Improvements in edema and microcirculation in chronic venous insufficiency with Pycnogenol® or elastic compression.

BACKGROUND: Chronic venous insufficiency (CVI) is the consequence of venous valve reflux and/or venous flow obstruction and resulting venous hypertension in the lower extremities. The aim of this prospective supplement registry study was to evaluate the efficacy of compression stockings or Pycnogenol® in controlling symptoms and edema in CVI and their efficacy on microcirculatory parameters. METHODS: Two comparable groups of 30 subjects with CVI were observed for 4 months. RESULTS: Elastic compression was less tolerated than Pycnogenol® with 12 subjects being unable to follow the compression routine. No side effects due to supplementation were observed; tolerability of the supplementation was optimal. Ambulatory venous pressure (AVP) and refilling time (RT) at inclusion indicated a significant increase in venous pressure and reflux (refilling time <16 seconds). AVP and RT did not change after 4 months. Microcirculatory and clinical measurements were comparable at inclusion between the 2 groups. After 4 months, skin resting flux (RF) and skin PO2-PCO2 were significantly improved with Pycnogenol® compared to compression (P<0.05). The significant increase in skin PO2 and the decrease in PCO2 after Pycnogenol® intake were ascribed to the decrease in the abnormally high skin resting flux, a sign of better perfusion and skin nutritional supply. Pycnogenol® reduced leg volume, on average by 18.3% in the evening compared to 4.4% of reduction with compression (P<0.05) showing an important effect on edema. The venous Clinical Severity Score (VCSS) and the composite symptom score (CSS) decreased significantly in the Pycnogenol® group compared to compression, indicating a better improvement in microcirculatory perfusion and nutritional supply produced by the supplementation of Pycnogenol® in comparison with compression. Pycnogenol® significantly improved microcirculation and clinical symptoms in comparison with compression. The decrease in local oxidative stress (OS) at the distal perimalleolar region with Pycnogenol® was significant in comparison with compression (P<0.05). A lower local OS is an important metabolic indication of a better capillary perfusion with better nutritional exchanges. At the end of the registry study, four small ulcerations and skin breaks in four limbs (between 3 and 5 mm of maximum diameters) were observed in the compression group. No ulcerations or skin breaks were observed in the Pycnogenol® group. CONCLUSIONS: Pycnogenol® relieved edema, improved microcirculation in CVI patients and reduced stationary, interstitial fluid in comparison with compression. Most symptoms of CVI are associated with interstitial water retention; the presence of extra fluid in limb tissues alters perfusion and nutrient supply. Pycnogenol® supplementation reduced water and fluid accumulation in CVI limbs and improved microcirculation and local oxidative stress thus showing important anti-edema effects.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

Angiographic Coronary Slow Flow Is Not a Valid Surrogate for Invasively Diagnosed Coronary Microvascular Dysfunction.

BACKGROUND: Ischemia with no obstructive coronary arteries is frequently caused by coronary microvascular dysfunction (CMD). Consensus diagnostic criteria for CMD include baseline angiographic slow flow by corrected TIMI (Thrombolysis In Myocardial Infarction) frame count (cTFC), but correlations between slow flow and CMD measured by invasive coronary function testing (CFT) are uncertain. OBJECTIVES: The aim of this study was to investigate relationships between cTFC and invasive CFT for CMD. METHODS: Adults with ischemia with no obstructive coronary arteries underwent invasive CFT with thermodilution-derived baseline coronary blood flow, coronary flow reserve (CFR), and index of microcirculatory resistance (IMR). CMD was defined as abnormal CFR (<2.5) and/or abnormal IMR (≥25). cTFC was measured from baseline angiography; slow flow was defined as cTFC >25. Correlations between cTFC and baseline coronary flow and between CFR and IMR and associations between slow flow and invasive measures of CMD were evaluated, adjusted for covariates. All patients provided consent. RESULTS: Among 508 adults, 49% had coronary slow flow. Patients with slow flow were more likely to have abnormal IMR (36% vs 26%; P = 0.019) but less likely to have abnormal CFR (28% vs 42%; P = 0.001), with no difference in CMD (46% vs 51%). cTFC was weakly correlated with baseline coronary blood flow (r = -0.35; 95% CI: -0.42 to -0.27), CFR (r = 0.20; 95% CI: 0.12 to 0.28), and IMR (r = 0.16; 95% CI: 0.07-0.24). In multivariable models, slow flow was associated with lower odds of abnormal CFR (adjusted OR: 0.53; 95% CI: 0.35 to 0.80). CONCLUSIONS: Coronary slow flow was weakly associated with results of invasive CFT and should not be used as a surrogate for the invasive diagnosis of CMD.

