Skin Microvascular Reactivity Research Articles

Microvascular reactivity in women with gestational diabetes mellitus studied during pregnancy.

AimTo compare microvascular reactivity assessed in the skin using laser Doppler fluximetry (LDF) in women with gestational diabetes mellitus (GDM) and gestational age-matched control during pregnancy.Methods110 pregnant women at ~33 weeks gestation participated in the study. Skin microvascular reactivity was evaluated by LDF, at rest, during the response to brief arterial occlusion (post occlusive hyperaemic response) and during sympathetically mediated vasoconstrictor response to deep inspiratory breath hold.ResultsNo statistically significant differences were found in the microvascular variables studied (resting and maximum rate flux, post-ischaemic reactive hyperaemia and deep inspiratory breath holds) between +GDM and –GDM groups women. In women with GDM there was a negative correlation between resting flux and the response to the oral glucose tolerance test (OGTT), r = -0.282 (p = 0.037). There was also a negative correlation between the response to the OGTT and the sympathetically mediated constrictor response to inspiratory breath holds (r = -.298, p = .030) but not in women with GDM (r = .102, r = .468).ConclusionAttenuated microvascular reactivity as an early marker of endothelial dysfunction is not present in women with GDM when assessed during pregnancy.

Prolonged (9 h) poikilocapnic hypoxia (12% O2) augments cutaneous thermal hyperaemia in healthy humans

The primary aim of this study was to investigate the effect of systemic poikilocapnic hypoxia on forearm cutaneous thermal hyperaemia. A secondary aim was to examine the relationship between the individual susceptibility to oxygen desaturation and cutaneous vasodilator capacity. Twelve healthy participants (seven male) were exposed to 9 h of normoxia and 12% poikilocapnic hypoxia in a temperature- and humidity-controlled environmental chamber. Skin blood flow was assessed at the ventral forearm using laser Doppler flowmetry combined with rapid local heating. After 6 min at baseline (skin temperature clamped at 33°C), local skin temperature was elevated at a rate of 0.5°C every 5 s up to 42°C to elicit a sensory axon response and then held constant for 30 min to cause a plateau. Skin blood flow was calculated as cutaneous vascular conductance [CVC; in perfusion units/mean arterial blood pressure (APU mmHg(-1))] and expressed in raw format and relative to heating at 44°C in normoxia (%CVC44). During hypoxaemia, vasodilatation was greater during the initial peak (raw, Δ0.35 APU mmHg(-1), P = 0.09; %CVC44, Δ18%, P = 0.05) and the plateau phase (raw, Δ0.55 APU mmHg(-1), P = 0.03; %CVC44, Δ26%, P = 0.02). The rate of rise in cutaneous blood flow during the initial peak was significantly greater during poikilocapnic hypoxia (P < 0.01). We observed a negative relationship between oxygen saturation in poikilocapnic hypoxia and the change in baseline (P = 0.06), initial peak (P = 0.01) and plateau phase of thermal hyperaemia (P = 0.01). Prolonged poikilocapnic hypoxia causes robust increases in CVC during both phases of thermal hyperaemia that are dependent on the oxygen saturation of the individual.

Differences in Skin Microcirculation on the Upper and Lower Extremities in Patients with Diabetes Mellitus: Relationship of Diabetic Neuropathy and Skin Microcirculation

During recent years, the role of microcirculation has received increasing attention especially for its potential pathogenic role in the development of diabetes complications, particularly diabetic foot syndrome. The aim of this study was to evaluate the differences in the skin microcirculatory reactivity on the upper and lower extremities (UE and LE, respectively) in the patient with type 2 diabetes mellitus (T2DM). We also evaluated the changes in the skin microcirculation independently of the individual test for peripheral diabetic neuropathy (DN) diagnosis (Semmes-Weinstein monofilaments, Bio-Thesiometer [Bio-Medical Instrument Co., Newbury, OH], and Neuropad(®) [TRIGOcare International GmbH, Wiehl, Germany]). Fifty-two patients with T2DM were enrolled. Microvascular reactivity was measured by laser Doppler iontophoresis, using 1% acetylcholine chloride (ACH) and 1% sodium nitroprusside. Significant reduction of perfusion was found in LE compared with UE when using ACH. In patients with DN skin microvascular reactivity on LE and UE was reduced, compared with patients without DN. Impaired skin microvascular reactivity to ACH (dominant on LE) was demonstrated in all patients who were positive in at least one of the tests for the presence of DN. Reactivity of the skin microcirculation is worse on the foot than on the hand. This study confirmed a close relationship of DN and impaired skin microcirculation. It seems that autonomous neuropathy (assessed using the Neuropad) precedes the manifestation of somatosensory neuropathy.

