Peak Cutaneous Vascular Conductance Research Articles

Medium- and longer-term cardiovascular effects of e-cigarettes in adults making a stop-smoking attempt: a randomized controlled trial

BackgroundSmoking is a major risk factor for cardiovascular disease and smoking cessation reduces excess risk. E-cigarettes are popular for smoking cessation but there is little evidence on their cardiovascular health effect. Our objective was to compare the medium- and longer-term cardiovascular effects in smokers attempting to quit smoking using e-cigarettes with or without nicotine or prescription nicotine replacement therapy (NRT).MethodsThis was a single-center, pragmatic three-arm randomized (1:1:1) controlled trial, which recruited adult smokers (≥ 10 cigarettes/day), who were willing to attempt to stop smoking with support (n = 248).Participants were randomized to receive behavioral support with either (a) e-cigarettes with 18 mg/ml nicotine, (b) e-cigarettes without nicotine, and (c) NRT.Flow-mediated dilation (%FMD) and peak cutaneous vascular conductance (CVCmax) responses to acetylcholine (ACh) and sodium nitroprusside (SNP), mean arterial pressure (MAP), and other outcomes were recorded at baseline, 3, and 6 months after stopping smoking. Data were analyzed using generalized estimating equations (GEE).ResultsAt 3- and 6-month follow-up, %FMD showed an improvement over baseline in all three groups (e.g., p < 0.0001 at 6 months). Similarly, ACh, SNP, and MAP improved significantly over baseline in all groups both at 3 and 6 months (e.g., ACh: p = 0.004, at 6 months).ConclusionsSmokers attempting to quit experienced positive cardiovascular impact after both a 3- and 6-month period. None of the groups (i.e., nicotine-containing and nicotine-free e-cigarettes or NRT) offered superior cardiovascular benefits to the others.Trial registrationClinicalTrials.gov NCT03061253. Registered on 17 February 2017.

SKIN MICROVASCULAR DYSFUNCTION IS IMPAIRED IN PATIENTS WITH SYSTEMIC VASCULITIS AND CORRELATE WITH THE DURATION OF THE DISEASE

Objective: Systemic Vasculitides (SVs) are a highly inflammatory group of diseases characterized by significant cardiovascular mortality. Microvascular damage closely linked with accelerated atherosclerosis and thrombosis represent core pathophysiologic mechanisms contributing to the excess CV risk of patients with SVs. Skin represents a very easy accessible tissue, facilitating mechanistic non-invasive microvascular studies. In this study we aimed to assess skin microvascular function (SMF) using Laser Speckle Contrast Imaging (LSCI) technique coupled with Post-Occlusive Reactive Hyperemia (PORH) in patients with SVs and investigate correlations with inflammatory status and disease characteristics. Design and method: We consecutively recruited 60 individuals including 15 with ANCA-Associated Vasculitis, 15 with Bechet disease and 30 healthy controls matched for age, sex and cardiovascular risk factors. SMF was assessed with LSCI coupled with PORH following a standardized protocol. Results are expressed as percentage increase of flux from baseline to the peak post-occlusive response, as cutaneous vascular conductance (CVC) during baseline (baseline CVC), peak CVC and as the percentage increase (CVC increase). CVC was calculated as the ratio of mean flux in each respective period divided by mean blood pressure (BP). Moreover, we investigated the correlation between SMF and disease duration as well as disease activity, as evaluated by the Birmingham Vasculitis Activity Score (BVAS) and biomarkers of acute inflammation(C-reactive protein and erythrocyte sedimentation rate). Results: No differences were found in office BP, and basic demographic parameters between groups. Patients with SVs presented a lower base to peak flux [207 (60.1) vs 143.7 (41.0) LSPUs, p &lt; 0.001] and CVC increase (190.0 ± 49.6 vs 149.6 ± 48.9 %, p = 0.002) compared to controls. Importantly, base to peak flux and CVC increase were significantly correlated with disease duration (p &lt; 0.001, r = -0.563 and p &lt; 0.001, r = 0.442 respectively). However, no significant correlation was found with disease activity markers and inflammatory status Conclusions: Patients with SVs exhibit impaired SMF as shown by a dynamic and reproducible method, namely LSCI combined with PORH. Moreover, skin microvascular impairment correlates with disease duration but not with disease activity, suggesting that a chronic, low-grade inflammatory background instead of acute inflammation may be responsible for cutaneous damage.

