Acceleration of the Development of Microcirculation Embolism in the Brain due to Capillary Narrowing.

BACKGROUND: Cerebral microvascular obstruction is critically involved in recurrent stroke and decreased cerebral blood flow with age. The obstruction must occur in the capillary with a greater resistance to perfusion pressure through the microvascular networks. However, little is known about the relationship between capillary size and embolism formation. This study aimed to determine whether the capillary lumen space contributes to the development of microcirculation embolism. METHODS: To spatiotemporally manipulate capillary diameters in vivo, transgenic mice expressing the light-gated cation channel protein ChR2 (channelrhodopsin-2) in mural cells were used. The spatiotemporal changes in the regional cerebral blood flow in response to the photoactivation of ChR2 mural cells were first characterized using laser speckle flowgraphy. Capillary responses to optimized photostimulation were then examined in vivo using 2-photon microscopy. Finally, microcirculation embolism due to intravenously injected fluorescent microbeads was compared under conditions with or without photoactivation of ChR2 mural cells. RESULTS: Following transcranial photostimulation, the stimulation intensity-dependent decrease in cerebral blood flow centered at the irradiation was observed (14%-49% decreases relative to the baseline). The cerebrovascular response to photostimulation showed significant constriction of the cerebral arteries and capillaries but not of the veins. As a result of vasoconstriction, a temporal stall of red blood cell flow occurred in the capillaries of the venous sides. The 2-photon excitation of a single ChR2 pericyte demonstrated the partial shrinkage of capillaries (7% relative to the baseline) around the stimulated cell. With the intravenous injection of microbeads, the occurrence of microcirculation embolism was significantly enhanced (11% increases compared to the control) with photostimulation. CONCLUSIONS: Capillary narrowing increases the risk of developing microcirculation embolism in the venous sides of the cerebral capillaries.

Assessment of Parafoveal Diabetic Macular Ischemia on Optical Coherence Tomography Angiography Images to Predict Diabetic Retinal Disease Progression and Visual Acuity Deterioration.

Importance: The presence of diabetic macular ischemia (DMI) on optical coherence tomography angiography (OCTA) images predicts diabetic retinal disease progression and visual acuity (VA) deterioration, suggesting an OCTA-based DMI evaluation can further enhance diabetic retinopathy (DR) management. Objective: To investigate whether an automated binary DMI algorithm using OCTA images provides prognostic value on DR progression, diabetic macular edema (DME) development, and VA deterioration in a cohort of patients with diabetes. Design, Setting, and Participants: In this cohort study, DMI assessment of superficial capillary plexus and deep capillary plexus OCTA images was performed by a previously developed deep learning algorithm. The presence of DMI was defined as images exhibiting disruption of fovea avascular zone with or without additional areas of capillary loss, while absence of DMI was defined as images presented with intact fovea avascular zone outline and normal distribution of vasculature. Patients with diabetes were recruited starting in July 2015 and were followed up for at least 4 years. Cox proportional hazards models were used to evaluate the association of the presence of DMI with DR progression, DME development, and VA deterioration. Analysis took place between June and December 2022. Main Outcomes and Measures: DR progression, DME development, and VA deterioration. Results: A total of 321 eyes from 178 patients were included for analysis (85 [47.75%] female; mean [SD] age, 63.39 [11.04] years). Over a median (IQR) follow-up of 50.41 (48.16-56.48) months, 105 eyes (32.71%) had DR progression, 33 eyes (10.28%) developed DME, and 68 eyes (21.18%) had VA deterioration. Presence of superficial capillary plexus-DMI (hazard ratio [HR], 2.69; 95% CI, 1.64-4.43; P < .001) and deep capillary plexus-DMI (HR, 3.21; 95% CI, 1.94-5.30; P < .001) at baseline were significantly associated with DR progression, whereas presence of deep capillary plexus-DMI was also associated with DME development (HR, 4.60; 95% CI, 1.15-8.20; P = .003) and VA deterioration (HR, 2.12; 95% CI, 1.01-5.22; P = .04) after adjusting for age, duration of diabetes, fasting glucose, glycated hemoglobin, mean arterial blood pressure, DR severity, ganglion cell-inner plexiform layer thickness, axial length, and smoking at baseline. Conclusions and Relevance: In this study, the presence of DMI on OCTA images demonstrates prognostic value for DR progression, DME development, and VA deterioration.

MACULAR SENSITIVITY AND CAPILLARY PERFUSION IN HIGHLY MYOPIC EYES WITH MYOPIC MACULAR DEGENERATION.

