DEFICIENCY OF MYELOID PHD PROTEINS AGGRAVATES ATHEROGENESIS VIA MACROPHAGE APOPTOSIS AND PARACRINE FIBROTIC SIGNALING Atherogenic effects of myeloid PHD knockdown

AIMS: Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular hypoxic responses, possibly influencing macrophage function in plaque hypoxia. Thus, we aimed to elucidate the role of myeloid PHDs in atherosclerosis. METHODS AND RESULTS: Myeloid-specific PHD knockout (PHDko) mice were obtained via bone marrow transplantation (PHD1ko, PHD3ko) or conditional knockdown through lysozyme M-driven Cre recombinase (PHD2cko). Mice were fed high cholesterol diet for 6–12 weeks to induce atherosclerosis. Aortic root plaque size was significantly augmented 2.6-fold in PHD2cko, and 1.4-fold in PHD3ko compared to controls but was unchanged in PHD1ko mice. Macrophage apoptosis was promoted in PHD2cko and PHD3ko mice in vitro and in vivo, via the hypoxia-inducible factor (HIF) 1α/BNIP3 axis. Bulk and single-cell RNA data of PHD2cko bone marrow-derived macrophages (BMDMs) and plaque macrophages, respectively, showed enhanced HIF1α/BNIP3 signalling, which was validated in vitro by siRNA silencing. Human plaque BNIP3 mRNA was positively associated with plaque necrotic core size, suggesting similar pro-apoptotic effects in human. Furthermore, PHD2cko plaques displayed enhanced fibrosis, while macrophage collagen breakdown by matrix metalloproteinases, collagen production, and proliferation were unaltered. Instead, PHD2cko BMDMs enhanced fibroblast collagen secretion in a paracrine manner. In silico analysis of macrophage-fibroblast communication predicted SPP1 (osteopontin) signalling as regulator, which was corroborated by enhanced plaque SPP1 protein in vivo. Increased SPP1 mRNA expression upon PHD2cko was preferentially observed in foamy plaque macrophages expressing ‘triggering receptor expressed on myeloid cells-2’ (TREM2hi) evidenced by single-cell RNA, but not in neutrophils. This confirmed enhanced fibrotic signalling by PHD2cko macrophages to fibroblasts, in vitro as well as in vivo. CONCLUSION: Myeloid PHD2cko and PHD3ko enhanced atherosclerotic plaque growth and macrophage apoptosis, while PHD2cko macrophages further activated collagen secretion by fibroblasts in vitro, likely via paracrine SPP1 signalling through TREM2hi macrophages

The Maastricht Acquisition Platform for Studying Mechanisms of Cell-Matrix Crosstalk (MAPEX): An Interdisciplinary and Systems Approach towards Understanding Thoracic Aortic Disease

Current management guidelines for ascending thoracic aortic aneurysms (aTAA) recommend intervention once ascending or sinus diameter reaches 5-5.5 cm or shows a growth rate of \u3e0.5 cm/year estimated from echo/CT/MRI. However, many aTAA dissections (aTAAD) occur in vessels with diameters below the surgical intervention threshold ofMoreover, during aTAA repair surgeons observe and experience considerable variations in tissue strength, thickness, and stiffness that appear not fully explained by patient risk factors. To improve the understanding of aTAA pathophysiology, we established a multi-disciplinary research infrastructure: The Maastricht acquisition platform for studying mechanisms of tissue-cell crosstalk (MAPEX). The explicit scientific focus of the platform is on the dynamic interactions between vascular smooth muscle cells and extracellular matrix (i.e., cell-matrix crosstalk), which play an essential role in aortic wall mechanical homeostasis. Accordingly, we consider pathophysiological influences of wall shear stress, wall stress, and smooth muscle cell phenotypic diversity and modulation. Co-registrations of hemodynamics and deep phenotyping at the histological and cell biology level are key innovations of our platform and are critical for understanding aneurysm formation and dissection at a fundamental level. The MAPEX platform enables the interpretation of the data in a well-defined clinical context and therefore has real potential for narrowing existing knowledge gaps. A better understanding of aortic mechanical homeostasis and its derangement may ultimately improve diagnostic and prognostic possibilities to identify and treat symptomatic and asymptomatic patients with existing and developing aneurysms

Haemodynamic optimisation of a dialysis graft design using a global optimisation approach

Disturbed flow and the resulting non-physiological wall shear stress (WSS) at the graft-vein anastomosis play an important role in arteriovenous graft (AVG) patency loss. Modifying graft geometry with helical features is a popular approach to minimise the occurrence of detrimental haemodynamics and to potentially increase graft longevity. Haemodynamic optimisation of AVGs typically requires many computationally expensive computational fluid dynamics (CFD) simulations to evaluate haemodynamic performance of different graft designs. In this study, we aimed to develop a haemodynamically optimised AVG by using an efficient meta-modelling approach. A training dataset containing CFD evaluations of 103 graft designs with helical features was used to develop computationally low-cost meta-models for haemodynamic metrics related to graft dysfunction. During optimisation, the meta-models replaced CFD simulations that were otherwise needed to evaluate the haemodynamic performance of possible graft designs. After optimisation, haemodynamic performance of the optimised graft design was verified using a CFD simulation. The obtained optimised graft design contained both a helical graft centreline and helical ridge. Using the optimised design, the magnitude of flow disturbances and the size of the anastomotic areas exposed to non-physiological WSS was successfully reduced compared to a regular straight graft. Our meta-modelling approach allowed to reduce the total number of CFD model evaluations required for our design optimisation by approximately a factor 2000. The applied efficient meta-modelling technique was successful in identifying an optimal, helical graft design at relatively low computational costs. Future studies should evaluate the in vivo benefits of the developed graft design

A Stopped Pilot Study of the ProGlide Closure Device After Transbrachial Endovascular Interventions

Purpose: To evaluate the feasibility and safety of the suture-mediated ProGlide device in closure of the brachial artery after endovascular interventions. Materials and Methods: From 2016 to 2017, a pilot study was performed using the ProGlide to achieve hemostasis after percutaneous access of distal brachial arteries >4 mm in diameter. In an interim analysis, the results were compared to a matched control group taken from a 60-patient historical cohort who underwent brachial artery access and manual compression to achieve hemostasis between 2014 and 2017. The primary outcome was access-related reintervention and the secondary outcome was the incidence of access-site complications. Results: Seven patients (mean age 67.9 years; 6 men) were enrolled in the study before it was stopped in 2017. Four patients experienced 6 access-site complications (neuropathy, hematoma, occlusion, and pseudoaneurysm). These resulted in 3 access-related reinterventions: surgical evacuation of a hematoma, thrombectomy of the occluded brachial artery, and surgical repair of the pseudoaneurysm. In the interim comparison to the 19 matched patients (mean age 61.9 years; 6 men), the ProGlide group had proportionally more patients experiencing access-related complications (57% vs 16% for manual compression, p=0.035) and resultant reinterventions (43% vs 11%, p=0.064). Based on this data the trial was stopped. Conclusion: Considering this experience, it is not advisable to use the ProGlide in transbrachial endovascular interventions due to the high incidence of complications and access-related reinterventions