Volume 43 · Issue 2 · March 2014 ISSN 0301-1526
Vasa European Journal of Vascular Medicine
2/14 www.vasa-journal.eu Vasa is listed in
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Vasa 2014; 43: 81 © 2014 Hans Huber Publishers, Hogrefe AG, Bern
Contents Volume 43, Issue 2, March 2014
Contents 81
83
Editorial
R. López-Mejías, F. Genre, C. González- Juanatey, M. A. González-Gay
145
Autoantibodies and biomarkers of endothelial cell activation in atherosclerosis Autoantikörper und Biomarker der Endothel aktivierung bei der Atherosklerose
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88
E. S. Debus
Vascunet registry validated Validierung des Vascunet Registers
L. Pfisterer, G. König, M. Hecker, T. Korff
100 R. Knur
Technique and clinical evidence of neuroprotection in carotid artery stenting Technik und klinische Evidenz der zerebralen Protektion bei der Karotisstentangioplastie
113
Original communications
C. Albert, M. von Schultzendorff, D. Şalaru, Z. Halloul, D. Dragun, H. Heidecke, P. R. Mertens
In arterial occlusive disease autoantibodies against ETAR and AT1R correlate with each other but are not associated with classical cardiovascular risk factors Autoantikörpertiter gegen AT1 R und ETAR korrelieren positiv bei peripherer arterieller Verschlußkrankheit, sind jedoch nicht mit dem Vorliegen klassischer Risiko faktoren assoziiert
124
V. S. Ellensen, I. Abrahamsen, J. Lorens, T. Jonung
Effects of and dalteparin on proliferation and migration of patient-derived vascular smooth muscle cells Auswirkungen von Enoxaparin und Dalteparin auf die Proliferation und Migration humaner vaskulärer glatter Muskelzellen
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C. Heilmaier, A. Koester, T. Moysidis, D. Weishaupt, K. Kröger
Abdominal aortic calcification and its distribution in normal-sized and aneurysmatic abdominal aortas Abdominelle Aortenverkalkung und ihre Verteilung in normalkalibrigen und aneurysmatischen Aorten
141
D. Bergqvist, M. Björck, T. Lees, G. Menyhei
Validation of the VASCUNET registry – pilot study VASCUNET Register Validierung – eine Pilot Studie
T. Lahmer, J. Pongratz, F. Härtl, U. Heemann, R. M. Schmid, H.-H. Eckstein
Acute ischemia of the lower leg caused by granulomatosis with polyangiitis Akute Ischämie der unteren Extremität als Erstmani festation einer Granulomatosis mit Polyangiitis
149
Reviews
Pathogenesis of varicose veins – lessons from biomechanics Pathogenese der Varizenbildung – Lehren aus der Biomechanik
Case reports
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Y. Gunduz, F. Altintoprak, K. Asil, G. Cakmak
An uncommon cause of abdominal pain and weight loss: the superior mesenteric artery syndrome Superior mesenterica Syndrom als ungewöhnliche Ursache von Bauchschmerzen und Gewichtsverlust
J. Shi, J. Lang, Y. Sun, J. Hou, H. Lv
A giant pulmonary arteriovenous malformation without hereditary hemorrhagic telangiectasia: successful interventional embolization using a PDA occluder Erfolgreiche Embolisation einer riesigen pulmonalen arteriovenösen Malformation
82 Imprint 159 From the societies
Author's personal copy (e-offprint) Vasa 2014; 43: 83 – 85 © 2014 Hans Huber Publishers, Hogrefe AG, Bern
R. López-Mejías et al.: Autoantibodies and biomarkers of endothelial cell activation in atherosclerosis DOI 10.1024/0301-1526/a000333
Editorial 83
Comment on Albert et al., page 113
Autoantibodies and biomarkers of endothelial cell activation in atherosclerosis Raquel López-Mejías1, Fernanda Genre1, Carlos González-Juanatey 2, and Miguel A. González-Gay 1 1
Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Rheumatology Division, IFIMAV, Santander, Spain 2 Cardiology Division, Hospital Lucus Augusti, Lugo, Spain
