TY - JOUR
AB - Summary Background Rheumatoid arthritis (RA) patients may suffer cardiovascular (CV) events much more than the general population, and CV disease is the leading cause of death in patients with RA. Our hypothesis was that impaired function of endothelial progenitor cells may contribute to endothelial dysfunction and the clinical CV events of patients with RA. Methods About 27 RA patients (9 males and 18 females) with an active disease and 13 healthy subjects who served as the control group (nine males and four females) were enrolled to this prospective study. The ability to grow in culture colony-forming units of endothelial progenitor cells (CFU-EPCs) was measured, as well as their endothelial function using high-resolution ultrasonography of the brachial artery, and levels of C reactive protein (CRP) in the serum. For statistical analysis, we used the Student’s t-test. Results As a group, patients with RA were older (P < 0.0001), had severe endothelial dysfunction (P<0.0001), with impaired ability to grow CFU-EPCs (P<0.0001), and a higher inflammatory state (P = 0001). No difference was observed in BMI. All RA patients had an active disease (DAS28 3.9 ± 0.9) for 9.2 ± 6.5 years. The same differences were observed in both genders. Conclusions Patients with RA had an impaired ability to grow EPCs and severe endothelial dysfunction. Inability to grow colonies of EPCs reflects the impaired regenerative capacity of patients with RA and may explain the endothelial dysfunction and the high CV event rate among patients with RA. Background RA is associated with a high rate of cardiovascular (CV) events, morbidity and mortality.1–3 Retrospective studies showed that patients with RA are at increased risk (almost double) to develop acute myocardial infarction compared with the healthy population.4 The high systemic inflammatory burden in RA seems to be an important mechanism that eventually leads to vascular inflammation, accelerated atherosclerosis and CV events.5 Traditional CV risk assessment (the Framingham and the systemic coronary risk evaluation [SCORE]) actually underestimates the real risk to develop acute myocardial infarction or acute stroke, because these models do not incorporate the impact of systemic inflammation and the effect of inflammation on the lipid profile.6 The European League Against Rheumatism (EULAR) suggested to multiply by 1.5, the estimated conventional risk scale of CV disease in patients with RA whose disease duration is more than 10 years, patients who have a positive Rheumatoid Factor or a positive anti-CCP and for patients with severe extra articular manifestations.7 Supportive evidence to this approach comes from studies showing that therapies against inflammation, like anti Tumor Necrosis Factor (TNF) therapy and methotrexate (MTX) or other disease modifying anti rheumatic drugs (DMARDs), reduce inflammation and decreased CV morbidity and mortality in patients with RA.8,9 Structural vascular disease estimated by the carotid intima thickness (IMT) was found to be increased in patients with RA.10,11 Endothelial function and arterial stiffness were also found to be impaired in patients with RA.12–14 Endothelial function and dysfunction and vascular damage and repair are dependent on bone marrow derived endothelial stem cells. Studies have shown a correlation between endothelial function measured by the brachial artery method and the number and function of endothelial progenitor cells (EPCs) in the peripheral blood. EPCs number and function were reduced in patients with CV risk factors who also had endothelial dysfunction (measured by the brachial artery reactivity method) and among patients with atherosclerosis.15 Patients with active RA had a decreased EPCs activity documented by flow cytometry.16 EPCs can be isolated from circulating mononuclear cells. Laboratory evidence suggests that these cells express a number of endothelial-specific cell-surface markers and exhibit numerous endothelial properties.15,17 Studies that measured EPCs in RA patients used flow cytometry methods, reflecting