PURPOSE: To evaluate the interrelationship between macular sensitivity and retinal perfusion density (PD) in eyes with myopic macular degeneration (MMD). METHODS: One hundred and thirty-eight highly myopic eyes from 82 adult participants were recruited. Macular sensitivity was evaluated using the Microperimeter MP-3. Retinal PD was measured using the PLEX Elite 9000 swept source optical coherence tomography angiography. Macular sensitivity values between different categories of MMD and its relationship with optical coherence tomography angiography measurements were evaluated using multivariable linear mixed models, adjusting for age and axial length. RESULTS: Macular sensitivity reduced with increasing severity of MMD (ß ≤ -0.95, P < 0.001), whereas the best-corrected visual acuity was not associated with MMD severity (P > 0.04). Persons who were older (ß = -0.08, P < 0.001), with longer axial length (ß = -0.32, P = 0.005), presence of macular diffuse choroidal atrophy (ß = -2.16, P < 0.001) or worse MMD (ß = -5.70, P < 0.001), and presence of macular posterior staphyloma (ß ≤ -2.98, P < 0.001) or Fuchs spot (ß = -1.58, P = 0.04) were associated with reduced macular sensitivity. Macular sensitivity was significantly associated with deep retinal PD in MMD (ß = 0.15, P = 0.004) but not with superficial retinal PD (P = 0.62). CONCLUSION: There was a strong correlation between reduced macular sensitivity and increasing MMD severity, even in mild MMD independent of the best-corrected visual acuity. Furthermore, macular sensitivity was correlated with deep retinal PD, suggesting a vasculature-function relationship in MMD.

The influence of the optical properties on the determination of capillary diameters.

Various clinically applicable scores and indices are available to help identify the state of a microcirculatory disorder in a patient. Several of these methods, however, leave room for interpretation and only provide clues for diagnosis. Thus, a measurement method that allows a reliable detection of impending or manifest circulatory malfunctions would be of great value. In this context, the optical and non-invasive method of shifted position-diffuse reflectance imaging (SP-DRI) was developed. It allows to determine the capillary diameter and thus to assess the state of the microcirculation. The aim of the present study is to investigate how the quantification of capillary diameters by SP-DRI behaves in different individuals, i.e. for a wide range of optical properties. For this, within Monte-Carlo simulations all optical properties (seven skin layers, hemoglobin) were randomly varied following a Gaussian distribution. An important finding from the present investigation is that SP-DRI works when the optical properties are chosen randomly. Furthermore, it is shown that appropriate data analysis allows calibration-free absolute quantification of the capillary diameter across individuals using SP-DRI. This underpins the potential of SP-DRI to serve as an early alert system for the onset of microcirculatory associated diseases.

Microvascular rarefaction in patients with cerebrovascular events.

Capillary density rarefaction and endothelial dysfunction contribute to chronic hypoperfusion and cerebral small vessel disease. Previous animal experiments revealed spatiotemporal microvascular remodeling directing post-stroke brain reorganization. We hypothesized that microcirculatory changes during acute cerebrovascular events could be reflected systemically and visualized sublingually. In a prospective observational trial in vivo sublingual sidestream darkfield videomicroscopy was performed in twenty-one patients with either acute stroke (n = 13 ischemic, n = 1 ischemic with hemorrhagic transformation and n = 2 hemorrhagic stroke) or transitory ischemic attacks (n = 5) within 24 h after hospital admission and compared to an age- and sex-matched control group. Repetitive measurements were performed on the third day and after one week. Functional and perfused total capillary density was rarefied in the overall patient group (3060 vs 3717 µm/mm2, p = 0.001 and 5263 vs 6550 µm/mm2, p = 0.002, respectively) and in patients with ischemic strokes (2897 vs. 3717 µm/mm2, p < 0.001 and 5263 vs. 6550 µm/mm2, p = 0.006, respectively) when compared to healthy controls. The perfused boundary region (PBR), which was measured as an inverse indicator of glycocalyx thickness, was markedly related to red blood cell (RBC) filling percentage (regarded as an estimate of microvessel perfusion) in the overall patient group (r = -0.843, p < 0.001), in patients with ischemic strokes (r = -0.82, p = 0.001) as well as in healthy volunteers (r = -0.845, p < 0.001). In addition, there were significant associations between platelet count or platelet aggregation values (as measured by whole blood impedance aggregometry) and microvascular parameters in the overall patient collective, as well as in patients with ischemic strokes. In conclusion, cerebrovascular events are associated with altered systemic microvascular perfusion.

