International Journal of Rheumatic Diseases 2015

ORIGINAL ARTICLE

Ambulatory arterial stiffness index and carotid intima-media thickness in hypertensive rheumatoid patients: a comparative cross-sectional study 1 3  1 Jadranka MOROVIC-VERGLES,   2 Jasna BADZAK,  Josko MITROVIC, Ivica HORVATIC,  3 and Stjepan GAMULIN4 Maristela STOJIC 1

Divisions of Clinical Immunology and Rheumatology, 2Nephrology, Department of Internal Medicine, Dubrava University Hospital, University of Zagreb School of Medicine, 3Department of Neurology, Dubrava University Hospital, and 4Department of Pathophysiology, School of Medicine, University of Zagreb, Zagreb, Croatia

Abstract Aim: Rheumatoid arthritis is associated with accelerated atherosclerosis. However, little is known about preclinical atherosclerosis in hypertensive rheumatoid arthritis patients. In this cross-sectional study we assessed the expression of preclinical atherosclerosis in hypertensive rheumatoid arthritis patients in comparison with matched hypertensive non-rheumatoid arthritis patients. Methods: The study included 52 hypertensive rheumatoid arthritis patients and 42 hypertensive non-rheumatoid arthritis patients. The patients were extensively examined clinically and laboratory tested. The expression of preclinical atherosclerosis was estimated by assessing ambulatory arterial stiffness index and common carotid intima-media thickness. Results: Arterial stiffness index and common carotid intima-media thickness were higher in hypertensive rheumatoid arthritis patients than in hypertensive non-rheumatoid arthritis patients. There was no correlation between arterial stiffness index and common carotid intima-media thickness with markers of inflammation and disease activity in hypertensive rheumatoid arthritis patients. Conclusion: The expression of subclinical atherosclerosis is more pronounced in hypertensive rheumatoid arthritis than in hypertensive non- rheumatoid arthritis patients. Key words: arterial hypertension, arterial stiffness, atherosclerosis, carotid intima-media thickness, rheumatoid arthritis.

INTRODUCTION Excessive cardiovascular comorbidity and mortality in rheumatoid arthritis (RA) are mostly due to premature and accelerated atherosclerosis in RA patients.1

Correspondence: Professor Jadranka Morovic-Vergles, Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Dubrava University Hospital, University of Zagreb School of Medicine, Av. G.  Suska 6, 10 040 Zagreb, Croatia. Email: [email protected]

Arterial hypertension (AH) is one of the major cardiovascular risk factors contributing to development of atherosclerosis. Atherosclerosis and AH are in a positive feedback relationship. Atherosclerotic vascular injury causing an increase of arterial stiffness and a decrease of arterial compliance increases blood pressure, which in turn augments vascular injury.2 Due to accelerated atherosclerosis in RA, a more pronounced vascular injury could be expected in AH RA patients than in AH nonRA ones. Subclinical atherosclerosis was not studied in detail in a subset of AH RA patients, and the aim of this

© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd

J. Mitrovic et al.

cross-sectional study was to compare the expression of preclinical atherosclerosis in AH RA and AH non-RA patients. The expression of atherosclerosis was assessed by calculating ambulatory arterial stiffness index (AASI)3 and measuring common carotid intima-media thickness (ccIMT).4

METHODS In this cross sectional study 52 AH RA patients were consecutively enrolled. A comparative group comprised 42 primary AH non-RA patients matched to age, sex, body mass index (BMI) and duration of AH. The diagnosis of RA and primary hypertension were established according to 1987 American College of Rheumatology (ACR) classification criteria5 and by exclusion of secondary hypertension,6 respectively. Patients with cerebrovascular or ischemic heart disease were excluded from the study. The antihypertensive medication was similar in both groups of patients. The study protocol was approved by the Ethics Committee of the Dubrava University Hospital, Zagreb, and a written informed consent (according to the Declaration of Helsinki) was obtained from all study participants. All participants underwent a detailed evaluation, including a detailed medical history, physical examination and the measurement of body height and weight. AH was treated according to the European Society of Hypertension and the European Society of Cardiology 2007 guidelines,6 and antihypertensive medication was similar in both groups of patients. Laboratory tests included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), total cholesterol (Chol), high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides (TG), creatinine and plasma glucose (Glc), and were performed using Olympus (Tokyo, Japan) autoanalyzers according to the manufacturer’s protocol. For RA group pain, the patients’ general health, functional status and disease activity were assessed using the Pain Visual Analogue Scale (VASP), General Health VAS (VASGH), Health Assessment Questionnaire (HAQ) and Disease Activity Score of 28 joints and CRP (DAS28-CRP) as described previously.7 Rheumatoid factor (RF) was determined by immunoturbidimetric method on the Olympus AU2700 analyzer. Anti-cyclic citrulinated peptide antibody (anti-CCP) was determined using the MEIA method (microparticle enzyme immunoassay) on Abbott AxSym analyzer (Abbott, Abbott Park, IL, USA) with cut-off of 5 U/mL.