Individuals with early onset (premature) coronary artery disease display impaired systemic microvascular endothelial function: studies using laser speckle contrast imaging

Purpose: Laser speckle contrast imaging (LSCI) provides an innovative approach to the non-invasive evaluation of systemic microvascular endothelial function. In the present work, we assessed skin microvascular reactivity in individuals with early onset coronary artery disease (EOCAD, diagnosis at less than 45 years of age) using LSCI coupled to pharmacological and physiological stimuli. Methods: Skin microvascular blood flow was continuously monitored in the forearm using LSCI. Acetylcholine (ACh) dose-response curves were performed using an iontophoresis micropharmacology system and post-occlusive reactive hyperemia (PORH) was analyzed after a 3-minute occlusion of blood flow to the forearm. Measurements of microvascular skin blood flow in arbitrary perfusion units (APU) were divided by mean arterial pressure to give cutaneous vascular conductance (CVC) in APU/mm Hg. The results were presented as mean ± SEM and were analyzed using two-tailed unpaired Student's t tests. Results: Fifty-eight patients with EOCAD aged 45±0.4 years (34 men) and 25 healthy age- and sex-matched individuals were included in the study. ACh- and PORH-mediated vasodilation was significantly reduced in EOCAD individuals. Area under the curve of ACh-induced vasodilation was of 6445±842 and 3975±540 APU/sec in controls vs. EOCAD, respectively; p=0.0087; figure 1). Increase in CVC resulting from PORH-induced vasodilation was of 0.46±0.03 and 0.38±0.02 APU/mmHg in controls vs. EOCAD, respectively; p=0.0182; figure 1). ![Figure][1] Conclusions: LSCI identifies systemic microvascular endothelial-dysfunction in individuals presenting with EOCAD and thus could be used as an early peripheral marker of the atherothrombotic disease. [1]: pending:yes

Effects of Polymorphisms of NOS3 and GNB3 Genes on Skin Microvascular Reactivity in Normal Pregnancy

We studied the relationship between endothelial NO-synthase gene (NOS3) and G protein β3 subunit gene (GNB3) polymorphisms and reactivity of skin microvessels during physiological gestation. T-786C NOS3 polymorphism influenced the maximum blood flow rate in skin microvessels and the severity of postocclusive reactive hyperemia during the third trimester of pregnancy. The relationship between G894T NOS3 polymorphism and the duration of postocclusive reactive hyperemia was revealed. C825T GNB3 polymorphism affects the duration and severity of postocclusive reactive hyperemia during the first and third trimesters of pregnancy. Thus, NOS3 and GNB3 polymorphisms affect blood flow in the skin microvessels during physiological gestation.

Relationships between emerging cardiovascular risk factors, z‐BMI, waist circumference and body adiposity index (BAI) on adolescents