Post-occlusive reactive hyperemia and skeletal muscle capillary hemodynamics.

Post-occlusive reactive hyperemia (PORH) is an accepted diagnostic tool for assessing peripheral macrovascular function. While conduit artery hemodynamics have been well defined, the impact of PORH on capillary hemodynamics remains unknown, despite the microvasculature being the dominant site of vascular control. Therefore, the purpose of this investigation was to determine the effects of 5 min of feed artery occlusion on capillary hemodynamics in skeletal muscle. We tested the hypothesis that, upon release of arterial occlusion, there would be: 1) an increased red blood cell flux (fRBC) and red blood cell velocity (VRBC), and 2) a decreased proportion of capillaries supporting RBC flow compared to the pre-occlusion condition. METHODS: In female Sprague-Dawley rats (n = 6), the spinotrapezius muscle was exteriorized for evaluation of capillary hemodynamics pre-occlusion, 5 min of feed artery occlusion (Occ), and 5 min of reperfusion (Post-Occ). RESULTS: There were no differences in mean arterial pressure (MAP) or capillary diameter (Dc) between pre-occlusion and post-occlusion (P > 0.05). During 30 s of PORH, capillary fRBC was increased (pre: 59 ± 4 vs. 30 s-post: 77 ± 2 cells/s; P < 0.05) and VRBC was not changed (pre: 300 ± 24 vs. 30 s post: 322 ± 25 µm/s; P > 0.05). Capillary hematocrit (Hctcap) was unchanged across the pre- to post-occlusion conditions (P > 0.05). Following occlusion, there was a 20-30% decrease in the number of capillaries supporting RBC flow at 30 s and 300 s-post occlusion (pre: 92 ± 2%; 30 s-post: 66 ± 3%; 300 s-post: 72 ± 6%; both P < 0.05). CONCLUSION: Short-term feed artery occlusion (i.e. 5 min) resulted in a more heterogeneous capillary flow profile with the presence of capillary no-reflow, decreasing the percentage of capillaries supporting RBC flow. A complex interaction between myogenic and metabolic mechanisms at the arteriolar level may play a role in the capillary no-reflow with PORH. Measurements at the level of the conduit artery mask significant alterations in blood flow distribution in the microcirculation.

Longitudinal Macular Retinal and Choroidal Microvasculature Changes in High Myopia.

Purpose: The purpose of this study was to determine the longitudinal changes in macular retinal and choroidal microvasculature in normal healthy and highly myopic eyes. Methods: Seventy-one eyes, including 32 eyes with high myopia and 39 healthy control eyes, followed for at least 12 months and examined using optical coherence tomography angiography imaging in at least 3 visits, were included in this study. Fovea-centered 6 × 6 mm scans were performed to measure capillary density (CD) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC). The rates of CD changes in both groups were estimated using a linear mixed model. Results: Over a mean 14-month follow-up period, highly myopic eyes exhibited a faster rate of whole image CD (wiCD) loss (-1.44%/year vs. -0.11%/year, P = 0.001) and CD loss in the outer ring of the DCP (-1.67%/year vs. -0.14%/year, P < 0.001) than healthy eyes. In multivariate regression analysis, baseline axial length (AL) was negatively correlated with the rate of wiCD loss (estimate = -0.27, 95% confidence interval [CI] = -0.48 to -0.06, P = 0.012) and CD loss in the outer ring (estimate = -0.33, 95% CI = -0.56 to -0.11, P = 0.005), of the DCP. The CD reduction rates in the SCP and CC were comparable in both groups (all P values > 0.05). Conclusions: The rate of CD loss in the DCP is significantly faster in highly myopic eyes than in healthy eyes and is related to baseline AL. The CD in the outer ring reduces faster in eyes with longer baseline AL.

To evaluate the microcirculation of retinochoroid capillary between acute and chronic central serous chorioretinopathy with OCTA.

