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Insulin-mediated muscle microvascular perfusion and its phenotypic predictors in humans.
Love, KM, Jahn, LA, Hartline, LM, Patrie, JT, Barrett, EJ, Liu, Z
Scientific reports. 2021;(1):11433
Abstract
Insulin increases muscle microvascular perfusion and enhances tissue insulin and nutrient delivery. Our aim was to determine phenotypic traits that foretell human muscle microvascular insulin responses. Hyperinsulinemic euglycemic clamps were performed in 97 adult humans who were lean and healthy, had class 1 obesity without comorbidities, or controlled type 1 diabetes without complications. Insulin-mediated whole-body glucose disposal rates (M-value) and insulin-induced changes in muscle microvascular blood volume (ΔMBV) were determined. Univariate and multivariate analyses were conducted to examine bivariate and multivariate relationships between outcomes, ΔMBV and M-value, and predictor variables, body mass index (BMI), total body weight (WT), percent body fat (BF), lean body mass, blood pressure, maximum consumption of oxygen (VO2max), plasma LDL (LDL-C) and HDL cholesterol, triglycerides (TG), and fasting insulin (INS) levels. Among all factors, only M-value (r = 0.23, p = 0.02) and VO2max (r = 0.20, p = 0.047) correlated with ΔMBV. Conversely, INS (r = - 0.48, p ≤ 0.0001), BF (r = - 0.54, p ≤ 0.001), VO2max (r = 0.5, p ≤ 0.001), BMI (r = - 0.40, p < 0.001), WT (r = - 0.33, p = 0.001), LDL-C (r = - 0.26, p = 0.009), TG (r = - 0.25, p = 0.012) correlated with M-value. While both ΔMBV (p = 0.045) and TG (p = 0.03) provided significant predictive information about M-value in the multivariate regression model, only M-value was uniquely predictive of ΔMBV (p = 0.045). Thus, both M-value and VO2max correlated with ΔMBV but only M-value provided unique predictive information about ΔMBV. This suggests that metabolic and microvascular insulin responses are important predictors of one another, but most metabolic insulin resistance predictors do not predict microvascular insulin responses.
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Cutaneous microvascular perfusion responses to insulin iontophoresis are differentially affected by insulin resistance after spinal cord injury.
La Fountaine, MF, Cirnigliaro, CM, Azarelo, F, Hobson, JC, Tascione, O, Swonger, KN, Dyson-Hudson, T, Bauman, WA
Experimental physiology. 2017;(9):1234-1244
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What is the central question of this study? What impact does insulin resistance have on cutaneous perfusion responses to insulin iontophoresis in vascular beds with markedly reduced or functionally ablated sympathetic nervous system vasomotor function resulting from spinal cord injury? What is the main finding and its importance? Persons with spinal cord injury have sublesional microvascular endothelial dysfunction, as indicated by a blunted cutaneous perfusion response to acetylcholine iontophoresis, and the presence of insulin resistance has a further confounding effect on endothelium-mediated changes to cutaneous perfusion in the lower extremities. Endothelium-mediated mechanisms that regulate skin blood flow might play an integral role in optimizing skin perfusion in vascular beds with sympathetic nervous system vasomotor impairment, such as in spinal cord injury (SCI). Insulin is a vasoactive hormone and second messenger of nitric oxide that facilitates endothelium-mediated dilatation. The effects of insulin resistance (IR) on sublesional cutaneous perfusion responses to insulin provocation have yet to be described in persons with SCI. Persons with SCI and an able-bodied (AB) cohort were divided into subgroups based upon fasting plasma insulin concentration cut-offs for IR (≥13.13 mIU ml-1 ) or insulin sensitivity (IS; <13.13 mIU ml-1 ), as follows: AB, IS (ABIS, n = 21); SCI, IS (SCIS, n = 21); AB, IR (ABIR, n = 9); and SCI, IR (SCIR, n = 11). Laser Doppler flowmetry characterized peak blood perfusion unit (BPU) responses (percentage change from baseline) to insulin, acetylcholine or placebo iontophoresis in the lower extremities; BPU responses were log10 transformed to facilitate comparisons, and the net insulin response (NetIns) BPU response was calculated (insulin minus placebo BPU response). The NetIns was significantly greater in both IS groups compared with their corresponding IR group. The acetylcholine-mediated BPU responses in the SCI subgroups were significantly lower than those in the ABIS group. The proportional BPU responses of NetIns to acetylcholine in the IS cohorts (i.e. ABIS and SCIS) were significantly greater (P < 0.05) than that of each IR subgroup. The presence of IR has a confounding effect on sublesional microvascular endothelium-mediated cutaneous perfusion responses to provocation. Preservation of endothelial sensitivity to its agonists appears to be an important modifiable risk factor to optimize cutaneous perfusion in the lower extremities of persons with SCI.
