Interpericyte tunnelling nanotubes regulate neurovascular coupling.

Signalling between cells of the neurovascular unit, or neurovascular coupling, is essential to match local blood flow with neuronal activity. Pericytes interact with endothelial cells and extend processes that wrap capillaries, covering up to 90% of their surface area1,2. Pericytes are candidates to regulate microcirculatory blood flow because they are strategically positioned along capillaries, contain contractile proteins and respond rapidly to neuronal stimulation3,4, but whether they synchronize microvascular dynamics and neurovascular coupling within a capillary network was unknown. Here we identify nanotube-like processes that connect two bona fide pericytes on separate capillary systems, forming a functional network in the mouse retina, which we named interpericyte tunnelling nanotubes (IP-TNTs). We provide evidence that these (i) have an open-ended proximal side and a closed-ended terminal (end-foot) that connects with distal pericyte processes via gap junctions, (ii) carry organelles including mitochondria, which can travel along these processes, and (iii) serve as a conduit for intercellular Ca2+ waves, thus mediating communication between pericytes. Using two-photon microscope live imaging, we demonstrate that retinal pericytes rely on IP-TNTs to control local neurovascular coupling and coordinate light-evoked responses between adjacent capillaries. IP-TNT damage following ablation or ischaemia disrupts intercellular Ca2+ waves, impairing blood flow regulation and neurovascular coupling. Notably, pharmacological blockade of Ca2+ influx preserves IP-TNTs, rescues light-evoked capillary responses and restores blood flow after reperfusion. Our study thus defines IP-TNTs and characterizes their critical role in regulating neurovascular coupling in the living retina under both physiological and pathological conditions.

Transcapillary PO2 Gradients in Contracting Muscles of Type I Diabetic Rats.

OBJECTIVE: This study aimed to clarify the effect of Type I diabetes (DIA) on transcapillary PO2 gradients, which are oxygen-driving factors between the blood and the interstitium, in the contracting muscle of rats. METHODS: Wistar male rats were divided into the diabetic (streptozocin i.p.) and sham groups. Microvascular and interstitial PO2 were measured in the extensor digitorum longus muscle during electrical stimulation-induced muscle contraction, using the phosphorescence quenching method. Transcapillary PO2 gradient, ΔPO2, was calculated as microvascular minus interstitial PO2. RESULTS: Resting microvascular PO2 was higher in the diabetic group than in the sham group (6.3 ± 1.7 vs. 4.7 ± 0.9 mmHg, p < 0.05) and remained for 180 s. Interstitial PO2 from rest to muscle contraction did not differ between the groups. The ΔPO2 was higher in the diabetic group than in the sham group at rest and during muscle contraction (4.03 ± 1.42 vs. 2.46 ± 0.90 mmHg at rest; 3.67 ± 1.51 vs. 2.22 ± 0.65 mmHg during muscle contraction, p < 0.05). Marked muscle atrophy was observed in the diabetic group. CONCLUSION: DIA increased microvascular and transcapillary PO2 gradients in the skeletal muscle. The enhanced PO2 gradients were maintained from rest to muscle contraction in diabetic muscle.

Relationship between nailfold videocapillaroscopic findings and cardiovascular risk factors.

BACKGROUND: Nailfold Videocapillaroscopy (NVC) is a valuable tool in the differential diagnosis of Raynaud's phenomenon (RP), present in certain Rheumatic diseases (RD). Knowing that many people have cardiovascular risk factors (CVRF), the main objective was to demonstrate that CVRF and carotid plaques produce NVC alterations. METHODS: Cross-sectional unicentric study carried out from 2020 to 2023. Four groups were formed: subjects with RD and RP, participants with RD without RP, subjects with RP without RD and finally participants without RP or RD (study group). Each subject exhibiting CVRF presented only a single risk factor. The variables collected were: sociodemographic, CVRF (diabetes, tobacco, alcohol (ALC), obesity (OBE), dyslipidemia and arterial hypertension (AH)), diseases, RP, treatments, tortuosities and NVC alterations (ramified capillaries, enlarged capillaries, giant capillaries, haemorrhages and density loss) and carotid ultrasound (CU). RESULTS: 402 subjects were included (76 % women, mean age 51 ± 16 years), 67 % had CVRF, 50 % RP and 38 % RD. Tortuosities were present in 100 % of CVRF participants. A statistically significant association was found between the presence of CVRF and all the NVC alterations: ramified capillaries (OR = 95.6), enlarged capillaries (OR = 59.2), giant capillaries (OR = 8.32), haemorrhages (OR = 17.6) and density loss (OR = 14.4). In particular, an association was found between giant capillaries with AH (p = 0,008) and OBE (p ã€ˆ0,001), and haemorrhages and density loss with ALC and OBE (p < 0,001). On the other hand, 40 subjects presented CU plaques (9.9 %), associated with enlarged capillaries (OR = 8.08), haemorrhages (OR = 4.04) and ramified capillaries (OR = 3.01). The pathological intima-media thickness was also associated with haemorrhages (OR = 3.14). CONCLUSIONS: There is a clear association between CVRF and ultrasound atherosclerotic findings in carotid with NVC alterations. These findings are of special interest for a correct NVC interpretation and to avoid false positives in the diagnosis of primary and secondary RP.