ABSTRACT: To investigate the difference in chorioretinal microcirculation between acute central serous chorioretinopathy (aCSC) and chronic central serous chorioretinopathy (cCSC) using optical coherence tomography angiography.In total, 65 patients previously diagnosed with central serous chorioretinopathy (33 aCSC and 32 cCSC) were included in our cross-sectional study. All patients underwent complete ophthalmologic assessment including logarithm of the minimum angle of resolution best-corrected visual acuity, fundus fluorescein angiography, and optical coherence tomography angiography. Sixty eyes of 60 refractive error and age matched healthy people were selected as control.The vessel density of inner retina in patients with aCSC were higher than that in patients with cCSC (51.32 ±â€Š2.01 vs 49.15 ±â€Š3.68, P = .004), however, the vessel density of superficial choroid layer in aCSC were significantly lower than that in cCSC (49.83 ±â€Š6.96 vs 53.42 ±â€Š6.28, P = .033). Further analysis of the data reveals the presence of a distinct choroidal neovascularization (CNV) in 8 patients (25%) with cCSC while there was no evidence of CNV in patients with aCSC.Our study can contribute to a better understanding of the difference in retinochoroid microcirculation between aCSC and cCSC. The vessel density of inner retina was lower and the vessel density of superficial choroid was higher in cCSC, and patients with cCSC were more susceptible to CNV than patients with aCSC.

Transcytosis within PVN capillaries: a mechanism determining both hypertension-induced blood-brain barrier dysfunction and exercise-induced correction.

Although hypertension disrupts the blood-brain barrier (BBB) integrity within the paraventricular nucleus of hypothalamus (PVN) and increases the leakage into the brain parenchyma, exercise training (T) was shown to correct it. Since there is scarce and contradictory information on the mechanism(s) determining hypertension-induced BBB deficit and nothing is known about T-induced improvement, we sought to evaluate the paracellular and transcellular transport across the BBB within the PVN in both conditions. Spontaneously hypertensive rats (SHR) and WKY submitted to 4-wk aerobic T or sedentary (S) protocol were chronically catheterized for hemodynamic recordings at rest and intra-arterial administration of dyes (Rhodamine-dextran 70 kDa + FITC-dextran 10 kDa). Brains were harvesting for FITC leakage examination, qPCR evaluation of different BBB constituents and protein expression of caveolin-1 and claudin-5, the main markers of transcytosis and paracellular transport, respectively. Hypertension was characterized by increased arterial pressure and heart rate, augmented sympathetic modulation of heart and vessels, and reduced cardiac parasympathetic control, marked FITC extravasation into the PVN which was accompanied by increased caveolin-1 gene and protein expression, without changes in claudin-5 and others tight junctions' components. SHR-T vs. SHR-S showed a partial pressure reduction, resting bradycardia, improvement of autonomic control of the circulation simultaneously with correction of both FITC leakage and caveolin-1 expression; there was a significant increase in claudin-5 expression. Caveolin-1 content was strongly correlated with improved autonomic control after exercise. Data indicated that within the PVN the transcytosis is the main mechanism governing both hypertension-induced BBB leakage, as well as the exercise-induced correction.

Simultaneous Measurement of Lung Diffusing Capacity and Pulmonary Hemodynamics Reveals Exertional Alveolar-Capillary Dysfunction in Heart Failure With Preserved Ejection Fraction.

Background Hemodynamic perturbations in heart failure with preserved ejection fraction (HFpEF) may alter the distribution of blood in the lungs, impair gas transfer from the alveoli into the pulmonary capillaries, and reduce lung diffusing capacity. We hypothesized that impairments in lung diffusing capacity for carbon monoxide (DLCO) in HFpEF would be associated with high mean pulmonary capillary wedge pressures during exercise. Methods and Results Rebreathe DLCO and invasive hemodynamics were measured simultaneously during exercise in patients with exertional dyspnea. Pulmonary pressure waveforms and breath-by-breath pulmonary gas exchange were recorded at rest, 20 W, and symptom-limited maximal exercise. Patients with HFpEF (n=20; 15 women, aged 65±11 years, body mass index 36±8 kg/m2) achieved a lower symptom-limited maximal workload (52±27 W versus 106±42 W) compared with controls with noncardiac dyspnea (n=10; 7 women, aged 55±10 years, body mass index 30±5 kg/m2). DLCO was lower in patients with HFpEF compared with controls at rest (DLCO 10.4±2.9 mL/min per mm Hg versus 16.4±6.9 mL/min per mm Hg, P<0.01) and symptom-limited maximal exercise (DLCO 14.6±4.7 mL/min per mm Hg versus 23.8±10.8 mL/min per mm Hg, P<0.01) because of a lower alveolar-capillary membrane conductance in HFpEF (rest 16.8±6.6 mL/min per mm Hg versus 28.4±11.8 mL/min per mm Hg, P<0.01; symptom-limited maximal exercise 25.0±6.7 mL/min per mm Hg versus 45.5±22.2 mL/min per mm Hg, P<0.01). DLCO was lower in HFpEF for a given mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, pulmonary arterial compliance, and transpulmonary gradient. Conclusions Lung diffusing capacity is lower at rest and during exercise in HFpEF due to impaired gas conductance across the alveolar-capillary membrane. DLCO is impaired for a given pulmonary capillary wedge pressure and pulmonary arterial compliance. These data provide new insight into the complex relationships between hemodynamic perturbations and gas exchange abnormalities in HFpEF.