HIGH MOBILITY GROUP BOX-1 IS INCREASED IN NEWLY DIAGNOSED ESSENTIAL HYPERTENSIVES AND CORRELATES WITH HYPERTENSION-MEDIATED TARGET ORGAN DAMAGE

Objective: Chronic immune-mediated inflammation is increasingly recognized as an important contributor to target organ damage (TOD) in essential hypertension (EH). High mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule which stimulates innate immunity, hence exerting significant proinflammatory properties including vascular inflammation and thrombosis. So far, no clinical data exist regarding the role of HMGB1 in EH and its association with vascular damage. Our objective was to measure HMGB1 levels in newly diagnosed, untreated patients with EH (UHTs) compared to normotensive controls (NTs) and correlate them with indices of macro- and microvascular dysfunction, which play a core role in the pathogenesis of TOD in EH. Design and method: HMGB1 was measured in serum with ELISA. Ambulatory and central blood pressure (BP) parameters, and pulse wave velocity (PWV), were measured by using the Mobil-O-Graph device. Skin microcirculation was assessed with Laser Speckle Contrast Imaging (LSCI) coupled with post-occlusive reactive hyperemia (PORH). Results are expressed as a percentage increase between peak and baseline perfusion (%), and the amplitude of PORH response defined as peak Cutaneous Vascular Conductance (CVC) minus baseline CVC. The CVC was calculated as the flux in each period divided by mean arterial pressure [(PUs)/mmHg]. Results: We consecutively enrolled 55 UHTs and 25 NTs matched for age and sex. HMGB1 levels were significantly higher in UHTs compared to NTs. HMGB1 showed a significant positive association with measures of macrocirculation including 24 h central systolic (0.325, p &lt; 0.01) and diastolic BP (0.371, p &lt; 0.01), day central systolic (0.353, p &lt; 0.01) and diastolic BP (0.402, p &lt; 0.01), and 24 h PWV (0.224, p &lt; 0.05) and day PWV (0.230, p &lt; 0.05) in the total study population. In addition, HMGB1 presented a significant negative association with skin microvascular parameters including base to peak flux (-0.247, p &lt; 0.05) and PORH amplitude (-0.225, p &lt; 0.01). Conclusions: HMGB1 is significantly increased in UHTs compared to NTs and correlates with indices of macro- and microvascular damage. These results reinforce the concept that immune system activation contributes to hypertension-mediated TOD from the very early stages and point towards intense research in order to investigate novel potential therapeutic targets related to EH.

Cold-induced vasodilation in abstinent smokers with and without a 12-hour nicotine patch.

This study was designed to identify the effects of a 12-h nicotine patch administration on cold induced vasodilation (CIVD) in healthy young chronic smokers following 16 h of abstinence from smoking. Two laser Doppler probes and temperature thermocouples were placed on the dorsal part of the distal phalanx of the middle and ring fingers of 7 smokers (>12 cigarettes/day). Following 16 h of abstinence from smoking, smokers were tested with and without administration of a 21mg transdermal nicotine patch (NicoDerm® ). Each participant's right hand was immersed in cold (~5°C) water for 40 min. Cutaneous vascular conductance (CVC) was calculated from non-invasive arterial finger blood pressure and skin blood flow and expressed as a percentage of peak CVC observed during hand skin heating to 44°C. For comparison purposes, the CIVD response of a non-smoking cohort without nicotine patch (n = 10) was also examined. Baseline CVC was similar in smokers and non-smokers (27.8 ± 12.6 CVC % peak). The initial vasoconstriction during cold-water immersion decreased skin blood flow to 4.0 ± 3.9 CVC % peak in both smokers and non-smokers. The onset of CIVD in smokers (4.5 ± 1.5 min) was delayed compared to non-smoker (3.3 ± 0.8 min, p < .05). The area under the CVC %peak-time curve during cold-water immersion averaged 1250 ± 388 CVC %peak · min in non-smokers which was larger (p < .05) than smokers with or without nicotine (789 ± 542 and 862 ± 517 CVC %peak · min, respectively). Chronic smoking impaired the CIVD response to cold-water immersion of the hand; however, the impaired CIVD response in 16 h of abstinence from smoking was not influenced by application of a 21mg transdermal nicotine patch.

HEMODIALYSIS AND PERITONEAL DIALYSIS PATIENTS HAVE SEVERELY IMPAIRED ENDOTHELIAL POST-OCCLUSIVE FOREARM VASODILATORY RESPONSE ASSESSED WITH LASER SPECKLE CONTRAST IMAGING

Abstract Objective: Endothelial dysfunction is associated with cardiovascular events and mortality in various disease states, including end-stage-renal-disease (ESRD). Novel technological approaches have emerged for real-time assessment of endothelial reactivity. This study examined forearm skin microcirculation using Laser Speckle Contrast Imaging (LSCI) before and after arterial occlusion in ESRD patients undergoing hemodialysis (HD) or peritoneal dialysis (PD). Design and method: Thirty-eight patients undergoing HD were matched in a 1:1 ratio with 38 PD patients (for age, sex and dialysis vintage) and 38 controls (for age and sex). Skin microvascular reactivity parameters assessed with LSCI included baseline perfusion, occlusion perfusion, and peak perfusion during post-occlusive reactive hyperemia (PORH); time to peak perfusion; proportional change from baseline to peak perfusion; baseline and peak cutaneous vascular conductance (CVC); proportional change from baseline to peak CVC; and the amplitude of the PORH response (calculated as the difference between peak and baseline CVC). Results: Baseline perfusion [HD: 46.97 ± 14.6; PD: 49.32 ± 18.07; controls: 42.02 ± 11.94 Laser-Specle-Perfusion-Units (LSPU), p = 0.097] and peak post-occlusion perfusion (104.77 ± 28.68 vs 109.04 ± 40.77 vs 116.96 ± 30.96 LSPU, p = 0.238) did not differ between groups. However, the post-occlusive vascular response was completely different, since time to peak response (HD: 7.24 ± 6.99; PD: 10.68 ± 9.45; controls: 11.11 ± 5.1 sec, p = 0.003) and the (%) increase from baseline to peak perfusion (HD: 133% ± 66; PD: 149% ± 125; controls: 187% ± 61, p = 0.001) was significantly lower in ESRD patients. ESRD patients had also lower levels of peak CVC, indicating the maximum capillary recruitment (HD: 1.05 ± 0.3; PD: 1.07 ± 0.44; controls: 1.57 ± 0.52 LSPU/mmHg, p &lt; 0.001), lower % increase of CVC at peak (p = 0.001), and lower amplitude of the PORH response (p = 0.001) (a measure of the difference between baseline and maximum capillary recruitment). Conclusions: Using this novel non-invasive technology endothelial post-occlusive skin vasodilatory response was found to be similar between HD and PD patients and significantly impaired compared to controls. Future studies are needed to assess the prognostic implications of this microcirculatory functional defect.

