From tissue iron retention to low systemic haemoglobin levels, new pathophysiological biomarkers of human abdominal aortic aneurysm

Summary

Iron deposits are observed in tissue of abdominal aortic aneurysm (AAA) patients, although the underlying mechanisms are not completely elucidated. Therefore we explored circulating markers of iron metabolism in AAA patients, and tested if they could serve as biomarkers of AAA. Increased red blood cell (RBC)-borne iron retention and transferrin, transferrin receptor and ferritin expression was observed in AAA tissue compared to control aorta (immunohistochemistry and western blot). In contrast, decreased circulating iron, transferrin, mean corpuscular haemoglobin concentration (MCHC) and haemoglobin concentration, along with circulating RBC count, were observed in AAA patients (aortic diameter >3 cm, n=114) compared to controls (aortic diameter <3 cm, n=88) (ELISA), whereas hepcidin concentrations were increased in AAA subjects (MS/MS assay). Moreover, iron, transferrin and haemoglobin levels were negatively, and hepcidin positively, correlated with aortic diameter in AAA patients. The association of low haemoglobin with AAA presence or aortic diameter was independent of specific risk factors. Moreover, MCHC negatively correlated with thrombus area in another cohort of AAA patients (aortic diameter 3–5 cm, n=357). We found that anaemia was significantly more prevalent in AAA patients (aortic diameter >5 cm, n=8,912) compared to those in patients with atherosclerotic aorto-iliac occlusive disease (n=17,737) [adjusted odds ratio=1.77 (95% confidence interval: 1.61;1.93)]. Finally, the mortality risk among AAA patients with anaemia was increased by almost 30% [adjusted hazard ratio: 1.29 (95% confidence interval: 1.16;1.44)] as compared to AAA subjects without anaemia. In conclusion, local iron retention and altered iron recycling associated to high hepcidin and low transferrin systemic concentrations could lead to reduced circulating haemoglobin levels in AAA patients. Low haemoglobin levels are independently associated to AAA presence and clinical outcome.

Keywords

Iron - transferrin - hepcidin - RBC - haemoglobin - anaemia

^* Equal contribution of these authors.

• References

• 1 Michel JB, Martin-Ventura JL, Egido J. et al. Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans. Cardiovasc Res 2011; 90: 18-27.
• 2 Martinez-Pinna R, Ramos-Mozo P, Madrigal-Matute J. et al. Identification of peroxiredoxin-1 as a novel biomarker of abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 2011; 31: 935-943.
• 3 Delbosc S, Diallo D, Dejouvencel T. et al. Impaired high-density lipoprotein antioxidant capacity in human abdominal aortic aneurysm. Cardiovasc Res. 2013 Epub ahead of print.
• 4 Nchimi A, Defawe O, Brisbois D. et al. MR imaging of iron phagocytosis in intraluminal thrombi of abdominal aortic aneurysms in humans. Radiology 2010; 254: 973-981.
• 5 Michel JB, Thaunat O, Houard X. et al. Topological determinants and consequences of adventitial responses to arterial wall injury. Arterioscler Thromb Vasc Biol 2007; 27: 1259-1268.
• 6 Weiss G. Iron metabolism in the anemia of chronic disease. Biochimica et Biophysica Acta 2009; 1790: 682-693.
• 7 Caligiuri G, Rossignol P, Julia P. et al. Reduced immunoregulatory CD31+ T cells in patients with atherosclerotic abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 2006; 26: 618-623.
• 8 Ramos-Mozo P, Madrigal-Matute J, Martinez-Pinna R. et al. Proteomic analysis of polymorphonuclear neutrophils identifies catalase as a novel biomarker of abdominal aortic aneurysm: potential implication of oxidative stress in abdominal aortic aneurysm progression. Arterioscler Thromb Vasc Biol 2011; 31: 3011-3019.
• 9 Li H, Rose MJ, Tran L. et al. Development of a method for the sensitive and quantitative determination of hepcidin in human serum using LC-MS/MS. J Pharmacol Toxicol Methods 2009; 59: 171-180.
• 10 Houard X, Rouzet F, Touat Z. et al. Topology of the fibrinolytic system within the mural thrombus of human abdominal aortic aneurysms. J Pathol 2007; 212: 20-28.
• 11 Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352: 1011-1023.
• 12 Eagleton MJ. Inflammation in abdominal aortic aneurysms: cellular infiltrate and cytokine profiles. Vascular 2012; 20: 278-283.
• 13 Martinez-Pinna R, Madrigal-Matute J, Tarin C. et al. Proteomic Analysis of Intraluminal Thrombus Highlights Complement Activation in Human Abdominal Aortic Aneurysms. Arterioscler Thromb Vasc Biol 2013; 33: 2013-2020.
• 14 Dejouvencel T, Féron D, Rossignol P. et al. Hemorphin 7 reflects hemoglobin proteolysis in abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 2010; 30: 269-275.
• 15 Kazi M, Thyberg J, Religa P. et al. Influence of intraluminal thrombus on structural and cellular composition of abdominal aortic aneurysm wall. J Vasc Surg 2003; 38: 1283-1292.
• 16 Klink A, Hyafil F, Rudd J. et al. Diagnostic and therapeutic strategies for small abdominal aortic aneurysms. Nat Rev Cardiol 2011; 08: 338-347.
• 17 Theurl I, Theurl M, Seifert M. et al. Autocrine formation of hepcidin induces iron retention in human monocytes. Blood 2008; 111: 2392-2399.
• 18 Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102: 783-788.
• 19 Sarnak MJ, Tighiouart H, Manjunath G. et al. Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol 2002; 40: 27-33.
• 20 Diehm N, Benenati JF, Becker GJ. et al. Anemia is associated with abdominal aortic aneurysm (AAA) size and decreased long-term survival after endovascular AAA repair. J Vasc Surg 2007; 46: 676-681.
• 21 Guralnik JM, Ershler WB, Schrier SL. et al. Anemia in the elderly: a public health crisis in haematology. Haematology Am Soc Haematol Educ Program 2005; 528-532.
• 22 Laustsen J, Jensen LP, Hansen AK. Accuracy of clinical data in a population based vascular registry. Eur J Vasc Endovasc Surg 2004; 27: 216-219.