the number of EPCs the peripheral circulation. However, no one studied their function and their ability to build colonies— a crucial event in regeneration of damaged blood vessels. We hypothesized that EPCs' function could be impaired and it might affect the endothelial repair in patients with RA. Methods The study was approved by the institutional review board of the Baruch Padeh Medical Center and every patient or a healthy volunteer had to sign a consent form before enrollment to the study. Only patients with an active long standing (more than 12 months) RA were recruited to the study. The selected patients did not have renal failure, type 2 or type 1 diabetes mellitus, hypertension, hypercholesterolemia, documented coronary artery disease, nor cancer. All patients were examined by an experienced Rheumatologist in the outpatient clinic and underwent a detailed assessment of disease activity using the disease activity scale (DAS28) (both, DAS-28 ESR and DAS-28 CRP). The DAS score already took into acount the swollen and tender joints. Forty subjects were recruited to this prospective study. Twenty-seven RA patients (9 males [mean age 54.4 ± 11.1 years old] and 18 females [mean age 51.7 ± 12.1 years old]) with an active RA (DAS28 was 4.2 ± 0.8 for males, 3.9 ± 1.0 for females). The average time of disease activity was 9.2 ± 6.3 years (males) and 9.2 ± 6.9 years (females). About 13 healthy volunteers (9 men [mean age 32.8 ± 3.1 years old] and 4 women [mean age 41.5 ± 16.4 years old]) served as the control group. All signed a consent form before enrollment to the study. Vascular studies Flow mediated diameter percent change (FMD%): All measurements of brachial artery diameter and FMD% were performed in the morning, in a quiet and dark room and at controlled ambient temperatures between 20°C and 26°C. Studies were conducted after an overnight fast of at least 10 h (water was permitted), with the subject supine, and after 10 min of rest. The subject's right arm was comfortably immobilized in the extending position, allowing for ultrasound scanning of the brachial artery 5–10 cm above the antecubital fossa. In each examination, recording of vessel images was followed by inflation of a cuff to a supra-systolic pressure (40–50 mmHg above median blood pressure) for 5 min. Subsequently, the cuff was deflated and the brachial artery diameter was imaged and recorded for 3 min. An FMD% of more than 10% is considered a normal response. Lower than 10% FMD% reflect endothelial dysfunction, which means a high likelihood of developing a CV event in the future. Subjects with negative FMD% results (the artery is constricted after stress and not dilated as was expected) have the worst prognosis. Growth of CFU-EPCs in culture Peripheral-blood mononuclear cells formed distinct colonies on fibronectin-coated dishes (Figure 1). We used a phase-contrast micrograph to detect an EPC characterized by a central cluster of rounded cells surrounded by radiating thin, flat cells (×200).18 It has been previously demonstrated that EPCs isolated in this fashion exhibit many endothelial characteristics, including expression of CD31, TIE2 and vascular endothelial growth factor receptor.19 Figure 1. View largeDownload slide Colonies of endothelial progenitor stem cells. Figure 1. View largeDownload slide Colonies of endothelial progenitor stem cells. The investigator who performed the laboratory experiments was blinded to the patients’ clinical data. Venous blood samples were drawn from an antecubital vein into ethylene diamine tetra acetic acid-containing tubes. Forty milliliters of blood were processed; peripheral blood mononuclear cells were isolated by Ficoll density-gradient centrifugation, washed twice in phosphate-buffered saline with 5% fetal bovine serum and re-suspended in media (EndoCult basal media with supplements; StemCell Technologies, Vancouver BC Canada, for EPC colony forming assay). Cells were plated on human fibronectin-coated plates (BIOCOAT; Becton Dickinson Labware Bedford Mass) at a density of 5 × 106 cells/well and incubated