Impaired Fibrinolysis in Patients with Isolated Aortic Stenosis is Associated with Enhanced Oxidative Stress.

Jakub Siudut,Ewa Wypasek,Jacek Legutko,Łukasz Wiewiórka,Joanna Natorska,Sylwia Wiśniowska-Śmiałek,Elżbieta Ostrowska-Kaim,Anetta Undas,Krzysztof Plens

doi:10.3390/jcm9062002

Abstract

Aortic stenosis (AS) has been associated with impaired fibrinolysis and increased oxidative stress. This study aimed to investigate whether oxidative stress could alter fibrin clot properties in AS. We studied 173 non-diabetic patients, aged 51–79 years, with isolated AS. We measured plasma protein carbonylation (PC) and thiobarbituric acid reactive substances (TBARS), along with plasma clot permeability (Ks), thrombin generation, and fibrinolytic efficiency, which were evaluated by two assays: clot lysis time (CLT) and lysis time (Lys50). Coagulation factors and fibrinolytic proteins were also determined. Plasma PC showed an association with AS severity, reflected by the aortic valve area and the mean and maximum aortic gradients. Plasma PC was positively correlated with CLT, Lys50, plasminogen activator inhibitor-1 (PAI-1), and tissue factor (TF) antigens. TBARS were positively correlated with maximum aortic gradient, Lys50, and TF antigen. Regression analysis showed that PC predicted prolonged CLT (>104 min; odds ratio (OR) 6.41, 95% confidence interval (CI) 2.58–17.83, p < 0.001) and Lys50 (>565 s; OR 5.83, 95% CI 2.23–15.21, p < 0.001). Multivariate regression analysis showed that mean aortic gradient, PC, α2-antiplasmin, PAI-1, and triglycerides were predictors of prolonged CLT, while PC, α2-antiplasmin, and fibrinogen were predictors of Lys50. Our findings suggest that elevated oxidative stress contributes to impaired fibrinolysis in AS and is associated with AS severity.

Highlights

Aortic stenosis (AS) is the most common valvular heart disease in high income countries
This study identifies new predictors of impaired fibrinolysis in AS patients, showing the significant contribution of protein carbonyls (PC) and antiplasmin activity, and highlights the relevance of a prothrombotic and hypofibrinolytic state in AS
This methodological difference might justify why oxidative stress has a crucial effect on impaired fibrinolysis in AS despite the various demographic and laboratory determinants of prolonged lysis time between these assays (Siudut et al manuscript in review)

Summary

Introduction

Aortic stenosis (AS) is the most common valvular heart disease in high income countries. The pathobiology of degenerative AS involves interrelated complex processes such as inflammation, oxidative stress, angiogenesis, fibrosis, and osteogenic differentiation. Recent studies have shown the essential role of oxidative processes in the pathogenesis of AS [4,5,6]. Low density lipoproteins (LDL) and lipoprotein(a) (Lp(a)) have been reported to infiltrate through the damaged endothelium and into the fibrosa and promote the recruitment of inflammatory cells into the aortic valve. In vitro studies have shown that oxidized LDL (Ox-LDL) and Lp(a) (Ox-PL) promote osteogenic differentiation and calcification in valvular cells, resulting in faster AS progression, and induce a pro-oxidant state [8,9,10]

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