Nail fold capillaroscopy in leprosy: Unveiling the microvascular changes.

BACKGROUND: Leprosy, a chronic infectious disease, is associated with various nail changes. Its etiopathogenesis is multifaceted, with microvascular damage being crucial. Nail fold capillaroscopy (NFC) emerges as a novel tool for detecting early vascular deficits in leprosy. The study aimed to assess and provide a complete clinical characterization of NFC changes in leprosy patients. METHODS: It is an observational cross-sectional study, done over a period of 1.5 year (January 2021 to august 2022) in a tertiary care hospital, encompassing 60 patients diagnosed with leprosy (18-60 years). After obtaining informed consent; detailed history, complete cutaneous and neurological examinations were conducted. All fingernails and toenails were examined for clinical changes. Subsequently, onychoscopy was performed using USB type of video-dermatoscope (Model AM7115MZT Dino-lite), a non-invasive tool. This was followed by NFC which was done for all fingernails and images were recorded by single operator, which were then assessed for quantitative and qualitive changes and statistical analysis was conducted using SPSS v20, with mean capillary density compared using Student's t-test, morphological change frequencies assessed by proportions, and group comparisons made using Chi-square or Fischer exact tests, with a significance threshold of p < 0.05. RESULTS: Among the 60 patients, 39 were in the lepromatous group, which included both borderline lepromatous (BL) and lepromatous leprosy (LL) patients, and 17 were in the tuberculoid group, which included borderline tuberculoid (BT) leprosy patients; 23.3 % had Type 1 reactions, and 18.3 % had Type 2 reactions. Nail fold capillaroscopy (NFC) showed microvasculature changes in 93.3 % of patients. The average capillary density was 6.8 ± 1.5 capillaries per mm, with the lepromatous group having a lower density (6.5 ± 1.09) compared to the tuberculoid group (7.0 ± 0.86). The most common NFC changes in the tuberculoid group were tortuous capillaries (70 %), capillary dropouts, and dilated capillaries (both 64.7 %). In the lepromatous group, capillary dropouts (82 %) were most frequent, followed by tortuous (69 %), receding (69 %), and dilated capillaries (66 %). A dilated and prominent subpapillary plexus was more common in the lepromatous group (35 %, p = 0.04). Patients with trophic changes in the lepromatous group had more capillary dropouts and bizarre capillaries. Capillary dropouts, dilated capillaries, and visible subpapillary venous plexus were more prevalent in patients with Type 2 reactions. CONCLUSION: NFC changes are prevalent in both tuberculoid and lepromatous leprosy, which may be an indicator of peripheral vascular compromise and trophic changes, especially in lepromatous leprosy. NFC can be an auxiliary tool for detecting microvascular abnormalities in leprosy patients.

Prolonged capillary refill time and short-term mortality of critically ill patients: A meta-analysis.

BACKGROUND: Prolonged capillary refill time (CRT) is an indicator of poor peripheral perfusion. The aim of the systematic review and meta-analysis was to evaluate the association of prolonged CRT and mortality of critically ill patients. METHODS: To achieve the objective of this meta-analysis, we conducted a thorough search of PubMed, Embase, Cochrane Library, and the Web of Science to identify relevant observational studies with longitudinal follow-up. The Cochrane Q test was utilized to assess between-study heterogeneity, and the I2 statistic was calculated to estimate the degree of heterogeneity. We employed random-effects models to combine the outcomes, considering the potential influence of heterogeneity. RESULTS: Eleven studies, encompassing 11,659 critically ill patients were included. During follow-up durations within hospitalization to 3 months, 1247 (10.7%) patients died. The pooled results indicated that a prolonged CRT at early phase of admission was significantly associated with an increased risk of all-cause mortality (risk ratio [RR]: 1.73, 95% confidence interval [CI]: 1.39 to 2.16, p < 0.001; I2 = 60%). Subgroup analyses showed that the association was not significantly modified by study design (prospective or retrospective), etiology of diseases (infection, non-infection, or mixed), or cutoff of CRT (>3 s, 3.5 s, or 4 s). The association between CRT and mortality was weaker in studies with multivariate analysis (RR: 1.43, 95% CI: 1.27 to 1.60, p < 0.001; I2 = 0%) as compared to that derived from studies of univariate analysis (RR: 6.27, 95% CI: 3.29 to 11.97, p < 0.001; I2 = 0%). CONCLUSIONS: Prolonged CRT at admission may be a predictor of increased short-term mortality of critically ill patients.

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.

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.

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.

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.

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.

Retinal microcirculation abnormalities in patients with systemic sclerosis: an explorative optical coherence tomography angiography study.