Robust Vascular Segmentation for Raw Complex Images of Laser Speckle Contrast Based on Weakly Supervised Learning.

Laser speckle contrast imaging (LSCI) is widely used for in vivo real-time detection and analysis of local blood flow microcirculation due to its non-invasive ability and excellent spatial and temporal resolution. However, vascular segmentation of LSCI images still faces a lot of difficulties due to numerous specific noises caused by the complexity of blood microcirculation's structure and irregular vascular aberrations in diseased regions. In addition, the difficulties of LSCI image data annotation have hindered the application of deep learning methods based on supervised learning in the field of LSCI image vascular segmentation. To tackle these difficulties, we propose a robust weakly supervised learning method, which selects the threshold combinations and processing flows instead of labor-intensive annotation work to construct the ground truth of the dataset, and design a deep neural network, FURNet, based on UNet++ and ResNeXt. The model obtained from training achieves high-quality vascular segmentation and captures multi-scene vascular features on both constructed and unknown datasets with good generalization. Furthermore, we intravital verified the availability of this method on a tumor before and after embolization treatment. This work provides a new approach for realizing LSCI vascular segmentation and also makes a new application-level advance in the field of artificial intelligence-assisted disease diagnosis.

Relation of Thrombolysis in Myocardial Infarction Frame Count to Invasively Measured Coronary Physiologic Indexes.

In the international guidelines, higher thrombolysis in myocardial infarction frame count (TFC) is indicated as evidence of coronary microvascular dysfunction (CMD). However, the association of TFC with invasively measured coronary physiologic parameters such as coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) remains unclear. Patients without significant epicardial coronary lesions underwent invasive coronary physiologic assessment using a thermodilution method in the left anterior descending artery. Corrected TFC (cTFC) was evaluated on coronary angiography. The cut-off values of CFR and IMR were defined as ≤2.0 and >25, and patients with abnormal CFR and/or IMR were defined as having CMD. This study aimed to assess whether cTFC >25, a cut-off value in the guidelines, was diagnostic of the presence of CMD. Of the 137 patients, 34 (24.8%) and 32 (23.3%) had cTFC >25 and CMD, respectively. The rate of CMD was not significantly different between patients with and without cTFC >25. cTFC was weakly correlated with at rest and hyperemic mean transit time and IMR, whereas no significant correlation was observed between cTFC and CFR. The receiver operating characteristic curve analysis showed the poor diagnostic ability of cTFC for abnormal CFR and IMR and the presence of CMD. In conclusion, in patients without epicardial coronary lesions, cTFC as a continuous value and with the cut-off value of 25 was not diagnostic of abnormal CFR and IMR and the presence of CMD. Our results did not support the use of cTFC in CMD evaluation.

[Assessment of microhaemodynamics and oxygenation in tissues after the vestibuloplasty with the use of a free dermal autograft in patients after the reconstructive jaw surgery with the use of the revascularized autografts]. / Otsenka sostoyaniya mikrogemodinamiki i oksigenatsii v tkanyakh posle vestibuloplastiki s ispol'zovaniem svobodnogo dermal'nogo autotransplantata u patsientov posle rekonstruktivnoi operatsii na chelyustyakh s primeneniem revaskulyarizirovannykh autotransplantatov.