The body adiposity index (BAI) has been recently proposed as an alternative index to body mass index (BMI) and waist circumference (WC) to evaluate adiposity in adults, with special focus on its ability to discriminate gender specificities on adiposity. Endothelial dysfunction, circulating endothelial cells (CECs), endothelin-1 and adipocytokines are all related to atherosclerosis and nowadays considered as markers of emerging cardiovascular (CV) risk. This study aimed to determine in normal weight and obese adolescents which measures of body composition (BAI and z-BMI) or distribution (WC) correlate better with emerging CV risk markers. Forty adolescents were selected according to BMI: normal weight (n = 20; 7 girls/13 boys, 14·7 ± 1·4 years, 53·4 ± 6·0 kg, z-BMI 0·6 ± 0·1) and obese ones (n = 20; 13 girls/7 boys, 14·1± 1·0 years, 86·7 ± 11·5 kg, z-BMI 2·7 ± 0·4). Body fat and fat mass were measured by dual-energy X-ray absorptiometry (DXA). Non-nutritive skin microvascular reactivity was evaluated by laser Doppler flowmetry with iontophoretic release of vasoactive drugs. Activated CECs were assessed by flow cytometric analysis. In adolescents, the measurement of % fat by DXA showed high correlation with BAI (ρ = 0·75, P < 0·0001), z-BMI (r = 0·84, P < 0·0001) and WC (r = 0·83, P < 0·0001). Endothelin-1 and activated CECs did not correlate with any anthropometric measures while adipocytokines expressed variable associations among them. Endothelium-dependent vasodilation showed higher correlation with BAI (r = -0·51, P < 0·0001) compared to z-BMI (r = -0·40, P < 0·001) or WC (r = -0·45, P < 0·001), specially on females. BAI was associated with emerging CV risk markers in adolescents but further research is needed to evaluate its potential in clinical and epidemiological sets.

Excellent reproducibility of laser speckle contrast imaging to assess skin microvascular reactivity

Objective We compared the inter-day reproducibility of post-occlusive reactive hyperemia (PORH) assessed by single-point laser Doppler flowmetry (LDF) and laser speckle contrast analysis (LSCI), and the reproducibility of local thermal hyperemia (LTH) assessed by LDF, laser Doppler imaging (LDI) and LSCI. We also tested whether skin blood flow assessment by LDF and by LSCI are correlated. Methods Skin blood flow was evaluated during PORH and LTH using LDF, LDI (for LTH only) and LSCI on the forearms of healthy volunteers, at a 7 day interval. Data are expressed as cutaneous vascular conductance (CVC), as a function of baseline and scaled to the thermal plateau. Reproducibility is expressed as within subject coefficients of variation (CV, in %) and intra-class correlation coefficients (ICC). Results Twenty-eight healthy participants were enrolled in this study. The reproducibility of the PORH peak CVC was better when assessed with LSCI compared to LDF (CV = 8%; ICC = 0.76 and CV = 30%; ICC = 0.54, respectively). Inter-day reproducibility of the LTH plateau was better when assessed with LSCI or LDI than LDF (CV = 15%, ICC = 0.66; CV = 17%, ICC = 0.51 and CV = 42%, ICC = 0.28 respectively). Finally, we observed significant correlation between simultaneous LDF and LSCI measurements of the PORH peak CVC (R = 0.54; p = 0.001). Conclusion The recently developed LSCI technique showed very good inter-day reproducibility for assessing PORH and LTH. Moreover, we showed significant correlation between LSCI and single-point LDF for PORH. However, more data are needed to evaluate the linearity between the LSCI signal and skin blood flow.

Relationship between skin microvascular reactivity, cerebral blood flow and hypoxaemia in children with sickle cell disease

