Microcirculation disorders in patients with severe COVID-19 and development of bacterial sepsis

It is believed that microcirculation dysfunction in sepsis primarily caused by damage of the endothelium by infectious agents and pro-inflammatory cytokines. Mechanisms of impaired microcirculation in the severe course of COVID-19 and sepsis likely to be similar. However, there are few reports studied microcirculation disorders in patients with COVID-19, and their results are sometimes contradictory. Objective. To assess the microcirculation of patients with severe Covid-19 and the development of bacterial sepsis using nail bed microscopy and laser Doppler flowmetry. Materials and methods. 16 intensive care unit COVID-19 patients subsequently diagnosed with bacterial sepsis were examined. Patients underwent vital capillaroscopy and an occlusive test using laser Doppler flowmetry. The average rate of capillary blood flow, the size of the perivascular zone, the density of capillaries, the presence of intravascular aggregates, the increase in the amplitude of the maximum post-occlusive blood flow and the average value of postocclusive blood flow relative to the initial one were valuated. Additionally, the level of serum proadrenomedullin was evaluated. Studies were performed on the day of admission and in dynamics. Results. By the capillaroscopy analysis, microcirculation disorders were detected in the form of a decrease in the linear speed of capillary blood flow (<400 μm/s), an extention of the perivascular zone (>100 μm), the circulation of microaggregates; the absence of postocclusive hyperemia was determined by an occlusive test. Secondary bacterial infection led to an even greater aggravation of microcirculation disorders: an increase of the perivascular zone, the progression of intravascular aggregation resulting in microthrombosis with a decrease of the density of the capillary network (according to capillaroscopy), as well as a sharp decrease of amplitude maximal increment of blood flow of post-осclusive circulation at the time of an occlusive sample. We also revealed a trend of negative correlation between the level of serum proadrenomedullin and the maximum increase in blood flow during the occlusive test. Conclusion. The secondary bacterial infection in patients with COVID-19 leads to a significant aggravation of microcirculation disorders with the development of perfusion deficiency and interstitial edema. The increased plasma proadrenomedullin level supports the concept of the significant role of endothelial dysfunction in the pathogenesis of severe COVID-10 and bacterial sepsis.

Speed of capillary blood flow and d-dimer levels in sickle cell anaemia patients in Calabar, cross river state

Background: The experience of painful episodes of ill health caused by sequelae of erythrocytes sickling, impaired blood flow, hypercoagulation and vaso-occlusion is one of the hallmarks of sickle cell disease. Preventing painful episodes and promoting the physical wellbeing of persons with sickle cell disease is usually a major objective in the management of the condition. The purpose of this study is to investigate capillary blood flow and D-Dimer activities in people with sickle cell anaemia.Methods: A total of 90 subjects (27 males and 63 females) participated in the study, the study comprised of 34 HbSS patients, three were in crisis and thirty-one in steady state, 9 sickle cell carriers (HbAS) and 47 HbAA were control subjects. The haemoglobin phenotype was determined using haemoglobin electrophoresis at alkaline pH (8.6), speed of capillary blood flow was estimated using vascular Doppler ultrasonographic technique and D-Dimer was determined using ELISA method.Results: Results obtained showed that there was a significant variation (p=0.042) in the mean levels D-Dimer among the groups. There was however no significant variations (p>0.05) in the other parameters among the groups. A post hoc analysis of mean D-Dimer in sickle cell patients, sickle cell carriers and controls showed that the sickle cell patients had significantly higher D-Dimer levels compared with controls.Conclusions: Sickle cells patients in steady state had higher D-Dimer levels compared with controls and sickle cell patients in crisis had lower speed of capillary blood flow when compared to sickle cell patients in steady state and controls.