MASKED HYPERTENSIVES AS ASSESSED WITH LASER SPECKLE CONTRAST IMAGING EXHIBIT IMPAIRED SKIN MICROVASCULAR REACTIVITY SIMILAR TO ESSENTIAL HYPERTENSIVE INDIVIDUALS

Objective: Laser Speckle Contrast Imaging (LSCI) is a novel method to dynamically assess skin microcirculation with very high resolution and reproducibility compared to other laser methods. Skin microcirculation has been proposed as a model of generalized microvascular function and a potential biomarker in cardiovascular prognosis. Masked hypertension is considered a hypertension phenotype of substantial cardiovascular risk similar to essential hypertension (EH). In this study we evaluated skin microvascular reactivity in masked hypertensives as compared to hypertensives and healthy, normotensive individuals using LSCI coupled with post-occlusive reactive hyperemia (PORH) test. Design and method: We included 20 newly diagnosed masked hypertensives aged 50.0 ± 9.0 and compared them to 70 never treated, newly diagnosed patients with EH aged 49.5 ± 8.7 and 40 healthy, normotensive individuals aged 48.5 ± 8.5 years. Hypertension phenotypes were defined according to standard office and ambulatory blood pressure monitoring (ABPM) criteria. The Mobil-O-Graph-NG (IEM, Stolberg, Germany) device was used for ABPM. All subjects underwent forearm skin perfusion recording under standardized conditions using a LSCI device (PeriCam PSI NR System, Perimed, Järfälla, Sweden) coupled with PORH. Data were analyzed by manufacturer's software (PIMSoft, Perimed). Results were expressed as i) the percentage increase of perfusion from baseline to peak condition (%), and ii) the amplitude of PORH response expressed as the peak cutaneous vascular conductance (CVC) minus baseline CVC. The CVC was calculated as the flux of each time interval divided by mean arterial pressure (perfusion units [PU]/mmHg). Results: Masked hypertensives showed significantly lower percentage increase of perfusion from baseline to peak condition as compared to controls (155.4 ± 48.11 vs 190.54 ± 45.88, p = 0.013) but not compared to hypertensives (155.4 ± 48.11 vs 150.6 ± 41.93, p = NS), respectively. In addition, PORH amplitude was significantly lower in masked hypertensives as compared to controls (0.62 ± 0.2 vs 0.76 ± 0.2, p = 0.02) but no difference was found compared to hypertensives (0.62 ± 0.2 vs 0.52 ± 0.1, p = NS), respectively. Conclusions: Masked hypertensives, when assessed with LSCI coupled with PORH, present impaired skin microvascular reactivity as compared to healthy controls. However, their skin microvascular responses were similar to those of hypertensives, highlighting a state of increased microvascular damage in this hypertension phenotype.

Haemodialysis and peritoneal dialysis patients have severely impaired post-occlusive skin forearm vasodilatory response assessed with laser speckle contrast imaging.