Pathophysiology of the Lymphatic System in Patients With Heart Failure: JACC State-of-the-Art Review.

The removal of interstitial fluid from the tissues is performed exclusively by the lymphatic system. Tissue edema in congestive heart failure occurs only when the lymphatic system fails or is overrun by fluid leaving the vascular space across the wall of the capillaries into the interstitial space. This process is driven by Starling forces determined by hydrostatic and osmotic pressures and organ-specific capillary permeabilities to proteins of different sizes. In this review, we summarize current knowledge of the generation of lymph in different organs, the mechanics by which lymph is returned to the circulation, and the consequences of the inadequacy of lymph flow. We review recent advances in imaging techniques that have allowed for new research, diagnostic, and therapeutic approaches to the lymphatic system. Finally, we review how efforts to increase lymph flow have demonstrated potential as a viable therapeutic approach for refractory heart failure.

The repetitive application of cold atmospheric plasma (CAP) improves microcirculation parameters in chronic wounds.

BACKGROUND: Chronic wounds, such as venous leg ulcers, diabetic foot ulcers, and pressure ulcers, impose a significant burden on patients and health care systems worldwide. Cold atmospheric plasma (CAP) accelerates wound healing and decreases bacterial load in chronic wounds in both in vitro and in vivo experiments. For the first time, we examined the effects of a repetitive application of CAP on the microcirculation in chronic wounds. HYPOTHESIS: The repetitive application of cold atmospheric plasma application further improves microcirculation in chronic wounds. METHODS: Twenty patients with chronic wounds were treated repetitively with CAP. The repetitive application consisted of three CAP sessions, each lasting 90 s and separated by a 10-minute microcirculation measuring period. Microcirculation parameters were assessed with combined Laser-Doppler-Flowmetry and spectrophotometry in a tissue depth of 2 mm. RESULTS: Tissue oxygen saturation was significantly increased after the first CAP application. The effect amplitude and duration were further increased after the second and third CAP application with a maximum increase by 16,7% (percent change; p = 0,004 vs. baseline) after the third application. There was no significant increase in capillary blood flow until the third CAP application. After the third CAP application, an increase by 22,6% (p = 0,014) was observed. Postcapillary filling pressure was not significantly increased over the measuring period. The repetitive application of CAP further enhances the microcirculation in chronic wounds compared to a single application. CONCLUSION: The repetitive application of CAP boosts and prolongs tissue oxygen saturation and capillary blood flow in chronic wounds compared to a single application. This insight could provide an impetus for new treatment protocols.

Evaluation of gingival microcirculation in patients with gestational diabetes mellitus.

OBJECTIVE: The aim of this study was to evaluate the possible microcircularity variations at periodontal mucous level in patients with gestational diabetes mellitus (GDM). MATERIAL AND METHODS: Overall 55 periodontally healthy and non-smoker participants were enrolled in the study by whom 30 were diagnosed with GDM (26 to 34 weeks pregnant) and 25 were systemically healthy unpregnant controls. The analysis was performed in the masticatory/gingival mucosa of maxillary anterior region and by the optical probe videocapillaroscopy technique equipped with 200× lenses. The following parameters were recorded: capillary loop visibility, capillary orientation to surface, microhemorrhages, capillary density and tortuosity. RESULTS: The average capillary density was significantly higher in participants with GDM (27 ± 5.46 no. loops/mm2) compared to controls (21.16 ± 3 no. loops/mm2) (P = 0.035) while increased tortuosity scores was observed in controls compared with the GDM group (P = 0.017). There was not any significantly difference between study groups among the other variables (P > 0.05). CONCLUSIONS: Capillary alterations including capillary density and tortuosity were demonstrated in gingival microcirculation of patients with GDM. These microcirculatory changes could provide us new understanding on the dynamics of the relationship between GDM and periodontal tissues.

Effect of Nimodipine on Macular and Peripapillary Capillary Vessel Density in Patients with Normal-tension Glaucoma Using Optical Coherence Tomography Angiography.