at 37°C in humidified 5% CO2. After 48 h, the non-adherent cells were re-plated onto fibronectin-coated 24-well plates at a density of 1 × 106 cells/well. After 5 days, CFUs (defined as a central core of rounded cells surrounded by elongated, spindle-shaped cells) were counted manually in 8 wells of a 24-well plate. The average number of CFUs per well is represented. A colony of EPCs consisted of multiple thin, flat spindle-like cells emanating from a central cluster of rounded oval cells. A central cluster alone without associated emerging cells, the ‘sunflower’ image, was not counted as a colony. Colonies were counted manually in a minimum of eight wells by observers who were unaware of the subjects’ clinical profiles. Statistical analysis Data are expressed as means ± SE. Patients were compared with healthy controls in age, vascular reactivity (FMD%), the ability to grow endothelial progenitor stem cells in culture, CRP level and BMI with the use of a two-tailed unpaired Student's t-test. The χ2 test was used for comparisons of categorical variables. Results Formation of CFU-EPCs We assessed whether EPCs’ growth correlated with RA activity, studying also gender effect on these correlations. The number of CFU-EPCs was significantly reduced in patients with RA. Males with RA had 6.8 ± 6.1 CFU-EPCs vs. 24.2 ± 4.4 CFU-EPCs in healthy subjects [P < 0.0001], and females with RA had 6.2 ± 8.1 CFU-EPCs vs. 22.2 ± 6.7 CFU-EPCs in healthy females [P = 0.008] (Table 1). Table 1. Vascular and stem cells’ function in patients with RA No Age (y) FMD% CFU-EPCs Length (y) CRP (mg) BMI DAS28 All RA Pts. 27 52.6 ± 11.7 −5.8 ± 7.7 6.4 ± 7.4 9.2 ± 6.5 7.6 ± 8.7 25.8 ± 4.4 3.9 ± 0.9 Controls 13 35.4 ± 9.2 20.3 ± 8.2 23.6 ± 5.2 0.2 ± 0.2 25.4 ± 4.1 P value <0.0001 <0.0001 <0.0001 0.001 0.776 Men RA Pts. 9 54.4 ± 11.1 −9.4 ± 6.8 6.8 ± 6.1 9.2 ± 6.3 7.7 ± 10.4 25.4 ± 3.2 4.2 ± 0.8 Controls 9 32.8 ± 3.1 15.0 ± 8.6 24.2 ± 4.4 0.27 ± 0.2 27.1 ± 3.8 P value 0.0002 <0.0001 <0.0001 0.06 0.326 Women RA Pts. 18 51.7 ± 12.1 −4.6 ± 7.4 6.2 ± 8.1 9.2 ± 6.9 5.7 ± 8.0 26.1 ± 4.9 3.9 ± 1.0 Controls 4 41.5 ± 16.4 27.3 ± 3.9 22.2 ± 3.9 0.26 ± 0.3 21.6 ± 2.6 P value 0.31 <0.0001 0.008 0.01 0.03 No Age (y) FMD% CFU-EPCs Length (y) CRP (mg) BMI DAS28 All RA Pts. 27 52.6 ± 11.7 −5.8 ± 7.7 6.4 ± 7.4 9.2 ± 6.5 7.6 ± 8.7 25.8 ± 4.4 3.9 ± 0.9 Controls 13 35.4 ± 9.2 20.3 ± 8.2 23.6 ± 5.2 0.2 ± 0.2 25.4 ± 4.1 P value <0.0001 <0.0001 <0.0001 0.001 0.776 Men RA Pts. 9 54.4 ± 11.1 −9.4 ± 6.8 6.8 ± 6.1 9.2 ± 6.3 7.7 ± 10.4 25.4 ± 3.2 4.2 ± 0.8 Controls 9 32.8 ± 3.1 15.0 ± 8.6 24.2 ± 4.4 0.27 ± 0.2 27.1 ± 3.8 P value 0.0002 <0.0001 <0.0001 0.06 0.326 Women RA Pts. 18 51.7 ± 12.1 −4.6 ± 7.4 6.2 ± 8.1 9.2 ± 6.9 5.7 ± 8.0 26.1 ± 4.9 3.9 ± 1.0 Controls 4 41.5 ± 16.4 27.3 ± 3.9 22.2 ± 3.9 0.26 ± 0.3 21.6 ± 2.6 P value 0.31 <0.0001 0.008 0.01 0.03 Table 1. Vascular and stem cells’ function in patients with RA No Age (y) FMD% CFU-EPCs Length (y) CRP (mg) BMI DAS28 All RA Pts. 27 52.6 ± 11.7 −5.8 ± 7.7 6.4 ± 7.4 9.2 ± 6.5 7.6 ± 8.7 25.8 ± 4.4 3.9 ± 0.9 Controls 13 35.4 ± 9.2 20.3 ± 8.2 23.6 ± 5.2 0.2 ± 0.2 25.4 ± 4.1 P value <0.0001 <0.0001 <0.0001 0.001 0.776 Men RA Pts. 9 54.4 ± 11.1 −9.4 ± 6.8 6.8 ± 6.1 9.2 ± 6.3 7.7 ± 10.4 25.4 ± 3.2 4.2 ± 0.8 Controls 9 32.8 ± 3.1 15.0 ± 8.6 24.2 ± 4.4 0.27 ± 0.2 27.1 ± 3.8 P value 0.0002 <0.0001 <0.0001 0.06 0.326 Women RA Pts. 18 51.7 ± 12.1 −4.6 ± 7.4 6.2 ± 8.1 9.2 ± 6.9 5.7 ± 8.0 26.1 ± 4.9 3.9 ± 1.0 Controls 4 41.5 ± 16.4 27.3 ± 3.9 22.2 ± 3.9 0.26 ± 0.3 21.6 ± 2.6 P value 0.31 <0.0001 0.008 0.01 0.03 No Age (y) FMD% CFU-EPCs Length (y) CRP (mg) BMI DAS28 All RA Pts. 27 52.6 ± 11.7 −5.8 ± 7.7 6.4 ± 7.4 9.2 ± 6.5 7.6 ± 8.7 25.8 ± 4.4 3.9 ± 0.9 Controls 13 35.4 ± 9.2 20.3 ± 8.2 23.6 ± 5.2 0.2 ± 0.2 25.4 ± 4.1 P value <0.0001 <0.0001 <0.0001 0.001 0.776 Men RA Pts. 9 54.4 ± 11.1 −9.4 ± 6.8 6.8 ± 6.1 9.2 ± 6.3 7.7 ± 10.4 25.4 ± 3.2 4.2 ± 0.8 Controls 9 32.8 ± 3.1 15.0 ± 8.6 24.2 ± 4.4 0.27 ± 0.2 27.1 ± 3.8 P value 0.0002 <0.0001 <0.0001 0.06 0.326 Women RA Pts. 18 51.7 ± 12.1 −4.6 ± 7.4 6.2 ± 8.1 9.2 ± 6.9 5.7 ± 8.0 26.1 ± 4.9 3.9 ± 1.0 