BackgroundEndothelial dysfunction is associated with cardiovascular events and mortality in various disease states, including end-stage renal disease (ESRD). Novel technological approaches have emerged for real-time assessment of endothelial reactivity. This study examined skin microcirculation using laser speckle contrast imaging (LSCI) before and after arterial occlusion in ESRD patients undergoing haemodialysis (HD) or peritoneal dialysis (PD).MethodsThe 38 HD patients were matched in a 1:1 ratio with 38 PD patients (for age, sex and dialysis vintage) and 38 controls (for age and sex). Skin microvascular reactivity parameters assessed with LSCI included baseline perfusion, occlusion perfusion and peak perfusion during post-occlusive reactive hyperaemia (PORH); time to peak perfusion; proportional change from baseline to peak perfusion; baseline and peak cutaneous vascular conductance (CVC); proportional change from baseline to peak CVC and amplitude of the PORH response (i.e. the difference between peak and baseline CVC).ResultsBaseline perfusion [HD: 46.97 ± 14.6; PD: 49.32 ± 18.07; controls: 42.02 ± 11.94 laser specle perfusion units (LSPU), P = 0.097] and peak post-occlusion perfusion (104.77 ± 28.68 versus 109.04 ± 40.77 versus 116.96 ± 30.96 LSPU, P = 0.238) did not differ significantly between groups. However, the post-occlusive vascular response was completely different since the proportional increase from baseline to peak perfusion (HD: 133 ± 66; PD: 149 ± 125; controls: 187 ± 61%, P = 0.001) was significantly lower in ESRD patients and time to peak response was lower in HD but similar in PD patients compared with controls (HD: 7.24 ± 6.99; PD: 10.68 ± 9.45; controls: 11.11 ± 5.1 s, Kruskal–Wallis P = 0.003; pairwise comparisons: HD versus controls, P = 0.002; HD versus PD, P = 0.154; PD versus controls, P = 0.406). ESRD patients also had lower levels of peak CVC, indicating the maximum capillary recruitment (HD: 1.05 ± 0.3; PD: 1.07 ± 0.44; controls: 1.57 ± 0.52 LSPU/mmHg, P < 0.001), lower proportional increase of CVC at peak (P < 0.001) and lower amplitude of the PORH response, a measure of the difference between baseline and maximum capillary recruitment (P = 0.001).ConclusionsUsing this novel non-invasive technology, endothelial post-occlusive forearm skin vasodilatory response was found to be similar between HD and PD patients and significantly impaired compared with controls. Future studies are needed to assess the prognostic implications of this microcirculatory functional defect.

P0162HEMODIALYSIS AND PERITONEAL DIALYSIS PATIENTS HAVE SEVERELY IMPAIRED ENDOTHELIAL POST-OCCLUSIVE FOREARM VASODILATORY RESPONSE ASSESSED WITH LASER SPECKLE CONTRAST IMAGING

Abstract Background and Aims Endothelial dysfunction is associated with cardiovascular events and mortality in various disease states, including end-stage-renal-disease (ESRD). Novel technological approaches have emerged for real-time assessment of endothelial reactivity. This study examined forearm skin microcirculation using Laser Speckle Contrast Imaging (LSCi) before and after arterial occlusion in ESRD patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) Method 38 patients undergoing HD were matched in a 1:1 ratio with 38 PD patients (for age, sex and dialysis vintage) and 38 controls (for age and sex). Skin microvascular reactivity parameters assessed with LSCI included baseline perfusion, occlusion perfusion, and peak perfusion during post-occlusive reactive hyperemia (PORH); time to peak perfusion; proportional change from baseline to peak perfusion; baseline and peak cutaneous vascular conductance (CVC); proportional change from baseline to peak CVC; and the amplitude of the PORH response (calculated as the difference between peak and baseline CVC). Results Baseline perfusion [HD: 46.97±14.6; PD: 49.32±18.07; controls: 42.02±11.94 Laser-Specle-Perfusion-Units (LSPU), p=0.097] and peak post-occlusion perfusion (104.77±28.68 vs 109.04±40.77 vs 116.96±30.96 LSPU, p=0.238) did not differ between groups. However, the post-occlusive vascular response was completely different, since time to peak response (HD: 7.24±6.99; PD: 10.68±9.45; controls: 11.11±5.1 sec, p=0.003) and the (%) increase from baseline to peak perfusion (HD: 133%±66; PD: 149%±125; controls: 187%±61, p=0.001) was significantly lower in ESRD patients. ESRD patients had also lower levels of peak CVC, indicating the maximum capillary recruitment (HD: 1.05±0.3; PD: 1.07±0.44; controls: 1.57±0.52 LSPU/mmHg, p&amp;lt;0.001), lower % increase of CVC at peak (p=0.001), and lower amplitude of the PORH response (p=0.001) (a measure of the difference between baseline and maximum capillary recruitment). Conclusion Using this novel non-invasive technology endothelial post-occlusive skin vasodilatory response was found to be similar between HD and PD patients and significantly impaired compared to controls. Future studies are needed to assess the prognostic implications of this microcirculatory functional defect.

Integrated Effects of Sympathetic Vasoconstriction and Local Vasodilation in Human Skeletal Muscle and Skin Microvasculature