PURPOSE: This study aimed to investigate the effect of nimodipine on peripapillary and macular capillary vessel density (VD) in patients with normal-tension glaucoma (NTG) using optical coherence tomography angiography (OCTA). METHODS: Sixty mg nimodipine was administered to 20 enrolled NTG patients for 3 months. Patients were treated with glaucoma medication simultaneously. The macular and peripapillary VD were measured automatically by OCTA at baseline, 1.5 h after administering nimodipine, and after 3 months of administering the drug. The retinal nerve fibre layer (RNFL), ganglion cell complex thickness, visual field (VF) testing, intraocular pressure (IOP), blood pressure and pulse rate in each subject were assessed during each follow-up. RESULTS: Compared with the baseline, the parafovea VD was higher (50.89 ± 4.26 versus 46.80 ± 5.40, P = .044) 1.5 h after administration of nimodipine. After administration of nimodipine for 3 months, the parafovea VD was obviously increased (51.14 ± 5.68 versus 46.80 ± 5.40, P = .039), while IOP, systolic blood pressure, mean arterial pressure and mean ocular perfusion pressure were decreased compared to baseline (all P < .05). No significant differences were found between the radial peripapillary capillary and disc VD. The parafovea VD was positively correlated with the administration of nimodipine (ß = 0.39, P = .004), RNFL thickness (ß = 0.49, P = .022), and VF mean deviation (ß = 0.4, P = .040) in the multivariate analysis. CONCLUSIONS: Nimodipine effectively increased superficial macular capillary VD, but did not affect peripapillary capillary VD in patients with NTG. This finding indicates that patients with NTG may benefit from the administration of nimodipine.

Cold atmospheric plasma improves cutaneous microcirculation in standardized acute wounds: Results of a controlled, prospective cohort study.

BACKGROUND: Given the high prevalence of wounds and their challenging treatment, the research of therapies to improve wound healing is of great clinical interest. In addition, the general consequences of developing chronic wounds constitute a large health economic aspect, which underscores the interest in the development of efficient treatment strategies. Direct cold atmospheric plasma (di_CAP) has been shown to have beneficial effects on microcirculation of human tissue (Kisch et al., 2016a). It also affects microbial settlements, which may have supportive effects on wound healing processes (Balzer et al., 2015). To treat these adequately, in our view, the positive effects on wound healing should be objectified by application on standardized wounds. However, wound healing is a complex process, depending on nutrient and oxygen supply by cutaneous blood circulation. In spite of microcirculation has been shown to improve in healthy skin by CAP, a quantification of the effect in a standardized wound model has never been evaluated (Kisch et al., 2016a). Based on this, we hypothesize that CAP also influences the microcirculation in standardized acute wounds in a prospective cohort study. METHODS: Microcirculatory data of 20 healthy subjects (14 males, 6 females; mean age 40.85 ± 15.84 years; BMI 26.83 ± 7.27 kg/m2) were recorded continuously at a standardized acute wound after skin transplantation (donor site) at the thigh. Under standardized conditions, microcirculatory measurements were performed using a combined laser Doppler and photospectrometry system. After baseline measurement, CAP was applied by a dielectric barrier discharge (DBD) plasma device for 90 s to the acute wound area. Immediately after the application, cutaneous microcirculation was assessed for 30 min (min) at the same site. RESULTS: After CAP application, tissue oxygen saturation immediately increased by 5% (92,66 ± 4,76% vs. Baseline 88,21 ± 6,52%, p < 0,01) in the first 60 s and remained significantly elevated for 4 min. Capillary blood flow increased by 19.3% within the first minute of CAP therapy (220.14 ± 65.91 AU vs. Baseline 184.52 ± 56.77 AU, p < 0.001). The statistically highly significant increase in blood flow continued over the entire measurement time. A maximum value was shown in the blood flow in the 15th minute (232.15 ± 58.90 AU, p < 0.001) according to CAP application. With regard to the output measurement, it represents a percentage increase of 25.8%. The measurement of post-capillary venous filling pressure at a tissue depth of 6-8 mm was 59.39 ± AU 12.94 at baseline measurement. After application, there were no significant changes. CONCLUSION: CAP increases cutaneous tissue oxygen saturation and capillary blood flow at the standardized acute wound healing model. These results support recently published data on wound healing after CAP treatment. However, further studies are needed to determine if this treatment can improve the reduced microcirculation in chronic wounds. Moreover, repetitive application protocols have to be compared with a single session treatment approach.

C3 Deficiency Leads to Increased Angiogenesis and Elevated Pro-Angiogenic Leukocyte Recruitment in Ischemic Muscle Tissue.