OBJECTIVES: To investigate subclinical and clinical abnormalities in retinal and choroidal vascular plexuses in patients with SSc by means of optical coherence tomography angiography (OCT-A). METHODS: A total of 20 consecutive SSc patients were recruited and compared with 20 healthy subjects. Quantitative analysis of vessel density (VD), choriocapillaris plexus flow index (CCP-FI) and choroidal vascularity index were performed on OCT-A images in the superficial capillary plexus (SCP), deep capillary plexus (DCP) and CCP for all patients. Images were further reviewed by two independent readers for the assessment of qualitative abnormalities, including tortuosity, rarefaction areas, megacapillaries and macular-foveal capillaries. RESULTS: The DCP-VD in the whole scan and in the perifoveal, superior, inferior, nasal and temporal regions was significantly lower in the SSc group. The CCP-FI was significantly higher in SSc patients. When comparing SSc patients with and without digital ulcers, significantly decreased SCP-VD was demonstrated in the whole, perifoveal, superior, inferior, temporal and nasal regions. No difference in any of the OCT-A parameters was observed when comparing patients with and without interstitial lung disease. Qualitative analysis of OCT-A revealed at least one abnormality in 95% of patients. CONCLUSION: We showed the ability of OCT-A to disclose early ocular vascular abnormalities in patients with SSc. Our results may represent a hypothesis-generating basis for exploring the potential role of OCT-A in diagnosis, monitoring and prognosis stratification in SSc.

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.

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.

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.

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 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.

Risk assessment in precapillary pulmonary hypertension: a comparative analysis.

BACKGROUND: Risk stratification is essential to assess mortality risk and guide treatment in patients with precapillary pulmonary hypertension (PH). We herein compared the accuracy of different currently used PH risk stratification tools and evaluated the significance of particular risk parameters. METHODS: We conducted a retrospective longitudinal observational cohort study evaluating seven different risk assessment approaches according to the current PH guidelines. A comprehensive assessment including multi-parametric risk stratification was performed at baseline and 4 yearly follow-up time-points. Multi-step Cox hazard analysis was used to analyse and refine risk prediction. RESULTS: Various available risk models effectively predicted mortality in patients with precapillary pulmonary hypertension. Right-heart catheter parameters were not essential for risk prediction. Contrary, non-invasive follow-up re-evaluations significantly improved the accuracy of risk estimations. A lack of accuracy of various risk models was found in the intermediate- and high-risk classes. For these patients, an additional evaluation step including assessment of age and right atrium area improved risk prediction significantly. DISCUSSION: Currently used abbreviated versions of the ESC/ERS risk assessment tool, as well as the REVEAL 2.0 and REVEAL Lite 2 based risk stratification, lack accuracy to predict mortality in intermediate- and high-risk precapillary pulmonary hypertension patients. An expanded non-invasive evaluation improves mortality risk prediction in these individuals.

Nailfold videocapillaroscopy: a novel possible surrogate marker for the evaluation of peripheral microangiopathy in pulmonary arterial hypertension.

Nailfold videocapillaroscopy (NVC) changes in systemic sclerosis (SSc) are correlated with vascular complications, such as pulmonary arterial hypertension (PAH), supporting a potential link between peripheral and internal organ vasculopathy. The current stage of knowledge regarding NVC and PAH is discussed, focusing on the assessment of peripheral microangiopathy and a potential relationship with functional, echocardiographic, and haemodynamic markers of cardiac dysfunction. A comprehensive literature search was carried out to identify all studies focusing on NVC findings in patients with PAH, diagnosed with right heart catheterization. The majority of the studies examined NVC findings in patients with SSc-PAH, while three studies reported NVC abnormalities in patients with idiopathic PAH. Besides the pulmonary vasculature, a systemic component of microangiopathy seems to be involved in PAH. Well-designed prospective trials are warranted to validate NVC as a biomarker, with clinical implications in the diagnostic evaluation, risk stratification, and overall management of PAH in the daily clinical setting.

Gut-liver-axis: Barrier function of liver sinusoidal endothelial cell.

Liver diseases are associated with the leaky gut via the gut-liver-axis. Previous studies have paid much attention to the effect of gut barrier damage. Notably, clinical observations and basic research reveal that the gut barrier damage seldom leads to liver injury independently but aggravates pre-existing liver diseases such as non-alcoholic fatty liver disease and drug-induced liver injury. These evidences suggest that there is a hepatic barrier in the gut-liver-axis, protecting the liver against gut-derived pathogenic factors. However, it has never been investigated which type of liver cell plays the role of hepatic barrier. Under physiological conditions, liver sinusoidal endothelial cell (LSEC) can take up and eliminate virus, bacteriophage, microbial products, and metabolic wastes. LSEC also keeps the homeostasis of liver immune environment via tolerance-inducing and anti-inflammatory functions. In contrast, under pathological conditions, the clearance function of LSEC is impaired, and LSEC turns into a pro-inflammatory pattern. Given its anatomical position and physiological functions, LSEC is proposed as the hepatic barrier in the gut-liver-axis. In this review, we aim to further understand the role of LSEC as the hepatic barrier. Future studies are warranted to seek effective treatments to improve LSEC health, which appears to be a promising approach to prevent gut-derived liver injury.