Atherosclerosis (ATS) is a chronic inflammatory disease that affects mainly large and medium sized arteries. This pathology is characterized by the formation and development of ATS plaques (a well-defined structure of lipids, necrotic cores, calcified regions, inflamed smooth muscle cells, endothelial cells, immune cells and foam cells [1]). ATS begins with endothelial dysfunction and structural vascular alterations leading to a subendothelial accumulation of lowdensity lipoprotein (LDL)). This disorder is the underlying cause of most cardiovascular (CV) diseases [2] (including myocardial infarction and stroke) and, therefore, a leading cause of death and morbidity worldwide. Although ATS had been described as an age-related process characterized by the passive accumulation of lipids in the vessel wall, recent studies have revealed that this pathology is a dynamic and complex condition where multiple pathogenic factors (such as classical CV risk factors, inflammation and a genetic background) contribute to cause and perpetuate the atherosclerotic damage [2]. Regarding the inflammatory mechanisms associated with ATS disease, many efforts have been performed to determine whether both innate and adaptive immune systems are associated with ATS initiation and progression. In this context, a relevant role of several molecules (such as autoantibodies and biomarkers of endothelial cell activation) has been demonstrated in the pathogenesis of ATS. An autoantibody is a protein produced by B-cells against one or more of the individual's own proteins and
several studies have revealed its implication in ATS development as pro or anti-inflammatory factors [3]. Among the different autoantibodies, those against angiotensin type-1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) have been proposed as relevant candidates implicated in the ATS pathogenesis. Recently, to clarify whether anti-AT1R and anti-ETAR autoantibodies are directly related to the ATS pathogenesis, Albert et al. [3] have conducted an elegant prospective study in 200 patients with proven ATS and manifestations of arterial disease. Interestingly, the authors showed that both anti-AT1R and anti-ETAR autoantibodies can be detected in a significant proportion of ATS patients. In addition, autoantibody concentrations were independent from classical risk factors [3]. Additionally, the authors detected a strong positive correlation between anti-ETAR and anti-AT1R titers. The results reported by Albert et al. are in accordance with previous studies that had revealed the effect of ETAR in vasoconstriction and cell proliferation and its contribution to the neointima formation after percutaneous coronary intervention in human coronary arteries [4]. Even more, the study performed by Albert et al. is in line with the fact that AT1R, involved in the inflammatory responses initiation via activation of nuclear factor kappa-B (NF-kB), is also associated with expression and severity of atherosclerotic lesions [5]. To the best of our knowledge, the study performed by Albert et al. is the first assessing the prevalence of anti-AT1R and anti-ETAR in an
ATS disease cohort and, therefore, the results obtained may shed light into the complex mechanisms underlying this disorder. Other autoantibodies have been implicated in the pathogenesis of ATS. A good example of that are those against epitopes of oxidized LDL (such as malondialdehyde (MDA)-lysine) that have been proposed as predictors of the progression of carotid ATS in Finnish men [6]. In addition, autoantibodies involved in different autoimmune disorders such as autoantibodies against antiβ2-glycoprotein I [7] or anti-apolipoprotein A-1 [8] (anti-Apo A-1) appear to be directly implicated in the ATS pathogenesis, evidencing the intricate relation between the immune system and the ATS process. Finally, autoantibodies against heat-shock protein (HSP) (molecule synthesized in large amounts when cells are exposed to stressful stimuli such as inflammation, infection and exposure to oxidizing agents) have been associated with both the presence and severity of coronary heart disease [9]. Besides the relevant role of autoantibodies in the ATS pathogenesis, many biomarkers of endothelial cell activation have been described as potential factors involved in the CV damage and, therefore, the assessment of these molecules might be of some help in the daily clinical practice. Among the different biomarkers of endothelial cell activation is Angiopoietin 2 (Angpt-2), a protein required for the formation of blood vessels that makes the endothelium responsive to inflamma-