Purpose of the study: to study the features of microhaemodynamics and oxygenation in soft tissues in the area of the plastically reconstructed jaw after the vestibuloplasty. MATERIALS AND METHODS: The study included 40 patients aged 20 to 65 (21 males and 19 females). The patients were divided into two groups: I group (14 patients) - patients after reconstructive surgery with the use a fibula autograft without the inclusion of a musculocutaneous «islet¼; II group (26 patients) - patients after reconstructive surgery with the use a fibula autograft with the inclusion of a musculocutaneous «islet¼. To correct the prosthetic bed soft tissues, all patients underwent vestibuloplasty with the use of a free dermal autograft. To study microcirculation in tissues, the laser Doppler flowmetry (LDF) method was used. Microcirculation status was assessed by microcirculation index characterizing the level of tissue blood flow; parameter «σ,¼ which determines the oscillability of the flow of red blood cells and by coefficient of variation, characterizing vasomotor activity of microvessels. According to the Wavelet analysis of LDF-grams the blood flow bypass was determined. An oxygenation study was carried out in the tissues of the plastically restored jaw by optical tissue oximetry, the results of which determined the oxygenation index and the specific oxygen consumption index. RESULTS: According to LDF data after vestibuloplasty, it was found that in I group, the microcirculation in soft tissues of the plastically reconstructed jaw restored in 21 days, and in II group in 2 months, which persisted at 6 months. In I group, the level of oxygenation and specific oxygen consumption normalized in 21 days, and in II group in 2 months, which persisted at 6 months. CONCLUSION: Based on the results of this functional study, it was found that before vestibuloplasty microcirculation and oxygenation indices in II group patients were lower than those in I group patients. After vestibuloplasty with the use of a free dermal autograft, microcirculation indices in II group patients restored in 2 months, while in I group patients those indices restored in 21 days.

Assessment of retinal and choroidal microcirculation after unilateral recession-resection surgery for horizontal strabismus by swept-source optical coherence tomography angiography.

This study explored the possible hemodynamic changes of the retina and choroid after horizontal strabismus surgery using swept-source optical coherence tomography angiography (SS-OCTA). 32 eyes of 32 patients who underwent unilateral horizontal rectus muscle recession-resection surgery were included. SS-OCTA examinations were performed preoperatively and one week postoperatively. Several OCTA measurements were used, including vessel density (VD) of the superficial vascular complex (SVC), VD of the deep vascular complex (DVC), VD of the choriocapillaris (CC), choroidal vascular index (CVI) and choroidal thickness (CT). No significant change in VD of SVC, DVC, and CC was observed whereas CT increased significantly with CVI unchanged. Recession-resection surgery for horizontal strabismus seemed not to significantly influence the microcirculation of the retina and CC in the early postoperative period. However, choroidal thickening happened with a constant CVI probably due to the postoperative inflammation. Further studies are needed to investigate the long-term effects of unilateral recession-resection surgery for horizontal strabismus on the microcirculation of the retina and choroid.

Intraoperative intravenous infusion of lidocaine increases total and small vessel densities of sublingual microcirculation: a randomized prospective pilot study.

OBJECTIVE: Multiple organ failure can occur as a result of postoperative complications. Research has indicated that the underlying mechanism of organ dysfunction is a microcirculation disorder. Because of its antioxidant and anti-inflammatory properties, lidocaine has the potential to improve microvascular blood flow. This study was performed to assess the effect of intraoperative intravenous lidocaine infusion on the microcirculation and determine the incidence of postoperative complications. METHODS: In this prospective randomized double-blind pilot study, 12 patients scheduled for abdominal surgery were randomly allocated to receive an intraoperative infusion of either 1% lidocaine or the same volume of 0.9% sodium chloride solution. The microcirculation was monitored using sidestream dark-field imaging and the vascular occlusion test combined with near-infrared spectroscopy. RESULTS: Lidocaine significantly increased the total vascular density and small vessel density after 2 hours of infusion, with preservation of 99% to 100% of the capillary perfusion in both groups. No patients developed organ failure. CONCLUSIONS: An increase in vessel density may be beneficial in major abdominal surgeries because it is associated with better tissue perfusion and oxygen delivery. However, this finding requires further investigation in patients with increased surgical risk. Overall, this study indicates that lidocaine has potential to improve microvascular perfusion.Research Registry number: 9549 (https://www.researchregistry.com/browse-the-registry#home/registrationdetails/650ffd27b3f547002bd7635f/).

Impaired microvascular circulation in distant organs following renal ischemia.