Both sympathetic vasoconstriction and locally-mediated vasodilation play important roles in regulation of blood flow to skeletal muscle and skin during exercise. However, the integrated effects of these two vascular regulatory mechanisms in microcirculation are unclear. PURPOSE: We aimed to investigate integration of sympathetic vasoconstriction and local vasodilation in the skeletal muscle and skin microvasculature in humans. METHODS: In 39 healthy volunteers, we measured blood flow index of flexor carpi radialis muscle using diffuse correlation spectroscopy and monitored skin blood flow at the proximal site by laser-Doppler flowmetry, simultaneously. We examined the effects of acute sympathoexcitation by forehead cooling on relatively weak or robust vasodilatory responses during post-occlusive reactive hyperemia (PORH) induced by 70 s or 10 min arterial occlusion at upper arm, respectively. To increase sympathetic tone during PORH, forehead cooling was begun 60 s before the occlusion release and ended 60 s after the release. RESULTS: The acute sympathoexcitation diminished the peak and duration of vasodilation in both skeletal muscle and skin in 70 s occlusion trials [peak skeletal muscle vascular conductance (MVC): 5.6 ± 0.4 vs. 4.1 ± 0.3, peak cutaneous vascular conductance (CVC): 3.4 ± 0.2 vs. 2.9 ± 0.2 AU, 50 % decay time of MVC: 19 ± 0.8 vs. 13 ± 0.6, 50 % decay time of CVC: 17 ± 1.0 vs. 14 ± 1.0 s, p < 0.05]. The sympathetic inhibition of vasodilation was blunted under robust vasodilatory stimuli produced by 10 min occlusion. This blunt of the sympathetic inhibition was greater in skeletal muscle than in skin, especially in those initial and peak vasodilation. Indeed, the sympathoexcitation reduced the peak vasodilation only in skin (peak MVC: 10.2 ± 0.9 vs. 9.7 ± 0.9, p > 0.05, peak CVC: 7.7 ± 0.5 vs. 6.5 ± 0.5 AU, p < 0.05) while it accelerated the initial vasodilation selectively in skeletal muscle (area of MVC during first 15 s of PORH: 75.2 ± 6.5 vs. 83.0 ± 6.9, p < 0.05, area of CVC: 51.6 ± 2.7 vs. 51.7 ± 3.4 AUs, p > 0.05). CONCLUSION: We conclude that, in humans, the integration of sympathetic vasoconstriction and local vasodilation has different effects in skeletal muscle and skin. Such different effects would be importantly involved in selective control of perfusion in microcirculation of different tissues.

REAL TIME ASSESSMENT OF MICROCIRCULATION IN HYPERTENSION USING LASER SPECKLE CONTRAST ANALYSIS

Objective: Skin microcirculation has been suggested as a model of generalized microvascular function. It has also been used as a window to access endothelial function in the microvasculature. In this study we evaluated endothelial dysfunction of skin microcirculation in hypertensive patients compared to healthy, normotensive individuals using Laser Speckle Contrast Analysis (LASCA), a novel tool to assess microcirculation non-invasively, in real time and with high reproducibility. Design and method: We studied a group of 26 untreated hypertensive patients with new-onset essential hypertension without cardiovascular comorbidities, mean age 50.5 ± 15.7 years and 13 healthy individuals matched for age, sex and body mass index. In all subjects, forearm skin blood flow was recorded under standardized conditions using a laser speckle contrast imager (PeriCam PSI NR System, Perimed, Järfälla, Sweden). Post-occlusive reactive hyperemia (PORH) was assessed following a standardized protocol and data were analyzed with signal processing software (PIMSoft, Perimed). The amplitude of PORH responses was expressed as a percentage increase between peak and baseline perfusion (%), baseline Cutaneous Vascular Conductance (CVC), peak CVC and peak CVC minus baseline CVC. The CVC was calculated as the flux divided by mean arterial pressure and expressed in perfusion units (PU)/mmHg. Results: Baseline perfusion was similar between the two groups. However, during PORH patients with hypertension showed significantly lower percentage increase from baseline to peak perfusion (145.9 ± 9.72 vs 181.68 ± 12.35 %, p = 0.019). In addition, baseline CVC (0.34 ± 0.019 vs 0.43 ± 0.03 PU/mmHg, p = 0.009) and peak CVC (0.82 ± 0.04 vs 1.2 ± 0.06 PU/mmHg, p < 0.001) were significantly lower in hypertensive patients compared to controls. Finally, PORH amplitude as expressed by peak CVC minus baseline CVC (0.48 ± 0.03 vs 0.76 ± 0.04 PU/mmHg, p < 0.001) was significantly lower in hypertensive patients compared to normotensives. Conclusions: Using LASCA, a non-contact, real-time, highly reproducible and sensitive technique for the assessment of skin microcirculation, we showed that hypertensive patients demonstrate impaired microvascular responses to stimulation tests. Endothelial dysfunction is present in the very early stages of essential hypertension, long before the establishment of overt cardiovascular disease, and LASCA may represent a novel, valuable tool for its assessment.

Penile microvascular endothelial function in hypertensive patients: effects of acute type 5 phosphodiesterase inhibition

The primary aim of this study was to evaluate penile endothelial microvascular function in patients with primary arterial hypertension and age-matched normotensive subjects using laser speckle contrast imaging (LSCI). Additionally, we analyzed the acute penile microvascular effects induced by oral phosphodiesterase type 5 inhibitor (sildenafil; SIL) administration. Endothelium-dependent microvascular reactivity was evaluated in the penises and forearms of hypertensive patients (aged 58.8±6.6 years, n=34) and age-matched healthy volunteers (n=33) at rest and 60 min following oral SIL (100 mg) administration. LSCI was coupled with cutaneous acetylcholine (ACh) iontophoresis using increasing anodal currents. Basal penile cutaneous vascular conductance (CVC) values were not significantly different between control subjects and hypertensive individuals. Penile CVC values increased significantly after SIL administration in control (P<0.0001) and hypertensive (P<0.0001) subjects. Peak CVC values were not different between the two groups during penile ACh iontophoresis before SIL administration (P=0.2052). Peak CVC values were higher in control subjects than in hypertensive subjects after SIL administration (P=0.0427). Penile endothelium-dependent microvascular function is, to some extent, preserved in patients presenting with primary arterial hypertension under effective anti-hypertensive treatment. LSCI may be a valuable non-invasive tool for the evaluation of penile vascular responses to phosphodiesterase type 5 inhibitor.