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Ambulatory blood pressure (ABP) was recorded using Oscar 2, Accu Win Pro V3 oscillometric monitor (Sun Tech Medical, Inc., Morrisville, NC, USA) programmed to take a reading every 20 min in the daytime (from 7.00. to 10.00 h) and every 30 min at nighttime (from 22.00 to 7.00 h the next day). From 24-h blood pressure reading, diastolic blood pressure (DBP) was plotted against systolic blood pressure (SBP) and slope of regression line, and AASI were calculated. AASI was defined as 1 minus regression slope.8 Measurement of IMT was performed by high-resolution B-mode ultrasonography with linear ultrasound transducers at frequencies > 7 MHz (model Pro Sound SSD - alpha 5, Aloka, Tokyo, Japan). The arterial wall segments were assessed in a longitudinal view, perpendicular to the ultrasound beam, with both walls clearly visualized. IMT was measured on the far wall of the arteries at the sites of greatest arterial thickness. Three measurements taken by two well-trained neurologists (JB, MS) were made 1 cm proximally from the carotid bulb on each side. These measurements were averaged to provide a mean IMT on each side and the mean value (left + right)/2 was taken as a measure of the wall thickness of the distal common carotid artery (ccIMT).9

Statistical analyses The normality of the data distribution was assessed using the Kolgomorov–Smirnov test. Values are presented as mean  SD, median (interquartile range), or percentage (confidence interval: CI) as appropriate. Comparisons were performed with Student’s t-test, Mann–Whitney U-test and chi-squared test for normally, non-normally distributed and categorical variables, respectively. The correlations between various parameters within groups were analyzed by Pearson correlation. P-values < 0.05 (two-tailed) were considered significant. All statistical analyses were performed using SPSS 17.0 software (SPSS Inc., Chicago, IL, USA).

RESULTS The RA and non-RA groups of patients (Table 1) were similar in age, sex, BMI and duration of AH. Mean SBP during ABP recording was higher in the RA group than in the non-RA group, while mean DBP was similar in both groups. Plasma Chol, LDL, TG and creatinine levels were similar in both groups, while HDL and Glc plasma levels were higher in the non-RA group. Inflammatory markers (plasma CRP level, ESR) and preclinical atherosclerotic indices (AASI and ccIMT) were higher in RA patients.

International Journal of Rheumatic Diseases 2015

Preclinical atherosclerosis in hypertensive RA

Table 1 Characteristics of hypertensive RA and non-RA patients Parameter General Age (years) Women, n, % (95%CI) BMI (kg/m2) Duration of hypertension, years SP mean (mmHg) DP mean (mmHg) ESR (mm/h) CRP (mg/L) Chol (mmol/L) HDL (mmol/L) LDL (mmol/L) TG (mmol/L) Creatinine (mmol/L) Glc (mmol/L) AASI ccIMT (mm) RA specific RA duration (years) DAS28-CRP HAQ VASP VASGH RF (IU/mL) Anti-CCP positive, n % (95%CI) Duration of glucocorticoid therapy, years

RA (n = 55)

Non-RA (n = 42)

P-value

60.1  11.10 39, 70.9 (57.9–81.2) 28.8  4.20 6.0 (2.0, 11.0) 138.5  17.81 80.7  10.97 25.0 (15.0, 44.0) 10.7 (4.1, 17.7) 5.56  1.169 1.45  0.351 3.44  1.0 1.48 (1.09, 1.71) 83.15  14.90 4.80 (4.30, 5.20) 0.4663  0.1550 0.9  0.26

56.7  11.74 30, 71.4 (56.4–82.2) 27.5  4.8 6.0 (2.0, 12.0) 130.6  13.55 79.21  9.03 15.0 (10.6, 20.0) 3.0 (1.8, 7.3) 5.56  1.177 1.64  0.538 3.32  1.048 1.19 (0.91, 2.07) 84.33  13.05 5.14 (4.76, 5.90) 0.3831  0.1723 0.74  0.23