Mortality in acute kidney injury (AKI) patients remains very high, although very important advances in understanding the pathophysiology and in diagnosis and supportive care have been made. Most commonly, adverse outcomes are related to extra-renal organ dysfunction and failure. We and others have documented inflammation in remote organs as well as microvascular dysfunction in the kidney after renal ischemia. We hypothesized that abnormal microvascular flow in AKI extends to distant organs. To test this hypothesis, we employed intravital multiphoton fluorescence imaging in a well-characterized rat model of renal ischemia/reperfusion. Marked abnormalities in microvascular flow were seen in every organ evaluated, with decreases up to 46% observed 48 hours postischemia (as compared to sham surgery, p = 0.002). Decreased microvascular plasma flow was found in areas of erythrocyte aggregation and leukocyte adherence to endothelia. Intravital microscopy allowed the characterization of the erythrocyte formations as rouleaux that flowed as one-dimensional aggregates. Observed microvascular abnormalities were associated with significantly elevated fibrinogen levels. Plasma flow within capillaries as well as microthrombi, but not adherent leukocytes, were significantly improved by treatment with the platelet aggregation inhibitor dipyridamole. These microvascular defects may, in part, explain known distant organ dysfunction associated with renal ischemia. The results of these studies are relevant to human acute kidney injury.

Cerebrovascular glycocalyx damage and microcirculation impairment in patients with temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is increasingly associated with blood-brain barrier dysfunction and microvascular alterations, yet the pathophysiological link is missing. An important barrier function is exerted by the glycocalyx, a gel-like layer coating the endothelium. To explore such associations, we used intraoperative videomicroscopy to quantify glycocalyx and microcirculation properties of the neocortex and hippocampus of 15 patients undergoing resective brain surgery as treatment for drug-resistant TLE, and 15 non-epileptic controls. Fluorescent lectin staining of neocortex and hippocampal tissue was used for blood vessel surface area quantification. Neocortical perfused boundary region, the thickness of the glycocalyx' impaired layer, was higher in patients (2.64 ± 0.52 µm) compared to controls (1.31 ± 0.29 µm), P < 0.01, indicative of reduced glycocalyx integrity in patients. Moreover, erythrocyte flow velocity analysis revealed an impaired ability of TLE patients to (de-)recruit capillaries in response to changing metabolic demands (R2 = 0.75, P < 0.01), indicating failure of neurovascular coupling mechanisms. Blood vessel quantification comparison between intraoperative measurements and resected tissue showed strong correlation (R2 = 0.94, P < 0.01). This is the first report on in vivo assessment of glycocalyx and microcirculation properties in TLE patients, confirming the pivotal role of cerebrovascular changes. Further assessment of the cerebral microcirculation in relation to epileptogenesis might open avenues for new therapeutic targets for drug-resistant epilepsy.

Red blood cell lingering modulates hematocrit distribution in the microcirculation.

The distribution of red blood cells (RBCs) in the microcirculation determines the oxygen delivery and solute transport to tissues. This process relies on the partitioning of RBCs at successive bifurcations throughout the microvascular network, and it has been known since the last century that RBCs partition disproportionately to the fractional blood flow rate, therefore leading to heterogeneity of the hematocrit (i.e., volume fraction of RBCs in blood) in microvessels. Usually, downstream of a microvascular bifurcation, the vessel branch with a higher fraction of blood flow receives an even higher fraction of RBC flux. However, both temporal and time-average deviations from this phase-separation law have been observed in recent studies. Here, we quantify how the microscopic behavior of RBC lingering (i.e., RBCs temporarily residing near the bifurcation apex with diminished velocity) influences their partitioning, through combined in vivo experiments and in silico simulations. We developed an approach to quantify the cell lingering at highly confined capillary-level bifurcations and demonstrate that it correlates with deviations of the phase-separation process from established empirical predictions by Pries et al. Furthermore, we shed light on how the bifurcation geometry and cell membrane rigidity can affect the lingering behavior of RBCs; e.g., rigid cells tend to linger less than softer ones. Taken together, RBC lingering is an important mechanism that should be considered when studying how abnormal RBC rigidity in diseases such as malaria and sickle-cell disease could hinder the microcirculatory blood flow or how the vascular networks are altered under pathological conditions (e.g., thrombosis, tumors, aneurysm).

Association between mean arterial pressure and sublingual microcirculation during major non-cardiac surgery: Post hoc analysis of a prospective cohort.