Controls 4 41.5 ± 16.4 27.3 ± 3.9 22.2 ± 3.9 0.26 ± 0.3 21.6 ± 2.6 P value 0.31 <0.0001 0.008 0.01 0.03 Vascular reactivity measurements There was a significant difference in the vascular reactivity of patients with RA compared to the healthy controls. The FMD% of patients with RA was −5.8 ± 7.7% vs. controls who had 20.3± 8.2% (P < 0.0001). Men with RA had endothelial dysfunction with an FMD% of −9.4 ± 6.8% vs. 15.0 ± 8.6% (P < 0.0001) (Table 1), and women with RA had endothelial dys3.8function of −4.6 ± 7.4% vs. 27.3 ± 3.9% (P < 0.0001) (Table 1). Interestingly, females with RA had a higher BMI compared with healthy females (26.1 ± 4.9 vs. 21.6 ± 2.6, P = 0.03), a phenomenon that was not found in men (25.4 ± 3.2 vs. 27.1 ± 3.8, P = 0.326). Discussion Our study shows that patients with RA with a long standing disease had higher levels of inflammatory markers and an impaired ability to grow colonies of endothelial stem cells in culture along with severe endothelial dysfunction. It has been shown that patients with RA tend to develop atherosclerosis at early stage of their inflammatory disease, with an increased intima media thickness and significantly lower levels of FMD%, which reflects an impaired nitric oxide bioavailability, leading to accelerated atherosclerosis through a nitric oxide dependent pathway.20 These observations were done at an early stage of the disease, less than 12 months of RA disease activity, which may suggest an independent vascular pathway that leads to accelerated atherosclerosis.21 Partial mechanistic explanation was found in a study that measured levels of asymmetric diendothemethyl arginine (ADMA), a competitive inhibitor to L arginine (the natural substrate of nitric oxide production through activated endothelial nitric oxide synthase), and found that ADMA levels were significantly higher in RA patients, and that these levels were inversely correlated with endothelial function of the patients (measured by the FMD% in the brachial artery method).22 Another study found that patients with RA had an impaired lipid profile with high levels of total and low density lipoprotein cholesterol and very low high density lipoprotein cholesterol levels, altogether with endothelial dysfunction and high levels of inflammatory markers.23 A genetic mechanistic pathway was suggested, through common genes that are involved in RA and in accelerated atherosclerosis. HLA-DRB1 alleles encoding a common sequence of amino acids (shared epitope alleles) have been associated with an increased incidence of erosions and extra articular manifestations of RA. It was found that patients with an increased incidence of CV events and endothelial dysfunction have the HLA-DrB1*04 shared epitope alleles, in particular, those who carry the HLA-DRB1*0404 allele.24–26A study from UK described an increased mortality risk among RA patients who carry the HLA-DRB1*0101/*0401 and 0404/*0404 genotypes.26 It has been shown that in atherosclerotic processes there is a lack of EPCs, like in diabetes mellitus, coronary artery disease and depression, leading to endothelial function and eventually to atherosclerotic clinical syndromes including coronary artery disease and peripheral artery disease.18 Impaired ability to grow colonies of stem cells is a long standing process that leads to CV disease and acute myocardial infarction,19 which may also be associated with cerebral vascular disease leading to acute ischemic stroke.27,28 Endothelial damage ultimately represents a balance between the magnitude of injury and the capacity for repair. Inability to repair means lack of regenerative power, lack of vasculogenesis and a vicious cycle of endothelial damage. This impaired ability to grow colonies of EPCs in patients with RA could be due to several mechanistic pathways: a long standing process of oxidative stress, lack of nitric oxide activity, a self-perpetuating process of deterioration of the nitric oxide reservoir.29 Another explanation could be a continuous endothelial damage or dysfunction leads to an eventual depletion or exhaustion of a