Abstract
Introduction
The patients with antiphospholipid syndrome (APS) associate an increased risk of atherosclerosis.
Objective
To determine the predictors of an abnormal ankle‐brachial index (ABI), surrogate measure of atherosclerosis, in patients with APS.
Methods
The ABI was measured according to standard recommendations in 106 patients. Traditional cardiovascular risk factors were assessed in all cases. A large spectrum of APS antibodies was determined in 73 patients.
Results
A total of 106 patients diagnosed with APS were included. 28.3% patients included were found to have low ABI. Anti‐beta 2‐glycoprotein I (aβ2GPI) IgG antibodies [4.00 (1.00‐79.00) vs 3.00 (0.00‐29.00) U/mL, P = 0.02] and antiprothrombin (aPT) IgM antibodies [4.50 (0.00‐82.00) vs 3.00 (0.00‐14.00) U/mL, P = 0.05] titers were found to be higher in patients with abnormal ABI. However, after multivariate regression analysis, only the aβ2GPI IgG titer remained predictor of low ABI (P = 0.04).
Conclusions
aβ2GPI IgG associated with impaired ABI in patients with APS. This relation might reflect their involvement in the atherosclerosis occurrence.
Keywords: ankle‐brachial index, antiphospholipid syndrome, beta‐2 glycoprotein I, cardiovascular risk
Abbreviations
- ABI
ankle‐brachial index
- aCL
anticardiolipin
- aPE
antiphosphatidylethanolamine
- aPL
antiphospholipid
- APLAs
antiphospholipid antibodies
- aPS
antiphosphatidylserine
- APS
antiphospholipid syndrome
- aPT
antiprothrombin
- aβ2GPI
anti‐β2 glycoprotein I
- HTN
hypertension
- LAC
lupus anticoagulant
- ox‐LDL
oxidized low‐density lipoprotein
- SLE
systemic lupus erythematosus
1. INTRODUCTION
The cardiovascular risk increase observed in patients with antiphospholipid syndrome (APS) is not completely explained by the traditional risk factors.1 Thus, the cardiovascular risk factors’ prevalence is similar in APS and other rheumatologic diseases or general population.2
Atherosclerosis is an inflammatory process,3 and also, in immune diseases, systemic inflammation is important 4 and plays also a pathogenic role for atherosclerosis progression, cytokines, and autoantibodies being involved in the vascular impairment.5 Moreover, antiphospholipid antibodies (APLAs) positivity may be related to the vasculopathy occurrence.1
Ankle‐brachial index (ABI) is a noninvasive test that can be used to identify asymptomatic patients with peripheral arterial disease 6 and also an efficient tool for subclinical atherosclerotic disease screening.7
In this research, we intended to determine the predictors of an abnormal ABI, surrogate marker for atherosclerosis in patients with APS, starting from traditional cardiovascular risk factors and continuing to diagnostic and nondiagnostic antiphospholipid antibodies (APLAs).
2. METHODS
A total of 106 patients fulfilling the APS criteria, diagnosed with both primary and secondary APS, consecutively admitted to the Internal Medicine Department of Colentina Clinical Hospital were prospectively enrolled in the present research. All patients had previous determinations of lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and anti‐β2 glycoprotein I antibodies (aβ2GPI) as well as history of thrombotic or pregnancy events sustaining the APS diagnosis.
The following exclusion criteria were used: active malignancy (solid or hematological), acute or chronic infections, granulomatous chronic diseases, age under 18 years, pregnancy or 6 months postpartum period, and severe chronic renal failure.
Demographic characteristics and the atherosclerosis traditional risk factors were prospectively recorded for each patient, namely age, gender, body mass index (BMI), waist circumference, waist‐hip ratio, disease duration, smoking history, diagnosis of arterial hypertension (HTN), dyslipidemia, diabetes, metabolic syndrome, systolic and diastolic blood pressure, pulse pressure (defined as differential between systolic and diastolic pressure), blood glucose levels, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Values of waist circumference and HDL cholesterol cutoff values were expressed according to gender as the normal ranges are different.
