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Flow-mediated-paradoxical vasoconstriction is independently associated with asymptomatic myocardial ischemia and coronary artery disease in type 2 diabetic patients.
Nguyen, MT, Pham, I, Valensi, P, Rousseau, H, Vicaut, E, Laguillier-Morizot, C, Nitenberg, A, Cosson, E
Cardiovascular diabetology. 2014;:20
Abstract
BACKGROUND To investigate whether flow-mediated dilation (FMD) impairment, which precedes overt atherosclerosis, is associated with silent myocardial ischemia (SMI) and asymptomatic coronary artery disease (CAD) in type 2 diabetes. METHODS Forearm FMD was measured by ultrasonography in 25 healthy control, 30 non-diabetic overweight or obese patients and 118 asymptomatic type 2 diabetic patients with a high cardiovascular risk profile. SMI (abnormal stress myocardial scintiscan and/or stress dobutamine echocardiogram) and CAD (coronary angiography in the patients with SMI) were assessed in the diabetic cohort. RESULTS FMD was lower in diabetic patients (median 0.61% (upper limits of first and third quartiles -1.22;3.2)) than in healthy controls (3.95% (1.43;5.25), p < 0.01) and overweight/obese patients (4.25% (1.74;5.56), p < 0.01). SMI was present in 60 diabetic patients, including 21 subjects with CAD. FMD was lower in patients with SMI than in those without (0.12% (-2.3;1.58) vs 1.64% (0;3.69), p < 0.01), with a higher prevalence of paradoxical vasoconstriction (50.0% vs 29.3%, p < 0.05). FMD was also lower in patients with than without CAD (-1.22% (-2.5;1) vs 1.13% (-0.4;3.28), p < 0.01; paradoxical vasoconstriction 61.9% vs 34.4%, p < 0.05). Logistic regression analyses considering the parameters predicting SMI or CAD in univariate analyses with a p value <0.10 showed that paradoxical vasoconstriction (odds ratio 2.7 [95% confidence interval 1.2-5.9], p < 0.05) and nephropathy (OR 2.6 [1.2-5.7], p < 0.05) were independently associated with SMI; and only paradoxical vasoconstriction (OR 3.1 [1.2-8.2], p < 0.05) with CAD. The negative predictive value of paradoxical vasoconstriction to detect CAD was 88.7%. CONCLUSIONS In diabetic patients, FMD was independently associated with SMI and asymptomatic CAD. TRIAL REGISTRATION Trial registration number NCT00685984.
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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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Abstract
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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The effect of glibenclamide on cutaneous laser-Doppler flux.
Cankar, K, Strucl, M
Microvascular research. 2008;(1):97-103
Abstract
The K(ATP) channels play a crucial role in regulation of vascular tone in conditions of hypoxia. Whether they contribute to peripheral blood flow regulation in human cutaneous microcirculation during a non-hypoxic state is the matter of conflicting in vivo studies that have used plethysmographic method. Our aim was therefore to elucidate the role of K(ATP) channels in human skin microcirculation in three different conditions that evoke different interplays of vascular mechanisms; during resting conditions, during the postocclusive vasodilatation and in the vasoconstriction response to local cold exposure. The laser-Doppler (LD) skin response was monitored in 12 healthy volunteers on the skin of the fingertips of both hands at rest, after the release of an 8-min digital arteries occlusion, and during local cooling of one hand at 15 degrees C. We compared the direct (at the measuring site) and the indirect (at the contralateral non-cooled hand) LD flux response after intradermal microinjection of saline solution (1 mul) and after a microinjection of the K(ATP) channel blocker glibenclamide (8 muM saturated solution) at the measuring site after obtaining the dose-dependent effect of glibenclamide. The effect of the saline solution was used as a reference value. There was a statistically significant lower resting LD flux after the microinjection of glibenclamide 273.6+/-36 PU when compared to the values obtained after the application of the saline solution 375.8+/-31 PU (paired t-test, p=0.016). Glibenclamide also significantly reduced the relative area under the LD flux curve during the PRH response 14551+/-2508 PU*s vs. 6402+/-1476 PU*s (paired t-test, p=0.01) and increased the principal frequency of postocclusive PRH oscillations 0.0931+/-0.01 Hz vs. 0.1309+/-0.02 Hz (p=0.01). In addition, glibenclamide significantly decreased the LD flux during both the direct and indirect response to local cold exposure when compared to the application of saline solution (paired t-test, p<0.01). Our results support the conjecture that ATP sensitive K(+) channels are importantly involved in blood flow regulation of human skin microcirculation in PRH response, in resting conditions as well as in microvascular local cold response.