presumed finite supply of EPCs.30 Interestingly, recent studies in animals have suggested that the exhaustion of stem cells may be an important determinant of a number of age-related conditions.31–33 An inverse correlation between EPCs number and the Framingham risk score was found in patients at risk to develop CV events and both in long standing and early RA patients.34 Studies that quantified the number of EPCs (CD34+/CD133+) in the peripheral blood of patients with RA using the flow cytometry method, found a significant negative correlation between EPCs and levels of pro-inflammatory cytokines (interleukin 1 and tumor necrosis factor α) and disease activity score in patients with seropositive RA.35–37 A recent study found that EPCs (measured by flow cytometry) and FMD% (measured by the brachial artery method) were both impaired in patients with active RA, however, after 24 weeks of anti-tumor necrosis factor α treatment, levels of EPCs were restored in parallel with an improvement in endothelial function.38 It has demonstrated that CD34+ cells count was lower in patients with RA, and their reactive oxygen species (ROS) level, expression of Toll-like receptor 3 and interleukin 1β expression were increased in comparison with healthy controls.39 The same group has shown in another study that in patients with RA ROS level, mRNA expression of manganese superoxide dismutase, catalase and the expression of NOX2 were higher while glutathione peroxidase type 1 antioxidant enzymes level was significantly lower.40 Both studies show the kink between inflammation, oxidative stress, the impaired antioxidant system and the impaired vascular responsiveness (endothelial dysfunction)— all lead to accelerated atherosclerosis in patients with RA. It is interesting to mention another study of our group where endothelial function was measured and compared with RA disease activity. Interestingly, the group of patients with the highest flow mediated percent change (FMD%) (who had a good endothelial function) had the lowest clinical RA scores and inflammatory laboratory parameters, which means that measuring endothelial function can estimate RA disease activity and severity, and also could be used as a practical tool for inflammatory activity score and as an early predictor of atherosclerosis in patients with RA.41 Study limitations The small size of our population sample study and the age difference between patients with RA and healthy controls are limiting factors that should be considered, however, our results should encourage performing future prospective studies with larger populations at different age groups, and in different duration of disease activity, to make firm conclusions and to better understand the phenomenon of RA and atherosclerosis. Summary This is the first study that evaluated the function of EPCs, i.e. their ability to create colonies and to regenerate damaged blood vessels. Patients with RA had an impaired ability to grow CFU-EPCs in culture and endothelial dysfunction. Inability to grow colonies of EPCs reflects the impaired regenerative capacity of patients with RA and may explain the mechanism of endothelial dysfunction, leading to the higher rate of CV events in patients with RA. Conflict of interest: None declared. References 1 Peters MJL , Symmons DPM , McCarey D , Dijkmans BAC , Nicola P , Kvien TK , et al. EULAR evidence based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis . Ann Rheum Dis 2010 ; 69 : 325 – 31 . Google Scholar CrossRef Search ADS PubMed 2 Meune C , Touzé E , Trinquart L , Allanore Y. 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Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
TI - Inhibition of endothelial progenitor cells may explain the high cardiovascular event rate in patients with rheumatoid arthritis
JO - QJM: An International Journal of Medicine
DO - 10.1093/qjmed/hcy099
DA - 2018-08-01
UR - https://www.deepdyve.com/lp/oxford-university-press/inhibition-of-endothelial-progenitor-cells-may-explain-the-high-vKF16UT5C0
SP - 525
EP - 529
VL - 111
IS - 8
DP - DeepDyve
ER -