Microvascular dysfunction in COVID-19: the MYSTIC study

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.

Case Report: Sublingual Microcirculatory Alterations in a Covid-19 Patient With Subcutaneous Emphysema, Venous Thrombosis, and Pneumomediastinum

“…Indeed, contrary to our results, Edul et al ( 9 ) showed a decline in RBC velocity accompanied by an increase in vessel density in patients suffering from Covid-19 pneumonia. Furthermore, Rovas et al ( 10 ) noted reductions in RBC velocity with decreases in vessel density in this cohort. Since hypoxemia induces both capillary recruitment and angiogenesis ( 9 ), differences might be related to the higher compromise of pulmonary oxygenation in our patient [PaO 2 /FiO 2 ratio, 112.5 mmHg vs. 122 ± 43 mmHg ( 9 ) vs. 194.88 (145.76–234.0) mmHg ( 10 )].…”

“…Furthermore, Rovas et al ( 10 ) noted reductions in RBC velocity with decreases in vessel density in this cohort. Since hypoxemia induces both capillary recruitment and angiogenesis ( 9 ), differences might be related to the higher compromise of pulmonary oxygenation in our patient [PaO 2 /FiO 2 ratio, 112.5 mmHg vs. 122 ± 43 mmHg ( 9 ) vs. 194.88 (145.76–234.0) mmHg ( 10 )]. Spontaneous pneumomediastinum associated with Covid-19 has occasionally been reported ( 11 ).…”

Vascular Endothelial Glycocalyx Damage in COVID-19

“…As shown in Table 2 , a total of 16 studies were included for the title and abstract screening, and 2 studies were excluded due to duplicates. After a total of 11 studies were not deemed eligible for full-text review, 6 reports [ 3 , 87 , 88 , 89 , 90 , 91 ] were included in the review. Figure 14 presents a flowchart depicting the selection process.…”

“…On the other hand, the vascular endothelial glycocalyx (VEGLX), the extracellular matrix covering vascular endothelial cells throughout the body, is also impaired by various risk factors, and there have been numerous reports of VEGLX damage in acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC), which may be closely related to vascular endothelial damage in severe COVID-19. Recently, circulating levels of fragmented VEGLX concentrations and real-time measurements of VEGLX in sublingual capillaries have been reported in patients with COVID-19 [ 3 ].…”

Impact of COVID‐19 on red blood cell rheology

“…Coronavirus disease 2019 (COVID‐19) is an infectious disease caused by severe acute respiratory coronavirus 2 (SARS‐CoV‐2). Among hospitalized patients, many have developed typical manifestations of sepsis‐like cold extremities, weak peripheral pulses or severe metabolic acidosis, indicating microcirculation dysfunction 1 . Microvascular dysfunction has been reported in sepsis 2,3 and could be partly caused by red blood cell (RBC) rheological alterations such as decreased RBC deformability (RBCD), 4 increased RBC aggregation 5 and abnormal RBC morphology/physiology 6 .…”