Microcirculation Disorders in Patients with Severe COVID-19

Impaired microcirculation due to endothelial dysfunction in COVID-19 is considered to be the most important link in the pathogenesis of this disease. However, due to the complexity of its instrumental assessment in critically ill patients, the data available in the literature on specific manifestations of endothelial dysfunction are very contradictory.The objective: to determine the most characteristic capillaroscopic signs of microvascular disorders and to assess the state of microcirculation regulation in patients with severe COVID-19.Subjects and Methods. When admitted to the intensive care unit, 60 patients with COVID-19 and 12 patients with chronic cardiovascular pathology without COVID-19 (Comparison Group) were examined. All patients underwent microscopy of the microcirculatory bed of finger nail bed; the following parameters were assessed: diameters of the venous, arterial and transitional parts of capillaries, height of capillary loops, density of capillaries per 1 mm of the length of the perivascular zone, the average linear velocity of capillary blood flow (LVCBF), and thickness of the perivascular zone. The presence of avascular zones, the number of capillaries in the visualized field with circulating aggregates in the lumen, and the shape of capillaries were taken into account. In addition, an occlusion test using laser Doppler flowmetry was performed in 32 patients with COVID-19. The maximum post-occlusive increase in blood flow at the moment of cuff deflation was assessed, as well as changes in the mean value of post-occlusive blood flow relative to the baseline within 3 minutes after cuff deflation.Results. In 53 (88.3%) patients with COVID-19, abnormalities corresponding to chronic microcirculatory changes in the form of predominance of pathological capillary forms were detected. Microaggregates in the lumen of capillaries and decreased linear velocity of blood flow were revealed in 100% of cases. When comparing groups of patients with different outcomes, statistically significant differences were revealed between the LVCBF parameters (in the survivors - 354.35 ± 44.78 pm/sec, in the deceased - 278.4 ± 26.59 pm/sec), as well as between the values of the perivascular zones thickness (95.35 ± 15.96 microns versus 159.93 ± 19.90 microns). The results of the post-occlusion test revealed a significant difference between the groups in terms of the maximum post-occlusion gain (39.42 ± 3.85 BPU in the group with a favorable outcome, 27.69 ± 3.19 BPU in the group with an unfavorable outcome, 47.23 ± 1.78 BPU in the control group). In both groups, there was no increase in this parameter relative to the initial blood flow. At the same time, in the control group, the average index of post-occlusive blood flow was higher than the initial level.Conclusions. Acute microcirculation disorders with decreased linear velocity of capillary blood flow, circulation of aggregates, increased thickness of the perivascular zone were detected in all patients with severe COVID-19 but especially in those with unfavorable outcomes. Vascular tone regulation disorders were manifested by the absence of reactive hyperemia in response to acute ischemia, as well as a decrease in maximal flow-induced increase. These changes fit into the concept of endothelial dysfunction. Signs of chronic microcirculation disorders in most patients increase the risk of severe COVID-19.

FC 016SPARSENTAN IMPROVES GLOMERULAR BLOOD FLOW AND AUGMENTS PROTECTIVE TISSUE REMODELING IN MOUSE MODELS OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