The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic and analyze the impact of the complement system on angiogenesis, we induced muscle ischemia in complement factor C3 deficient (C3-/-) and wildtype control mice by femoral artery ligation (FAL). At 24 h and 7 days after FAL, we isolated the ischemic gastrocnemius muscles and investigated them by means of (immuno-)histological analyses. C3-/- mice showed elevated ischemic damage 7 days after FAL, as evidenced by H&E staining. In addition, angiogenesis was increased in C3-/- mice, as demonstrated by increased capillary/muscle fiber ratio and increased proliferating endothelial cells (CD31+/BrdU+). Moreover, our results showed that the total number of leukocytes (CD45+) was increased in C3-/- mice, which was based on an increased number of neutrophils (MPO+), neutrophil extracellular trap formation (MPO+/CitH3+), and macrophages (CD68+) displaying a shift toward an anti-inflammatory and pro-angiogenic M2-like polarized phenotype (CD68+/MRC1+). In summary, we show that the deficiency of complement factor C3 increased neutrophil and M2-like polarized macrophage accumulation in ischemic muscle tissue, contributing to angiogenesis.

Nailfold capillaroscopy: A sensitive method for evaluating microvascular involvement in children with SARS-CoV-2 infection.

OBJECTIVES: The hyperinflammatory state and the viral invasion may result in endothelial dysfunction in SARS-CoV-2 infection. Although a method foreseeing microvascular dysfunction has not been defined yet, studies conducted in patients diagnosed with COVID-19 have demonstrated the presence of endotheliitis. With this study, we aimed to investigate the microvascular circulation in patients diagnosed with COVID-19 and multisystem inflammatory syndrome in children (MIS-C) by nailfold videocapillaroscopy (NVC). METHODS: Thirty-one patients with SARS-CoV-2 infection, 25 of whom were diagnosed with COVID-19 and 6 with MIS-C and 58 healthy peers were included in the study. NVC was performed in eight fingers with 2 images per finger and 16 images were examined for the morphology of capillaries, presence of pericapillary edema, microhemorrhage, avascular area, and neoangiogenesis. Capillary length, capillary width, apical loop, arterial and venous width, and intercapillary distance were measured from three consecutive capillaries from the ring finger of the non-dominant hand. RESULTS: COVID-19 patients showed significantly more capillary ramification (p < 0.001), capillary meandering (p = 0.04), microhemorrhage (p < 0.001), neoangiogenesis (p < 0.001), capillary tortuosity (p = 0.003). Capillary density (p = 0.002) and capillary length (p = 0.002) were significantly lower in the patient group while intercapillary distance (p = 0.01) was significantly longer compared with healthy volunteers. Morphologically, patients with MIS-C had a higher frequency of capillary ramification and neoangiogenesis compared with COVID-19 patients (p = 0.04). CONCLUSION: Abnormal capillary alterations seen in COVID-19 and MIS-C patients indicate both similar and different aspects of these two spectra of SARS-CoV-2 infection and NVC appears to be a simple and non-invasive method for evaluation of microvascular involvement.

Week to week variability of pulmonary capillary blood volume and alveolar membrane diffusing capacity in patients with heart failure.

BACKGROUND: Alveolar-capillary membrane diffusing capacity for carbon monoxide (DMCO) and pulmonary capillary volume (Vcap) can be estimated by the multi-step Roughton and Foster (RF, original method from 1957) or the single-step NO-CO double diffusion technique (developed in the 1980s). The latter method implies inherent assumptions. We sought to determine which combination of the alveolar membrane diffusing capacity for nitric oxide (DMNO) to DMCO ratio, an specific conductance of the blood for NO (θNO) and CO (θCO) gave the lowest week-to-week variability in patients with heart failure. METHODS: 44 heart failure patients underwent DMCO and Vcap measurements on three occasions over a ten-week period using both RF and double dilution NO-CO techniques. RESULTS: When using the double diffusing method and applying θNO = infinity, the smallest week-to-week coefficient of variation for DMCO was 10 %. Conversely, the RF method derived DMCO had a much greater week-to-week variability (2x higher coefficient of variation) than the DMCO derived via the NO-CO double dilution technique. The DMCO derived from the double diffusion technique most closely matched the DMCO from the RF method when θNO = infinity and DMCO = DLNO/2.42. The Vcap measured week-to-week was unreliable regardless of the method or constants used. CONCLUSIONS: In heart failure patients, the week-to-week DMCO variability was lowest when using the single-step NO-CO technique. DMCO obtained from double diffusion most closely matched the RF DMCO when DMCO/2.42 and θNO = infinity. Vcap estimation was unreliable with either method.