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Endothelial and neural regulation of skin microvascular blood flow in patients with diabetic peripheral neuropathy: effect of treatment with the isoform-specific protein kinase C beta inhibitor, ruboxistaurin.
Brooks, B, Delaney-Robinson, C, Molyneaux, L, Yue, DK
Journal of diabetes and its complications. 2008;(2):88-95
Abstract
PURPOSE This article aims to study the effects of ruboxistaurin (RBX) on skin microvascular blood flow (SkBF) and evaluate the relationship between endothelial and neural control of SkBF in patients with diabetic peripheral neuropathy (DPN). METHODS We studied 11 placebo- and 9 RBX (32 mg/day)-treated patients who participated in a 1-year, double-masked, randomized, Phase 3 study of RBX for treatment of DPN sensory symptoms. Patients had type 1 or type 2 diabetes, a detectable sural sensory nerve action potential, and Neuropathy Total Symptom Score-6 (NTSS-6) >6 points. SkBF was measured by laser Doppler velocimetry, combined with iontophoresis of acetylcholine and sodium nitroprusside, at baseline, 3 months, and 1 year. Sensory symptoms and electrophysiology were also evaluated during the study. The relationship between endothelial and neural control of SkBF at baseline was assessed using linear regression. RESULTS No significant differences (RBX vs. placebo) were demonstrable for post-iontophoresis SkBF [fold increase from basal state (1 year): endothelium-dependent, 3.6 vs. 8.6; endothelium-independent, 3.7 vs. 2.0; C fiber-mediated, 1.7 vs. 2.0; P>.05] or sensory symptoms [NTSS-6 total score (1 year): 7.7 vs. 6.0 points; P=.4]. There were also no significant between-group differences in nerve conduction parameters, except for placebo peroneal nerve conduction velocity, which demonstrated a statistically significant improvement of unknown clinical importance (Z=2.1; P=.034). At baseline, C fiber-mediated vasodilatation correlated well with endothelium-dependent vasodilation (r=.7, P<.01) but not with endothelium-independent vasodilatation (r=-.1, P=.7). CONCLUSIONS RBX demonstrated no effect on SkBF or sensory symptoms after 1 year in this cohort. The correlation between C fiber-mediated and endothelium-dependent SkBF at baseline suggests that improving endothelial function could affect the microcirculation not only locally but also via the neurovascular arcade.
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Nitric oxide and noradrenaline contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin.
Houghton, BL, Meendering, JR, Wong, BJ, Minson, CT
The Journal of physiology. 2006;(Pt 3):811-20
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Abstract
The initial skin blood flow response to rapid local heating is an axon reflex, which may be mediated by calcitonin gene-related peptide and substance P released from C-fibres. We investigated the role of nitric oxide (NO) and noradrenaline on the temperature threshold for the axon reflex during gradual local heating. 36 subjects participated in two studies. Using microdialysis, we examined the following interventions: NO synthase inhibition (10 mM N(G)-nitro-L-arginine methyl ester, L-NAME); low-dose NO infusion (1.0 microM sodium nitroprusside, SNP); adrenergic blockade (10 mM bretylium tosylate); and low-dose (0.1 microM) noradrenaline infusion. Laser-Doppler flowmetry was used to measure red blood cell flux. Skin was heated at a rate of 0.1 degrees C min(-1) from 33 degrees C to 40 degrees C. Compared to control skin sites, the axon reflex response was shifted to a higher temperature in 4 subjects in the L-NAME sites (control, 37.0 +/- 0.3 degrees C, n = 16; L-NAME, 39.8 +/- 0.1 degrees C, n = 4; P < 0.001) and absent in 12 subjects. The response was also absent in L-NAME plus low-dose SNP sites and not altered by low-dose SNP infusion alone. Adrenergic blockade, with and without low-dose noradrenaline infusion, also abolished the axon reflex response in all subjects. Low-dose noradrenaline infusion alone shifted the axon reflex to a significantly lower temperature threshold compared to control sites (control, 38.2 +/- 0.5 degrees C; noradrenaline, 37.7 +/- 0.4 degrees C, P < 0.05, n = 5). These results suggest that endogenous NO and noradrenaline contribute to the temperature threshold of the axon reflex response during gradual local heating of the skin.
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Clinical microneedle injection of methyl nicotinate: stratum corneum penetration.
