To the best of our knowledge, the present in vivo study is the first to address the microvasculature of long COVID individuals in a detailed, diameter class-wise manner. The number of small capillaries, but not of the supply vessels, were markedly reduced, very similar to the pattern found during severe COVID-19 infection [4].
In addition, capillary recruitment of COVID long-term patients remains significantly reduced. While healthy controls succeed in maintaining a constant capillary VRBC (almost horizontal slope), long COVID patients as well as acute COVID-19 patients fail to do so (steeper slopes). This finding reflects a persistent fixed number of perfused capillaries, which is insensitive to local tissue variations of metabolic demand [8].
To what extent this capillary rarefication is mechanical or/and functional remains unclear. Pretorius et al. revealed common clotting pathologies in plasma of acute and long COVID patients, further supporting the existence of persistent microthrombi [10]. Besides that, an insufficient recovery of the initial inflammation accompanied by persistent immunological abnormalities might also be responsible for the observed capillary impairment [6]. Previous studies focusing on the pulmonary [11], exertional [12] and myocardial [13] microcirculation of long COVID individuals showed local impairment of the microcirculation. Our data complement these findings and point to a systemic and long-lasting capillary rarefication. This finding could possibly explain the functional impairment observed in long COVID syndrome. A subtle but exciting feature of the long-haul COVID group is, that the RBC velocities are the highest in our long COVID cohort (indicated by parallel shift of the slope to the upper right). We speculate that this finding could represent a compensatory mechanism to meet metabolic demands. Considering that the measurements were taken at physical rest, it is quite conceivable that this presumed compensatory mechanism is exhausted more quickly during exertion than in healthy individuals, possibly explaining long COVID symptoms. Here, we previously were able to present data on persistent exertional impairment caused by (micro-) circulatory reduction of the oxygen pulse during sequential, bicycle cardiopulmonary exercise test [12].
In the TUN-EndCOV Study, Charfeddine et al. reported a significant microvascular and endothelial dysfunction in a post-COVID cohort, evaluated by finger thermal monitoring after occlusion and reperfusion of the hand [14]. Specifically, long COVID individuals showed a higher endothelial quality index and a slower response to the reperfusion phase. This finding was partially reversed after oral intake of sulodexide, a highly purified mixture of glycosaminoglycans, that includes fast-moving heparin and dermatan sulfate [15]. Indeed, our data imply that long COVID individuals respond inadequately to local variations of tissue metabolic demand. Therefore, it is intriguing to speculate, that this delayed response after reperfusion might be the functional result of the observed capillary rarefication and the impaired capillary recruitment of the remaining capillaries in the long COVID individuals.
Regarding endothelial glycocalyx, previous studies have shown a trend towards partial recovery of the glycocalyx in the first months following the acute infection [16, 17]. Ikonomidis et al. evaluated PBR values of post-COVID individuals 12 months after infection, showing persistent glycocalyx impairment [18]. Here we demonstrate completely restored glycocalyx dimensions in long COVID individuals about 1.5 years after the acute infection. Mechanistically, glycocalyx thinning is tightly controlled, among others by the endothelium specific Angiopoietin(Angpt)/Tie2 system. We have shown that Angpt-2 activates heparanase release from the endothelium which leads to enzymatic degradation of the endothelial glycocalyx [19]. Indeed, we and others showed that both heparanase and Angpt-2 levels are elevated during the acute infection [4, 20]. Recent studies in long COVID reported normalized heparanase and Angpt-2 levels [21], consistent with restored glycocalyx dimensions. In this regard, our data once again highlight differential regulation of microcirculation parameters and glycocalyx dimensions, a finding we first observed in critically ill patients with bacterial sepsis [22].
We acknowledge some limitations. First, our pilot study had a small sample size and is mostly hypothesis-generating. Our study is observational and does not demonstrate causality between microvascular damage and post-COVID symptoms. Second, we included a historical cohort to better understand the microvascular changes. However, all microvascular parameters were assessed under the same conditions using the same GlycoCheck camera by the same experienced investigator. Third, plasma samples are not available in our long COVID patients, so we cannot perform further analyses of endothelial markers. Fourth, the capillary recruitment was calculated post-hoc in a per group analysis; meanwhile a per individual analysis has become available which might provide even more accurate results.