0.152 0.955 0.143 0.948 0.019 0.491 < 0.001 < 0.001 0.999 0.037 0.568 0.178 0.683 0.008 0.016 < 0.001

7.0 (3.0, 10.0) 4.94  1.33 1.33  0.78 58.09  20.74 58.73  18.89 150.3  227.23 38, 69.1 (56.079.2) 4.6  4.4

ND ND ND ND ND ND ND ND

Results are mean  SD, median (interquartile range), or numbers and percentages (confidence interval) as appropriate. RA, rheumatoid arthritis; NS, not significant; CI, confidence interval; BMI, body mass index; SP, systolic blood pressure; DP, diastolic blood pressure; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; Chol, plasma cholesterol; TG, plasma trigycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Glc, plasma glucose; ND, not done; DAS28-CRP: Disease Activity Score of 28 joints and CRP; HAQ, Health Assessment Questionnaire; VASP: Pain Visual Analog Scale; VASGH, General Health Visual Analog Scale; RF, rheumatoid factor; anti-CCP, anti-cyclic citrulinated peptide antibody.

In RA patients ASSI showed positive correlation (Table 2) with ccIMT, and age of patients, while ccIMT showed positive correlation with age of patients and RF level and negative correlation with HDL level. There was no correlation between either AASI or ccIMT and other variables examined (duration of AH, BMI, CRP, ESR, Chol, LDL, TG, creatinine, and with RA-specific variables, except RF, results not shown). In non-RA patients there was no correlation either between AASI and ccIMT (Table 2) or between these variables and other variables examined (results not shown).

DISCUSSION AH contributes to development of atherosclerosis and ccIMT and pulmonary wedge pressure are validated indices for assessment of subclinical hypertensive vascular damage.6 Subclinical atherosclerosis was not studied in detail in the subset of AH RA patients.

International Journal of Rheumatic Diseases 2015

Table 2 Correlations between AASI and ccIMT and various variables in hypertensive RA and non-RA patients Variable

AASI r

ccIMT P

RA patients (n = 55) ccIMT 0.332 0.013 Age 0.546 < 0.001 RF 0.081 0.185 HDL 0.047 0.734 Non-RA patients (n = 42) ccIMT 0.164 0.30

r

0.549 0.274 0.272

P

< 0.001 < 0.05 0.05

RA, rheumatoid arthritis; AASI, ambulatory arterial stiffness index; ccIMT, common carotid intima-media thickness; r, Pearson’s correlation coefficient; NS, not significant; RF, rheumatoid factor; HDL, highdensity lipoprotein.

Our results clearly show increase of both AASI and ccIMT in AH RA patients compared to well-matched AH non-RA patients. The meaningful differences between

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groups in laboratory variables were only in inflammatory markers (CRP plasma level and ESR), which were higher in the RA group. Statistically significant differences in other laboratory variables (HDL and Glc plasma levels) can be considered clinically insignificant because their values were within the reference range. AASI reflects a dynamic relationship between SBP and DBP and indirectly includes arterial stiffness. For a given increase in DBP the increase in SBP is higher as arterial compliance is lower. AASI is independently associated with age, SBP, DPB and 24-h pulse pressure. AASI is in correlation with indices of arterial stiffness: pulse wave velocity (PWV) and augmentation index (Alx). It may be considered as composite indices of arterial function, including arterial stiffness.3 Increased arterial stiffness can explain higher SBP in RA patients. The association of AASI and ccIMT in the RA group, unlike the non-RA group, indicates more pronounced atherosclerosis in the former than in the later. A number of studies showed an increase of ccIMT and arterial stiffness assayed by PWV and Alx in RA patients compared to healthy controls,4,10 indicating augmented preclinical atherosclerosis in RA patients. Increased arterial stiffness and ccIMT predict cardiovascular events in general11 and particularly in RA patients.12 It was proposed that chronic inflammation promotes development of both premature atherosclerosis1,10 and AH13 in RA. However, association of inflammatory markers with either ccIMP4,14 or AH7,13 in RA were not consistently found. We did not find association of inflammatory markers (CRP, ESR) and RA activity (DAS28-CRP) with either AASI or ccIMT, which is consistent with findings of the majority of studies included in a systematic review. These studies reported no association between inflammatory markers with either arterial stiffness or ccIMT in RA patients.15 Association of AH with RA is controversial. Several studies showed an increased prevalence of AH in RA but others did not.13 Our results from the population study concerning prevalence of AH in RA and osteoarthritis patients indicate that apparent higher prevalence of AH in RA is rather due to confounding effects of age and BMI than to specific features of the disease.7 One-point measurements of highly changeable variables (CRP, ESR, DAS28-CRP) in a cross-sectional study involving long-standing treated RA patients are not adequate indices of chronic inflammation and disease activity burden. The proper assessment of the relationship of chronic inflammation and disease activity with preclinical atherosclerosis indices requires a longitudi-