Sivamani, RK, Stoeber, B, Wu, GC, Zhai, H, Liepmann, D, Maibach, H
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI). 2005;(2):152-6
Abstract
BACKGROUND/PURPOSE In recent years, microneedles were proposed as a method to painlessly deliver drugs past the stratum corneum. Microneedles have been fabricated in several designs, but limited studies have tested microneedle injections in humans. In this work, we compare microneedle injections with topical application (TA) to investigate if microneedles enhance in vivo drug delivery past the stratum corneum. METHOD In vitro tests were used to measure microneedle pressures and injection volumes. In vivo microneedle injections were performed on the volar forearm of 11 healthy volunteers. Two sets of microneedles, pointed and symmetric, were used to develop microneedle/syringe apparatuses that were used to inject approximately 1 microL of 0.1 M methyl nicotinate, and were compared against TA. A Laser Doppler Perfusion Monitor was used to record maximum blood flow and the time to maximum blood flow at the treatment sites. RESULTS Pointed and symmetric microneedle-injected sites showed a significantly faster time to maximum blood flow than TA. The pointed microneedle injections also resulted in a higher maximum blood flux. Volunteers reported feeling pressure but no pain from the microneedles during the injections. CONCLUSION The microneedles aid in bypassing the stratum corneum and enhance drug delivery through it. The design of the microneedle influences its delivery capabilities, because the pointed microneedles seem to be less susceptible to clogging during the injection.
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Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia.
Koh, KK, Han, SH, Quon, MJ, Yeal Ahn, J, Shin, EK
Diabetes care. 2005;(6):1419-24
Abstract
OBJECTIVE Improvement in endothelial function is predicted to improve insulin sensitivity, and this may be one mechanism by which fenofibrate decreases the incidence of coronary heart disease. We hypothesize fenofibrate improves endothelial function by enhancing insulin sensitivity. RESEARCH DESIGN AND METHODS We administered placebo or fenofibrate 200 mg daily for 8 weeks to 46 patients with primary hypertriglyceridemia (24 had metabolic syndrome). This study was randomized, double blind, placebo controlled, and crossover in design. RESULTS Compared with placebo, fenofibrate decreased total cholesterol, non-HDL cholesterol, apolipoprotein B, and triglycerides and increased HDL cholesterol and apolipoprotein A-I (all P < 0.001) while tending to decrease LDL cholesterol (P = 0.069). Fenofibrate significantly improved percent flow-mediated dilator response to hyperemia by 48 +/- 5% (P < 0.001) and lowered plasma levels of high-sensitivity C-reactive protein (hsCRP) relative to baseline measurements from 0.80 to 0.70 mg/l (P = 0.001) and fibrinogen levels by 16 +/- 3% (P < 0.001). Compared with placebo, fenofibrate therapy significantly increased plasma levels of adiponectin by 14 +/- 5% (P = 0.008) and increased insulin sensitivity (assessed by quantitative insulin sensitivity check index [QUICKI]) by 6 +/- 2% (P = 0.048). There were significant correlations between percent changes in adiponectin levels and percent changes in flow-mediated dilation (r = 0.401, P = 0.006), hsCRP (r = -0.443, P = 0.002), or QUICKI (r = 0.292, P = 0.049). Multivariate regression analysis showed that only changes in adiponectin levels persisted as an independent predictor of changes in flow-mediated dilation (r = 0.504, P = 0.013). Overall, we observed similar results in 24 patients with metabolic syndrome. CONCLUSIONS Fenofibrate therapy significantly improved percent flow-mediated dilator response to hyperemia, reduced inflammation marker levels, increased adiponectin levels, and improved insulin sensitivity in hypertriglyceridemic or metabolic syndrome patients.
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Effects of the apparent transverse relaxation time on cerebral blood flow measurements obtained by arterial spin labeling.
St Lawrence, KS, Wang, J
Magnetic resonance in medicine. 2005;(2):425-33
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Abstract
Previous modeling studies have predicted that a significant fraction of the signal in arterial spin labeling (ASL) experiments originates from labeled water in the capillaries. Provided that the relaxation times in blood and tissue are similar, ASL data can still be analyzed with the conventional one-compartment Kety model. Such studies have primarily focused on T1 differences and have neglected any differences in transverse relaxation times (T2 and T2*). This is reasonable for studies at lower fields; however, it may not be valid at higher fields due to the stronger susceptibility effects of deoxygenated blood. In this study a tracer kinetic model was developed that includes T2* differences between capillary blood and tissue. The model predicts that a reduction in blood T2* at higher fields will attenuate the capillary contribution to the ASL signal. This in turn causes an underestimation of CBF when ASL data are analyzed with the one-compartment Kety model. We confirmed this prediction by comparing ASL data collected at 1.5 and 4 T, and at multiple gradient echoes (19, 32, 45, and 58 ms). A decrease in resting-state CBF with echo time (TE) was observed at 4 T, but not at 1.5 T. These results suggest that at higher fields AST data should be collected using gradient-echo techniques with short TEs, or with spin-echo techniques. Furthermore, the sensitivity of the CBF measurements to venous T2* may affect the interpretation of concurrent ASL/BOLD studies.