Sickle cell disease (SCD) is the most common genetic disorder in the UK. Increasing evidence suggests that autonomic function is altered in SCD, and if sympathetic drive is increased, this might increase the vascular tone of the intracranial arteries, leading to narrowing and increased velocities. Deep inspiratory gasps generate a vasomotor reflex characterised by sympathetic mediated transient vasoconstriction of skin arterioles. The aim of this study was to assess the relationship between autonomic reactivity, oxygen saturation (SpO₂) and cerebral blood flow velocity (CBFV) in children with SCD. <h3>Methods</h3> Autonomic reactivity was assessed using the inspiratory gasp vascular responses (IGVR) in 71 children with SCD (median age 7.8, range 2.8–15.3) years and 26 controls (7.7, 3.2–12.8). Cutaneous blood flux was measured by laser Doppler fluximetry (VMS and VP1T probe, Moor Instruments UK) on the pulp of the index finger of the non-dominant hand at rest and during three deep inspiratory gasps. CBFV was measured in the middle cerebral artery (MCA) and basilar artery (BA) using transcranial Doppler (DopplerBox, ScanMed, UK); daytime and minimum nocturnal SpO₂ using pulse oximetry (Masimo, Irvine CA). <h3>Results</h3> Mean resting blood flux (MRBF), IGVR, CBFV in the right and left MCA and BA were all higher in SCD compared to controls (p=0.002, p=0.001, p&lt;0.0001, p&lt;0.0001, p&lt;0.0001, respectively), while SPO₂ and minimum nocturnal SpO₂ were lower (p&lt;0.0001, p=0.026). In an analysis including SCA patients and controls, MRBF and IGVR were inversely correlated with SPO₂ (r=−0.286, −0.269; p=0.011, 0.019). Left and right MCA and BA velocities were correlated with MRBF (r=0.241, 0.364, 0.283; p=0.47, 0.002, 0.022, respectively) and IGVR (r=0.420, 0.307, 0.451; p&lt;0.0001, p=0.011, p&lt;0.0001). SpO₂ was inversely correlated with maximum CBFV in MCA and BA (r= −0.223, −0.276; p=0.044, 0.015). In multiple linear regression, IGVR predicted maximum MCA CBFV (r²=0.097, p=0.011); SpO₂ predicts IGVR (r²=0.058 p=0.037) but not CBFV. IGVR predicts CBFV independently of SpO₂ in a stepwise model. <h3>Conclusion</h3> The study provides evidence of increased MRBF, sympathetic tone and CBFV in children with SCD and low SpO₂ which may improve understanding of the pathogenesis and prevention of cerebrovascular disease and neurological complications.

Skin microvascular reactivity in trained adolescents

Whilst endothelial dysfunction is associated with a sedentary lifestyle, enhanced endothelial function has been documented in the skin of trained individuals. The purpose of this study was to investigate whether highly trained adolescent males possess enhanced skin microvascular endothelial function compared to their untrained peers. Seventeen highly and predominantly soccer trained boys (V(O)(2)(peak): 55 +/- 6 mL kg(-1) min(-1)) and nine age- and maturation-matched untrained controls (V(O)(2)(peak): 43 +/- 5 mL kg(-1) min(-1)) aged 13-15 years had skin microvascular endothelial function assessed using laser Doppler flowmetry. Baseline and maximal thermally stimulated skin blood flow (SkBF) responses were higher in forearms of trained subjects compared to untrained participants [baseline SkBF: 11 +/- 4 vs. 9 +/- 3 perfusion units (PU), p < 0.05; SkBF(max): 282 +/- 120 vs. 204 +/- 68 PU, p < 0.05]. Similarly, cutaneous vascular conductance (CVC) during local heating was superior in the forearm skin of trained versus untrained individuals (CVC(max): 3 +/- 1 vs. 2 +/- 1 PU mmHg(-1), p < 0.05). Peak hyperaemia following arterial occlusion and area under the reactive hyperaemia curve were also greater in forearm skin of the trained group (peak hyperaemia: 51 +/- 21 vs. 35 +/- 15 PU, p < 0.05; area under curve: 1596 +/- 739 vs. 962 +/- 796 PUs, p < 0.05). These results suggest that chronic exercise training in adolescents is associated with enhanced microvascular endothelial vasodilation in non-glabrous skin.

Reproducibility of a local cooling test to assess microvascular function in human skin

In the present study we aimed to assess the reproducibility of skin microvascular reactivity while fast cooling locally with a custom-designed laser-Doppler flowmetry (LDF) probe. Twenty-two healthy volunteers underwent local 15 degrees C cooling on the forearm during 5 (protocol 1, n=12) or 30 min (protocol 2, n=10). Skin blood flow was concomitantly assessed using LDF. Measurements were repeated after 30 min (protocol 1) or 7 days (protocols 1 and 2). Data were expressed as cutaneous vascular conductance (CVC) and percentage of baseline (%BL). Within subject coefficients of variation (CV) and intra-class correlation coefficients (ICC) were calculated. Immediate reproducibility of the 5-min cooling was very good, either expressed as CVC or %BL (CV were 8% and 18%; ICC were 0.85 and 0.78, respectively). However, the 30-min cooling was the most reproducible at 1 week, either as CVC or %BL (CV were 26% and 23%; ICC were 0.86 and 0.75, respectively). Local cooling was well tolerated by all volunteers. We propose in the present work a reproducible 30-min LDF cooling test. Such a tool could be of great interest to assess microvascular reactivity to local cooling in diseases such as Raynaud's syndrome, and to further evaluate drugs for such diseases.