Effects of supervised exercise training on lower-limb cutaneous microvascular reactivity in adults with venous ulcers

PurposeTo investigate the effects of a 12-week supervised exercise programme on lower-limb cutaneous microvascular reactivity in adults with venous leg ulceration.MethodsThirty-eight adults with unilateral venous ulceration who were being treated with lower-limb compression therapy (58% male; mean age 65 years; median ulcer size 5 cm2) were randomly allocated to exercise or control groups. Exercise participants (n = 18) were invited to attend thrice weekly sessions of lower-limb aerobic and resistance exercise for 12 weeks. Cutaneous microvascular reactivity was assessed in the gaiter region of ulcerated and non-ulcerated legs at baseline and 3 months using laser Doppler fluxmetry coupled with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Cutaneous vascular conductance (CVC) was calculated as laser Doppler flux (AU)/mean arterial pressure (mmHg).ResultsThirty-seven participants completed follow-up assessments. Median session attendance was 36 (range 2–36). Analyses of covariance revealed greater peak CVC responses to ACh in the exercise group at 3 months in both the ulcerated (adjusted difference = 0.944 AU/mmHg; 95% CI 0.504–1.384) and non-ulcerated (adjusted difference = 0.596 AU/mmHg; 95% CI 0.028–1.164) legs. Peak CVC responses to SNP were also greater in the exercise group at 3 months in the ulcerated leg (adjusted difference = 0.882 AU/mmHg; 95% CI 0.274–1.491), but not the non-ulcerated leg (adjusted difference = 0.392 AU/mmHg; 95% CI − 0.377 to 1.161).ConclusionSupervised exercise training improves lower-limb cutaneous microvascular reactivity in adults with venous leg ulceration.

Endothelial-derived hyperpolarization contributes to acetylcholine-mediated vasodilation in human skin in a dose-dependent manner

Cutaneous acetylcholine (ACh)-mediated dilation is commonly used to assess microvascular function, but the mechanisms of dilation are poorly understood. Depending on dose and method of administration, nitric oxide (NO) and prostanoids are involved to varying extents and the roles of endothelial-derived hyperpolarizing factors (EDHFs) are unclear. In the present study, five incremental doses of ACh (0.01-100 mM) were delivered either as a 1-min bolus (protocol 1, n = 12) or as a ≥20-min continuous infusion (protocol 2, n = 10) via microdialysis fibers infused with 1) lactated Ringer, 2) tetraethylammonium (TEA) [a calcium-activated potassium channel (KCa) and EDHF inhibitor], 3) L-NNA+ketorolac [NO synthase (NOS) and cyclooxygenase (COX) inhibitors], and 4) TEA+L-NNA+Ketorolac. The hyperemic response was characterized as peak and area under the curve (AUC) cutaneous vascular conductance (CVC) for bolus infusions or plateau CVC for continuous infusions, and reported as %maximal CVC. In protocol 1, TEA, alone and combined with NOS+COX inhibition, attenuated peak CVC (100 mM Ringer 59 ± 6% vs. TEA 43 ± 5%, P < 0.05; L-NNA+ketorolac 35 ± 4% vs. TEA+L-NNA+ketorolac 25 ± 4%, P < 0.05) and AUC (Ringer 25,414 ± 3,528 vs. TEA 21,403 ± 3,416%·s, P < 0.05; L-NNA+ketorolac 25,628 ± 3,828%(.)s vs. TEA+L-NNA+ketorolac 20,772 ± 3,711%·s, P < 0.05), although these effects were only significant at the highest dose of ACh. At lower doses, TEA lengthened the total time of the hyperemic response (10 mM Ringer 609 ± 78 s vs. TEA 860 ± 67 s, P < 0.05). In protocol 2, TEA alone did not affect plateau CVC, but attenuated plateau in combination with NOS+COX inhibition (100 mM 50.4 ± 6.6% vs. 30.9 ± 6.3%, P < 0.05). Therefore, EDHFs contribute to cutaneous ACh-mediated dilation, but their relative contribution is altered by the dose and infusion procedure.