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Effect of intravitreal ranibizumab on the ocular circulation of the untreated fellow eye.
Sugimoto, M, Nunome, T, Sakamoto, R, Kobayashi, M, Kondo, M
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2017;(8):1543-1550
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PURPOSE To evaluate the effects of unilateral intravitreal ranibizumab (IVR) on the ocular circulation of the fellow eyes. METHODS Fifteen eyes of 15 patients with macular edema (average age 69.6 ± 11.8 years) were studied. Eleven eyes had diabetic macular edema (DME) and four eyes had macular edema associated with a branch retinal vein occlusion. Each eye received 0.5 mg of IVR. The blood circulation on the optic nerve head of the treated and untreated eyes were determined by laser speckle flowgraphy (LSFG, Softcare Co., Ltd) before, 1 day, and 1 week after the IVR. The mean blur rate (MBR) and the relative changes of the MBRs determined as dMBR(%) = 100-(MBR before/MB after) × 100) were evaluated. The central macular thickness (CMT) and the rate of reduction in the thickness (dCMT = 100-(CMT before/CMT after) × 100) were also evaluated. RESULTS The mean dMBR was significantly higher in the treated eyes than the untreated eyes at 1 day (-16.4 ± 17.0% vs 2.31 ± 19.3%) and at 1 week (-12.0 ± 14.6% vs 4.50 ± 25.9%) after the IVR (P = 0.02, paired t tests). CONCLUSION These findings indicate that if ranibizumab enters the systemic circulation, the concentration is not high enough to affect the ocular circulation of the fellow eyes.
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Neurovascular microcirculatory vasodilation mediated by C-fibers and Transient receptor potential vanilloid-type-1 channels (TRPV 1) is impaired in type 1 diabetes.
Marche, P, Dubois, S, Abraham, P, Parot-Schinkel, E, Gascoin, L, Humeau-Heurtier, A, Ducluzeau, PH, Mahe, G
Scientific reports. 2017;:44322
Abstract
Microvascular dysfunction may have an early onset in type 1 diabetes (T1D) and can precede major complications. Our objectives were to assess the endothelial-dependent (acetylcholine, ACh; and post-occlusive hyperemia, PORH), non-endothelial-dependent (sodium nitroprusside, SNP) and neurovascular-dependent (local heating, LH and current induced vasodilation, CIV) microcirculatory vasodilation in T1D patients compared with matched control subjects using a laser speckle contrast imager. Seventeen T1D patients - matched with 17 subjects according to age, gender, Body-Mass-Index, and smoking status - underwent macro- and microvascular investigations. The LH early peak assessed the transient receptor potential vanilloid type 1 channels (TRPV1) mediated vasodilation, whereas the plateau assessed the Nitirc-Oxyde (NO) and endothelium-derived hyperpolarizing factor (EDHF) pathways. PORH explored sensory nerves and (EDHF), while CIV assessed sensory nerves (C-fibers) and prostaglandin-mediated vasodilation. Using neurological investigations, we observed that C-fiber and A-delta fiber functions in T1D patients were similar to control subjects. PORH, CIV, LH peak and plateau vasodilations were significantly decreased in T1D patients compared to controls, whereas there was no difference between the two groups for ACh and SNP vasodilations. Neurovascular microcirculatory vasodilations (C-fibers and TRPV 1-mediated vasodilations) are impaired in TD1 patients whereas no abnormalities were found using clinical neurological investigations. Clinicaltrials: No. NCT02538120.
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Assessing the effects of a short-term green tea intervention in skin microvascular function and oxygen tension in older and younger adults.
Wasilewski, R, Ubara, EO, Klonizakis, M
Microvascular research. 2016;:65-71
Abstract
Green tea consumption has been associated with a reduction in cardiovascular disease risk factors. However, there is little evidence examining its potential differing effect between younger and older populations, whilst little is known on its effect on the circulatory system when oxygen demand is higher. Therefore the aim of this study was to evaluate the short-term effects of green tea consumption on microvascular functioning in both an older and younger population. Fifteen young [24 (4.0)] and fifteen older [61 (4.0)] participants, consumed two cups of green tea daily for 14days. We used Laser Doppler Flowmetry (LDF) to assess cutaneous microvascular function and Transcutaneous Oxygen monitoring (TcPO2) to assess skin oxygen tension. Systolic and diastolic blood pressure were also assessed on both visits. We observed significant improvements in axon-mediated microvascular vasodilation for the younger group [1.6 (0.59) vs 2.05 (0.72), p<0.05] and the older group [1.25 (0.58) vs 1.65 (0.5) p<0.05]. Improvements in skin oxygen tension were also noted for both groups in both noted TcPO2 measures (i.e. 1.25 (0.58) vs 1.65 (0.5) (p<0.05), for ΔTcPO2max for the older group, between visits) respectively. Improvements were also observed for systolic blood pressure in both the younger [120 (10) vs 112 (10), p<0.05] and older group [129 (12) v 124 (11), p<0.001]. In conclusion, we observed statistically-significant improvements in microvascular function and skin oxygen tension. Our results suggest that green tea may prove beneficial as a dietary element in lifestyle interventions aiming to lower cardiovascular disease risk, in both older and younger populations.