Lifestyle intervention improves microvascular reactivity and increases serum adiponectin in overweight hypertensive patients

Background and aims Obesity and hypoadiponectinemia are often associated with high blood pressure. Moreover, microvascular dysfunction is reported to be an early event in patients with hypertension and may be involved in the pathogenesis of organ damage. Methods and results We investigated the impact of 8-week moderate-intensity aerobic training on adiponectin plasma levels and skin microvascular reactivity in 24 overweight sedentary patients (18 men, age 44 ± 6 years, body mass index 28 ± 3 kg/m 2) with never-treated grade 1 essential hypertension. Twenty-four age- and sex-matched hypertensive patients, who were examined twice at 8-week intervals in the absence of exercise training, served as controls. Exercise training was followed by a significant reduction in waist circumference (from 97 ± 9 to 95 ± 9 cm, p < 0.05) and an increase in adiponectin plasma levels (from 11.9 ± 3 to 12.5 ± 4 mg/L, p < 0.05). An inverse correlation was found between adiponectin change and waist circumference change ( r = −0.43, p < 0.05). The area under the curve after post-occlusive reactive hyperemia at skin laser-Doppler examination increased significantly after aerobic training (from 876 ± 539 to 1468 ± 925 PU/s, p < 0.001). A positive correlation was found between exercise-induced variations of post-occlusive reactive hyperemia and adiponectin plasma levels ( r = 0.41, p < 0.05). Office or 24-h blood pressure values did not change significantly. Conclusion In sedentary overweight patients with mild hypertension, moderate aerobic training improves cutaneous microvascular reactivity and adiponectin plasma levels. These changes precede blood pressure reduction and may serve as biomarkers of the efficacy of non-drug treatment in hypertensive patients.

C011 Expression and reproducibility of skin microvascular reactivity assessed with laser doppler flowmetry

The study of microvascular function can be routinely performed in humans using laser Doppler flowmetry (LDF) of the skin. Post-occlusive reactive hyperemia (PORH) and local thermal hyperemia (LTH) are used as tools to investigate endothelial and neurovascular microvascular functions. Sodium nitroprusside (SNP) iontophoresis is a commonly used technique to assess non endothelium-dependent skin microvascular function. However, there is no consensus over their reproducibility and variation over time, with room temperature, prandial status, and stress. Our objective was to test the reproducibility of those techniques on the finger and on the forearm, and their physiological variations. We performed local heating up to 44 °C, 5 min postocclusive hyperemia and SNP iontophoresis in fourteen healthy volunteers, at day 0, day 7 and month 6. We also tested the impact of a standard meal, of variations of room temperature, and of a psychological stress (Stroop test). Cutaneous blood flow was recorded with LDF probes. Data are expressed as cutaneous vascular conductance (CVC) in mV/mmHg, as % of maximal vasodilation and as a function of baseline. Reproducibility data are expressed as intra-subject coefficient of variation (CV) and intraclass correlation coefficients (ICC). One-week reproducibility of PORH and LTH on the finger pad is very good when expressed as CVC raw values (CV=12.6 to 23.7 %, ICC>0.71). On the dorsum of the finger and the forearm, reproducibility was better when expressed as a % of maximal vasodilation (CV=11.9 to 26.4 %, ICC>0.55). SNP iontophoresis did not lead to a vasodilation on the finger pad. On the dorsum and the forearm, its reproducibility was poor. Room temperature had a significant influence LTH and PORH hyperemia parameters, especially on the finger pad. Reproducibility was very good for both PORH and LTH, but the way of expressing data plays a key role. Reproducibility of SNP iontophoresis was poor. Room temperature (especially when elevated) influenced both PORH and LTH responses on the finger pad, highlighting the need for temperature-controlled conditions while performing these tests.