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An improved model for the measurement of myocardial perfusion in human beings using N-13 ammonia.
Hickey, KT, Sciacca, RR, Chou, RL, Rodriguez, O, Bokhari, S, Bergmann, SR
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2005;(3):311-7
Abstract
BACKGROUND Oxygen 15 water and nitrogen 13 ammonia are widely used for the quantitative measurement of myocardial perfusion with positron emission tomography. However, blood flow obtained with N-13 ammonia by use of the conventional 2-compartment model frequently underestimates flow by 30% to 50% compared with O-15 water. We hypothesized that this discrepancy is a result of the model configuration of N-13 ammonia and investigated changes to the mathematical model to determine whether more accurate measurements of perfusion could be obtained. METHODS AND RESULTS Twelve healthy volunteers were sequentially studied with O-15 water and N-13 ammonia at rest and during maximal coronary vasodilation with adenosine. Perfusion measurements obtained with the conventional and modified models were compared with values obtained with O-15 water. The conventional N-13 ammonia model underestimated flow by 37% +/- 16% at rest and by 20% +/- 24% with stress when compared with flows obtained with O-15 water. The modified model yielded flow values closer to the line of identity than the conventional model (y = 1.07x + 0.04 vs y = 0.69x + 0.08; respectively; P < .01). CONCLUSIONS Model changes made N-13 ammonia myocardial blood flow estimates more comparable to those obtained with O-15 and may allow for better comparison of flows obtained with these two tracers in the future. Further efforts are warranted to evaluate the accuracy of flow models in human subjects.
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Lanreotide effect on splanchnic blood flow in healthy subjects: effect of the rate of infusion.
Sieber, CC, Beglinger, C, Bart, S, Tschoepl, M, Currie, G, Larsen, F, Drewe, J
Clinical pharmacology and therapeutics. 2004;(1):70-9
Abstract
BACKGROUND Somatostatin is a naturally occurring peptide advocated for the management of hemodynamic complications of chronic liver diseases. The route of administration (bolus application or constant infusion) has been a question of debate. AIM: Our aim was to explore the effects of the somatostatin analog lanreotide, given as a bolus injection or continuous infusion, on food-stimulated hemodynamics in humans. METHODS Twelve healthy subjects (6 men and 6 women) were studied in a double-blind, double-dummy, randomized, crossover study. After a baseline period of 60 minutes, each subject received either a placebo bolus injection and an intravenous infusion of 100 microg/h lanreotide over a period of 8 hours or a placebo infusion over a period of 8 hours and an 800-microg lanreotide bolus injection. Simultaneously, a liquid test meal (Ensure Plus, 6.3 kJ/mL; Abbott Laboratories, Abbott Park, Ill) was perfused intraduodenally at 3 mL/min over a period of 8 hours. Diastolic blood pressure, heart rate, and superior mesenteric arterial and portal venous volume flows were measured at regular intervals by use of echo-Doppler technology. Plasma lanreotide levels were determined at defined intervals. RESULTS Lanreotide as a 100-microg/h infusion for 8 hours was bioequivalent with lanreotide as an 800-microg bolus injection (mean area under the plasma concentration-time curve [AUC] extrapolated to infinity [AUC( infinity )], 1844.3 ng.min/L versus 1971.0 ng.min/L; AUC(infinity) ratios, 0.99; confidence interval, 0.95-1.02), and clearance was identical (479.2 mL/min versus 413.4 mL/min, P >.05). As expected, significant differences were observed in maximum plasma concentrations (75.58 ng/mL versus 4.85 ng/mL, P <.001) after infusion and bolus injections, respectively. Lanreotide at 100 microg/h over a period of 8 hours was well tolerated and abolished food-stimulated splanchnic hyperemia in both the superior mesenteric artery and the portal vein (mean AUC above baseline values [AUC(ab)], 37.25 L/min.min and 0.51 L/min.min, respectively). In contrast, the same dose of lanreotide given as a bolus injection only temporarily blunted postprandial hyperemia (mean AUC(ab) for superior mesenteric artery, 251.4 L/min.min, P <.001; mean AUC(ab) for portal vein, 194.95 L/min.min, P <.001), and subjects had significantly more side effects. CONCLUSION On the basis of tolerability and hemodynamic effects, an intravenous infusion of lanreotide seems superior to a bolus injection of the same dose.