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Peripheral Microvascular Vasodilatory Response to Estradiol and Genistein in Women with Insulin Resistance.
Wenner, MM, Taylor, HS, Stachenfeld, NS
Microcirculation (New York, N.Y. : 1994). 2015;(5):391-9
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OBJECTIVE E2 enhances vasodilation in healthy women, but vascular effects of the phytoestrogen GEN are still under investigation. IR compromises microvascular function. We therefore examined the interaction of E2 , GEN, and IR on microvascular vasodilatory responsiveness. METHODS We hypothesized that E2 and GEN increase microvascular vasodilation in healthy women (control, n = 8, 23 ± 2 year, BMI: 25.9 ± 2.9 kg/m2) but not in women with IR (n = 7, 20 ± 1 year, BMI: 27.3 ± 3.0 kg/m2). We used the cutaneous circulation as a model of microvascular vasodilatory function. We determined CVC with laser Doppler flowmetry and beat-to-beat blood pressure during local cutaneous heating (42 °C) with E2 or GEN microdialysis perfusions. Because heat-induced vasodilation is primarily an NO-mediated response, we examined microvascular vasodilation with and without L-NMMA. RESULTS In C, E2 enhanced CVC (94.4 ± 2.6% vs. saline 81.6 ± 4.2% CVCmax , p < 0.05), which was reversed with L-NMMA (80.9 ± 7.8% CVCmax , p < 0.05), but GEN did not affect vasodilation. Neither E2 nor GEN altered CVC in IR, although L-NMMA attenuated CVC during GEN. CONCLUSIONS Our study does not support improved microvascular responsiveness during GEN exposure in healthy young women, and demonstrates that neither E2 nor GEN improves microvascular vasodilatory responsiveness in women with IR.
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Non-Invasive Measurement of Skin Microvascular Response during Pharmacological and Physiological Provocations.
Iredahl, F, Löfberg, A, Sjöberg, F, Farnebo, S, Tesselaar, E
PloS one. 2015;(8):e0133760
Abstract
INTRODUCTION Microvascular changes in the skin due to pharmacological and physiological provocations can be used as a marker for vascular function. While laser Doppler flowmetry (LDF) has been used extensively for measurement of skin microvascular responses, Laser Speckle Contrast Imaging (LSCI) and Tissue Viability Imaging (TiVi) are novel imaging techniques. TiVi measures red blood cell concentration, while LDF and LSCI measure perfusion. Therefore, the aim of this study was to compare responses to provocations in the skin using these different techniques. METHOD Changes in skin microcirculation were measured in healthy subjects during (1) iontophoresis of sodium nitroprusside (SNP) and noradrenaline (NA), (2) local heating and (3) post-occlusive reactive hyperemia (PORH) using LDF, LSCI and TiVi. RESULTS Iontophoresis of SNP increased perfusion (LSCI: baseline 40.9±6.2 PU; 10-min 100±25 PU; p<0.001) and RBC concentration (TiVi: baseline 119±18; 10-min 150±41 AU; p = 0.011). No change in perfusion (LSCI) was observed after iontophoresis of NA (baseline 38.0±4.4 PU; 10-min 38.9±5.0 PU; p = 0.64), while RBC concentration decreased (TiVi: baseline 59.6±11.8 AU; 10-min 54.4±13.3 AU; p = 0.021). Local heating increased perfusion (LDF: baseline 8.8±3.6 PU; max 112±55 PU; p<0.001, LSCI baseline 50.8±8.0 PU; max 151±22 PU; p<0.001) and RBC concentration (TiVi: baseline 49.2±32.9 AU; max 99.3±28.3 AU; p<0.001). After 5 minutes of forearm occlusion with prior exsanguination, a decrease was seen in perfusion (LDF: p = 0.027; LSCI p<0.001) and in RBC concentration (p = 0.045). Only LSCI showed a significant decrease in perfusion after 5 minutes of occlusion without prior exsanguination (p<0.001). Coefficients of variation were lower for LSCI and TiVi compared to LDF for most responses. CONCLUSION LSCI is more sensitive than TiVi for measuring microvascular changes during SNP-induced vasodilatation and forearm occlusion. TiVi is more sensitive to noradrenaline-induced vasoconstriction. LSCI and TiVi show lower inter-subject variability than LDF. These findings are important to consider when choosing measurement techniques for studying skin microvascular responses.