Skin blood flowmotion and microvascular reactivity investigation in hypercholesterolemic patients without clinically manifest arterial diseases

Fourier spectral analysis of forearm skin laser Doppler flowmetry (LDF) signal was performed in fifteen hypercholesterolemic patients (HP), without clinically manifest arterial diseases, and in fifteen age-matched healthy control subjects (CS), in order to investigate skin blood flowmotion (SBF). The LDF frequency intervals studied were: 0.01-1.6 Hz total spectrum, as well as 0.01-0.02 Hz (endothelial), 0.02-0.06 Hz (sympathetic), 0.06-0.2 Hz (myogenic), 0.2-0.6 Hz (respiratory) and 0.6-1.6 Hz (cardiac). Skin microvascular reactivity (MVR) to acetylcholine (ACh) and to sodium nitroprusside (SNP) iontophoresis was also investigated. HP showed a lower post-ACh increase in power spectral density (PSD) of the 0.01-0.02 Hz SBF subinterval compared to CS (1.80+/-1.73 PU(2)/Hz vs 3.59+/-1.78 PU(2)/Hz, respectively; p<0.005), while they did not differ in MVR from CS. In eleven HP the 0.01-0.02 Hz SBF subinterval showed a higher post-ACh PSD increase near to the statistical significance after 10 weeks of rosuvastatin therapy (10 mg/day) compared to pretreatment test (3.04+/-2.95 PU(2)/Hz vs 1.91+/-1.94 PU(2)/Hz; p=0.07). The blunted post-ACh increase in PSD of the 0.01-0.02 Hz SBF subinterval in HP suggests a skin endothelial dysfunction in these patients. This SBF abnormality showed a tendency to improve after rosuvastatin therapy in eleven treated patients.

Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes

Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at increased cardiovascular risk due to an accelerated atherosclerotic process. The present study aimed to compare skin microvascular function, pulse wave velocity (PWV), and a variety of hemostatic markers of endothelium injury [von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA), tissue factor pathway inhibitor (TFPI), and the soluble form of thrombomodulin (s-TM)] in patients with NIDDM. 54 patients with NIDDM and 38 sex- and age-matched controls were studied. 27 diabetics had no overt micro- and/or macrovascular complications, while the remainder had either or both. The forearm skin blood flow was assessed by laser-Doppler imaging, which allowed the measurement of the response to iontophoretically applied acetylcholine (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation), as well as the reactive hyperemia triggered by the transient occlusion of the circulation. Both endothelial and non-endothelial reactivity were significantly blunted in diabetics, regardless of the presence or the absence of vascular complications. Plasma vWF, TFPI and s-TM levels were significantly increased compared with controls only in patients exhibiting vascular complications. Concentrations of t-PA and PAI-1 were significantly increased in the two groups of diabetics versus controls. In NIDDM, both endothelium-dependent and -independent microvascular skin reactivity are impaired, whether or not underlying vascular complications exist. It also appears that microvascular endothelial dysfunction is not necessarily associated in NIDDM with increased circulating levels of hemostatic markers of endothelial damage known to reflect a hypercoagulable state.

Skin Microvascular Reactivity in Children and Adolescents with Type 1 Diabetes in Relation to Levels of Physical Activity and Aerobic Fitness

No studies to date have evaluated the relationship between exercise and microvascular function in youth with type 1 diabetes mellitus (T1DM). Twenty-nine complication free children and adolescents with T1DM were assessed for skin microvascular reactivity, aerobic fitness (VO2peak) and physical activity. VO2peak but not physical activity was significantly and independently associated with maximal hyperemia of the skin microcirculation (p < .01). No significant associations were found between venoarteriolar reflex (VAR) vasoconstriction and VO2peak or physical activity. Aerobic fitness may be an important indicator or mediator of effective microvascular endothelial function in youth with T1DM.