The ABI was assessed using a handheld Doppler‐based device and a blood pressure cuff applied to both arms and ankles. The systolic blood pressure was measured twice at each brachial artery and once at each dorsalis pedis and tibialis posterior arteries after 5 minutes of supine position. The ABI was then calculated for the right, respectively, the left side as the ratio between the highest value of the ankle blood pressure and the highest value of the brachial blood pressure.
Serums of 73 patients were collected at baseline and successively stored at −70°. A large spectrum of antiphospholipid antibodies (APLAs) was then determined in one step for all serums: IgG and IgM anticardiolipin antibodies (aCL), IgG and IgM anti‐β2 glycoprotein I antibodies (aβ2GPI), IgG and IgM antiphosphatidylserine antibodies (aPS), IgG and IgM anti phosphatidylethanolamine antibodies (aPE), and IgG and IgM antiprothrombin antibodies (aPT). All determinations were carried out by enzyme‐linked immunosorbent assay (ELISA) from Aesku Diagnostics, Wendelsheim, Germany, and the analyzer Chemwell 2910, Awareness Technology, Palm City, Florida, USA.
2.1. Statistical analysis
Variables were expressed as mean ± standard deviation and median (min, max) according to their distribution. T‐independent, chi‐square, and the Mann‐Whitney test when appropriate were used to compare two groups. Parameters that proved to be statistically significant in univariate analysis were then tested in a forward conditional multivariate regression model. The cutoff of P probability for rejecting the null hypothesis was 0.05. SPSS 16.0 software (SPSS Inc, Chicago, Illinois, USA) was used for the statistical analysis.
3. RESULTS
3.1. Study cohort
A total of 106 patients with APS were included. The majority was female gender, with a female‐to‐male ratio of 92:14. The mean ABI value was 0.91 ± 0.18. According to the ABI value, two groups were defined: first group (30 patients) with an ABI value lower than 0.9 (low ABI) and a second one (76 patients) with ABI values equal or higher than 0.9. Only one patient had high ABI (>1.40).
General characteristics of the patients as well as the risk factors traditionally associated with atherosclerosis are listed in Table S1.
When compared to patients with normal ABI, those with low ABI were older both at inclusion (51.1 ± 13.2 vs 42.1 ± 11.1 years, P = 0.001) and at the APS diagnosis (42.9 ± 13.4 vs 36.1 ± 10.6 years, P = 0.07).
In regard to the traditional cardiovascular risk factors, the presence of HTN (63.3% vs 32.9%, P = 0.008) and diabetes (23.3% vs 6.6%, P = 0.02) was significantly higher in patients with low ABI. Also, the values of the pulse pressure (53.8 ± 12.4 vs 48.7 ± 9.8 mm Hg, P = 0.02) and the fasting glucose levels (95.3 ± 17.6 vs 84.6 ± 15.9 mg/dL, P = 0.004) were higher in the low ABI group.
3.2. Antiphospholipid antibodies
In 73 patients—86% of feminine gender, age at inclusion 44.9 ± 0.18 years, and disease duration 3.0 (1.0‐29.0) years—an extended APLA was searched.
For this group of patients, the prevalence of cardiovascular risk factors was as follows: smoking (31.5%), HTN (35.6%), dyslipidemia (53.4%), diabetes (8.2%), and metabolic syndrome (8.2%). Moreover, the pulse pressure value was 48.7 ± 9.5 mm Hg, waist‐hip ratio 0.9 ± 0.1, fasting glucose 88.7 ± 17.4 mg/dL, total cholesterol 191.1 ± 41.3 mg/dL, LDL cholesterol 115.6 ± 33.4 mg/dL, HDL cholesterol 58.7 ± 13.2 mg/dL, and triglycerides 98.8 ± 51.2 mg/dL.
Of the tested APLAs, only the titers of IgG aβ2GPI and IgM aPT were significantly higher in the group of patients with low ABI when compared with normal ABI: 4.0 (1.0‐79.0) vs 3.0 (0.0‐29.0) U/mL, P = 0.02; and 4.5 (0.0‐82.0) vs 3.0 (0.0‐14.0) U/mL, P = 0.05, respectively. No significant differences were found for the other APLAs tested (Table S2).