Increasing acclimation period improves the reproducibility of short-heating local thermal hyperemia

ObjectivesThe axon reflex (AR) can be induced by the activation of afferent C-fibers during local skin heating. The previously used long-heating local thermal hyperemia (LTH) protocols tested AR flare by normalizing to endothelial-mediated maximal vasodilatation to adjust capillary heterogeneity when the recording sites were randomly selected. The AR flare induced by short local heating can be reproducible without using the data from subsequent longer heating for normalization when the recording sites were fixed with holders in the same session. The aim of this study was to investigate the effect of acclimation period on the intersession reproducibility of short-heating LTH when the recording sites were relocated after a longer interval of 1–3days. MethodsAfter 30 or 60min acclimation, LTH with 5min heating was assessed on bilateral human forearms using single-point laser Doppler flowmetry. The test was repeated at the same recording sites again at the same time 1–3days later. Baseline and heating blood flux were analyzed and the data were expressed as different forms. Reproducibility of two tests was assessed using coefficient of variation (CV) and intra-class correlation coefficient (ICC) statistics. ResultsThe intersession reproducibility of peak cutaneous vascular conductance (CVC) (CV=18.38%, ICC=0.82), peak CVC change (CV=20.38%, ICC=0.83) and 4min area-under-the-curve (AUC) (CV=18.66%, ICC=0.75) of the right forearm and time to peak (CV=16.84%, ICC=0.52) of the left forearm were acceptable after 30min acclimation. When the acclimation period was increased to 60min, all of these data except 4min AUC of both sides reached an acceptable level. ConclusionsThe AR flare induced by short local heating is reproducible when the recording sites are relocated by a predefined rule. The reproducibility of LTH on right forearm is different from that on left forearm, and increasing acclimation period improves the reproducibility.

Inhibition of Nitric Oxide Synthase Attenuates Cutaneous Vasodilation During Warm Moxibustion-Like Thermal Stimulation in Humans

This study investigated if nitric oxide (NO) and/or prostaglandin (PG) are responsible for cutaneous vasodilation during warm moxibustion-like thermal stimulation (WMTS). For two protocols, two microdialysis membranes were placed in the medial forearm skin. In the first protocol (n=8), the sites were randomly assigned and perfused with N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME), an NO synthase inhibitor or Ringer's solution (control site). Similarly, two microdialysis membranes were placed in the medial forearm skin in the second protocol (n=6). One site was perfused with ketorolac (Keto), the cyclo-oxygenase (COX) pathway inhibitor, and the other site was perfused with Ringer's solution (control site). In both protocols, cutaneous vasodilation was induced using WMTS with an electronic warm moxibustion treatment appliance. After 10 minutes of baseline recording, WMTS was applied to the forearm skin for 20 minutes and recovery was monitored over a period of 20 minutes. Skin blood flow (SkBF) at each site was measured using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial blood pressure (BP). The study was conducted in a laboratory at the Kansai University of Health Sciences. The subjects were 14 healthy male volunteers. WMTS was applied to the medial forearm skin using an electronic warm moxibustion treatment appliance. SkBF, skin temperature (Tsk), core body temperature (Tc), heart rate (HR), and BP were outcome measures. In the first protocol, peak CVC values during WMTS at the site perfused with l-NAME were significantly decreased, compared to those at the control site (p<0.05). In the second protocol, peak CVC values during WMTS did not differ between the control site and the Keto site (p>0.05). These data demonstrate that NO is involved in the mechanism of cutaneous vasodilation induced by WMTS. Furthermore, increases in CVC despite inhibition of the COX pathway suggest that PG does not contribute to cutaneous vasodilation during WMTS.

Axon reflex-related hyperemia induced by short local heating is reproducible

ObjectivesThe axon reflex (AR) flare is induced by antidromic activation of afferent C-fibers during nociceptive stimulation. This response has been suggested to be modulated by sympathetic activity and basal level of nitric oxide. In previously used protocols of local thermal hyperemia (LTH), AR flare has been used in combination with maximal vasodilatation to study the integrated endothelial function. The aim of this study was to investigate the intra-session reproducibility of short heating-induced AR flare, the specific neural-mediated portion of LTH, and to compare the reproducibility between different forms of data expression. MethodsShort-heating LTH was assessed using single-point laser Doppler flowmetry (LDF) on bilateral volar surface of the forearm in 10 men and 10 women. The blood flux measurement included a non-heating process for 5min, followed by a quick heating process from 33°C to 42°C for 5min. The test was repeated 45min later at the same recording sites with fixed holders. Baseline and heating blood flux were recorded and expressed as different forms of data. Reproducibility was assessed using coefficient of variation (CV) and intra-class correlation coefficient (ICC) statistics. ResultsThe reproducibility of peak cutaneous vascular conductance (CVC) (CV=16.02–17.31%, ICC=0.77–0.78), peak CVC change (CV=14.30–18.12%, ICC=0.80–0.86), and the 4min area-under-the-curve (CV=18.37–18.70%, ICC=0.60–0.78) was acceptable. The time to peak flux of each recording site ranged from 90 to 209s and all the peak fluxes have been achieved before 4min of heating. ConclusionsSingle-point LDF is a reproducible technique of assessing AR flare on volar surface of the forearm when the heating period is reduced to 5min and the recording sites are fixed. Using this new protocol, short-heating LTH has a potential to be used to evaluate the effects of acute physical or chemical interventions between two short-heating LTH tests to further explore the pathophysiological meaning of heating-induced AR flare.