Background and Aims Preliminary preclinical and emerging clinical evidence indicates strong antiproteinuric actions of dual endothelin type A (ETA) and angiotensin II type 1 (AT1) receptor antagonism with sparsentan. These nephroprotective effects have been more pronounced in different experimental and clinical settings compared to current standard of care using an AT1 receptor blocker (ARB). Considering the broad spectrum of renal actions of endothelin (ET) and angiotensin II (Ang II), inhibition of both pathways using sparsentan is postulated to target multiple renal cell types via a variety of renoprotective mechanisms. The aim of this study was to determine glomerular action of sparsentan as compared to the ARB losartan (Los) by direct visualization of effects on renal hemodynamics and tissue remodeling in the intact living kidney. Method Intravital multiphoton microscopy (MPM) of the glomerular vasculature and filtration barrier structure and function was performed in genetically engineered mice combined with traditional urinalysis and histology-based phenotyping. Glomerular hemodynamic parameters (afferent and efferent arteriole (AA and EA) diameters and single nephron glomerular filtration rate (SNGFR)) and podocyte calcium entry, as a measure of cell injury, were quantitatively visualized in the FSGS model Pod-GCaMP5/Tomato TRPC6 transgenic mice (1.5 years of age), in which TRPC6 is overexpressed together with the calcium reporter GCaMP5 in podocytes. Single cell identification and fate tracking of cells of the renin lineage (CoRL) was performed over time using a second physiologic control mouse model, Ren1d-Confetti mice that feature a multicolor CFP/GFP/YFP/FP reporter. Three groups of mice in each model received treatment with either vehicle (CTRL), the ARB losartan (Los; 10 mg/kg/day), or sparsentan (120 mg/kg/day) for 6 weeks (FSGS model) or 2 weeks (control physiology model). Results Both Los and sparsentan treatment attenuated the acute ET + Ang II-induced elevation of podocyte calcium by ∼80%, and the development of albuminuria, and glomerulosclerosis and tissue fibrosis in the FSGS model. Notably, sparsentan prevented the ET + Ang II increases in podocyte calcium more than Los and was significantly more effective in dilating both AA and EA (Fig. 1A, B), increasing SNGFR (Fig. 1C), increasing capillary blood flow (2-fold; p&lt;0.0001 vs. CTRL), and decreasing albuminuria (20%; p&lt;0.05 vs. CTRL). Sparsentan also preserved p57+ podocyte number by 50% compared to Los (p&lt;0.0001 vs. Los). Similarly, pretreatment with sparsentan was more effective in preventing glomerular arteriolar vasoconstriction induced by acute ET + Ang II iv injection compared to Los (p&lt;0.05 vs. Los). Following a 2-week treatment in control healthy Ren1d-Confetti mice, sparsentan resulted in a more robust increase compared to Los in the number of Confetti+ cells, clones, and individual cells per clone in the glomeruli and AA (Fig. 1D-F). Renal tubule segments also showed active cellular remodeling in response to sparsentan. Conclusion Serial MPM imaging directly visualized several mechanisms underlying beneficial antiproteinuric and structural effects of sparsentan in both FSGS and in the normal mouse kidney and differences between dual ETA/AT1 receptor antagonism of sparsentan and a mono-selective ARB. The sparsentan-induced glomerular hemodynamic pattern was driven by both AA and EA dilation resulting in an increase in capillary blood flow. Compared to Los, sparsentan was more effective in attenuating ET/Ang II-induced podocyte injury and in activation of resident progenitor cells and tissue remodeling. These findings suggest multiple layers of renal protective actions by dual ETA and AT1 receptor antagonism.

Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimer’s disease mouse model

Increased incidence of stalled capillary blood flow caused by adhesion of leucocytes to the brain microvascular endothelium leads to a 17% reduction of cerebral blood flow (CBF) and exacerbates short-term memory loss in multiple mouse models of Alzheimer’s disease (AD). Here, we report that Vascular Endothelial Growth Factor (VEGF) signaling at the luminal side of the brain microvasculature plays an integral role in the capillary stalling phenomenon of the APP/PS1 mouse model. Administration of the anti-mouse VEGF-A164 antibody, an isoform that inhibits blood brain barrier (BBB) hyperpermeability, reduced the number of stalled capillaries within an hour of injection, leading to an immediate increase in average capillary blood flow but not capillary diameter. VEGF-A inhibition also reduced the overall eNOS protein concentrations, increased occludin levels, and decreased the penetration of circulating Evans Blue dye across the BBB into the brain parenchyma, suggesting increased BBB integrity. Capillaries prone to neutrophil adhesion after anti-VEGF-A treatment also had lower occludin concentrations than flowing capillaries. Taken together, our findings demonstrate that VEGF-A signaling in APP/PS1 mice contributes to aberrant eNOS/occludin- associated BBB permeability, increases the incidence of capillary stalls, and leads to reductions in CBF. Reducing leucocyte adhesion by inhibiting luminal VEGF signaling may provide a novel and well-tolerated strategy for improving brain microvascular blood flow in AD patients.