3.3. Multivariate analysis
In a forward stepwise regression model analyzing parameters associated with ABI in univariate analysis, only the IgG aβ2GPI titer remained predictor of a low ABI (P = 0.04). None of the traditional risk factors of subclinical cardiovascular atherosclerosis analyzed proved to be independent risk factor for impaired ABI in the patients with APS included.
4. DISCUSSION
Ankle‐brachial index is a useful screening tool for subclinical atherosclerosis and a facile method for the global cardiovascular risk evaluation.6 Impaired ABI is seven times more frequent in patients with APS than controls,8 and APLAs presence might be directly involved in the vasculopathy development.1
In patients with SLE, the occurrence of APS has an additive deleterious effect, determining more aggressive arterial atherosclerosis, especially in young patients.9 Also, the abnormal low ABI was identified in patients with APS presenting pregnancy pathology and it was hypothesized that a diffuse vascular impairment might contribute to pregnancy loss in patients with APS.10 There are also data that did not show any correlation of the abnormal ABI neither with the cardiovascular risk factors nor with the APLAs positivity.11 To might have final conclusions, there is also the need of standardized testing in APS.12
Starting from these data, we evaluated the ABI in patients with primary and secondary APS. The group of APS patients with low ABI presented significant higher age, associated HTN and diabetes, higher blood glucose levels, higher pulse pressure values, and lower HDL cholesterol levels in males. Regarding the ten diagnostic and nondiagnostic APLAs tested, we found statistically significant higher titers of aPT IgM and aβ2GPI IgG in patients with low ABI. However, after multivariate analysis, only the aβ2GPI IgG titer was identified as predictor for an impaired ABI in patients with APS.
The aβ2GPI IgG is diagnostic criteria antibodies,13 have pathogenic role in APS,14 and proved good discriminating accuracy for the APS diagnosis.15 The interaction between the oxidized low‐density lipoprotein (ox‐LDL), β2GPI, and aβ2GPI is proposed as pathogenic mechanism for atherogenesis development. Ox‐LDL, an important component of the atherosclerotic lesions,16 is localized in the atherosclerotic plaque in the proximity of β2GPI and lymphocytes.17 The β2GPI probably has antiatherogenic properties, and so the aβ2GPI antibodies might have proatherogenic effects after inclusion in complexes with ox‐LDL and β2GPI.18 However, there are other conflicting data showing that the APLAs have no relation with atherosclerotic plaques,19 but only with the APS thrombotic phenomenon.20
The present research has several limitations. It is a cross‐sectional study without prospective follow‐up of the patients included. The LAC was not determinate as all determinations were carried out on conserved serum. Nevertheless, a large number of APLAs were tested, ten criteria and noncriteria APS antibodies.
In conclusion, we found a high prevalence of an abnormal ABI in the patients with APS tested. The aβ2GPI IgG titer was independently associated with impaired ABI, possibly reflecting the role of disease itself in the vasculopathy pathogenesis.
Supporting information
Caraiola S, Jurcut C, Dima A, Jurcut R, Baicus C, Baicus A. Impaired ankle‐brachial index in antiphospholipid syndrome: Beyond the traditional risk factors. J Clin Lab Anal. 2019;33:e22617 10.1002/jcla.22617
Funding information
This work was supported by CNCSIS‐UEFISCSU, project number PNII—IDEI 2008 code ID_906 (contract 1227).