OBJECTIVE: To test the hypothesis that there is an association between mean arterial pressure (MAP) and sublingual perfusion during major surgery, and perhaps an identifiable harm threshold. METHODS: This post hoc analysis of a prospective cohort included patients who had elective major non-cardiac surgery with a duration of ≥2 h under general anesthesia. We assessed sublingual microcirculation every 30 min using SDF+ imaging and determined the De Backer score, Consensus Proportion of Perfused Vessels (Consensus PPV), and the Consensus PPV (small). Our primary outcome was the relationship between MAP and sublingual perfusion which was evaluated with linear mixed effects modeling. RESULTS: A total of 100 patients were included, with MAP ranging between 65 mmHg and 120 mmHg during anesthesia and surgery. Over a range of intraoperative MAPs between 65 and 120 mmHg, there were no meaningful associations between blood pressure and various measures of sublingual perfusion. There were also no meaningful changes in microcirculatory flow over 4.5 h of surgery. CONCLUSIONS: In patients having elective major non-cardiac surgery with general anesthesia, sublingual microcirculation is well maintained when MAP ranges between 65 and 120 mmHg. It remains possible that sublingual perfusion will be a useful marker of tissue perfusion when MAP is lower than 65 mmHg.

Prognostic effects of microcirculation-assisted adjustment of venoarterial blood flow in extracorporeal membrane oxygenation: A prospective, pilot, randomized controlled trial.

OBJECTIVE: The study explored the clinical efficacy of microcirculation-assisted blood flow adjustment in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO). METHODS: This prospective, pilot, randomized controlled trial was conducted from 2018 to 2021; enrolled patients were randomly assigned to the microcirculation or control group at a 1:1 ratio. Microcirculatory and clinical data were collected within 24 h (T1) and at 24-48 h (T2), 48-72 h (T3), and 72-96 h (T4) after ECMO initiation and were compared between the groups following the intention-to-treat (ITT) principle. The primary outcome was the Sequential Organ Failure Assessment (SOFA) score at T2. In addition to ITT analysis, analysis based on the as-treated (AT) principle was performed. RESULTS: A total of 35 patients were enrolled in this study. At T2, the SOFA score did not significantly differ between the microcirculation and control groups (16 [14.8-17] vs. 16 [12.5-18], P = 0.782). Generalized estimating equation analysis demonstrated a significantly greater reduction in the SOFA score over time in the microcirculation-AT group than in the control-AT group (estimated difference: -0.767, standard error: 0.327, P = 0.019). The lactate level at T2 was significantly lower in the microcirculation-AT group (2.7 [2.0-3.6] vs. 4.1 [3.0-6.6] mmol/L, P = 0.029). No significant difference in the 30-day survival rate was noted between the groups. CONCLUSION: This prospective pilot study demonstrated the feasibility of microcirculation-assisted VA-ECMO blood flow adjustment despite no significant clinical benefit for critically ill patients. More efforts in personnel training and newer technologies may help achieve microcirculation optimization.

Influence of high-energy laser therapy to the patellar tendon on its ligamentous microcirculation: An experimental intervention study.

Laser therapeutic applications, such as the use of high energy lasers (HILT), are widely used in physical therapy, but basic studies on the mechanisms of action of HILT on tendinous/ligamentous tissue are largely lacking. The aim of this study was to investigate microcirculatory changes of the patellar tendon by HILT. 21 healthy volunteers were included in the present investigation. Before and after HILT, as well as 10 minutes later, the microcirculation was measured by noninvasive laser Doppler and white light spectroscopy (O2C device). Tissue temperature was recorded at the measurement time points using thermography. Blood flow increased significantly by 86.38 arbitrary units (AU; p < 0.001) after the intervention and by 25.76 AU (p < 0.001) at follow-up. Oxygen saturation increased by 20.14% (p < 0.001) and 13.48%, respectively (p < 0.001), whereas relative hemoglobin decreased by 6.67 AU and 7.90 AU, respectively. Tendon temperature increased by 9.45° and 1.94° Celsius, respectively. Acceleration of blood flow by improving the flow properties of erythrocytes and platelets may have caused the results. HILT could be a therapeutic perspective for tendon pathologies with impaired microcirculation, although further studies are needed to validate the experimental results.

Haemodynamic and metabolic adaptations in coronary microvascular disease.