Effect of hypohydration and altitude exposure on skin blood flow responses to local heating

It is unknown whether hypohydration (HYPO) or hypobaric hypoxia alter skin blood flow (SkBF) responses to local heating. We hypothesized that HYPO (4% of body weight) and acute altitude (ALT, 3,048 m) would decrease forearm SkBF responses to local heating and that ALT‐HYPO together would result in a further decline. Four healthy young men (23 ± 6 years, 175 ± 5 cm, 74 ± 5 kg) completed 4 trials each: a) sea‐level–euhydrated (SL‐ EUH); b) SL‐HYPO; c) ALT‐EUH; and d) ALT‐HYPO. Local thermal control of cutaneous vascular conductance (CVC) was assessed by local heating to 42°C for 30 min. CVC was calculated as laser‐Doppler flow/mean arterial pressure and analyzed for initial peak (~2–4 min after onset of warming), and plateau (last 3–5 min of warming). Initial peak CVC values were 1107 ± 593, 673 ± 273, 619 ± 241 and 784 ± 440 % of baseline for SL‐EUH, SL‐HYPO, ALT‐EUH, and ALT‐HYPO, respectively. Plateau CVC values were 1585 ± 797, 1340 ± 609, 962 ± 396 and 1082 ± 869 % of baseline. There were no significant influences of HYPO or ALT (P &gt; 0.05 for all), although HYPO and ALT reduced initial peak SkBF by 29–44% and plateau SkBF by 15–39%. Based on these pilot data, 14–18 subjects would be required to give 80% power to detect statistical differences in initial peak and plateau SkBF responses during local heating as a result of hypohydration and altitude exposure.The opinions contained herein are not official and do not reflect Army/DOD views

The role of protein kinase G in the cutaneous vascular response to whole body heat stress in humans

We tested the hypothesis inhibition of protein kinase G would attenuate active vasodilation to an extent similar to NO synthase (NOS) inhibition. Five subjects were instrumented with 3 microdialysis fibers were placed on the ventral forearm and each site randomly assigned a drug treatment: 1) lactated Ringer's (control; CON); 2) 10 mM L-NAME to inhibit NOS; 3) 16 mM of the PKG-inhibitor, Rp-cGMPS (Rp). All drugs were infused for 45 min, after which subjects underwent whole body heating (WBH) via water perfused suits sufficient to raise oral temperature 0.8°C above baseline. Systemic arterial pressure (SAP) was monitored and skin blood flow was measured via laser-Doppler flowmetry (LDF). At the end of WBH, subjects were cooled and peak skin blood flow was achieved via infusion of 56 mM nitroprusside and cutaneous vascular conductance (CVC) was calculated as SAP/LDF. Data were normalized to peak values (%CVCpeak). A larger than normal dose of nitroprusside was required to overcome inhibition of PKG. There was no statistical difference in raw peak CVC values. During WBH, CVC averaged 70±3 %CVCpeak in CON, 41±3 %CVCpeak in L-NAME (p < 0.01 vs. CON and Rp), and 55±4 %CVCpeak in Rp (p < 0.01 vs. CON). From these data it appears NO in AVD is working through both a PKG-dependent pathway as well as a PKG-independent pathway as evidenced by the greater reduction in AVD in L-NAME compared to Rp-cGMPS sites.

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.

The effect of 48 weeks of aerobic exercise training on cutaneous vasodilator function in post-menopausal females

Skin blood flow (SkBF) and endothelial-dependent vasodilatation decline with ageing and can be reversed with exercise training. We tested whether 48 weeks of training could improve SkBF and endothelial function in post-menopausal females; 20 post-menopausal subjects completed the study. SkBF was measured by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF/blood pressure. Resting CVC was measured at 32 degrees C and peak CVC at 42 degrees C. Cutaneous endothelial-dependent and -independent vasodilatations were determined by the iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively. All assessments described were performed at entry (week 0), and after 6, 12, 24, 36, and 48 weeks of training. Resting CVC measures did not change (P > 0.05) throughout the study. Peak CVC increased (P < 0.05) after 24 weeks (7.2 +/- 1.2 vs. 11.6 +/- 1.4 AU mmHg(-1)) and at the 36- and 48-week assessments (13.0 +/- 1.7 and 14.9 +/- 2.1 AU mmHg(-1), respectively). Responses to ACh also increased (P < 0.05) at the 24-week assessment (5.1 +/- 2.1 vs. 8.55 +/- 2.3 AU mmHg(-1)) and increased further at the 36 and 48-week assessments (11.6 +/- 3.7 and 13.2 +/- 3.9 AU mmHg(-1), respectively). Cutaneous responses to SNP increased (P < 0.05) after 36 weeks (8.7 +/- 2.1 vs. 13.02 +/- 2.23 AU mmHg(-1) at 36 weeks). VO(2max) increased after 12 weeks (23.5 +/- 0.7 vs. 25.4 +/- 0.9 ml kg(-1) min(-1)) and improved (P < 0.05) further throughout the study (31.6 +/- 1.8 ml kg(-1) min(-1) at week 48). Aerobic exercise produces positive adaptations in the cutaneous vasodilator function to local heating as well as in cutaneous endothelial and endothelial-independent vasodilator mechanisms. Aerobic capacity was also significantly improved. These adaptations were further enhanced with progressive increases in exercise intensity.