Nailfold capillaroscopic changes of sleep apnea patients.

BACKGROUND: Obstructive Sleep Apnea Syndrome (OSAS) have frequent association with comorbidities and this makes it an independent risk factor for cardiovascular disease. Not only endothelial dysfunction, but also arterial stiffening, increased inflammatory mediators, oxidative stress after hypoxemia that develops due to OSAS, cause vascular pathologies in all diameters of vessels. Nail bed capillaroscopy is a simple, noninvasive, useful method to examine microcirculation and evaluate nail bed capillary abnormalities in diseases that cause vascular damage. The aim of this study is to examine microvascular changes in the nail bed of OSAS patients by capillaroscopy. METHODS: 59 OSAS patients and 60 healthy cases (totally 119) were included. One single attended polysomnography was applied with Embla N7000 series (RemLogic Eastmed, Natus); and apnea-hypopnea index (AHI), oxygen de-saturation index >4% (ODI4%), minimum oxygen saturation (SaO2 Min.), total duration of oxygen desaturation, comorbidities, body mass index (BMI), smoking habit, sleep questionnaire applications were analyzed. Nailfold capillaroscopy was performed using a digital dermoscope (Molemax II, X30) and all images were evaluated for capillary density, capillary loop enlargement, capillary tortuosity, branching vessels, micro hemorrhages, avascular areas and splinter hemorrhages. RESULTS: The prevalence rates of all capillaroscopy findings were significantly higher in the patient group (p < 0.05). There was an inverse and moderate relationship between AHI and mean saturation (p < 0.05). A statistically significant correlation was detected between the presence of hypertension (HT) and the severity of capillary tortuosity (CT) (p = 0.002), avascular area (AA) (p = 0.004), and periungual cyanosis (PUC) (p = 0.042); also between smoking habit and intensity of capillary dilatation, enlargement dilatation-enlarged giant capillaries (CELON) (p = 0.004), CT (p = 0.018) findings. Capillary distribution (CD), CELON, CT and AA findings were significantly higher in the group with low mean saturation (p < 0.05). DM was found to be significantly higher in individuals with high Epworth Sleep Scale (ESS) (p = 0.035). CONCLUSION: In this study; 1) the nail bed capillaroscopy was used to examine vascular damage in OSAS, and 2) irregularities detected in the distal nail bed specific to a disease have been mentioned for the first time. It has been shown that endothelial damage is particularly related to the severity of hypoxia. HT and smoking history causes endothelial damage independent of the severity of the disease and hypoxia. Also, ESS may be more determinant in the screening of sleep disorders in diabetic patients.

Nailfold capillary changes in newly diagnosed hypertensive patients: An observational analytical study.

INTRODUCTION: Nail Fold capillaroscopy (NFC) is used to evaluate microvascular changes in the horizontally lying capillaries in the proximal nail fold. Arterial hypertension affects the microvascular beds producing structural changes. Our objective was to evaluate qualitative and quantitative NFC changes in newly diagnosed hypertensives as compared to age and sex matched normotensive controls and to determine association, if any, with microvascular changes visualized on fundoscopy. MATERIALS AND METHODS: This observational, analytical study involved 41 newly diagnosed hypertensives (18-60 years) with 41 normotensive age and sex matched normotensive controls. The mean capillary density (MCD) and morphological changes were assessed for all, while fundoscopy was done for study group participants. The collected data was statistically analyzed. RESULTS: The MCD in newly diagnosed hypertensives (5.21 ± 0.90 capillaries/mm) was significantly lower than normotensive controls (6.50 ± 0.65 capillaries/mm) (p < 0.001) in our study. Qualitative morphologic changes were more common in hypertensive patients including meandering capillaries, capillary dilation, avascular areas, bushy capillaries, and microhemorrhages (p value <0.001). Capillary disarray (73.17%) was a unique morphologic change seen significantly more commonly in study group (p < 0.001). Among hypertensives, MCD was lesser in patients with retinopathy (p = 0.125) and with microalbuminuria, while avascular areas and dilated capillaries were significantly more common. CONCLUSION: Our study supports the role of NFC with USB dermatoscope in detecting unique microvascular morphological alterations in hypertensives, which were more frequent as well as distinctive, as compared to healthy controls. A good correlation with fundoscopic features and microalbuminuria suggests that it could be useful in predicting/detecting cardiovascular, or renal complications early, with an advantage of easy accessibility and repeatability.