422, P = 0.025). The effects of BMI, sex, RA duration, and ESR and hs-CRP levels on AASI were not present in multivariate linear regression analysis (P > 0.05) (Table 5).
Discussion This study is the first to show that AASI, which is an indicator of arterial stiffness, is higher in RA patients compared with healthy individuals. In addition, this study also shows the presence of RA to be an independent risk factor of high AASI. There is a very close relationship between systolic and diastolic BP in the arterial system. In a healthy, compliant artery, the increase in diastolic BP is higher than systolic BP whereas in a stiff artery, the tendency for diastolic BP to increase compared with systolic BP decreases. The higher increase in diastolic BP compared with systolic BP is known as a regression slope and it can be derived from 24-h ABPM. AASI, however, is expressed as 1 − regression slope and is a parameter reflecting arterial stiffness. The regression slope approaches ‘1’ whereas the AASI value approaches ‘0’ when there is a higher unit increase in diastolic BP compared with a unit increase in systolic BP. The opposite is true for a stiffer artery and AASI will approach ‘1’ [9]. In this study, the average AASI of RA patients was found to be significantly higher than that of the control group, that is AASI was found to be close to ‘1’. The increase in arterial stiffness is a consequence of vascular fibrosis and elastic fiber degradation of large arteries, resulting in a decrease in arterial compliance. Decreased arterial compliance, which is a major determinant of an increase in systolic BP, is an independent risk factor for stroke, coronary heart disease, and heart Distribution of ambulatory arterial stiffness index according to dipper status
Table 3
AASI
0.60
All patients RA Control
0.40
Dipper (n = 25)
Nondipper (n = 41)
P
0.37 ± 0.10 0.37 ± 0.07 0.36 ± 0.11
0.45 ± 0.12 0.50 ± 0.12 0.39 ± 0.09
0.008* 0.003* 0.433
RA, Rheumatoid arthritis. *P< 0.05.
Determination of independent predictors of ambulatory arterial stiffness index by multiple linear regressiona analysis
Table 4
0.20
P > 0.05 Variables
P > 0.05 0.00 Control
95% CI
RA
The difference between the control group and the rheumatoid arthritis patients in terms of AASI as well as the difference in women and men in both the groups. AASI, ambulatory arterial stiffness index; RA, rheumatoid arthritis.
RA Age BMI Sex Dipper
B
SE
β
P
Lower
Upper
0.072 0.001 –0.006 0.039 0.077
0.027 0.001 0.004 0.030 0.028
0.304 0.088 –0.187 0.155 0.316
0.010* 0.456 0.116 0.188 0.007*
0.018 –0.002 –0.014 –0.020 0.022
0.126 0.004 0.002 0.098 0.132
B, unstandardized coefficient; CI, confidence interval; RA, rheumatoid arthritis; β, standardized coefficient. a RA and dipper status were found to be independent predictors in analysis after adjustment of age, sex, and BMI. *P< 0.05.
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258 Blood Pressure Monitoring 2015, Vol 20 No 5
Predictors of ambulatory arterial stiffness index in the rheumatoid arthritis population
Table 5
95% CI Variables Age BMI Nondipper Duration of RA VAS score DAS28 score RF hs-CRP ESR
B ± SE
β
P
Lower
Upper
0.048 ± 0.017 0.060 ± 0.058 1.374 ± 0.381 0.002 ± 0.002 0.384 ± 0.138 0.825 ± 0.312 1.176 ± 0.169 0.199 ± 0.169 0.005 ± 0.16
0.485 0.174 0.554 0.174 0.671 0.796 0.422 0.205 0.067
0.010* 0.314 0.002* 0.279 0.011* 0.014* 0.025* 0.251 0.757
0.013 –0.060 0.585 –0.002 0.097 0.180 0.159 –0.151 –0.029
0.083 0.180 2.162 0.006 0.670 1.470 2.192 0.549 0.039
B, unstandardized coefficient; CI, confidence interval; ESR, erythrocyte sedimentation rate; hs-CRP, high-sensitive C-reactive protein; RA, rheumatoid arthritis; RF, rheumatoid factor; VAS, visual analogue scale; β, standardized coefficient. *P< 0.05.
