Abstract 328: Coagulation Proteases are Potential Regulators in the Development of Exercise-Related Endofibrosis

Abstract

Background: High performance athletes can develop symptomatic arterial flow restriction during exercise, caused by endofibrosis. The disease is an poorly understood condition, characterized by fibrosis of the external iliac artery. Pathophysiological processes involved in the development of endofibrosis are unknown. However, evidence shows that coagulation enzymes such as thrombin and factor Xa (FXa) can influence pro-fibrotic processes, mainly mediated through activation of protease activated receptors (PAR). Aim: We investigated the immunohistochemical characteristics of endofibrotic lesions to determine the potential role of coagulation proteases and their receptors in development of endofibrosis. Methods: 19 arterial endofibrotic specimens were collected during endarterectomy. As controls 20 arterial segments of the external iliac artery were collected post mortem from individuals who donated their body to medical science, with no medical history of cardiovascular disease. Acquired arteries were paraffinized and cut in tissue sections for immunohistochemical staining. Data were analyzed using a Mann-Whitney U test. A 2-tailed p<0.05 was considered as statistically significant. Results: Endofibrotic segments contained a neo-intima, resulting in an intraluminal stenosis (42±14%). Compared to the intima of controls, endofibrotic lesions were highly positive for collagen (47±16% vs 15±5%, p=0.0001) and elastin (38±9% vs 16±4%, p=0.0003). These findings were accompanied by significantly increased alpha smooth muscle actin expression (51±10% vs 36±11%, p=0.01), which morphologically appeared to be myofibroblasts in endofibrotic lesions; which were hardly present in controls. In addition, PAR1 (49±17% vs 22±10%, p=0.0003) and PAR4 (39±8% vs 10±4%, p<0.0001) were upregulated and proenzymes of their activators, prothrombin and factor X were abundantly present in endofibrosis. Conclusion: This is the first study to show that myofibroblasts, and the subsequent collagen and elastin production, might be key factors in the development of endofibrosis. The special association suggests that these processes may be regulated through activation of PARs by coagulation proteases, which needs to be established in further studies.