2,3,7,8-TCDD exposure, endothelial dysfunction and impaired microvascular reactivity

Vascular function was examined in subjects with long-term high level of serum 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) during their follow-up visits. Their earlier mean peak TCDD level at the time of exposure in 1965-1968 was estimated in the range of 3300-74 000 pg/g lipids. Ten former pesticide production workers heavily exposed to TCDD (age 57 +/- 2 years, TCDD about 170 pg/g lipids) were examined in 2001. Extended group of 15 TCDD-exposed men (age 59 +/- 3 years, TCDD about 130 pg/g lipids) underwent the same examination in 2004. Findings were compared with a control group of 14 healthy men (age 54 +/- 2 years). Skin microvascular reactivity (MVR) was measured by laser Doppler perfusion monitoring in the forearm during post-occlusive reactive hyperemia (PORH) and thermal hyperemia (TH). Several parameters of MVR in men exposed to TCDD were significantly impaired, compared with the control group and further progression of the impairment of MVR has been observed between years 2001 and 2004. Serum concentration of E-selectin and inhibitor of tissue plasminogen activator 1 (PAI-1) was significantly higher in exposed subjects (56.0 +/- 18.4 ng/mL versus 40.0 +/- 12.0 ng/mL, P = 0.022 and 90.9 +/- 33.3 ng/mL versus 45.0 +/- 18.0, P = 0.002, respectively). In addition, PORH in the forearm was significantly negatively associated with SOD activity (r = -0.77, P = 0.009) as well as the velocity of perfusion increase during TH (r = -0.68, P = 0.03) and TH% (r = -0.78, P = 0.008). Our data document the presence of endothelial dysfunction in TCDD-exposed men.

Characteristic Features of in vivo Skin Microvascular Reactivity in CADASIL

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is caused by mutations in the Notch3 receptor expressed at the surface of vascular smooth muscle cells. The functional consequences of the disease at the peripheral microcirculation level are incompletely elucidated. In this study, we aimed to assess, in vivo, the endothelium-dependent and independent vasodilation of the skin microvasculature in CADASIL patients. Twenty-three affected subjects were compared with 23 gender and age-matched controls. The brachial artery endothelium-dependent and endothelium-independent vasodilation were assessed after forearm cuff occlusion and nitroglycerin administration. Skin vasoreactivity to transcutaneous administration of acetylcholine and sodium nitroprussiate, and after postocclusive hyperemia were measured by Laser Doppler flowmetry. The maximum changes in the diameter of the brachial artery after the cuff release or after nitroglycerin administration did not differ between patients and controls. With iontopheresis, only the peak value of the dose response was found decreased in normocholesterolemic patients after nitroprussiate administration. The postocclusive test revealed a large increase of the time to peak value and whole duration of the hyperemic response in CADASIL patients. The results of this study show that the skin vasoreactivity is altered in CADASIL. Particularly, the kinetics of reactive hyperemia after cuff occlusion is dramatically changed with a lengthened and delayed response. This characteristic pattern may be related to the specific ultrastructural modifications related to Notch3 gene mutations involving smooth muscle cells in the microvasculature.

Impairment of skin microvascular reactivity in hypertension and uraemia

Uraemia and hypertension are associated with higher risk for cardiovascular complications. Endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. The aim of the present study was to evaluate endothelial function in the forearm skin microcirculation of patients with essential hypertension, in hypertensive haemodialysis patients and in normotensive control subjects. We performed laser Doppler flowmetry with iontophoresis of acetylcholine (ACh) and of sodium nitroprusside (SNP) as well as the post-occlusive reactive hyperaemia test (PORH) in 16 normal control subjects (CONT), in 16 patients with essential hypertension (EHT) and in 16 haemodialysis patients with essential hypertension (DHT). Plasma levels of endothelin-1, big-endothelin and von Willebrand factor (vWF) were also measured. The average hyperaemic response to the higher dose of ACh iontophoresis was 801+/-110% in CONT, 563+/-69 % in EHT and 308+/-64% in DHT (P<0.05, between all comparisons). Vasodilation to the higher dose of SNP was 791+/-79% in CONT, 633+/-72% in EHT and 355+/-69% in DHT (NS, P<0.001 compared with controls, respectively). The average peak flow during PORH was significantly lower in both the EHT and DHT groups compared with controls (294+/-39, 267+/-59 and 429+/-45%, respectively, P<0.05). Levels of endothelin-1, big endothelin, vWF and vWF activity were significantly higher in the DHT group (P<0.05, compared with controls). In hypertensive haemodialysis patients, both endothelium-dependent and -independent vasodilation was impaired. The observed increase in plasma markers of endothelial damage indicated a progression of vascular disease.