Author's personal copy (e-offprint) R. López-Mejías et al.: Autoantibodies and biomarkers of endothelial cell activation in atherosclerosis
Vasa 2014; 43: 83 – 85 © 2014 Hans Huber Publishers, Hogrefe AG, Bern
84 Editorial
tory cytokines. Angpt-2 has been implicated in the severity, early onset and development of CV disease in patients with rheumatoid arthritis (RA) (the prototype of chronic inflammatory pathology associated with accelerated atherosclerosis and high CV mortality) [10]. Another molecule, Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) receptor super-family that up-regulates endothelial adhesion molecule production and increases leukocyte adhesion to endothelial cells, has been associated with endothelial activation and carotid ATS in patients with severe RA [11]. Rheumatologists have evidenced the potential beneficial effect of the anti-tumor necrosis factor (anti-TNF)-α therapy on the ATS progression in different chronic inflammatory rheumatic diseases. This effect has led to a decrease in the CV mortality of patients with chronic inflammatory rheumatic diseases undergoing treatment with biologic drugs [12]. Interestingly, several studies have disclosed a correlation between several biomarkers of endothelial cell activation and inflammation following the administration of anti-TNF-α drugs in these patients. In this regard, TNF-α blockade in patients with ankylosing spondylitis (AS) (another disease associated with accelerated ATS and increased risk of CV disease) is associated with significant decrease of the Angpt-2 circulating levels [13]. In this context, a link between some features of metabolic syndrome (that contributes to the increased CV morbidity and mortality in the general population and especially in chronic inflammatory rheumatic diseases) in AS patients undergoing anti-TNF-α therapy and concentrations of asymmetric dimethylarginine (ADMA) (endogenous protein that triggers a reduction in nitric oxide production) has been observed
[14]. Finally, an association between different biomarkers of endothelial cell activation implicated in the development of the atherosclerotic disease has also been described in patients with rheumatic diseases. In this regard, Osteopontin (OPN) (a phosphorylated glycoprotein that promote atherosclerotic plaque instability) concentrations correlated with Angpt-2 serum levels in nondiabetic AS patients undergoing TNF-α antagonist therapy [15]. In conclusion, in recent years major advance in the knowledge of the mechanisms implicated in the ATS has taken place. Since this pathology is a leading cause of death and morbidity worldwide, an important step forward might be to identify high-risk patients who would benefit from active therapy. The use of autoantibodies and biomarkers of endothelial cell activation may help us in the attempt of establishing adequate stratification of the CV risk of our patients. Therefore, the results derived from these studies may be useful in the management of the patients as well as in the search of new therapeutic targets and development of new drugs aimed to decrease the development of ATS disease.
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Acknowledgments Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases studies have been supported by grants from “Fondo de Investigaciones Sanitarias” PI06 / 0024, PS09 / 00748 and PI12 / 00060, and RD12 / 0009/0013 (RIER) from “Instituto de Salud Carlos III” (ISCIII) (Spain).
