Microvascular dysfunction in COVID-19: the MYSTIC study
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ORIGINAL PAPER
Microvascular dysfunction in COVID-19: the MYSTIC study Alexandros Rovas1 · Irina Osiaevi1 · Konrad Buscher1 · Jan Sackarnd2 · Phil‑Robin Tepasse3 · Manfred Fobker4 · Joachim Kühn5 · Stephan Braune6 · Ulrich Göbel7 · Gerold Thölking1,8 · Andreas Gröschel9 · Hermann Pavenstädt1 · Hans Vink10 · Philipp Kümpers1 Received: 16 September 2020 / Accepted: 28 September 2020 © The Author(s) 2020
Abstract Rationale Pre-clinical and autopsy studies have fueled the hypothesis that a dysregulated vascular endothelium might play a central role in the pathogenesis of ARDS and multi-organ failure in COVID-19. Objectives To comprehensively characterize and quantify microvascular alterations in patients with COVID-19. Methods Hospitalized adult patients with moderate-to-severe or critical COVID-19 (n = 23) were enrolled non-consecutively in this prospective, observational, cross-sectional, multi-center study. Fifteen healthy volunteers served as controls. All participants underwent intravital microscopy by sidestream dark field imaging to quantify vascular density, red blood cell velocity (VRBC), and glycocalyx dimensions (perfused boundary region, PBR) in sublingual microvessels. Circulating levels of endothelial and glycocalyx-associated markers were measured by multiplex proximity extension assay and enzyme-linked immunosorbent assay. Measurements and main results COVID-19 patients showed an up to 90% reduction in vascular density, almost exclusively limited to small capillaries (diameter 4–6 µm), and also significant reductions of VRBC. Especially, patients on mechanical ventilation showed severe glycocalyx damage as indicated by higher PBR values (i.e., thinner glycocalyx) and increased blood levels of shed glycocalyx constituents. Several markers of endothelial dysfunction were increased and correlated with disease severity in COVID-19. PBR (AUC 0.75, p = 0.01), ADAMTS13 (von Willebrand factor-cleaving protease; AUC 0.74, p = 0.02), and vascular endothelial growth factor A (VEGF-A; AUC 0.73, p = 0.04) showed the best discriminatory ability to predict 60-day in-hospital mortality. Conclusions Our data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19. Keywords COVID-19 · Sublingual microscopy · Endothelial glycocalyx · Endotheliopathy · Microcirculation Abbreviations ACE2 Shed ectodomain of angiotensin-converting enzyme 2 receptor ADAMTS13 A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 AKI Acute kidney injury Alexandros Rovas and Irina Osiaevi have contributed equally and are both considered first authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09753-7) contains supplementary material, which is available to authorized users. * Philipp Kümpers [email protected] Extended author information available on the last page of the
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