REFERENCES
- 1. Soltész P, Kerekes G, Dér H, et al. Comparative assessment of vascular function in autoimmune rheumatic diseases: considerations of prevention and treatment. Autoimmun Rev. 2011;10:416‐425. [DOI] [PubMed] [Google Scholar]
- 2. Medina G, Gutiérrez‐Moreno AL, Vera‐Lastra O, et al. Prevalence of metabolic syndrome in primary antiphospholipid syndrome patients. Autoimmun Rev. 2011;10:214‐217. [DOI] [PubMed] [Google Scholar]
- 3. Ross R. Atherosclerosis‐an inflammatory disease. N Engl J Med. 1999;340:115‐126. [DOI] [PubMed] [Google Scholar]
- 4. Dima A, Opris D, Jurcut C, et al. Is there still a place for erythrocyte sedimentation rate and C‐reactive protein in systemic lupus erythematosus? Lupus. 2016;25:1173‐1179. [DOI] [PubMed] [Google Scholar]
- 5. Hahn BH, Grossman J, Chen W, et al. The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. J Autoimmun. 2007;28:69‐75. [DOI] [PubMed] [Google Scholar]
- 6. Greenland P, Abrams J, Aurigemma GP, et al. Prevention Conference V: beyond secondary prevention: identifying the high‐risk patient for primary prevention: noninvasive tests of atherosclerotic burden: writing Group III. Circulation. 2000;101:E16‐E22. [DOI] [PubMed] [Google Scholar]
- 7. Jiménez M, Dorado L, Hernández‐Pérez M, et al. Ankle‐brachial index in screening for asymptomatic carotid and intracranial atherosclerosis. Atherosclerosis. 2014;233:72‐75. [DOI] [PubMed] [Google Scholar]
- 8. Ambrosino P, Lupoli R, Di Minno A, et al. Markers of cardiovascular risk in patients with antiphospholipid syndrome: a meta‐analysis of literature studies. Ann Med. 2014;46:693‐702. [DOI] [PubMed] [Google Scholar]
- 9. Erdozain J‐G, Villar I, Nieto J, et al. Predictors of peripheral arterial disease in SLE change with patient's age. Lupus Sci Med. 2017;4:e000190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Christodoulou C, Zain M, Bertolaccini ML, et al. Prevalence of an abnormal ankle‐brachial index in patients with antiphospholipid syndrome with pregnancy loss but without thrombosis: a controlled study. Ann Rheum Dis. 2006;65:683‐684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Barón MA, Khamashta MA, Hughes GRV, et al. Prevalence of an abnormal ankle‐brachial index in patients with primary antiphospholipid syndrome: preliminary data. Ann Rheum Dis. 2005;64:144‐146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Ke K, Strango ZI, Harper PE, et al. Influence of phosphatidylethanolamine concentration and composition on the detection of antiphosphatidylethanolamine antibodies by ELISA. J Clin Lab Anal. 2016;30:689‐696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295‐306. [DOI] [PubMed] [Google Scholar]
- 14. Ozawa N, Makino T, Matsubayashi H, et al. β2‐GPI‐dependent and independent binding of anticardiolipin antibodies in patients with recurrent spontaneous abortions. J Clin Lab Anal. 1994;8:255‐259. [DOI] [PubMed] [Google Scholar]
- 15. Dima A, Caraiola S, Jurcut C, et al. Extended antiphospholipid antibodies screening in systemic lupus erythematosus patients. Rom J Intern Med. 2015;53:321‐328. [DOI] [PubMed] [Google Scholar]
- 16. Ylä‐Herttuala S, Palinski W, Rosenfeld ME, et al. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989;84:1086‐1095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. George J, Harats D, Gilburd B, et al. Immunolocalization of beta2‐glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression. Circulation. 1999;99:2227‐2230. [DOI] [PubMed] [Google Scholar]
- 18. Hasunuma Y, Matsuura E, Makita Z, et al. Involvement of beta 2‐glycoprotein I and anticardiolipin antibodies in oxidatively modified low‐density lipoprotein uptake by macrophages. Clin Exp Immunol. 1997;107:56973. [DOI] [PubMed] [Google Scholar]
- 19. Bilora F, Boccioletti V, Girolami B, et al. Are antiphospholipid antibodies an independent risk factor for atherosclerosis? Clin Appl Thromb Hemost. 2002;8:103‐113. [DOI] [PubMed] [Google Scholar]
- 20. Petri M. Update on anti‐phospholipid antibodies in SLE: the Hopkins’ Lupus Cohort. Lupus. 2010;19:419‐423. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials