In line with the ESC mission, newly presented content is made available to all for a limited time (4 months for ESC Congress, 3 months for other events). ESC Professional Members, Association Members (Ivory & above) benefit from year-round access to all the resources from their respective Association, and to all content from previous years. Fellows of the ESC (FESC), and Professionals in training or under 40 years old, who subscribed to a Young Combined Membership package benefit from access to all ESC 365 content from all events, all editions, all year long. Find out more about ESC Memberships here.
Sub-topic : Pulmonary Circulation, Pulmonary Embolism, Right Heart Failure – Pathophysiology and Mechanisms
Session type : Moderated Posters
Authors : TM Hofbauer (Vienna,AT), A Alimohammadi (Vienna,AT), J Altmann (Vienna,AT), S Sharma (Vienna,AT), AS Ondracek (Vienna,AT), R Sadushi-Kolici (Vienna,AT), V Seidl (Vienna,AT), A Mangold (Vienna,AT), IM Lang (Vienna,AT)
The ESC does not have the copyright for the slides and video of this presentation
1Medical University of Vienna, Cardiology - Vienna - Austria
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the obstruction of pulmonary vessels by organized thrombotic and fibrotic lesions. Efferocytosis refers to the engulfment of apoptotic cells (ACs) by phagocytes, a process that is facilitated by bridging proteins. Milk fat globule-epidermal growth factor 8 (MFG-E8) connects phosphatidylserine on ACs with integrin alpha-v beta-III on phagocytes. MFG-E8-deficient mice develop auto-immune disease closely resembling systemic lupus erythematosus. In humans, decreased MFG-E8 levels were observed in patients with coronary heart disease and chronic obstructive pulmonary disease. Whether defective efferocytosis is involved in failure to resolve thrombi in CTEPH remains unknown.
We aimed to assess whether deficiency in MFG-E8 is responsible for of chronic non-resolving thrombosis in CTEPH.
We employed a murine model of chronic thrombosis by inferior vena cava ligation, in MFG-E8 knockout (KO) or wild-type (WT) mice to assess thrombus formation and resolution. Thrombus size at days 3, 7, 14 and 28 after ligation was assessed using either histologic trichrome stainings (n=4-13 per group and time point) or in vivo high-frequency ultrasound (n=10 per group and time point). We furthermore recruited CTEPH patients (n=60, 53% female, mean age 56±11 years) and sex- and age-matched healthy controls for measurement of MFG-E8 plasma levels using ELISA. In CTEPH patients, hemodynamic measurements were performed. Human lung specimens harvested during surgery for CTEPH or from healthy controls, and isolated monocytes from whole blood of CTEPH patients or controls were analyzed using RT-qPCR.
We observed substantially increased thrombus volume in MFG-E8 KO mice compared to WT, which persisted until day 14 after ligation. In human CTEPH patients, MFG-E8 in plasma was increased compared to healthy controls. Similarly, CTEPH monocytes displayed higher concentrations of MFG-E8 mRNA. Conversely, MFG-E8 expression of CTEPH pulmonary artery specimens was downregulated. No correlations between MFG-E8 levels and hemodynamic parameters were observed.
MFG-E8 plays an important role in thrombus resolution. In CTEPH, dysregulation of efferocytosis via impaired MFG-E8 expression in the pulmonary arteries, might drive persistence of thrombus in pulmonary arteries. The absence of a correlation between MFG-E8 and hemodynamic measures argues against pressure as a confounder of the observation.
ESC 365 is supported by Bayer, Boehringer Ingelheim and Lilly Alliance, Bristol-Myers Squibb and Pfizer Alliance, Novartis Pharma AG and Vifor Pharma in the form of educational grants. The sponsors were not involved in the development of this platform and had no influence on its content.
Our mission: To reduce the burden of cardiovascular disease