Kidney oxygenation during water diuresis and endothelial function in patients with type 2 diabetes and subjects at risk to develop diabetes

The aim of the present study was to examine the relationship among water diuresis-induced changes in renal oxygenation, endothelial function, and various metabolic parameters in type 2 diabetic patients and healthy subjects at risk of type 2 diabetes. Thirty-eight subjects with type 2 diabetes (D: age, 54 ± 10 years, mean ± SD, 24 men) and 7 healthy subjects with parental history of type 2 diabetes or with impaired glucose tolerance (IGT) (relatives [R]: age 46 ± 11 years, 4 men) were included. Laser Doppler imaging scanning was used to measure vasodilatation in the forearm skin in response to iontophoresis of 1% acetylcholine (Ach) and 1% sodium nitroprusside (SNP), and ultrasound was used to measure the flow-mediated dilation (FMD) and nitroglycerin-induced dilation (NID) in the brachial artery. Renal oxygenation was assessed by magnetic resonance imaging (MRI) before and during water diuresis. A decrease in the magnetic parameter R2∗ implies an increase in oxygenation. Renal medullary oxygenation did not improve with diuresis in either group (D: −0.5 ± 1.9, R: −0.4 ± 2.1, P = not significant [NS]). The renal cortical oxygenation showed a small, but statistically significant, improvement after diuresis in the 2 groups (D: −0.6 ± 1.1, R: −0.5 ± 0.5, P < .05). There were no correlations between the change in cortical R2∗ (R2∗ post-minus R2∗ prewater diuresis) and the micro- and macrovascular reactivity. The postdiuresis renal cortical R2∗ was negatively correlated with both the Ach- and SNP-induced skin vasodilation (% change over baseline)( r = −.40, P < .01 and r = − .39, P < .05, respectively), while no correlation existed with the FMD and NID. The baseline renal cortical oxygenation was also negatively correlated with the SNP-induced skin vasodilation ( r = −.36, P < .05) and positively correlated with the fasting plasma glucose, total cholesterol, and vascular cell adhesion molecule (VCAM) concentrations ( r = .34, P < .05, r = .31, P < .05 and r = .37, P < .05, respectively). These preliminary findings suggest an association between the kidney cortical oxygenation and the skin microvascular reactivity, glycemia, and lipidemia. Water diuresis failed to produce an improvement in renal medullary oxygenation in both patients with diabetes and subjects at risk for diabetes.

Microvascular reactivity in patients with hypercholesterolemia: the effect of lipid lowering treatment

Impaired NO-dependent vasodilation of resistance vessels is an early marker of an increased risk of atherosclerosis; utility of the examination of microcirculation, however, is far less established. We have therefore tested the hypothesis that hypercholesterolemia is associated with an impaired microvascular reactivity and that this defect is at least partially reversible by lipid-lowering treatment. Twenty-seven otherwise healthy patients with severe hypercholesterolemia (HLP) were examined at rest and then after 10 weeks of atorvastatin treatment (20 mg/day). Skin microvascular reactivity (MVR) was examined by laser-Doppler flowmetry. Baseline MVR values of the studied group were compared to healthy control subjects, HLP patients with coronary artery disease (CAD) and diabetic patients with and without diabetic retinopathy. MVR was normal in HLP subjects without CAD. On the contrary, MVR was impaired in HLP patients with CAD. There was no effect of atorvastatin on MVR, despite the profound reduction of serum lipids. MVR values did not correlate with cholesterol levels. In diabetic subjects, the MVR was substantially impaired only in patients with retinopathy. In the subjects without retinopathy, MVR was either normal (type I diabetes) or moderately impaired (type II diabetes). MVR was thus normal in HLP patients without manifest vascular disease and was not influenced by lipid lowering therapy. Impairment in the MVR was only evident in subjects with HLP and severe CAD. These results suggest that microcirculation is not involved in the early vascular dysfunction induced by HLP and that MVR rather reflects changes which appear later in the course of the atherosclerotic disease.