References 1 Woollard KJ, Geissmann F. Monocytes in atherosclerosis: subsets
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and functions. Nat Rev Cardiol 2010; 7: 77 – 86. Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 2011; 17: 1410 – 1422. Albert C, Schultzendorff MV, Salaru DL, Halloul Z, Dragun D, Heidecke H, Mertens PR. In arterial occlusive disease autoantibodies against ETAR and AT1R correlate with each other but are not associated with classical cardiovascular risk factors. VASA 2014; 43: 113 – 123 Shirai N, Naruko T, Ohsawa M, Ikura Y, Sugama Y, Hirayama M, Kitabayashi C, Ehara S, Inoue T, Itoh A, Haze K, Tanzawa K, Yoshiyama M, Yoshikawa J, Ueda M. Expression of endothelin-converting enzyme, endothelin-1 and endothelin receptors at the site of percutaneous coronary intervention in humans. J Hypertens 2006; 24: 711 – 721. Gross CM, Gerbaulet S, Quensel C, Kramer J, Mittelmeier HO, Luft FC, Dietz R. Angiotensin II type 1 receptor expression in human coronary arteries with variable degrees of atherosclerosis. Basic Res Cardiol 2002; 97: 327 – 333. Salonen JT, Yla-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssonen K, Palinski W, Witztum JL. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992; 339: 883 – 887. Lopez LR, Dier KJ, Lopez D, Merrill JT, Fink CA. Anti-beta 2-glycoprotein I and antiphosphatidylserine antibodies are predictors of arterial thrombosis in patients with antiphospholipid syndrome. Am J Clin Pathol 2004; 121: 142 – 149. Vuilleumier N, Reber G, James R, Burger D, de Moerloose P, Dayer JM, Roux-Lombard P. Presence of autoantibodies to apolipoprotein
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A-1 in patients with acute coronary syndrome further links autoimmunity to cardiovascular disease. J Autoimmun 2004; 23: 353 – 360. 9 Zhu J, Quyyumi AA, Rott D, Csako G, Wu H, Halcox J, Epstein SE. Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for an autoimmune component of atherogenesis. Circulation 2001; 103: 1071 – 1075. 10 Lopez-Mejias R, Corrales A, Genre F, Hernandez JL, Ochoa R, Blanco R, Gonzalez-Juanatey C, Martin J, Llorca J, Gonzalez-Gay MA. Angiopoietin-2 serum levels correlate with severity, early onset and cardiovascular disease in patients with rheumatoid arthritis. Clin Exp Rheumatol 2013; 31: 761 – 766. 11 Dessein PH, López-Mejias R, González-Juanatey C, Genre F, Miranda-Filloy JA, Llorca J, González-Gay MA. Independent Relationship of Osteoprotegerin Concentrations with Endothelial Activation and Carotid Athero sclerosis in Patients with Severe
Rheumatoid Arthritis. J Rheumatol 2014 Feb 1. [Epub ahead of print]. 12 Greenberg JD, Kremer JM, Curtis JR, Hochberg MC, Reed G, Tsao P, Farkouh ME, Nasir A, Setoguchi S, Solomon DH; CORRONA Investigators.. Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis 2011; 70: 576 – 82. 13 Genre F, Miranda-Filloy JA, LopezMejias R, Carnero-Lopez B, Ochoa R, Rueda J, Gonzalez-Juanatey C, Blanco R, Llorca J, Gonzalez-Gay MA. Antitumour necrosis factoralpha therapy modulates angiopoietin-2 serum levels in nondiabetic ankylosing spondylitis patients. Ann Rheum Dis 2013; 72: 1265 – 1267. 14 Genre F, López-Mejías R, Miranda-Filloy JA, Carnero-López B, Gómez-Acebo I, Blanco R, Ochoa R, Rueda J, González-Juanatey C, Llorca J, González-Gay MA. Asymmetric dimethylarginine serum levels in non-diabetic ankylosing
spondylitis patients undergoing TNF-alpha antagonist therapy. Clin Exp Rheumatol 2013; 31: 749 – 755. 15 Genre F, Lopez-Mejias R, Miranda-Filloy JA, Ubilla B, CarneroLopez B, Gomez-Acebo I, Blanco R, Ochoa R, Arias-Bajo M, Rueda-Gotor J, Paz-Carreira J, Gonzalez-Juanatey C and Llorca J and Gonzalez-Gay MA. Correlation between two biomarkers of atherosclerosis, osteopontin and angiopoyetin-2, in non-diabetic ankylosing spondylitis patients undergoing TNF-alpha antagonist therapy. Clin Exp Rheumatol. 2013 Dec 2. [Epub ahead of print].
Correspondence address Dr. Miguel A. González-Gay, MD PhD Hospital Universitario Marqués de Valdecilla, IFIMAV Avenida de Valdecilla, s/n 39008 Santander Spain
[email protected] 