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nal study with time-integrated data regarding inflammation and disease activities. AAIS derived from ABP is a simple and readily accessible index of vascular function, but further studies including PWV and Alx measurements are required to show if AAIS is a surrogate index of arterial stiffness and its value as a predictive factor for cardiovascular events.3 In conclusion, the results show a more pronounced subclinical atherosclerosis in hypertensive RA patients than in hypertensive non-RA patients, indicating that additional proatherogenic factors are involved in the development of atherosclerosis in RA patients. Further studies are necessary to evaluate a mutual effect of preclinical atherosclerosis and AH on cardiovascular risk in RA patients.

ACKNOWLEDGEMENTS This work was supported by a grant from the Ministry of Science, Education and Sport, the Republic of Croatia (198-1081874-0183 to JMV).

COMPETING INTERESTS The authors declare that they have no competing interests.

REFERENCES 1 Van Doornum S, McColl G, Wicks IP (2002) Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? Arthritis Rheum 46, 862–73. 2 Jankowski P, Bilo G, Kawecka-Jaszcz K (2007) The pulsatile component of blood pressure: its role in the pathogenesis of atherosclerosis. Blood Press 16, 238–45. 3 Kollias A, Stergiou GS, Dolan E, O’Brien E (2012) Ambulatory arterial stiffness index: a systematic review and meta-analysis. Atherosclerosis 224, 291–301. 4 van Sijl AM, Peters MJ, Knol DK et al. (2011) Carotid intima media thickness in rheumatoid arthritis as compared to control subjects: a meta-analysis. Semin Arthritis Rheum 40, 389–97. 5 Arnett FC, Edworthy SM, Bloch DA et al. (1988) The American Rheumatism Assocciation 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31, 315–24. 6 Mancia G, De Backer G, Dominiczak A et al. (2007) 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 28, 1462–536.

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Preclinical atherosclerosis in hypertensive RA

7 Morovic-Vergles J, Salamon L, Marasovic-Krstulovic D et al. (2013) Is the prevalence of arterial hypertension in rheumatoid arthritis and osteoarthritis associated with disease? Rheumatol Int 33, 1185–92. 8 Li Y, Wang JG, Dolan E et al. (2006) Ambulatory arterial stiffness index derived from 24-hour ambulatory blood pressure monitoring. Hypertension 47, 359–64. 9 Touboul PJ, Hennerici MG, Meairs S et al. (2007) Mannheim carotid intima-media thickness consensus (2004– 2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 23, 75–80. 10 Pieringer H, Pichler M (2011) Cardiovascular morbidity and mortality in patients with rheumatoid arthritis: vascular alterations and possible clinical implications. QJM 104, 13–26.

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11 Lane HA, Smith JC, Davies JS (2006) Noninvasive assessment of preclinical atherosclerosis. Vasc Health Risk Manag 2, 19–30. 12 Gonzalez-Juanatey C, Llorca J, Martin J, Gonzalez-Gay MA (2009) Carotid intima-media thickness predicts the development of cardiovascular events in patients with rheumatoid arthritis. Semin Arthritis Rheum 38, 366–71. 13 Panoulas VF, Metsios GS, Pace AV et al. (2008) Hypertension in rheumatoid arthritis. Rheumatology (Oxford) 47, 1286–98. 14 Hannawi S, Haluska B, Marwick TH, Thomas R (2007) Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Res Ther 9, R116. 15 Sandoo A, Veldhuijzen van Zanten JJ, Metsios GS, Carroll D, Kitas GD (2011) Vascular function and morphology in rheumatoid arthritis: a systematic review. Rheumatology (Oxford) 50, 2125–39.

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Ambulatory arterial stiffness index and carotid intima-media thickness in hypertensive rheumatoid patients: a comparative cross-sectional study.

Rheumatoid arthritis is associated with accelerated atherosclerosis. However, little is known about preclinical atherosclerosis in hypertensive rheuma...
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