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Monitoring microcirculatory alterations in oral squamous cell carcinoma following photodynamic therapy.
Milstein, DM, van Kuijen, AM, Copper, MP, Karakullukçu, B, Tan, IB, Lindeboom, JA, Fokkens, WJ, Ince, C
Photodiagnosis and photodynamic therapy. 2012;(1):69-75
Abstract
BACKGROUND One of the mechanisms through which photodynamic therapy (PDT) is thought to elicit tumour destruction is by producing microvascular damage and obstruction of nutritive blood flow. The aim of this study was to directly monitor and quantify microcirculatory changes following tissue illumination by PDT for oral squamous cell carcinoma. METHODS Ten consecutive patients receiving PDT for a carcinoma in situ, a T1 or T2 tumour in the oral cavity without evidence of lymph node metastasis were selected for this study. Tumour and marginal healthy mucosa total capillary density (TCD) and functional capillary density (FCD) inside the field of illumination were measured and compared using sidestream dark-field (SDF) imaging prior to tissue illumination, immediately after PDT, and again after 15min. RESULTS Baseline mean tumour TCD was 21.2±5capillaries per square millimetres (cpll/mm²) and 24.9±19cpll/mm² in the surrounding marginal healthy tissue; there were no significant differences between tumour and healthy tissue or time points. Comparisons between baseline and post-illumination time points revealed significant differences in both tumour and healthy tissue FCD (P<0.05). No significant differences in FCD were observed between the two tissues. CONCLUSIONS Our findings using SDF imaging demonstrate that PDT significantly attenuates tumour and marginal healthy tissue perfusion by directly disrupting the functionality of the microcirculation.
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A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease.
Kutlar, A, Ataga, KI, McMahon, L, Howard, J, Galacteros, F, Hagar, W, Vichinsky, E, Cheung, AT, Matsui, N, Embury, SH
American journal of hematology. 2012;(5):536-9
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Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD.
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Aescin: microcirculatory activity. Effects of accessory components on clinical and microcirculatory efficacy.
Luzzi, R, Feragalli, B, Belcaro, G, Cesarone, MR, Cornelli, U, Dugall, M, Hosoi, M
Panminerva medica. 2011;(3 Suppl 1):51-5
Abstract
AIM: This study was performed to test the hypothesis that the heparin and phosphatidylcholine (PDC) included in Aescin gel formulations had the main role of allowing a better penetration of Aescin without important pharmacodynamic effects. Heparin and PDC should be considered as "enhancers". They do not have - at the dosage used - a specific or independent action. An open, registry study of patients - a group with chronic venous insufficiency (CVI) and a group of patients with diabetic microangiopathy were completed. METHODS In patients with CVI and in patients with diabetic microangiopathy, we used a commercial gel preparation containing Aescin, PDC and heparin (group A). The first group of patients used the full complex. The second group used the complex without PDC (group B) and the third (group C) used the complex without heparin. RESULTS In both studies the different groups of patients were comparable. In CVI patients (mean age 44.5; SD 2.4; range 40-50) venous microangiopathy was present at the perimalleolar region. Aescin produced comparable microcirculatory results with and without the two other components. Transcutaneus PO2 [TcPO2] increased in all groups. Transcutaneus PCO2 (TcCO2) decreases. The increased Laser Doppler Flux (LDF) (typical of CVI) decreased towards normality. The local Plasma Free Radicals [PFR] levels decreased as the result of better skin perfusion (P<0.05). Comparable data were observed in subjects with diabetic microangiopathy (mean age 46.5; SD 3.1). In these patients the compound was applied at the dorsum of the foot. TcPO2 increased with treatment. TcPCO2, skin flux and PFR decreased towards normal levels (P<0.05). CONCLUSION In conclusion Aescin improves the microcirculation and PFR. Heparin and PDC - included in the gel - have an ancillary role. An improved perfusion and nutrition of the skin was observed both in diabetic and venous microangiopathy. This may possibly contribute in the reduction of the incidence of ulceration associated with diabetic and venous microangiopathy. Aescin-based products may be included in a more complex management plan, including several systemic and local treatments.