OBJECTIVE: We aimed to evaluate the microcirculatory resistance (MR) and myocardial metabolic adaptations at rest and in response to increased cardiac workload in patients with suspected coronary microvascular dysfunction (CMD). METHODS: Patients with objective ischaemia and/or myocardial injury and non-obstructive coronary artery disease underwent thermodilution-derived microcirculatory assessment and transcardiac blood sampling during graded exercise with adenosine-mediated hyperaemia. We measured MR at rest and following supine cycle ergometry. Patients (n=24) were stratified by the resting index of MR (IMR) into normal-IMR (IMR<22U, n=12) and high-IMR groups (IMR≥22U, n=12). RESULTS: The mean age was 57 years; 67% were males and 38% had hypertension. The normal-IMR group had increased IMR response to exercise (16±5 vs 23±12U, p=0.03) compared with the high-IMR group, who had persistently elevated IMR at rest and following exercise (38±19 vs 33±15U, p=0.39) despite similar exercise duration and rate-pressure product between the groups, both p>0.05. The normal-IMR group had augmented oxygen extraction ratio following exercise (53±18 vs 64±11%, p=0.03) compared with the high-IMR group (65±14 vs 59±11%, p=0.26). The postexercise lactate uptake was greater in the high-IMR (0.04±0.05 vs 0.11±0.07 mmol/L, p=0.004) compared with normal-IMR group (0.08±0.06 vs 0.09±0.09 mmol/L, p=0.67). The high-IMR group demonstrated greater troponin release following exercise compared with the normal-IMR group (0.13±0.12 vs 0.001±0.05 ng/L, p=0.03). CONCLUSIONS: Patients with suspected CMD appear to have distinctive microcirculatory resistive and myocardial metabolic profiles at rest and in response to exercise. These differences in phenotypes may permit individualised therapies targeting microvascular responsiveness (normal-IMR group) and/or myocardial metabolic adaptations (normal-IMR and high-IMR groups).

Microcirculation and Physical Exercise In Hypertension.

Hypertension is associated with important alterations in the morphology of small arteries and arterioles. Vascular-specific manifestations are changes in the structure and function of vascular smooth muscle cells, extracellular matrix, perivascular tissues, and endothelial cells. Arteriole and capillary remodeling and capillary rarefaction have been observed in hypertensive animals and human beings which contribute to increased vascular resistance. An impairment of different angiogenetic factors, such as VEGF (vascular endothelial growth factor), VEGFR-2 (vascular endothelial growth factor receptor-2), TIMP-1 (tissue inhibitor matrix metalloproteinases-1), and TSP-1 (thrombospondin-1), seems to be responsible for the reduction of the microvascular network. Exercise training has been shown to improve vascular structure and function in hypertension not only in the large arteries but also in the peripheral circulation. Exercise training may regress microvascular remodeling and normalize capillary density, leading to capillary growth possibly by increasing proangiogenic stimuli such as VEGF. Exercise enhances endothelium-dependent vascular relaxation through nitric oxide release increase and oxidative stress reduction. Other mechanisms include improved balance between prostacyclin and thromboxane levels, lower circulating levels of endothelin-1, attenuation of infiltration of immune cells into perivascular adipose tissue, and increase of local adiponectin secretion. In addition, exercise training favorably modulates the expression of several microRNAs leading to a positive modification in muscle fiber composition. Identifying the bioactive molecules and biological mechanisms that mediate exercise benefits through pathways that differ from those used by antihypertensive drugs may help to improve our knowledge of hypertension pathophysiology and facilitate the development of new therapeutic strategies.

Coronary microvascular dysfunction is an independent predictor of developing cancer in patients with non-obstructive coronary artery disease.

AIMS: Cardiovascular disease and cancer share common pathogenesis and risk factors. Coronary microvascular dysfunction (CMD), reflecting impaired coronary microvascular dilation in response to stress, is related to a higher risk of major cardiovascular events; however, its association with cancer has not been explored. METHODS AND RESULTS: A retrospective study on 1042 patients with non-obstructive coronary artery diseases (NOCADs) was performed. Data regarding demographic, clinical history, diagnostic coronary reactivity test, and cancer occurrence were collected. Coronary microvascular dysfunction was defined as coronary flow reserve (the ratio of hyperaemic blood flow to resting blood flow) ≤2.5. Thirty-four per cent had CMD (67.4% female and the average age was 52.4 ± 12.2 years). Of 917 patients with no history of cancer, 15.5% developed cancer during follow-up [median of 9 (4, 16) years]. Kaplan-Meier analysis showed that CMD patients had lower cancer-free survival compared with those without CMD (log-rank P = 0.005). Cox proportional hazard analyses showed that after adjusting for age, sex, hypertension, diabetes, smoking, and glomerular filtration rate, CMD is independently associated with cancer [hazard ratio, 1.4; 95% confidence interval (CI), 1.09-2.04; P = 0.04]. The rate of major adverse cardiovascular events (MACE) was significantly higher in CMD patients compared with that in non-CMD patients who had a previous history of cancer [odds ratio (OR), 2.5; 95% CI, 1-6.2; P = 0.04] and those with no history of cancer (OR, 1.4; 95% CI, 1.01-1.9; P = 0.044). CONCLUSION: Coronary microvascular dysfunction is associated with cancer incidence in patients presenting with NOCADs. This study emphasizes follow-up in patients with CMD to evaluate the risk of MACE as well as potential malignant diseases.