failure [6,17]. AASI, which is an indicator of arterial stiffness, has been associated with an increased risk of cardiovascular mortality in hypertensive patients and stroke in the general population [7,18]. Arterial stiffness is affected by a number of clinical factors including advanced age, hypertension, diabetes mellitus, hyperlipidemia, and obesity [19]. In our study, individuals with these clinical risk factors have been excluded and participants with similar profiles in terms of age, sex, and BMI have been included. Therefore, the objective of this study was to evaluate the effect of RA on arterial stiffness independent of other risk factors. Rheumatic arthritis is a disease in which chronic inflammatory processes play an important role. Inflammation in the vascular bed results in extracellular matrix deposition, vascular smooth muscle cell hyperplasia, T-lymphocyte and macrophage infiltration, ED, and fibrosis [20,21]. These changes are very similar to atherosclerosis in the arterial system. Moreover, there is evidence of early atherosclerosis in RA patients without any cardiovascular disease or risk factors [22]. All these processes lead to arterial stiffness in RA. In this study, AASI was not found to be associated with disease duration whereas a significant relation was found between parameters of disease severity such as VAS, DAS28, and RF and AASI. In contrast, a study evaluating arterial stiffness in RA patients by PW analysis and augmentation index has shown a significant relation with disease duration and not with disease severity parameters, and this has been attributed to arterial stiffness being related to cumulative inflammatory disease rather than acute systemic inflammation [5]. The association between AASI and RA disease scores and inflammatory markers and the lack of significance between disease duration and the AASI value as shown by this study supports the hypothesis that ‘severity of activity of disease/inflammation’ affects the arterial system more than ‘the time spent with the disease’. High titer of RF is a marker of severe clinical course. Those RA patients who are RF positive are at a higher risk for more aggressive disease, including
inflammation outside the joints [23]. In contrast, the lack of association with ESR and hs-CRP, both of which are important inflammatory markers, may be because of the small number of patients. It is known that nondipper status is closely related to cardiac autonomic dysregulation, target organ damage, and ventricular repolarization [24,25]. Besides, studies have shown cardiac autonomic function to be affected in RA patients compared with normal individuals [26,27]. In this study, AASI of nondippers was significantly higher than that of dippers in the RA group. In addition, nondipper status was found to be a predictor of high AASI in the entire population as well as the RA group. Similar to this result, Lee et al. [28] showed nondipper status to be an independent predictor of high AASI and the authors concluded that AASI is affected by autonomic dysregulation. However, although the proportion of nondipper individuals was similar in the two groups (63.6% in the RA group vs. 60.6% in the control group, P = 0.800), a significant association between AASI and nondippers was not found in the control group. The significant relation between AASI and nondipper status found in the entire population may be because of the strong association between AASI and nondipper status in the RA patient group. Therefore, AASI as a composite parameter not only indicates arterial compliance and stiffness but also provides valuable information on cardiac autonomic function because of its association with the diurnal cycle and nondipper status [29,30]. The limitations of our study include the small sample size in the patient as well as the control group, no use of electrographic, echocardiographic, or other imaging techniques, and the lack of analysis of different laboratory values. The fact that only patients without any cardiovascular risk factors were included may bring into question the results of this study because in the real world, most RA patients have several cardiovascular risk factors. Nevertheless, it should be kept in mind that the possible confounding factors described above as exclusion criteria might have diluted the true association between AASI and RA. All patients in this study were under one of the three combination therapies of diseasemodifying antirheumatic drugs and most of the patients were receiving methotrexate and leflunomide. Although these drugs are considered in similar groups, the possible effects of every drug and combinations on the results have not been evaluated in this study. Finally, this study is cross-sectional in design and the patients were not followed up in terms of cardiovascular end-points; thus, the possible association between AASI and these endpoints has not been evaluated. The findings of this study will need confirmation in larger studies. As a conclusion, our study showed that AASI, which is an indicator of arterial stiffness, is higher in RA patients
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Arterial stiffness in rheumatoid arthritis Karakulak et al. 259
compared with healthy individuals. As shown in this study, the presence of RA is a predictor of higher AASI as is nondipper status, which has also been shown in other studies. In addition, in the RA group, indicators of disease activity including severity scores and inflammatory and autoimmune markers were found to be predictors of high AASI independent of disease duration. When the prognostic significance of AASI is considered, RA patients with higher AASI should be followed closely for future adverse cardiovascular outcomes. Therefore, AASI should be studied more frequently in a larger RA population as well in other diseases involving both the cardiac and the arterial systems.
12
13 14
15
16
17
Acknowledgements The authors thank Hakan Cakir for his statistical analyses in this study.
18
19
Conflicts of interest
There are no conflicts of interest.
20
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