The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells.

Vasculogenic mimicry (VM) is an endothelium-independent tumor microcirculation that provides adequate blood supply for tumor growth. The presence of VM greatly hinders the treatment of glioblastoma (GBM) with anti-angiogenic drugs. Therefore, targeting VM formation may be a feasible therapeutic strategy for GBM. The research aimed to evaluate the roles of BUD13, CDK12, MBNL1 in regulating VM formation of GBM. BUD13 and CDK12 were upregulated and MBNL1 was downregulated in GBM tissues and cells. Knockdown of BUD13, CDK12, or overexpression of MBNL1 inhibited GBM VM formation. METTL3 enhanced the stability of BUD13 mRNA and upregulated its expression through m6A methylation. BUD13 enhanced the stability of CDK12 mRNA and upregulated its expression. CDK12 phosphorylated MBNL1, thereby regulating VM formation of GBM. The simultaneous knockdown of BUD13, CDK12, and overexpression of MBNL1 reduced the volume of subcutaneously transplanted tumors in nude mice and prolonged the survival period. Thus, the BUD13/CDK12/MBNL1 axis plays a crucial role in regulating VM formation of GBM and provides a potential target for GBM therapy.

Evaluation of the impact of blood donation on tissue perfusion and sublingual microcirculation in dogs: A pilot study.

The objective was to assess the feasibility of the sublingual microcirculation evaluation in dogs by using Sidestream Dark Field (SDF) imaging device and to evaluate the impact of blood donation on sublingual microcirculation and tissue perfusion. Before and after blood sampling, macrocirculatory parameters and tissue perfusion parameters were collected. After quality assessment, four videos per individual and per period were retained for analysis. Data were presented as median (1st quartile - 3rd quartile). The evaluation of the sublingual microcirculation with SDF was feasible in sedated dogs: good quality videos could be recorded in 10/12 dogs (83%). The median blood donation volume was 14 mL/kg (13-15). A significant association between the volume of blood collected and the increase in heart rate was observed: for each milliliter of blood drawn, heart rate increased by 1 bpm (CI95% = [0.2, 2], P = 0.03). Blood collection was associated with a significant increase of shock index (estimate = 0.17, CI95% = [0.02, 0.32], P = 0.04). After blood donation, lactate concentration significantly decreased (before: 2.1 (1.7-2.8), after: 1.1 (0.8-1.7) mmol/l, P = 0.009). No significant variation of the microcirculatory parameters was observed. In conclusion, sublingual evaluation of the microcirculation with SDF technology is feasible in dogs. In the present condition, blood donation did not significantly alter microcirculation. These results need to be confirmed in a larger population.

Liver-secreted fluorescent blood plasma markers enable chronic imaging of the microcirculation.

Studying blood microcirculation is vital for gaining insights into vascular diseases. Blood flow imaging in deep tissue is currently achieved by acute administration of fluorescent dyes in the blood plasma. This is an invasive process, and the plasma fluorescence decreases within an hour of administration. Here, we report an approach for the longitudinal study of vasculature. Using a single intraperitoneal or intravenous administration of viral vectors, we express fluorescent secretory albumin-fusion proteins in the liver to chronically label the blood circulation in mice. This approach allows for longitudinal observation of circulation from 2 weeks to over 4 months after vector administration. We demonstrate the chronic assessment of vascular functions including functional hyperemia and vascular plasticity in micro- and mesoscopic scales. This genetic plasma labeling approach represents a versatile and cost-effective method for the chronic investigation of vasculature functions across the body in health and disease animal models.